Antimicrobial Resistance -

OFFICIAL JOURNAL OF THE AUSTRALIAN SOCIETY FOR MICROBIOLOGY INC.OFFICIAL JOURNAL OF THE AUSTRALIAN SOCIETY FOR MICROBIOLOGY INC.

Volume 28 No. 4 November 2007ASM 2008 Melbourne

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Antimicrobial ResistanceBad Bugs, No Drugs – As Antibiotic Discovery Stagnates

A Public Health Crisis Advances quotes from WHO & IDSA.

November 2007Volume 28Number 4

OFFICIAL JOURNAL OF THE AUSTRALIAN SOCIETY FOR MICROBIOLOGY INC.

Page 195

Vertical Transmission 150

From the Editors 151

First Words 152Towards an integrated approach to the problem 152 antimicrobial resistance in Australia

In Focus 154Recent WHO initiatives for antimicrobial 154 resistance control

Global antibacterial resistance issues 157

Molecular science of antimicrobial resistance 160

Antimicrobial resistance in animals and impacts on 163 food safety and public health

Antimicrobial resistance - a public health issue? 165

Resistance to antiviral agents: balancing good and evil 169

Impact of antifungal resistance in Australia 171

Resistance testing in parasites: a review 176

Antimicrobial resistance in veterinary medicine - 179 issues and controversies from an Australian perspective

A resistant culture - ‘superbugs’ in Australian hospitals 182

An overview of emerging community based 186 antimicrobial resistance

AMR and tuberculosis: Voldemort returns? 191

Epidemic potential and antimicrobial resistance 195 in Clostridium difficile

Australian Government attempts at regulatory and 198 other control of antimicrobial resistance

An ongoing national program to reduce antibiotic 201 prescription and use

ASM Affairs 204

Carrick Citation for two ASM members 204

EDSIG 206

The Antimicrobial Special Interest Group of 207 The Australian Society for Microbiology

Book reviews 210

Award Nominations 211

ASM New Members 214

What’s On 215

Who’s Who 216

Page 170

Page 210

Cover photo: Dihydropteroate synthase (J. Mol. Biol. (2005) 348, 655-70), showing amino acids (in green) involved in resistance to sulfa drugs, the oldest chemically-synthesized antibiotics that target bacteria, fungi and parasites. Insert photo shows Jonathan Natoli, Hospital Scientist Concord Hospital working with drug resistant organisms. Photos are courtesy of Peter Iliades (WEHI) and John Merlino.

MICROBIOLOGY AUSTRALIA • NOVEMBER 2007 149

Keryn Christiansen

President ASM

It is with great pleasure that I welcome Liz Harry to the roles of Vice-President Scientific

Affairs and Chair of the National Scientific Advisory Committee (NSAC). Liz will be well

known to many of our members. She is an associate professor at the Institute for the

Biotechnology of Infectious Diseases, at the University of Technology, Sydney, where

she heads a team of twelve research and postdoctoral students. Liz has been very active

within The Australian Society for Microbiology (ASM). She has been a committee member

in the NSW branch for the last three years, was chair-elect of that branch in 2006, and

chair in 2007. She has served on the national council and is also on the subcommittee for

the visiting speakers program. Although already acquainted with Liz, I really got to know

her when we both attended ‘Science Meets Parliament’ earlier this year. I was impressed

by her energy, her enthusiasm for the discipline and her commitment to her students

and to ASM. I feel confident that she will make a major contribution to the society and

look forward to working with her on the executive committee. Liz takes over from Hatch

Stokes who is now the President-Elect.

Hatch has been Vice-President of Scientific Affairs for the last three-and-a-half years,

providing great leadership as Chair of the NSAC and as a member of the executive

committee. Currently Hatch has undertaken to conduct negotiations with the UK Society

for General Microbiology to establish a scientific exchange scholarship similar to that

recently established with the American Society for Microbiology. Both these scholarships

will provide our members with the valuable opportunity to present at either the US or

UK annual scientific meetings and to visit relevant research institutions. I will keep you

informed on the progress of these negotiations,

In 2009 our society will be fifty years old. To celebrate this achievement, Way back When

– Consulting Historians have been contracted to research and write a history of the ASM,

that reflects the society’s past, present and future. A jubilee management committee

chaired by David Ellis, with members Hatch Stokes, Peter Coloe, Lyn Gilbert, Ailsa

Hocking and Dick Groot Obink, has been established to oversee and direct this project.

Oral history interviews have already started and the ASM 2009 Annual Scientific Meeting

in Perth will be a focal point for the project, but it is intended that this material will be

available to all members in a format that is yet to be decided by the committee. The

realisation of this project will be a worthy celebration of the development and growth

of the ASM.

I remind members to plan now to attend the 2008 Annual Scientific Meeting in Melbourne

(6–10 July). Hopefully many of you will be generating the data that will become the basis

for an abstract submission. The local organising committee (LOC), with Sue Cornish as

chair and Danilla Grando as chair of the scientific programmme subcommittee, has been

working hard with NSAC to provide an interesting and stimulating program. I thank all

members of the LOC and NSAC for their tireless work for the ASM. The many hours taken

to put together the annual meeting are contributed on a voluntary basis and the society

is indebted and greatly enriched by this commitment.

Vertical Transmission

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150 MICROBIOLOGY AUSTRALIA • NOVEMBER 2007


From the Editors

This is our last edition of Microbiology Australia for 2007 and we take this opportunity to wish you a Happy Christmas (yes it is next month!). We hope it has been a rewarding year for all of you.

Over the past year Microbiology Australia has continued to undergo improvements as we, along with the editorial board and Cambridge Media, seek to make this a ‘must read’ journal that is informative and increases our awareness of the diversity of our discipline.

We thank members who have offered to be guest editors or to join the editorial board and proffered suggestions for improvements. We welcome Linda Blackall as the most recent new member of the editorial board. Linda has a wealth of professional experience and was guest editor for the last edition. Next year she will be guest editor of an edition that focuses on how climate change

will affect microbiology, especially within Australia. Linda is also to chair an international conference on “Microbial Diversity - Sustaining the Blue Planet” (see ‘What’s On’ in this edition).

An initiative instigated by the ASM executive is to release new editions of Microbiology Australia to relevant sections of the media (especially science writers). It is in the charter of the ASM to communicate the importance of our work to the public and Microbiology Australia is an excellent vehicle for achieving this, with its up-to-date and authoritative articles from Australia’s leading experts. The contents of recent editions have been requested for the training of medical students, or for submissions to our federal and state governments and much has gone to policy makers both within Australia and internationally. No doubt this edition will also be closely read by those who formulate health policies.

Next year there will be further cosmetic improvement to Microbiology Australia and, most importantly, more great content. Additionally, the editorial board has planned for the presentation of some topics that will have condiderable interest and importance to ASM members. Topics for 2008 will include the new industrial microbiology revolution, new legislative changes that will affect microbiology labs, climate change and how it will affect microbiology.

We trust that you will continue to enjoy Microbiology Australia. Please remember that we welcome your comments and suggestions for future editions.

Best wishes from Ian and Jo Macreadie.

NATA

www.bioball.com.au email [email protected] phone (02) 8877 9150mobile 0401 504 558

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Australia Micro Mag #81E16F.pdf 31/7/07 10:29:18 AM


First Words

“The threat is real, the science is in, the time for action is now!” A familiar refrain that for most of us is associated with the debate surrounding global warming, but surely equally applicable to the situation surrounding its microbiological equivalent – antimicrobial resistance (AMR). We are all well aware of AMR and the consequences of its emergence and spread, following the recognition of this phenomenon when the ‘antibiotic era’ began only a few decades ago. Perhaps we have been somewhat complacent about AMR, in that we have relied overmuch on the continuing development of new and better antimicrobial agents. As the efficacy of older antimicrobials wanes and the supply of new agents declines in the face of increasing AMR, some have suggested that we may be facing a ‘post-antibiotic era’.

This edition of Microbiology Australia provides an overview of the current situation and effects of AMR, especially with regard to Australia. The topic is extensive and the ramifications wide, so the contributions in this edition are aimed to provide only a flavour of the intricacies of the overall problem of AMR, the mechanisms involved, and the known and possible means by which AMR may be contained.

Enormous benefits have accrued in terms of individual wellbeing and, at a public health level, control of infectious disease following the discovery, clinical application and manipulation of naturally occurring compounds (antibiotics) and synthetic agents (chemotherapeutic agents) active against microbial pathogens. However, AMR is also a natural phenomenon and its effects, amplified by continuing exposure and over-exposure to antimicrobials, have seen the progressive and now accelerating erosion of these benefits for the treatment of bacterial, viral, parasitic and fungal infections. A precise definition of AMR is surprisingly difficult, as some forms of interest to microbiologists are not necessarily of clinical relevance and phenotypic expression does not always mirror all underlying genetic alterations. One

John Merlino

Convenor/Chair Antimicrobial SIGEmail: [email protected]

World Health Organization (WHO) source suggests the following definition:

AMR is the expression of the ability of microbes to resist the actions of naturally occurring or synthetically produced compounds inimical to their survival. In a clinical context, AMR refers to a reduction in clinical efficacy so that either the benefits for the individual of treatment with an antimicrobial drug or the benefits to general public health are compromised.

While most attention surrounding AMR has focused on issues affecting human health – predictably most of this on bacterial resistance – this edition of Microbiology Australia attempts to take a wider view. It is perhaps pertinent to remember that of the three infectious diseases – tuberculosis (TB), malaria and HIV/AIDS – regarded by the United Nations as the most significant for human health worldwide, the control of all three is materially affected by AMR, but only one has a bacterial cause. In this edition, a summary of WHO efforts aimed at containment of antimicrobial resistance in general follows, taking the broader ‘antimicrobial’ as opposed to the narrower ‘antibiotic’ view, and an overview of bacterial antibiotic resistance is provided in the contribution by Robert Moellering.

Resistance mechanisms to antibacterial agents are reviewed by Jon Iredell and John Merlino in a timely summary of the current status of these phenomena. It is important to remember that although AMR may impact adversely on an individual infected with a resistant organism, there are also significant public health issues that emerge as a result of AMR. We are reminded that the public health issues surrounding antibacterial resistance are two-fold. David Jordan discusses issues arising from interaction between animal and human AMR from a public health perspective. Keryn Christensen points out that AMR is an important public health issue in its own right, being responsible for significant mortality

Towards an integrated approach to the problem of antimicrobial resistance in Australia

John Tapsall

Director, WHO Collaborating Centre for STD, SydneyEmail: [email protected]

and morbidity with major economic implications. Further, while the very real problems of AMR in animal health and husbandry impinge on human health, sometimes significantly, they are often used to excuse poor practice with regard to the use of antibiotics in human health. Mary Barton presents data on AMR in veterinary practice in Australia while reminding us that antibiotic treatment is also necessary for animal wellbeing.

Examples of problems resulting from increasing AMR are provided in a number of articles. Chris Coulter addresses the specific topic of the global threat of MDR and extensively drug-resistant TB and describes national and international efforts directed at TB control. The real and seemingly inexorable increase in AMR in hospitals and the wider community leads to repeated attention in the popular press. Contributions by Lyn Gilbert and Tom Gottlieb and Elaine Cheong illustrate continuing, new and emerging problems of AMR in other pathogens of local and global significance. Consequences of antibiotic misuse in the form of Clostridium difficile infection and the emergence and spread of virulent subtypes of this organism are reported by Tom Riley. The broader implications of AMR in parasitic infections less commonly encountered in Australia, but nonetheless very relevant, are described by Harsha Sheory, while David Smith and David Speers provide a picture of antiviral resistance and its consequences in diseases of major importance. The origins and impact of resistance to antifungal agents is discussed by David Ellis, Sharon Chen and Tanya Sorrell.


First Words

Finally a series of papers describes Australian attempts to date

for the containment of AMR. The broader picture of principles of

AMR containment is set out in Figure 1 of the WHO article. Local

efforts at AMR containment by means of government regulatory

and other control measures and at a practical level through

activities of the National Prescribing Service, are set out by John

Turnidge and Lyn Weekes respectively. One aspect not covered

here – deliberately, because of space limitations – is that of

surveillance of AMR regarded by the WHO in its Global Strategy

as one of the two ‘fundamental requirements’ for any attempt at

control of AMR. Of course, surveillance should not be limited to

assessment of resistance itself, but optimised by also monitoring

how much antimicrobial is used and how well this use is applied.

No one would suggest that in Australia we are anywhere near

addressing the issue of AMR containment in the coordinated

and comprehensive manner suggested by world experts and a

number of authors imply that management of AMR in Australia is

hampered by lack of critical data.

Thus, AMR is an important, systemic, chronic and worsening

problem in Australia, as it is elsewhere. The means by which AMR

can be contained are well established and proven. However, this

requires an integrated approach with the political will, resources

and long-term commitment to make success feasible – a little bit

like global warming and in its own way just as important?


In Focus

BackgroundThe 11 September 2001 (9/11) was to have been a high-point

in the implementation of the WHO Global Strategy. This WHO

initiative in the area of AMR followed a 1998 World Health

Assembly (WHA) resolution (WHA 51.17). Resources in the

form of external funding and expertise of national bodies,

non-government organisations (NGOs) and individuals were

mobilised, and internally a specific taskforce was established that

linked many existing WHO programs. (The WHA is the governing

body of the WHO and comprises the member states of the

WHO meeting in session annually in Geneva. While the WHO

headquarters are in Geneva, it has a regional structure and its

activities are country-based. Australia is part of the Western Pacific

Regional Organization [WPRO], one of six regions in total.)

The WHO Global StrategyThe WHO Global Strategy was progressively developed by a

thorough process of multi-disciplinary consultation. ‘Global’

refers not to a geographical perspective, but to a comprehensive

country-based and cross-cutting approach to control of AMR in

both animal and human health. The WHO Global Strategy is a

guide for individual member states for control of AMR and:

Recent World Health Organization initiatives for antimicrobial resistance control

The World Health Organization (WHO) overseeing of antimicrobial

resistance (AMR) containment issues in the last decade has varied

in intensity. From 1999 onwards, concerted focus from the WHO

led to the development of a multi-disciplinary framework for

AMR containment at a country level. However, implementation

of the WHO Global Strategy for the Containment of Antimicrobial

Resistance 1 (the Global Strategy) was overtaken first by events

in the USA in 2001 and later by related and other bio-security

issues. By 2003, loss of funding and a restructured WHO saw

AMR initiatives curtailed. Interest in AMR at the WHO has been

recently rekindled and it is hoped that renewed attention will

again be focused on this issue by the WHO and its member

states.

John Tapsall

Department of Microbiology,The Prince of Wales Hospital,Randwick NSW 2031

Figure 1. The Antimicrobial Resistance Containment and Surveillance (ARCS) strategy. The inter-relationships between the major issues and priority interventions

that together comprise the WHO Global Strategy for Containment of Antimicrobial Resistance 1. (Reproduced with kind permission from the Bulletin of the World

Health Organization 2.)


In Focus

... provides a framework of interventions to slow the emergence

and reduce the spread of antimicrobial-resistant organisms

through:

• Reducing the disease burden and spread of infection.

• Improving access to appropriate antimicrobials.

• Improving use of antimicrobials.

• Strengthening health systems and their surveillance

capacities.

• Enforcing regulations and legislation.

• Encouraging the development of appropriate new drugs

and vaccines.

Because it was a country-based approach, the WHO Global

Strategy also provided a program for implementation in the form

of more than sixty recommendations for the guidance of member

states. These included a core set of recommendations for

prioritisation of the Global Strategy comprising two ‘fundamental’

and fourteen ‘first priority’ interventions. The two fundamental

policy recommendations recognised the role of microbiology

and the need for relevant laboratory resources, and included

a requirement for an overarching and empowered national

taskforce in each member state to coordinate and oversee the

process of AMR control.

The antimicrobial resistance containment and surveillance (ARCS) approach in the WHO Global StrategyThe intersections of the fourteen first priority, multi-disciplinary

based recommendations for control of AMR were set out

diagrammatically in a companion Antimicrobial Resistance

Containment and Surveillance (ARCS) document 2. The structure

of the ARCS diagram (Figure 1) is based on the premise that

ultimately AMR is contained by proper use of antimicrobials and

this interaction is shown as the core section of the diagram.

‘ARCS’ are found on either side of the diagram. The ARC on right

side deals with ‘supply – side’ issues, such as drug availability

and evaluation and regulation of use through prescribing.

While relevant to Australia and implemented here through

regulatory bodies such as the Therapeutic Goods Administration,

these issues are even more important in settings where drug

supply, regulation and oversight is not well established. All too

frequently, antibiotics often of poor quality are freely available off-

prescription in what is euphemistically described as the ‘informal

health sector’. Equivalent arrangements for veterinary medicines

are in place in Australia, but also are often poorly regulated in

some countries. The ARC on the left side deals with the ‘demand-

side’ of the equation. This includes highly important factors, such

as consumer and prescriber demand for antibiotics and reducing

disease prevalence.

Each issue depicted on the outside of each ARC is then linked

to a corresponding ‘priority intervention’ aimed at limiting its

effect. Underpinning the supply and demand interventions are

the essential surveillance components required for AMR control

– how much antibiotic is used, how well it is used and, most

importantly, surveillance of AMR itself. The basic premise is that

the integrated ‘global’ approach should be implemented in toto

if AMR is to be contained.

While this ARCS diagram is quite detailed, it can also be

simplified for specific purposes. For example, although it was

designed for ‘country as a whole approach’ it is equally adaptable

for local regional or even hospital use. The relationships between

control of multi-resistant organism in hospitals, disease control,

laboratory practice and surveillance is shown in Figure 2.

Other measures accompanying the WHO Global StrategyThe WHO Global Strategy document is part of a WHO integrated

approach and a series of accompanying guidelines and position

papers were also produced 3. Some were disease specific (relating

mainly to diseases of public health importance) while others set

standards for surveillance of AMR and still others considered

the role of hospital infection and control of multi-resistant

organisms. Thus, the package was an integrated global package

and had already achieved a considerable degree of expert

consensus (including significant input from Australian sources)

during its preparation.

Additionally, the WHO has available the WHONET 4 facility – a free,

Windows® based database for the management of laboratory

Figure 2. A simplified ARCS 2 diagram showing the close relationship between

antimicrobial resistance containment, disease control and antimicrobial

resistance surveillance.

E P I D E M I C A L E R T A N D R E S PO N S E

Human/Animal Infection

AMR Containment

Disease Burden

Monitoring Drug Resistance

Disease control and

prevention

Diagnostics

Appropriate treatment regimens

Rational Drug Use

Antimicrobials

DrugProcurement

ARCS: Antimicrobial ResistanceContainment and Surveillance (abridged)


In Focus

information. This was developed and provided by a WHO

collaborating centre in Boston with the objectives to assist in the

handling of locally derived data and to promote international

collaboration. The program is widely used, although there are no

users listed from Australia, and it is continually updated.

What went wrong?The launch of the WHO Global Strategy scheduled for 9/11 in

Washington DC was necessarily postponed, but even by December

2001 when the package was finally released at the Interscience

Conference on Antimicrobial Agents and Chemotherapy (ICAAC),

again in Washington DC, other events were overtaking AMR as a

priority issue for decision makers. Bio-terrorism in particular, and

bio-security issues in general, influenced at first by the deliberate

spread of anthrax spores and reinforced by events such as

outbreaks of severe acute respiratory syndrome (SARS) and avian

influenza, saw a diversion of resources and interest from AMR.

During 2002–2003 the WHO strove to re-direct and maintain the

interest and to roll out the Global Strategy approach, convening

follow-up implementation meetings with relevant partners and

WHO regional offices, and electronically disseminating the

Global Strategy in several languages. The WHO attempted

to establish a ‘Global Atlas’ of AMR that was only partially

successful, and also produced, with the CDC, a manual for

susceptibility testing of pathogens of public health importance

and further defined standards for laboratories undertaking AMR

surveillance3. At a regional level, the WPRO organised a workshop

for WHO member states in Manila in 2005. Several countries,

notably South Korea, had made major strides forward in their

efforts at AMR control, while others had committed resources

and teams to this process. The WHONET was widely used in the

WPRO. However, in 2003 there was another major re-structure at

the WHO headquarters and this, coupled with progressive loss of

funding from important donors, saw the AMR team dispersed and

AMR responsibilities assigned to an under-resourced section.

What next for the WHO and AMR?The issue of AMR has not gone away. Major, expensive initiatives

for the control of TB, HIV/AIDS and malaria were introduced and

continued through a UN Global Fund for their control, and it

was soon realised that progress in these areas would be severely

hampered by the extra costs and burdens of any failed treatments

due to AMR. Similarly, the reliance on antivirals for public health

control of possible epidemics of respiratory diseases would be

similarly compromised by emerging resistance. New versions

of older problems also reappeared: more drug-resistant TB,

community-acquired MRSA with attendant costs, vancomycin-

resistant enterococci, and drug-resistant respiratory and genital

tract pathogens. Additionally more sophisticated analyses became

available to estimate the economic burden of AMR.

On this basis and because of a continuing belief in the importance

of the issue, several national bodies and NGOs continued their

agitation for further action by the WHO in the area of AMR

that saw yet another resolution at the WHA in 2005; WHA58.27

called on member states to renew their initiatives with regard to

AMR and for a progress report at the 2007 WHA. At the time of

writing, the details of the 2007 WHA re-examination of progress

of the WHO on AMR were not available, but it is thought that a

number of member states and NGOs would prefer still greater

commitment and that further progress reports will be sought

from the organisation at the next two WHAs. This desire was also

reflected in a separate resolution on rational use of medicines

that included antibiotics (WHA60.16).

It is hoped that the combination of these two resolutions will see

a dedicated team re-established within the WHO to facilitate the

collaboration needed at all levels of the WHO and to again work

in a truly multidisciplinary way to contain AMR and promote

rational use of medicines.

The basis for appropriate interventions to contain the emergence

and spread of AMR at an international, regional, country and

local (hospital) level has been firmly established by the earlier

endeavours described above. With wider support inside and

outside the WHO, it is anticipated that any renewed initiatives

will be supported and sustained with a happier and more

productive outcome.

References1. World Health Organization. WHO global strategy for containment of

antimicrobial resistance. WHO, Geneva 2001. WHO/CDS/CSR/DRS/2001.2 Available from http://www.who.int/drugresistance/en/ Accessed 13 July 2007.

2. Simonsen GS, Tapsall JW, Allegranzi B et al. The ARCS Approach – A Public Health Tool for antimicrobial resistance containment and surveillance. Bull World Health Org 2004; 82:928-34.

3. World Health Organization. Providing technical guidance on interventions. http://www.who.int/drugresistance/guidance/en/index.html Accessed 13 July 2007.

4. WHONET http://www.who.int/drugresistance/whonetsoftware Accessed 13 July 2007.

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In Focus

The clinical use of antimicrobial agents has spawned, as an

unwanted consequence, the widespread emergence of bacteria

resistant to these valuable drugs. During the past fifty years,

resistant organisms have caused problems throughout the world,

as will be documented in this brief paper.

Without question, the discovery and clinical application of

antibacterial agents represents one of the shining achievements

of medical science in the 20th century. Dozens of effective

antimicrobial agents have been discovered during the past sixty

years 1. However, with the discovery of each new agent, bacteria

have found ways to develop resistance. Indeed, this has been a

problem since the dawn of the antibiotic era, but antimicrobial

resistance was noted even before this. In the early 20th century,

ethylhydrocupreine (optochin) was tried for the treatment of

pneumococcal pneumonia and a trial in 1917 was terminated

because of drug toxicity; the emergence of resistance to the

drug during therapy was also noted. This appears to have been

the first documentation of the emergence of resistance to an

antimicrobial agent in humans 1,2. With the discovery of each new

class of antimicrobial agents, beginning with the sulfonamides in

the 1930s and penicillin in the 1940s, resistance has developed

and has become a truly worldwide problem. Initially, medical

scientists overcame the problems of resistance by discovering

and developing new classes of antimicrobial agents that were

effective against resistant organisms 1. However, in the past

twenty years, that developmental pipeline has been progressively

drying up and, with the possible exception of the oxazolidinones,

no new classes of agents have been discovered for more than

two decades 3.

In most instances, antimicrobial resistance emerges in response

to pressure from clinical, agricultural, aquacultural, or industrial

use of antimicrobial agents, but in some instances resistant

organisms are found in communities in the absence of the

Global antibacterial resistance issues

Robert C Moellering Jr

Shields Warren-Mallinckrodt Professor of Medical Research, Harvard Medical School, and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USADepartment of MedicineBeth Israel Deaconess Medical Center, 110 Francis Street, Suite 6A Boston, MA 02215 USATel: 617-632-7437 Fax: 617-632-7439Email: [email protected]

heavy use of antimicrobial agents. In the late 1960s and early

1970s, my colleagues and I obtained stool and other cultures

from indigenes of the highlands of Malaita, British Solomon

Islands, an area where antibiotics had never been used. Although

neither streptomycin nor tetracycline had been used in these

communities, we found organisms that already contained

plasmids bearing genes mediating resistance to tetracycline and

streptomycin 4. Although difficult to prove, we had assumed that

resistance of this type occurs because many of the organisms

that produce antibiotics are present in nature and it may provide

for exposure of organisms (especially enteric pathogens) to

antibiotics in the absence of their clinical use. Subsequent studies

have confirmed this and documented a remarkable ability of

soil organisms to inactivate antibiotics. In some cases, such as

inactivation of daptomycin, this mechanism has not yet been

seen among clinical isolates 5. The recent description of multi-

resistant bacteria in remote areas of Bolivia appears to be another

and even more dramatic example of the fact that the occurrence

of multiply-resistant bacteria is not always limited to areas of high

antibiotic consumption in the clinical arena 6.

It is often impossible to pinpoint the origin of antibiotic

resistant clones because this is dependent upon the likelihood

of a qualified investigator identifying the first resistant clones

and then carrying out the appropriate studies to characterize

them. In the case of Staphylococcus aureus, some of the earliest

studies documenting the explosive emergence of resistance to

penicillin in this organism were carried out in the early 1940s

by Dr Maxwell Finland at the Boston City Hospital in Boston,

Massachusetts 7. Prior to the use of penicillin, virtually all

strains of S. aureus were susceptible to penicillin. Following its

introduction for clinical use at the Boston City Hospital in the

early 1940s, there was rapid emergence of resistance and by 1947,

32% of S. aureus showed high-level resistance. In 1951, after less

than a decade of use of penicillin, 73% of S. aureus were highly

resistant to penicillin, virtually all of which were resistant because

they produced penicillinase 8. For a number of years after this,

the prevalence of penicillin resistance among hospital acquired

stains of S. aureus was noted to be considerably higher in the

hospital than among community-acquired strains. However,

by 1967 this resistance seemed to have equalised in Boston at

about 82–84% for both inpatient and outpatient isolates and this

approximate percentage was maintained over the ensuing ten

years 9. These organisms have spread throughout the world, and

at present more than 90% of all isolates of S. aureus are penicillin

resistant.


In Focus

Penicillin resistance in Streptococcus pneumoniae is not due to

the effect of a beta-lactamase like penicillinase, but to alterations

in penicillin binding proteins (PBP), leading to ‘mosaic genes’

that have lower affinity for penicillin 10. The first penicillin

resistant pneumococci were described by Australian investigators

among a group of indigenous men from the highlands of New

Guinea, where the organisms had presumably become resistant

because of the administration of long-acting penicillins to this

population to prevent pneumococcal respiratory diseases 11.

Penicillin resistant pneumococci were subsequently identified

among gold miners in South Africa 12 and, as has been the case

with so many other resistant bacteria, they have now spread

around the world. There is virtually no part of the world in which

these organisms do not presently occur 13,14.

Because the greatest pressure from antibiotic use is generated in

hospitals (especially intensive care units) it is not surprising that

these are the source of some of the most resistant pathogens

throughout the world. Multiresistant gram-negative bacteria

including Pseudomonas aeruginosa, Acinetobacter baumanii,

and other non-fomenters are classically found in intensive

care units. Enteric bacteria (especially Klebsiella pneumoniae

and Escherichia coli [E. coli]) have acquired genes mediating

the production of so-called extended-spectrum β-lactamases

(ESBLs), which are able to hydrolyse a broad spectrum of

penicillins and extended spectrum cephalosporins 15. Originally,

most of the organisms containing ESBLs remained susceptible

to carbapenems but, in recent years, organisms producing a

broad variety of chromosomally mediated and transferable

carbapenemases have emerged in hospitals throughout the world

and this has now become a global problem with interspecies

dispersion of these genes 16. Many of the organisms containing

these carbapenemases are literally resistant to all β-lactamases

and in some instances, such as the outbreak of infections due to

KPC-2-producing Klebsiella pneumoniae in New York City, there

have been significant mortality rates since the organisms were

resistant to all antimicrobial agents except the polymyxins 17.

Of course, the development of resistance is not limited to intensive

care units in developed countries. An excellent illustration of this

can be seen in a very large outbreak of dysentery due to Shigella

dysenteriae type 1 that began in 1968 and was initially caused by

antibiotic-susceptible organisms 18. As the epidemic continued, the

Shigella acquired a plasmid mediating resistance to streptomycin,

tetracycline, chloramphenicol and the sulfonamides. Morbidity

and mortality from this epidemic were particularly severe, partly

because local health authorities were initially unaware of the fact

that they were dealing with antibiotic-resistant Shigella. More

than 12,500 deaths were recorded in Guatemala during the first

year alone 18. As the epidemic spread northward, the organism

acquired new antimicrobial resistance genes and on reaching

Mexico City in 1972 it had become resistant to ampicillin, in

addition to streptomycin, the sulfonamides, tetracycline, and

chloramphenicol 19.

It was hoped that resistance to sulfonamides could be

prevented by the use of the combination of trimethoprim plus

sulfamethoxazole since the combination worked on consecutive

steps in the same metabolic pathway and provided synergistic

inhibition and killing of many organisms, including Shigella and

E. coli 20. Trimethoprim-sulfamethoxazole (TMP-SMX) was first

used clinically in the early 1970s, but by the late 1970s occasional

isolates of Shigella resistant to TMP-SMX were noted. In the

early 1980s in Zaire, an epidemic of diarrhea due to Shigella

dysenteriae occurred in which the organisms were resistant

to chloramphenicol, sulfonamides, tetracycline, streptomycin,

ampicillin, and TMP-SMX. Rapid emergence of resistance was also

noted in India, Mexico, Brazil, Chile and Thailand. Moreover, in

many of these countries, plasmid-mediated resistance to TMP-

SMX was also found among E. coli 21. Antimicrobial resistance

has also become a problem in other enteric pathogens in the

developing world. An epidemic of typhoid fever in 1996 in

Tajikistan was related to overflow of sewage, contaminated

municipal water and ultimately person-to-person spread. By

1999, more than 24,000 cases of typhoid fever had been

reported. More than 90% of the S. typhi were multidrug resistant

and 82% of the isolates tested were resistant to ciprofloxacin22.

The possibility of spread of these multiresistant strains of

Salmonella to other developing countries is of grave concern,

since the fluoroquinolones represent the most effective agents

we currently have for treating typhoid fever.

More recently, decreased effectiveness of the fluoroquinolones in

treating cholera has been documented in Bangladesh 23. Of even

greater concern is a report showing that between September

2004 and March 2005 multiresistant Vibrio cholerae 01 emerged

in Bangladesh; 79% of fifty-four strains tested were resistant

to erythromycin, azithromycin (which was more effective than

ciprofloxacin in the earlier New England Journal of Medicine

study23), TMP-SMX, tetracycline, and furazolidine 24!

An even more dramatic example of the emergence of important

multiresistant pathogens in a developing country was related to

the discovery of a multiresistant strain of Yersinia pestis from

a patient in Madagascar with bubonic plague. The strain was

resistant to chloramphenicol, tetracycline and streptomycin, as

well as to the sulfonamides, ampicillin, kanamycin, spectinomycin

and minocycline. All of these resistance genes were carried on a

plasmid (presumably from a strain of Enterobacteriaceae) that

easily could be transferred to other virulent strains of Yersinia

pestis. Subsequently, other patients from Madagascar infected

with this organism have been described 25. This discovery also


In Focus

raises the disturbing possibility that such multiresistant strains

could be used in bioterrorism attacks throughout the world.

Neisseria gonorrhoeae have developed resistance to multiple

antimicrobial agents but until recently, the fluoroquinolones

could be relied upon for effective oral therapy, at least in most

western countries. For a number of years, disturbing reports of

a high prevalence of fluoroquinolone resistance have emanated

from Asia and the Western Pacific in annual reports from World

Health Organization programs 26 (see Figure 1). The prevalence of

fluoroquinolone resistance subsequently increased dramatically

in Europe 27. Although as yet not approaching those in Asia or

Europe, more recently the prevalence of these organisms in the

United States has risen to a level that has prompted the Centers

for Disease Control and Prevention (CDC) to suggest that the

fluoroquinolones no longer be used for primary treatment of

gonorrhea in the United States 28. Once again, a problem first

described in one part of the world (Asia) has developed into a

global problem.

As noted at the onset of this paper, antimicrobial agents are

among the most important discoveries of the 20th century, but

their utility is constantly being threatened by the emergence of

antimicrobial resistance. Although the prevalence of resistance

to antimicrobials among various bacterial pathogens varies from

place to place, it is truly a worldwide problem and deserves all of

the attention that medical science can apply.

References1. Moellering RC Jr. Past, present and future of antimicrobial agents. Am J Med

1995; 99(Suppl 6A):11S-18S.

2. Moore HF, Chesney AM. A study of ethylhydrocupreine (optochin) in the treatment of acute lobar pneumonia. Arch Intern Med 1970; 19:611.

3. Spellberg B, Powers JH, Brass EP et al. Trends in antimicrobial drug development: implications for the future. Clin Infect Dis 2004; 38:1279-86.

4. Gardner P, Smith DH, Beer H et al. Recovery of resistance (R) factors from a drug-free community. Lancet 1969; 2:774-6.

5. D’Costa VM, McGrann KM, Hughes DW et al. Sampling the antibiotic resistome. Science 2006; 311:374-7.

6. Bartoloni A, Bartalesi F, Mantella A et al. High prevalence of acquired

antimicrobial resistance unrelated to heavy antimicrobial consumption. J Infect

Dis 2004; 189:1291-4.

7. Finland M, Frank PF, Wilcox C. In vitro susceptibility of pathogenic staphylococci

to seven antibiotics. Am J Clin Path 1950; 20:325-34.

8. Finland M. Changes in the susceptibility of selected pathogenic bacteria to

widely used antibiotics. Ann N Y Acad Sci 1971; 182:5-20.

9. Barrett FF, Casey JI, Wilcox C et al. Bacteriophage types in antibiotic

susceptibility of Staphylococcus aureus. Arch Intern Med 1970; 125:867-73.

10. Dowson CG, Hutchison A, Brannigan JA et al. Horizontal transfer of penicillin-

binding protein genes in penicillin-resistant clinical isolates of Streptococcus

pneumoniae. Proc Natl Acad Sci USA 1989; 86:8842-6.

11. Hansman D, Bullen MM. A resistant pneumococcus. Lancet 1967; 2:264-265.

12. Koornhof HJ, Wassas A, Klugman K. Antimicrobial resistance in Streptococcus

pneumoniae: a South African perspective. Clin Infect Dis 1992; 15:84-94.

13. Yu VL, Chiou CCC, Feldman C et al. An international prospective study of

pneumococcal bacteremia: correlation with in vitro resistance, antibiotics

administered and clinical outcome. Clin Infect Dis 2003; 37:230-7.

14. Song J-H, Jung S-I, Ko KS et al. High prevalence of antimicrobial resistance

among clinical Streptococcus pneumoniae isolates in Asia (an ANSORP study).

Antimicrob Agents Chemother 2004; 48:2101-7.

15. Bradford PA. Extended-spectrum β-lactamases in the 21st century:

characterization, epidemiology, and detection of this important resistance

threat. Clin Microbiol Rev 2001; 14:933-51.

16. Queenan AM, Bush K. Carbapenemases: the versatile beta-lactamases. Clin

Microbiol Rev 2007; 20:440-58.

17. Woodford N, Tierno PM Jr, Young K et al. Outbreak of Klebsiella pneumoniae

producing a new carbapenem-hydrolyzing class A beta-lactamase, KPC-3, in a

New York Medical Center. Antimicrob Agents Chemother 2004; 48:4793-9.

18. Gangarosa EJ, Bennett JV, Wyatt C et al. From the CDC: An epidemic-associated

episome? J Infect Dis 1972; 126:215-8.

19. Olarte J, Filloy L, Galindo E. Resistance of Shigella dysenteriae type 1 to

ampicillin and other antimicrobial agents: strains isolated during a dysentery

outbreak in a hospital in Mexico City. J Infect Dis 1976; 133:572-5.

20. Hitchings GH. Mechanism of action of trimethoprim-sulfamethoxazole. J Infect

Dis 1973; 128:S433-36.

21. Murray BE, Alvarado T, Kim KH et al. Increasing resistance to trimethoprim-

sulfamethoxazole among isolates of Escherichia coli in developing countries. J

Infect Dis 1985; 152:1107-13.

22. Tarr PE, Kuppens L, Jones TC et al. Considerations regarding mass vaccination

against typhoid fever as an adjunct to sanitation and public health measures:

potential use in an epidemic in Tajikistan. Am J Trop Med Hyg 1999; 61:163-

70.

23. Saha D, Karim MM, Khan WA et al. Single-dose azithromycin for the treatment

of cholera in adults. N Engl J Med 2006; 354:2452-62.

24. Guerrant RL. Cholera – still teaching hard lessons. N Engl J Med 2006;

354:2500-2.

25. Galimand M, Guivoule A, Gerboud G et al. Multidrug resistance in Yersinia

pestis mediated by a transferable plasmid. N Engl J Med 1997; 337:677-80.

26. The WHO Western Pacific Gonococcal Antimicrobial Surveillance Programme.

Surveillance of antibiotic resistance in Neisseria gonorrhoeae in the WHO

Western Pacific Region, 2005. Commun Dis Intell 2006; 30:430-3.

27. Martin IMC, Hoffmann S, Ison CA, ESSTI Network. European Surveillance

of Sexually Transmitted Infections (ESSTI): the first combined antimicrobial

susceptibility data for Neisseria gonorrhoeae in Western Europe. J Antimicrob

Chemother 2006; 58:587-93.

28. Anon. Centers for Disease Control and Prevention (CDC). Update to CDC

sexually transmitted diseases treatment guidelines, 2006: fluoroquinolones no

longer recommended for treatment of gonococcal infections. MMWR 2007;

56:332-6.

Figure 1. Proportion of Neisseria gonorrhoeae isolates less sensitive (MIC 0.06

– 0.5 mg/l) or resistant (MIC >1 mg/l) to ciprofloxacin in selected countries

in the WHO Western Pacific region, 2005 26.

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In Focus

The study of bacterial resistance to antimicrobial agents is a

complex science that requires an understanding of the genetic,

molecular and physiological mechanisms of resistance, and the

effect of antibiotic selection pressures on bacterial populations in

different environments 1-4.

A variety of transmissible genetic elements (Table 1) allow

bacterial cells to survive and deal with antimicrobial agents 2 and

these are increasingly found together in multi-drug resistant

(MDR) organisms. Beta-lactamases and MDR efflux systems are

intrinsic to certain species of gram-negative bacteria – proteins

and pumps. Acquired resistance mechanisms involve mutations

in genes targeted by the antibiotic and/ or transfer of resistance

determinants borne on plasmids, bacteriophages, transposons

and other mobile genetic elements 5. Exchange of transmissible

genes may be achieved by transformation (incorporation

of external DNA in plasmids or even as naked DNA), by

bacteriophage transduction, and by conjugation (plasmids and

conjugative transposons). Transfer may occur between different

genera and even between gram-positive and gram-negative

bacteria 1,2,5. Even if a plasmid enters a cell that contains another

plasmid with which it is incompatible, genetic material on

either plasmid may move to the chromosome, and although

a plasmid may be subsequently lost, the cell gains (or retains)

the resistance. Gram-positive bacteria such as staphylococci,

which are less adapted to a densely populated polymicrobial

environment than most of their gram-negative counterparts,

also share and accumulate resistance determinants via these

mechanisms. Many staphylococci show increased resistance to

heavy metals, antiseptics and wide range/classes of antimicrobial

agents. As in the gram-negative bacteria and the conjugative

plasmids that move between them, multiple resistance genes in

Molecular science of antimicrobial resistance

John Merlino

National Chair/Convenor ASM Antimicrobial SIGDepartment of Microbiology & Infectious DiseasesConcord Hospital, SydneyEmail: [email protected]

Jon Iredell

Centre for Infectious Diseases & MicrobiologyUniversity of Sydney/ Westmead Hospital, SydneyEmail: [email protected]

staphylococci are often clustered together with other resistance

genes on the chromosome where they are stably replicated 3,6,7.

In gram-negative bacteria, the ability to acquire genes from a

common pool is an important adaptation. Most also have a

number of specific gene capture mechanisms. Genetic elements

such as insertion sequences (IS) may contribute to the formation

of composite transposons (in which DNA is flanked by matching

IS), provide promoter sequences, and even mobilise adjacent

material directly from IDAba1 8 and an ISEcp1 9. A sophisticated

and epidemiologically important gene capture and expression

system was first described by two Australian scientists, Hatch

Stokes and Ruth Hall 1,10,11. This system integrates ‘gene cassettes’

of different types and is often part of a fully functional transposon

system 12. The system comprises a characteristic integrase which

allows ‘capture’ of the cognate gene cassette and provides a

promoter for its expression 1,2,4.

While the acquisition of a new resistant determinant in both

gram-positive and gram-negative bacteria may be a rare event,

it can be selected and propagated once it has occurred. The

more bacteria are exposed to antimicrobial agents in industrial,

hospital and domestic settings, the more rapid the spread among

groups of bacterial and human populations 1,2.

The intensity of exposure to antibiotics is an important parameter

in terms of selection and maintenance of antibiotic-resistant

bacteria. The ecological balance between susceptible and resistant

bacteria will depend on the amount and type of antibiotic used.

Table 2 summarises some of the major mechanisms of resistance

and classes of antibiotic targets associated with mutations,

drug destruction and inactivation or modification and efflux

mechanisms 1.


In Focus

In bacterial biofilms, there may be additional mechanisms

responsible for the protection of bacteria from external insult13.

Susceptible bacteria that appear not to have a known genetic

basis can have a reduced susceptibility in a biofilm state. Several

hypotheses on the mechanisms of resistance to antibiotics in

bacterial biofilms have been proposed: slow or incomplete

penetration of the antibiotic in the biofilm; altered chemical

microenvironment within the biofilm; a subpopulation of

microorganisms in a biofilm forms a unique and highly protected

phenotypic state, a cell differentiation similar to spore formation.

Survivors might consist of 1% or less of the original population,

but they persist despite continued exposure to the antibiotic 13.

These processes are in many ways the most important in clinical

medicine, where clinical infection is commonly of this type – the

minimal inhibitory concentration of an aminoglycoside antibiotic

for an organism such as P. aeruginosa in a stressed biofilm in an

infected intravascular catheter may be 1,000-fold higher than in

the vegetative conditions in the diagnostic laboratory where the

determination of antibiotic susceptibility was made.

In a future of diminishing investment in antibiotic drug

discovery and development, preservation of existing drugs will

Mobile genetic element Characteristic(s) Resistance determinant(s) and examples

Plasmid Variable size (1-> 100kb), R factor: multiple resistances conjugative and mobile

Insertion sequence (IS) Small (<2.5 kb) contains terminal inverted ISAba1, IS26. repeats, and specifies a transposase.

Composite (compound) transposon Flanked by insertion sequences and/or Tn5: kan, bleo and str inverted repeats.

Complex transposon Large (>5 kb), flanked by short terminal Tn1 and Tn3: ß-lactamases repeats, and specifies a transposase and Tn7: tmp, str, spc reconbinase. Tn1546: glycopeptides

Conjugative transposon Promotes self-transfer Tn916: tet Tn1545: tet, ery, and kan

Transposable bacteriophage A bacterial virus that can insert into the mu chromosome

Other transposable elements Other than composite, complex, and Tn4: amp, str, sul, and Hg conjugative transposons Tn1691: gen, str, sul, chl, and Hg

Integron gene cassette capture and expression; Class 1: Multiple single often part of a multidrug resistance region determinants in gene cassettes including emerging carbapenemases and ESBLs

Table 1. Mobile genetic elements allowing antimicrobial resistance to develop in gram-positive and gram-negative bacteria 2.

Abbreviations: amp = ampicillin; bleo = bleomycin; chl = chloramphenicol; ery = erythromycin; fus = fusidic acid; gen = gentamicin; Hg = mercury; kan = kanamycin; spc = spectinomycin; str = streptomycin; strp = streptothricin; sul = sulfonamide; tet = tetracycline; tmp = trimethoprim; van = vancomycin; qac = quaternary ammonium compounds.

Mechanisms of resistance Class or antibiotic type

Drug inacativation penicillin, cephalosporins

Drug modification chloramphenicol, aminoglycosides, macrolides

Target mutation rifampicin, quinolones

Target substitution trimethoprim, sulphonomides, mupirocin

Target modification macrolides, tetracycline

Active efflux tetracycline, chloramphenicol, macrolides, fluoroquinolones

Table 2. Common major mechanisms of resistance to various classes of antibiotics 1.


In Focus

be increasingly important. Intelligent management of antibiotic

resistance gene flux requires us to understand the existing

ecology and the effect of drug selection pressure upon this. At

present, we have at best a limited knowledge. Despite an excellent

understanding of likely genes and biological mechanisms, and

awareness of the importance of this knowledge, most city

hospitals and microbiology laboratories could neither tell you

the genes that are responsible for antibiotic resistance in their

own intensive care units, nor their likely patterns of inheritance

and transmission in response to selection pressure. Developing

and managing this sort of complex information effectively is our

urgent immediate task 14.

References1. Levy SB. The science of resistance. In: Henderson D & Levy SB (Eds). Resistant

organisms: global impact on continuum of care (International Congress and Symposium Series 220). London:Royal Society of Medicine Press Limited, 1997.

2. Alekshun MN, Levy SB. Molecular mechanisms of antibacterial multidrug resistance. Cell 2007; 128:1037-50.

3. Tenover FC. Development and spread of bacterial resistance to antimicrobial agents: an overview. Clin Infect Dis 2001; 33 (Suppl 3):108-15.

4. Walsh C. Molecular mechanisms that confer antibacterial drug resistance. Nature 2000; 406:775-81.

5. Merlino J. Antimicrobial susceptibility testing: concepts, definitions and practices. Transmission and resistance between bacteria. In: antimicrobial susceptibility testing: methods and practices with an Australian perspective. 2004 Chapter 1, pages 11-22. Australian Society for Microbiology. Snap Printing, Sydney, Australia.

6. Courvalin P, Trieu-Cuot P. Minimising potentional resistance: the molecular view. Clin Infect Dis 2001; 33 (Suppl 3): 138-146.

7. Hooper DC. Minimizing potential resistance: the molecular view – a comment on Courvalin and Trieu-Cuot. Clin Infect Dis 2001; 33 (Suppl 3): 157-60.

8. Nordmann P, Naas T, Fortineau N et al. In the coming new decade; multidrug resistance and prospects for treatment of Staphylococcus aureus, Enterococcus spp. and Pseudomonas aeruginosa in 2010. Curr Opin Microbiol 2007; 10:1-5.

9. Robin F, Delmas J, Schweitzer C et al. Evolution of TEM-type enzymes: biochemical and genetic characterization of two new complex mutant TEM enzymes, TEM-151 and TEM-152, from a single patient. Antimicrob Agents Chemother 2007; 51:1304-9.

10. Hall RM, Stokes HW. Integrons: Novel DNA elements which capture genes by site-specific recombination. Genetica 1993; 90:115-32.

11. Stokes HW, Hall RM. A novel family of potentially mobile DNA elements encoding site-specific gene-integration: integrons. Molec Micro 1989; 3:1669-83.

12. Liebert C, Hall RM, Summers AO. Transposon Tn21, flagship of the floating genome. Mol Biol Rev 1999; 63:507-22.

13. Stewart PS, Costerton JW. Antibiotic resistance of bacteria in biofilms. Lancet 2001; 358:135-8.

14. Sintchenko V, Iredell JR, Gilbert L. Pathogen profiling for diseases management and surveillance. Nat Rev Microbiol 2007; 5:464-70.

Photos taken at the Antimicrobial SIG (ASIG) Workshop Adelaide

ASM members listen attentively to the lecturer Professor Tom Riley from the University of WA

Stephen Tristram from the University of TasmaniaDr. John Merlino (left) Chair/Convenor and Dr. Peter TaylorSouth Eastern Area Laboratory Services, Sydney


In Focus

Few issues in applied microbiology excite as much debate as the threatened transfer of antimicrobial resistance (AMR) from animals to cause disease in humans. Yet, almost four decades after the first warning of the potential risk to human health from the use of antimicrobials in agriculture 1, and after a plethora of national and international reports with similar conclusions 2-8, broad agreement is lacking on key elements of scientific fact, responsibilities and interventions. This article briefly considers some areas of concern and misunderstanding in the debate about public health impacts from the use of antimicrobials in animals. What is clear is that progress requires viewing the problem from the context of ‘the whole system’ rather than from the narrow confines of specific disciplines, professional groups, institutions, or commercial interests.

Science of resistance or resistance to science?Popular debate about the public health impact of antimicrobial use in animals has often resulted in over-simplification of technical facts for marketing of information to the broader population. Inevitably this has distorted the accuracy of scientific arguments, propagated misconceptions amongst professionals, and blurred the boundary between science and politics. Most importantly, it has portrayed the subject as a single scientific issue when it is in fact a complex network of related issues. Within this network each issue is defined by a specific combination of factors including the type of antimicrobial, the species of animal being treated, how animals are managed and housed, antimicrobial usage practices (dose and route of administration), the likelihood and effectiveness of human exposure, genetic mechanisms for resistance and the nature and severity of the disease in humans possibly caused by the emergence of resistance in animals. The diversity of these possibilities ensures that AMR from animals cannot be dealt with by a single discipline or single profession and that expertise from a range of backgrounds is essential for progress. Diversity and complexity also provides conditions ideal for dissemination of pseudoscience, whether it be deliberate and motivated by vested interest, or unintentional and well meaning

Antimicrobial resistance in animals and impacts on food safety and public health

David Jordan

Principal Research ScientistWollongbar Agricultural InstituteNew South Wales Department of Primary IndustriesWollongbar NSW 2478Tel: (02) 6626 1200Fax: (02) 6628 1744Email: [email protected]

but founded on ignorance. Therefore, perhaps the greatest challenge for the joint management of AMR in animals, food and humans is to sift out what is genuinely known from what is unknown.

Drugs of high importanceWith the demise in the use of antimicrobials as growth promoters the focus of attention in Australia has shifted to improving the management of those drugs used in animals that are also of ‘high importance’ in human medicine. Of greatest concern are third generation cephalosporins (specifically ceftiofur), streptogramins (virginiamycin), glycopeptides (vancomycin for humans, avoparcin for animals), gentamicin and fluoroquinolones. Avoparcin has been unavailable in Australia since 2000 and gentamicin and fluoroquinolone drugs have never been registered in this country for use in food animals. However, the use of ceftiofur in Australia is contentious because the analogous drugs in human medicine are highly valued as reserve agents and their use in healthcare is tightly controlled. In contrast, veterinarians are able to readily prescribe ceftiofur for use in food animals where it is typically targeted against infections having a substantial economic impact. Fears do exist that the use of ceftiofur in Australian livestock will escalate and promote emergence of extended spectrum beta-lactam-resistance in human pathogens in this country. In North America, epidemiological data for AMR in Salmonella suggests that that this has already occurred for some zoonotic strains, most notably serovars typhimurium and newport that typically already have resistance to five other antimicrobials 9,10. The implications for human health where these organisms emerge in livestock are substantial because non-typhoidal Salmonella infections are one of the most common food-borne infections. A small proportion of these cases, develop an invasive form of disease where the pathogen escapes the gut to colonise blood and tissues. Resistance of these pathogens to third generation cephalosporins makes effective therapy highly problematic and mortality very likely 11.


In Focus

There are additional concerns related to the frequency with which drugs of medium importance are administered, including for example, the inclusion of macrolide antimicrobials (e.g. tylosin) in the diet of intensively managed livestock. In some cases industries have made great progress in reducing reliance on these and other drugs by finding alternative control measures including, for example, vaccines for respiratory pathogens in poultry and by applying enhanced bio-security at the herd and flock level to prevent disease transmission on a large scale. Unfortunately, not all infectious diseases of livestock can be so effectively managed without antimicrobials and more solutions of this nature are needed.

AMR and foodFood can be a very efficient vehicle for bringing a large number of people into contact with a potential hazard. Thus, from a population perspective, food-borne exposure is regarded as the most critical pathway for transfer of AMR from animals to humans. Not all foods of animal origin pose an equal risk of exposure to the organisms of concern and not all antimicrobial resistance in food microflora should be attributed to use of antimicrobials in animals. In qualitative terms, there is a gradient of risk according to the antimicrobial use practices of each farm and industry, the extent of contamination of the raw food commodity with enteric bacteria, and the practices occurring within the food chain affecting the occurrence of cross-contamination and the effectiveness of any ‘kill steps’ prior to consumption (e.g. cooking and pasteurisation). Moreover, the consequences resulting from exposure are in most instances very difficult to quantify. This is especially so with respect to genetic determinants of resistance found in commensal organisms and which are often present in raw foods (e.g. enterococci and various Enterobacteriaceae). The literature is rich with assertions and counter assertions on the health threat posed by genetic determinants of resistance per se. Once again this highlights the need for each specific issue to be considered individually and divorced from the emotive, exaggerated reasoning that often characterises the debate.

Concerns about the safety of food and the widening gap between urban and rural Australia has allowed some damaging misconceptions about antimicrobial use in food production to proliferate. One of the most ludicrous and common implies that most farm animals receive antimicrobials on a daily basis – a contention that cannot possibly be supported by data on the amount of antimicrobials available for use in agriculture3. These misconceptions are very divisive and cause harm by drawing attention away from specific issues of antimicrobial use in animals and man where valuable progress is achievable. Establishing a system for reporting objective data on the amounts of antimicrobials (type, quantity, frequency and species) used in animals and man is one such area that desperately requires attention.

Economic driversMarket forces can be a powerful incentive for farmers and food producers to meet higher standards of quality. However, there are presently few indications that Australian consumers are willing to place concerns about AMR above those of the price

they pay for foods of animal origin. Further, many farmers are discouraged from using less antimicrobials in their livestock because it might feasibly increase the amount of disease, so raise the cost of production, and force their commodities to be less competitive. Most farm enterprises in Australia have low rates of return on capital and this combined with increased competition from global markets means that farmers must vigorously pursue efficiency to remain viable.

International markets may be a more important stimulus for raising quality than domestic markets. The decisions that some livestock owners make about antimicrobial use must strictly align with the expectations of consumers and regulators in foreign markets. One advantage that Australia has enjoyed in food safety is a red-meat and dairy sector based firmly on grazing. Under these conditions antimicrobials become less relevant to the health needs of livestock because animals do not acquire the bacterial diseases of their intensively managed counterparts. Historically, this natural tendency to avoid antimicrobial use has been of enormous benefit in meeting the requirement for low residues of antimicrobials in exported commodities. In the future it may also be useful for demonstrating superiority of product with respect to levels of antimicrobial resistant bacteria. Here farmers need to understand there are critical differences between residues and resistance. Residues can be immediately controlled once the source is detected by modifying the ways drugs are used. However, resistance is a persistent issue because reversion of pathogens and commensals to full susceptibility might only occur in the long term if at all. Therefore, many Australian farmers have an opportunity to distinguish their commodities in the international marketplace on the basis of quality by pursuing practices that place low reliance on antimicrobials and select less for resistance in a demonstrable way.

References1. Swann MM. Report of the joint committee on the use of antibiotics in animal

husbandry and veterinary medicine. London: Her Majesty’s Stationary Office, 1969.

2. WHO. The Medical Impact of Antimicrobial Use in Food Animals. Report of a WHO Meeting, Berlin, Germany, 13–17 October 1997. Geneva: World Health Organisation, 1997.

3. JETACAR. The use of antibiotics in food-producing animals: antibiotic resistant bacteria in animals and humans. Report of the Joint Expert Advisory Committee on Antibiotic Resistance (JETACAR). Canberra: Commonwealth Department of Health and Aged Care, Commonwealth Department of Agriculture, Fisheries and Forestry – Australia, 1999.

4. OTA. Impacts of Antibiotic-Resistant Bacteria. Washington DC:US Congress, Office of Technology Assessment, OTA-H-629, 1995.

5. MAFF. A Review of Antimicrobial Resistance in the Food Chain: Ministry of Agriculture Food and Fisheries UK, 1998.

6. Anon. Uses of antimicrobials in food animals in Canada: impact on resistance and human health. Veterinary Drugs Directorate, Health Canada, 2002.

7. WHO. WHO global strategy for containment of antimicrobial resistance. Geneva: World Health Organisation, 2001.

8. FAO/WHO/OIE. Joint FAO/OIE/WHO expert workshop on non-human antimicrobial usage and antimicrobial resistance: scientific assessment. Geneva: Food and Agriculture Organization, World Health Organization and the World Organization for Animal Health, 2003.

9. Ray KA, Warnick LD, Mitchell RM et al. Prevalence of antimcrobial resistance among Salmonella on midwest and northeast USA dairy farms. Prev Vet Med 2007; 79:204-23.

10. Anon. Canadian integrated program for antimicrobial resistance surveillance (CIPARS) 2005, preliminary results. Guelph: Health Canada, 2007.

11. Miriagou V, Tassios PT, Legakis NJ et al. Expanded-spectrum cephalosporin resistance in non-typhoid Salmonella. Int J Antimicrob Agents 2004; 23:547-55.


In Focus

With any decision to label a disease a public health issue comes

an implicit understanding that action must be taken and that

there should be a government intervention or management

plan – but there is no standard definition of what constitutes a

public health issue. Most often the factors considered are the

number of cases, the vulnerability of the affected group and

rapidity of spread, and the levels of morbidity and mortality

caused. The cost to the community – either directly in managing

the disease or in loss of work or productivity – is also an

important factor. We can all think of infectious diseases that fit

these criteria; meningococcal meningitis, because it kills young

healthy adults and children rapidly; pandemic influenza because

Antimicrobial resistance – a public health issue?

Keryn Christiansen

Department Microbiology & Infectious DiseasesPathWest Laboratory MedicineRoyal Perth HospitalPO Box X2213 Perth WA 6847Tel: (08) 9224 2442Fax: (08) 9224 1989Email: [email protected]

it has the potential to kill many rapidly; sexually transmitted

diseases carrying with them social stigma and the potential to

cause sterility; tuberculosis with its transmissability and protracted

and potentially lethal course; and food borne infections causing

large outbreaks. Where does antimicrobial resistance (AMR) fit

in this and is it a public health issue? To answer this question we

must look at the evidence.

Are there large numbers of infections due to antimicrobial resistant organisms? Although it is recognised that there are many infections due to

antimicrobial resistant organisms, with many anecdotal reports

and case series, validated prevalence or incidence data are

sparse. There are even less data available on burden of disease

caused by AMR organisms. However, there are surveillance data

showing proportions of isolates from clinical disease that exhibit

resistance. The following table attempts to consolidate what

information is available for Australia and other countries for

comparison, when appropriate*.

Do antimicrobial resistant organisms cause increased morbidity and mortality?A number of publications show an association between AMR in

Staphylococcus aureus, enterococci and gram-negative bacilli

HA-MRSA CA-MRSA N. gonorrhoea ESßL VRE XDR S. pneumoniae % S. aureus % S. aureus FQ R K. pneumoniae E. faecium TB penicillin non % of susceptibility MDR

Australia 31.9% 1 15.3%2 28.6%3 8.8%4 7.2%5 0%6 28%7

(overall)

Hong Kong 95.1% 8 11.6% 9 60.8% 10

Japan 76.9%8 10%9

USA 59.5% 11 (ICU) 13.3% 12 20.6%11 (ICU) 28.5% 11 (ICU) 3% 13 30% 10

Singapore 35.6% 9

HA-MRSA = hospital associated methicillin-resistant Staphylococcus aureus; CA-MRSA = community associated methicillin resistant Staphylococcus aureus; FQ = fluoroquinolone; R = resistant; EsßL = extended spectrum ß lactamase; VRE = vancomycin resistant enterococcus; XDR TB = extensively resistant Mycobacterium tuberculosis; MDR TB = multidrug-resistant Mycobacterium tuberculosis.

*As there may be variations between the states of Australia, overall data only are given. The source documents will provide greater detail if required. European data have not been included as it is not possible to give any representative figure. There are wide variations between member states and non-EU countries. Data can be obtained through the Euro Surveillance website (www.eurosurveillance.org).

Table: Resistance rates in clinical isolates from Australia, USA and Asia-Pacific region.


In Focus

and increases in mortality and morbidity. There is debate on

the method chosen for measuring such outcomes, but when

controlled for disease severity and other confounding variables

a significant increase in mortality can be demonstrated. This

has been shown for methicillin-resistant Staphylococcus aureus

(MRSA) relative to methicillin-susceptible S. aureus (MSSA) for

bacteraemia (OR 1.93; P<0.001) 14, and surgical site infection (OR

3.4 P 0.003) 15, and for patients infected with vancomycin-resistant

Enterococcus (VRE) compared with non-infected patients (RR

2.1 P 0.04) 16. Emergence of resistance during therapy for gram-

negative infections has also been shown to increase mortality;

for Pseudomonas aeruginosa (RR 3.0 P 0.02)17 and Enterobacter

species developing resistance to third generation cephalosporins

(RR 5.02 P 0.01)18.

Studies in various parts of the world have demonstrated

greater morbidity and mortality associated with antimicrobial

resistant organisms associated with food borne disease. In the

USA, FoodNet studies have shown that patients infected with

antimicrobial resistant non-typhoidal salmonella are more likely

to have bloodstream infection and to be hospitalised than patients

with pansusceptible infection 19. Also in a case controlled study 20

persons with ciprofloxacin-resistant Campylobacter infection

had a longer duration of diarrhoea than those with ciprofloxacin-

susceptible infection. Similarly, in Canada21 patients infected with

S. enterica serotype typhimurium, both DT104 and non-DT104,

had higher hospitalisation rates if the organisms were resistant to

the main therapeutic agents. In a Danish study 22, patients with

infection with S. typhimurium with multiresistance were 4.8-

times more likely to die than the general population, and 10.3-

times more likely to die if quinolone resistance was present.

Mycobacterium tuberculosis is of enormous public health

importance. Globally it kills more than 2 million people each

year and is the second leading cause of death due to infectious

disease after HIV/AIDS. Most cases potentially can be treated

with current antituberculous drugs – imagine if this were not the

case. What if not only our first line drugs were ineffective as with

multidrug resistant TB (MDR-TB) but also our second line. This

is a reality. Extensively drug resistant tuberculosis (XDR-TB) has

now been reported throughout the world, with the highest rates

in Korea, Eastern Europe and Russia23. This signals the potential

for a return to outcomes that were seen in the pre-antimicrobial

era when almost 50% of patients with the disease died. We are

fortunate that in Australia we have not yet seen XDR-TB 6 but with

high prevalence in countries in the Asia Pacific region, together

with the prevalence of air travel and increased exchange (e.g.

students), it is inevitable that we will.

Is there rapid transmission?Whenever an infectious disease that can cause severe infection

spreads rapidly within a community there are cries for public

health action. Consider the attention given to meningococcal

disease, pandemic influenza, and legionella outbreaks. We are

seeing the rapid spread of community associated MRSA (CA-

MRSA) in all states of Australia. Many of the strains of CA-MRSA

also possess a toxin, Panton-Valentine leukocidin (PVL) that is

associated with severe disease such as necrotising pneumonia,

necrotising fasciitis, severe skin and soft tissue infections, and

osteomyelitis. These types of infections are being reported more

frequently 2 and mortality or severe morbidity have occurred

in the Australian community 24-26. A number of PVL positive

CA-MRSA strains have been identified, with the most common,

the Queensland clone, also being the most widely distributed 2. In the USA, CA-MRSA was reported for the first time in 1999

with the death of four previously healthy children. Within a

few years the predominant CA-MRSA strain (USA300), which is

PVL positive, has spread across the USA. In a study reported in

2006 27, adult patients presenting to emergency departments

with skin and soft tissue infection were enrolled in eleven states

in the USA. The prevalence of MRSA was 59%, of which 97%

were the USA300 strain. This same strain has recently been

reported in Canada28, Denmark29 and now Australia (Gram-

Positive Laboratory, PathWest Laboratory Medicine Royal Perth

Hospital. Six monthly report July 2006-December 2007.) In

Western Australia the public health threat of PVL positive CA-

MRSA has been recognised and a program to control spread

is underway. The emergence of staphylococci, both resistant

to methicillin and possessing additional toxin genes, has been

described as a convergence of antimicrobial resistance and

virulence 30. Therefore, we also should be greatly concerned

about the increasing number of reports 2,31 indicating that these

more virulent strains are entering our hospitals and causing

infections in our more vulnerable patients. We have been fighting

hospital associated MRSA for many years and the prospect of a

more virulent opponent is certainly a major public health issue.

In addition, fatal or severe post-influenza community associated

MRSA pneumonia has recently been documented 32. It is alarming

to contemplate the combination of pandemic influenza and

necrotising pneumonia due to CA-MRSA.

Are vulnerable groups involved?The young, the elderly and the immunocompromised are all

targets for infections by AMR organisms. These are the groups in

whom antimicrobial usage is greatest and hence where selective

pressure for AMR is greatest. VRE and MRSA infections in hospitals

are common in intensive care and transplant units. Drug resistant

Streptococcus pneumoniae and CA-MRSA are noted for causing

infection in children. The development of an effective conjugate


In Focus

vaccine for S. pneumoniae has reduced invasive pneumococcal

disease in children in areas where there has been high vaccine

uptake. However, there is now the emergence of invasive disease

due to non-vaccine serotypes. One of these serotypes, 19A,

reported in the USA states of Massachusetts 33 and Texas 34, has

resistance to penicillin and ceftriaxone. The vulnerable, under

two years age group, will potentially have a resurgence of invasive

infections that will pose therapeutic challenges. New vaccines

will undoubtedly be developed but selection of non-vaccine

strains will almost certainly re-emerge. The first cases of CA-

MRSA in the USA were recognised in children and there is now

a very large body of literature devoted to CA-MRSA infections in

children in many areas of the world. Adults are also infected but it

is often when disease affects young healthy children that a public

health issue is first recognised.

Is there increased cost to the community?Costs due to AMR have mostly been measured as increased

costs associated with therapeutic management of the patient

– usually of drug therapy, increased length of stay in hospital – or

as costs incurred in controlling the organisms in the hospital

environment. There is a lack of research on costs due to loss of

work or productivity. Also, control of resistance in the community

is rarely undertaken although there is an intervention in Sweden

for penicillin-resistant S. pneumoniae. Hospital studies show

increased costs for infections due to MRSA 15,37,38 vancomycin-

resistant enterococci and resistant gram-negatives 17,18,40-42. The

cost of infection control within a hospital to eradicate an organism

such as VRE can be high. In my own hospital, eradication of VRE

cost A$2.7 million 43. The Swedish experience in the community

also had societal costs with exclusion of children from daycare

centres until negative for DRSP 44.

What then the conclusion?Yes – infections due to AMR organisms do occur in significant

numbers. Yes – infections due to AMR organisms cause increased

morbidity and mortality. Yes – infections due to AMR organisms

can be rapidly transmitted. Yes – AMR organisms cause infections

in the vulnerable members of society. Yes – the overall the cost of

AMR in Australia and globally is huge and probably in the many

billions of dollars.

Based on the evidence, there is only one conclusion. Yes – AMR

is a very significant public health issue.

References1. Australian Group on Antimicrobial Resistance Staphylococcus aureus survey

2005 Antimicrobial Susceptibility Report. http://antimicrobial-resistance.com. 8-8-2007.

2. Australian Group on Antimicrobial Resistance Staphylococcus aureus community survey 2004 Antimicrobial Susceptibility Report. http:// antimicrobial-resistance.com. 8-8-2007.

3. The WHO Western Pacific Gonococcal Antimicrobial Surveillance Programme. Surveillance of antimicrobial resistance in Neisseria gonorrhoeae in the WHO Western Pacific Region 2005. Commun Dis Intell 2006; 30:430-3.

4. Australian Group on Antimicrobial Resistance Gram–Negative Survey 2004 Antimicrobial Susceptibility Report. http://antimicrobial-resistance.com. 8-8-2007.

5. Australian Group on Antimicrobial Resistance Enterococcus spp survey 2005 Antimicrobial Susceptibility Report. http://antimicrobial-resistance.com. 8-8-2007.

6. Lumb R, Bastian I, Gilpin C et al. Tuberculosis in Australia: Bacteriologically confirmed cases and drug resistance 2005. Commun Dis Intell 2007; 31:80-6.

7. Australian Group on Antimicrobial Resistance Streptococcus pneumoniae 2005 Antimicrobial Susceptibility Report. http://antimicrobial-resistance.com. 8-8-2007.

8. Wang SA, Harvey AB, Conner SM et al. Antimicrobial resistance for Neisseria gonorrhoeae in the United States, 1988 to 2003: the spread of fluoroquinolone resistance. Ann Intern Med 2007; 147:81-8.

9. Hirakata Y, Matsuda J, Miyazaki Y et al. SENTRY Asia-Pacific Participants. Regional variation in the prevalence of extended-spectrum beta-lactamase-producing clinical isolates in the Asia-Pacific region (SENTRY 1998-2002). Diagn Microbiol Infect Dis 2005; 52:323-9.

10. Felmingham D. Comparative antimicrobial suceptibility of respiratory tract pathogens. Chemother 2004; 50(Suppl 1):3-10.

11. National Nosocomial Infection Surveillance (NNIS) System Report data summary from January 1992 through June 2004, Issued October 2004. Am J Infect Control 2004; 32:470-85.

12. Update to CDC’s Sexually Transmitted Disease Treatment guidelines, 2006: Fluoroquinolones no longer recommended for treatment of gonococcal infections. Morb Mortal Wkly Rep 2007; 56:332-6.

13. Extensively Drug Resistant Tuberculosis United States 1993-2006. Morb Mortal Wkly Rep 2007; 56:250-3.

14. Cosgrove SE, Sakoulas G, Perencevich EN et al. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 2003; 36:53-9.

15. Engemann JJ, Carmeli Y, Cosgrove SE et al. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infection. Clin Infect Dis 2003; 36:592-8.

16. Carmeli Y, Eliopoulos G, Mozaffari E et al. Health and economic outcomes of vancomycin-resistant enterococci. Arch Intern Med 2002; 162:2223-8.

17. Carmeli Y, Troillet N, Karchmer AW et al. Health and economic outcomes of antimicrobial resistance in Pseudomonas aeruginosa. Arch Intern Med 1999; 159:1127-32.

18. Cosgrove SE, Kaye KS, Eliopoulos GM et al. Health and economic outcomes of the emergence of third-generation cephalosporin resistance in Enterobacter species. Arch Intern Med 2002; 162:185-90.

19. Varma JK, Molbak K, Barrett TJ et al. Antimicrobial-resistant nontyphoidal Salmonella is associated with excess bloodstream infections and hospitalisations J Infect Dis 2005; 191:554-61.

20. Nelson JM, Smith KE, Vugia DJ et al. Prolonged diarrhea due to ciprofloxacin-resistant Campylobacter infection. J Infect Dis 2004; 190:1150-7.

21. Martin LJ, Fyfe M, Dore K et al. Multi-Provincial Salmonella Typhimurium case-control study steering committee. Increased burden of illness associated with antimicrobial-resistant Salmonella enterica serotype Typhimurium infections. J Infect Dis 2004; 189:377-84.

22. Helms M, Vastrup P, Gerner-Smidt P et al. Excess mortality associated with antimicrobial drug-resistant Salmonella typhimurium. Emer Infect Dis 2002; 8:490-5.

23. Shah NS, Wright A, Bai GH et al. Worldwide emergence of extensively drug-resistant tuberculosis. Emer Infect Dis 2007; 13:380-7.

24. Peleg AY, Munckhof WJ. Fatal necrotising pneumonia due to community-acquired methicillin-resistant Staphylococcus aureus (MRSA). Med J Aust 2004; 181:228-9.

25. Nimmo GR, Playford EG. Community-acquired MRSA bacteraemia: four additional cases including one associated with severe pneumonia. Med J Aust 2003; 178:245.

26. Collins N, Gosbell IB, Wilson SF. Community-acquired MRSA bacteraemia. Med J Aust 2002; 177:55-6.

27. Moran GJ, Krishnadasan A, Gorwitz RJ et al for the EMERGEncy ID Net Study Group. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006; 355:666-74.

28. Gilbert M, MacDonald J, Gregson D et al. Outbreak in Alberta of community-acquired (USA300) methicillin-resistant Staphylococcus aureus in people with a history of drug use, homelessness or incarceration. Can Med Assoc J 2006; 175:149-54.

29. Larsen AR, Stegger M, Goering RV et al. Emergence and dissemination of the methicillin resistant Staphylococcus aureus USA 300 clone in Denmark (2000-2005). Euro Surveill 2007;12.

30. Chambers HF. Community-associated MRSA resistance and virulence converge. N Engl J Med 2005; 352:1485-7.

31. Seybold U, Kourbatova EV, Johnson JG et al. Emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 genotype as a major cause of health care-associated blood stream infections. Clin Infect Dis 2006; 42:647-56.

32. Adam H, McGeer A, Simor A. Fatal case of post influenza community-associated MRSA pneumonia in an Ontario teenager with subsequent familial transmission. Can Commun Dis Rep 2007; 15:45-8.

33. Severe methicillin-resistant Staphylococcus aureus community-acquired pneumonia associated with influenza – Lousiana and Georgia, December 2006-January 2007. Morb Mortal Wkly Rep 2007; 56:325-329.

34. Pelton SI, Huot H, Finkelstein JA et al. Emergence of 19A as virulent and multidrug resistant Pneumococcus in Massachusetts following universal immunization of infants with pneumococcal conjugate vaccine. Pediatr Infect Dis J 2007; 26:468-72.

35. Messina AF, Katz-Gaynor K, Barton T et al. Impact of the pneumococcal conjugate vaccine on serotype distribution and antimicrobial resistance of invasive Streptococcus pneumoniae isolates in Dallas, TX, children from 1999 through 2005. Pediatr Infect Dis J 2007; 26:461-7.

36. From the Centers for Disease Control and Prevention. Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus – Minnesota and North Dakota, 1997-1999. JAMA 1999; 282:1123-5.

37. Herold BC, Immergluck LC, Maranan MC et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA 1998; 279:593-8.

38. Greiner W, Rasch A, Kohler D et al. Clinical outcome and costs of nosocomial and community-acquired Staphylococcus aureus bloodstream infection in haemodialysis patients. Clin Microbiol Infection 2007; 13:264-8.

39. Shorr AF, Tabak YP, Gupta V et al. Morbidity and cost burden of methicillin-resistant Staphylococcus aureus in early onset ventilator-associated pneumonia. Crit Care 2006; 10:R97.

40. Carmel Y, Eliopoulos G, Mozaffari E et al. Health and economic outcomes of vancomycin-resistant enterococci. Arch Intern Med 2002; 162:2223-8.

41. Evans HL, Lefrak SN, Lyman J et al. Cost of gram-negative resistance. Crit Care Med 2007; 35:89-95.

42. Lee SY, Kotapati S, Kuti JL et al. Impact of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species on clinical outcomes and hospital costs: a matched cohort study. Infect Control Hosp Epidemiol 2006; 27:1226-32.

43. Daxboeck F, Budic T, Assadian O et al. Economic burden associated with multi-resistant gram-negative organisms compared with that for methicillin-resistant Staphylococcus aureus in a university teaching hospital. J Hosp Infect 2006; 62:214-8.

44. Christiansen KJ, Tibbett PA, Beresford W et al. Eradication of a large outbreak of a single strain of vanB vancomycin-resistant Enterococcus faecium at a major Australian teaching hospital. Infect Control Hosp Epidemiol 2004; 25:384-90.

45. Hogberg L, Henriques Normark B, Ringberg H et al. The impact of active intervention on the spread of penicillin-resistant Streptococcus pneumoniae in Swedish day-care centres. Scand J Infect Dis 2004; 36:629-35.

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In Focus

Resistance to antiviral agents: balancing good and evil

Antiviral agents have been difficult to find and we still have only

a handful that meet the safety and effectiveness we have come

to expect from antibacterial agents. Some, because of these

limitations, are reserved for serious conditions such as HIV,

hepatitis B (HBV), hepatitis C and CMV in immunocompromised

patients. The widespread use of antivirals has been a phenomenon

of the last one to two decades, following on from the development

of the nucleoside analogues for herpes viruses. Not unexpectedly,

it is only in the very recent past that we have had to confront the

problems of resistance of viruses to antiviral agents 1, though

this already poses significant management problems for some

conditions.

For a number of reasons, resistance to antiviral agents is less

common than has been seen with antibacterials.

Firstly, most viral infections are either acute, like influenza, or

a reactivation of latent infection like cold sores or shingles, so

the virus is only active for a few days and there is little time for

resistance to develop, and if the antiviral is used unnecessarily,

such as in prescribing a neuraminidase inhibitor (NI) for a patient

without influenza, there is no virus to be exposed to the antiviral.

Even with long-term suppressive therapy of herpes simplex virus

(HSV) infections, the periods of attenuated viral replication that

occur in many people during therapy do not lead to emergence

of stable resistant virus. This is very different from the situation

with antibacterial agents, as there are always bacteria in the gut

and on the skin and mucosal surfaces, that will be exposed and

can become resistant. Interestingly, there is one partial parallel,

where the use of reverse transcriptase inhibitors (RTIs) for

treatment of either HIV or HBV in patients with co-infection can

result in cross-resistance in the other virus.

Secondly, the acquisition of antiviral resistance often makes

viruses less fit so that they disappear once the antiviral is ceased,

as is usual with HSV resistant to aciclovir and penciclovir,

influenza resistant to neuraminidase inhibitors and HBV resistant

to lamivudine.

Thirdly, even if the viruses are fit, such as amantadine-resistant

influenza A, they do not persist in communities, presumably

because there is no reservoir for them that is equivalent to the

human gut, skin or mucosal surfaces. However, there is growing

concern that chronically immunosuppressed individuals may

become significant sources for resistant viruses, as has been

seen for influenza resistant to Nls 2. These patients could act as

reservoirs for the rare, fit resistant viruses or allow time for less fit

viruses to develop increased transmissibility and pathogenicity.

Fourthly, viruses neither easily exchange genetic information and

never across species nor do they possess resistance plasmids, so

spread of antibiotic resistance genes, as is seen in bacteria, does

not occur.

However, antiviral resistance has emerged and is a particular

problem in immunocompromised patients. These patients usually

require long-term antiviral therapy, creating a situation where

viruses continue to replicate in the presence of the antiviral,

albeit at a reduced level, driving the selection of resistant mutants

without an effective immune system to deal with them. There

are many examples of this, including HIV resistance to RTIs and

protease inhibitors (PIs), HSV resistance to aciclovir and CMV

resistance to ganciclovir. A similar situation occurs in lamivudine

treatment of chronic hepatitis B where, although the patients are

usually not overtly immunosuppressed, their carrier state exists

because of an inability of their immune system to control HBV.

David Smith and David Speers

Division of Microbiology and Infectious DiseasesPathWest Laboratory Medicine WAHospital Ave, Nedlands WA 6009Tel: (08) 9346 3122Fax: (08) 9346 3960Email: [email protected]


In Focus

Recently there has been concern about neuraminidase inhibitor

resistance in influenza, particularly in Japan where several million

courses of oseltamivir are used each year. Trial data indicated that

oseltamivir resistance was very uncommon, but in 2004 there

were reports of influenza A resistance rates of 16–18% in treated

children in Japan 3 possibly due to lower antiviral doses used in

children. Community-wide surveillance found a resistance rate

of only 0.3% 4, suggesting that resistant virus was not circulating.

However, a report earlier this year found high resistance rates in

influenza B with suggestion of transmission of the resistant virus

to close contacts 5. As yet it remains unclear whether this was a

localised phenomenon or an indicator of an emerging problem.

Resistance to zanamivir remains a rare phenomenon. There is

ongoing international monitoring of NI resistance though the

Neuraminidase Inhibitor Susceptibility Network 5.

Antiviral susceptibility testing is uncommon, as there is limited

demand. With very few exceptions, there is no evidence for the

stable circulation of resistant viruses in the community, despite

extensive surveillance for aciclovir resistance in HSV and for NI

resistance in influenza. Nor is the emergence of resistance a

significant problem other than in specific situations of prolonged

treatment of chronic infections such as hepatitis B and HIV.

Therefore, resistance testing is generally undertaken only in

situations of failure of therapy; e.g the lamivudine treated patient

with rising HBV-DNA levels. HIV is now the exception, as resistant

viruses are known to circulate in the HIV infected community. The

range of antiviral agents used is large and resistance and cross-

resistance patterns are complex, so that laboratory measures of

resistance are important for proper patient management.

Testing for antiviral resistance is still in its infancy. It is technically

more challenging than antibacterial resistance testing because

traditional methods relying on visual detection of viral growth

are influenced by a large number of variables. These include the

type of cell line, difficulty in maintaining stability of the medium

during prolonged incubation, the nature and stability of the cell

line, the varying ability of viruses to produce reliable plaques (or

the inability to get reliable growth in any in vitro system), lack

of standardisation of methods for determining plaque numbers,

and many others. A variety of modifications have been used to

detect viral growth by methods other than plaque formation,

including use of monoclonal antibodies, PCR detection of

product, assays of enzyme activity (e.g. neuraminidase inhibition

for the NIs), but all remain technically demanding. Even the

easiest combinations such as HSV and aciclovir (Figure 1),

are only done in highly specialised laboratories. Determining

meaningful breakpoints is difficult and will vary with the assay

system used 6. Therefore, there has been considerable interest

in the use of genotypic methods such as sequencing to identify

mutations likely to confer antiviral resistance. This has reached

its highest level with the virtual phenotypes for HIV resistance,

where the mutations associated with resistance to the RTIs and

PIs are used to predict likely failure of therapy. It is also proving

useful for determining nucleoside analogue resistance in HSV

and CMV 1 and NI resistance in influenza.

One approach to prevention of emergence of resistance has

been the use of combinations of antiviral agents. For example,

monotherapy for HIV or HBV commonly leads to resistance, so

antiviral combinations are now standard for HIV treatment and

are often recommended for HBV.

There remain a large number of significant viral infections for

which we still have no effective antiviral agents, including most of

the respiratory viruses, gastrointestinal viruses and arboviruses.

Of those that we have, many are below our desired standards

of both safety and effectiveness. Therefore, we can expect the

supply of antiviral agents to continue to expand. We cannot

afford to be complacent about antiviral resistance in the future

but neither should we restrict the availability of potentially useful

agents due to exaggerated fears of resistance. Of course, care

should be taken to use antiviral agents appropriately, particularly

in situations where stable or persisting resistant viruses may

emerge.

The balancing act will continue!

References1. Griffiths PD. Resistance in viruses other than HIV. Int J Infect Dis 2002;

6(Suppl1):S32-7

2. Baz M, Abed Y, McDonald J et al. Characterization of multidrug-resistant influenza A/H3N2 viruses shed during 1 year by an immunocompromised child. Clin Infect Dis 2006; 43:1562-4.

3. Kiso M, Mitamura K, Sakai-Tagawa Y et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004; 364:759-65.

4. Monto AS, McKimm-Breschkin JL, Macken C et al. Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use. Antimicrob Agents Chemother 2006; 50:2395-402.

5. Hatakeyama S, Sugaya N, Ito M et al. Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. JAMA 2007; 297:1435-42.

6. Weinberg A, Leary JJ, Sarisky RT et al. Factors that affect in vitro measurement of the susceptibility of herpes simplex virus to nucleoside analogues. J Clin Virol 2007; 38:139-45.

Figure 1: Plaque reduction assay for determining herpes simplex virus susceptibility to aciclovir. The Vero cell monolayer is stained with methylene blue.


In Focus

The last two to three decades have seen a major increase in

invasive fungal infections (IFIs), a small, but increasing proportion

of which are caused by pathogens with partial or complete

resistance to antifungal drugs. The increase in IFIs has largely

been associated with the increase in immunocompromised and

critically ill patients. Opportunistic infections with relatively drug-

resistant environmental fungi account for much of the resistance.

In addition, amongst the only fungal species to colonise humans,

Candida, two species that are resistant (C. krusei) or relatively

resistant (C. glabrata) to fluconazole have emerged. In part this

is explained by the selection pressure exerted by widespread use

of fluconazole. Together with the introduction of new antifungal

drugs with selective and/or variable antifungal activity, these

changes have stimulated interest in understanding mechanisms

and origins of resistance, the identification of resistance in

the laboratory and its relationship to clinical outcomes, and in

surveillance of clinical isolates and populations at risk of IFIs.

Definitions of resistancePrimary drug resistance is that identified in vitro without

previous exposure to an antifungal drug. Secondary resistance

is stable resistance that is induced by exposure to an antifungal

drug in vivo or in vitro. Most examples of resistance in fungal

Impact of antifungal resistance in Australia

David Ellis

Mycology Unit, Women’s and Children’s Hospital, Adelaide, South Australia

pathogens are primary in type. A notable exception is resistance

of yeasts to flucytosine. This is seen frequently when flucytosine

is used as a single agent to treat such infections.

Mechanisms of resistanceMost information is available for resistance of yeasts to azole

drugs. There are three distinct types of mechanism: 1) Failure

of accumulation of drug within the fungal cell due to increased

efflux (via upregulation of multidrug efflux transporter genes),

or reduced influx; 2) Reduced affinity for the P450-dependent

enzyme target of azoles, Erg11p (lanosterol 14α-demethylase) or,

in some cases, upregulation of the responsible gene ERG11; 3)

Altered sterol composition. Resistance secondary to upregulation

of the multidrug transporter genes is the most common

mechanism 1.

Identification of resistance in vitro and correlation with clinical outcomeSusceptibility testing for yeasts and filamentous fungi has been

standardised by the Clinical and Laboratory Standards Institute

(CLSI, formerly NCCLS) using broth dilution methods. These

are still subject to inter- and intra-laboratory variability especially

Sharon Chen

Centre for Infectious Diseases and Microbiology and University of Sydney, Westmead, New South Wales

Tania SorrellCentre for Infectious Diseases and

Microbiology, 3rd level, ICPMR

Building, Westmead Hospital,

Darcy Road, Westmead Hospital,

Westmead NSW 2145 AUSTRALIA

Tel: (02) 9845 6012

Fax: (02) 9891 5317

Email:

[email protected]


In Focus

when testing filamentous fungi. As an example, breakpoints

aimed at correlating susceptibility with clinical outcome have

been established for fluconazole, itraconazole and voriconazole

when tested against Candida albicans, but in limited clinical

settings, e.g. oropharyngeal candidiasis in HIV-infected patients 3.

For some drugs, e.g. amphotericin B, testing on solid agar seems

to be more reproducible.

Clinical outcomes are influenced not only by intrinsic susceptibility

of the fungus, but also dose and pharmacokinetics of the drug,

timing of initiation of therapy and host response factors. Thus,

knowledge of the minimal inhibitory concentration (MIC) of drug

can only be a guide to antifungal selection even in settings where

it has been correlated with clinical outcome. In general, MIC

predicts clinical resistance more accurately than susceptibility.

It has been suggested that with Candida, a MIC indicative of

susceptibility will correlate with clinical responsiveness 60% of

the time and a MIC predictive of resistance will correlate with

clinical responsiveness 40% of the time 2.

Surveillance for resistanceMICs are useful in identifying trends in antifungal susceptibility

(or resistance) in common and emerging pathogens over

time. Data from the Australian Mycology Reference Laboratory

(Women’s and Children’s Hospital, Adelaide) of the rates of

resistance of selected pathogens, recorded from 1989–2006, are

shown in Figure 1. Fluconazole resistance in C. albicans and

Cryptococcus neoformans peaked around 1993–1994 at the

height of the HIV/AIDS epidemic in Australia. However, since

the introduction of HAART in late 1996, resistance rates have

dropped dramatically (Figure 1). Resistance to itraconazole

among Aspergillus fumigatus is uncommon and appeared to

peak around 2003, but has since declined with the introduction

of voriconazole.

The rates of resistance to antifungal drugs vary with the fungal

species and antifungal agent for a given species (Tables 1 and

2). Among Candida species recovered from blood, resistance

to amphotericin B and flucytosine remain rare. Candida krusei

was predictably resistant to fluconazole but all isolates were

susceptible to voriconazole and posconazole. Azole resistance

among C. glabrata was substantial (Table 1) with 10% of

isolates cross-resistant to all azoles, including voricoanzole and

posaconazole. Of note, nearly 10% of Candida parapsilosis,

Candida guilliermondi and C. krusei had MICs to caspofungin

that were considered ‘resistant’ (Table 1). Table 2 shows that

although there are no break points established for voriconazole

susceptibility for moulds, resistance to voriconazole among

Aspergillus species has not been encountered in Australia. The

survey of Scedosporium and other mould isolates indicates that

in vitro resistance is common for most antifungal agents but

Scedosrpoium apiospermum is susceptible to voriconazole and

posconazole (Table 2).

Resistance to flucytosineThere is a high prevalence of flucytosine resistance in yeasts

in the US (up to 8% of C. albicans blood stream isolates in a

recent report) 4. This contrasts with figures of 1.6% in Australia

and 0.2% in Europe (current article) 5. The major problem with

flucytosine is the frequency and speed at which isolates develop

resistance during therapy. Since this has been identified as a

major cause of treatment failure, monotherapy with flucytosine is

not recommended. Combination therapy with AMB significantly

reduces clinical resistance and flucytosine is now mainly used with

AMB for treatment of neuro- or disseminated cryptococcosis.

Resistance to polyenesWith most fungal species the range of MICs of amphotericin B

determined by CLSI-based methods is too small to discriminate

effectively between ‘resistant’ and ‘susceptible’. Although E-tests

and other solid agar based methods appear promising, to date,

no solution to this problem has been agreed upon. Temporal

trends of amphotericin B susceptibility among Candida species

in Australia indicate that MICs of most species remain low at <

1.0 mg/L with the exception of C. krusei (MIC90 1.0 mg/L).

It is recognised that certain Candida species (specifically C.

lusitaniae, C. lipolytica, C. krusei, C. guillermondii and some

C. albicans) are intrinsically resistant to, or have a propensity to

0

5

10

15

20

25

30

35

40

45

50

89 90 91 92 93 94 95 96 97 98 99 0 1 2 3 4 5 6

Figure 1. Percentage resistance (y axis) over time (1989–2006; x axis) for Candida albicans against fluconazole (blue line), Cryptococcus neoformans against fluconazole (red line) and Aspergillus fumigatus against itraconazole (yellow line).


In Focus

develop resistance to, AMB 6 but it has been difficult to estimate

this prevalence with certainty. Whilst resistance to AMB can be

readily induced in vitro, the rate at which secondary resistance

develops during therapy cannot be effectively quantified.

However, the consensus of opinion leaders is that it is low 1, a

view supported by our data (Table 1). Failure of AMB therapy

including breakthrough candidemia, attributable to development

of AMB resistance, has also remained uncommon 1 with only

isolated cases of acquired resistance among Candida species

described, especially in cancer patients 7. In cancer patients

there is some evidence of a correlation between failure of AMB

therapy and in vitro resistance and clinicians should remain

vigilant for treatment failure. The emergence of Candida and C.

neoformans strains with cross-resistance to azoles and polyenes

has been occasionally reported in HIV infected patients after

prolonged azole exposure 1.

Primary resistance to AMB has emerged in parallel with an

increase in infections due to uncommon environmental fungi.

In Australia, a substantial (70–>95%) of Scedosporium and

Fusarium isolates are resistant to amphotericin B (Table 2)

consistent with that in the US 8. Primary resistance to AMB

has been encountered in non-fumigatus Aspergillus species,

particularly A. terreus, the recently described species A. lentulus

and other species within the Clade fumigatus 9. Although our

results indicate that resistance to AMB is uncommon in Australia,

given differences in susceptibility, species level identification

of Aspergillus isolated from clinically important body sites is

recommended.

Resistance to triazole antifungal agents The clinical consequences of triazole resistance are most obvious

in Candida infections, particularly those associated with AIDS.

There is unequivocal evidence that the use of azoles particularly,

but not exclusively, fluconazole is a risk factor for secondary

azole resistance arising after long-term treatment of oesophageal

candidiasis as reviewed by Sanglard and Odds 1. Fluconazole

resistance rates of up to 41% were demonstrated 10. Widespread

azole use is also believed to explain the appearance of C.

dubliniensis in this population – a species notable for its ability

to rapidly develop stable resistance to fluconazole in vitro 11.

Since the fall in oesophageal candidiasis following the success

of HAART for HIV infection, azole-resistant isolates are now

rare (Figure 1). This epidemiological curve suggests that the

emergence and disappearance of fluconazole resistance was

a function of selective pressure exerted on Candida by the

prolonged duration and level of drug exposure. Prolonged

maintenance of such selective pressure would be expected

induce stable resistance and lead to therapeutic failure.

Although the widespread use of azoles as monotherapy in patients

with disseminated candidiasis and other deep-seated infections,

could create a serious problem 12 there is little evidence of large-

scale emergence of resistant Candida strains or species in the

Table 1. Candida resistance* rates for blood stream isolates (Australian Candidemia Study).

Species (no.) Antifungal agent (frequency [%] resistance to)

AMB 5FC FLU ITR VOR POS CAS

C. albicans (447) 0 1.6 0 0 0 0 0

C. parapsilosis (182) 0 0.5 0.5 1 0 0 0

C. glabrata (167) 0 0 23 86 10† 10 0

C. krusei (46) 0 0 91 9 0 0 0

C. tropicalis (46) 0 0 0 0 0 0 0

C. dubliniensis (22) 0 4 0 0 0 0 0

C. guilliermondii (11) 0 0 0 36 0 0 0

C. lusitaniae (8) 0 0 0 0 0 0 0

*Resistance is defined as the following MICs (ug/ml): AMB >4; 5FC >32; FLU >64; ITR >1; VOR >4; POS >2; CAS >2 (no breakpoints have been established for posaconazole or caspofungin). † All voriconazole-resistant strains showed cross resistance to all other azoles, but were susceptible to amphotericin B and caspofungin.


In Focus

clinical setting 1. In many epidemiological studies of candidemia,

decreases in the prevalence of C. albicans and increases in non-

albicans Candida species (especially C. glabrata) have been

reported. This is important as candidemia due to non-albicans

Candida species has been associated with increased attributable

mortality 13. MIC data from Australia (Table 1) and elsewhere

confirm that C. glabrata in particular is less susceptible to

fluconazole and itraconazole than C. albicans, and C. krusei is

intrinsically resistant. Selection pressure from the routine use of

fluconazole prophylaxis has resulted in the emergence of C. krusei

and C. glabrata infections, including candidemia, in patients with

haematological stem cell transplantations. However, examination

of published MIC results does not reveal a temporal increase in

the prevalence of resistance among blood isolates of Candida 1; a

finding supported by our Australian data. Furthermore, although

there is evidence that rates of azole-resistant Candida isolates

vary between geographical regions and institutions 14, there is

no evidence that resistant strains predominate in any particular

institution. A review of the susceptibility of recently tested

isolates in North America and Europe also showed low rates of

fluconazole and itraconazole resistance in C. albicans 1.

Since the introduction of voriconazole in 2002, similar concerns

regarding emergence of resistant strains have arisen. Our data

Table 2. Aspergillus, Scedosporium, Fusarium and Rhizopus resistance rates.

Species (n) Frequency (%) of resistance to:

AMB ITR VOR POS*

A. flavus (28) 32 0 0 0

A. fumigatus (191) 6 2 0 0

A. niger (26) 0 0 0 0

A. terreus (29) 48 0 0 0

S. apiospermum (87) 70 26 0 0

S. prolificans (134) 93 100 81 100

F. oxysporium (14) 78 56 33 nd

F. solani (21) 86 100 14 nd

Rhizopus sp. (9) 0 71 100 0

*For the purposes of this article resistance is defined as the following MICs (ug/ml): AMB >4; ITR >1; VOR >4; POS >2 (No breakpoints have been established for moulds; nd = not done).

Table 3. Synergy testing results for S. prolificans against terbinafine in combination with voriconazole or itraconazole.

Drug combination ∑FIC < 0.5 ∑FIC > 0.5-4 ∑FIC > 4 (S) (NS) (A)

Voriconazole/Terbinafine (n=109) 94 (86.2%) 15 (13.8%) 0

Itraconazole/Terbinafine (n=93) 56 (60.2%) 37 (39.8%) 0

The summation of the fractional inhibitory concentration (ΣFIC) was calculated as follows: (MIC agent A in combination/MIC agent A alone) + (MIC agent B in combination/MIC agent B alone). Synergy was defined as a ΣFIC of ≤ 0.5; No synergy >0.5 - 4; Antagonism > 4.


In Focus

indicate almost all Candida species are very susceptible to

voriconazole. A small subset (10%) of C. glabrata isolates were

resistant (MICs ≥4); these exhibited cross-resistance to all azoles

including posaconazole (Table 1). Resistance to multiple triazole

drugs including itraconazole, voriconazole and posaconazole was

reported recently in A. fumigatus in the Netherlands 16. MICs of

other filamentous fungi are not always predictable. For example,

voriconazole exhibits relatively high MICs against Scedosporium

prolificans compared with S. apiospermum and these are often

associated with therapeutic failure (Table 2). Fusarium isolates

show variable MICs against voriconazole and posaconazole and

the only azole with activity against zygomycetes is posaconazole.

For some intrinsically resistant moulds, like S. prolificans, in

vitro synergy studies for the combination of voriconazole and

terbinafine may prove useful (Table 3). Terbinafine appears to

be synergistic with voriconazole and itraconazole against most

isolates of S. prolificans. Anecdotal experience indicates that

combination therapy results in clinical benefit.

Resistance to echinocandins Because the echinocandins have been in clinical use only since

2001, the clinical significance of strains which test ‘resistant’ in

vitro is unclear. As seen in Table 1, caspofungin is highly active

against all Candida species including C. parapsilosis in Australia

(MIC901.0 mg/L). Based on MIC determinations for blood stream

isolates, MICs of caspofungin and other echinocandins are higher

for C. parapsilosis than for other common Candida species (this

article, 16). This difference has raised concern that C. parapsilosis

might respond less well than other Candida or require higher

doses of drug. However, in clinical trials there has been no

evidence of reduced responsiveness of small numbers of C.

parapsilosis infections to echinocandin therapy 17. In another

analysis, MIC results of caspofungin for Candida species did not

correlate with clinical outcome 18. On the basis of these limited

data, in vitro susceptibility results may not be clinically useful.

Cross-resistance between echinocandins is usually complete.

We found no increased MICs (‘resistance’) to caspofungin among

Australian isolates of Aspergillus species At the time of writing,

the drug is only licensed for the salvage treatment of invasive

aspergillosis (IA). However, there are numerous case reports

detailing its efficacy in the primary therapy of IA. Other moulds

including Scedosporium, Fusarium and the zygomycetes are

resistant to all echinocandins.

ConclusionThe selection of an antifungal agent is dependent on both the

causative pathogen and clinical setting. Resistance to currently

available antifungal drugs is uncommon among Candida species

with two main exceptions – C. krusei is resistant to fluconazole and

up to 30% of C. glabrata isolates may be azole-resistant, including

10% that are resistant to voriconazole and posaconazole. Azole

resistance in Aspergillus species is rare. Many non-Aspergillus

moulds are less susceptible or resistant to most currently

available antifungal agents. Antifungal susceptibility testing for

clinically significant fungal isolates is recommended.

References1. Sanglard D, Odds F. Resistance of Candida species to antifungal agents: molecular

mechanisms and clinical consequences. Lancet Infect Dis 2002; 2:73-85.

2. Rex JH & Pfaller MA. Has antifungal testing come of age? Clin Infect Dis 2002; 35:982-9.

3. National Committee for Clinical Laboratory Standards Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard NCCLS document M27-A2. 2nd ed. Wayne, PA:National Committee for Clinical Laboratory Standards Wayne, 2002.

4. Pfaller MA, Jones RN, Messer SA et al. National surveillance of nosocomial blood stream infections due to Candida albicans – frequency of occurrence and antifungal susceptibility in the Scope program. Diag Microbiol Infect Dis 1998; 31:327-32.

5. Barchiesi F, Arzeni D, Caselli F et al. Primary resistance o flucytosine among clinical isolates of Candida spp. J Antimicrob Chemother 2000; 45:408-9.

6. Collin B, Clancy CJ, Nguyen MH. Antifungal resistance in non-albicans Candida species. Drug Res Update 1999; 2:9-14

7. Nolte FS, Parkinson T, Falconer DJ et al. Isolation and characterisation of fluconazole- and amphotericin B-resistant Candida albicans from blood of two patients with leukemia. Antimicrob Agents Chemother 1997; 41:196-9.

8 Berenguer J, Rodriguez-Tudela JL, Richard C et al. Deep infections caused by Scedosporium prolificans. A report on 16 cases in Spain and a review of the literature. Scedosporium Prolificans Spanish Study Group. Medicine (Baltimore) 1997; 76:256-65.

9. Balerjee SA, Gribskov JL, Hanley E et al. Aspergillus lentulus sp. nov., a new sibling species of A. fumigatus. Eukaryotic Cell 2005; 4:625-32.

10. Canuto MM, Rodero FG. Antifungal drug resistance to azole and polyenes. Lancet Infect Dis 2002; 2:550-63.

11. Moran GP, Sullivan DJ, Henman MC et al. Antifungal drug susceptibilities of oral Candida dubliniensis isolates from human immunodeficiency-virus (HIV)-infected and non-HV-infected subjects and generation of stable fluconazole–resistant derivatives in vitro. Antimicrob Agents Chemother 1997; 41:617-23.

12. Pappas PG, Rex JH, Sobel JD et al. Guidelines for treatment of candidiasis. Clin Infect Dis 2004; 38:161-89.

13. Kremery V. Is there in vivo-in-vitro correlation between antifungal susceptibility, species of Candida spp. and clinical outcome? Int J Antimicrob Agents 2000; 16:537-9.

14. Pfaller MA, Jones RN, Doern GV et al. Bloodstream infections due to Candida species: SENTRY Antimicrobial Surveillance Program in North America and Latin America, 1997-1998. Antimicrob Agents Chemother 2000; 44:747-51.

15. Verweij PE, Mellado E, Melchers WJG. Multiple-triazole-resistant aspergillosis. New Eng J Med 2007; 356:1491-3.

16. Park S, Kelly R, Nielsen Khan J et al. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother 2005; 49:3264-73.

17. Colombo A, Perfect J, DiNubile M et al. Global distribution and outcomes for Candida species causing invasive candidiasis: results from an international randomized double-blind study of caspofungin versus amphotericin B for the treatment of invasive candidiasis. Eur J Clin Microbiol Infect Dis. 2003; 22:470-4.

18. Kartsonis N, Killar J, Mixson L et al. Caspofungin susceptibility testing of isolates from patients with esophageal or invasive candidiasis: relationship of MIC to treatment outcome. Antimicrob Agents Chemother 2005; 49:3616-23.


In Focus

Resistance testing in parasites: a review

Harsha Sheorey

Consultant Medical MicrobiologistSt Vincent’s Hospital, MelbournePO Box 2900Fitzroy 3065 Victoria, AustraliaTel: 61 3 9288 4066Fax: 61 3 9288 4068Email:[email protected]

IntroductionThe burden of parasitic diseases in the world is enormous and

41% of the world’s population lives in areas where malaria is

transmitted. Each year 350–500 million cases of malaria occur

worldwide, and over one million people die, most of them

young children in sub-Saharan Africa 1. About 2 billion people are

affected worldwide, of whom 300 million suffer associated severe

morbidity 2. At least 1 billion people – one sixth of the world’s

population, or 1 in 6 persons, suffer from one or more neglected

tropical diseases (NTDs), most of which are parasitic 3.

Some parasitic diseases are endemic in Australia with potential

of outbreaks in schools (head lice), daycare centres (Giardia),

swimming pools (Cryptosporidium) and amongst Indigenous

Australians in the ‘top end’ of the country 4.

Failure to respond to antiparasitic drugs is a major concern

in many parts of the world. The biggest concern is with

antimalarial drugs for Plasmodium falciparum, which has

now become resistant to a number of drugs. Resistance has

also been reported in other protozoa (Leishmania), helminths

(particularly veterinary helminths) and in arthropods (lice and

mites). Testing for resistance in parasites is very difficult,

not well standardised and hence, not routinely available

in diagnostic laboratories. This article will briefly review the

methods that have been used by various scientists and highlight

the complexity of testing in parasites. Some of the techniques are

developed for testing effects of new antiparasitic drugs and can

be used to look for resistance.

Failure to respond is not always resistanceFailure to respond to treatment is not always due to resistance

to the drug (see table 1). True resistance may be inherent or

acquired. Most antiparasitic drugs have a specific and narrow

spectrum of activity. Moreover, the complex life cycle of parasites

means passing through different stages from eggs or cysts

to trophozoites or larvae and adult forms. Each phase is

morphologically very different to the previous stage, particularly

in helminths and drugs that act on one stage may be completely

inactive against other stages. Acquired resistance is due to misuse

or improper use of the drug (e.g. chloroquine in malaria or

antimony compounds in Leishmania and antihelminthic drugs

in veterinary parasites)

Mechanisms of resistanceThe mechanisms of resistance in parasites have been studied and

essentially are similar to other microorganisms; namely efflux,

modulation of transport, target modification, bypass, transport

defects, drug modification, alteration in binding affinities,

reduced concentration or lack of enzyme, enzyme turnover

etc. Genetic markers for these have been identified and can be

detected by molecular techniques 5,6. However these are not

available routinely.

Why is it so difficult to test for resistance?Parasites are difficult to isolate in simple culture methods, such

as artificial media. It is possible to culture some protozoa, e.g.

Acanthamoeba on non-nutrient agar, but others are not. Many

parasites have a complex life cycle involving different hosts and

different stages will require different conditions of growth. Cell

lines and experimental animals are difficult to maintain in routine

laboratories and procedures to isolate and maintain parasites in

these can be very labour intensive and costly.

Table 1: Reasons for failure to respond to treatment.

Reinfection

Inadequate drug levels Wrong dose Improper uptake (diet, gut factors) Interaction (drugs, alcohol)

Immuno-suppression

Sequestration in tissues (pancreas, gall bladder)

True resistance – inherent or acquired

Unknown causes


In Focus

Standardisation of the method used, especially culture methods

is of growing importance. Two networks have been created with

the objective of using a standardised in vitro assay method: the

Paludisme network of laboratories in French-speaking countries

and the Red Amazonica para la Vigilancia de la Resistencia a las

Drogas Antimalaricas. Since 2000, the World Health Organization

(WHO) has been working with the University Sains Malaysia in

Penang, Malaysia, which manufactures pre-dosed plates for in

vitro tests. Quality control of the plates has been supervised

since 2002 by the Institut de Medecine Tropicale du Service de

Sante des Armees in Marseille, France 7.

How is resistance detected?

Resistance may be either presumed (clinical failure) or tested for

in the laboratory. Various ways are:

• Casereportsandpassivedetectionoftreatmentfailure.

• In vitro tests:

• macro-andmicro-techniques(microscopy,EIAetc).

• faecaleggcountreductiontest,comparisonwithreference

strains.

• In vivo tests:

• Animalmodels,egghatchtest,larvalparalysistest,etc.

• Molecular techniques for resistance genes, e.g. dhfr gene,

pfmdr1 gene, etc.

Principles of the testsTable 2 provides a summary of parasites where resistance has

been reported and lists the methods used for detection of this

resistance. (A full list of references is available on request).

Table 2: Summary of parasites in which resistance is reported, and the methods used.

Parasite (group) Antiparasitic drugs Method for resistance testing used

Plasmodium falciparum all antimalarial Various

Plasmodium vivax antifolate Molecular (dhfr mutation)

Acanthamoeba various Microtitre assay

Tube dilution assay

Entamoeba metronidazole Microtitre assay

Tube dilutions assay

Giardia metronidazole Microtitre assay

Animal model

Trichomonas metronidazole Microtitre assay

Pouch technique

Toxoplasma pyrimethamine Molecular (dhfr mutation)

Leishmania antimony compounds, Various

amphotericin B

Trypanosoma brucii pentamidine, Direct counting

suramin, Enzyme hydrolysis

melarsoprol Molecular

Schistosoma praziquantel Animal model

Hookworms pyrantel, mebendazole Clinical and parasitological criteria

Filarial worms ivermectin, DEC Clinical and parasitological criteria

Veterinary helminths various Various

Pediculus permethrin, pyrethrine Exposing lice in vitro

Sarcoptes permethrin, ivermectin Exposing mites in vitro


In Focus

Protozoa

In general, it is easier to test for resistance in protozoa 8. It is

possible to culture some as they have a relatively simple life

cycle. Resistance in certain protozoa, such as malarial parasite,

is very common in certain parts of the world. Resistance in

other protozoa, e.g. Giardia, is relatively uncommon, although

recently this seems to be increasing.

Malaria

Most work has been done on malarial parasites 9 especially

Plasmodium falciparum. A number of tests including the

WHO microtest, radioisotope assay, pLDH (parasite lactate

dehydrogenase) enzyme assay, DELI (double site enzyme linked

LDH immuno-detection test) and HRP2 (histidine rich protein 2)

assay have been developed. Some of these have been approved

for use in the field by WHO 10.

Helminths

Helminths are much more difficult to culture. In addition, they

pass through a complex life cycle and it is not always possible

to grow and test for all stages of the parasite outside its natural

host.

Reports of drug resistance have been made in every livestock

host and to every anthelmintic class. In some regions of the

world, the extremely high prevalence of multi-drug resistance

(MDR) in nematodes of sheep and goats threatens the viability

of small ruminant industries. Resistance in nematodes of horses

and cattle has not yet reached the levels seen in small ruminants,

but evidence suggests that the problems of resistance, including

MDR worms, are also increasing in these hosts. There is an

urgent need to develop both novel non-chemical approaches

for parasite control and molecular assays capable of detecting

resistant worms. The role of molecular diagnosis for resistance

to antiparasitic drugs will be the way of the future. A number of

tests have been applied in veterinary parasitology 11 and can be

applied to humans, but none have been developed, adapted or

adequately validated in human cases.

Arthropods

In general these are tested by exposing the insects to the agent

used for treatment in the laboratory and comparing the outcome

with maintained colonies of reference strains (fully sensitive) or

by combining with results of clinical outcome 12.

Conclusions

Parasitic diseases, particularly malaria, veterinary helminths and

soil transmitted helminths, are big global problems. Failure to

respond (or resistance to drugs) is increasing. Standardised

resistance testing for antiparasitic drugs is currently not available

in medical laboratories. Hence, the incidence of resistance in

various parasites is not accurately known. The WHO is helping

to make some progress in producing standardised field kits for

malaria. Given the technical difficulties and complexity of testing

parasites and with the advent and progress in molecular biology,

these techniques should be available in the future for resistance

testing in parasites.

References1. World Health Organisation 2007 http://www.who.int/mediacentre/factsheets/

fs094/en/index.html. July 2007.

2. Schistosomiasis and soil-transmitted helminth infections. WHO Weekly

epidemiological record 2006; 81:145-64.

3. World Health Organisation NTD 2007 Control of Neglected Tropical Diseases.

http://www.who.int/neglected_diseases/en/. July 2007.

4. McCarthy JS, Garrow SC. Parasite elimination programs: at home and away.

Med J Aust 2002; 176:456-7.

5. Ouellette M. Biochemical and molecular mechanisms of drug resistance in

parasites. Trop Med Intl Health 2001; 6:874-82.

6. Secor WE & Nguyen-Dinh P. Mechanisms of resistance to antiparasitic agents.

In: Editors: Murray PR, Baron EJ, Jorgensen JH, Landry ML & Pfaller MA. Section

Editor: Garcia LS. Manual of Clinical Microbiology (9th Ed). Washington DC:

ASM Press, 2007:2240-9.

7. Susceptibility of Plasmodium falciparum to antimalarial drugs: report on

global monitoring: 1996-2004. http://www.who.int/malaria/resistancefalciparum.

htmlhttp://www.who.int/malaria/toolsformonitoring.html. July 2007.

8. Nguyen-Dinh P, Secor WE. Suseptibility test methods: Parasites. In: Editors:

Murray PR, Baron EJ, Jorgensen JH, Landry LM & Pfaller MA. Section Edior:

Garcia LS. Manual of Clinical Microbiology (9th Ed). Washington DC:ASM

Press, 2007:2250-6.

9. Noedl H, Wongsrichanalai C, Wernsdorfer WH. Malaria drug-sensitivity testing:

new assays, new perspectives. Trends Parasitol 2003; 19:175-81.

10. World Health Organisation. In vitro micro-test (Mark III) for the assessment

of the response of Plasmodium falciparum to chloroquine, mefloquine,

amodiaquine, sulfadoxine/pyrimethamine and artemisinin. 2001. http://

www.who.int/csr/drugresist/malaria/en/markiii.pdf. July 2007.

11. Geerts S, Gryseels B. Drug resistance in human helminths: current situation

and lessons from livestocks. Clin Microbiol Rev 2000; 13:207-22.

12. Walton SF, Myerscough MR, Currie BJ. Studies in vitro on the relative efficacy

of current acaricides for Sarcoptes scabiei var hominis. Trans Royal Soc Trop

Med Hyg 2000; 94:92-6.


In Focus

Antimicrobial resistance in veterinary medicine – issues and controversies from an Australian perspective

Mary D Barton

Professor of Microbiology University of South Australia

Antimicrobial resistance in veterinary isolates came to renewed

prominence in the late 1990s in response to the recognition

of an association between the use of avoparcin as a growth

promotant in livestock feeds and vanA vancomycin resistance

in enterococcal pathogens in humans 1. Since then there have

been many regulatory changes in many countries that have

resulted in a reduction in use of antimicrobial growth promoters

(AGPs) in livestock feeds. The EU has banned the use of most

growth promoters and in Australia post-JETACAR avoparcin (a

glycopeptide) has been voluntarily withdrawn from the market

by the manufacturer (in 2000), recommendations have been

made to restrict the use of virginiamycin (a streptogrammin) to

a prescription-only medicine for treatment and prevention of

some specific conditions, and a review of macrolide AGPs is in

the wings. In addition, many of the industries have voluntarily

reduced or ceased their use of some of these products. For

example, the pig industry stopped use of avoparcin in 1997 and

the use of virginiamycin has been curtailed in the meat chicken

industry.

Australia has a very strict national system for registration of

all chemicals (including antibiotics) used in animals generally

and in food producing animals in particular. As a result of

JETACAR almost all antibiotics used in animals – except for some

products used in pet fish and aviary birds and the remaining

AGPs – are prescription-only medicines. Use of antimicrobials by

veterinarians is regulated by state control of use legislation as well

as label restraints imposed as part of the registration process. As a

result of these processes, unlike the situation in Europe and the

USA (and in less-regulated countries in other parts of the world),

fluoroquinolones and gentamicin have never been registered for

therapeutic use in food producing animals and chloramphenicol

was de-registered in 1982, although use of these antibiotics is

permitted in cats and dogs. The range of AGP growth promoters

is also much more limited than in the USA, for example. Thus it

is important not to simply extrapolate reports of AMR in animals

from overseas countries to the Australian situation.

Glycopeptide, streptogrammin and high-level gentamicin resistance in enterococci Many of the AGPs target gram-positive bacteria and as a result of

extensive use of these in pigs, chickens and intensively reared

cattle, enterococci resistant to glycopeptides and quinupristin-

dalfopristin (a streptogrammin) has been reported in foods of

animal origin (particularly meats) and in humans consuming

such products in Europe in particular 2.

Australian studies of human gut carriage of enterococci have

failed to detect vanA VRE 3. It should be emphasised that only

the vanA glycopeptide resistance determinant is associated with

avoparcin use, with other determinants such as vanB selected

by use of glycopeptides in human medicine 4. In Australia vanA

VRE were found in chickens in a study conducted prior to the

withdrawal of avoparcin from the market 5. However, a pig study

carried out in 1998 (twelve months after voluntary withdrawal of

avoparcin) found no vanA VRE, although vanC VRE (intrinsically

resistant to glycopeptides) were common (R Pratt & M Barton,

unpublished). When the same area of pig production was re-

sampled in 2003/2004, even vanC VRE had disappeared (H Peng

& M Barton, unpublished). The disappearance of vanA VRE

from livestock following withdrawal of avoparcin has been well

documented in Europe, although the decline has been delayed

in some countries due to co-location of vanA with resistance

determinants to other antibiotics still used in those countries 1,6,7.


In Focus

Virginiamycin resistance was found in more than 90% of isolates

of E. faecium from Australian chicken isolates collected in 20005

and pig isolates from the 1998 survey (R Pratt & M Barton,

unpublished); however, in the 2003/2004 survey resistance

in pig isolates had fallen to around 10% (H Peng & M Barton,

unpublished). It should be noted that E. faecalis is intrinsically

resistant to streptogramins 8. Widespread virginiamycin resistance

in E. faecium isolates from animals exposed to this AGP has been

reported overseas 9. No high-level gentamicin resistance was

found in isolates in the Australian studies although this has been

found overseas 10,11.

Multi-drug resistance in salmonellaAntibiotic resistance is common in Australian animal salmonella

isolates. The 2006 IMVS Salmonella Reference Laboratory Annual

Report 12 noted that no salmonella isolates (human and animal)

were resistant to fluoroquinolones but interestingly nalidixic acid

resistance was detected in human (3.4%) and pig (3.6%) isolates

and in raw meats other than chicken meat (2.4%). Some ceftiofur

(third generation cephalosporin) resistance was seen in cattle

(0.4%) and human (0.2%) isolates. Overall, pig isolates were

more resistant than cattle isolates, followed by meat chicken and

raw meats other then chicken isolates; 45-60% of pig isolates

were resistant to ampicillin, tetracycline, streptomycin and

sulphonamides. Multiple resistance was noted in human isolates,

with 8% acquired overseas against 3% acquired in Australia.

Resistance to four or more antibiotics was demonstrated in pig

(37%), cattle (10%) and meat chicken (3.5%) isolates. However,

it is important to note that multiple resistance strains such as

Salmonella typhimurium DT104 13 and Salmonella newport

14,15, which cause significant animal and human infections in

Europe and North America, are not present in Australian

livestock. It is interesting to speculate that this may be linked to

the absence of fluoroquinolone use in livestock and the so-far

somewhat restricted use of third generation cephalosporins such

as ceftiofur.

Fluoroquinolone and macrolide resistance in Campylobacter jejuniC. jejuni is not a pathogen in animals but a zoonotic infection

transferred via the food chain when foods of animal origin

are contaminated during processing. The emergence of

fluoroquinolone resistance in human isolates in Europe quickly

followed the introduction of fluoroquinolones to treat enteric

and respiratory infections in pigs and chickens 16. Australian

studies have found no fluoroquinolone resistance in pigs or

chickens 5,17. Australian human isolates are largely sensitive to

fluoroquinolones 18,19 and these studies suggested that the more

resistant strains were acquired overseas. It is interesting to note

that resistance to erythromycin is also relatively uncommon

in chicken 5 and human isolates, in contrast to pig isolates 17

(presumably mostly C. coli) where resistance to erythromycin

and clindamycin is very common. The resistance rates in humans

are consistent with those reported overseas 20.

Extended spectrum β-lactamases (ESBLs) and Amp-C β-lactamasesESBLs have not been systematically investigated in Australian

livestock although there are increasing numbers of reports from

overseas countries 21,22. Ceftiofur is the only third generation

cephalosporin currently registered for use in animals in Australia.

It is registered for use in cattle for treatment of respiratory

disease but control of use legislation in most states would allow

its use in other food producing animals because it is registered

for use in one food producing species. Ceftiofur resistance has

not been detected in salmonella isolates from pigs or chickens12

or from E. coli collected from pigs in 2003/2004 (H Peng & M

Barton, unpublished). However, ESBLs have been reported in

Enterobacter spp. isolated from dogs 23. AmpC β-lactamases

have not been reported from Australian livestock, although

ampicillin resistance is reasonably widespread in E coli and

Salmonella 5,12,17, although multi-drug resistant E. coli expressing

AmpC β-lactamases have been isolated from dogs in a veterinary

teaching hospital environment as well as from rectal swabs of

staff working in the hospital 24. Ceftiofur is registered for use in

dogs and cats and if the use of ceftiofur increases, or other third

generation cephalosporins are introduced, it is likely that ESBLs

and AmpC β-lactamases will become more common in isolates

from Australian animals.

Methicillin-resistant Staphylococcus aureusWhile there have been sporadic reports of methicillin-resistant

Staphylococcus aureus (MRSA) in animals since 1972, since 1999

there has been a marked increase in the number of papers on

this topic 25,26. MRSA has been reported in bovine mastitis isolates

and various isolates from dogs, cats, horses and, most recently,

pigs. With application of molecular tools it has become clear that

the isolates from cats and dogs are identical with human hospital

acquired strains 27,28 but that strains from horses often belong

to less usual types 29. MRSA have been found in dogs and cats

in Australia 28 and there are anecdotal accounts of infections in

foals, but it has not been reported from cattle 30. Since the end

of 2005 it has been clear MRSA has become established in pigs

in The Netherlands and France 31 and that pig farmers and their

families have been infected with these distinctive pig strains 32,33.

MRSA has not been reported in Australian pigs. While it is easy to

accept that animals could be temporarily colonised with human

strains of S. aureus, it is difficult to understand the selection

pressure that is driving persistent colonisation and allowing these

strains to re-infect humans. Antistaphylococcal penicillins such as

cloxacillin are often used to treat mastitis in dairy cattle but are

not commonly used in other species, at least in Australia.

In conclusion, although AMR is present in Australian bacterial

isolates from animals, the livestock industries have responded


In Focus

to concerns and resistance rates in enteric bacteria from pigs

has declined. The removal of avoparcin from the market has

reduced the exposure of Australians to the vanA glycopeptide

resistance determinant, the absence of fluoroquinolones

from the livestock market has protected Australians from

fluoroquinolone resistant campylobacter and salmonella, and

the absence of fluoroquinolones and constrained use of ceftiofur

may be contributing to the absence of highly resistant Salmonella

serovars.

References1. Wegener HC. Antibiotics in animal feed and their role in resistance development.

Curr Opin Microbiol 2003; 6:439-45.

2. Klare I, Konstabel C, Badstüber D et al. Occurrence and spread of antibiotic resistances in Enterococcus faecium. Int J Food Microbiol 2003; 88:269-90.

3 Padiglione AA, Grabsch EA, Olden D et al. Faecal colonization with vancomycin-resistant enterococci in Australia. Emerg Infect Dis 2000; 6:534-6.

4. Kühn I, Iversen A, Finn M et al. Occurrence and relatedness of vancomycin-resistant enterococci in animals, humans and the environment in different European regions. Appl Environ Microbiol 2005; 71:5383-90.

5. Barton MD, Wilkins J. Antibiotic resistance in bacteria isolated from poultry. Rural Industries Research and Development Corporation Publication No 1/105 Report of RIRDC Project No USA-9A. 2001.

6. Sørum M, Johnsen PJ, Aasnes B et al. Prevalence, persistence and molecular characterization of glycopeptide-resistant enterococci in Norwegian poultry and poultry farmers 3 to 8 years after the ban on avoparcin. Appl Environ Microbiol 2006; 72:516-21.

7. Manson JM, Smith JMB, Cook G. Persistence of vancomycin resistant enterococci in New Zealand broilers after discontinuation of avoparcin use. Appl Environ Microbiol 2004; 70:5764-8.

8. Duh RW, Singh KV, Malathum K, Murray BF. In vitro activity of 19 antimicrobial agents against enterococci from healthy subjects and hospitalized patients and use of an ace gene probe from Enterococcus faecalis for species identification. Microb Drug Resist 2001; 7:39-46.

9. Rshberger E, Oprea ST, Donabedian SM et al. Epidemiology of antimicrobial resistance in enterococci of animal origin. J Antimicrobial Chemother 2005; 55:127-30.

10. Jackson CR, Fedorka-Cray PJ, Barrett JB et al. High-level aminoglycoside resistant enterococci isolated from swine. Epidemiol Infect 2005; 133:367-71.

11. Hayes JR, English LL, Carr LE et al. Multiple-antibiotic resistance of Enterococcus spp. isolated from commercial poulty production environments. Appl Environ Microbiol 2004; 70:6005-11.

12. Australian Salmonella Reference Centre Annual Report. Institute of Medical and Veterinary Science, Frome Road, Adelaide, South Australia, 2006.

13. Humphrey T. Salmonella Typhimurium definitive type 104 – a multi-resistant Salmonell. Int J Food Microbiol 2001; 67:173-86.

14. Berge ACB, Adaska JM, Sischo WM Use of antibiotic susceptibility patterns and pulsed-field gel electrophoresis to compare historic and contemporary isolates of multi-drug resistant Salmonella enterica subsp. enterica serovar Newport. Appl Environ Micobiol 2004; 70:318-23.

15. Poppe C, Martin L, Muckle A et al. Characterisation of antimicrobial resistance of Salmonella Newport isolated from animals, the environment and animal food products in Canada. Can J Vet Res 2006; 70:105-14.

16. Allos BM. Campylobacter jejuni infections: update on emerging issues and trends. Clin Infect Dis 2001; 32:1201-6.

17. Hart WS, Heuzenroeder MW, Barton MD. Antimicrobial resistance in Campylobacter spp., Escherichia coli and enterococci associated with pigs. J Vet Med B 2004; 51:216-21.

18. Sharma H, Unicomb L, Forbes W et al. Antibiotic resistance in Campylobacter jejuni isolated from humans in the Hunter Region, New South Wales. Commun Dis Intell 2003; 27:S80-S88.

19. Unicomb LE, Ferguson J, Stafford RJ et al. Low-level fluoroquinolone resistance among Campylobacter jejuni isolates in Australia. Clin Infect Dis 2006; 42:1368-74.

20. Gibreel A, Taylor DE. Macrolide resistance in Campylobacter jejuni and Campylobacter coli. J Antimicrobial Chemother 2006; 58:243-55.

21. Cloeckaert A, Praud K, Doublet B et al. Dissemination of an extended-spectrum-β-lactamase blaTEM-52 gene-carrying IncI1 plasmid in various Salmonella enterica serovars isolated from poultry and humans in Belgium and France between 2001 and 2005. Antimicrobial Agents Chemother 2007; 51:1872-5.

22. Li X-Z, Mehotra M, Ghimire S et al. β-lactam resistance and β-lactamases in bacteria of animal origin. Vet Microbiol 2007; 121:197-214.

23. Sidjabat HE, Hanson ND, Smith-Moland E et al. Identification of plasmid-mediated extended-spectrum and AmpC beta-lactamases in Enterobacter spp. isolated from dogs. J Med Microbiol 2007; 56:426-34.

24. Sidjabat HE, Townsend KM, Lorentzen M et al. Emergence and spread of two distinct clonal groups of multi-drug resistant Escherichia coli in a veterinary teaching hospital in Australia. J Med Microbiol 2006; 55:1125-34.

25. Leonard FC, Markey BK. Meticillin-resistant Staphylococcus aureus in animals: a review. Vet J 2007; doi 10.1016/j.tvjl.2006.11.008

26. Malik S, Peng H, Barton MD. Antibiotic resistance in staphylococci associated with cats and dogs. J Appl Microbiol 2005; 99:1283-93.

27. Strommenger B, Kehrenberg C, Kettlitz C et al. Molecular characterization of methicillin-resistant Staphylococcus aureus from pet animals and their relationship to human isolates. J Antimicrobial Chemother 2006; 57:461-5.

28. Malik S, Coombs GW, O’Brien F et al. Molecular typing of methicillin-resistant staphylococci from cats and dogs. J Antimicrobial Chemother 2006; 58:428-31.

29. Moodley A, Stegger M, Bagcigil AF et al. Spa typing of methicillin-resistant Staphylococcus aureus isolated from domestic animals and veterinary staff in the UK and Ireland. J Antimicrobial Chemother 2006; 58:1118-23.

30. Barton MD, Pratt R, Hart WS. Antibiotic resistance in animals. Commun Dis Intell 2003; 27:S121-S128.

31. de Neeling AJ, van den Broek MJM, et al. High prevalence of methicillin-resistant Staphylococcus aureus in pigs. Vet Microbiol 2007; 122:366-72.

32. Armand-Lefevre L, Ruimy R, Andremont A. Clonal comparison of Staphylococcus aureus isolates from healthy pig farmers, human controls and pigs. Emerg Infect Dis 2005; 11:711-4.

33. Huijsdens XW, van Dijke BJ, Spalberg E et al. Community-acquired MRSA and pig farming. Ann Clin Microbiol Antimicrobials 2006; 5:26 doi:10.1186/1476-0711-5-26.

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In Focus

A resistant culture - ‘superbugs’ in Australian hospitals

GL Gilbert

Centre for Infectious Disease and Microbiology, ICPMR, Westmead Hospital

IntroductionAntimicrobial resistance is not new in Australian hospitals. In 1946, shortly after penicillin became available for treatment of civilians, a penicillin resistant Staphylococcus aureus strain caused ~50% of staphylococcal surgical wound infections at the Royal Prince Alfred Hospital (RPAH), in Sydney 1. During the 1950s, another virulent penicillin resistant S. aureus strain (phage type 80/81) emerged in neonatal units in Sydney and spread to other hospitals in Australia and overseas, to the families of affected infants and to the general community, causing serious soft tissue infections, osteomyelitis, pneumonia and septicaemia 1,2.

Methicillin was introduced in Australia in 1961 and methicillin resistant S. aureus (MRSA) was first identified at RPAH in 19653. By the 1970s, MRSA was endemic in many major hospitals in the eastern states 4,5 but largely excluded from Western Australian hospitals by a systematic ‘search and destroy policy 6. Enhanced, statewide surveillance and control policies recently implemented in Queensland and South Australia, have led to a reduction in previously high MRSA rates 7, but they remain high in New South Wales and Victoria 8.

Since 1994, vancomycin-resistant enterococci (VRE) have caused intermittent outbreaks and have become endemic in some clinical units in Australia. Multiresistant gram-negative infections, due to the spread of novel resistance genes into potentially pathogenic Enterobacteriacae and other opportunistic pathogens, can cause serious and occasionally untreatable sepsis.

Epidemiological data on healthcare associated infections (HCAI) and multiresistant organisms (MRO) in Australia are limited. There are no national surveillance data and there are significant differences between states and territories, and in some jurisdictions between hospitals, in screening and control policies. Despite a strong consensus among infection control experts that a national approach to surveillance control is needed, there has been limited administrative support and resource allocation in some jurisdictions. However, there are encouraging signs that the disease burden and public health importance of

antibiotic resistance and HCAI are at last being recognised by health administrators and bureaucrats. For example, the New South Wales Department of Health has recently published recommendations for MRO control and allocated funds to implement them 9 and the Australian Commission on Safety and Quality in Healthcare has nominated healthcare acquired infections as one of nine priority patient safety programs 10.

MRSAThere have been wide variations in MRSA rates in different Australian states. In 1967, 6% of S. aureus isolates at RPAH were MRSA; by 1970 this increased to 73%, after a virulent strain was introduced from New Caledonia 4. In Victoria, fewer than 2% of S. aureus isolates were MRSA before 1975 but by 1979 this had risen to 20–40% in thirty-one metropolitan hospitals 5.

Among 19,000 clinical S. aureus isolates collected between 1989 and 1999 from twenty-one Australian teaching hospitals, 20% were MRSA. In 1989 proportions varied from 20–40% in Brisbane, Melbourne and Sydney, to <5% in Adelaide and Perth. By 1999 rates had increased overall, but the greatest increase was from <5%–~35% in Adelaide. Most isolates (>95%) were multiresistant MRSA except in Perth, where most were non-multiresistant, reflecting mainly community acquired MRSA on a background of infrequent hospital acquisition 11.

A review of S. aureus bacteraemias in seventeen Australian hospitals between 1999 and 2002, showed that 51% were hospital acquired and of these, 40% were due to MRSA – compared with 12% of community onset episodes 12. Based on these data, it was estimated that ~1500 MRSA bloodstream infections occur each year in Australia. Although bloodstream infections represent only a small proportion of significant MRSA infections, they provide an objective measure of MRSA disease burden. Ratios of MRSA to methicillin susceptible S. aureus (MSSA) and community acquired to HCA bacteraemias reflect the quality of hospital infection control and antibiotic prescribing and are useful surveillance measures 13. The most recent data on HCA MRSA bacteraemias in different Australian states and territories, whilst approximate, probably quite accurately reflect relative rates; they show the lowest rates in states with the most comprehensive MRSA control programs (Table 1) 8.

Although there have been increases in community acquired, non-multiresistant MRSA infections, most MRSA bloodstream infections in Australia are HCA and a significant proportion is preventable14. They are associated with (generally) higher mortality, longer hospital stays and higher costs than infections due to MSSA 15. There are strong ethical and economic imperatives to reduce their rates. The continued low rates of HCA MRSA bacteraemias in Western Australia and many European countries and falling rates following the introduction of improved surveillance and control programs in some Australian states, indicate that this is possible.


In Focus

The majority of hospital associated MRSA isolates in the eastern states of Australia are multiresistant epidemic MRSA Aus-2/3 strains, which belong to one of the most widely distributed multiresistant hospital clones worldwide. A significant and probably increasing minority belong to the highly transmissible EMRSA-15 strain, which emerged and spread widely in the United Kingdom during the 1990s 16 and was first identified in Australia in 2001 17. The main characteristics of these two MRSA strains are shown in Table 2.

Vancomycin intermediate and resistant S. aureusDespite forty years of extensive and sometimes inappropriate medical use of vancomycin and the veterinary use of another glycopeptide (avoparcin), glycopeptide resistance in MRSA was not identified until the 1990s. S. aureus isolates with reduced susceptibility to vancomycin (VISA) were first reported in Japan in 1997 and in Australia in 2001 18,19. VISA strains have since been reported in many countries. Definitions vary, but generally they are defined as S. aureus with vancomycin minimum inhibitory concentrations (MIC) of 4–16 mg/L. Some strains with vancomycin MIC <4 mg/L contain a resistant subpopulation (heterogeneous (h)VISA). The prevalence and clinical significance of VISA in Australia (and elsewhere) are uncertain because of difficulty identifying them. Conventional susceptibility testing methods are relatively insensitive. High inoculum E-tests are more reliable but usually performed only on the basis of clinical suspicion. Confirmation requires ‘population analysis profiling’, which is time-consuming and not widely available 19.

Development of VISA does not involve major genetic change. It is an adaptive response to sublethal vancomycin exposure causing thickening of the staphylococcal cell wall with increased production and turnover of D-alanine-D-alanine residues (which bind glycopeptides) in the peptioglycan layer, involving several genes 20. Vancomycin MIC can increase during treatment, especially in patients with high MRSA bacterial loads (such as endocarditis) or suboptimal vancomycin levels, leading to persistent bacteraemia and treatment failure 19.

Several separate incidents of transmission of vanA (encoding high level glycopeptide resistance) from Enterococcus faecium to S. aureus – causing vancomycn resistance (VRSA) – have been described since 2002 in the USA 21. So far, VRSA has not occurred in Australia, but the risk will remain while high rates of MRSA (and VRE – see below) colonisation and vancomycin use continue in some Australian hospitals.

VREMedically significant VRE were first described in England and Europe in 1988 22,23. There was strong circumstantial evidence that the emergence of VRE in humans was associated with widespread use of avoparcin for growth promotion and prophylaxis in animals24. This was supported by the fact that VRE could be isolated quite commonly, from farm animals and healthy people in Europe 25, although hospital outbreaks were relatively uncommon. Within a few years, VRE also emerged in the USA 26. Vancomycin was much more widely used in hospitals in the USA than in Europe, but avoparcin had not been used in animals.

This was reflected by the fact that in the USA VRE was not found in healthy people or animals, but it spread rapidly among hospitalised patients. Recently, VRE represented 14–25% of all clinically significant enterococci and contributed significantly to excess mortality among infected patients 27.

In Europe and the USA, VRE are mainly Enterococcus faecium, in which high level vancomycin and teicoplanin resistance are mediated by vanA. Most hospital outbreaks of VRE are caused by a single virulent genotype, with a variant enterococcal surface protein (esp) gene, which differs from those found in animals and healthy people in Europe 28.

In Australia, VRE was first isolated in 1994 from a liver transplant patient at the Austin Hospital, Melbourne, and there have been numerous reports of ‘outbreaks’ (and many others not reported) since then 29. In Australia, too, most VRE are E. faecium but, in contrast to Europe and the USA, most carry vanB 29 and are typically susceptible to teicoplanin with low level vancomycin resistance, although MICs vary widely. Avoparcin was used in animals in Australia until ~2000, but limited data suggest that neither vanA nor vanB VRE were common in animals. The origin of VRE in Australia is unknown, but vanB can be found in gram-positive anaerobes, especially Clostridium spp. in the normal faecal flora 30, which are a potential reservoir of transmission to enterococci 31.

Several VRE outbreaks in Australian hospitals have been reported and successfully controlled, albeit at considerable cost 32-34. There are no national surveillance data on the prevalence of VRE. Outbreaks (mainly of colonisation) occur, particularly in renal dialysis, transplant, haematology and intensive care units, where there is widespread and often repeated use of antibiotics, such as third generation cephalosporins, which select out enterococci, and vancomycin, which select for VRE. Risk factors for VRE transmission among critically or chronically ill patients, especially if immuno-suppressed (and prone to diarrhoea), include: inadequate hand hygiene (by ambulatory patients and visitors as well as busy staff); environmental contamination and too few isolation rooms. Screening for VRE carriage is complicated by difficulties in detection of vanB strains, which often have low level resistance. Moreover, hospitals and units at risk from VRE are also those most likely to have high levels of MRSA endemicity and isolation of the VRE colonised patient may compromise MRSA control because of competition for limited resources 34.

Multiresistant gram-negative bacteriaAntibiotic resistance in gram-negative bacteria is more complex than in gram-positive bacteria. Their resistance genes are more varied, more readily transmissible and more difficult to define and identify 35. The bacterial species and resistance genes involved at different times and places in Australia in recent years include: various Enterobacteriaceae containing extended spectrum betalactamases (ESBL) including E. coli 36 and Klebsiella pneumoniae containing bla-SVH and ctx-M

37,38; carbapenem resistant Acinetobacter baumannii carrying the serine protease gene blaOXA-23

39,40; and various Enterobacteriaceae and Pseudomonas aeruginosa carrying the metalloenzyme blaIMP-4

41,42.


In Focus

The mechanisms of transmission and expression of these genes are complex. Screening of high-risk patients by PCR, for relevant resistance genes – rather than phenotypically resistant species – is a logical approach, but interpretation is complicated by bacterial host-dependent variation in expression 43 and possible changes in the prevalent resistance genes. Moreover, the predictive values of this approach have not yet been evaluated. On the other hand, there is increasing evidence that unless appropriate control measures are instituted, resistance genes can become established and increasingly difficult to manage.

ConclusionIn some Australian hospitals, the rates of preventable, serious and potentially fatal HCAI due to MROs are unacceptably high. The urgent need to address this is at last being recognised nationally, although in some states (e.g. New South Wales and Victoria) where the problems are greatest and have been entrenched the longest, it will not be easy to achieve adequate control. The most important prerequisite is a major culture change with acceptance of responsibility and commitment of resources by health administrators and senior clinicians, and personal accountability by all healthcare workers for best infection control practice (including hand hygiene and antibiotic prescribing). Among other requirements are consistent, continuous surveillance with rapid feedback to clinicians and appropriate responses; more sensitive, faster screening and strain typing methods, and adequate staffing and better physical resources (such as single rooms) in hospitals. The cost of these measures will be more than repaid in reduced morbidity and mortality and shorter hospital stays.

References1. Rountree PM. History of staphylococcal infection in Australia. Med J Aust 1978;

2:543-6.

2. Rountree PM, Beard MA. Further observations on infection with phage type 80 staphylococci in Australia. Med J Aust 1958; 2:789-95.

3. Rountree PM, Beard MA. Hospital strains of Staphylococcus aureus, with particular reference to methicillin-resistant strains. Med J Aust 1968; 2:1163-8.

4. Rountree PM, Vickery AM. Further observations on methicillin-resistant staphylococci. Med J Aust 1973; 1:1030-4.

5. Pavillard R, Harvey K, Douglas D et al. Epidemic of hospital-acquired infection due to methicillin-resistant Staphylococcus aureus in major Victorian hospitals. Med J Aust 1982; 1:451-4.

6. Dailey L, Coombs GW, O’Brien FG et al. Methicillin-resistant Staphylococcus aureus, Western Australia. Emerg Infect Dis 2005; 11:1584-90.

7. Cooper C, Ochota MA. Surveillance of hospital-acquired methicillin-resistant Staphylococcus aureus in South Australia. Commun Dis Intell 2003; 27(6).

8. Ferguson J. Healthcare-associated methicillin-resistant Staph aureus (MRSA) control in Australia and New Zealand. Aust Infect Control 2007; 12:60-6.

9. NSW Department of Health. Reducing the burden of multiple resistant organisms (MROs): Proceedings of the MRO summit convened by NSW Health, Sydney 2005. Sydney. http://www.health.nsw.gov.au/health_pr/infection/prof/links.html.

10. Australian Commission on Safety and Quality in Healthcare. One-year work plan 2007/8. Nine priority programs, 2007. http://www.safetyandquality.org/

11. Nimmo GR, Bell JM, Mitchell D et al. Antimicrobial resistance in Staphylococcus aureus in Australian teaching hospitals, 1989-1999. Microb Drug Resist Mechanisms Epidemiol Dis 2003; 9:155-60.

12. Collignon P, Nimmo GR, Gottlieb T et al. Australian Group on Antimicrobial R. Staphylococcus aureus bacteremia. Aust Emerg Infect Dis 2005; 11:554-61.

13. Collignon PJ, Wilkinson IJ, Gilbert GL et al. Health care-associated Staphylococcus aureus bloodstream infections: a clinical quality indicator for all hospitals. Med J Aust 2006; 184:404-6.

14. Collignon PJ, Grayson ML, Johnson PD. Methicillin-resistant Staphylococcus aureus in hospitals: time for a culture change. Med J Aust 2007; 187:4-5.

15. Cosgrove SE, Sakoulas G, Perencevich EN et al. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 2003; 36:53-9.

16. Johnson AP, Pearson A, Duckworth G. Surveillance and epidemiology of MRSA bacteraemia in the UK. J Antimicrob Chemother 2005; 56:455-62.

17. Pearman JW, Coombs GW, Grubb WB et al. A British epidemic strain of methicillin-resistant Staphylococcus aureus (UK EMRSA-15) in Western Australia. Med J Aust 2001; 174:18.

18. Ward PB, Johnson PD, Grabsch EA et al. Treatment failure due to methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin. Med J Aust 2001; 175:480-3.

Table 1. Estimated recent annual rates of healthcare-associated bacteraemiasa

Jurisdiction Population x 105 b Cases per annum c Incidence/100,000 population

Australian Capital Territory 3.3 30 9

New South Wales 67.7 500 7.4

Northern Territory (Darwin) 1.2 16 13.3

Queensland 39.6 133 3.4

South Australia 15.4 37 2.4

Tasmania 4.7 3 0.64

Victoria 50.2 300 6.0

Western Australia 20.1 22 1.1

Total 1,040

Notes:a. Data are based on 1–5 year periods between 2000 and 2006, using different surveillance methods 8

b. Populations (rounded to nearest 100,000) from Australian Bureau of Statisticsc. Data for New South Wales and Victoria are approximate and probably underestimates; they are averaged over several years


In Focus

19. Howden BP, Ward PB, Johnson PD et al. Low-level vancomycin resistance in Staphylococcus aureus--an Australian perspective. Eur J Clin Microbiol Infect Dis 2005; 24:100-8.

20. Cetinkaya Y, Falk P, Mayhall CG. Vancomycin-resistant enterococci. Clin Microbiol Rev 2000; 13:686-707.

21. Weigel LM, Donlan RM, Shin DH et al. High-level vancomycin-resistant Staphylococcus aureus isolates associated with a polymicrobial biofilm. Antimicrob Agents Chemother 2007; 51:231-8.

22. Uttley AH, George RC, Naidoo J et al. High-level vancomycin-resistant enterococci causing hospital infections. Epidemiol Infect 1989; 103:173-81.

23. Leclercq R, Derlot E, Duval J et al. Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium. N Engl J Med 1988; 319:157-61.

24. Collignon PJ. Vancomycin-resistant enterococci and use of avoparcin in animal feed: is there a link? Med J Aust 1999; 171:144-6.

25. Bonten MJ, Willems R, Weinstein RA. Vancomycin-resistant enterococci: why are they here, and where do they come from? Lancet Infect Dis 2001; 1:314-25.

26. Frieden TR, Munsiff SS, Low DE et al. Emergence of vancomycin-resistant enterococci in New York City. Lancet 1993; 342:76-9.

27. DiazGranados CA, Zimmer SM, Klein M et al. Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis. Clin Infect Dis 2005; 41:327-33.

28. Willems RJ, Homan W, Top J et al. Variant esp gene as a marker of a distinct genetic lineage of vancomycin-resistant Enterococcus faecium spreading in hospitals. Lancet 2001; 357:853-5.

29. Bell JM, Paton JC, Turnidge J. Emergence of vancomycin-resistant enterococci in Australia: phenotypic and genotypic characteristics of isolates. J Clin Microbiol 1998; 36:2187-90.

30. Ballard SA, Pertile KK, Lim M et al. Molecular characterization of vanB elements in naturally occurring gut anaerobes. Antimicrob Agents Chemother 2005; 49:1688-94.

31. Launay A, Ballard SA, Johnson PD et al. Transfer of vancomycin resistance transposon Tn1549 from Clostridium symbiosum to Enterococcus spp. in the gut of gnotobiotic mice. Antimicrob Agents Chemother 2006; 50:1054-62.

32. Christiansen KJ, Tibbett PA, Beresford W et al. Eradication of a large outbreak of a single strain of vanB vancomycin-resistant Enterococcus faecium at a major Australian teaching hospital. Infect Control Hospital Epidemiol 2004; 25:384-90.

33. Cooper E, Paull A, O’Reilly M. Characteristics of a large cluster of vancomycin-

resistant enterococci in an Australian hospital. Infect Control Hospital

Epidemiol 2002; 23:151-3.

34. Bartley PB, Schooneveldt JM, Looke DF et al. The relationship of a clonal

outbreak of Enterococcus faecium vanA to methicillin-resistant Staphylococcus

aureus incidence in an Australian hospital. J Hospital Infect 2001; 48:43-54.

35. Iredell J, Thomas L, Espedido B. Beta-lactam resistance in the gram negatives:

increasing complexity of conditional, composite and multiply resistant

phenotypes. Pathol 2006; 38:498-506.

36. Hirakata Y, Matsuda J, Miyazaki Y et al. Regional variation in the prevalence of

extended-spectrum β-lactamase-producing clinical isolates in the Asia-Pacific

region (SENTRY 1998-2002). Diag Microbiol Infect Dis 2005; 52:323-9.

37. Howard C, van Daal A, Kelly G et al. Identification and minisequencing-

based discrimination of SHV β-lactamases in nosocomial infection-associated

Klebsiella pneumoniae in Brisbane, Australia. Antimicrob Agents Chemother

2002; 46:659-64.

38. Paterson DL, Hujer KM, Hujer AM et al. Extended-spectrum β-lactamases in

Klebsiella pneumoniae bloodstream isolates from seven countries: dominance

and widespread prevalence of SHV- and CTX-M-type β-lactamases. Antimicrob

Agents Chemother 2003; 47:3554-60.

39. Valenzuela JK, Thomas L, Partridge SR et al. Horizontal gene transfer in a

polyclonal outbreak of carbapenem-resistant Acinetobacter baumannii. J Clin

Microbiol 2007; 45:453-60.

40. Playford EG, Craig JC, Iredell JR. Carbapenem-resistant Acinetobacter

baumannii in intensive care unit patients: risk factors for acquisition, infection

and their consequences. J Hospital Infect 2007; 65:204-11.

41. Peleg AY, Franklin C, Bell JM et al. Dissemination of the metallo-β-lactamase

gene blaIMP-4 among gram-negative pathogens in a clinical setting in Australia.

Clin Infect Dis 2005; 41:1549-56.

42. Espedido B, Iredell J, Thomas L et al. Wide dissemination of a carbapenemase

plasmid among gram-negative bacteria: implications of the variable phenotype.

J Clin Microbiol 2005; 43:4918-9.

43. Iredell JR, Sintchenko V. Screening for antibiotic resistant Gram-negative

bacteria. Lancet Infect Dis 2006; 6:316-7.

Table 2. Characteristics of the major hospital MRSA strains in Australia.

“Hospital” MRSA strains: Aus-2/3 EMRSAb UK EMRSA-15 Characteristics:

Sequence type (ST) 239 22

Clonal complex (CC) 8 22

SCCmec type III IV

Urease +ve -ve

Antibiogram (2003)a Resistant >97% to ery, gent, tet, cipro, trimc 100% to cipro; 69% to eryc

Susceptible >95% to fus, rif, mupc 100% to gent, tet, trim, fus, rif, mupc

% of all MRSA (2003)1 Aus-2, 43%/Aus-3, 22% = 65% 9%

% of “hospital” MRSA, (2003)1 Aus-2, 58%/ Aus-3,29% = 87% 12%

Notes:

a. Based on report of Australian Group on Antibiotic Resistance (AGAR) Staphylococcus aureus Program, 2003 (SAP 2003). ~100 consecutive isolates from individual patients attending 23 hospitals around Australia – total 2,184 - were tested. Overall ~25% of isolates were non-multiresistant community MRSA strains. Of the 75% “hospital” or epidemic MRSA strains <1% belonged to other clones.

b. Aus 2 and Aus 3 strains are distinguished on the basis of their susceptibility (Aus 2) or resistant (Aus 3) to mercuric compounds.

c. Isolates were tested for susceptibility to 8 antibiotics: ery = erythromycin; gent = gentamicin; tet = tetracycline; cipro = ciprofloxacin; trim = timethoprim; mup = mupirocin


In Focus

An overview of emerging community based antimicrobial resistance

Tom Gottlieb

Senior Specialist in Infectious Diseases & Microbiology Department of Microbiology & Infectious Diseases, Concord HospitalHospital Road, Concord, NSW, 2139Tel: (02) 9767 7533Fax: (02) 9767 7868Email: [email protected]

The development of community antimicrobial resistance should

not surprise any budding microbiologist. Bacteria are highly

adaptable and mutations are acquired or selected in response

to any number of stresses. In the 21st century the major

‘stressor’ is profligate human and veterinary antibiotic use,

and inappropriate antimicrobial use in food and agricultural

sectors. Worldwide, resistance in the community has been

well described in many bacterial species (Table 1). In this

overview, we focus on community resistance in three bacterial

species – Streptococcus pneumoniae, Staphylococcus aureus

and Neisseria gonorrhoeae. In all three human antibiotic use

provides the greatest selection pressure.

Streptococcus pneumoniaeWorldwide S. pneumoniae is the major bacterial cause of

community acquired pneumonia, upper respiratory tract

infections, (including sinusitis and otitis media), and childhood

and adult meningitis. Resistance has implications for empiric

treatment; in turn empiric respiratory prescribing, whether

uncontrolled or through local guidelines, impacts on continuing

community antibiotic resistance selection pressures.

Penicillin resistant isolates of S. pneumoniae were first detected

independently in the 1970s, from South Africa, Papua New

Guinea and Australia 1. In Australasia these were sporadic cases,

though it led to a labelling of Australia on the S. pneumoniae

resistance map. In the early 1990s, penicillin non-susceptibility

emerged rapidly, with resistance rates of up to 30–50% reported

from Europe, the United States and East Asia in particular. In

some settings penicillin resistance was linked to a shift to the use

of oral cephalosporins 2. Susceptibility rates have varied widely

according to reporting countries, site of infection (e.g. invasive

vs non-invasive), and to pneumococcal serotype. However,

resistance has not been confined to β-lactam antibiotics and

Elaine Cheong

Staff SpecialistInfectious Diseases & MicrobiologyConcord Repatriation General HospitalConcord NSW 2139 AustraliaTel: +61 2 9767 7537Fax: +61 2 9767 7868Email: [email protected]

of concern is the evolution of resistance in other antibiotic

classes, especially macrolides and fluoroquinolones, multi-drug

resistance and the potential to compromise treatment availability.

Recently penicillin non-susceptibility appears to have stabilised in

many western countries, however macrolide resistance continues

to increase. Macrolide resistance has been linked to usage,

particularly of longer-acting macrolides 3. Penicillin and macrolide

resistance rates continue to reside at high levels in parts of Asia. In

Vietnam as example; in 2000/01, 92% penicillin non-susceptibility

was reported, of which 71% was high level resistance 4.

Key to interpretation of the data is an understanding of the

clinical implications of resistance and worldwide trends. Despite

resistance, there have been no bacteriologically confirmed reports

of failure of intravenous penicillin therapy in pneumococcal

pneumonia 3,5. In pneumonia, worsened outcomes have been

retrospectively reported when penicillin MICs were ≥4 mg/L 6,7.

In Australia strains with an MIC ≥4 mg/L remain uncommon,

in the 2005 AGAR study 8, 1.6% had MICs ≥4 mg/L (Figure 1).

Hence despite in vitro pneumococcal resistance, intravenous

penicillin and high-dose oral amoxicillin remain the currently

recommended antibiotics in Australia 9. Conversely, even low level

Figure 1. S. pneumoniae – Etest MICs: AGAR 2005 studies.


In Focus


penicillin resistance has an adverse impact on penicillin therapy

for meningitis. In contrast to β-lactams, there is a confirmed

association between macrolide resistance and therapeutic failures

in bacteraemic S. pneumoniae 10,11. Newer fluoroquinolones,

(e.g. moxifloxacin, levofloxacin) are effective drugs, particularly

for infection by multi-drug resistant strains. Rising resistance

rates have been documented (France 3% 12, Hong Kong 14% 13),

and correlate with increasing levels of use. Resistance has been

linked with therapeutic failures 14.

National surveillance studies aid the formulation of therapeutic

guidelines in monitoring their ongoing relevance and to link in

with vaccination strategies. The Australian Group on Antimicrobial

Resistance (AGAR), a national laboratory network, has performed

periodic studies of S. pneumoniae susceptibility since 1989, the

last in 2005 8.

In the AGAR studies, penicillin non-susceptibility has continued

to increase, albeit at a slower rate than first observed in the early

1990s, reaching a national level of 28% in 2005 (Figures 2 and 3).

This increase has occurred in both penicillin intermediate and

resistant categories. In 1989, 1% of strains tested were penicillin

non-susceptible (intermediate resistance). By 2005 the penicillin

intermediate group had increased to 16.3% and this level of

resistance has remained steady over the past six years. However,

the rate of S. pneumoniae high-level resistance nationally has

increased from 0% in 1989, to 5.9% in 1999 and 11.7% in 2005,

and resistance in non-invasive isolates with an MIC ≥2 mg/L rose

from 6.9% to 13.3%. The higher rates in non-invasive infection

may relate to differing serotypes involved in invasive and

bloodstream infections and the selective pressure of community

antibiotic use in upper respiratory tract infections.

In 2005 erythromycin resistance was documented in 22.7%

of isolates, a rise of 5% since 1999. Similarly, increases were

primarily in non-invasive isolates. A macrolide-lincosamide-

streptogramin B (MLSB) phenotype, suggestive of an ermB

(high-level) resistance mechanism was present in 62.6%. The

AGAR study data suggests that macrolides should not be used as

sole empiric therapy for invasive respiratory tract infections.

There were extremely low levels of fluoroquinolone resistance

(0.1%). The low fluoroquinolone resistance levels are likely to

relate to restrictions placed on their use. To date, Australian

guidelines have not endorsed fluoroquinolone use as first

line therapy in community acquired pneumonia. Tetracycline

resistance in invasive isolates was below 10% and trimethoprim-

sulphamethoxazole resistance fell from 37.8% in 2002 to 31.0%

in 2005. It is notable that the tetracycline and folate synthesis

inhibitor drugs were the two classes of antibiotics to show

a >50% reduction in community prescribing over the past

fourteen years 15.

Regular AGAR surveillance studies of S. pneumoniae resistance

have allowed a much clearer picture of changing susceptibility

and provide an indirect measure of our prescribing policies.

Although resistance appears to have reached a stable threshold,

rates of ‘high-level’ penicillin resistance and multi-resistance

continue to rise worldwide 16.

Staphylococcus aureusAs a major human pathogen causing significant mortality and

morbidity S. aureus, with its constantly evolving antimicrobial

resistance, continues to be a challenge for scientists,

microbiologists and clinicians.

Whilst methicillin-resistant S. aureus (MRSA) has been a well-

established pathogen in hospitals and healthcare settings, its

emergence as a community pathogen has only been recognised

in more recent times. Since the 1990s, multiple community

epidemics of infections caused by MRSA occurred worldwide,

including the USA 17, Canada 18, New Zealand 19 and Australia20.

The foci of these infections (often necrotising skin and soft

tissue infections) within communities included the paediatric

population 21, indigenous peoples and within community

institutions such as prisons 22. Figure 2. Trends in national S. pneumoniae resistance – AGAR 1994–2005.

SXT = trimethoprim-Sulphamethoxazole; Ery = erythromycin; Tet = tetracycline Pen I = penicillin intermediate; Pen R = penicillin resistant.

Figure 3 S. pneumoniae: penicillin and macrolide resistance by region – AGAR 2005 study.


In Focus


The isolates causing these community onset staphylococcal

infections have been commonly called ‘community MRSA’

(cMRSA), in an attempt to distinguish them from hospital

or healthcare associated infections. However, apart from the

community acquisition of these infections, there are several

features that distinguish them from traditional MRSA infections.

These include the lack of usual risk factors for MRSA acquisition 21,

susceptibility to a wider range of non beta-lactam antimicrobials,

and the presence of specific virulence factors. Of note is the

presence of the toxin Panton-Valentine leukocidin (PVL), which

is associated with the skin and soft tissue infections and primary

necrotising pneumonias 23. At a molecular level, MRSA isolates

harbour the mec gene (encoding for beta lactam resistance) as

part of a mobile genetic element staphylococcal chromosome

cassette mec (SCCmec). In cMRSA isolates, these cassettes

(designated as class IV or V), are smaller and suggest the potential

for easy transfer between and amongst staphylococci.

In Australia, the evolution and spread of cMRSA has been well

documented. First observations in the 1990s of community

acquired MRSA infections in Western Australia (WA-MRSA) 24,

were followed soon after by reports in the eastern states.

Some of these strains appear to have originated from the

Pacific Islands (‘Western Samoan Phage Pattern’ [WSPP-MRSA]),

and in 2000, another strain emerged in Queensland (QLD-

MRSA)25. Concurrently, there was recognition of community-

onset infections with heathcare associated non-multiresistant

MRSA strains (such as the ‘epidemic’ MRSA or EMRSA-15 strain

originally from the United Kingdom).

National surveillance by the AGAR network of laboratories has

provided ongoing data in the form of alternate-year community

surveys of S. aureus (Staphylococcus aureus Surveillance

Programme), whereby one hundred consecutive, non-duplicate

S. aureus isolates are collected by each of the participating

laboratories from non-hospitalised patients (including those

in long-term care facilities but excluding day surgery and

dialysis patients). Information on antimicrobial susceptibility,

epidemiology and typing for the years 2000, 2002 and 2004 has

been analysed and reported 26.

In summary, these community surveys show that 26,27:

• The percentage of S. aureus isolates that are methicillin

resistant has increased from 11.7% in 2000 to 15.3% in 2004.

• The percentage of cMRSA isolates as a proportion of all S.

aureus isolates has increased from 4.7% in 2000 to 7.3% in

2004.

• Geographical differences were noted with some states

reporting lower percentages of cMRSA (Tasmania and Victoria

2%) than others (Northern Territory 20% and Western

Australia 11%).

• In 2004, twelve cMRSA clones were identified with the

predominant being WA-1 MRSA, QLD-MRSA and WSPP-

MRSA.

• Overall,46.4%ofcMRSAwerepositiveforPVL.

The information from these surveys demonstrates that cMRSA

is becoming a common pathogen in many regions of Australia.

In the 2004 AGAR survey, cMRSA isolates accounted for >10% of

all clinical outpatient isolates in Darwin, Brisbane and Perth 26.

This has significant implications for local antibiotic prescribing

practices for the treatment of staphylococcal infections in the

community. It has been suggested that an arbitrary threshold of

10% or more of S. aureus isolates with methicillin resistance be

used for consideration of specifically tailoring empiric antibiotic

treatment strategies to account for cMRSA infections 28.

Whilst obtaining specimens for culture and susceptibility testing

was often not considered to be part of routine management

for community infections in the past, the increasing prevalence

of cMRSA has made this practice more important. Antibiotic

susceptibility profiles can assist the clinician in the appropriate

choice of antibiotics to treat these infections. At present S. aureus

isolates with multiple resistances to non beta-lactam antibiotics

does not appear to be a significant problem in Australia, with

60.3% of cMRSA isolates being resistant to beta-lactam agents

only, and only 1.5% with resistance to three non beta-lactams 26, 27.

However, a recent study based within an ambulatory care centre

in the USA, suggests that multi-drug resistance is emerging in

cMRSA (USA 300 strain). High rates of resistance to erythromycin

(96%), clindamycin (57%), levofloxacin (85%) and tetracycline

(30%) were demonstrated. In addition, 18% of the isolates

were resistant to all four of these non-betalactams 29. These

developments are concerning as they suggest that the acquisition

of antibiotic resistance in cMRSA occurs readily with continued

antibiotic use and selection pressure. The potential spread of a

multi-resistant cMRSA would greatly limit the clinician’s options

for therapy.

Neisseria gonorrhoeaeThe causative agent of gonorrhoea, N. gonorrhoeae is a well-

known human pathogen whose importance is often forgotten,

given its antiquity. However, it continues to cause significant

morbidity with increasing antimicrobial resistance the focus of

concerns in managing the scope of this global public health

issue 30. Surveillance of antimicrobial resistance is important in

the development of local empiric treatment regimens, which

in turn affects disease outcomes for individuals, and in addition

importantly impacts upon ongoing transmission of infection.

The World Health Organisation (WHO) Western Pacific

Gonococcal Surveillance Programme has documented over the

last decade or so, the spread of quinolone resistant gonococci


In Focus


throughout our Asian and Pacific neighbours. In 2005, countries

such as China and Korea were reporting rates in excess of 90% of

N. gonorrhoeae isolates being resistant to the fluoroquinolone

ciprofloxacin 31.

Locally, data on gonococcal antimicrobial resistance is collected

and reported on quarterly by the Australian Gonococcal

Surveillance Programme (AGSP). On the home front, increasing

rates of antimicrobial resistance among local isolates are a concern.

Figures 4 and 5 32, demonstrate the significant percentages of

isolates with penicillin and quinolone resistance, and the regional

differences in susceptibility results. Nationally in 2006, 34% and

37.8% of gonococci were resistant to penicillin and quinolones

respectively; increases from the preceding two years. Of great

concern, the most recent data from the AGSP in the first quarter

of 2007 supports an ongoing upward trend in resistance rates

with record rates of quinolone resistance nationally (51.6% of all

N. gonorrhoeae isolates). Once again, New South Wales carries

the burden of resistance with 66.8% isolates tested as quinolone

resistant 33.

The WHO recommends that once resistance to an antimicrobial

of 5% or more in isolates obtained from the community

is demonstrated, that treatment programs be modified to

account for this 34. Given the above data, the evidence is that

quinolones cannot be used reliably to treat gonococcal infections

(the exception being perhaps in the Northern Territory).

Unfortunately, this leaves injectable agents such as ceftriaxone

as the mainstay for treatment in Australia. Currently, 0.6%

of surveyed N. gonorrhoeae isolates have raised ceftriaxone

minimum inhibitory concentrations (in the range 0.06–0.25

mg/L) 32. The rates for ceftriaxone resistance have remained low

and stable since 2001, but it is notable that such isolates are in

general also resistant to both penicillin and quinolones. Thus,

Table 1. Examples of emerging community bacterial resistance.

Source Bacterial species Resistance

Respiratory Streptococcus pneumoniae ß-lactam (penicillin, cephalosporin), macrolide, fluoroquinolone, MDR

Haemophilus influenzae ß-lactam

Mycobacterium tuberculosis rifampicin, isoniazid (MDR) + quinolones, others (XDR)

Gastrointestinal / Enterobacteriaceae (eg. E. coli), amino-penicillins, trimethoprim 3rd gen cephalosporin, Urinary ESBL+ Enterococcus faecalis fluoroquinolone, vancomycin (VRE), amino-penicillins Salmonella typhi TMP-SMX, fluoroquinolone

Genital Tract Neisseria gonorrhoeae penicillin, fluoroquinolones

Skin / Soft tissue Staphylococcus aureus, methicillin (ß-lactam), macrolide Streptococcus pyogenes

Zoonotic Salmonella sp ß-lactam, TMP-SMX, fluoroquinolones

Campylobacter jejuni 3rd gen cephalosporin (ESBL), MDR fluoroquinolones

Yersinia pestis MDR

MDR = multi drug resistant; XDR = extremely drug resistant; TMP-SMX = trimethoprim-sulphamethoxazole

0 %

2 0 %

4 0 %

6 0 %

8 0 %

1 0 0 %

N S W V IC Q ld N T W A S A A u s

P P N G

R R

L S

F S

Figure 4. Australian Gonococcal Surveillance Programme.

Penicillin resistance of gonococcal isolates, Australia, 2006 by region.FS = fully sensitive to penicillin, MIC < = 0.03 mg/LLS = less sensitive to penicillin, MIC 0.06 – 0.5 mg/LRR = relatively resistant to penicillin, MIC > = 1 mg/LPPNG, penicillinase-producing N. gonorrhoeae

0

10

20

30

40

50

60

NSW V IC Q LD NT SA W A AUS

%

All Q RNG

LS Q RNG

R Q RNG

Figure 5. Australian Gonococcal Surveillance Programme.

Percentage of gonococcal isolates that were less sensitive to ciprofloxacin (LS QRNG, MIC 0.06 – 0.5 mg/L) or with higher level ciprofloxacin resistance (R QRNG, MIC 1 mg/l or more) and all strains with altered quinolone susceptibility, by region, Australia, 2006.


In Focus

with limited treatment options and ongoing antibiotic selection

pressure, it would appear inevitable, that with time rates of

resistance to ceftriaxone will also increase.

In this review we have briefly covered issues of antimicrobial

resistance in three pathogens which are common causes of

community acquired infections. The evolution of antimicrobial

resistance in all three is a dynamic process, and thus continued

surveillance in the form of local, national and global surveys are

important in providing data that can be utilised to appropriately

guide antimicrobial prescribing guidelines and formulate public

health strategies. Introduction and maintenance of effective

vaccination programs as well as continuing promotion of prudent

community prescribing are crucial to maintaining effective

control on resistance.

AcknowledgmentsWe would like to thank AGAR for permission to reproduce

Figures 1–3. Many thanks also to Professor John Tapsall and

the Australian Gonococcal Surveillance Programme (AGS) for

the most recent data and Figures 4–5 taken from the AGS 2006

Annual Report and first quarterly figures for 2007.

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penicillin in Australia and New Guinea. Med J Aust 1974; 2:353-6

2. Baquero F. Trends in antibiotic resistance of respiratory pathogens: an analysis and commentary on a collaborative surveillance study. J Antimicrob Chemother. 1996; 38(A):S117-32.

3. Klugman KP. Clinical impact of antibiotic resistance in respiratory tract infections Int J Antimicrob Agents 2007; 29(1):S6-S10.

4. Song J, Jung S, Ko K et al. High prevalence of antimicrobial resistance among clinical Streptococcus pneumoniae isolates in Asia (an ANSORP study). Antimicrob Agents Chemother 2004; 48:2101-7.

5. Pallares R, Liñares J, Vadillo M et al. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 1995; 333:474-80.

6. Chiou C. Does penicillin remain the drug of choice for pneumococcal pneumonia in view of emerging in vitro resistance? Clin Infect Dis 2006; 42:234-7.

7. Feikin DR, Schuchat A, Kolczak M et al. Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997. Am J Public Health 2000; 90:223-9

8. Gottlieb T, Collignon P, Robson J et al. Streptococcus pneumoniae Survey. AGAR 2005 Antimicrobial Susceptibility Report. http://antimicrobial-resistance.com/ (under AMR Surveillance). 27-7-07.

9. Therapeutic guidelines: antibiotic. Thirteenth edition. Melbourne:Therapeutic Guidelines Ltd, 2006.

10. Daneman N, McGeer A, Green K et al. Resistance in bacteremic pneumococcal disease: implications for patient management. Clin Infect Dis 2006; 43:432-8.

11. Lonks J, Garau J, Medeiros A. Implications of antimicrobial resistance in the empirical treatment of community-acquired respiratory acquired respiratory tract infections: the case for macrolides. J Antimicrob Chemother 2002; 50(S2):87-92.

12. Reinert R, Reinert S, van der Linden M et al. Antimicrobial susceptibility of Streptococcus pneumoniae in eight European countries from 2001 to 2003. Antimicrob Agents Chemother 2005; 49:2903-13.

13. Canton R, Morosini M, Enright M et al. Worldwide incidence, molecular epidemiology and mutations implicated in fluoroquinolone-resistant Streptococcus pneumoniae: data from the global PROTEKT surveillance

programme. J Antimicrob Chemother 2003; 52:944-52.

14. Davidson R, Cavalcanti R, Brunton J et al. Resistance to levofloxacin and failure

of treatment of pneumococcal pneumonia. N Engl J Med 2002; 346:747-50.

15. Drug Utilisation Subcommittee, Pharmaceutical Benefits Branch, Health Access

and Financing Division, Commonwealth Department of Health and Ageing.

16. Pallares R, Fenoll A, Liñares J, The Spanish Pneumococcal Infection Study

Network. The epidemiology of antibiotic resistance in Streptococcus

pneumoniae and the clinical relevance of resistance to cephalosporins,

macrolides and quinolones. Int J Antimicrob Agents 2003; 22:S15-24.

17. Pate KR, Nolan RL, Bannerman TL et al. Methicillin-resistant Staphylococcus

aureus in the community. Lancet 1995; 346:978.

18. Taylor G, Kirkland T, Kowalewska-Grochowska K et al. A multistrain cluster of

methicillin-resistant Staphylococcus aureus based in a native community. Can

J Infect Dis 1990; 1:121-6.

19. Heffernan H, Davies H, Brett M. Current epidemiology of MRSA in New

Zealand. Lablink 1997; 4:25-6.

20. Maguire GP, Arthur AD, Boustead PJ et al. Emerging epidemic of community-

acquired methicillin-resistant Staphylococcus aureus infection in the Northern

Territory. Med J Aust 1996; 164:721-3.

21. Herold BC, Immergluck LC, Maranan MC et al. Community-acquired methicillin-

resistant Staphylococcus aureus in children with no identified predisposing

risk. JAMA 1998; 279: 593-8.

22. Centers for Disease Control and Prevention. Methicillin resistant Staphylococcus

aureus infections in correctional facilities – Georgia, California and Texas,

2001–2003. Morb Mort Wkly Rep 2003; 52:992-6.

23. Lina G, Piemont Y, Godail-Gamot F et al. Involvement of Panton-Valentine

leukocidin-producing Staphylococcus aureus in primary skin infections and

pneumonia. Clin Infect Dis 1999; 29:1128-32.

24. Udo EE, Pearman JW, Grubb WB. Genetic analysis of community isolates of

methicillin-resistant Staphylococcus aureus in Western Australia. J Hosp Infect

1993; 25:97-108.

25. Munkhof WJ, Schoonveldt J, Coombs GW et al. Emergence of community-

acquired methicillin resistant Staphylococcus aureus (MRSA) infection in

Queensland, Australia. Int J Infect Dis 2003; 7:259-61.

26. Nimmo GR, Coombs GW, Pearson JC et al for the Australian group for

Antimicrobial Resistance (AGAR). Methicillin-resistant Staphylococcus aureus

in the Australian community: an evolving epidemic. Med J Aust 2006; 184:384-8.

27. Coombs GW, Christiansen K, Pearson JC et al. Staphylococcus aureus

Programme 2004 Community Survey. MRSA Epidemiology and Typing Report.

AGAR 2004. http:// antimicrobial-resistance.com. 27-7-07.

28. Daum RS. Skin and soft-tissue infections caused by Methicillin-Resistant

Staphylococcus aureus. N Engl J Med 2007; 357:380-90.

29. Han LL, McDougal LK, Gorwitz RJ et al. High frequencies of clindamycin and

tetracycline resistance in Methicillin-resistant Staphylococcus aureus Pulse-

Field Type USA 300 collected at a Boston Ambulatory Health Center. J Clin

Microbiol 2007; 45:1350-2.

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41:S263-8.

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Figures 1–3 are presented with the permission of the Australian

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resistance.com/).


In Focus

AMR and tuberculosis: Voldemort returns?

Christopher Coulter

Director Queensland Mycobacterium Reference LaboratoryPathology QueenslandRoyal Brisbane and Women’s HospitalHerston, QLD 4029 Australia

There has been significant progress in implementing global

tuberculosis (TB) control strategies in the last decade. Indeed,

in all but sub-Saharan Africa, the incidence of TB appears to

be declining. While only the Western Pacific region reached

the World Health Organization (WHO) imposed 2005 STOP TB

program targets, worldwide case detection and treatment success

has greatly improved. Why is there no celebration?; the number

of new cases continues to steadily rise, particularly in China, India

and the African continent and an alarming proportion of those

infected with TB are also infected with HIV. Just as Voldemort,

the embodiment of evil in JK Rowling’s Harry Potter novels,

appears defeated but returns stronger than ever, mortality and

morbidity of TB is increasing significantly in parts of the globe

where antimicrobial resistance has emerged.

Rates of TB in Australia (5–6 per 100,000 population) are amongst

the lowest in the world and have been for many years 1. The

majority of cases are seen in migrants to Australia who acquired

their initial infection overseas, only to present years later in their

new home. Rates in Indigenous Australians are of concern (5.9

per 100,000), but numerically represent a small number of clinical

cases. The incidence in non-Indigenous Australian-born citizens


In Focus

is <1 per 100,000. However complacency cannot be allowed to

alter Australia’s historic doggedness in fighting TB. A resurgence

in multidrug resistant TB (MDR-TB) in the USA in the 1990s

taught public health officials and government policy makers what

happens when TB control programs are neglected.

To the very near north of Australia, Papua New Guinea (PNG) has

a TB incidence estimated at 250 per 100,000 and HIV co-infection

prevalence rate of 9.7% 2. PNG is so close to Australia that nearly

half the cases of TB diagnosed in far north Queensland during

1998–2002 originated in PNG nationals from the Western Province

seeking medical treatment in the Torres Strait under the Torres

Strait Treaty 3. Of the sixty bacteriological confirmed cases from

the Torres Strait during 2000–2006, fifteen (25%) were defined

as MDR-TB 4. In 2005, MDR-TB from the Torres Strait accounted

for half of the twelve MDR-TB cases recorded in Australia 5. Other

high burden countries are either regionally close or recognised

as countries of frequent origin for migrants to Australia.

What is MDR-TB?MDR-TB is defined as M. tuberculosis resistant to rifampicin and

isoniazid. Such isolates may also be resistant to other agents.

Rifampicin and isoniazid are the cornerstone drugs of TB therapy.

Without rifampicin, ‘short course therapy of six months duration

is not possible for treating pulmonary TB.

What are the mechanisms of antimicrobial resistance in M. tuberculosis?Rifampicin inhibits protein synthesis by binding to RNA

polymerase at the ribosomal level. Mutations in the rpoB

gene, which encodes for the beta chain of mycobacterial RNA

polymerase, account for >95% of phenotypic resistance.

Isoniazid requires activation by mycobacterial cellular catalase

and then acts by inhibition of a protein required for mycolic acid

and thus cell wall synthesis. This protein is the inhA protein and

catalase is encoded by the kat genes. InhA and katG mutations

account for approximately 80% of known isoniazid resistance.

Other documented defects are known but for a significant

proportion of strains, especially with low level resistance, the

mechanism of resistance is yet to be elucidated 6,13.

Methods of resistance are summarised in Table 1.

What is the clinical significance of MDR-TB?MDR-TB is associated with worse outcomes. Treatment is longer

– usually eighteen months or more – and second line agents must

be invoked. Table 2 outlines both first and second line agents.

Second line agents are generally more difficult to use, because

they either require iv access, are difficult to obtain, more

expensive and/or prone to adverse reactions. When MDR is

suspected or proven, at least two new drugs must be used in

the regimen. Adherence is critical and directly observed therapy

should be used. Effective infection control strategies aimed

at preventing airborne spread of TB must be implemented

particularly in the healthcare setting.

To date there has not been a strong financial incentive for

pharmaceutical companies to manufacture second line agents or

to develop novel antimicrobial agents active against TB.

While successful outcome for treating MDR-TB may be as high

as generally expected in some parts of the world (approx 77%),

lower outcomes in both developed and developing countries

have been reported (52%) 7 and contrasts with success rates of

>85% seen in the Western Pacific for predominately, but not

exclusively, drug susceptible disease 8. Surgery is often required

to successfully manage MDR-TB.

Co-infection with both HIV and TB is associated with significantly

poorer outcome, especially in the absence of highly active

antiretroviral therapy. The potent combination of drug resistance

and HIV is no more apparent than in Tugela Ferry, South Africa.

Extensively drug resistant TBIn 2005 in Tugela Ferry, a small town in the KwaZulu-Natal

province of South Africa, high mortality was noted in patients

co-infected with TB and HIV 9. Drug susceptibility testing

identified fifty-three patients with MDR-TB so resistant that new

terminology was coined: extensively drug resistant TB (XDR-TB).

XDR is defined as resistance to rifampicin and isoniazid plus any

fluoroquinolone and at least one of the three injectable second

line agents (amikacin, kanamycin or capreomycin). Of the fifty-

three patients, fifty-two died with a median survival of only

sixteen days, and 55% claimed never to have been previously

treated for TB, strongly suggesting primary acquisition of a drug

resistant strain. Of forty-four patients able to be tested, all were

HIV positive.

XDR-TB has been described in other parts of the world. A recent

collaborative study by the Centers for Disease Control (CDC)

and the WHO Supranational Reference Laboratories examined

17,690 isolates from forty-nine countries, documenting MDR

in 20% and XDR in 2% 10. Cases of XDR-TB have been reported

from many countries but rates were highest in Latvia and South

Korea, where XDR represented 15% and 19% respectively of

MDR-TB cases. A recent retrospective analysis of seventy MDR-


In Focus

TB cases from Australia during 2000–2005 revealed two cases of

XDR-TB (unpublished data Australian Mycobacterium Laboratory

Network AGM Minutes 2007.).

How does antimicrobial drug resistance emerge?Whatever the degree of resistance the causative factors are

the same. Wild strain M. tuberculosis is innately susceptible to

first and second line agents. However, tubercle bacilli are not

inert and a spontaneous mutation rate conferring resistance

to one or more agents occurs at a frequency of approximately

1 in 1 million replications for isoniazid and ethambutol, and

1 in 108 for rifampicin. Combination antimicrobial therapy in

adequate dosage for long enough prevents the selection of

mutant resistant clones. Conversely, resistance is fostered when

inappropriate regimens are prescribed, when adherence is poor

(and not monitored), when duration of therapy is too short and

when TB control programs are poorly coordinated and poorly

resourced. Inappropriate use of second line drugs sees the

emergence of XDR-TB.

What is the role of the laboratory?Timely and accurate laboratory diagnosis is critical to good TB

Antimicrobial agent Mechanism of Mechanism of Frequency causing

resistance: gene resistance: enzyme resistance (% isolates)

Isoniazid Inh A Enoyl ACP reductase <10 – 51%

katG Catalase peroxidase 60-70

oxaR-ahpC Alkyl hydrpreductase 20

ndh NADH dehydrogenase II –

Rifampicin rpoB RNA polymerase subunit B >95

Ethambutol Emb A,B C Arabinosyl transferase 69

Pyrazinamide pncA Pyrazinamidase 70-100

Streptomycin rpsL Ribosomal protein 60

subunit12

rrs 16s rRNA <10

strA Aminoglycoside

phosphotransferase –

Fluoroquinolones gyr A, gyrB DNA gyrase >90

Table 1 6,12,13

control. For individual patients the acid fast stain is perhaps

the most cost effective diagnostic and life saving strategy in

microbiology worldwide. As it is smear positive patients who

account for the sickest (in the absence of HIV) and most

contagious patients, prompt identification of acid-fast bacilli

(AFB) in sputum samples enables both initiation of directly

observed therapy (in most countries) and opportunity to control

transmission. In Australia, all diagnostic microbiology laboratories

must be capable of performing a direct AFB stain by the Zeihl

Neelson method. Secondary and tertiary laboratories performing

TB culture should be able to decontaminate and concentrate

sputum samples by centrifugation prior to microscopy and

culture.

For many years, laboratories performing culture and susceptibility

testing were, in the main, confirming susceptibility to first line

drugs. This is no longer the case. In regions where MDR and

XDR exist, each day that susceptibility testing remains pending is

potentially another day on inappropriate therapy that is conducive

to the development of further drug resistance. While Australia

expects its laboratories to be able to perform AFB staining and

culture samples from all suspect cases, it is an unfortunate reality

that many countries struggle to be able to reliably do so, even

in the setting of treatment failure. First and second line DST


In Focus

is another step again. The WHO recognises the importance of

capacity building in laboratories in high burden countries and

is directing a significant proportion of resources to this. In the

first instance, laboratories must be strengthened to provide

culture for patients failing standard therapy when drug resistance

is suspected. The next step is to ensure such isolates receive

accurate quality assured confirmation of identification, first line

and, if necessary, second line drug susceptibility testing.

Even in resource rich reference labs, M. tuberculosis cannot be

induced to speed its growth any further than biologically possible.

Even with automated broth culture, using only phenotypic

methods, first line susceptibility would not be expected until

three–five weeks after incubation commenced. The use of

molecular detection of resistance genes represents a way

forward. Detection of rifampicin resistance is attractive because

most resistance is mediated by mutations in the rpoB gene and

is strongly linked with multiresistance; monoresistance is rare.

Traditional PCR and sequencing can be directed at this gene but

commercial amplification and line probe methods represent a

simpler method that could be adopted by reference laboratories

in high burden countries that otherwise lack molecular expertise.

Our laboratory in Brisbane has been working with the Central

Reference Laboratory in Kenya to implement just such a strategy,

to enable the rapid identification of drug resistant strains.

Encouraging results have also been reported using such line

probe assays directly with sputum samples so that time to culture

positivity is not a delaying factor 11.

The futureIt is clear that a worldwide strengthening of laboratory capacity to

diagnose TB and to perform drug susceptibility testing is critical.

There is renewed interest in development of novel TB drugs

and for the broader application of combination drugs that make

compliance easier and prescribing mistakes less likely. Resources

are now being directed also at vaccine development, but for the

time being we have only the incompletely active BCG vaccine,

first used in 1921.

Australia remains the lucky country with respect to TB burden.

Geographically we have high burden countries as our near

neighbours and it is only by remaining diagnostically vigilant,

technically competent, public health resourced and politically

motivated that the spectre of drug resistant TB will be kept at bay.

In the Harry Potter novels, the villain Voldemort never actually

went to Australia – but he could have . . .

References1. Roche P. Bastian I, Krause V et al. National Tuberculosis Advisory committee

for the Communicable Diseases Network Australia. Tuberculosis notifications in Australia, 2005. Commun Dis Intell 2007; 31:71-9.

2. WHO Report 2006 Global Tuberculosis Control. Surveillance, Planning, Financing. World Health Organization.

3. Simpson G, Clarke P, Knight T. Changing patterns of tuberculosis in Far North Queensland. Med J Aust 2006; 184:252.

4. Gilpin C, Simpson G, Vincent S et al. Evidence of primary transmission of multi-drug resistant tuberculosis in the Western Province of Papua New Guinea. Med J Aust (in press).

5. Lumb R, Bastian I, Gilpin C et al. Australian Mycobacterium Reference laboratory Network. Tuberculosis in Australia: bacteriologically confirmed cases and drug resistance, 2005. Commun Dis Intell 2007; 31:80-6.

6. Sharma SK, Mohan Q. Multi-drug resistant tuberculosis. Ind J Med Res 2004; 120:354-76.

7. Schluger NW. Diagnosis and treatment of drug resistant tuberculosis. Up To Date: www.uptodate.com. Last updated April 2007.

8. Dye C, Hosseini M, Watt C. Did we reach the 2005 targets for tuberculosis control? Bull World Health Organization 2007; 85:364-9.

9. Gandhi NR, Moll A, Sturm AW et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368:1575-80.

10. Shah NS, Wright A, Bai GH et al. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis 2007; 13:380-7.

11. Somoskovi A, Dormandy J, Mitsani D et al. Use of smear-positive samples to assess the PCR-based genotype MTBDR assay for rapid, direct detection of the Mycobacterium tuberculosis complex as well as its resistance to isoniazid and rifampin. J Clin Microbiol 2006; 44:4459-63.

12. Rattan A, Kalia A, Ahmad N. Multidrug-resistant Mycobacterium tuberculosis: molecular perspectives. Emerg Infect Dis 1998; 4:195-209.

13. Guo H, Seet Q, Denkin S et al. Molecular characterization of isoniazid resistant clinical isolates of Mycobacterium tuberculosis from the USA. J Med Microbiol 2006; 55:1527-31.

First line agents

Rifampicin

Isoniazid

Ethambutol

Pyrazinamide

Streptomycin

Second line agents

Amikacin

Kanamycin

Capreomycin

Fluoroquinolones: ofloxacin, moxifloxacin

Cycloserine

Ethionamide

PAS

Table 2.


In Focus

Epidemic potential and antimicrobial resistance in Clostridium difficile

Thomas V Riley

Microbiology & ImmunologyThe University of Western AustraliaQueen Elizabeth II Medical CentreNedlands 6009 Western AustraliaAndDivision of Microbiology & Infectious DiseasesPathWest Laboratory MedicineQueen Elizabeth II Medical CentreNedlands 6009 Western AustraliaTel: 61 8 9346 3690Fax: 61 8 9346 2912Email: [email protected]

Clostridium difficile is the most commonly diagnosed cause

of infectious hospital-acquired diarrhoea 1. C. difficile was first

isolated in 1935 but not identified as the main causative agent

of antibiotic-associated diarrhoea (AAD) and pseudomemranous

colitis (PMC) (Figure 1) until 1977 2,3. The spectrum of disease

caused by C. difficile ranges from asymptomatic colonisation

to colitis that can progress to more severe PMC. Complications

include colonic perforation and death 4. The term C.

difficile-associated diarrhoea (CDAD) is used to describe the

symptomatic manifestations of the disease, thus excluding

asymptomatic colonisation. Hospital inpatients with CDAD are

generally elderly and have several comorbid conditions. The

majority of these patients have been exposed to antimicrobials

that reduce ‘colonisation resistance’ of the large intestine

allowing subsequent infection with C. difficile. Whether infection

progresses to disease is determined by many factors such as

antibiotic exposure, age and comorbidities, and others that are as

yet unknown. Acquisition of C. difficile is facilitated by its ability

to form spores (Figure 2) that are resistant to many disinfectants,

allowing it to remain viable in the hospital environment for long

periods of time. Toxigenic isolates of C. difficile usually produce

two toxins, toxin A and toxin B, and these are thought of as the

major virulence factors 5. CDAD is a major financial burden on

healthcare systems, with patients spending an extra one–three

weeks in hospital costing US$5–10,000 per episode 6.

Epidemic C. difficileThere is now great concern worldwide about CDAD, following

the recent emergence in Canada 7, the USA 8, and now Europe 9 of a highly virulent strain of C. difficile (called PCR ribotype

027 in Europe and NAP1 in the USA). Rates of detection of C.

difficile have risen dramatically, the C. difficile disease has been

more severe, and attributable mortality was >10% in those aged

>60 years 7. There has been much discussion on what might be

driving this epidemic of CDAD in various parts of the world and

the likelihood of the epidemic strain becoming established in

Australia. This discussion has focused on several areas, including

the role of gastric acid suppressants, the role of animal reservoirs,

the emergence of a more virulent strain and the development of

antimicrobial resistance.

One possible novel risk factor is exposure to gastric acid

suppressants such as histamine-2 receptor inhibitors or proton

pump inhibitors. These agents have been more commonly

prescribed in recent years and may be associated with increased

rates of CDAD in the community 10, although some case-control

studies with hospital patients show no association 7,11. Since its

Figure 1. Pseudomembranous colitis.


In Focus

discovery C. difficile has been associated with animals. Early

investigations showed, for example, that 40% of cats and dogs

attending a veterinary clinic haboured C. difficile; however,

there was no relationship with human strains 12. More recently, C.

difficile has been shown to be associated with diarrhoeal diseases

in pigs 13, cattle 14 and horses 15. Rupnik 16 has recently suggested

the possibility of C. difficile being part of a zoonosis.

In addition to toxins A and B, some strains of C. difficile produce

a binary toxin (actin-specific ADP-ribosyltransferase, CDT), first

reported in 1988 but not considered important until now 7,8,17.

Binary toxin producers make up the majority of strains isolated

in the large outbreaks of disease overseas 7,8 and binary toxin has

been thought of as an additional virulence factor. Barbut et al 17

show a correlation between binary toxin production and severity

of diarrhoea, and more community-acquired CDAD was caused

by binary toxin producers. However, the significance of binary

toxin clearly needs further investigation as strains of C. difficile

that produce binary toxin only, and no toxin A or B, do not cause

disease in the hamster model 18.

Antimicrobial resistanceWhile all of the above is true, the most likely driver of the current

epidemic is antimicrobial resistance. C. difficile isolates are

typically susceptible in vitro to metronidazole and vancomycin,

and show variable susceptibility to other antimicrobial agents. The

relative risk of CDAD following antimicrobial therapy increases

if the strain of C. difficile is resistant to the antimicrobial19.

Resistance to various antimicrobial agents appears to be increasing 20. In Spain, the prevalence of metronidazole resistance was

6.3% in a study of 415 isolates of C. difficile and, although full

resistance to vancomycin was not found, the prevalence of

intermediate resistance was 3.1% 21. Another study in an Israeli

hospital found the prevalence of metronidazole resistance was

2% 22. The mechanism of metronidazole resistance is unknown,

but resistance is frequently associated with inefficient activation

of the drug 23.

Resistance to macrolide-lincosamide-streptogramin (MLS) agents

such as erythromycin or clindamycin is mediated by a 23S

ribosomal RNA methylase encoded by a group of homologous

erm genes 24. An investigation of outbreaks that occurred in

four hospitals in the USA between 1992 and 1998 found a new

clindamycin-resistant strain to be responsible 24. More recently,

a clindamycin-resistant toxin A-/B+ strain was found to be

widely disseminated in two hospitals in Warsaw, Poland 25. In a

study at the Royal Hospital in Edinburgh, Scotland, clindamycin

resistance was extremely common, with only 8% of clinical

isolates susceptible 26.

The resistance traits described above have been known about for

some years. However, it is resistance to the newer fluoroquinolone

antimicrobials that is thought to be playing a major role in the

emergence and spread of the PCR ribotype 027 strain responsible

for the epidemics in North America and Europe, and excessive

fluoroquinolone use appears to be a contributing factor in these

recent outbreaks 27. The problem of fluoroquinolone resistant

C. difficile was first brought to our attention in 2004 with a

report of an outbreak at a long-term care facility in the USA 28.

In an accompanying editorial, Dale Gerding correctly identified

that this was an issue of previously uncommon fluoroquinolone

resistance in C. difficile, while the gastrointestinal tract anaerobe

flora remained susceptible 19. C. difficile develops resistance

to fluoroquinolones soon after exposure. Ackermann et al 29

describe 33 moxifloxacin resistant toxigenic isolates (MIC ≥16

mg/L) where resistance was significantly associated with prior

quinolone exposure and mutations in the gyrA gene.

All the newer fluoroquinolones including gatifloxacin and

levofloxacin and, somewhat surprisingly, the older ciprofloxacin

have been implicated 27. Ciprofloxacin has always been thought

of as a low risk antimicrobial for inciting CDAD 30; however,

once C. difficile becomes resistant to the later fluoroquinolones

it is also resistant to ciprofloxacin and the resistance trait may

become more important for initiation of disease. Both gyrA and

gyrB mutations have now been implicated in fluoroquinolone

resistance in C. difficile 31. The current outbreak strain of C.

difficile (PCR ribotype 027) has been recognised for over twenty

years, but older strains of the same ribotype are susceptible to

fluoroquinolones. It is likely that increasing fluoroquinolone

usage is acting as a selective pressure, prompting the emergence

of this strain. Two other common strains in UK hospitals, PCR

ribotypes 001 and 006, have significantly greater resistance to

erythromycin, imipenem and levofloxacin 32. This resistance may

Figure 2. Sporulating C. difficile (courtesy of Professor S P Borriello).


In Focus

give them a selective advantage over other C. difficile strains, and

explain their high prevalence.

ConclusionsAt the time of writing, no epidemic strains of C. difficile have

been detected in Australia (Elliott B, Chang BJ, Riley TV;

unpublished observations), and we have found a low prevalence

(1–2%) of strains resistant to the newer fluoroquinolones in both

eastern and western Australia. These strains were collected over

the last two–three years. Similar low resistance levels have been

reported previously for a selection of strains collected during

the 1990s in Sydney 33, suggesting that there have been no

significant changes in susceptibility patterns during this period.

It remains to be seen whether this will continue. What is required

is continued monitoring of the situation, with periodic regular

testing of isolates for changes in susceptibility patterns, as well as

molecular typing to conclusively establish the presence of strains

with epidemic potential. This will require diagnostic laboratories

in Australia to make significant changes in their methods, as

many have moved away from culturing for C. difficile and are

using EIA kits in order to save money. In the interests of public

health, there is a case for spending comparatively small sums

of money now, on surveillance and preparedness, rather than

later (as has happened overseas) when patients and healthcare

systems have suffered.

References1. Riley TV. The epidemiology of Clostridium difficile-associated diarrhoea. Rev

Med Microbiol 1994; 5:117-22.

2. George WL, Sutter VL, Finegold SM. Antimicrobial agent-induced diarrhea – a bacterial disease. J Infect Dis 1977; 136:822-8.

3. Larson HE, Price AB, Honour P. Clostridium difficile and the aetiology of pseudomembranous colitis. Lancet 1978; 1:1063-6.

4. Kelly CP, LaMont JT. Clostridium difficile infection. Ann Rev Med 1998; 49:375-90.

5. Riley TV. Nosocomial diarrhoea due to Clostridium difficile. Curr Opinions Infect Dis 2004; 17:323-7.

6. Wilcox MH, Cunnliffe JG, Trundle C et al. Financial burden of hospital acquired Clostridium difficile infection. J Hosp Infect 1996; 34:23-30.

7. Loo VG, Poirier L, Miller MA et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Eng J Med 2005; 353:2442-9.

8. McEllistrem MC, Carman RJ, Gerding DN et al. A hospital outbreak of Clostridium difficile disease associated with isolates carrying binary toxin genes. Clin Infect Dis 2005; 40:265-72.

9. Kuijper Ed J, van den Berg RJ, Debast S et al. Clostridium difficile ribotype 027, toxinotype III, the Netherlands. Emerg Infect Dis 2006; 12:827-30.

10. Dial S, Delaney JAC, Barkun AN et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 2005; 94:2989-95.

11. Pepin J, Saheb N, Coulombe M-A et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005; 41:1254-60.

12. O’Neill G, Adams JE, Bowman RA et al. A molecular characterisation of Clostridium difficile isolates from humans, animals and their environments. Epidemiol Infect 1993; 111:257-64.

13. Songer GJ, Anderson MA. Clostridium difficile: an important pathogen of food

animals. Anaerobe 2006; 12:1-4.

14. Rodrigues-Palacios A, Stempfli H, Duffield T et al. Clostridium difficile PCR

ribotypes in calves, Canada. Emerg Infect Dis 2006; 12:1730-6.

15. Baverud V. Clostridium difficile infections in animals with special reference to

the horse. A review. Vet Q 2002; 24:203-219.

16. Rupnik M. Is Clostridium difficile-associated infection a potentially zoonotic

and foodbourne disease? Clin Microbiol Infect 2007; 13:457-9.

17. Barbut F, Deere D, Lalande V et al. Clinical features of Clostridium difficile-

associated diarrhoea due to binary toxin (actin-specific ADP-ribosyltransferase)-

producing strains. J Med Microbiol 2005; 54:181-5.

18. Geric B, Carman RJ, Rupnik M et al. Binary toxin-producing, large clostridal

toxin-negative Clostridium difficile strains are enterotoxic but do not cause

disease in hamsters. J Infect Dis 2006; 193:1143-50.

19. Gerding DN. Clindamycin, cephalosporins, fluoroquinolones, and Clostridium

difficile-associated diarrhea: this is an antimicrobial resistance problem. Clin

Infect Dis 2004; 38:646-8.

20. Spigaglia P, Mastrantonio P. Comparative analysis of Clostridium difficile

clinical isolates belonging to different genetic lineages and time periods. J Med

Microbiol 2004; 53:1129-36.

21. Pelaez T, Alcala L, Alonso R et al. Reassessment of Clostridium difficile

susceptibility to metronidazole and vancomycin. Antimicrob Agents Chemother

2002; 46:1647-50.

22. Bishara J, Bloch Y, Garty M et al. Antimicrobial resistance of Clostridium

difficile isolates in a tertiary medical center, Israel. Diagn Microbiol Infect Dis

2006; 54:141-4.

23. Land KM, Johnson PJ. Molecular basis of metronidazole resistance in pathogenic

bacteria and protozoa. Drug Resist Update 1999; 2:289-94.

24. Johnson S, Samore MH, Farrow KA et al. Epidemics of diarrhea caused by a

clindamycin-resistant strain of Clostridium difficile in four hospitals. N Engl J

Med 1999; 341:1645-51.

25. Pituch H, van Belkum A, van den Braak N et al. Recent emergence of an

epidemic clindamycin-resistant clone of Clostridium difficile among Polish

patients with C. difficile-associated diarrhea. J Clin Microbiol 2003; 41:4184-7.

26. Drummond LJ, McCoubrey J, Smith DG et al. Changes in sensitivity patterns

to selected antibiotics in Clostridium difficile in geriatric in-patients over an

18-month period. J Med Microbiol 2003; 52:259-63.

27. Pepin J, Saheb N, Coulombe M-A et al. Emergence of fluoroquinolones as the

predominant risk factor for Clostridium difficile-associated diarrhea: a cohort

study during an epidemic in Quebec. Clin Infect Dis 2005; 41:1254-60.

28. Gaynes R, Rimland D, Killum E et al. Outbreak of Clostridium difficile infection

in a long-term care facility: association with gatifloxacin use. Clin Infect Dis

2004; 38:640-5.

29. Ackermann G, Tang-Feldman YJ, Schaumann R et al. Antecedent use of

fluoroquinolones is associated with resistance to moxifloxacin in Clostridium

difficile. Clin Microbiol Infect 2003; 9:526-30.

30. Golledge CL, Carson CF, O’Neil GL et al. Ciprofloxacin and Clostridium

difficile-associated diarrhoea. J Antimicrob Chemother 1992; 30:141-8.

31. Dridi l, Tankovic J, Burghoffer B et al. gyrA and gyrB mutations are implicated

in cross-resistance to ciprofloxacin and moxifloxacin in Clostridium difficile.

Antimicrob Agents Chemother 2002; 46:3418-21.

32. John R, Brazier JS. Antimicrobial susceptibility of polymerase chain reaction

ribotypes of Clostridium difficile commonly isolated from symptomatic

hospital patients in the UK. J Hosp Infect 2005; 61:11-4.

33. Leroi MJ, Siarakas S, Gottleib T. E test susceptibility testing of nosocomial

Clostridium difficile isolates against metronidazole, vancomycin, fusidic acid

and the novel agents moxifloxacin, gatifloxacin, and linezolid. Eur J Clin

Microbiol Infect Dis 2002; 21:72-4.


In Focus

Australian Government attempts at regulatory and other control of antimicrobial resistance

John Turnidge

Division of Laboratory MedicineWomen’s and Children’s Hospital72 King William RoadNorth Adelaide SA 5006Tel: (08) 8161 6873Fax: (08) 8161 6189Email: [email protected]

Antimicrobial resistance has been on the government agenda in

Australia since the early 1980s. At that time the National Health

and Medical Research Council (NHMRC) established a working

party composed of human and veterinary microbiologists to

look at antibiotic use and, in particular, the risks of using them

in stockfeed 1. This action was taken in response to continuing

reports from overseas, particularly the United Kingdom, of

resistant and multi-resistant Salmonella species being selected

in food animals and spread to humans 2. The working party

report made a number of regulatory recommendations in

terms of resistance surveillance and scheduling. None of these

recommendations were adopted directly, but the national

regulators continued to call on NHMRC for advice and in various

guises the NHMRC maintained a working group on antibiotics

and resistance until 1997, when it was decided that antimicrobial

resistance was no longer a priority issue. As the regulators still

wished to receive advice, the Therapeutic Goods Administration

(TGA) took temporary responsibility for maintaining the expertise

or the working party.

Then in 1997, news emerged from Europe of an association

between the use of a particular stockfeed antimicrobial,

avoparcin, and vancomycin-resistant enterococci in humans.

This news made it to the media and questions were raised in

Canberra about its relevance to Australia, as avoparcin was widely

used in food animal production in Australia. This initiated the

establishment of the Joint Expert Technical Advisory Committee

on Antimicrobial Resistance (JETACAR) – a committee of medical,

scientific, veterinary and regulatory experts – to consider the

evidence for a link between antimicrobial use in food animals

and resistant bacteria threatening human health. In its report of

September 1999, JETACAR concluded that the evidence strongly

supported a link, but that this needed to be considered in the

context of all antimicrobial resistance issues 3 (Figure 1). It made

22 recommendations, designed to initiate an assault on resistance

generally, and focusing only initially on resistance coming through

the food chain. The Australian Government responded in August

2000, essentially agreeing to adopt all the recommendations; only

some of the recommendations have actually been implemented.

As part of the implementation of JETACAR recommendations,

two groups were established. The first was under the NHMRC as

the Expert Advisory Group on Antimicrobial Resistance (EAGAR).

The second was the Commonwealth interdepartmental JETACAR

Implementation Group (CIJIG).

Many of the subsequent achievements in terms of control of

antimicrobial resistance have been regulatory. They include:

Figure 1. The JETACAR Report.


In Focus

• Establishment of specific sections related to antimicrobial

resistance (resistance risk assessment) in the documentation

required to be submitted for the registration of new

antibacterials, or for the extension of indications for registered

antibacterials, by the TGA for human agents and by the

Australian Pesticides and Veterinary Medicines Authority

(APVMA) for veterinary agents.

• Reviewoftheschedulingofallantibacterials,withsubsequent

establishment of all antibacterials for human, veterinary and

agricultural use as ‘prescription’ only (S4), with the exception

of the stockfeed group of ionophores (which have no human

analogues).

• Requirement of government agencies to request advice

from EAGAR, among whose roles include the review of

the risk assessments and recommendations for registration

emanating from the TGA and APVMA, as well as providing

advice on the listing and level of access to new antibacterials

on the Pharmaceutical Benefits Scheme (PBS).

Together these three points have created a gatekeeper function

for the introduction and potential use of new antibacterials in

Australia. They have been quite successful so far in controlling

access to fluoroquinolones. Unlike almost all other countries,

fluoroquinolones have been prevented from being registered

for use in food producing animals in Australia, and access to

fluoroquinolones, both parenteral and oral, has been restricted

through the PBS. As a result, Australia has one of the lowest

rates of fluoroquinolone resistance in gram-negative bacteria of

anywhere in the world.

A considerable number of recommendations from JETACAR have

been addressed in part. In broad terms, a number of largely pre-

existing entities have been used to indicate that some parts of

some recommendations have been addressed. What currently

exists under the government umbrella (federal and state) is:

Resistance surveillance

• AustralianGrouponAntimicrobialResistance(AGAR;http://

www.antimicrobial-resistance.com). AGAR runs regular

point-prevalence studies of resistance in Staphylococcus

aureus, enteric gram-negatives, Streptococcus pneumoniae.

Enterococcus species and Haemophilus influenzae.

• NationalNeisseriaNetwork 4, including resistance surveillance

for Neisseria gonorrhoeae and meningitidis.

• PneumococcalWorkingPartyoftheCommunicableDiseases

Network Australia 5.

• The OzFoodNet (http://www.ozfoodnet.org.au), which

includes antimicrobial resistance as part of national salmonella

surveillance.

• State mycobacterial reference laboratories – work

cooperatively to provide ongoing surveillance of resistance

in Mycobacterium tuberculosis.

Antimicrobial usage surveillance

• The TGA collects volume data on annual imports of

antimicrobial for human and non-human purposes.

• The Drug Utilisation Subcommittee of the Pharmaceutical

Benefits Advisory Committee regularly monitors usage of

non-hospital agents.

• Anationalprogram,basedonaSouthAustraliansystem,of

monitoring antimicrobial use in Australian hospitals.

• A single pilot study on the prevalence of resistance in

indicator organisms from food animals.

Infection prevention strategies

• Efforts to establish a national program for infection and

multi-resistant organism (MRO) surveillance in hospitals have

waxed and waned over the years. The new federal Safety and

Quality Commission is re-considering this recommendation.

Victoria currently has the VICNIS surveillance program,

and South and Western Australia have MRO surveillance

programs

• The federal government continues to strongly support the

implementation of appropriate vaccines to the community.

• Producersintheintensivefoodanimalindustryarepromoting

the search for effective alternatives to antimicrobials.

Education

• The National Prescribing Service (NPS) (http://www.nps.

org.au/) is a federally funded organisation with the mission

to improve on the quality of medicine use in Australia. The

board of the NPS has been a strong supporter of rational

antimicrobial use and has funded and developed a range of

campaigns including annual ‘Common Colds Need Common

Sense’ public education campaigns, general practitioner

education and detailing programs, and a major study into the

management of community-acquired pneumonia in public

hospital emergency departments.

• The Therapeutic Guidelines – Antibiotic continues to be

developed and updated biennially. The organisation is


In Focus

independent of government, but has a long history in

setting the ‘standard of care’ for antimicrobial use in the

community and in hospitals. A similar product for the

veterinary profession was developed by the Postgraduate

Foundation in Veterinary Science of Sydney University. The

penetration and utility of this product is unclear, and the

current second edition is now somewhat dated.

• Attempts toencouragemedicalcolleges to includeprudent

use of antimicrobial education into their training programs

was unsuccessful. In contrast, the chicken and pork industries

have been proactive in developing prudent use guidelines for

their producers.

Research

• Individual applicants have received project grants from the

NHMRC over the years. There is not a specific program

focused on antimicrobial resistance.

• Anumberofveterinaryresearchorganisationshaveactively

promoted and funded research activities in the food producing

animal area.

Figure 2. The WHO Global Strategy.

Overall, the implementation of the JETACAR recommendations

has been patchy and uncoordinated. The implementation

committee (CIJIG) has effectively been disbanded. Nevertheless,

the challenge of controlling antimicrobial resistance need not

be a daunting one. The approach to control needs to be multi-

faceted, as no single strategy is known to be effective. So

many different professional groups have a stake in controlling

antimicrobial resistance, and coordination between the

professions is essential. Neither the bacteria nor their resistance

genes respect professional boundaries!

Blueprints for tackling resistance have been published by

many authorities. The JETACAR report is an early version.

More sophisticated versions exist, the most helpful being that

produced by the World Health Organisation (WHO) 5 (Figure

2). Other countries have started to build effective containment

programs, with Denmark and Sweden leading the way. The

federated nature of Australia has held back progress in the

development and implementation of a national, coordinated

and effective resistance containment system. The gains that have

been made are in jeopardy of dissipating as more ‘exciting’ public

health issues are emerging, and attention and resources are

channelled elsewhere. As microbiology professionals we all have

the obligation to convince our non-microbiological colleagues of

the importance of containing antibiotic resistance.

References1. National Health and Medical Research Council. Antibiotics in Stockfeed: report

of the NH&MRC Working Party on Antibiotics in Stockfeeds. June 1986.

2. UK Joint Committee of Houses of Parliament. Report on the Use of Antibiotics

in Animal Husbandry and Veterinary Medicine (‘Swann Report’). London:Her

Majesty’s Stationary Office, November 1969.

3. Joint Expert Technical Advisory Committee on Antimicrobial Resistance. The

Use of Antibiotics in food-producing animals: antibiotic resistant bacteria in

animals and humans. Commonwealth Department of Health and Aged Care;

Commonwealth department of Agriculture, Fisheries and Forestry. September,

1999. At: http://www.health.gov.au/internet/wcms/publishing.nsf/Content/

health-pubhlth-strateg-jetacar-index.htm. June 2007.

4. The National Neisseria Network. The National Neisseria Network 1979–200?

Commun Dis Intell 2000; 24:190-3.

5. Roche P, Krause V, Cook H et al. Invasive pneumococcal disease in Australia,

2005. Commun Dis Intell 2007; 31:96-100

6. World Health Organisation. WHO Global Strategy for the Containment of

Antimicrobial Resistance, WHO 2001.


In Focus

An ongoing national programme to reduce antibiotic prescription and use

Lynn M Weekes*, Judith M Mackson, Margaret A Artist and Sonia Wutzke

National Prescribing ServiceLevel 7, 418A Elizabeth StreetSurry Hills NSW 2010Tel: (02) 8217 8702Email: [email protected]

High levels of antibiotic use have been associated with higher

levels of antimicrobial resistance. The National Prescribing

Service (NPS) has been running national programs to reduce

prescription and use of antibiotics in Australia since 1999. These

programs have used a range of strategies to influence general

practitioners, community pharmacists and consumers. Over

time, there have been modest changes in consumer attitudes

towards antibiotics and antibiotic prescription rates continue to

decline.

The NPS was a newly established organisation in 1999 when the

JETACAR report was released and noted that unnecessary use of

antibiotics exposes the community to unwarranted medication

use and contributes to the development of antimicrobial

resistance 1. Reducing the prescription and use of antibiotics in

the Australian community was one of the NPS early program

objectives for quality use of medicines and it remains a major

priority today.

Many factors contribute to the unnecessary use of antibiotics

including the knowledge and beliefs of doctors and consumers,

direct patient requests, perceptions of patient demand, culture

and norms and the health setting 2,3. Perceived patient pressure

is a strong predictor of the decision to prescribe antibiotics in

general practice 4,5. It has been suggested that while doctors

feel uncomfortable prescribing antibiotics, they do not want to

damage the therapeutic relationship with the patient or they

may not have the time required to explain their decision 6.

Perceived patient pressure often stems from common beliefs in

the community that antibiotics hasten recovery from respiratory

infections and prevent more serious disease 7.

Against this background, the NPS began a multifaceted program

to reduce antibiotic use with a particular emphasis on respiratory

infections. The intensity of the program has varied from year

to year but generally there have been both consumer and

health professional arms to the program (Table 1). The tag line

‘common colds need common sense’ has been used for the

consumer campaigns 8 and fairly consistent messages have been

provided to health professionals and consumers (Table 2).

Omnibus data show modest changes in consumer knowledge

and attitudes to use of antibiotics for coughs and colds (Table

3) as well as changes in the self-reported use of antibiotics.

Comparison of successive yearly consumer surveys shows a

significant decrease from 10.8% in 1999 to 7.4% in 2004, in the

self-reported use of antibiotics to treat cold, cough or flu.

Drug utilisation data show a continuing decline in antibiotic

use in Australia: from about 25 defined daily doses? (DDD) per

1000 population per day in 1996 to 21.5 DDD/1000/day in 2006.

There is a parallel decline in use of the nine antibiotics most

commonly used for respiratory infections (Figure 1). Similarly,

doctors are less likely to write a prescription for antibiotic for

upper respiratory tract infection presentation, with the incidence

falling from 51.1% in 1999 to 50. 5% in 2005, with a low of 49.6%

in 2002 9.

The NPS antibiotic program is typical of many around the world

that take a regional or national approach to controlling use and

minimising resistance 10,11. These have been prevalent in both

high and low income countries and while a range of different

interventions has been used there is much consistency. Studies

in the United States, using materials from the Centre for Disease

Control and Prevention targetted parents and family physicians,

and demonstrated a significant increase in the knowledge of

parents that antibiotics are not needed for colds 12. A UK study

in the first winter of the campaign on antibiotic treatment in

primary care and national advice to the public 11 reported a


In Focus

Health professionals Consumers

1999 Prescribing feedback with written educational materials for GPs, newsletter, academic detailing, clinical audit, patient educational material (non-prescription for symptomatic management).

2000 Prescribing feedback with written educational materials for Editorial in general media. GPs, newsletter, academic detailing, clinical audit, case studies for individuals, patient educational material (non- prescription for symptomatic management), letter to pharmacists, case study for pharmacists.

2001 Prescribing feedback with written educational materials for Billboard advertising; small amount of TV GPs, newsletter, academic detailing, clinical audit, case and radio advertising; editorial in general studies for individuals and small group meetings, patient media; community grants programme to educational material (non-prescription for symptomatic encourage local action, website; pamphlets, management), letter to pharmacists, case study for stickers for children. pharmacists.

2002 Prescribing feedback with written educational materials for Billboard advertising; small amount of TV GPs, newsletter, academic detailing, clinical audit, case and radio advertising; editorial in general studies for individuals and small group meetings, patient media; community grants programme to educational material (non-prescription for symptomatic encourage local action; website; pamphlets; management), letter to pharmacists, case study for stickers for children. pharmacists.

2003 As for 2002. Radio advertising; editorial in general media; website; pamphlets; stickers for children.

2004 As for 2002. Billboard advertising; small amount of TV and radio advertising; editorial in general media; community grants programme to encourage local action; website; pamphlets; stickers for children.

2005 Case study for individuals only. Children’s story book; website; pamphlets; stickers for children; posters; newsletter articles for childcare centres; child care staff education.

2006 Clinical audit, case study, prescribing feedback with written Radio advertising; a second children’s educational materials for GPs, newsletter, pharmacist letter. story book; website; pamphlets; stickers

for children; posters; newsletter articles for childcare centres; editorial for general media; direct mail to child care centres, schools, community centres and libraries; child care staff education.

2007 Prescribing feedback with written educational materials for Television advertising; website; pamphlets; GPs, newsletter, academic detailing, clinical audit, case stickers for children’s services and schools on studies for individuals and small group meetings, patient hygiene; colouring-in sheets; posters; story educational material (non-prescription for symptomatic books; newsletter articles for schools and management), letter to pharmacists, case study for pharmacists. childcare centres; editorial in general media;

direct mail to schools; childcare centres; community centres and libraries; primary school writing competition; primary school and childcare staff education programme; workforce strategy with large recruitment company.

Table 1. Activities offered for NPS antibiotics program each year.


In Focus

Health professionals Consumers

• Mostupperrespiratorytractinfectionsdonotrequirean • Antibioticswon’thelpacommoncold. antibiotic.

• Whenanantibioticisneeded,firstlineagentsshouldbe • Youwon’tgetbettermorequicklybytakingantibiotics prescribed: amoxycillin for sinusitis and otitis media or for a common cold. penicillin V for sore throat.

• Secondlineagentssuchasroxithromycinandamoxycillin/ • Thecommoncoldisavirusandantibioticsdon’thelp clavulanate should be restricted to patients who have failed – instead of using antibiotics for a common cold, use first line therapy. common sense.

• Cefaclorhasaverylimitedroleintreatmentofrespiratory • Youneedtotakeiteasy.Youneedtorelievethesymptoms. infections. You need to see a doctor if it gets worse.

• Reviewyourprescribinganddiscussrealisticexpectations • Visityourdoctororpharmacistformoreinformationorif with patients. symptoms persist.

Table 2. Some of the key messages supported by the NPS antibiotics program

Actions taken 1999 2000 2001 2003 2004 % % (change)* % (change)* % (change)* % (change)*

Took non-prescription medicine 67.5 68.9 (↑ 1.4) 69.4 (↑ 1.9) 70.5 (↑ 3.0) 70.1 (↑ 2.6)

Rested at home 56.8 54.4 (↓ 2.4) 53.7 (↓ 3.1) 60.7 (↑ 3.9) 57.5 (↑ 0.7)

Asked pharmacist for advice 20.2 20.6 (↑ 0.4) 21.9 (↑ 1.7) 22.4 (↑ 2.0) 22.4 (↑ 2.2)

Visited a doctor 23.3 21.8 (↓ 1.5) 19.3 (↓ 4.0) 20.3 (↓ 3.0) 18.0 (↓ 5.3)**

Took antibiotics 10.8 10.0 (↓ 0.8) 10.1 (↓ 0.7) 9.8 (↓ 1.0) 7.4 (↓ 3.4)**

Table 3. Percentage of respondents to a community survey reporting the actions they took for their most recent cough, cold or flu.

Source: National annual consumer survey data* Percentage point change relative to 1999** Statistically significant change at p<0.05 level.

Figure 1 Antibiotic prescription in Australia 1995–2006: all antimicrobials as defined by Anatomical Classification Code J01 and a subset of nine antibiotics commonly used for respiratory infections

Source: Drug Utilisation Subcommittee of Pharmaceutical Benefits Advisory Committee 2007


In Focus

Carrick Citation for two ASM members

reduction in prescribing rates and positive changes in attitudes

in the community.

As well as multifaceted programs, individual strategies have been

used in many studies. Delayed prescriptions, patient information

leaflets and ‘non-prescriptions’ that prescribe symptomatic

management have all been used and elements of these are

incorporated into the NPS program.

Programs to reduce antibiotic use remain important. Australia

still has a relatively high rate of antibiotic use in ambulatory

care at 21 DDD/1000/day compared with the lowest rates in

Europe, which are found in the Netherlands at 10.0 DDD/1000/

day. Moreover, a correlation has been demonstrated between

community use of antibiotics and antibacterial resistance rates.

Goossens et al 13 showed higher rates of antibiotic resistance in

high consuming countries in eastern and southern Europe than

in northern Europe where usage trends are lower. In Australia we

have been recently reminded of the increase in the prevalence of

community acquired methicillin-resistant Staphylococcus aureus

isolates from 4.7% in 2000 to 7.3% in 2004 14.

The NPS antibiotic program continues to be an important part

of Australia’s quality use of medicines strategy. Significant gains

have been made in recent years but antibiotic usage rates are still

well above world’s best practice and there is a continued need

to work in this area.

References1. JETACAR. The use of antibiotics in food producing animals and humans:

antibiotic resistant bacteria in animals and humans. Commonwealth Department of Health and Aged Care, Commonwealth Department of Agriculture, Fisheries and Forestry. 1999 Canberra.

2. Belongia EA, Schwartz B. Strategies for promoting judicious use of antibiotics by doctors and patients. Br Med J 1998; 317:668-71.

3. Radyowijati A, Haak H. Improving antibiotic use in low income countries: an overview of evidence on determinants. Soc Sci Med 2003; 57:733-44

4. Britten N, Ukoumunne O. The influence of patient’s hopes of receiving a prescription on doctors’ perceptions and the decision to prescribe: a questionnaire survey. Br Med J 1997; 315:1506-10.

5. Cockburn J, Pitt S. Prescribing behaviour in clinical practice: patients’ expectations and doctors’ perceptions of patients’ expectations- a questionnaire study. Br Med J 1997; 315:520-23.

6. Davey P, Pagliari C, Hayes A. The patient’s role in the spread and control of bacterial resistance to antibiotics. Clin Microbiol Infect 2002; 8(suppl):43-68.

7. Vanden Eng J, Marcus R, Hadler JL et al. Consumer attitudes and use of antibiotics. Emerging Infect Dis 2003; 9:1128-35.

8. Wutzke SE, Artist MA, Kehoe LA et al. Evaluation of a national programmeme to reduce inappropriate use of antibiotics for upper respiratory tract infections: effects on consumer awareness, beliefs, attitudes and behaviour in Australia. Health Promot Internat 2006; 22:53-62.

9. BEACH Data supplied to NPS by BEACH (Bettering the Evaluation and Care of Health) General Practice Statistics and Classification Unit, 2003, University of Sydney.

10. Finch RG, Metlay JP, Davey PG et al. Educational interventions to improve antibiotic use in the community: report from the International Forum on Antibiotic Resistance colloquium. Lancet Infect Dis 2002; 4:44-53.

11. Parsons S, Morrow S, Underwood M. Did local enhancement of a national campaign to reduce high antibiotic prescribing affect public attitudes and prescribing rates? Eur J Gen Pract 2004; 10:18-23.

12. Trepka MJ, Belongia EA, Chyou PH et al. The effect of a community intervention on parental knowledge and awareness of antibiotic resistance and appropriate antibiotic use in children. Pediatrics 2001; 107:10.1542/peds.107.1.e6.

13. Goossens H, Ferech M, Vander Stichele R et al, ESAC Project Group. Outpatient antibiotic use in Europe and association with resistance: a cross-national study. Lancet 2005; 365:579-87.

14. Nimmo GR, Coombs GW, Pearson JC et al. Methicillin-resistant Staphylococcus aureau in the Australian community: an evolving epidemic. Med J Aust 2006; 184:384-8.

Chris Burke receiving the Carrick Citations from Professor John Hay

ASM Affairs


ASM Affairs

Cheryl Power (University of Melbourne) and Chris Burke

(University of Tasmania) were recently awarded Carrick Citations

for Outstanding Contributions to Student Learning. The citations

are awarded annually by the Carrick Institute and recognise all

aspects of teaching in higher education. Each award provides a

grant of $10,000 to the recipient to further develop their teaching

and learning programmes. Cheryl and Chris were presented

with their awards by Professor John Hay, Vice Chancellor of

the University of Queensland, at a very pleasant ceremony in

Melbourne on 8 August 2007. No other discipline received

two specific mentions and no other professional society was

mentioned; this was commented on later, with someone asking if

it was contagious! The Australian Society for Microbiology (ASM)

has long shown considerable support for education through

awards and by sponsoring microbiology educationalists to the

national scientific meetings. It would be an excellent outcome if

these citations were to act as a stimulus for further development

of microbiology education in Australia. The nucleus is there

through the active Education Special Interest Group (SIG), which

has consistently organised workshops for the advancement of

teaching and learning in microbiology.

Cheryl’s citation was for exceptional dedication and leadership

in the development of learning and teaching in microbiology,

particularly through the ASM Education SIG.

Cheryl’s mission for nearly fifteen years has been to involve all

members in educational issues and to provide opportunities,

particularly at the annual scientific meetings, for educators

to develop friendships and discuss and exchange ideas and

resources. She warmly acknowledges the support of the ASM,

which has always recognised and valued the importance of

teaching and learning and, in a very practical way, encouraged

and promoted a large number of educational activities.

Chris’s citation was for sustained enthusiasm and commitment

to student-centred learning of the scientific method in order

to achieve positive learning outcomes in undergraduate

microbiology.

Chris has long been interested in promoting scientific thinking in

students. He is involving aspects of enquiry-based learning into

microbiology education so that students can learn how to think

as scientists within the discipline of microbiology. He expanded

upon this in an opinion piece in Microbiology Australia 1.

There are many other excellent teachers in the ASM and most

certainly there will be other Carrick awards for microbiology

educators in future years. We urge all members involved in higher

education to consider applying for a Carrick Award. Details for all

the Carrick Awards can be found at http://www.carrickinstitute.

edu.au/carrick/go/home/awards.

In a similar vein, remember that the ASM annually provides the

David White Teaching Award and the Teachers Travel Award to

cover expenses to attend the annual scientific meeting! Anyone

of these awards would make a fine addition to your curriculum

vitae! For those wishing to improve their understanding of how

to develop their teaching rationally to further improve student

learning, Spencer Benson describes the American Society for

Microbiology Scholars-in-Residence programme elsewhere in

this edition of Microbiology Australia.

References1. Burk, C. Should it be microbiology or should it be science? Microbiology

Australia 2007; 28(3):133-4.

Professor John Hay and Cheryl Power with her Carrick Citation.


ASM Affairs

At the 2007 Australian Society for Microbiology meeting I had

the pleasure of meeting and working with numerous members

who were deeply committed to improving student learning

in microbiology. Through formal and informal conversations I

learned that in Australia, teaching has always been an important

component of microbiology. In Australia, the United States and

Europe there is growing awareness and concern about science

education and whether we are meeting the needs of our students

and disciplines, as we journey further into this new century.

To a large measure science teaching remains very much the

same as it did fifty years ago. Faculty primarily use didactic

lectures that are focused on content coverage, disconnected

from research and inquiry, and have little direct impact on

EDSIGMeeting the needs of microbiology education in 2010:become a scholarly teacher

Spencer Benson

University of Maryland [email protected]

enduring understanding. Many microbiology faculty are deeply

interested in and committed to improving their teaching and

student learning, but they tend to make changes in an anecdotal

fashion, without awareness or reference to what is known about

how people learn, what works in increasing student learning, or

how to adequately assess if a given pedagogy change improves

student learning. Consequently, these dedicated, committed,

well-meaning faculty tend to re-invent pedagogical approaches,

perpetuate ineffective teaching and learning practices, and fail

to move science education forward in a timely, effective or far-

reaching fashion. Equally damning is that these faculty fail to

make public the fruits of their work so that others within the

disciple can build upon it.

To address the need to improve microbiology education, in

2005 the American Society for Microbiology launched its ‘ASM

Scholars-in-Residence’ (ASMSiR). ASMSiR provides opportunities

and mechanisms for faculty to:

• Betterunderstandwhatisknownaboutstudentlearning.

• Developandresearchtestablequestionsregardingteaching

and student learning.

• Participate in a community of practice dedicated to

microbiology education.

• Increase dissemination of new microbiology education

knowledge through various publication venues.

ASMSiR is a stunning success, with more than forty faculty (both

US and international) actively engaged in improving microbiology

education through individual scholarship in teaching and

learning. ASMSiR serves as a national/international model for

an effective approach to educational reform in the sciences,

fostering scholarship in teaching and learning, professional

responsibility of faculty to evaluate their own teaching practices,

and public sharing of their work within the microbiology, science

and education communities.

Through continued support of the American Society

for Microbiology and a grant from the US National Science

Foundation, ASMSiR will continue through to 2010. Australian

microbiologists/biologists are encouraged to apply to be ASMSiR

Fellows and join a growing community of dynamic like-minded

faculty, from various institutions and microbiology disciplines,

who are reshaping undergraduate science education.

Information on ASMSiR is available at http://www.asmcue.org/

index.asp?bid=2332 or by contacting the American Society for

Microbiology. Applications for the 2008 ASMSiR cohort will be

due in early 2008.


ASM Affairs

John Merlino

Convenor/Chair Antimicrobial SIGEmail: [email protected]

Under the leadership of President-Elect Prof Lyn Gilbert, the

National Council of the The Australian Society for Microbiology

(ASM) decided that a clear need existed for a methodology,

science-driven, multidiscipline based antimicrobial special

interest group (SIG) under the ASM umbrella. In 2003, the ASM

Antimicrobial Special Interest Group (ASIG) was reformed (see

logo Figure 1) to provide active exchange of information to those

within the ASM interested in antimicrobials; I was appointed

national convenor and elected chair. Since then the response

and support from ASM membership has been overwhelming and

quite remarkable, with over 700 members both nationally and

internationally joining the group. ASIG is the largest SIG within

the ASM and is very active with other SIGs and other national

health related and international antimicrobial groups.

The objectives and aims of the ASIG are to:

• FostertheassociationwiththeASMofpersonsinterestedin

antimicrobials.

• EstablishcloselinksbetweenASMmemberswhomayalsobe

part of other antimicrobial groups.

• Promote investigations, methodologies and advance up-

to-date knowledge on antimicrobial issues by facilitating

communication and discussion nationally and internationally

with other antimicrobial societies and ASM members.

• Assist in organising effective annual scientific meetings

incorporating up-to-date antimicrobial issues so that ASM

members can interact, participate or discuss relevant issues.

A major aim of the ASM ASIG is to review drafted and released

policies (National Pathology Accreditation Advisory Council

[NPAAC], NATA etc), articles and issues on antimicrobial resistance

with our members online or at meetings, while promoting the

science of microbiology together with the codes of practice for

microbiologists. Issues discussed have set the scene for several

symposia and very successful attended workshops at Annual

National Scientific Meetings held by the ASB (Table 1). ASIG also

The Antimicrobial Special Interest Group of The Australian Society for Microbiology

provides ASM members with links and up-to-date information on

current local and international issues on antimicrobial resistance

from various groups, hopefully with regional, national and global

rewards.

In response to ASIG members for up-to-date information on

antimicrobial resistance testing, on behalf of ASIG a handbook

Antimicrobial Susceptibility Testing: Methods and Practices with

an Australian Perspective was published in 20041 (Figure 2).

This was supported by the ASM New South Wales Branch (mainly

through the efforts of Steven Siarakas and Tom Olma) and the

National Standing Clinical Committee. The handbook focuses on

standardised methods and some that are not standardised but are

useful for detecting antimicrobial resistance during susceptibility

testing by the bench microbiologist. Authors of each section

went to great lengths in providing updated information on such

testing; such information was never previously included in issues

of antimicrobial updates. The handbook covers specialised

areas of bacterial resistance, antiviral drug resistance, antifungal

and resistance to parasites. Areas of veterinary testing and new

methods and developments in antimicrobial combination testing

for cystic fibrosis were also included. This ASM ASIG handbook

was very well received by many practicing microbiologists

and teaching groups in Australia and overseas. Susceptibility

testing to detect antimicrobial resistance in microbiology is a

challenging, continuing educational science and the handbook

is currently undergoing revision, with an updated edition due in

the near future.

Through the generosity of industry The bioMérieux ASM

Identifying Resistance Award was also established. This is a

recognition award to an individual on the basis of career

achievements in the field of the identification of bacterial

resistance to antimicrobials in a clinical setting. The award

committee (ASM president, ASIG chair and ASIG committee

member) takes into account the quality and originality of the

published research and service to Australasian microbiology in

general. The award is based on the entire career of the recipient,

rather than on a single achievement. Five awards have been

made by ASM to outstanding ASIG members, since the award was

established in 2003 (Table 2).


ASM Affairs

ASIG is part of the ASM. I would encourage any microbiologist

with an interest in antimicrobials to join ASM and be a part of the

excitement that is microbiology, sharing in the many benefits that

ASM membership provides – including free membership in ASIG.

Newsletters are available by email to registered members or

affiliates of ASIG and information is posted on the website (www.

theasm.com.au/asig). The continued success of the reformed

ASM ASIG will involve members and other SIGs of the ASM

working together to find more effective ways to educate,

Year Award Recipient Recognition

2003 Ruth Hall With Hatch Stokes first described the basis of an integron in gene

cassettes and increased our awareness of its molecular implication in

Gram-negative antimicrobial resistance. Researcher and educator.

2004 Jan Bell Contributions to national and international surveys and groups on

antimicrobial resistances.

2005 Clarence Fernandes Contributions to national surveys. Educator.

2006 Sydney Bell The establishment and developments of antibiotic susceptibility testing

by the CDS method in Australia.

2007 Jon Iredell Contributions of molecular methods of detecting β-lactamases and

spread of metallo-β-lactamses in Gram-negative bacteria. Researcher and

educator.

Table 2. Past recipients of the The bioMérieux ASM Identifying Resistance Award

Year Annual ASM Scientific Meeting Themes/Issues Discussed

2003 New Zealand Antimicrobial Resistance: Problems and Issues for Discussion

– Medical & Veterinary Testing

2004 Sydney Antimicrobial Resistance and Mechanisms of Resistance A

Practical Approach in Detecting Bacterial Resistance

2005 Canberra Resistance markers, Nucleic Acid Technology, Bacterial

Population Analysis and Applications for the routine

Laboratories in Detecting Resistance. What does the future hold

in detecting and screening for resistance for our laboratories?

2006 Queensland Laboratory Detection Update of Multi-Resistant Organisms

2007 Adelaide Susceptibility Testing & Emerging Resistance Seen in Unusual

Organisms

Table 1. Issues on antimicrobial resistances discussed by the Antimicrobial Special Interest Groups at Annual ASM Scientific Meetings.

communicate and resolve antimicrobial resistance problems

with other professional groups, policy makers and the general

public.

References1. Merlino J, Barton MD, Bell SM, Gatus Bj, Pham JN, Rafferty DL, Benn RA, Ellis

D, Handke R, Harbour C, Hill D, Rose B, Ferris W, Aaron S, Iredell J, Thomas L, Valenzuela J, Limb R, Pitman C, Dwyer DE, Sheorey H, Tapsal J & Members of the National Neisseria Network of Australia and Tristram S. Antimicrobial Susceptibility Testing: Methods and Practices with an Australian Perspective 2004. Australian Society for Microbiology. Snap Printing, Sydney, Australia.


ASM Affairs

Figure 2. The handbook, titled Antimicrobial Susceptibility Testing: Methods and Practices with an Australian Perspective, published in 2004 on behalf of the ASM ASIG.

Figure 1. Official national ASM ASIG Logo for the reformed ASIG.

Antimicrobial Special Interest Group (ASIG)The Australian Society for Microbiology

National Branch

NATIONAL SCIENTIFIC ADVISORY COMMITTEE

DIVISIONAL CHAIRS 2010

CALL FOR EXPRESSIONS OF INTEREST

Expressions of interest are requested for the following positions on the National Scientific Advisory

Committee (NSAC)

Division 1 Chair (2010) Medical and Veterinary Microbiology

Division 2 Chair (2010) Virology

Division 3 Chair (2010) General, Applied and Environmental Microbiology

Division 4 Chair (2010) Microbial Genetics, Physiology and Pathogenesis

The successful appointees will serve a three-year term of office, concluding at the end of the ASM

2010 Annual Scientific Meeting, to be held in Sydney. It is envisaged that the divisional representatives

will be researchers and scientists with enthusiasm, good organisational and communication skills, broad knowledge and an excellent or developing reputation

in the divisional field.

The primary responsibilities of the Division Chairs will be to:

• OrganisethesymposiumcomponentoftheASM2010 Sydney Annual Scientific Meeting.

• ProvideinputandadvicetotheorganisersoftheASM 2010 Sydney Annual Scientific Meeting.

• Providescientificadvicetothesocietyasamember of NSAC.

ASM fellows, members, senior associate or associate members interested in serving in these exciting and challenging new honorary positions should submit a brief CV (no more than two pages), together with an appropriate covering letter to, Assoc Prof Liz Harry,

(Vice-President, Scientific Affairs) at the national office, by email to:

[email protected] Closing date: 21 December 2007.

Antibiotic Susceptibility Testing by the CDS Method: A Manual for Medical and Veterinary Laboratories. 4th Edition 2006 by the CDS Users Group

As the national chair and convenor of the Australian Society for Microbiology (ASM) Antimicrobial Special Interest Group (ASIG), I would like to congratulate the CDS Users Group coordinators on the release of the 4th Edition of this manual.

Susceptibility testing in microbiology is a challenging, continuing, educational science and this new edition will provide valuable up-to-date information for many bench microbiologists who are contemplating the use of the CDS method and susceptibility disc testing in general.

On close inspection the 4th Edition has been broadened and closely revised to include several new techniques and interpretations for more bacterial species, anaerobic bacteria and yeasts. To my knowledge, the guide for the estimation of the measure of uncertainty for antimicrobial discs susceptibility is the first publicised in Australia by Australians, and will provide valuable information for many microbiologists and regulatory bodies in quality assurance.


Book Reviews

The ASM ASIG congratulates and acknowledges the valuable contribution and efforts made by its members and many others to update this valuable 4th Edition and hopes that the method continues to gain recognition nationally and internationally.

Antimicrobial resistance is an issue of great significance for public health at local, national and global level. This new 4th edition of the CDS manual provides a valuable contribution to the Australian antimicrobial literature and ASM is proud to be associated with its release.

In September 2007 an online version of the 4th Edition was published on the updated CDS website, which has moved to http://web.med.unsw.edu.au/cdstest/. The on-line version has been completely reformatted to be user-friendly and can be searched by using the site-based Google search engine. Also the CDS website has been designed to include a confidential database that will be used to collect and store data on antibiotic resistance that is determined by a single uniform method of susceptibility testing.

John Merlino National Chair and Convenor Antimicrobial SIGAustralian Society for Microbiology

Prof Sydney Bell with Dr J Pham and J Cheng at the launch of the CDS users 4th Edition Manual.

Consultation, Conflict, Cooperation and Controversy: A history of the establishment of the CSIRO’s Australian Animal Health Laboratory by Bill Snowdon

The establishment of the CSIRO Australian Animal Health Laboratory (AAHL) has a long history; that Australia needed a high security laboratory was first suggested in 1962, but it took years of discussion and debate, sometimes with conflicting argument, before the need for and functions of the laboratory were determined. Then, it was not until 1974 that the Federal Government decided that the laboratory should be built. Construction was delayed, but commenced in 1978 and three years later, in 1981, controversy erupted over the laboratory’s need to import exotic disease viruses, in particular the foot and mouth disease virus. The laboratory was officially opened in 1985.

This book covers the period leading up to the decision to build the laboratory, the feasibility study that ensued, the government decision making, the site selection, the design and construction, and the management and operation for the first four years. The controversy and its consequences are covered in detail as are the roles of the various participants including Australian and overseas scientists, scientific organisations, government officials, livestock industry organisations, politicians and the media.

The final chapter is a personal one, as it represents the author’s own perspectives on the events and the people who were directly involved.

Enquiries about purchasing the book should be addressed to the author/publisher Bill Snowdon by post to 2/1 Frank Street, Newtown, Victoria 3220 Australia, by email to [email protected], or by telephone 61 3 5221 6389; or the Australian Animal Health Laboratory; telephone 61 3 5227 5000 or fax 61 3 5227 5555.


ASM Affairs

2008 ASM Frank Fenner AwardNominations for the 2008 ASM Frank Fenner Award are invited

from associate members, senior associate members, members

and fellows of The ASM of at least three years standing at the

time of application.

Such members must have been engaged in research for no more

than 15 years since acquiring their doctorate, although allowance

is made when there has been significant career interruption.

The purpose of the Frank Fenner Award is to recognise

distinguished contributions to Australian research in microbiology

by scientists in a formative stage of their career, rather than

senior scientists for a lifetime of achievement. Applicants need to

show that their research was work done substantially in Australia

or, for those recently returned from overseas, is work ongoing in

Australia that will enhance Australia’s national and international

reputation in microbiology.

The award, which consists of a bronze plaque, plus AU$1,000 will

be given at the ASM Awards Ceremony at the ASM 2009 Perth

Conference. The recipient is required to present the Fenner

Plenary Presentation at the ASM 2009 Perth Annual Scientific

Meeting (6-10 July 2009) – to facilitate this, the recipient will

be entitled to complimentary full conference registration, daily

lunches, return economy flights within Australia and up to six

nights conference accommodation.

Applicants must submit a 50-word summary of their CV along

with their application by email or mail to the ASM national office.

Closing date for applications: 31 March 2008.

ASM Research Trust FellowshipIn awarding the ASM Research Trust Fellowship, the ASM aims to

promote excellence in microbiology through support to younger

microbiologists for specified research projects leading to career

advancement; or to Australian microbiologists returning from

overseas studies to assist them to re-establish their careers in

Australia.

The purpose of the ASM Research Trust Fellowship is to do either

or both of the following:

• Fund an individual to undertake scientific research in

microbiology and related fields in Australia.

• Fundanindividualemployedbyanotherbodytoundertake

scientific research in those areas that may prove to be of

value to Australia.

The ASM Research Trust Fellowship comprises any amount up to

a maximum $7,500.

Closing date for applications: 31 March 2008.

David White Excellence in Teaching AwardNominations are invited for the David White Excellence in Teaching Award from MASM members of the ASM of at least five years standing, to recognise excellence in the teaching and/or innovation in the teaching of microbiology in Australia.

The David White Excellence in Teaching Award, comprising a plaque and $1,000, will be presented at the ASM 2008 Annual Scientific Meeting and the recipient will be invited to conduct at the same meeting a workshop on aspects of teaching microbiology.

Closing date for nominations: 31 March 2008.

ASM Foundation Travel GrantThe ASM Foundation Travel Grant sponsors Australian microbiologists, especially those in the formative stages of their careers, to undertake professional development in appropriate laboratories in Australia or New Zealand.

The ASM Foundation Travel Grant provides funding to assist with:

• ShortpostgraduaterefreshercoursesinAustraliaonaspectsof microbiology.

• VisitsbyinternationalorAustralianspecialistmicrobiologiststo or within Australia for specific purposes that would benefit many members of the ASM.

• VisitsbyAustralianspecialistmicrobiologiststointernationalsymposia or advances courses, with the prime object that the knowledge gained will be disseminated to other Australian microbiologists upon return of the specialist.

• Overseas visits by Australian specialist microbiologists on‘lecture exchange programs’ with other learned societies.

• ASMscholarshipforpostgraduatetrainingofmembers.

• Other purposes recommended by the ASM FoundationCommittee and deemed by the ASM National Council to be consistent with the aims of the ASM Foundation Committee.

The ASM Foundation Travel Grant usually comprises any amount to a maximum $2,000. Applicants who have secured significant funding (50%) from other sources will be assessed more favourably.

Biannual closing dates for applications are:

31 January 2008

31 July 2008

Nominations are invited for the following awards and prizes. For further information, go to the ASM website at www.theasm.com.au or contact Michelle Jackson at the national office on 03 9867 8699 or email [email protected]


ASM Affairs

ASM Distinguished Service AwardThe ASM Dinstinguished Service Award facilitates the recognition of outstanding service or contribution to the ASM by individuals or organisations.

Individuals or organisations deemed worthy of recognition for distinguished service to the ASM may be nominated, in writing and in confidence, by individual ASM members or branches and addressed to the ASM president or national office.

Nominations should include a summary of the contribution made by the nominated individual or organisation to the ASM.

Closing date for nominations: 31 March 2008.

ASM Teachers Travel AwardThe ASM Teachers Travel Award is intended to encourage ASM members involved in teaching microbiology at the tertiary level, to attend the ASM 2008 Annual Scientific Meeting. Applicants may be employed on a full-time, part-time or sessional basis.

To apply for the ASM Teachers Travel Award, applicants must submit their CV and should include a description of their current employment, a letter of recommendation from their head of department or equivalent confirming the involvement of the applicant in and commitment to a teaching program within the department, and a brief synopsis of the applicant’s area of special interest in education.

The brief synopsis of the applicant’s area of special interest in education will provide the basis for a presentation by the successful applicant of a poster or participation in a session organised by the Education Special Interest Group at the ASM 2008 Annual Scientific Meeting.

The ASM Teachers Travel Award comprises a framed certificate and up to a maximum $1,000 in travel expenses for the recipient to attend The ASM 2008 Annual Scientific Meeting.

Closing date for Applications: 31 March 2008.

Vic Skerman Student PrizeThe Vic Skerman Student Prize is awarded annually to a student member of the ASM who, whilst enrolled as a student member, has contributed the best review article to Microbiology Australia for the period 1 July – 30 June. A 50-word summary of the applicant’s CV must be submitted with their application.

The Vic Skerman Student Prize comprises a framed certificate and $500, and is presented at the ASM 2008 Annual Scientific Meeting.

Closing date for applications: 31 March 2008

ASM BD Student Awards

The BD Awards are intended to partly offset travel and accommodation expenses for one student member from each

of the seven ASM state brances – VIC, NSW, QLD, SA/NT, WA, ACT, TAS – to attend the ASM 2008 Annual Scientific Meeting.

Each BD Award comprises the cost of a return economy airfare, conference registration, and an allowance for accommodation.

All postgraduate microbiology students who have submitted or are intending to submit an abstract for the ASM 2008 Annual Scientific Meeting are invited to apply, especially those in the final year of their higher degree program. If not currently a student member of the ASM, applicants must be eligible for membership and must pay for such at the time of their application for the award.

Finalists for the BD Awards will be selected on the basis of their abstract and a presentation summary, which should be submitted to their ASM state branch for consideration.

BD Award recipients must then present their paper as an oralk presentation at the BD Student Awards Plenary session at the ASM 2008 Melbourne Annual Scientific Meeting.

Previous BD Award recipients are not eligible to re-apply. Contact your local ASM state branch for further details.

Please check the closing date with your local state branch

(Note: state branches must notify ASM of their recipient

by 31 March 2008).

bioMerieux ASM Identifying Resistance AwardThe bioMerieux ASM Identifying Resistance Award is intended to recognise individual career achievement in the field of identifying bacterial resistance to antimicrobials in a medical setting. The applicant must be a financial member of the ASM.

The applicant must submit a CV that includes a list of publications

and the names, addresses and email addresses of two referees,

together with a brief summary of the applicant’s contribution to

the study of bacterial resistance to antimicrobials in a medical

setting.

The bioMerieux ASM Identifying Resistance Award comprises

a framed certificate, a $1,000 cash prize, and the provision of

flights and accommodation for the recipient to attend the Awards

Ceremony at the ASM 2008 Annual Scientific Meeting.

Closing date for Applications: 31 March 2008

Pfizer ASM Mycology Encouragement AwardThe Pfizer ASM Mycology Encouragement Award is intended

to assist a laboratory scientist/technician in the field of medical

mycology, to attend and make a presentation in that field at the

ASM 2008 Annual Scientific Meeting. The applicant must be a

financial member of the ASM.

The presentation, at the ASM 2008 Annual Scientic Meeting, of a

paper or poster in the field of medical mycology is a necessary

requirement and may be based on original research, case reports,


ASM Affairs

a new or updated methodology, a review, a particular mycosis

etc.

Applicants must submit a CV that includes a description of their

current position and the names, addresses and email addresses

of two referees, together with a brief synopsis of their intended

presentation and a copy of the abstract to be submitted for either

an oral or poster presentation.

The Pfizer ASM Mycology Encouragement Award comprises a

framed certificate, a cheque for $500, and to facilitate attendance

at the ASM 2008 Annual Scientific Meeting, a return economy

airfare, conference registration and an allowance of $120 per day

towards five nights accommodation.


Merck Sharp & Dohme ASM Mycology AwardThe Merck Sharp & Dohme ASM Mycology Award is intended to

recognise an individual on the basis of career achievement in the

field of mycology. The applicant must be a financial member of

The ASM.

Applicants must submit a CV that includes a list of publications

and the names, addresses and email addresses of two referees,

together with a brief summary of their contributions to

mycology.

The Merck Sharp & Dohme ASM Mycology Award comprises a

plaque, a $1,000 cash prize, and up to a maximum $1,000 in travel

expenses for the recipient to attend the Awards Ceremony at the

ASM 2008 Annual Scientific Meeting.


Oxoid ASM Culture Media AwardThe Oxoid ASM Culture Media Award is intended to encourage

and assist an individual to attend the ASM 2008 Annual Scientific

Meeting to make a presentation on the use of cultural media. The

applicant must be a financial member of the ASM.

The presentation of a paper or poster relevant to the use of

culture media in microbiology at the ASM 2008 Annual Scientific

Meeting is a necessary requirement and may be based on original

research, a method of evaluation or validation, or review of a

culture based diagnostic method. For example, this may include

improved isolation methods, rapid or presumptive identification,

or novel ways of using culture media.

Applicants must submit a CV, a description of their current

employment and the names, addresses and email addresses of

two referees, together with a brief synopsis of their intended

presentation and a copy of the abstract to be submitted for

presentation.

Oxoid ASM Culture Media Award comprises a plaque, a $1,000

cash prize, and up to a maximum $1,000 in travel expenses for

the recipient to attend the Awards Ceremony at The ASM 2008

Annual Scientific Meeting.


Roche ASM Molecular Diagnostic AwardThe Roche ASM Molecular Diagnostic Award is intended to assist

an individual working in the field of infectious diseases diagnosis,

to attend and make a presentation on the use of PCR in that field

at the ASM 2008 Annual Scientific Meeting. The applicant must be

a financial member of the ASM.

The presentation of a paper/oral presentation on the use of

PCR in the field of infectious disease diagnosis at the ASM 2008

Annual Scientific Meeting is a necessary requirement and may be

based on original research, case presentations or a review of a

PCR method used to diagnose an infectious disease.

Applicants must submit a CV that includes a description of

their current employment and the names, addresses and email

addresses of two referees, together with a brief synopsis of their

intended presentation and a copy of the abstract to be submitted

for presentation.

The Roche ASM Molecular Diagnostic Award comprises a plaque,

a $1,000 cash prize, and up to a maximum $1,000 in travel

expenses for the recipient to attend the Awards Ceremony at The

ASM 2008 Annual Scientific Meeting.

Closing date for Applications: 31 March 2008

Previous issues

of

Microbiology Australia

can be found in

pdf format

on the ASM website.

www.theasm.com.au

ASM NEW MEMBERS


ASM Affairs

ACT

Raphael Wong

Aaron Greenup

Christian Samundsett

Johanne Leslie Carpenter

NSW

Michelle Moffitt

Danijel Meljkuti

Chirstopher Rodrigues

Christopher Blyth

Jacqueline Wiley

NT

James McLeod

QLDKym Whitlock

Sirdaarta P

Robert Reed

Thomas Harding

Selena Blackwell

Samantha Dando

Eliza Xinpei Ho

Yu Ling Kelly Quek

Senel Idrisoglu

SAJill Harris

John Sfakinos

Thuy Chinh Dinhpham

Nicole Taylor

TASRio Kim

Rhiannon Wray

Janette Lisson

Flora Cheong

VICKristin Leslle

James Whisstock

Mahendra Siwan

Ee Xiang Leong

Merline Varghese

Hans Netter

Alan Cowman

Cecillia Lai

Deric Renton

WA

Cynthia Pek Yun Tan

Sharon Sanders

Lesley Mutch

NEW ZEALAND

Sheryl Young

SOUTH AFRICA

Gerhard Weldhagen

SWEDEN

Sandstrom Gunnar

Matthew Francis

ASM SuStAiNiNg MEMBERSAbbott Diagnostics Division

BioMerieux Australia Pty Ltd

Millipore Australia Pty Ltd

Wyeth Australia Pty Ltd

Bio Mediq (DPC)

Oxoid Australia Pty Ltd

Bio Rad Laboratories

BD

Panbio

Dade Behring Diagnostics

Diagnostic Technology

Roche Diagnostics Australia

Blackaby Diagnostics

Corbett Research

Inverness Medical Professional

Diagnostics Australia

www.theasm.com.au

MeetingsContributions listing relevant meetings are welcome. Please send to: [email protected]

2007

21 – 24 November Kololi, The Gambia

Antibiotics Resistance in Africa

Website: http://www.mangosee.com/antibiotics2007

2008

21 – 23 February Stamford Plaza Sydney, New South Wales

Antimicrobials 2008

Annual Scientific Meeting of the Australia Society for

Antimicrobials

Website: http://www.antimicrobials2008.com


8 – 10 May 2008 The Carrington Hotel, Katoomba (Blue Mountains) NSW

Viruses in May 2008

Viruses in May is an annual intensive clinical virology

update for clinicians, scientists and trainees in this

discipline. Register early as places are strictly limited.

The program includes:

• Virusstructureandfunction

• Newmoleculardiagnostictechniques

• Viraldiseasesurveillance

• Antiviraltherapy

In addition there will be intensive clinical updates on:

• Treatmentandpreventionofspecificviralinfections

• Infectionintheimmunocompromisedpatient

Convenors: Prof Bill Rawlinson & Dr Monica Lahra

Conference Management: Australian Society for

Microbiology

Website: www.virusesinmay.com

1 – 5 June Boston MA The American Society for Microbiology

108th General Meeting

Website: www.asm.org

6 – 10 July Melbourne Convention Centre VICASM 2008 Melbourne Australia’s premier microbiology scientific meeting & exhibition for 2008!

Chair: Sue CornishConference Management: Australian Society for MicrobiologyJanette Sofronidis, Conference ManagerTel: (03) 9867 8699Email: [email protected] Website: www.asm2008.orgConfirmed speakers include: Laureate Professor Peter C Doherty, Prof Jay Hinton, Dr Gopinath Balakrish Nair, Dr Liliane Grangeot-Keros, Prof Terri Camesano, Ms Lynne Garcia, Prof Malic Peiris, Prof Stephen Goff, Prof Craig Roy, Prof Tony Pugsley, Prof Alan Cowman (Rubbo Orator).

7 – 22 August Cairns Convention Centre, Cairns, QueenslandISME12 Microbial Diversity – Sustaining the Blue Planet

Website: http://www.microbes.org/symposia_future.aspEmail: [email protected]

7 – 10 September Cairns Convention Centre, Cairns, Queensland

13th International Symposium on Staphylococci and Staphylococcal Infections

Conference Chair: Graeme NimmoEmail: [email protected] Website: www.isssi2008.comHosted by Australian Society for Antimicrobials with collaboration from ASM.

12 – 13 September Crowne Plaza Hotel, Alice Springs NTTriState 2008

Conference Management: Australian Society for MicrobiologyTel: (03) 9867 8699Stay tuned for website, registration and programme details.


ASM AffairsWhat’s On


Who’s Who

Australian Society for Microbiology Incorporated

Division 2Virology

Division 3AquaSIG – Water Microbiology Mr Simon Rockliff ACT Health ACT Government Analytical Laboratories Micro Section, Locked Bag 5, Western Creek ACT 2611 Tel: (02) 6205 8701 Fax: (02) 6205 8703 Email: [email protected]

Computers Mr Paul Hakendorf Flinders Medical Centre Clinical Epidemiology & Health Outcomes Unit, Bedford Park SA 5042 Tel: (08) 8204 3950 Ext 4451 Email: [email protected]

Cosmetics & Pharmaceuticals Dr Paul Priscott AMS Laboratories, 118 Hattersley Street Rockdale NSW 2216 Tel: (02) 9567 8544 Email: [email protected]

Culture Media Mr Peter Traynor Oxoid Australia Pty Limited 20 Dalgleish Street, Thebarton SA 5031 Tel: 1800 33 11 63 Email: [email protected]

Education Ms Cheryl Power University of Melbourne Dept Microbiology Parkville VIC 3052 Tel: (03) 8344 0332 Email: [email protected]

Food Microbiology Sofroni Eglezos Technical Manager EML Consulting Services Qld Pty Ltd 1/148 Tennyson Memorial Avenue Tennyson QLD 4105 Tel: (07) 3848 3622 Fax: (07) 3392 8495 Mobile: 0410 664 530 Email: [email protected] Web: www.eml.com.au

Laboratory Management Captain Dennis Mok, MASM 2nd Division, Randwick Barracks Randwick NSW 2031 Email: [email protected]

Microbial Ecology Dr John Bowman University of Tasmania Antarctica CRC GPO Box 252-80, Hobart TAS 7001 Tel: (03) 6226 2776 Email: [email protected]

Probiotic & Enteric Microbial Diversity SIG Dr James Chin, NSW Agriculture PO Box 128, Glenfield NSW 2167 Tel: (02) 4640 6359 Email: [email protected]

Rapid Methods Vacant

Students Vacant

Division 4Molecular Microbiology Dr Peter Lewis School of Environmental & Life Sciences University of Newcastle Callaghan NSW 2308 Tel: (02) 4921 5701 Fax: (02) 4921 6923 Email: [email protected]

NATIONAL COUNCIL EXECUTIVEPresident Assoc Prof Keryn ChristiansenPresident Elect Prof Hatch StokesVice-President, Scientific Affairs Assoc Prof Liz HarryVice-President, Corporate Affairs Adj Assoc Prof Silvano Palladino

BRANCH DELEGATESACT Dr Nick MedveczkyNSW Mr Ian CarterQLD Dr Sandra HallSA Dr Eveline BartowskyTAS Dr Louise RoddamVIC Sue CornishWA Suellen BlackabyNT (sub branch) Mr Kevin Freeman

Chair, National Scientific Advisory Committee Assoc Prof Liz HarryChair, National Examinations Board Prof Peter ColoeChair, National Qualifications Committee Dr Ruth FoxwellConvenor, Visiting Speakers Program Dr Mary BartonEditor, Microbiology Australia Prof Ian Macreadie/Mrs Jo MacreadieRegistrar, National Examinations Board Prof Peter TimmsPublic Officer of the Society Dr Ruth FoxwellCaretaker General Manager Michelle JacksonConference Manager Janette SofronidisEvent Coordinator & Registration Services Meg Lukies

Membership Services Lina Raco

BRANCH SECRETARIESACT: Dr Nicholas Medveczky TGAL Immunology PO Box 100 Woden ACT 2606 Tel: (02) 6232 8491 Email: [email protected]

NSW: Kerry Varettas Senior Hospital Scientist SEALS Microbiology St George Hospital Gray Street, Kogarah NSW 2217 Tel: (02) 9350 3325 Fax: (02) 9350 3349 Email: [email protected]

QLD: Dr Patrick Blackall Animal Research Institute Locked Mail Bag 4 Moorooka QLD 4105 Tel: (07) 3362 9498 Email: [email protected]

SA: Dr Eveline Bartowsky Research Microbiologist The Australian Wine Research Institute PO Box 197, Glen Osmond SA 5064 Tel: (08) 8303 6600 Email: [email protected]

TAS: Ms Sarah Foster LGH, Cnr Franklin and Charles Streets Launceston TAS 7250 Tel: (03) 6348 7670 Email: [email protected]

VIC: Ms Sue Cornish Mayfield Education Centre 2-10 Camberwell Road Hawthorn East VIC 3123 Tel: (03) 9811 9012 Email: [email protected]

WA: Miss Nicola Barrett PathWest Microbiology and Infectious Diseases QE2 Medical Centre, SCGH Hospital Avenue, Nedlands WA 6009 Tel: (08) 9224 2444 Email: [email protected]

NT (sub branch): Mr Kevin Freeman 12 Beacon Court, Palmerston NT 0830 Tel: (08) 8922 8685 Email: [email protected]

CONVENORS OF ASMSTANDING COMMITTEESASM Foundation Dr Ray Akhurst CSIRO, Division of Entomology GPO Box 1700, Canberra ACT 2601 Tel: (02) 6246 4123 Email: [email protected]

BioSafety Mr Lee Smythe, Supervising Scientist WHO/FAO/OIE Collaborating Centre for Reference & Research on Leptospirosis Queensland Health Scientific Services 39 Kessels Rd, Coopers Plains QLD 4108 Tel: (07) 3274 9064 Fax: (07) 3274 9175 Email: [email protected]

Clinical Microbiology Dr Stephen Graves Director of Microbiology Hunter Area Pathology Service (HAPS) John Hunter Hosp, Newcastle NSW 2300 Tel: (02) 4921 4420 Mobile: 0407 506 380 Fax: (02) 4921 4440 Email: [email protected]

Ethics Committee Emeritus Prof Nancy Millis University of Melbourne School of Microbiology, Parkville VIC 3052 Tel: (03) 9344 5707 Email: [email protected]

National Scientific Advisory Committee Assoc Prof Liz Harry University of Technology Sydney Inst. for Biotech. of Infect. Diseases Broadway NSW 2007 Tel: (02) 9514 4173 Fax: (02) 9514 4021 Email: [email protected]

Publications/Editorial Board Dr Ailsa HockingCSIRO, Div Food Science & Technology PO Box 52, North Ryde NSW 2113 Tel: (02) 9490 8520 Email: [email protected]

Research Trust Advisory & Development Committee Assoc Prof Elizabeth Dax National Serology Reference Laboratory 4 Fl, Healy Building 41 Victoria Parade, Fitzroy VIC 3065 Tel: (03) 9418 1111 Email: [email protected]

CONVENORS OF ASM SPECIAL INTEREST GROUPSDivision 1Antimicrobials John Merlino Concord Repatriation General Hospital Microbiology and Infectious Diseases Hospital Road, Concord NSW 2173 Tel: (02) 9767 6658 Email: [email protected]

Mycobacteria Dr Janet Fyfe Mycobacterium Reference Laboratory Victorian Infectious Diseases Reference Laboratory, 10 Wreckyn Street North Melbourne VIC 3051 Tel: (03) 9342 2617 Fax: (03) 9342 2666 Email: [email protected]

Mycology Dr Weiland Meyer, Westmead Hospital ICPMR CIDMLS Microbiology Level 2, Room 3114A Darcy Road, Westmead NSW 2145 Tel: (02) 8344 5701 Email: [email protected]

Mycoplasmatales Dr Steven Djordjevic Elizabeth Macarthur Agricultural Institute Private Mail Bag 8, Camden NSW 2570 Tel: (02) 4640 6426 Email: [email protected]

Ocular Microbiology Dr Mark Willcox University of New South Wales Rupert Myers Building, Sydney NSW 2052 Tel: (02) 9385 7524 Email: [email protected]

Parasitology & Tropical Medicine Dr Andrew Butcher Senior Medical Scientist Adjunct Senior Lecturer University of South Australia Institute of Medical & Veterinary Science The Queen Elizabeth Hospital Department of Clinical Microbiology & Infectious Diseases 28 Woodville Road, Woodville SA 5011 Tel: (08) 8222 6728 Fax: (08) 8222 6032 Email: [email protected]

Public Health Microbiology Dr Geoffrey Hogg University of Melbourne Microbiological Diagnostic Unit Parkville VIC 3052 Tel: (03) 8344 5713 Email: [email protected]

Clinical Serology & Molecular David Dickeson Serology Manager, Centre for Infectious Diseases & Microbiology Lab Services Level 3, ICPMR, Westmead Hospital Westmead NSW 2145 Tel: (02) 9845 6861 Fax: (02) 9633 5314 Email: [email protected]

Veterinary Microbiology Dr Glenn Browning The University of Melbourne Vet Preclinic Centre Gratton Street, Parkville VIC 3052 Tel: (03) 8344 7342 Email: [email protected]

Womens & Childrens MicrobiologyConvenor: Dr Suzanne Garland Royal Children’s Hospital Microbiology, 132 Grattan Street Melbourne VIC 3000 Tel: (03) 9344 2476 Email: [email protected]: Mr Andrew Lawrence Women’s & Children’s Hospital Microbiology & Infectious Diseases Dept 72 King William Rd, Nth Adelaide SA 5006 Tel: (08) 8161 6376 Fax: (08) 8161 6051 Email: [email protected]

Documents

Antimicrobial Resistance -