Bacterial Pneumonia and Emerging Antibiotic Resistance€¦ · Bacterial Pneumonia and Emerging Antibiotic Resistance ECCMID 2012 Curetis Symposia Proceedings April 1, 2012 London,

Bacterial Pneumonia and Emerging Antibiotic Resistance ECCMID 2012 Curetis Symposia Proceedings April 1, 2012 London, UK

Pneumonia is a major problemJean-Louis Vincent

Pneumonia-causing pathogens and their resistances David Livermore

Challenges and opportunities in testing respiratory tract infections Ingo Autenrieth, Berit Schulte

Would faster molecular testing make a difference in the current standard of care?A Microbiologist’s point of viewChristine Ginocchio

Would faster molecular testing make a difference in the current standard of care?A Clinician’s point of viewAntoni Torres

Health Economic Modeling of the impact of fast pneumonia testingAnne Thews

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Preface

Preface

At ECCMID 2012 held in London April 2012 Curetis AG sponsored an Integrated Symposium focusing on

Bacterial Pneumonia and Emerging Antibiotic Resistance

The symposium was shared by two leading scientists in the infectious disease area: Prof. Dr. Christine Ginoc-chio, New York and Prof. Dr. Keith Klugman, Atlanta.

The workshop was intended to support Curetis AG`s first product release – the Unyvero™ P50 Pneu-monia Application using the Unyvero™ System.

Five internationally re-owned experts:

Prof. Dr. Jean-Louis Vincent, Brussels• Prof. David Livermore, Norwich• Prof. Ingo Autenrieth, Tübingen• Prof. Christine Ginocchio, New York• Prof. Antoni Torres, Barcelona•

gave presentations and discussed the latest informa-tion on pneumonia. Their talks regarding this severe acute infection raised concerns about growing anti-biotic resistance as a major burden for today‘s health care systems. In addition, they discussed whether such lung infections would benefit from faster and more comprehensive diagnostics.

The talks clearly indicated the need to balance antibiotic treatment to cure patients but to limit treatment with re-gard to antibiotic steward ship as illustrated in Figure 1.

Figure 1 The balance of antibiotic treatment

All experts agreed about the high demand for faster re-sults in pneumonia testing. Such quick results are a pre-requisite for giving adequate antibiotic treatment as ear-ly as possible in order to improve the standard of care.

These experts have agreed to contribute to this ECCMID Symposium Proceeding in order to capture their high profile presentations. The management of Curetis would like to express our deep thanks to all of the authors.

We have added an additional chapter about an econo-mic model Curetis AG has developed in cooperation with Halteres Associates, an highly recognized IVD in-dustry consulting firm, to demonstrate the potential me-dical and economic benefits of fast molecular testing.

Sincerely yours

Anne ThewsHead of Medical AffairsCuretis AG

Curetis Symposium ECCMID London 2012

ContentCuretis Symposium ECCMID London 2012

Content

Pneumonia is a major problem 06Jean-Louis VincentThere is an increasing incidence of gram-negative and mixed lung infections in acutely ill patients as well as a growing percentage of multidrug resistant bacteria. Results were obtained from two very large international studies (SOAP, EPIC II) that collected data from criti-cally ill patients in the intensive care unit. Data collected both on the incidence as well as the type of infections show a similar set of findings and outcomes, namely that unsuccessful management of severe infections is largely caused by the long delay in determining the identity of the pathogen and its antibiotic sensitivity.

Pneumonia-causing pathogens 12 and their resistances David LivermoreLevels of antibiotic resistance are rising around the world and threatening the future availability of use-ful antibiotics for treating serious infections such as pneumonia. Antibiotic resistance occurs by different mechanisms in different pathogens. The presence of resistance with poorly defined mechanisms pre-sents a huge detection challenge. In this article, the temporal spread of antibiotic resistance throughout Europe and the rest of the world will be discussed.

Challenges in testing respiratory 18 tract infections Ingo Autenrieth, Berit SchulteDue to the increasing prevalence of antibiotic resis-tant bacteria, selection of appropriate antibiotic thera-py for different types of pneumonia has become much more challenging. Today, pathogen identification and antibiotic sensitivity are based on time-consuming culture-based microbiology technology. New molecu-lar diagnostic technologies are being developed that can rapidly identify the pathogen and determine anti-biotic sensitivity in hours. The Curetis pneumonia pa-nel is highly specific and has excellent sensitivity for detecting pathogens. The correlation between genoty-pe and phenotype is reproducibly between eighty and one hundred percent. Moreover, genotype resistance testing may provide valuable results to optimize ear-ly antibiotic therapy for the treatment of pneumonia.

Would faster molecular testing make a 26difference in the current standard of care? A Microbiologist’s point of view Christine GinocchioMicrobiology culture technology is currently the stan-dard of care for determining treatment of pneumonia. But traditional microbiology methods are slow and can delay treatment of patients with the appropriate targeted antibiotic therapy. With rising antibiotic resistance, there is a need to develop new technologies that can carry out pathogen identification and antibiotic resistance testing within hours, not days. With new techniques currently being developed, this goal can be realized.

Would faster molecular testing make a 32 difference in the current standard of care? A Clinician’s point of view Antoni TorresUnder the current paradigm for treatment of pneumo-nia, the clinician must wait up to forty-eight to seventy-two hours to identify the causative microorganisms using standard microbiological culture techniques. However, treatment is required immediately and so the clinician must make potentially life-saving deci-sions without the benefit of knowing the responsible pathogen(s). Routine availability of rapid accurate, mo-lecular diagnostic tests might result in fewer inapprop-riate and inadequate antibiotic treatments.

Health Economic Modeling of the 38 impact of fast pneumonia testing Anne ThewsUnyvero™ Solution is a new multiplexed molecular as-say targeting pneumonia patients. A Health Economic (HE) model for application of this assay is discussed. Based on data published in peer-reviewed journals, the model studies the impact of this test in ventilator-associated pneumonia (VAP). The model compares the current standard of care, microbiological culture, to the new multiplexed assay. It shows that Unyvero™ Solution offers significant cost savings as well as a gain in qua-lity-adjusted life years (QALY) for a typical VAP patient.

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07

Introduction The respiratory tract is the most common source of in-fection in acutely ill patients and is one of the leading causes of death in these patients. Pneumonia can oc-cur inside the hospital or outside in the community. Greater incidence of both types of pneumonia is associ-ated with increasing antimicrobial resistance, which can both result in higher rates of morbidity and mortality as well as raise the economic burden of treating pneumo-nia. An antibiotic therapy should be given as early as possible after an initial pneumonia diagnosis (hit hard and early3). The therapeutic regimen chosen needs to take into account local antibiotic resistance patterns as well as a host of other factors and variables. Data from two large international studies conducted in patients in the intensive care unit have greatly contributed to our understanding of the growing incidence of gram-nega-tive and mixed infections as well as the growing threat of multi-drug resistant organisms around the world.

Pneumonia most frequent infectionTwo large international studies were conducted to coll-ect data on the incidence of infection and characteris-tics of critically ill patients in the intensive care unit (ICU). The first of these studies, “Sepsis Occurrence in Acutely ill Patients” (SOAP) was a multiple-center observational study of over three thousand patients admitted to ICUs across twenty-four European countries.1 The study was conducted over a two-week period from May 1 to May 15, 2002. The second study entitled, “The Extended Prevalence of Infection in Intensive Care,” (EPIC II) was designed as a one-day prospective, point prevalent stu-dy with follow-up conducted on a single day, May 8, 2007.2 It was a follow-on studyfrom the original EPIC study published in 1995.4 The EPIC II study included over fourteen thousand ICU patients treated world-wide across seventy-five participating countries.

Table 1 summarizes the major clinical and microbio-logical findings in the SOAP and EPIC II studies. As Table 1 shows, in the SOAP study, twenty-five percent of patients were initially diagnosed with sepsis upon admission to the ICU and this number increased to thirty-seven percent over the two week study period due to patients succumbing to sepsis while in the ICU.In the EPIC II study, over seven thousand pa-tients or fifty-one percent of the total number in the study were diagnosed with an infection. Nearly eighty-five percent of the infected patients were diagnosed with sepsis. The frequency of lung infections ranged from sixty-eight to sixty-four per

cent, respectively, in the SOAP and EPIC II studies.

Table 1 Clinical and Microbiology Findings SOAP and EPICS II Studies

The next most frequent infections were infections in the abdomen and bloodstream. Lung infection was the big-gest problem in patients from all countries who participa-ted in EPIC II. The mean value for lung infection globally was sixty-three percent with the highest and lowest ra-tes seen in Russia and Africa, respectively (seventy-one and forty-seven percent). The frequency of infections in the abdomen was fairly constant with an average of nineteen percent and a range from seventeen to twenty-one percent. See centerfold.

Figure 1 Infection in ICU

Pneumonia is a major problemJean-Louis VincentUniversité Libre de Bruxelles, Belgium

AbstractLung infections are a grave problem in acutely ill patients. Moreover, there is an increasing incidence of gram-negative and mixed infections as well as a growing percentage of multidrug resistant bacteria in acutely ill patients. The impact of these trends will be discussed as they relate to the manage-ment of severe sepsis and different types of pneumonia such as hospital- and community-acquired pneumonia. Results from two very large interna-tional studies that collected data from critically ill patients in the intensive care unit on the incidence and type of lung infections will be summarized here. The results from both studies show a similar set of findings and out-comes.

KeywordsSOAP, EPIC II, sepsis, hospital acquired pneumonia, ventilator acquired pneumonia


Infection rate correlates with length oftime in ICUThe length of time patients were in the ICU prior to the study day was shown to correlate directly with in-creasing rates of infection.5 As illustrated in Figure 1 there is a linear correlation between the infection rate, which increased from thirty to over seventy percent, with length of time in the ICU from one day to up to seven to ten days. Infection rates reached a plateau between seventy and eighty percent in patients ca-red for in the ICU longer than seven to ten days.

Gram-negative infections are increasing worldwideCharacterizing the microorganisms in infected ICU patients was a vital component of the EPIC II study.6

With over seven thousand infected ICU patients in seventy-five countries, these data provided valuable information about the geographical distribution of pa-thogens as well as their patterns of microbial resis-tance on a worldwide scale. The global distribution of gram-positive and gram-negative organisms is shown in the graphic in the centerfold. In all continents of the world, with the exception of North America, the meanfrequency of infections with gram-negative organismswas higher than for gram-positive organisms, with a worldwide mean value of forty-seven per-cent gram-positive and sixty two percent gram-negative organisms. The remainder of the infec-tions included mixed infections, which are quite common (twenty-three percent in SOAP) and fungal in-fections (seventeen to nineteen percent in both studies).

Another important finding from the SOAP and EPIC II studies is that gram-negative organisms are increasing in frequency. While the frequency of gram-positive or-ganisms was similar in the two studies (forty percent in SOAP, forty-seven percent in EPIC II), the frequency of immune organisms rose from thirty-eight percent in SOAP to sixty-two percent in EPIC II. This is a concer-ning trend because the frequency of multi-drug resis-tant (MDR) gram-negative organisms is also increasing. Staphylococcus species including S.aureus and S. epidermidis were the most abundant gram-positive organisms in infected ICU patients. For S. aureus, the fre-quency of MRSA ranged from a high of twenty-one per-cent in Africa to a low of nine percent in Western Europe. These data are shown in the graphic in the centerfold. In the case of gram-negative infections, Pseudomonas was the most frequent organism found in infected ICU

patients (twenty percent), followed by Klebsiella (thir-teen percent) and Acinetobacter (nine percent). The global distribution of these major gram-negative pa-thogens can be seen in the graphic in the centerfold.The frequency of gram-negative organisms was par-ticularly high in Central and South America as well as Eastern Europe, as both regions reported elevated fre-quencies of gram-negative organisms compared with the mean values worldwide. The high values for Pseu-domonas infections are troubling because Pseudomo-nas is difficult to treat and is associated with increased mortality in ICU patients. When length of time in the ICU was compared with the infection rate and associ-ated pathogens, Pseudomonas infections accounted for the greatest percentage of infections in patients treated in the ICU for longer than four to six days.2

Figure 2 Rules for therapy

Rules for antimicrobial therapySeveral approaches are typically applied in parallel when treating patients with severe infections, e.g. sep-sis. These could include infection control, hemody-namic stabilization and modulation of the immune re-sponse as shown is Figure 2. In the case of infection control, early and effective antibiotic therapy is the key to successful management. Without the knowledge of the causative pathogens, initial antibiotic thera-py is empiric and consists of a broad-spectrum anti-biotic or a combination of antibiotics. The knowledge of important factors such as prior antibiotic therapy and local antibiotic resistance patterns are important for establishing sufficient empiric treatment schemes.

The rules of choosing an antibiotic therapy are several-fold and include:

Give the appropriate antibiotic or antibiotic com-• bination, which is effective against the infectious pathogens.Start adequate antibiotic therapy as early as possi-• ble at the right dose, via the correct route of admi-nistration to maximize exposure of the antibiotic at the infection site.

The importance of providing appropriate and adequate antibiotic therapy is a vital component of successful treatment for severe infections as numerous publishedstudies have demonstrated that inadequate an-tibiotic therapy increases the mortality rate.4-16 These studies clearly demonstrate that if inappropriate and/or inadequate antibiotic therapy is administered to patients with a variety of severe infections, the mortality rate and mean duration of hospital stay is significantly increased. For example, in patients with community ac-quired blood stream infections, giving an inappropriate empiric therapy is a predictor of mortality in the patients. Patients in septic shock who received inappropriate treatment have a survival rate of less than twenty percent. In a study published by Fraser in 2006, in 920 patients with sepsis, thirty-six percent of patients given inappro-priate therapy had greater than twenty percent mortality, whereas sixty-four percent of patients receiving appro-priate therapy had only a twelve percent mortality rate.

Challenges in CAP Treatment Community Acquired Pneumonia (CAP) is pneumo-nia that originates outside of the hospital in the com-munity. Treatment guidelines for CAP are based on what we know about antibiotic resistance come from studies of hospital acquired infections and thus we might underestimate or miss the presence of MDR in the community. It is hard to define treatment for MDR in the community, as treatments are hospital-specific. This means that up to thirty percent of empiric therapies are wrong. Drug resistant organisms occur in CAP, albeit at a lower level than in nosocomial pneumonia infections.

Similar to the treatment of other severe infections, early antibiotic therapy is associated with a better outcome in treating CAP. There have been numerous publications that demonstrate giving adequate and appropri-ate antibiotic therapy early in the course of treat-ment is beneficial.17-22 However, besides the growing

threat of multi-drug resistant bacteria, CAP is also characterized by the presence of mixed or poly-microbial infections, which is a risk factor for inap-propriate initial antibiotic therapy and is associated with increased mortality in this patient population.23

VAP – poor medical outcomeVentilator Acquired Pneumonia (VAP) is a lung infection that occurs in patients who are infected in the hospital ICU during mechanical ventilation for breathing diffi- culties. The data from numerous studies confirm a similar picture described above for patients with CAP, namely that inadequate antibiotic therapy increases mortality rates.24-35 In several studies, where inapprop-riate antibiotic therapy was given, the mortality rate was greater than fifty percent.24, 29-31 This number dropped to thirty three percent when appropriate antibiotic thera-py was administered, which was also associated with a shorter duration of mechanical ventilation and fewer days in the ICU.28,33 Inappropriate therapy is linked to the presence of resistant organisms such as Pseudomonas aeruginosa, Staphylococcus aureus and Acinetobacter.

Ventilator acquired pneumonia can be further cha-racterized by the length of invasive mechanical ven-tilation. Early-onset VAP is defined as onset of pneu-monia within four days or less after mechanical ventilation. Late-onset VAP is characterized by onset of symptoms after five or more days of mechanical venti-lation. The etiology of early- and late-onset VAP differs. Typical community organisms are more frequent in early-onset VAP, whereas opportunistic and antibiotic-resistant pathogens, such as MRSA and Pseudomo-nas aeruginosa are more common in late-onset VAP.

Other risk factors for VAP that increase the likelihood of being infected with drug resistant pathogens include:4,6

Hospitalization for at least five days• Hospitalization in an acute care facility or • a nursing home within the last three monthsClose contact with someone known to be • infected or colonized with an MDR pathogenAntibiotic therapy within the last thirty days• Presence of an IV catheter for several days• Chronic hemodialysis• Prolonged wound care treatment• Immunosuppression•

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Pneumonia is a major problem Curetis Symposium ECCMID London 2012

Figure 3 Survival in Pneumonia

Figure 3 is an illustration showing how overall survival in community and hospital acquired pneumonia is af-fected by the type of pathogen (sensitive or resistant toantibiotics), the site of infection (community or hospi-tal acquired) and concomitant risk factors that vary ac-cording to other diseases the patients may have. Not surprisingly, the chances of survival are the lowest in HAP patients infected with drug resistant bacteria andpatients with CAP have the highest probability of survival.

Guiding antibiotic therapyTypical clinical measurements used to diagnose a pati-ent with severe infection include:

Evidence of signs and symptoms such as increa-• sed fever, increased white blood cell count etc.Evidence of lung infection as determined by a • clinical examination, a positive X-ray and the pre-sence of purulent sputumMicrobiological findings such as tracheal aspirate • and bronchiolavage samples.

The use of antibiotics is based on the presence and se-verity of the symptoms listed above. If a patient is di-agnosed with severe infections, combination antibiotictherapy is the preferred treatment strategy.37, 38 Com-bination antibiotic therapies increases the chances of being effective and when given early, avoids the delay in adding another antibiotic later. This empiric antibiotic therapy with wide coverage is typically given in ge-nerous doses at the outset, however with the growing incidence of drug-resistance it might fail and support the development of new resistances. Thus, once the bacteriological data are available after two to three days, the antibiotic spectrum should be narrowed and adjus-

ted based on the microbiological findings. Since micro-biology culture techniques are very slow, in most cases these data is provided too late in the decision process.

The additional use of molecular diagnostic techno-logies used in parallel to identify the pathogen rapid-ly could assist in the decision making process to se-lect the appropriate antibiotic therapy and thus may improve medical outcome.

ConclusionsPneumonia is a real medical challenge. The results of large multicenter studies delivered a clearer picture of the severity of the problem on a worldwide scale. A con-founding issue in the successful management of pneu-monia is the long delay in determining the identity of the pathogen and its antibiotic sensitivity. Current guideli-nes for the treatment of pneumonia are based on the standard of care, which delays the identification of thepathogen by two to three days due to the time it takes to culture the organism. One way to reverse the current upward trend in the spread of MDR and to control thegrowing incidence of gram negative- and mixed in-fections is to implement new diagnostic technologies to speed up the process of pathogen and resistance identification. Rapid, accurate tests are needed which enable clinicians to identify microorganisms and deter-mine antibiotic sensitivity quickly. The additional use of molecular diagnostic technologies used in parallel to identify the pathogen rapidly could assist in the de-cision making process to select the appropriate anti-biotic therapy and thus may improve medical outcome.

1Vincent J-L, Sakr Y, Sprung CL, et al. 2006. Crit. Care Med.

34:344-353.2Vincent J-L, Rello J, Marshall J, et al. 2009. JAMA. 302:2323-2329.3Quotation Paul Ehrlich, 1913.4Vincent J-L, Bihart D, Suter PM. et al. 1995. JAMA. 274:639-644.4Celis et al., Chest 93: 318-24, 19885Torres et al., Am Rev Respir Dis 142: 523-8, 19906Kollef, JAMA 270: 1965-9, 19937Kollef et al., Ann Intern Med 122: 743-9, 19958Alvarez-Lerma et al, Intensive Care Med 22: 387 94, 19969Rello et al., Am J Respir Crit Care Med 156: 196-200, 199710Luna et al, Chest 111: 676-85, 199711Kollef & Ward, Chest 113: 412-20, 199812Heyland et al., Am J Respir Crit Care Med 159:1249-56, 199913Ibrahim et al., Chest 118: 146-55, 200014Dupont et al., Intensive Care Med 27: 355-60, 200115Iregui et al., Chest 122: 262-8, 200216Rello et al., Crit Care Med 32: 2183-90, 200417Kahn et al., JAMA 264: 1969-73, 199018McGarvey and Harper, QRB 19: 124-30, 199319Meehan et al, JAMA 278: 2080-4, 199720Gleason et al., Arch Intern Med 159: 2562-7, 199921Rello et al., Intensive Care Med 28: 1030-5, 200222Houck et al., Arch Intern Med 164: 637-44, 200423Cilloniz C et al., Crit. Care 15:R209, 201124Celis et al., Chest 93: 318-24, 198825Torres et al., Am Rev Respir Dis 142: 523-8, 199026Kollef, JAMA 270: 1965-9, 199327Kollef et al., Ann Intern Med 122: 743-9, 199528Alvarez-Lerma et al., Intensive Care Med 22: 387-94, 1996

29Rello et al., Am J Respir Crit Care Med 156: 196-200, 199730Luna et al., Chest 111: 676-85, 199731Kollef & Ward, Chest 113: 412-20, 199832Heyland et al., Am J Respir Crit Care Med 159:1249-56, 199933Dupont et al., Intensive Care Med 27: 355-60,200134Iregui et al., Chest 122: 262-8, 200235Rello et al., Crit Care Med 32: 2183-90, 200436Vincent JL et al., Drugs 70: 1927-1944, 201037Micek et al., Antimicrob. Agents Chemoth. 54:1742, 201038Kumar et al., Crit. Care Med. 38: 1651 and 1773,2010

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Pneumonia is a major problem Curetis Symposium ECCMID London 2012

Jean-Louis Vincentis Professor of intensive care at the Université Libre de Bruxelles and Head of the Department of Intensive Care at the Erasme University Hospital in Brus-sels. He is presently Secretary General of the World Federation of Societies of Intensive and Critical Care Medicine, a Past-President of the European Society of Intensive Care Medicine, the European Shock Society, and the International Sepsis Forum. He received several awards (Society of Critical Care Medicine, American College of Chest Physicians, European Society of Intensive Care Medicine and Belgian FRS-FNRS).

CorrespondenceProf. Dr. Jean-Louis VincentProfessor of Intensive Care MedicineULB Hôpital ErasmeRoute de Lennik 8081070 Bruxelles,Belgium

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Introduction Pneumonia is categorised according to the loca-tion of onset. Community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) are the ma-jor, well-defined types of pneumonia and HAP can be further divided into ventilator–acquired (VAP) and non-ventilator acquired pneumonia. The major pa-thogens of CAP are Streptococcus pneumoniae and Haemophilus influenzae, whilst staphylococci and En-terobacteriaceae are more important in HAP and VAP, with Pseudomonas aeruginosa and Acinetobacter bau-mannii becoming more likely where the patient has been hospitalized or ventilated for a prolonged period.

Some authors recognise a third type of pneumonia, ter-med ‘Healthcare-associated pneumonia HCAP’, occur-ring in healthcare settings outside of the hospital, such as nursing homes and other long-term care facilities and with a microbial aetiology that overlaps both CAP and HAP.1 Others argue that the classical pathogens of CAP still dominate in long-term care facilities and that most ‘HCAP’ patients really have underlying problems such as chronic obstructive pulmonary disease or bron-chiectasis, which anyway have a bacteriology closer to that of HAP.

Antibiotic resistance is increasingly prevalent among important pneumonia pathogens in many parts of the world, and is a growing public health concern. Infec-tions by resistant strains result in greater morbidity and mortality, as empirical therapy is more likely to prove ineffective, and increase the cost of treatment.

As strains become more resistant to first- and second-line therapies, there is a growing need to replenish the supply of antibiotics, but antibiotic development has slowed in recent years, confounded both by low disco-very rates and regulatory hurdles as well as by the finan-cial reality that antibiotics are less profitable to the phar-maceutical industry than many long-term treatments.2

Antibiotic resistance trends in Europe: community pneumoniaThe main pathogens of community acquired pneumonia are S. pneumoniae and H. influenzae; other important agents are ‘atypicals’ such as Mycoplasma, Chla- mydophilia and Legionella.

Results from the European Antimicrobial Resistance Surveillance network (EARS-Net)3 show that the pro-portion of S. pneumoniae bacteraemias due to strains

non-susceptible to penicillin or resistant to erythromycinincreased from 2000 to 2010 in several European coun-tries (see maps in the centerfold).1 Moreover, despite the growing recent availability of modern conjugate vacci-nes directed against the pneumococcal serotypes whe-re resistance is most prevalent, there has been no dra-matic, Europe-wide reduction in resistance from 2005 to 2010. Reductions nevertheless have been seen in par-ticular regions or countries, for example in Scandinavia and the United Kingdom, where a previously prevalent serotype 14 macrolide-resistant strain has been subs-tantially displaced since the deployment of the vaccine.4

Data from the Health Protection Agency (courtesy AP Johnson), covering the UK except Scotland, confirm the EARS-net finding that erythromycin resistance among bloodstream pneumococci decreased between 2004 and 2011 from approximately fourteen percent to four percent. But show that resistance increased in respira-tory pneumococci from fourteen percent in 2007 (when surveillance began) to nearly eighteen percent in 2011. Such data suggest that vaccine deployment is affec-ting only invasive disease. Non-susceptibility to peni-cillin among pneumococci from blood and respiratory infections in the United Kingdom remained low and steady at around three- and six percent, respectively.

International data on resistance prevalence in H. in-fluenzae are scantier than for S. pneumonia following the termination of previous international surveys such as the Alexander Project. Nevertheless local trends may be striking, and a multicenter surveillance in Spain showed that the prevalence of ampicillin resistance in H. influenzae dropped from approximately thirty-eight percent of isolates in 1996 to sixteen percent in 2007.5

The proportion of isolates with ß-lactamase decreased from over twenty-five percent to fifteen percent over the period whilst those with non ß-lactamase resistance al-most disappeared, falling from thirteen percent to one percent.5 Such benign trends can, however, hide con-cerning shifts. In Spain Garcia-Cobos,6 found great di-versity among circulating isolates with non-ß-lactama-se-mediated ampicillin resistance, with some showing markedly reduced cefotaxime susceptibility. This diver-sity implies that H. influenzae has great potential to evol-ve and to adapt rapidly to confront ß-lactam challenges.

Pneumonia-causing pathogens and their resistances David M LivermoreNorwich Medical School, University of East Anglia, Norwich, UK

AbstractThe prevalence of antibiotic-resistant bacteria is rising around the world. Given the lack of new antibiotics, this development is threatening our capacity to treat serious infections such as pneumonia. In this article, the temporal trends of resistance among pneumonia pathogens throughout Europe and the rest of the world are discussed, and the major resistance mechanisms of these pathogens are outlined.

KeywordsAntibiotic resistance, resistance mechanisms, pneumonia


Hospital pneumoniaThe pathogens of hospital pneumonia are more diverse than those of community pneumonia, prominently in-cluding S. aureus, Enterobacteriaceae and – particularly in late onset disease - P. aeruginosa and A. baumannii.

In the case of S. aureus, methicillin resistance has long been prevalent in most countries outside Scan-dinavia and the Netherlands. Although improved in-fection control has recently reduced the MRSA rate across much of Europe, these reductions are not universal and, even where they have been achie-ved, MRSA still remains a frequent pathogen.

In the case of Enterobacteriaceae there have marked increases in resistance to cephalosporins and quino-lones in the past decade,7 and some countries (inclu-ding Greece, Cyprus, Hungary and Italy) are now also reporting substantial numbers Klebsiella (and few of other Enterobacteriaceae) isolates resistant even to carbapenems; elsewhere in Europe, Enterobacteria-ceae with carbapenemases are increasingly becoming established, at least locally, including in pneumonia.8

Among relevant non-fermenters, P. aeruginosa shows very variable resistance rates across Europe, low in the north and west, and much higher in the sou-th and east, independently of antibiotic class. This is illustrated on the maps in the centrefold, show-ing resistance rates in 2010 to aminoglycosides, carbapenems, ceftazidime and fluoroquinolones.1

A. baumannii has long been widely resistant to anti-biotics except carbapenems and, since around year 2000, this pathogen has become substantially more resistant even to carbapenems,9 leaving only colistin and tigecycline as widely active in vitro – and neither of these is an ideal antibiotic for therapy in pneumonia.

Figure 1 Resistance mechanism among CAP pathogens

Resistance mechanisms among CAP pathogensIf pathogen identification and resistance detection is to move from classical culture-based microbio-logy to molecular methods, as with the Unyvero™ system, it is necessary for these new methods to re-cognize prevalent resistance mechanisms. These are complex, variable, and can entail either muta-tion or acquisition of foreign DNA, with the impor-tance of their mechanisms contingent on the species. Mechanisms of antibiotic resistance in the pathogens of CAP are summarized In Table 1. In S. pneumoniae, re-sistance to macrolides and tetracycline depends largely on acquired genes, as does tetracycline and trimetho-prim resistance in H. influenzae whereas, in both spe-cies, quinolone resistance is mutational. Resistance to ß-lactams involves a complex mixture of mutation and mosaic gene formation in S. pneumoniae,10, 11 as does low-level ampicillin resistance in H. influenzae. High-level ampicillin resistance in H. influenzae depends on acquisition of the blaTEM gene. In pneumonia (unlike meningitis) low-level resistance to ß-lactams in thesespecies in can be overcome by increased dosage.

Resistance mechanisms among HAP pathogensThe varied pathogens of HAP and VAP demonstrate a wide diversity of resistance mechanisms.

In the case of MRSA, methicillin resistance is determi-ned by the acquired (though rarely transferred) mecA gene, which is easily detected by PCR. On the other hand ‘resistance’ to vancomycin – the drug most often used in MRSA pneumonia – is far more complex. True vancomycin resistance, with MIC >2 mg/L, is extremely rare, but there are assertions, not universally confirmed, that MICs of 2 mg/L are associated with poorer outco-mes than MICs of <1 mg/L, including in pneumonia.12

The mechanism(s) responsible for these slightly elevated high vancomycin MICs are unclear and testing is con-founded by wide MIC ranges (0.25 to 2mg/L) counted as acceptable for control strains by the CLSI and EUCAST.

Most resistance in Enterobacteriaceae is associated with acquired resistance genes, often carried by plasmids, variously encoding ß-lactamases, aminoglycoside mo-difying enzymes, rRNA methylases, antifolate by-pass enzymes or tetracycline efflux pumps. The carbapenem resistance emerging in Klebsiella pneumoniae involves the genes encoding KPC, IMP, VIM, NDM, OXA-48 car-bapenemases, all of which are detectable by PCR.13

Extended-spectrum ß-lactamases (ESBLs) present a more complex story: most are CTX-M types, which al-ways have ESBL activity, but others – the TEM and SHV ESBLs- are point mutants of narrower-spectrum en-zy-mes. A few resistances in Enterobacteriaceae are large-ly or entirely mutational: the best example is quinolone resistance, which mostly occurs by mutation of gyrA/B and parC/E genes. The genetic mechanisms of resistance to a very few antibiotics – notably polymyxins and nitrofu-rantoin – remain poorly defined even after 50 years of use.

Several multiply-resistant Enterobacteriaceae clonal clones have become internationally disseminated. Two major examples are, firstly, the E. coli ST131 lineage, which commonly carries the CTX-M-15 ESBL (or, more rarely, other CTX-M ESBLs) along with multiple other resistance and, secondly, ST258 K. pneumoniae with KPC carbapenemases which is now disseminated in the USA, Israel, Greece and Italy14-16 and scattered else-where in Europe, South America and Asia. Members of the ST258 lineage usually are resistant to all antibiotics except colistin, gentamicin and tigecycline, but vari-ants resistant to colistin are circulating in Greece, and have been found in Hungary and the Uited Kingdom.

In contrast to Enterobacteriaceae, P. aeruginosa – a particularly problematic gram-negative pathogen with inherent resistance to many antibiotic classes – largely accrues further resistance to relevant treatments by mu-tation, with gene acquisition. being much rarer.17 Mutati-onal changes conferring important resistances include:

Up-regulation of chromosomal AmpC ß-lacta-• mase, resulting in resistance to penicillins and cephalosporinsUp-regulation of efflux, compromising (depending • on the particular pumps affected) all antibiotics except imipenem and polymyxinLoss of porin OprD, resulting in resistance or redu-• ced susceptibility to carbapenemsReduced cytoplasmic membrane transport, resul-• ting in resistance to aminoglycosidesDNA gyrase mutations resulting in resistance to • quinolonesMultiresistant• P. aeruginosa strains usually have combination of these mutations though a few have acquired genes include for ß-lactamases and carbapenemases.

A. baumannii acquires antibiotic resistance by a num-ber of mechanisms. Resistance is often associated with acquired genes, as in Enterobacteriaceae, with

these variously compromising penicillins, aminoglyco-sides, tetracyclines, antifolates and chloramphenicol. In some cases these genes are carried on plasmids, as in Enterobacteriaceae; in others they are chromoso-mally integrated, often on large ‘resistance islands’.18 Resistance to carbapenems may involve acquired car-bapenemase genes but can also arise by ISAba1-me-diated activation of the chromosomal blaoxa-51-like gene which occurs in all A. baumannii isolates but which is not ordinarily expressed. Activation arises because the transposable ISAba1 element, inserted upstream of the carbapenemase gene provides an efficient promoter, which blaoxa-51-like ordinarily lacks. 19 ISAba1 can similar-ly activate the chromosomal ampC ß-lactamase gene of A. baumannii increasing cephalosporin resistance.19

ConclusionsAntibiotic resistance is a growing public health chal-lenge that complicates the treatment of pneumonia, whether community or hospital acquired. Several con-clusions can be drawn, all relevant to the molecular detection of resistance:

The pathogens that are associated with different • types of pneumonia are well known. Ongoing surveillance over the past ten years has shown that resistance rates and trends vary by country in Europe and the rest of the world.The conjugate pneumococcal vaccine has proved • lifesaving, and has reduced the prevalence of some resistant lineages of pneumococci. However serotype replacements have occurred and effects on the prevalence of non-bacteraemic pneumonia are far less clear. Antibiotic resistance occurs by different mecha-• nisms in different pathogens. Gene acquisitions, mutation and gene of mosaics are all important. The general pattern is that resistance mostly arises by gene acquisition in Enterobacteriaceae, Acine-tobacter, and S. aureus. Mosaics are important in transformation-competent species such as pneu-mococci, whereas gene mutation is the predomi-nant mechanism in P. aeruginosa.The occurence of low-level resistance with poorly • defined mechanisms presents a huge detec-tion challenge, particularly for future molecular methods. For example, the mechanism behind slightly raised vancomycin MICs in some MRSA is not well understood.The challenge to molecular resistance detection is • to seek and represent this diversity of resitance; the potential is that detection will be far swifter

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Pneumonia-causing pathogens and their resistances Curetis Symposium ECCMID London 2012

than by classical culture-based microbiology, per-mitting much swifter refinement of antibiotic thera-py, to the benefit of both the individual patient and of antibiotic stewardship.

1 Ewig s et al., Cite Curr Opin Infect Dis. 2012 Apr;25(2):166-75.2 Theuretzbacher U. Int J Antimicrob Agents. 2012 Apr;39(4):295-9.

Epub 2012 Feb 143 http://ecdc.europa.eu/en/activities/surveillance/EARS-Net4 Livermore DM. Int J Antimicrob Agents. 2012 Apr;39(4):283-94. Epub

2012 Mar 3. Review5 Pérez-Trallero E, Antimicrob Agents Chemother. 2010 Jul;54(7):2953-

9. Epub 2010 May 36 Garcia-Cobos S. et al., Antimicrob. Agents Chemother. 51:2564-2573.

20077 Livermore DM et al., J Antimicrob Chemother 2007 Feb;59(2):165-74 8 Cantón R et al, Clin Microbiol Infect. 2012 May;18(5):413-319 Woodford N et al., FEMS Microbiol Rev. 2011 Sep;35(5):736-55.10 Hakenbeck R, et al., Future Microbiol. 2012 Mar;7(3):395-410.

Review.11 Choi EY et al. Intensive Care Med. 37:639-647201112 Haque NZ.et al., Chest 138:1356-1362. 201013 Cuzon G, et al, J Antimicrob Chemother. 2012 Aug;67(8):1865-9.14 Giakkoupi P et al. J Antimicrob. Chemother. 66:1510-1513. 201115 Woodford N et al., FEMS Microbiol. Rev. 35:736-755 201116 Andrade LN et al, Antimicrob. Agents Chemother. 55:3579 17 Livermore DM, Clin. Infectious Diseases 34:634-640 200218 Post V, et al., J Antimicrob Chemother. 2010 Jun;65(6):1162-70. Epub

2010 Apr 719 Turton JF et al., FEMS Microbiol Lett. 258:72-7. 2006

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Pneumonia-causing pathogens and their resistances Curetis Symposium ECCMID London 2012

David Livermoreworked at the London Hospital Medical College from 1980 until 1997, when he joined the Health Protection Agency (HPA), becoming Director of its Antibiotic Resistance Monitoring and Reference Laboratory in 1998, where he remained until October 2011. Since then he has had a split role, as Professor of Medical Microbiology at the University of East Anglia and Lead on Antibiotic Resistance for the HPA. He has broad interests on the evolution, mechanisms and epide-miology of antibiotic resistance.

CorrespondenceDavid LivermoreProf. of Medical MicrobiologyNorwich Medical School,IFR2/Innovations Centre,University of East Anglia,Norwich NR4 7TJ

19

Introduction Pneumonia is a common and serious infection in the community as well as in hospitals. In Germany, se-ven hundred and fifty thousand cases of Community Acquired Pneumonia (CAP) occur every year and five to ten cases of Hospital Acquired Pneumonia (HAP) are diagnosed in every one thousand hospital-patient admissions. Pneumonia can result in high morbidi-ty and in mortality as high as twenty-five to fifty per-cent. Known critical outcome factors include delaying antimicrobial therapy, pathogen virulence, co-morbi-dity risk factors, the immune status of the patient and underlying lung pathology. Treatment of pneumonia accounts for the majority of antibiotics prescribed.

Due to the growing incidence of antibiotic resistant bac-teria, testing for multi-drug resistance (MDR) is a requi-rement in selecting the appropriate antibiotic therapy. Standard tests using microbiology culture methods are time-consuming since the pathogen must first be grown in culture for up to two days before antibiotic sensitivity tests are performed. Molecular diagnostic tools could both speed up pathogen identification and determine genes associated with antibiotic resistance. Both ad-vances would be highly desirable. Using rapid, accurate molecular diagnostics, clinicians might be able to se-lect appropriate, targeted antibiotic therapy for patients with pneumonia much earlier than can be done today.

Gram-negative pathogens are abundant in pneumoniaThe spectrum of pathogens that cause pneumonia va-ries from one form of pneumonia to another. Apart from gram-positive pathogens Streptococcus pneumoniae and Staphylococcus aureus, gram-negative organisms such as Pseudomonas aeruginosa, Klebsiella sp., Acinetobacter and Enterobacteriaceae are abundant. Moreover, multidrug resistant gram-negative pathogens are increasing in frequency. They are hard to treat and are responsible for increased morbidity and mortality.

The most frequent pathogens that cause CAP are Streptococcus pneumoniae (thirty-seven percent) and Chlamydophila pneumoniae and Haemophilus in-fluenzae that occur in thirteen and eleven percent of cases, respectively. In HAP, the spectrum is different: Staphylococcus aureus and Pseudomonas aeruginosa are the major pathogens. These are present in approxi-mately twenty-seven to twenty-eight percent of cases. In contrast, Staphylococcus aureus is present in only three percent of CAP. The spectrum in Ventilator Acqui-

red Pneumonia (VAP) is similar to HAP, except that Aci-netobacter baumannii and Enterobacteriaceae are pre-sent at fairly high levels (seven percent and six percent), compared to low to undetectable levels in HAP and CAP. The variable pathogen spectrum presents a challenge in selecting appropriate antibiotic therapy. Because of the time delay to identify the pathogen, initial an-tibiotic therapy is empiric and is based on guide-lines that have been developed and published by different authoritative societies and associations.1-3

Figure 1 Increase in multi-resistant pathogens in Intensive Care Units

(SARI) (http://www.inarchive.com/de/i/ipse-freiburg.de)

MDR Pathogens are increasing in German inten-sive care unitsFigure 1 illustrates the growing problem in gram-ne-gative MDR pathogens in German intensive care units (ICUs). The project, Surveillance of Antibiotic Use and Bacterial Resistance in Intensive care Units (SARI) tra-cked the incidence of MDR pathogens from 2001 to 2009 in fifty five ICUs in Germany.4 There was an overall, steady increase of all drug resistant pathogens moni-tored, which included methicillin-resistant Staphylococ-cus aureus (MRSA), vancomycin-resistant Enterococci (VRE), imipenem-resistant Acinetobacter baumannii, 3rd generation cephalosporin-resistant Escherichia coli (CREC) and Klebsiella pneumoniae. Of particular con-cern is the striking increase in CREC, which was barely detectable in 2001 but increased ten-fold in less than ten years. Other pathogens, such as imipenem-resistant Acinetobacter baumannii and VRE, also increased over seven- and six-fold, respectively over the study period.4

Similar results were obtained by the European Antimi-crobial Resistance Surveillance network (EARS-Net).5

Challenges in testing respiratory tract infectionsIngo B. Authenrieth, B. SchulteUniversity Hospital Tübingen, Germany

AbstractDue to the increasing prevalence of antibiotic resistant bacteria, selection of appropriate antibiotic therapy for different types of pneumonia has become much more challenging. Over the past decade, both the diversity of gram-ne-gative pathogens associated with respiratory tract infections and the antibiotic resistance associated with those pathogens has risen dramatically. Today, pathogen identification and antibiotic sensitivity are based on time-consuming culture-based microbiology technology, which takes several days to complete. This delay requires that antibiotic therapy is initiated without this critical infor-mation. However, new molecular diagnostic technologies are being developed that can rapidly identify the pathogen and determine antibiotic sensitivity in hours. These technologies may provide an opportunity to accelerate treatment decisions so that appropriate targeted antibiotic therapy can be initiated much sooner. Now, multiplexed molecular diagnostic platforms are becoming commercially available that can determine within a few hours and in a single assay both the identity of a pathogen or pathogens as well as their antibiotic sensitivity. How-ever, there are few data available describing the phenotype-genotype correlati-on for antibiotic susceptibility testing. This article will review our first results in comparing phenotype and genotype in MDR bacteria.

KeywordsGram-negative organisms, antibiotic resistance, multiplexed molecular diag-nostics, respiratory tract infections, pneumonia


From 2002 to 2009, the proportion of CREC and MRSA was monitored in 198 laboratories in twenty-two coun-tries. The proportion of MRSA remained constant at approximately twenty to twenty-two percent of total S. aureus infections throughout the study period. How-ever, the percentage of CREC rose during the study period from approximately 2.5 percent in 2002 to over nine percent in 2009. Both studies confirm the troub-ling increase in rates of multi-resistant gram-negative pathogens in ICUs and on general hospital wards.

Current testing procedures for respiratory tract infectionsOne challenge in diagnostic testing is that samples are heterogeneous but answers have to be uniform. Sample types come from a broad range of body fluids such as spu-tum, tracheobronchial aspirate, bronchoalveolar lavage fluid as well as pleural puncture, blood culture, urine and serum. Figure 2 shows the variety of sample types that are routinely analyzed in clinical microbiology laboratories.

Figure 2 Range of sample types in LRT testing

Despite the great differences in viscosity, particulate content and pH, pathogen identification must be car-ried out in a reproducible and reliable way. Today, the standard method involves traditional microbial culture. Antibiotic susceptibility testing is typically carried out in a second culture step using a standard battery of tests. Both steps are time consuming and can take up to forty-eight hours. Moreover, they are not always reli-able since some pathogens (e.g., Chlamydophila, Pneu-

mocystis) are hard to culture and there is limited detec-tion of some resistance pathways (e.g., ß-lactamases). Other classic microbiology methods include serology in which seroconversion or immunoglobulin titers are measured to confirm the presence of organisms such as C. pneumoniae, L. pneumophila and M.pneumoniae. Urinary antigen tests can detect L. pneumophila and S. pneumoniae. The disadvantages of antigen tests are low sensitivity, in the range of seventy percent or lower.10

Rapid, molecular diagnostic assays can identify pathogens in hoursThere are some molecular diagnostic tests availablebased on polymerase chain reaction (PCR), which can identify organisms including C. pneumoniae, L. pneumophila, M. pneumonia and P. jirovecii. However, there is a need for robust diagnostic technology that can provide accurate and reproducible pathogen detec-tion rapidly in hours. A number of molecular assays have been developed that decrease the detection time of pa-thogens. Most of these assay methods rely on conven-tional PCR or real time PCR and have been described in detail in several recent publication.6,7 It is still too early to validate the clinical utility of these molecular diagnostic tests but it will be important that tests are standardized appropriately, be thoroughly evaluated in clinical trials for sensitivity and specificity, and be widely available.7 Not all limitations have been addressed by currently available rapid, molecular diagnostic methods. Most tests only detect a small spectrum of pathogens and only a few resistance determinants are available in rapid assay format. Antibiotic sensitivity testing largely still depends on the need to culture the organism. This delay may have a negative clinical impact on treating lung infections. However, one can imagine a future where rapid detection of pathogens, and resistance mechanisms are determi-ned in standardized assays that will enable clinicians to diagnose respiratory tract infections in real time and ini-tiate appropriate antibiotic therapy as early as possible.

A Comprehensive Multiplexed Molecular Diagnostics PlatformCuretis AG (Holzgerlingen, Germany) has developed a novel, multiplexed diagnostic panel.8 An early version of this panel used for the current analysis contained markers for seventeen pathogens chosen due to their prevalence in patients hospitalized due to pneumo-nia. The panel also contained twenty-two antibiotic resistance markers that are most relevant for the lung pathogens on the panel. The panel was designed to target over ninety percent of pneumonia-associated

Figure 3 Curetis panel

pathogens and to predict clinically relevant anti-biotic resistance information, including MDR testing.

Genotype identification of the seventeen pathogens is based on differentiating 23S rRNA sequences and can simultaneously detect the presence or absence of twen-ty-two resistance markers. The complete assay was performed using a PCR-based multiplex assay and was based on eight multiplex PCR reactions carried out using an ep gradient Mastercycler® made by Eppendorf.8 Pathogen identification and antibiotic sensitivity were thus measured simultaneously and were able to provide real-time, relevant information about the presence or ab-sence of pathogens and their antibiotic resistance genes.8

The resistance genes and pneumonia pathogens that are present on the Curetis panel are listed in Figure 3. In our study, the multiplexed PCR assay was used to assess the presence of MDR in gram-negative bacte-ria in 239 clinical isolates containing 196 Enterobac-teriaceae, including forty-three non-fermenting orga-nisms.9 Nearly two hundred isolates were defined as MDR with resistance to at least three antibiotic clas-ses. Detection of MDR was achieved by three classi-cal Ambler class A beta-lactamases (tem, shv, ctx-M)and two families of plasmid encoded ampC ge-nes (Ambler class C). In addition, an integrase gene, int1 was included as a surrogate marker for MDR.9

The experiment shown in Figure 4 measured the sensi-tivity and specificity of pathogen detection in 239 isolatesusing the molecular diagnostics assay. The results were compared to the values obtained by traditional clini-cal microbiology. The results show that ninety percent of pathogens were identified correctly. There were no false positive results of non-MDR phenotypes. Sensi-tivity ranged from ninety-one percent to one hundred percent and specificity was one hundred percent for all isolates tested.

Figure 4 Pathogen detection: sensitivity and specificity

We carried out to determine the correlation between phenotype and genotype in Escherichia coli.9

(continued on page 24)

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Challenges in testing respiratory tract infections Curetis Symposium ECCMID London 2012

71,6%

17,4%

21,4%

NA

28,1%

2322

Summary of the EPIC II Study and EARS-Resistance Data Summary of the EPIC II Study and EARS-Resistance Data

Gram-neg 55,3%

3,9%

8,8%

yes

13,3%

Gram-pos 50,1%

27,3%

17,4%

56,8%

16,6%

Gram-neg 63,2%

3,9%

9,7%

yes

5,6%

Gram-pos 38,5%

22,1%

10,9%

49,3%

21,1%

Gram-neg 70,4%

13,9%

16,3%

26,2%

Gram-pos 38,5%

19,3%

11,2%

66,3%

17,4%

Gram-neg 57,9%

15,8%

17,5%

yes

17,5%

Gram-pos 50,9%

29,8%

21,1%

46,7%

17,4%

Gram-neg

Gram-pos 50,8%

22,1%

10,9%

70,8%

20,1%

Gram-neg 74,5%

19,0%

20,2%

yes

27,7%

Gram-pos 33,3%

15,4%

9,7%

66,2%

17,2%

Gram-neg 56,4%

4,0%

11,1%

NA

13,8%

Gram-pos 52,9%

27,7%

8,9%

56,8%

17,1%

kpc

kpc

kpc

kpc

kpc

kpc

Source: European Centre for Disease Prevention and Controlhttp://ecdc.europa.eu/en/activities/surveillance/EARS-net/database/Pages/database.aspxJean-Louis Vincent et al: International Study of the Prevalence and Outcomes of Infection in Intensive Care Units. EPIC-II. JAMA. 2009;302(21):2323-2329

P. aeruginosa Resistance in EuropeEARS data, 2010

Please see also ´Pneumonia-causing pathogens and their resistances´, D.Livermore

Prevalence of macrolide resistance in bloodstream pneumococci, 2000 and 2010 (EARS-Net Database)

Prevalence of penicillin non-susceptibility in bloodstream pneumococci, 2000 and 2010 (EARS-Net Database)

Please see also ´Pneumonia-causing pathogens and their resistances´, D.Livermore

Please see also ´Pneumonia is a major Problem´, J-L Vincent

Aminoglycosides (R)

Carbapenems (R)

Ceftazidime (R)

Fluoroquinolones (R)

Pneumonia

Abdomen

Gram-neg

Acinetobacter

Klebsiella

KPC

Pseudomonas

kpc

Gram-pos

Staphylococcus

MRSA

In this experiment, ninety-three clinical E. coli isolates containing a wide range of different antibiotic resis-tance genes, with phenotypic resistance to penicillin, CREC, carbapenem, gyrase inhibitor resistance and MDR were analyzed by the Curetis PCR bioassay to determine the genotype. The phenotype was deter-mined by standard antibiotic susceptibility testing. The results showed a good correlation between the phenotype and genotype for penicillin-, 3rd generati-on cephalosporin-, carbapenem- and gyrase inhibitor resistance with sensitivity ranging from eighty-three percent to one hundred percent.9 MDR was assessed in this study by the presence of int1 and showed a phenotype-genotype correlation of fifty-three percent. In addition we compared the phenotype-genotype correlation for Pseudomonas aeruginosa. This pheno-type-genotype comparison study was carried out with twenty-eight clinical Pseudomonas aeruginosa isola-tes. The range of antibiotic resistance included peni-cillin-, carbapenem-, gyrase inhibitor-resistance and MDR. Genotype was determined using the Curetis PCR bioassay and the results were compared with the phe-notype, which was measured by antibiotic susceptibi-lity testing. Sensitivity of the genotype assay ranged from eighty-six percent for MDR and carbapenem to one hundred percent for the other types of resistance.9

ConclusionsRapid molecular diagnostic assays have the potenti-al to speed up pathogen and resistance identification, which may enable clinicians to make an early, infor-med diagnosis in patients with pneumonia. The Curetis panel is highly specific and has excellent sensitivity for detecting pathogens. The correlation between geno-type and phenotype is reproducibly between eighty and one hundred percent. Moreover, genotype resis-tance testing may provide valuable results to optimize early antibiotic therapy for the treatment of pneumonia. A multicenter clinical study with patient samples to determine the specificity and sensitivity of Curetis Unyvero™ Solution for respiratory tract in-fection samples is underway and a clinical study to address the impact of molecular diagnostics using the Curetis bioassay on clinical outcomes in pati-ents with respiratory tract infections will be initiated. The clinical trials will need to show a benefit in terms of decreased antibiotic use, positive effects on anti-microbial resistance, better patient outcomes, and decreased overall cost.

1. Woodhead et al., Clin. Microbiol. Infect. 17 (Suppl. 6):E1-E59 20012. American Thoracic Society; Infectious Diseases Society of America

Am. J. Respir. Crit. Care Med.171:388-415. 20053. Höffken G et, AWMF 082/001, 20094. Mattner F et al., Dtsch Arztebl Int. 108:39-45. 2012.5. Add EARS-Net ref6. Endimiani A et al., Clin. Infectious Dis. 52:S373-S383 20017. Nolte F. Clin. Infectious Dis. 47:S123-S126.20088. Barth S et al., Eur Infectious Dis. 2012;6(1):14-89. Schulte B et al., ECCMID Poster 2012 2959, 201010. Macros MA, et al., Eur Respir J. 2003 Feb;21(2):209-14.

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Challenges in testing respiratory tract infections Curetis Symposium ECCMID London 2012

Ingo Autenriethstudied medicine at the Universities of Ulm (GER) and Dundee (UK) and received his training in Medical Microbiology and Hygiene at the University of Würzburg. After his habilitation he was a postdoc at the Swiss Institute for Experimental Cancer Research, Lausanne (CH), and Professor of Medical Microbiology at LMU Munich.Since 2000 he has been Professor for Medical Microbiology and Hygiene at Eberhard-Karls-Universität Tübingen. He currently serves as Dean of the Medical Faculty.

CorrespondenceProf. Dr. Ingo Autenrieth Chair for Medical Microbiology and Hygiene, Medical FacultyInstitut für Med. Mikrobiologie und HygieneElfriede-Aulhorn-Str. 672076 TübingenGermany

IntroductionIdentification of non-viral respiratory pathogens in a pa-tient with pneumonia is currently a slow process. Using traditional culture-based microbiology methods, it can take from twenty to sixty hours before initial informationabout the types of organisms causing the infection and an appropriate targeted antibiotic therapy is recom-mended to the clinician. Since pneumonia can be a life-threatening infection, starting appropriate antibiotic therapy as quickly as possible is critical. If a patient is not treated initially with the appropriate antibiotic regi-men, this can result in increased morbidity or mortality.

In attempting to identify respiratory pathogens quickly and reliably, clinical microbiologists have traditionally faced a critical and insurmountable delay due to the need to culture the organism. The standard of care thus requires generally eighteen to twenty four hours to grow the pathogen(s) from a patient sample and an additional six to forty-eight hours to identify the pathogen and to carry out antibiotic sensitivity testing. With the steady

Figure 1 Comparing traditional and modern Microbiology

rise of antibiotic resistance, rapid pathogen identifica-tion is a key component in identifying those patients who require treatment and promoting the use of targeted therapies.1 Combined with accurate antibiotic sensitivity testing, this information should be beneficial in decrea-sing the use of broad-spectrum antibiotics and promo-ting good antibiotic stewardship.2 The need for increa-sed speed to identify respiratory pathogens has been a driving force for both established and start-up compa-nies to develop new technologies to solve the problem.

New platform technology developmentsMany new platform technologies have focused on au-tomation of the standard microbiology procedures. Technologies have been developed that incorporate both pathogen identification and susceptibility testing in a fully automated system (e.g., bioMerieux’ Vitek® 2, Microscan’s Walkaway®). These technologies also re-quire a culture step to grow the organism and typically take from five to twenty-four hours following the culture

27

Would faster molecular testing make a difference in the current standard of care?A Microbiologist`s point of view Christine Ginocchio North Shore-LIJ Health System School of Medicine, New York, USA

AbstractMicrobiology culture technology is currently the standard of care for the treat-ment of pneumonia. Traditional microbiology methods are slow and can delay treatment of patients with the appropriate targeted antibiotic therapy. With rising antibiotic resistance, there is a need to develop new technologies that can carry out pathogen identification and antibiotic resistance testing within hours, not days. A number of technologies are in development that can bring automated, molecular diagnostic approaches into play. These approaches may allow to shorten the sample-to-answer timeframe and provide an accurate treatment recommendation. The time course could thus be reduced from up to three days to a few hours. If these new platforms can perform successfully in a variety of clinical situations and can respond rapidly to emerging pathogens, pandemic infectious diseases and other potential threats, they have the potential to change the standard of care for the treatment of pneumonia. Over time, the use of molecular technolo-gies should permit microbiology testing to move closer to the patient and farther away from the centralized clinical microbiology laboratory. Rapid, fully or par-tially automated molecular diagnostic technologies have the potential not only to improve patient care but also to help the community by decreasing antibiotic resistance in the population and improve and promote good antibiotic steward-ship.

KeywordsPneumonia, molecular diagnostics, rapid pathogen identification, antibiotic sensitivity testing


period to obtain results for pathogen identification and antibiotic sensitivity testing. Some companies have developed automated plate reading. This advance im-proves the efficiency of the laboratory technician but does not circumvent the need to culture the micro-organism and thus does not significantly impact the twenty- to sixty-hour timeline to deliver results to the clinician. Several companies such as Bruker and bio-Mérieux have been successful in greatly accelerating the time to pathogen identification with MALDI-TOF mass spectrometry, these systems can identify the pathogen within fifteen minutes from culture isolates. Figure 1 depicts how automation coupled with traditi-onal microbiology culture has improved the process of pathogen identification. However, even though patho-gen identification can be accomplished very rapidly, the technology does not address the need for antibiotic sensitivity testing, which is a critical and time-consu-ming component of identifying the appropriate therapy for the patient. Instead of requiring three to four days using manual culturing techniques, it is now possible with the use of modern technologies such as automated plate reading and MALDI-TOF, to cut this time in half, to one and a half to two days. However, although the problem of pathogen identification has been solved, the need for initial culture to perform antibiotic sensitivity testing is still the rate limiting and often costly step.

New challenges for the microbiology laboratoryWith the rising problem of drug and multi-drug resis-tance, clinical microbiologists are often faced with the need to carry out supplemental susceptibility testing.3 These tests include the D test, the Extended Spectrum ß-lactamase (ESBL) confirmatory test, the Modified Hodge Test to screen for the presence of Klebsiella carbapenemase (KPC) and the metallo ß-lactamase test. These tests can add another eighteen to twen-ty-four hours to the overall time before initial diagno-sis and also add significant increased overall costs, To conclude, even with modern techniques still current commercially available microbiology methods take too long and are too slow for clinicians to adjusted an-tibiotic therapy for patients with pneumonia in time.

The diagnostic challengeTo identify respiratory pathogens in conjunction with antibiotic resistance markers rapidly within hours as opposed to days, new technology is needed. This can only be accomplished by the development of mole-cular diagnostic technologies that no longer depend

on the need to grow and culture the organism. Com-panies such as Idaho Technologies (www.idahotech.com) and Curetis AG (www. Curetis.com) are develo-ping molecular diagnostic technologies to deliver on this goal. By incorporating new multiplexed molecular analysis, these technologies can combine pathogen identification and antibiotic sensitivity testing in a single automated procedure within hours after collecting the patient sample. Figure 2 is an illustration of the simp-licity of steps required to go from the patient bedside to making a rapid informed targeted therapy decision.

Figure 2 Molecular-based approaches

Molecular diagnostics will change the standard of careOver the long term, combining traditional microbiolo-gy procedures with molecular diagnostic approaches will change the standard of care for patients. Slow microbiology procedures, typically carried out in large, centralized clinical laboratories might be replaced or supplemented over time by fully automated, fast mo-lecular diagnostic tests that can be performed close to the patient. Automation and simplification of molecu-lar diagnostic platforms will facilitate adoption of mo-lecular testing platforms in contexts in which specially trained microbiology technicians are in short supply. Furthermore, treatment decisions must be made

in a variety of clinical testing scenarios. Therefo-re, molecular diagnostic platforms must be tailored to support a variety of clinical testing needs across a continuum of care including microbiologists, clinici-ans and administrators. In addition to patient diag-nostic and antimicrobial therapy testing, other tes-ting needs must be addressed. These needs include:

Support of clinical trials and clinical • microbiology researchBiosurveillance at the unit, hospital and • regional levels Sentinel laboratory surveillance •

All of these diverse testing needs must be successfully addressed in order to promote better clinical manage-ment and improve overall patient outcomes and costs. Additionally, new technology platforms need to adapt to emerging infectious diseases and constantly chan-ging infectious disease threats. Recent examples in-clude the August 1999 West Nile outbreak, the Sep-tember 2001 anthrax postal office contamination biothreat, the 2003 SARS outbreak, the April 2009, pandemic H1N1 infection and the persistent th-reat of avian influenza, which first appeared in 1997. Diagnostic impact of new molecular diagnostic technologies.Increasing antibiotic resistance is becoming a major bur-den for healthcare systems as resistance adds time and costs to therapy and often results in increased length of hospital stay and increased mortality. Infections with multidrug resistant (MDR) strains that do not respond to any therapy option are increasing at a steady and alarming rate. Figure 3 a-d is an illustration of the situation in the New York greater area: the frequency of infection with me-thicillin resistant Staphylococcus aureus (MRSA) has increased from 20% in the early 90’s to over 60% from 1999 onwards. Acinetobacter resistance to several an-tibiotics including Imipenem, Meropenem and Unasyn can be as high as 50 to 90% in a sampling of com-munity hospitals. Similarly, antibiotic resistant strains of Klebsiella carbapenemase (KPC) are present in community hospitals (CH) and a tertiary care facility (TC) in the range of 5% to 35%, with significant variati-on from year to year over a seven-year period. Finally, there have been many documented increases in adult Clostridium difficile-associated disease (CDAD) infec-tions. Figure 3 illustrates the changes in age-specific CDAD per 10,000 people in the US from 2000- 2005.4 One conclusion from these data is that despite wide- Figure 3 a-d Resistance situation in the New York greater area

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Would faster molecular testing make a difference in the current standard of care? A Microbiologist`s point of view


spread efforts to promote antibiotic stewardship pro-grams, the situation is not improving. Molecular-based tests that allow accurate clinical decisions to be made in hours as opposed to days offer a promising ap-proach to this problem – however it remains to be pro-ven over time, if there is a positive diagnostic impact by decreasing antibiotic resistance in the population.

Prerequisites for successful implementationThe incorporation of a rapid, molecular diagnostic platform into the decision making process for patho-gen identification and selection of appropriate targe-ted antibiotic therapy will yield numerous and measu-rable benefits for patients, healthcare providers and payers. Improving the turnaround time to hours (from days) will have a positive impact on patient manage-ment and outcome. Current diagnostic services will improve, laboratory costs will decrease, and those la-boratory procedures that still occur will require less technician support and decreased ancillary testing.

However, successful implementation of such molecular diagnostic platforms must demonstrate and satisfy a number of important criteria before it will be widelyadopted. These include:

Consistently perform at a high level of technical • proficiencyProduce accurate clinical results that correlate • with the diseaseHave high positive and negative predictive values • that can discriminate between a true infection versus colonizationProvide an initial informative screening tool that • can be followed up with standard culture

Multiplexed diagnostic platforms have the potential to demonstrate superior clinical utility by early diagnosis that improves proper care, and decreases morbidity and mortality. Some of the benefits may include the following:

Permit more appropriate use of anti-virals and/or • antibioticsAllow effective institution of infection control • measuresIncrease efficiency of hospital bed utilization, • decrease the length of hospitalization and thus decrease overall costsShorten treatment times through an improved and • faster workflowDecrease the “fear factor” in the community •

Provide relevant surveillance and epidemiology • data as well as identify “unusual” patterns or potential outbreaksProvide physician and patient satisfaction •

ConclusionIn conclusion, many criteria need to be fulfilled to make this future a reality. However, molecular technology has the potential to address the major problems faced by clinicians when treating patients with respiratory infec-tions. If the use of rapid molecular diagnostic testing can be successfully implemented, it has the potential to change the standard of care for patients with pneu-monia, improve patient management, outcomes and overall costs and promote good antibiotic stewardship.

1Ginocchio CC. CID 54 (Suppl. 4) S312-S325, 20012MacDougall C et al., Clin. Microbiol. Rev. 18:638-656. 20053Low DE. Clin. Microbiol. Infect. Suppl 3:9-20. 20024Zilberberg MD et al., Emerging Infectious Diseases 14:929-931, 2008

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Christine C. Ginocchio, PhD, MT (ASCP)is the Senior Medical Director and Chief, Division of Infectious Disease Diag-nostics, Professor, Departments of Pathology and Laboratory Medicine and Molecular Medicine, Feinstein Institute for Medical Research, North Shore-LIJ Health System School of Medicine. She is Co-Editor-in-Chief of the Journal of Clinical Virology and President of the Pan American Society for Clinical Virology.

CorrespondenceProf. Christine Ginocchio, PhDChief, Division of Infectious Disease Diagnostics Department of Pathology and Laboratory MedicineNorth Shore-LIJ Health System Laboratories10 Nevada DriveLake Success, NY 11042,United States of America

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IntroductionTreating a critically ill patient diagnosed with pneu-monia is both challenging and vital as lung infec-tions can be life threatening. At the time of initi-al diagnosis, the etiology is usually unknown and the clinician must make potentially life-saving de-cisions based on an incomplete clinical picture.

Selecting appropriate antibiotic therapy in a timely fa-shion is critically important as early antibiotic therapy correlates with overall decreased mortality. The time taken to make this decision is known at the therapeu-tic turnaround time (TTAT).1 TTAT consists of the time taken from when the first test is ordered based on a diagnostic hypothesis to receiving the test results and initiating appropriate treatment. In conditions such as diabetes and circulatory shock, for which there are rapid, standardized tests such as glucose monito-ring and measuring blood lactate levels, TTAT can be carried out successfully using point-of-care testing.1 The clinical situation in treating pneumonia patients is much more complex. Community-acquired-, hospital-acquired- and ventilator-acquired-pneumonia are good examples of serious infections illustrating the challenges clinicians face in making an accurate, timely diagnosis and initiating appropriate therapy. Microbiology culture technology is the standard for identifying pathogens as-sociated with pneumonia, and thus requires from forty-eight to seventy-two hours before the pathogen is iden-tified. Urinary antigens are not always available as the urine stick test has poor sensitivity and cannot be multi-plexed. This delay requires that the clinician prescribes empiric antibiotic therapy at the outset of treatment.

Figure 1 Initiating antibiotic treatment

Treatment of Community Acquired Pneumonia (CAP) In ninety to ninety-five percent of cases of Commu-

nity Acquired Pneumonia (CAP), initial antibiotic the-rapy is empiric. Pathogens that cause CAP vary by geographical area as well as by underlying risk fac-tors.2 In a significant percentage of CAP patients, infections can be polymicrobial, viral in nature, or contain pathogens, which are multi-drug resistant (MDR). For these kinds of infections, it would be use-ful to have a rapid molecular diagnostic test to assist with the diagnosis and the decision making process. A key aspect is the time it takes to start antibiotic treatment. As Figure 1 shows, if antibiotic thera-py is delayed for more than six-hours after arriving at the emergency room, the mortality rate is increased. By six hours, sixty-five percent of patients have recei-ved antibiotics but the remaining thirty-five percent have not. Even after twelve hours, over ten percent of pati-ents have not received antibiotic therapy. These stu-dies emphasize the importance of beginning early anti-biotic treatment as quickly as possible after diagnosis.

There are several variables that influence the choice of empiric treatment of patients diagnosed with CAP. As patient-specific etiological information is often un-available at the time of diagnosis, initial antibiotic therapy must take into consideration local patterns of microbial etiology, as well as risks factors asso-ciated with the initial severity of illness in the patient. In a study of 3,523 patients diagnosed with CAP, pa-tients were stratified into low-, intermediate- and high-risk categories and were treated accordingly.3 As shown in Figure 2, newly diagnosed CAP patients were treated either as low risk outpatients (fifteen per-cent) or intermediate or high risk inpatients (eighty-five percent), according to the age of the patient, comor-bidities and the initial severity of the illness. Inpatients were either treated on the hospital ward or in the ICU according to their pneumonia severity index. Microbi-al etiology was determined in 1,474 patients and was shown to vary according to their site of care and cor-responding pneumonia severity scores.3 Streptococ-cus pneumoniae infections and mixed infections in-creased in frequency in patients treated in the hospital ward and the ICU compared with outpatients. Thirty five percent of outpatients compared with up to forty three percent in hospitalized and ICU patients were in-fected with Streptococcus pneumoniae. In contrast, in-fection with atypical organisms including Mycoplasma pneumoniae, Chlamydophila pneumoniae and Coxiel-la burnetti as well as Legionella pneumophila showed

Would faster molecular testing make a difference in the current standard of care?A Clinician`s point of viewAntoni TorresUniversity of Barcelona, Barcelona, Spain

AbstractInitial selection of appropriate antibiotic therapy for a patient with pneumonia is a critical early step in the successful management of the disease. Under the current paradigm, the clinician must wait up to forty-eight to seventy-two hours to identify the causative microorganisms using standard microbiological culture techniques. However, treatment is required immediately and so the clinician must make potentially life-saving decisions without the benefit of knowing the responsible pathogen(s). In most cases, broad spectrum or empiric antibiotic therapy is given as early as possible after diagnosis. However, the increasing presence of mixed infections and the ever-present and increasing probability of multi-drug resistant pathogens further complicates this decision. Thus the availability of rapid molecular diagnostic tests could be beneficial in identifying responsible pathogens early in the diagnostic process to guide the clinician to-wards prescribing adequate and appropriate antibiotic therapy.

KeywordsCommunity associated pneumonia, Hospital-acquired pneumonia, Ventilator associated pneumonia, molecular diagnostics


the opposite trend. Infections with atypical bacteria, including Legionella, decreased from thirty-six per-cent in outpatients to sixteen and fourteen percent in patients treated in the hospital ward and the ICU, respectively. There was a similar decrease in the fre-quency of viral infections from three percent in the ICU compared with nine percent in the outpatient populati-on. These data confirm that atypical bacterial pathogens are a low-risk condition and are found in patients with mild forms of community acquired infections. However, infections with pathogens such as S. pneumoniae as well as mixed infections were associated with increasing mortality and correlated well with increasing disease severity and need for greater level of inpatient care.

Figure 2 Etiology of CAP

Another important variable that must be taken into con-sideration when selecting the initial antibiotic therapy is assessing the probability of the presence of a polymi-crobial or mixed infection. A prospective observational study was carried out to evaluate the outcome of poly-microbial infection in ICU patients diagnosed with severe CAP.2 The study consisted of 362 patients who were ad-mitted to the intensive care unit within twenty-four hours after presentation. In this group of patients, 196 patients (fifty-four percent) had a diagnosed etiology of which, 157 were infected with a single pathogen and thirty-nine patients were diagnosed with mixed infections. Patients with mixed infections included thirty-three cases with two pathogens and six cases with three pathogens. The results showed that in patients infected with a single pathogen, ninety percent received appropriate empiric antibiotic therapy. By contrast, in patients diagnosed with more than one pathogen, nearly forty percent were treated inappropriate empiric therapy. Pathogens most frequently associated with inadequate treatment were MRSA in ten cases, and Streptococcus pneumoniae, Pseudomonas aeruginosa and gram-negative enteric bacilli in nine cases each.2 Since mixed infections are becoming more frequent, these results support the need

to initiate broad empiric antibiotic therapy early after di-agnosis as well as highlight the importance of identifying the pathogens as quickly as possible to initiate appro-priate targeted therapy. The frequency of MDR is incre-asing in the general population also. Prina has shown that MRSA strains of Staphylococcus aureus, MDR strains of Pseudomonas aeruginosa and ESBL+ Entero-bacter species are increasing in the general population.

Treatment of Hospital Acquired Pneumonia (HAP)Hospital-acquired pneumonia (HAP) is a frequent and severe infection in patients treated in intensive care units. In patients diagnosed with HAP, eighty percent of initial antibiotic treatment is empiric. Inadequate in-itial treatment is associated with worse outcomes and a greater economic cost. Similar to CAP, polymicrobial infections occur frequently in twenty-five percent of di-agnosed patients. Drug resistant pathogens are com-mon and although it is helpful to carry out gram stains and to quantitate intracellular organisms in bronchi-olavage fluid, the delay of up to seventy-two hours to obtain definitive microbiology culture results requires that initial treatment is started without this information.

In 2010, organisms known to be associated with HAP were studied at the national level in Spain. Many dif-ferent pathogens were shown to play a role in HAP (Informe 2010). The results showed that the most fre-quent organisms are Pseudomonas aeruginosa, Sta-phylococcus aureus and Acinetobacter baumanii, all of which are known to be associated with increasing MDR.

Treatment guidelines for adults with different type of pneumonia are a useful tool in guiding empirical anti-biotic therapy e.g., guidelines for treating HAP were published by the American Thoracic Society and the In-fectious Diseases Society of America or other European societies. They are based on classifying patients into two groups according to the time of onset of infection (early versus late onset) and the presence or absence of risk factors for infection with potentially drug-resistant microorganisms. Since guidelines are based on scien-tific evidence and expert recommendations, it is impor-tant to validate them in the clinical setting. Therefore, a study was conducted in 276 HAP patients treated in the ICU.4 Two patients groups were selected according the guidelines: group one consisted of thirty-eight early onset patients without potentially drug-resistant micro-organisms and group two consisted of 238 patients with either late onset infection or had risk factors for poten-tially drug resistant microorganisms. The results of the

validation study were striking. Microbial prediction was lower in group one (fifty percent correct) than group two (ninety-two percent correct). The major cause for this discrepancy was the presence of potentially drug resis-tant microorganisms in twenty-six percent of patients in group one. Ten patients in group one were infected with Pseudomonas aeruginosa and MRSA. Adherence to the guidelines produced a more adequate treatment trended towards a better clinical response in group two but it did not impact mortality or length of stay in the hospital.4 Although the number of patients in group one was small, these results highlight the limitations of treatment guidelines since they do not predict well the presence of potentially drug-resistant microorganisms, which are increasing in frequency throughout the world.

Treatment of Ventilator Acquired Pneumonia (VAP)A number of published studies have demonstrated that inappropriate initial empiric therapy is associated with increased mortality in Ventilator Acquired Pneumonia (VAP).5-9 Figure 3 illustrates that percent mortality can be greater than ninety percent with inappropriate initial empiric therapy 6, 8 and as low as twenty five percent in other clinical studies.5 In all studies, patients did bet-ter if they were treated with adequate antibiotic the-rapy. When pathogens associated with inappropriate therapy were determined, they consisted of organisms that are known to be difficult to treat and have a high level of MDR such as Pseudomonas spp., Staphylo-coccus aureus, Acinetobacter and Enterobacteriacae.

Figure 3 Mortality after inappropriate initial empiric therapy

Application of molecular diagnostics in the treatment of VAP Faster detection of respiratory pathogens and their associated antibiotic resistances would be a welcome addition to the clinician’s toolkit for treating VAP and other serious forms of pneumonia. Molecular diag-

nostic kits and assays for some single pathogens are becoming available and are being used to assist in ra-pid diagnosis of microorganisms. For example, RT-PCR can detect directly the presence of MRSA within fifty minutes after receiving a tracheal aspirate sample.10

(Cercenado, ICAAC abstract, 2009) Some potential benefits of rapid molecular diagnostic testing include:

Obtain immediate diagnosis and treatment• Minimize further testing• Avoid unnecessary admissions• Avoid unnecessary antibiotics• Shorten length of hospital stay• Decrease costs of treatment.•

Treatment costs associated with pneumonia are highThe need for mechanical ventilation of a pneumonia pati-ent is often the primary reason for admission to an ICU.11

Table 1 Costs of VAP

Although this can be a life-saving procedure for the patient, it is associated with a number of risks. Ac-cording to the National Nosocomial Infection Surveil-lance system, the frequency of VAP is increased in ICU patients and is associated with increased mortality, lon-ger stays in the ICU and the hospital, and higher costs of treatment. Table 1 shows outcomes and costs of VAP in ICU patients in a suburban medical center. Patients who develop VAP during their hospital stay require longer ICU and hospital length of stay. The increased level of care and need for additional invasive procedures drastically increase healthcare costs. The total average hospital costs for a pneumonia patient without VAP is approximately $21,000. The average cost jumps to over $70,000 in patient with VAP, due to a greatly increa-sed mean length of stay in the ICU from four to twen-ty six days, and a corresponding increase in hospital length of stay from thirteen to thirty eight days (Table 1). The treatment of late onset VAP is even more ex-pensive as it further increases hospital length of stay in days and is associated with increased mortality.12,13

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ConclusionsPneumonia is a serious, potentially life-threatening di-sease associated significant morbidity and mortality as well as high economic costs. Pneumonia is a global health economic issue that is getting more costly as the prevalence of MDR pathogens continues to increase around the world. Molecular diagnostics offers a poten-tial solution to the problem by addressing some of the critical steps in making a successful timely diagnosis and initiating adequate antibiotic therapy. Having rou-tine availability of rapid accurate, molecular diagnostic tests might result in fewer inappropriate and inadequate antibiotic treatments by increasing the percentage of pathogen-directed targeted treatments, thus producing better outcomes and significantly decreasing the cost of treatment.

1Kost GJ et al.,Chest 115:1140-1154. 1999.2Cilloniz et al., Critical Care 15:R209. 20113Cilloniz et al., Thorax 66:340-346. 2011.4Ferrer M et al., Clinical Infectious Diseases 50:945-952. 20105Alvarez-Lerma F. Intensive Care Med. 22:387-394. 1996.6Celis R et al., Chest 93:318-324. . 1988. 7 Kollef MH et al., Chest113:412-420. 19988Luna CM, Vujacich et al., Chest 111:676–685. 19979Rello J at al., Am J Respir Crit Care Med. 156:196–200 199710Cercenado ICAAC abstract 200911Warren DK et al., Crit. Care Med. 31:1312-1317. 200312Rello J et al., Chest 122:2115-2121. 200213Kollef MH at al., Chest 108:1655-1662. 1995.

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Antoni Torresis chief of the Respiratory ICU and Professor at the Faculty of Medicine at the University of Barcelona. He coordinates a project on LRTI of the Spanish Society of Pneumology and Thoracic Surgery and on Pneumonia of Ciberes. He actively participates in many European projects like GRACE, Theraedge and MOSAR and is member of the editorial board of the 14 international journals.

CorrespondenceProf. Antoni TorresHead of Intensive Care UnitDepartment of Pneumology and Respiratory AllergyClinical Institute of the Thorax.Hospital Clínic of Barcelona.

Cap de Secció UVIRServei de PneumologiaCatedràtic de MedicinaHospital ClínicVillarroel, 17008036 BarcelonaSpain

39

IntroductionAdoption of new diagnostics in today’s healthcare systems is driven by clinical utility as well as econo-mic factors. Despite demonstrating improvement in medical outcome in clinical studies, hospital adminis-tration and payers demand assessment of total cost of ownership prior to investing in new technologies. Clinical trials demonstrating an economic benefit for new approaches are difficult to design, time-consuming and expensive. Thus health economic models can be used to demonstrate the medical and the economic value of a new diagnostic tool. This article describes a model that was built to show the benefit of fast mul-tiplexed molecular diagnostics in pneumonia testing – the Curetis AG product called Unyvero™ Solution – based on published data in peer-reviewed journals.

Rational for HE modelsA Health Economic (HE) model tries to under-stand the balance of the benefits of a certain new technology compared to its costs (see Figure 1).

Figure 1 Balance of costs and benefits in health care

Therefore HE models focus on key cost drivers that impact implementation decisions of a given procedure. They capture:

1. direct medical cost e.g.; Hospitalizaotion• Primary drug costs• Physician visits• Diagnostic procedures •

2. direct non-medical costs e.g.; Transportation •

3. indirect costs e.g.; Reduced work productivity. •

In addition these models assess the life years gained and the Quality of Life defined by:

Personal perception of health• Pain• Mobility• Ability to function in daily living• Ability to work• Level of emotional well being• Feeling of energy • Social interactions.•

A quality-adjusted life year (QALY) takes into account both quantity and the quality of life generated by healthcare in-terventions. It is the arithmetic product of life expectancy and a measure of the quality of the remaining life years.

Most often these models build on Cost Benefit or Ef-fectiveness Analysis a comparative analysis of alter-native courses of action in terms of cost, clinical and quality of life outcomes and quantifying incremental cost-effectiveness (Figure 2).

Figure 2 Concept of HE models

Pneumonia – a medical and economic burdenHospital acquired infections are a serious challenge in today’s healthcare settings. Pneumonia, for example, is associated with high mortality rates and high costs of treatment.1,2 The difficulty in managing these infections is complicated by the fact that when patients present with acute symptoms, the clinician must quickly deci-de upon an anti-microbial therapy, usually within hours. Accurate and specific diagnostic information is fre-quently not available. Current diagnostic platforms are based on traditional microbiology culture techniques and typically take 48-72 hours to provide a diagnosis of the specific pathogen and associated resistances. This delay requires that initial antibiotic therapy is em-piric and is adjusted when the specific pathogens and their associated resistances are determined. As a re-

Health economic modeling of the impact of fast pneumonia testing Anne ThewsCuretis AG, Holzgerlingen, Germany

AbstractIn an era of cost cutting in health care budgets around the world, the imple-mentation of any new diagnostic test can present a challenge, even if its clinical utility can be proven. Both hospital administrators and payors would be interes-ted in understanding the total cost of ownership of new diagnostic procedures as well as the potential cost savings before investing into new products. The demonstration of the economic impact of new technologies in clinical trials is cumbersome but health economic modeling can address those needs. This article discusses the Health Economic (HE) model for a new multiplexed mole-cular assay (Unyvero™ Solution) targeting pneumonia patients. Based on data published in peer-reviewed journals, the model studies the impact of this test in ventilator-associated pneumonia (VAP). The model compares the current stan-dard of care, microbiological culture, to the new multiplexed assay. It shows the potential of significant cost savings as well as a gain in quality-adjusted life years (QALY) for a typical VAP patient.

KeywordsHE model, VAP, multiplexed molecular testing, costs, quality-adjusted life-years

sult, approximately thirty-eight percent of patients may receive inadequate or inappropriate treatment leading to significant increases in morbidity and mortality. 2,3

as shown in Table 2. A meta-analysis of seven publi-cations showed an average mortality of 28.9 percent which was used as input variable for the HE Model.

Table 2 Mortality Rates

In addition, inadequate treatment can increase the length of hospital stay as well as time spent in the intensive care unit, which results in increased healthcare costs. Based on the review of 4 publications, the model used the average LOS and costs as illustrated in Table 3. 1,2,3,4

Consequently, there is a window of time during the early stages of clinical management of the pneumonia patient when fast, multiplexed diagnostics can play a vital role by providing both medically effective and cost-effective care.

Table 3 Average LOS and Costs in VAP

Pneumonia Health Economic modelingWe conducted an extensive economic analysis as it relates to fast testing of pneumonia. The goal was to objectively assess, by use of a Health Economic model, the potential economic effects of implementation of fast

multiplexed assay for pneumonia. The economic assess-ment was focused on ventilator-associated pneumonia, an important subset of hospital-acquired pneumonia. The model is based on published data comparing medical and economical outcome in patients having received adequate treatment with a cohort that had received inadequate antimicrobials. The hypothe-sis is that the results of the fast molecular-based tes-ting enables earlier adequate antibiotic treatment and therefore has the potential to cut costs and save lives.

This analysis included comparisons of healthcare costs (expressed as cost benefit or cost effectiveness) per patient managed both by standard-of-care today and by medical care that we envision will be availa-ble with the Curetis system, see Figure 3a and 3b.

Figure 3 Comparison of current practice (3a) to new approach using

the fast molecular assay (3b)

In addition, the analyses included estimates of in-creased number of life years and/or quality-adjusted life years gained from use of the Curetis’ solution.

The model, developed in cooperation with Halteres Associates LLC, incorporated the following variables:

Percentage of patients who receive inadequate • versus adequate therapyCosts of anti-microbial therapy• Costs per day in hospital and / or ICU• Mortality due to adequate versus inadequate • therapyNumber of cultures run per patient• Median age of patient• Life expectancy of average patient• Sensitivity of testing• Costs of standard of acre versus the • Unyvero™ assay

True-positives, respectively false-negatives are defined as illustrated in Figure 4.

Figure 4 Definition of true-positive and false-negative results

Outcome of the HE model The results of the health economic analysis are presen-ted in Table 4. Looking at the overall costs per VAP patient with above US $ 30 k, the proportion of costs for dia-gnostics does not fall into account at all. The re-sults of the modeling demonstrated that patient management based on fast molecular testing withtechnologies like the Unyvero™ Solution compared

to current practice based on traditional microbiologycan be cost-saving with of up to $785 for a patient 1. with pneumonia. These numbers do not include the incremental value of life years saved (Figure 5 a) may save 0.9 life years per patient, which could be 2. valued at $45,000, assuming a $50,000 willingness to pay per incremental life year saved /Figure 5 b).

Fast molecular testing saves has the potential to save cost and could provide incremental life years and thus Curetis Unyvero™ Pneumonia tests dominates current culture methods.

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Health economic modeling of the impact of fast pneumonia testing

Table 4 Impact of Curetis` solution

for pneumonia on economics of

managing patients

Figure 5a and 5b Results of the VAP HE Model

Conclusion This economic analysis focused on estimating the value of time to obtaining a rapid diagnostic result for the treat-ment of VAP. The ultimate value of achieving the analyti-cal results in one work shift could have a major impact on cost savings and the potential to gain in quality of life..

Thus Curetis Unyvero™ P50 Pneumonia Application do-minates current cultured–based pneumonia diagnostics.

1.Rello J et al, Am J Respir Crit Care Med 1997;156:196–2002. Kollef et al, CHEST 2005; 128:3854–3862.3. Kollef et al CHEST 1999; 115:462–474). 4. Rello et al, Am J Respir Crit Care Med 1997;156:196–2005 Rello et al, Eur Respir Rev 2007; 16: 103, 33–39. 6 Ost D E, American Journal of Respiratory and Critical Care Medicine

2003; 168(9): 1060-1067

Acknowledgment

David A. Hendricks, PhD, Harald Rinde MD, MBA and Louis J. Rice-

berg, PhD at Halteres Ascociates, (Emeryville, California, US) which

have developed the model in 2009.

Halteres Ascociates, LCC

5858 Horton Street, Suite 550

Emeryville, CA 94608-2170

www.halteresassociates.com

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Health economic modeling of the impact of fast pneumonia testing Notes

Anne Thews, MDis Head of Medical Affairs and co-founder of Curetis AG. Before joining Curetis, Anne Thews was Marketing Manager at Philips Medical Systems. She previously held leading marketing and sales support positions at Beckman Coulter. She has a strong industry track re-cord during the past 20 years. She combines professi-onal experience as a marketing specialist with internati-onal responsibilities as a trained medical doctor and as manager in charge of a clinical diagnostics laboratory for many years (University Hospital Mainz, Germany).

CorrespondenceDr. Anne ThewsDirector Medical AffairsCuretis AG Max-Eyth-Str 4271088 HolzgerlingenGermany

Contact:

Curetis AGMax-Eyth-Str. 4271088 HolzgerlingenGermany

Phone: +49 (0)7031 / 49195-10E-Mail: [email protected]

www.curetis.com

Documents

Bacterial Pneumonia and Emerging Antibiotic Resistance€¦ · Bacterial Pneumonia and Emerging Antibiotic Resistance ECCMID 2012 Curetis Symposia Proceedings April 1, 2012 London,