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Uppsala University Faculty of Pharmacy Department of Pharmaceutical Biosciences Division of Pharmacokinetics and Drug Therapy
The Burden of Antibiotic Resistance - development and pilot test of a questionnaire
in intensive care units
Kristina Ivarsson
Undergraduate thesis in Drug Therapy D, 20 p Master of Science in Pharmacy, spring term 2007
Supervisors: Liselotte Högberg, PhD, Department of Medical Sciences, ReAct, Uppsala University Cecilia Stålsby Lundborg, Associate professor MScPharm, PhD, Division of IHCAR, Karolinska Institutet
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Burden of Antibiotic Resistance –development and pilot test of a questionnaire in intensive care units
Kristina Ivarsson, 20 p. Supervisors: Liselotte Högberg, PhD, Department of Medical Sciences, ReAct, Uppsala University
Cecilia Stålsby Lundborg, Associate professor MScPharm, PhD, Division of IHCAR, Karolinska Institutet
Examiner: Margareta Hammarlund-Udenaes
Background: Over the years antibiotics have brought many serious infectious diseases
under control and have saved millions of lives. But these gains are now seriously
jeopardized by the emergence and spread of resistant bacteria. Especially intensive care
units (ICU) worldwide are faced with increasingly rapid emergence and spread of
antibiotic resistant bacteria. Antibiotic resistance in the ICUs has made treating infections
very difficult, and in some cases impossible. It has emerged as an important variable
influencing patient mortality and overall resource use in the ICU setting.
Aim: The general aim of this pilot study was to develop and test the feasibility of a pilot
questionnaire targeting physicians´ experience on the burden antibiotic resistant bacterial
infections at their ICU.
Method: A questionnaire was developed and pre-tested. The final version was distributed
to physicians from different parts of the world. This pilot study was a cross-sectional
study with both a qualitative and a quantitative component. In total about 120 were sent
out.
Result: The results demonstrate that a majority of the respondents consider antibiotic
resistance to be a burden at their ICU monthly or more often. Of the respondents 50%
had encountered a patient that had died of an infection without any therapy options due to
antibiotic resistance. None of the respondents do never experience burden at the ICU.
Conclusion: Overall this small study has highlighted a number of alarming findings.
Antibiotic resistant bacterial infections constitute a burden at ICUs worldwide. Assessing
the implications of increasing prevalence of antibiotic resistant bacteria is important. A
larger study needs to be completed in order to get significant results.
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Contents 1. Introduction ................................................................................ 5
1.1 Global problem........................................................................................................ 5 1.2 Emerging resistance ................................................................................................ 6 1.3 Common infections and the pathogens ................................................................. 6 1.4 Intensive care units - a risk environment ............................................................. 7 1.5 Consequences........................................................................................................... 8
1.5.1 Burden for the intensive care unit ...................................................................... 8 1.5.2 Mortality as a consequence of inadequate initial therapy .................................. 8 1.5.3 Mortality as a consequence of inaccessibility or too high cost for the patient .. 9 1.5.4 No treatment options .......................................................................................... 9
1.6 No new antibiotics ................................................................................................. 10 1.7 The need to visualize the burden of antibiotic resistance .................................. 10
2. Objectives .................................................................................. 11 2.1. General aim .......................................................................................................... 11 2.2. Specific objective .................................................................................................. 11
3. Material and method ............................................................... 12 3.1 Study design ........................................................................................................... 12 3.2 Questionnaire development.................................................................................. 12 3.3 Participants ............................................................................................................ 12 3.4 Data collection ....................................................................................................... 13
3.4.1 E-mail ............................................................................................................... 13 3.4.2 ISICEM ............................................................................................................ 14
3.5. Data analysis ......................................................................................................... 14 3.6 Ethical considerations ........................................................................................... 14
4. Results ....................................................................................... 15 4.1 Experience of no adequate or sub-optimal antibacterial therapy and death of the patient .................................................................................................................... 15
4.1.1 Primary cause of admission ............................................................................. 16 4.1.2 Age of patient ................................................................................................... 17 4.1.3 Causing microorganism ................................................................................... 18 4.1.4 Inadequate or sub-optimal antibacterial agent ................................................. 18
4.2 The respondents’ point of view of antibiotic resistance .................................... 19 4.2.1 Acquired infections: hospital or community .................................................... 19 4.2.2 Burden at the ICU ............................................................................................ 20 4.2.3 Inaccessibility at the hospital/pharmacy .......................................................... 21 4.2.4 Too high cost for the patient ............................................................................ 23
5. Discussion .................................................................................. 25 5.1 Result discussion ................................................................................................... 25
5.1.1 Cases were no adequate or only suboptimal antibacterial therapy was available and the outcome was death ....................................................................................... 25 5.1.2 The respondents’ point of view........................................................................ 26
5.2 Methodological discussion .................................................................................... 28
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5.2.1 Selection bias ................................................................................................... 29 5.2.2 Interviewer bias ................................................................................................ 29 5.2.3 Recall bias ........................................................................................................ 29 5.2.4 Reflection of reality or not ............................................................................... 29 5.2.5 Cause of death .................................................................................................. 30
6. Conclusion ................................................................................ 31 7. Future recommendations ........................................................ 32 8. References ................................................................................. 33 Appendix 1. Questionnaire ................................................................ 35 Appendix 2. Cover letter .................................................................. 36
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1. Introduction The introduction of antibiotics into clinical practice in the 1940’s can be considered as
one of the most important therapeutic developments in the history of medicine. Over the
years antibiotics have brought many serious infectious diseases under control and have
saved millions of lives. But these gains are now seriously jeopardized by the emergence
and spread of resistant bacteria (WHO 2002). The present worldwide increase in resistant
bacteria and the downward trend in the development of new antibiotics have severe
health and economic consequences. Curable diseases are becoming incurable as once
effective medicines become ineffective, as many of the bacteria that cause infectious
diseases are no longer responding to antibiotics.
1.1 Global problem Resistance to antibiotics is an international problem and a global approach for action is
urgent. No country on its own can isolate itself from resistant bacteria as pathogens are
spreading across national borders and the spread is escalating as a result of the increasing
globalization, with increased travelling, migration, and trade (Smith and Coast 2002).
The spreading is also facilitated through poor hygiene and infection control and
overcrowding (Okeke et al 2005). Mortality as a result of infectious diseases represent
one-fifth of global deaths and bacterial infections are the biggest cause to disease in
developing countries (WHO 2002 and WHO 2003).
The circumstances in developed countries, Europe, the United States and Australia, differ
from those in developing countries, Africa, Asia and South America. The economic and
health costs are far more serious in developing countries than in the developed countries.
Developing countries are yet burden with the highest rate of resistance to first line
antibiotics and for many people in these countries it’s not possible with a change of
therapy to second or third line antibiotics while these drugs often are unavailable or
unaffordable (Kunin 1993). For example the drugs needed to treat multi-drug resistant
forms of tuberculosis are over 100 times more expensive than the first-line drugs used to
treat non-resistant forms (Pablos-Mendez et al 2002). Antibiotic resistance is a medical as
well as an economic problem. Infections caused by resistant bacteria are more difficult to
6
treat, requiring drugs that are often more expensive and more toxic (WHO 2002).
Although, in developed countries even after all advances in therapeutics and the
availability of a large number of antibiotics a person can die due to antibiotic resistance
(Kunin 1993).
1.2 Emerging resistance Antibiotic resistance is a naturally occurring biological phenomenon. It can be considered
as a natural response to the selective pressure of the drug (Normark and Normark 2002).
However the phenomenon is reinforced manifold by human use and misuse. Antibiotic
use is the single most important factor responsible for increased antibiotic resistance. The
relationship between antibiotic use and resistance is complex. Overuse as well as
underuse, underuse through not taking a full course for example, plays an important role
in driving resistance. Resistance is emerging for various reasons in different settings. In
high-income countries it is mostly due to high consumption. While in developing
countries inappropriate use through lack of access, poor compliance, inadequate dosing,
wrongly selected or poor quality of available drugs encourages the development of
resistance (Byarugaba 2004).
Bacteria can become resistant to antibiotics either by spontaneous mutations or by
horizontal gene transfer. Mutational resistance occurs after random mutations in a
bacterial population, resulting in a domination of the altered and resistant bacteria.
Resistant bacteria can also pass on their resistance genes to other related bacteria through
conjugation, whereby plasmids carrying the genes jump from one organism to another.
Resistance usually has a biological cost for the bacteria, but compensatory mutations
accumulate rapidly that abolish this fitness cost, explaining why many types of resistance
may never disappear in a bacterial population (Normark and Normark 2002).
1.3 Common infections and the pathogens The bacterial infections which contribute most to human disease are also those in which
emerging and antibiotic resistance is most evident: respiratory tract infections, diarrhoeal
diseases, meningitis, sexually transmitted infections, and hospital acquired infections
7
(WHO 2002). Antibiotic resistance patterns are continually changing. Multi drug resistant
Gram-negative bacteria are an important cause of hospital-associated infections. These
bacteria can survive for a long period of time in adverse environment and once having
entered the host, can lead to long-term colonization. Therapeutic options are limited in
infections caused by Gram-negative bacteria such as Klebsiella pneumoniae,
Pseudomonas aeruginosa, Acinetobacter baumanii, Escherichia coli etc. Among the
Gram-positive bacteria methicillin-resistent Staphylococcus aureus (MRSA) and
vancomycin-resistant enterococcus (VRE) are important causes to nosocomial infections
worldwide (Kapil 2005). Approximately half of the Staphylococcus aureus strains in the
United States are methicillin-resistant and associated with difficult treatments (Nordberg
2005). Data from intensive care units in the United States demonstrate alarming numbers
of the resistance magnitude. For example MRSA accounted for almost 60% of
staphylococcal infections and VRE accounted for 28% of enterococcal infections
(Strausbaugh et al 2007).
1.4 Intensive care units - a risk environment Hospitals are a critical component of the antibiotic resistance problem worldwide.
Especially intensive care units (ICU) are faced with increasingly rapid emergence and
spread of antibiotic resistant bacteria (Fridkin 2001). The intensive care environment is
unique with frequent use of broad-spectrum antibiotics, crowding of patients with high-
levels of disease acuity, reductions in nursing staff, and the presence of chronically and
acutely ill patients. It is also the eventual site of treatment for many patients with severe
infections due to resistant pathogens acquired in the community (Kollef 2001). In clinical
settings cross transmission, introduction of medical devices, medical disruption of the
gastric barrier and decreased colonisation resistance create opportunities for colonisation
by resistant nosocomial pathogens. Hospital hygiene, such as handwashing and changing
gloves before and after contact with patients, and infection control measures are therefore
crucial for prevention of the transmission of resistant bacteria (Kollef 2001). Antibiotic
resistance in the ICUs has made treating infections very difficult, and in some cases
impossible (Fridkin 2001). It has emerged as an important variable influencing patient
mortality and overall resource use in the ICU setting (Kollef 2006).
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1.5 Consequences The consequences are severe. Infections caused by resistant bacteria fail to respond to
treatment, resulting in prolonged illness and greater risk of death. Treatment failures also
lead to longer time of infectivity, and the patients are therefore more likely to transmit the
pathogens they carry (WHO 2002). However the consequences are most evident in severe
infections in hospital settings, especially at ICUs (Nordberg et al 2005b). Infections due
antibiotic resistant bacterial strains tend to be more severe in critical ill patients and
greater mortality can be expected (Kollef et al 1999). For example a study demonstrated
that in critically ill patients MRSA have a higher attributable mortality than MSSA (Blot
et al 2002).
1.5.1 Burden for the intensive care unit
Nosocomial infections continue to compromise the ability of hospitals to prevent deaths
and effect cures worldwide. Resistant nosocomial infections adversely affect patient
prognosis, increase the cost of patient management (Okeke et al 2005). Antibiotic
resistance is adding to the economical burden of the hospital through additional
investigations, increased cost of treatment, increased risk of complications, prolonged
hospital stay, and costs associated with isolation of patients (Kapil 2005).
1.5.2 Mortality as a consequence of inadequate initial therapy
Studies in ICUs demonstrated significantly higher mortality among patients that received
inadequate empirical therapy compared with those given adequate therapy. Resistant
bacteria persistently cause delay in the administration of appropriate therapy. This shows
that clinical efforts such as precise diagnostics are important and can improve the
outcome of critically ill patients (Kollef et al 1999). Time to antibiotic treatment is
important. Studies illustrate that mortality increases with time to treatment. A study in
Belgium shows that the mortality rate increased manifold when adequate antibiotic
treatment is introduced after more then four hours versus less than four hours (Laterre
2007).
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1.5.3 Mortality as a consequence of inaccessibility or too high cost for the patient
When infections become resistant to first-line therapy, treatment has to be changed to
second-line or third-line therapies, which are much more expensive. Furthermore,
second-line therapies require more complicated dosing, have more side-effects, and may
need a greater degree of medical attention (Okeke et al 2005). In developing countries
these therapies often are unaffordable or unavailable, with the result that some diseases
can no longer be treated (WHO 2002). In these countries there is a dependency on
unofficial sources that have led to inappropriate use. In many contexts antibiotics are
perceived as ‘strong medicines’, capable of curing almost any kind of disease. Newer,
more expensive drugs are in general considered more potent and make people willing to
buy them even if they cannot afford a full course. This results in inadequate dosing and
encourages the development of resistance. In industrialized countries the financing of
health services range from general taxation in Scandinavia to private health insurance in
the United States. Compared to most developing countries where the financing of health
services, including drugs, consists of out-of-pocket payments from patients (Nordberg et
al 2005ba).
1.5.4 No treatment options
Most alarming of all are infections where bacteria have developed resistance for nearly
all currently available antibiotics on the market leaving us without any treatment options.
In today’s society a growing number of people need effective antibiotic treatment.
Susceptible groups who depend on effective antibiotics are the ageing population, high-
risk patients such as those having cytostatic therapy for cancer, transplantations surgery,
or implantation of prostheses, immune compromised patients, and premature babies with
undeveloped immune defence (Nordberg et al 2005b). Consequently the emergence of
antibiotic resistance is jeopardizing other medical advantages. The worst scenario which,
unfortunately is not an unlikely one, is that dangerous pathogens will eventually acquire
resistance to all previously effective antibiotics, thereby giving rise to uncontrolled
epidemics of bacterial diseases that can no longer be treated.
10
1.6 No new antibiotics A downward trend in the development of new antibiotics has created an urgent need for
new compounds. As long as there have been options to switch from one class of
antibiotics to another the resistance problem has been overcome. In the past new drugs
were able to help out after older antibiotics were lost to resistance. The decelerating
development of new antibiotics has economical grounds. The pharmaceutical industry
don’t find research in new antibiotics economic defendable. One motive is the emerging
resistance, which makes the durability of antibiotics insecure. Another is that antibiotic
treat people and the short period of use make it less attractive than drugs for chronic
diseases (Tickell 2005).
1.7 The need to visualize the burden of antibiotic resistance Antibiotic resistance has contributed to higher morbidity and mortality of previously
treatable infectious diseases and since antibiotic resistance is not itself a disease entity it’s
mainly an invisible problem (Byarugaba 2004 and Nordberg et al 2005b). The problem is
largely a “faceless threat” as the consequences, such as mortality or prolonged morbidity,
are hidden within different clinical syndromes. Even though antibiotic resistance has
emerged as an important determinant of mortality in the ICU it is still an invisible
problem, at least for people outside the medical field. Despite high mortality rates in
infections, death certificates are generally not designed to register whether the causative
microorganism was resistance to the antibiotic therapy given or not (Nordberg 2005).
This is very unfortunate when as long as there is no system to report to, antibiotic
resistant bacterial infection will continue to be an invisible cause of death.
Data on how antibiotic resistance is affecting clinical practice today is urgently needed, in
order to guide decision makers, health care professionals and the public. ReAct, Reaction
on Antibiotic Resistance, is an international coalition of individuals, organisations and
networks committed to combating antibiotic resistance as a global threat to health. One of
their strategies is to make the burden of the antibiotic resistance more transparent to
policy makers and the public, and advocating that governments set up effective systems
to reduce it.
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2. Objectives
2.1. General aim The general aim of this pilot study was to develop and test the feasibility of a pilot
questionnaire targeting physicians´ experience on the burden of antibiotic resistant
bacterial infections at their ICU. The long-term aim was to make ReAct and its work
against antibiotic resistance visible.
2.2. Specific objective The specific objective was
- through this questionnaire present how frequently the targeted physicians reported
to have encountered antibiotic resistant bacterial infections where the outcome for
the patient was death, and describe the characteristics of these patients and
infections
- through this questionnaire illustrate the opinions of the targeted physicians on the
consequences antibiotic resistant bacterial infections have on their clinical
practice
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3. Material and method
3.1 Study design A short questionnaire was developed and pre-tested. The final version was distributed to
ICU-physicians around the world. This pilot study was a cross-sectional study with both a
qualitative and a quantitative component. The questionnaire included both open and
closed questions.
3.2 Questionnaire development Potential questions to be included in the questionnaire were discussed with supervisors
and a few physicians. The questionnaire was made short, as that was considered essential
to increase the response rate. It was decided that it should not exceed one page.
The questionnaire was divided into two sections, the first section asking the physicians if
they had encountered any bacterial infection for which no or only sub-optimal
antibacterial therapy was available or possible to acquire, and where the outcome for the
patient was death. If yes, they were asked more in detail about the specific case. In the
second, qualitative part, all physicians were asked some questions regarding their view on
antibiotic resistance (including those answering no to the initial question). The
questionnaire included a combination of questions with fixed response alternatives and
open questions. Questions with fixed response alternatives were used to make it easier for
the responders to fill the questionnaire and to make it easier to analyze the answers.
The final version was pre-tested at a small number of physicians active at an ICU in
Sweden. For the complete questionnaire, see appendix 1.
3.3 Participants The study population consists of physicians active at ICUs. Focus was on ICUs because it
addresses the setting with the most vulnerable patients, the highest rate of infections and
ICU settings are faced with increasingly rapid emergence and spread of antibiotic
13
resistant bacteria (Fridkin 2001). All nations were considered, and the study aimed to get
a broad geographical coverage though sufficient knowledge in English was an inclusion
criteria.
Participants were identified in two ways. Through ReAct’s network a number of contacts
with hospital association were identified and contacted by e-mail. If they were not
intensive care physicians themselves, they were asked to distribute the questionnaire and
the cover letter to colleagues active in intensive care. In addition, participant physicians
at the 27th International Symposium on Intensive Care and Emergency Medicine
(ISICEM) held in Brussels, Belgium, March 27-30, 2007 were targeted on site.
3.4 Data collection 3.4.1 E-mail
About 40 questionnaires were distributed through e-mail, and one reply was received
(figure 1). No information was available on how many physicians the contacts
approached by e-mail distributed the questionnaire to, so the number of non-respondents
is unknown. The e-mail included a cover letter (see appendix 2) that gave a brief
background to the subject. The questionnaire was also available on ReAct´s homepage, to
increase the access and make it easier for the participants to respond. The questionnaire
was sent out between; March 15 to April 10, 2007. Reminders were e-mailed out to non-
respondents approximately within 3 weeks after the first questionnaire was sent out. May
15, 2007 the study was closed. The one questionnaire sent back were included in the
study. Distributing the questionnaires via e-mail has the disadvantage that no further
explanations can be given, but as an advantage there is no interviewer bias and it is an
easy way to get in touch with persons worldwide.
Number of questionnaire that was e-mailed out: ~40
Respondents: 1 Non-respondents: ?
14
Figure 1. Data collection by e-mail: respondents and non-respondents
3.4.2 ISICEM
At the ISICEM meeting the physicians were contacted personally by the investigator and
asked to fill in the questionnaire on site. Distributing the questionnaire in person has the
advantages that the interviewer has the opportunity for explanations. Approximately 140
were asked to fill in the questionnaire and 31 of them did respond and were included in
the study. About 50 asked to participate in the study weren’t physicians or physicians
active at an ICU and couldn’t therefore be included in the study, about 50 rejected to fill
in the questionnaire and a good 5 had too poor knowledge in English and were thereby
excluded (figure 2).
Figure 2. Data collection at the ISICEM meeting: Respondents and non-respondents
3.5. Data analysis A database was created in Excel. Data were analysed descriptively using the same
database.
3.6 Ethical considerations As data is only presented in aggregated form, no individual respondents, hospitals or
patients are identifiable. The respondents were informed that their responses would be
treated confidentially and only be presented on country or regional level.
Numbers asked to answer the questionnaire:
~140
Too poor knowledge in English: >5
Non-physicians or non-active physicians: ~50
Respondents: 31 Non-respondents: ~50
Excluded: ~55
15
4. Results Thirty-two ICU-physicians completed the questionnaire and were included in the present
analysis. Countries represented were Australia, Austria, Belgium, Czech Republic,
Denmark, Finland, France, Germany, Greece, Italy, Japan, Portugal, Slovakia, Sweden,
United Arab Emirates, United Kingdom, and United States.
4.1 Experience of no adequate or sub-optimal antibacterial therapy and
death of the patient Of all the respondents, half (n:16) had encountered a patient with bacterial infection for
which no adequate or only sub-optimal anti-bacterial therapy was available or possible to
acquire and where the outcome was death. The map (see figure 3) and table I illustrates
the country distribution of the patients with the outcome death.
Figure 3. Map illustrating where the deaths due to antibiotic resistance occurred.
16
Table I. Country distribution
Country
Encountered a bacterial infection for
which no adequate or only sub-optimal
anti-bacterial therapy was available or
possible to acquire, and the outcome for
the patient was death.
Yes No
Australia 1 1
Austria 1 1
Belgium 2 1
Czech Republic 1 2
Denmark 1
Finland 1
France 2 1
Germany 1
Greece 1
Italy 1
Japan 2
Portugal 1
Slovakia 1
Sweden 1
United Arab Emirates 1
United Kingdom 2 5
United States 1
Total 16 16
4.1.1 Primary cause of admission
The most frequent primary cause of admissions for the patient that had died due to
antibiotic resistance were pneumonia (4/16) and burns (4/16) were the most common
cause of admission to the ICU, followed by sepsis (2/16) and peritonitis (2/16). The
number of patients and their initial diagnosis are summarised in figure 4.
17
0
1
2
3
4
5
PneumoniaBurns
Sepsis
Peritonitis
Haemorrage
Polytrauma
Esophagual perforation
Hematologic dise
ase
Primary cause of admission
Num
ber o
f cas
es
Figure 4. Primary cause of admission to the ICU for the patients with outcome death.
4.1.2 Age of patient
Half of the deaths were in the age group 41-65 years. Four of the deaths were in the age
group 16-40 years and four in the age group over 65 years. No cases in the age group 0-
15 years were reported (figure 5).
Figure 5. Age of patients with the outcome death per age group. Total number of cases is given in each
section of the circle.
18
4.1.3 Causing microorganism
The results show that the Gram-negative bacteria (12/16) (Acinetobacter, E. coli,
Pseudomonas and Klebsiella) were the bacteria most frequent causing deaths due to
antibiotic resistance among the reported cases. Also MRSA (3/16) was frequently
occurring as a cause, see figure 6. The country distribution of the causing microorganism
is illustrated in table II.
0
1
2
3
4
5
6
7
Acinetobacter E.coli Pseudomonas Klebisella MRSA/MRSE CandidaAlbicans
Microorganism
Num
ber o
f cas
es
Figure 6. Likely causing microorganism.
4.1.4 Inadequate or sub-optimal antibacterial agent
The participants were asked to specify what antibacterial agent/s used on the patient that
was/were considered to be inadequate or sub-optimal. The physicians responded to this
question with one or more antibiotic, see table III.
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Table III. Antibiotics* considered being inadequate or sub-optimal and the causing
microorganisms. Antibiotic group Carbapenems Penicillins Cephalosporins Glycopeptides Polymyxins Antimycotics Glycyl-
cycline Microorganism
Acinetobacter 3 1 1 1 3 1
E.coli 1
Pseudomonas 4 2 1 1
Klebsiella 1
MRSA/MRSE 1 1 1
Candida Albicans 1
Total 7 4 3 3 5 1 1
*Carbapenems: meropenem and imipenem. Penicillins: amoxicillin and piperacillin. Cephalosporins: all.
Glycopeptides: vancomycin. Polymyxins: Colistin. Antimycotics: all. Glycylcycline: tigecycline.
4.2 The respondents’ point of view of antibiotic resistance All respondents, whether they encountered an antibiotic bacterial infection with no
treatment options or not, responded the questions about their opinion on antibiotic
resistance.
4.2.1 Acquired infections: hospital or community
The physicians were asked where they thought the most antibiotic resistant bacterial
infections were acquired. A majority of the respondents (29/32) answered in hospital, see
figure 7. Both the two respondents that have answered that they thought most of the
antibiotic resistant infections are acquired in community have not had a patient that had
died due to an antibiotic resistant bacterial infection.
20
Acquisition of infection
29
2 1
Hosptial Community Don´t know
Figure 7. Acquisition of antibiotic resistant bacterial infections.
4.2.2 Burden at the ICU
The participants were asked how often they considered antibiotic resistant bacterial
infections to be a problem/burden for the ICU. More than 19 out of all 32 respondents
experience a burden weekly or more often and 26 experience a burden monthly or more
often, see figure 8.
How often do you consider antibiotic resistant bacterial infections to be a problem/burden for
the ICU?
0
5
10
15
Daily Weekly Monthly Rarely NeverNum
ber o
f res
pons
es
Yes No
Figure 8. Burden at the ICU. The division of yes and no indicates if the responder has encountered death
due antibiotic resistance or not.
21
Of the physicians that had encountered death due to antibiotic resistant bacterial infection
11 answered that they experienced a burden daily or weekly, while 8 of the physicians
that had not encountered death experienced a burden daily or weekly, see figure 8. None
of the respondents answered that they never consider antibiotic resistant bacterial
infections to be a burden. Those that experienced burden daily were from Australia,
Austria, Belgium, Portugal, United Kingdom, and United States, see table IV.
Table IV. Country distribution – burden.
Daily Weekly Monthly Rarely Never Australia Austria Belgium Portugal United Kingdom (2) United States
Belgium Czech Republic France Germany Italy Japan (2) United Arab Emirates United Kingdom (4)
Australia Austria Belgium Czech Republic Denmark Finland Greece
Czech Republic France (2) Slovakia Sweden United Kingdom
4.2.3 Inaccessibility at the hospital/pharmacy
The participants were asked how often they come across that adequate antibacterial
agents couldn’t be used due to inaccessibility at the hospital or the pharmacy. About 22
out of 32 encountered this problem rarely or never, see figure 9.
22
How often adequate antibiotic therapy can't be used due to inaccessibility?
0
5
10
15
Daily Weekly Monthly Rarely Never
Num
ber o
f res
pons
es
Yes No
Figure 9. How often adequate antibiotic therapy can’t be used due to inaccessibility. The division of yes
and no indicates if the responder has encountered death due to antibiotic resistance or not.
The country distribution on how often the participants come across that adequate
antibiotic can’t be used due to inaccessibility is illustrated in table V.
Table V. Country distribution - inaccessibility.
Daily Weekly Monthly Rarely Never Belgium Japan
United Arab Emirates Austria (2) Denmark France Germany Japan United Kingdom
Australia Belgium Czech Republic (3) Finland France Italy Portugal Slovakia Sweden United Kingdom (3)
Australia Belgium France United Arab Emirates United Kingdom (3) United States
23
4.2.4 Too high cost for the patient
The participants were asked to answer how often they come across that adequate
antibacterial agents couldn’t be used due to too high cost for the patient. Half of the
respondents never came across the problem see figure 10. Five of the respondents came
across this dilemma monthly or more often and they were from Belgium (1), Japan (1),
Germany (1) and the Czech Republic (2). The respondent that came across the problem
daily was from Belgium. Both the two respondents that answered daily and weekly had
encountered death due to antibiotic resistant bacterial infection. Of the respondents that
had not encountered death, 27 rarely or never came across that adequate therapy couldn’t
be given due to too high cost for the patient, see figure 10.
How often do you come across that adequate antibacterial agents can't be used due to too high
cost for the patient?
0
5
10
15
20
Daily Weekly Monthly Rarely Never
Num
ber o
f res
pons
es
Yes No
Figure 10. How often adequate antibiotic therapy can’t be used due to too high cost for the patient. The
division of yes and no indicates if the responder has encountered death due to antibiotic resistance or not.
Below, table VI, illustrate the country distribution on how often the respondents come
across that adequate antibiotic can’t be used due to too high cost for the patient. In most
countries this is not seen as a problem. Notice that, the countries in the daily and weekly
column are also represented in the never column.
24
Table VI. Country distribution – too high cost for the patient.
Daily Weekly Monthly Rarely Never Belgium Japan Czech Republic (2)
Germany
Austria (2) Czech Republic Finland France (2) Italy Slovakia United Kingdom (2) United Arab Emirates
Australia (2) Belgium (2) Denmark France Greece Japan Portugal Sweden United Kingdom (5) United States
25
5. Discussion
5.1 Result discussion This is one of the first studies with the aim of visualizing the burden that antibiotic
resistance imposes at ICUs. The results highlight the need for urgent action to contain the
problem, as it already today is a serious problem. Of the respondents 16/32 had
encountered a patient that had died of an infection without any therapy options due to
antibiotic resistance and a majority thought that the antibiotic resistant bacterial
infections are acquired in the hospital. Over 26/32 of all respondents (including those
who had not experienced a antibiotic-resistant relate death) stated that antibiotic
resistance was a burden for the ICU every month or more frequent, and 19/32 stated that
they experienced antibiotic resistance related burden on a weekly basis.
5.1.1 Cases where no adequate or only suboptimal antibacterial therapy was
available and the outcome was death
The questionnaire only asked about the last case of death, presumably have the
respondents that answered yes had more cases of death due to antibiotic resistance. Due
to the low number of respondents, case characteristics can not be extrapolated to a larger
patient population. It should also be remembered that the questionnaire only asked for
cases were the outcome was death, and the burden due to prolonged morbidity and
complications is not reflected in this study.
The ages of the patients that had died due to an antibiotic resistant bacterial infection,
were younger then presumed. This result was a bit surprising as the most vulnerable are
young children and the elderly with high susceptibility to infections and reduced immune
response (Nordberg 2005). But it is hard to draw conclusion about the ages when without
any background information on the patients, for example underlying diseases. None of
the patients were under the age of 16 years, this can be a result of that many hospitals
have a special unit for children.
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Potentially high-risk antibiotic resistant bacteria are Pseudomonas, Acinetobacter and
Staphylococcus, which also the result shows to be the most common causing
microorganisms. Previous studies have shown that the most important cause of hospital-
associated infections are the Gram-negative bacteria such as Pseudomonas,
Acinetobacter, E. coli, Klebsiella (Kapil 2005).
The results show four cases where colistin was considered to be inadequate or sub-
optimal. This is alarming as colistin today is used for treatment of infections caused by
multi resistant bacteria where no other treatment is available. Colistin is among the old
antibiotics that previously have been discarded due to its toxicity and side effects but that
today is used as a last alternative. Very few physicians are experienced in its use. There is
no standardised dosing of colistin because it was never subject to the regulations that
modern drugs are subject to (Ruef 2007).
Resistance to imipenem and meropenem, which are two of the most active antibiotics to
treat Gram-negative bacteria, is also an alarming finding. Seven of the respondents (7/16)
considered therapy with imipenem and meropenem to be inadequate or sub-optimal.
Moreover, the results show two cases of vancomycin therapy failure. Therapy with
vancomycin is often seen as standard treatment for MRSA. Tigecycline is a new class of
antibiotic specially designed for antibiotic resistant infections. It was approved within the
European Union as late as 2006 (Medical Products Agency 2007). One respondent had
experienced resistance to tigecycline. One out of sixteen is a high number and it also
illustrates how fast resistance can arise. Even the few new products that reach the market
suffer from the increasing resistance.
5.1.2 The respondents’ point of view
A majority of the physicians believe that most antibiotic resistant bacterial infections are
acquired in the hospital. This was expected as all of the participants work at ICUs, which
are particularly faced with the increasingly rapid emergence and spread of antibiotic
resistant bacteria (Fridkin 2001). The hospital acquired infections, that often are resistant
to antibiotic therapy, create a dilemma where it involves a risk to be hospitalized. The
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two respondents that answered the community is where most antibiotic resistant bacterial
infections are acquired have not had a patient that have died due to antibiotic resistance.
That might be that they don’t experience a problem at their hospitals and have another
view of the matter, which also showed in their further answers.
More than half of the respondents considered antibiotic resistant bacterial infections to be
a burden at their ICU weekly or more often. None of the respondents answered that they
never consider antibiotic resistant bacterial infections to be a burden. How the
respondents interpreted the words burden and problem are individual. The burden and
problem considered at the ICUs could both be in a medical and an economical context.
Anyhow, these are disturbing findings, but not surprising. The emerging resistance
contribute to a higher morbidity and mortality, increased risk of complications, more
expensive and complicated therapies, increased length of hospitalization, isolations of
patients (Nordberg et al 2005b). Obviously, above mentioned examples are time-
consuming for the physicians, constitute a large cost for the ward/hospital, and of course
it must be frustrating for the physician to be without treatment options for a infection that
previously could have been treated.
Antibiotic resistance increases the risk of choosing the wrong antibiotic and contribute to
time losses when the empirical therapy is in-effective. Providing appropriate antibiotic
therapy promptly is crucial for successful treatment. The three respondents that answered
that they came across that adequate antibacterial agents couldn’t be used due
inaccessibility at the hospital or pharmacy daily or weekly are from Belgium, Japan and
the United Arab Emirates. I presume that at least in Belgium and Japan it is not
impossible to get access to adequate antibiotics (if available on the market) but it is a
matter of time. It is very important to get adequate treatment as soon as possible. Two out
of the above mentioned three respondents had encountered a bacterial infection for which
no adequate or only sub-optimal anti-bacterial therapy was available or possible to
acquire, and where the outcome for the patient was death.
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The financing of health services differs in different parts of the world. If resistance to
first-line antibiotic occur, a switch to second- or third-line is associated with higher
expenses. This can put physicians in situations where adequate antibiotics can’t be used
due to too high cost for the patient. Fifty percent of the respondents had never come
across this, but 16% came across this situation monthly or more often. They were from
Belgium, Japan, Germany and the Czech Republic. The respondent from Belgium came
across the problem daily. No further study of what kind of financing system that exists in
above mentioned countries has been conducted. Maybe due to naivety, but I didn’t expect
that patients in Europe would come across that they couldn’t receive adequate therapy
due to too high cost for the patient. Additional two other respondents, also from Belgium,
never came across this problem. The same is with a respondent in Japan that has problem
with too high costs for patients weekly while in the mean time another respondent from
Japan never come across this. The varying answer within the same countries might be
due to different financial systems at different hospitals or that the different hospitals have
patients from varying society classes.
5.2 Methodological discussion It appeared that the questionnaire was feasible and applicable. For example, very few
don’t know answers give an indication of the feasibility and the applicability of the
questionnaire. However, this study has several limitations. The results do not qualify as
quantitative statistical survey due to biased selection of participating physicians and due
to the low response rate. But the results can be seen as a description of the respondents’
views and opinions on the matter. A greater population is needed to generalize the results.
This pilot study can however give an idea about the situation.
Participation was on voluntary basis. Several limiting factors influenced the low response
rate. At the ISICEM meeting the physicians were asked to fill in the questionnaire at site.
Several of the approached persons didn’t have time or felt like to answer. It was hard to
find people with the correct inclusion criteria willing to answer. The response rate was
62% at the ICICEM-meeting. The distribution of the questionnaire by e-mail totalled in
one respondent. That is very unsatisfactory. When the questionnaire is sent out by e-mail
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a response frequency of 20-30% is expected. Even though the physicians e-mailed were
selected through ReActs network contacts, all of whom are all committed to combating
antibiotic resistance, and through personal contacts, the response rate was low. Lack of
time is probably the major limiting factor. To increase the response rate a second
reminder could have been sent out and reminder through phone calls could have been
carried out.
5.2.1 Selection bias
Physicians attending the ISICEM meeting in Brussels don’t represent physicians active at
ICUs as a whole. The respondents that answered the questionnaire might have more
problems with antibiotic resistant bacterial infections and be more versed in the area and
thereby were willing to answer the questionnaire or vice versa. Some of the non-
respondents might not want to confess the problems. They might see it as suffer a defeat
to report about patient that have died due to an antibiotic resistant bacterial infection. Or
maybe they don’t have any problems at all and don’t see a reason to answer.
5.2.2 Interviewer bias
The interviewer could have influenced the participants. They could have thought the
interviewer expected a specific answer and thereby chosen to answer that way. To avoid
this, questions were designed so as there should not have been considerations of “right”
or “wrong” answers.
5.2.3 Recall bias
Some of the questions in the questionnaire may have been subject to recall bias. It is hard
for a physician to remember details about a specific patient. This was taken in
consideration when developing the questionnaire. The only detailed questions dealt with
the last patient that had died. Anyhow a trust was put in the respondents’ good memory.
5.2.4 Reflection of reality or not
It is impossible to evaluate whether the contributions from the physicians reflect reality
or are truly reprehensive of ICUs as a whole. The extent of antibiotic resistance varies on
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a global, regional and even institutional basis. Local differences can be as great as
differences between countries. A respond from one physician is not reprehensive for
her/his country or city. This descriptive study of the physicians that responded – doesn’t
reflect ”reality”, although the respondents do reflect their reality.
5.2.5 Cause of death
The type of outcome examined in this study was in-hospital mortality only, which is
relatively easy to define. But did the patient die of the infection or the infection due to
antibiotic resistance? Maybe the patient would have died anyway. It is very hard to tell
when antibiotic resistance is not a disease itself. The absence of evidence is not evidence
of absence.
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6. Conclusion Overall this small study has highlighted a number of alarming findings. Antibiotic
resistant bacterial infections constitute a burden at ICUs worldwide. The result from the
questionnaire implicate that 50% of the respondents considered antibiotic resistant
bacterial infections to be a burden at their ICU weekly or more often. Assessing the
implications of increasing prevalence of antibiotic resistant bacteria is important. A larger
study needs to be completed in order to get significant results.
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7. Future recommendations
- For future studies another distribution strategy is desired. Distribution of
questionnaires through personal meetings, at congresses for example, via
professional associations and other organizational networks could hopefully
increase the response rate and also improve the uneven selection of participants.
Distribution via mail instead of e-mail can be considered. Presumably, it is easier
to ignore e-mail than mail. Though, it makes it more complicated and more
expensive to send out mails rather than e-mails.
- Data on how antibiotic resistance is affecting clinical practice today is urgently
needed, in order to guide decision makers, health care professionals and the
public. The questionnaire developed in this study can be used as a model in future
more extensive research.
- Further development of the questionnaire can be considered.
• divide the question about burden into two parts; medical burden and
economical burden.
• add a question about prolonged morbidity and other complications.
• add a question about approximately how many cases of mortality due to
antibiotic resistance a year. But no detailed questions about those cases.
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8. References Articles Blot S, Vandewoude K, Hoste E, Colardyn F. Outcome and Attributable Mortality in Critically Ill Patients With Bacteremia Involving Methicillin- Susceptible and Methicillin-Resistant Staphylococcus aureus. Arch of Intern Med 162: 2229-2235 (2002) Byarugaba D.K. A view on antimicrobial resistance in developing countries and responsible risk factors. International Journal of Antimicrobial Agents 24: 105-110 (2004) Fridkin S. Increasing prevalence of antimicrobial resistance in intensive care units. Critical Care Medicine 29 (4): N64-N68 (2001) Hanberger H. Stora skillnader i antibiotikaresistens på Europas intensivvårdsavdelningar. Läkartidningen 98(44): 4827-4828 (2001) Kapil A. The challenge of antibiotic resistance: Need to contemplate. Indian J Med Res 121: 83-91 (2005) Kollef M. Is Antibiotic Cycling the Answer to Preventing the Emergence of Bacterial Resistance in the Intensive Care Unit? Clin Infect Dis 43: S82-S88 (2006) Kollef M, Fraser V. Antibiotic Resistance in the Intensive Care Unit. Ann Intern Med 134: 298-314 (2001) Kollef M., Sherman G., Ward S., Fraser V. Inadequate antimicrobial treatment if infections: a risk factor for hospital mortality among critically ill patients. Chest 115(2): 462-474 (1999) Kunin C. Resistance to Antimicrobial Drugs-A Worldwide Calamity. Ann Intern Med 118 (7): 557-561 (1993) Nordberg P, Stålsby Lundborg C, Tomson G. Consumers and providers. Could they make better use of antibiotics? Int J of Risk and Safety in Medicine 2005;17: 117-25 (2005a) Normark BH, Normark S. Evolution and spread of antibiotic resistance. J Intern Med 252(2): 91-106 (2002) Okeke I. Laxminarayan R. Bhutta Z. Duse A. Jenkins P. O´Brien T. Pablos-Mendez A. Klugman K. Antimicrobial resistance in developing countries. Part I: recent trends and current status. Lancet Infect Dis 5: 481-493 (2005) Okeke I. Laxminarayan R. Bhutta Z. Duse A. Jenkins P. O´Brien T. Pablos-Mendez A. Klugman K. Antimicrobial resistance in developing countries. Part II: strategies for containment. Lancet Infect Dis 5: 568-580 (2005)
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Pablos-Mendez A. Gowda,D. K. and Frieden T. R. Controlling multidrug-resistant tuberculosis and access to expensive drugs: a rational framework. Bull World Health Organ 80(6): 489-495 (2002) Radyowijati A. Haak H. Determinants of Antimicrobial use in the developing world. Soc Sci Med.57(4): 733-744 (2003) Ruef C. Antibiotic Resistance – Running Out of Treatment Options. Infection 35(1): 1 (2007) Smith R. and Coast J. Antimicrobial resistance: a global response. Bull World Health Organ 80(2): 126-133 (2002) Strausbaugh LJ. Siegel JD. Weinstein RA. Preventing transmission of multi-drug resistant bacteria in health care settings: a tale of 2 guidelines. Clin Infect Dis 42(6): 828-835 (2007) WebPages Medical Products Agency – Sweden URL:http://www.lakemedelsverket.se/Tpl/MonographyPage____6035.aspx [2007-05-22] ReAct: Publication Tickell S. The Antibiotic Innovation Study - Expert Voices on a Critical Need (2005) URL:http://soapimg.icecube.snowfall.se/stopresistance/Innovation%20study%20april%20low%20res.pdf [2007-03-12] World Health Organization: Factsheet (2002) URL:http://www.who.int/mediacentre/factsheets/fs194/en/print.html [2007-03-12] World Health Organisation: Background report Nordberg P. Monnet D. Cars O. Antibacterial drug resistance: Options for concerted action. Priority Medicines for Europe and the World Project. Department of Medicines Policy and Standards. World Health Organization (2005b) URL:http://mednet3.who.int/prioritymeds/report/background/antibacterial.doc [2007-02-01] World Health Organization: The world health report 2003 – shaping the future (2003) URL:http://www.who.int/whr/2003/en/ [2007-02-14] Lecture Laterre Pierre-Francois, Brussels, Belgium. ISICEM. [2007-03-28]
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Appendix 1. Questionnaire
Hospital name:…………………………...… City and country:…………….…................ Ward name:………………………………… Number of beds:…………………….......... Name and title:……………………………... Contact details:…........................................ Have you encountered any bacterial infections for which no adequate or only sub-optimal anti-bacterial therapy was available or possible to acquire, and where the outcome for the patient was death? Yes No If yes, please answer question 1-4 in section A about your latest case, and question 5-9 in section B. If no, please proceed to section B, and answer question 5-9. A. The Patient 1. Primary cause of admission to the ICU? Please specify:……………...……………………………………………………………..................... 2. Age of the patient? <1 year 1-5 years 6-15 years 16-40 years 41-65 years >65 years Don’t know 3. Likely causing microorganism? Please specify:………………………………………………...……………………………………..... 4. What antibacterial agent/s used on the patient was/were considered to be inadequate or sub-optimal? Please specify: ………………………..…………………………………………………………………………………
B. Your opinion on antibiotic resistance 5. In your opinion where are most bacterial infections resistant to antibiotics acquired? Hospital Community Don’t know 6. How often do you consider antibiotic resistant bacterial infections to be a problem/burden for the ICU? Daily Weekly Monthly Rarely Never Don’t know 7. How often do you come across that adequate antibacterial agents can’t be used due to inaccessibility at the hospital/pharmacy? Daily Weekly Monthly Rarely Never Don’t know 8. How often do you come across that adequate antibacterial agents can’t be used due to too high cost for the patient? Daily Weekly Monthly Rarely Never Don’t know 9. General comments:….…….………………………………………………………..……………………. …………………………………………………………………………………………………………...…...
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Appendix 2. Cover letter
Uppsala 2007-XX-XX
On behalf of ReAct – Action on Antibiotic Resistance, Uppsala University, Sweden. I’m inviting you to
participate in a survey on the burden of antibiotic resistant bacterial infections in intensive care. Attached to
this letter is a short questionnaire that asks a few questions on your professional experience and opinion on
the impact of antibiotic resistance in your practice. This questionnaire is sent out to physicians active at
intensive care units around the world.
The questionnaire should take no longer than 5 minutes to complete. Please, send your answer to us the
latest XX, 2007. The questionnaire can also be downloaded at http://www.reactgroup.org/dyn//,43,.html
This survey is part of ReAct´s (Action on Antibiotic Resistance)* work to visualize the burden of antibiotic
resistance in clinical practice today, and is undertaken as part of my undergraduate thesis in Master of
Science in Pharmacy at Uppsala University in Sweden. Your responses will be treated confidentially and
will only be presented on country or regional level. No individual respondents or hospital will be
identifiable. The results will be presented in an undergraduate thesis and possibly in an article in a peer-
reviewed journal. The report will be available from June 2007 from ReAct’s home page:
www.reactgroup.org and can also be e-mailed or mailed to all respondents whom would like so.
Please feel free to contact me on telephone +46(0)18-471 66 14 or e-mail [email protected] if
you have any further questions.
Supervisors for the thesis work are Liselotte Högberg and Cecilia Stålsby-Lundborg.
Chairperson of ReAct is Prof Otto Cars.
Yours sincerely, Tina Ivarsson
*) ReAct, Action on Antibiotic Resistance, is a coalition that links a wide range of
individuals, organizations and networks around the world taking concerted action to
respond to antibiotic resistance. ReAct’s mission is that current and future generations of
people around the globe should have access to effective treatment of bacterial infections.
Read more on www.reactgroup.org
