JAC Advance Access originally published online on September 20, 2007
Journal of Antimicrobial Chemotherapy 2007 60(5):1124-1130; doi:10.1093/jac/dkm356
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Risk factors of carbapenem-resistant Klebsiella pneumoniae infections: a matched case–control study
1 Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece 2 Department of Medicine, Tufts University School of Medicine, Boston, MA, USA 3 Department of Medicine, Henry Dunant Hospital, Athens, Greece 4 Department of Medicine, University Hospital of Heraklion, Heraklion, Greece 5 Intensive Care Unit, Henry Dunant Hospital, Athens, Greece 6 Department of Microbiology, Henry Dunant Hospital, Athens, Greece 7 Department of Microbiology, University Hospital of Heraklion, Heraklion, Greece
* Correspondence address. Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Greece. Tel: +30-694-611-0000; Fax: +30-210-683-9605; E-mail: m.falagas{at}aibs.gr
Received 7 June 2007; returned 27 July 2007; revised 17 August 2007; accepted 21 August 2007
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Abstract |
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Background: Carbapenems are frequently used to treat infections due to extended-spectrum ß-lactamase-producing Klebsiella pneumoniae. Thus, the emergence of infections due to carbapenem-resistant K. pneumoniae (CRKp) is a major public health concern.
Objectives: To identify risk factors associated with the development of CRKp infections.
Methods: We conducted a matched case–control study in two hospitals (Henry Dunant Hospital, Athens, Greece and University Hospital of Heraklion, Crete, Greece). The controls were selected among patients with carbapenem-susceptible K. pneumoniae (CSKp) and were matched with CRKp cases for site of infection.
Results: One hundred and six patients were included in our study (53 cases and 53 controls). Mortality was 30.1% and 33.9% for patients with CRKp and CSKp infections, respectively (P = 0.83). Bivariable analysis showed that exposure to anti-pseudomonas penicillins (P = 0.004), carbapenems (P = 0.01), quinolones (P < 0.001) and glycopeptides (P < 0.001), as well as admission to the intensive care unit (P = 0.002), tracheostomy (P = 0.02), chronic obstructive pulmonary disease (P = 0.04), surgery with use of foreign body (P = 0.04) and mechanical ventilation (P = 0.02) were associated with CRKp infection. The multivariable analysis showed that exposure to fluoroquinolones [odds ratio (OR) 4.54, 95% confidence intervals (CIs) 1.78–11.54, P = 0.001] and exposure to antipseudomonal penicillins (OR 2.57, 95% CI 1.00–6.71, P = 0.04) were independent risk factors for CRKp infections.
Conclusions: Our data suggest that prior exposure to fluoroquinolones and antipseudomonal penicillins are independent risk factors for the development of CRKp infections.
Keywords: imipenem , meropenem , polymyxins , colistin , multidrug-resistant , mortality
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Introduction |
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Klebsiella pneumoniae, one of the most important Gram-negative bacterial pathogens, has caused worldwide concern because of its ability to produce extended-spectrum ß-lactamases (ESBLs). Therefore, clinicians have frequently used carbapenems as a tool to treat patients with infections because of ESBL-producing K. pneumoniae.1 Unfortunately, owing to the selective pressure put on the bacterium, K. pneumoniae strains resistant to carbapenems have emerged.2–5 The need for the treatment of patients with infections due to carbapenem-resistant Gram-negative bacteria6 such as K. pneumoniae (but also Pseudomonas aeruginosa and Acinetobacter baumannii) has led to the revival of polymyxins as a therapeutic solution.7
There are few reports regarding the risk factors for acquisition of carbapenem-resistant K. pneumoniae (CRKp).8,9 We performed a matched case–control study to evaluate potential risk factors for isolation of CRKp infections in patients hospitalized in two tertiary medical centres in Greece.
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Design of the study
A matched case–control study was conducted at ‘Henry Dunant’, a 450 bed tertiary-care hospital in Athens, Greece and the 650 bed University Hospital of Heraklion, Crete, Greece. Data were extracted from patient records by S. V. or F. C. at the Henry Dunant Hospital and D. K. at the University Hospital of Heraklion.
Patients with infections caused by CRKp hospitalized during the period 1 October 2000 to 1 May 2006 and 1 October 2003 to 1 May 2006 at the Henry Dunant Hospital and the University Hospital of Heraklion, respectively, were identified from the databases of the Microbiology Laboratories of the hospitals.
For each patient with CRKp infection, we selected a matched control patient from the pool of patients with carbapenem-susceptible K. pneumoniae (CSKp) infections. We used a stepwise matching technique to identify the appropriate control patient matched to a case for the site of infection, age ± 5 years and length of hospital stay up to isolation of CRKp ±3 days and year of hospital admission.
Identification of CRKp and other pathogens was performed using routine microbiological methods. Susceptibility testing for meropenem and imipenem was performed by both the disc diffusion method and an automated broth microdilution method (bioMerieux, Vitek II, Hazelwood, MO, USA). CRKp was defined as such when the MIC level was 
16 mg/L. Susceptibility testing for ertapenem was not performed.
Definitions of infections and outcomes
Infections were defined based on guidelines from the Centers for Disease Control and Prevention.10 The primary outcome measure was in-hospital mortality. Secondary outcome was the outcome of the infection and this was assessed as either favourable (cure and improvement) or unfavourable (stable and deterioration).
We collected data from all available medical records including site of infection, age, sex, length of hospital stay and hospital admission. Microbiological data included the causative organism isolated from the site of infection, the date of isolation and the in vitro susceptibilities to several antibiotics, including colistin. In addition, the type of infection, the causative pathogen and the clinical outcome were determined by two blinded reviewers (P. I. R. and M. E. F.). For patients with more than one episode of infection due to K. pneumoniae, only data relevant to the first episode were collected and analysed. The exposure to various risk factors was taken into consideration in the analysis, only if it had occurred prior to the development of the infection. Variables analysed as risk factors included sex, co-morbidity, prior hospitalization and surgery, intensive care unit (ICU) admission, and events and procedures related to ICU (mechanical ventilation, tracheotomy, etc.), severity of illness [assessed with Acute Physiology and Chronic Health Evaluation (APACHE) II score for patients admitted to the ICU], administration of special treatments (defined as administration of steroids, chemotherapy and blood products) and, finally, previous exposure to various antibiotic agents. Exposure to a specific antimicrobial agent was considered significant to be included in our analysis only if (i) that exposure had occurred only during the hospitalization in which infection developed and (ii) the antibiotic had been administered for at least 3 consecutive days prior to the development of the infection.
Discrete variables for the matched case–control pairs were compared by McNemar's test; for continuous variables we used the Wilcoxon test. Variables associated with CRKp infections in the bivariable analysis (P < 0.05) were included in a backward, conditional stepwise multivariable logistic regression model. For the analysis of risk factors for mortality, we used Mann–Whitney and t-tests for the categorical and continuous variables, respectively. Variables associated with mortality in the bivariable analysis (P < 0.05) were included in a backward, stepwise multivariable logistic regression model. All statistical analyses were performed using SPSS 13.0 (SPPS Inc., Chicago, IL, USA).
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Study population
From 1 October 2000 to 1 May 2006 and from 1 October 2003 to 1 May 2006, there were 25 patients and 28 patients with CRKp infection at the Henry Dunant Hospital (all 25 were ICU patients) and the University Hospital of Heraklion (14 of these 28 patients were ICU patients), respectively. We selected an equal number of controls from each hospital (25 and 28 controls from the Henry Dunant Hospital and the University Hospital of Heraklion, respectively). Matching was achieved for all 53 cases (100%) for the first criterion of matching (site of infection), for 44 cases (83.01%) for age and only for 3 cases (5.66%) for length of hospital stay up to isolation of the K. pneumoniae strain. Hence, the matched analysis included only the site of infection as a matching variable (otherwise one would have to disregard the number of patients that did not match from the analysis or proceed to an unmatched analysis).
In the group of the 53 cases, the following sites of infection were identified: bacteraemia was present in 14 patients (8 and 6 patients in the Henry Dunant Hospital and the University of Heraklion hospital, respectively), pneumonia in 12 (8 and 4), urinary tract infections in 12 (1 and 11), surgical site infection in 8 (4 and 4), catheter-related infection in 4 (4 and 0) and genital tract infections in 3 patients (0 and 3). The risk of acquisition of K. pneumoniae for different types of infections varies (as genital tract infections due to K. pneumoniae are relatively rare).
In Table 1, we present the results of the bivariable analysis of matched data regarding risk factors associated with CRKp infections. Statistically significant differences between cases and controls were observed for history of COPD (P = 0.04), admission to the ICU (P = 0.002), need for mechanical ventilation (P = 0.02), prior use of anti-pseudomonas penicillins (P = 0.004), fluoroquinolones (P < 0.0001), glycopeptides (P < 0.001), carbapenems (P = 0.01), presence of tracheostomy (P = 0.02) and surgery with use of foreign body (P = 0.04). The multivariable analysis for matched data showed that prior use of fluoroquinolones [odds ratio (OR) 4.54, 95% OR 1.78–11.54, P = 0.001] and antipseudomonal penicillins [OR 2.60, 95% confidence interval (CI) 1.00–6.71, P = 0.04] were independent risk factors for CRKp infections.
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In Table 2, we present the results of the bivariable analysis of risk factors associated with death (in-hospital mortality) (comparators in this analysis are the survivors and the deceased patients). Age, admission to the ICU, APACHE II score at ICU admission, use of carbapenems, special treatments and rhinogastric tube in place were identified as risk factors for hospital mortality because of K. pneumoniae infections (irrespective of whether this was carbapenem-susceptible or carbapenem-resistant). The multivariable analysis showed that APACHE II score was the only independent risk factor for mortality in the studied group of patients (OR 1.15, 95% CI 1.04–1.28, P = 0.007).
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Outcome
In our study, 16 of 53 patients (30.1%) with an infection due to CRKp died during hospitalization when compared with 18 of 53 (33.9%) of their matched controls (P = 0.83). Favourable outcomes of infection in the cases and their matched control group were achieved in 62.2% and 58.4%, respectively (P = 0.83). In a subset analysis of 14 patients with CRKp bacteraemia and their matched controls, no statistical difference was found regarding patient outcome and infection outcome. Thirty-seven of the 53 patients with CRKp infections received appropriate antibiotic treatment (according to the results of the in vitro susceptibility testing), whereas 16 received inappropriate antibiotic treatment. In the group that received appropriate antibiotic treatment, intravenous colistin was the antibiotic used in 36 out of the 37 patients (97.2%), whereas one patient received intravenous tetracycline. In the group that received antibiotics discordant from the in vitro results, 8 out of the 16 patients (50%) received a carbapenem combination [4 meropenem (2 of them received additionally an aminoglycoside, 1 additionally tetracycline and 1 a fluoroquinolone) and 4 imipenem/cilastatin (1 of them additionally an aminoglycoside)], 4 (25%) received other ß-lactams (2 received ampicillin/sulbactam plus fluoroquinolone and one piperacillin/tazobactam plus doxycycline) and 4 (25%) received fluoroquinolones (1 of them in addition to doxycycline). Eleven out of 37 patients who received appropriate antibiotic treatment died, whereas 5 out of the 16 patients who received inappropriate antibiotics died (P = 0.9).
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Discussion |
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The main finding of our analysis is that prior use of quinolones and antipseudomonal penicillins was an independent risk factor associated with the development of CRKp infections. In addition, the APACHE II score at ICU admission was associated with death among the studied patients (cases and controls). Methodological principles suggest that the appropriate control group, for the majority of studies in the field of antibiotic resistance, that ideally represents the source or base population is, for studies of hospital-acquired pathogens, the cohort of all hospitalized patients. One exception is if the specific question is, ‘What are the risk factors for developing antibiotic-resistant pathogen X among patients with antibiotic-susceptible pathogen X?’.11 The selection of controls in our study was in accordance to the question ‘What are the risk factors for developing CRKp among patients with CSKp?’ The appropriate control group for this research question is patients who previously had a susceptible organism isolated.
It is interesting that in the only other relevant study in the literature, the previous use of carbapenems and cephalosporins were identified as independent risk factors for acquisition of CRKp, whereas the use of fluoroquinolones was negatively associated with the isolation of CRKp.8 However, in that study, the controls were randomly selected; this methodological approach may explain the difference of the findings regarding the role of fluoroquinolones as a potential risk factor for CRKp. Special attention is always required when interpreting the results of a case–control study focusing on infections due to multidrug-resistant bacteria.11,12 Increased fluoroquinolone use has been associated with increased fluoroquinolone resistance among Gram-negative bacilli in a large US study.13 In the same study, ciprofloxacin-resistant K. pneumoniae and ciprofloxacin-susceptible K. pneumoniae were associated with a 3.2% and 0.5% imipenem resistance, respectively.
It is noteworthy that fluoroquinolone use has also been associated with the acquisition of multidrug-resistant (including carbapenem resistance) P. aeruginosa and polymyxin- only-susceptible A. baumannii.14 Even though case–control studies only attempt to highlight associations and by no means can imply causality, we can speculate that previous administration of fluoroquinolones either results in a selective pressure and overgrowth of non-susceptible strains or facilitates the activation of intrinsic mechanisms that confer resistance to multiple antibiotic drug classes (e.g. drug-efflux mechanisms).
In our study, prior use of an antipseudomonal penicillin (only combinations of an antipseudomonal penicillin with an inhibitor were studied) was found to be an independent risk factor for the development of CRKp. There are no previous studies in the literature reporting antipseudomonal penicillins as a risk factor for CRKp. In a study examining the acquisition of multidrug- resistant (including imipenem-resistant) P. aeruginosa in ICU patients, the use of piperacillin (but not piperacillin/tazobactam) was found to be a risk factor in the univariate analysis only.15 A stepwise manner of evolution of resistance is associated with the exposure to a variety of antipseudomonal antibiotics (including piperacillin/tazobactam) in the case of imipenem-resistant P. aeruginosa.16
There is a scarcity of information about risk factors and outcome for CRKp infections, despite the universal concern regarding the emergence of outbreaks because of CRKp.17–22 In a case series describing the outcome of eight patients with CRKp infections in the surgical intensive care setting, six of eight patients died (mortality 75%).9 One of the two patients who survived in that study received quinolone, whereas the other patient received imipenem. Faecal surveillance specimens put into broth containing an imipenem disc have been used to screen samples for carbapenem-resistant nosocomial pathogens including K. pneumoniae.23 In another reported outbreak, the outcome of carbapenemase KPC-3 K. pneumoniae infections in 24 patients in ICUs was reported. Eight out of 24 patients died (mortality 33%).18 In an outbreak due to carbapenemase KPC-2 K. pneumoniae, three out of four patients with true infection survived (hospital mortality 25%).19 Two of these patients had a urinary tract infection: one patient was successfully treated with a regimen that included piperacillin/tazobactam and imipenem and the other was successfully treated with imipenem and amikacin. One patient with bacteraemia was successfully treated with imipenem and amikacin. One patient with respiratory tract infection in this group died despite receiving treatment with ciprofloxacin and polymyxin.
Our patient population with CRKp nosocomial infection showed an overall mortality that was not different from the mortality of the control group (APACHE II score in the CRKp group was comparable with that of controls). This may be explained by the fact that in both hospitals participating in the study, there is a significant use of polymyxins for the treatment of severe multidrug-resistant infections. This means that the mortality of the CRKp could be possibly higher, if polymyxins were not used. There was no statistical difference regarding hospital mortality between patients with CRKp who received appropriate (colistin in the vast majority) versus inappropriate treatment.
By further examining the characteristics of patients who died (with either CRKp or CSKp) versus those characteristics of the survivors, mortality was associated in the bivariable analysis with increased age, APACHE II score, admission to the ICU, use of carbapenems and special treatments. APACHE II score, a well-known prognostic factor, was the only independent risk factor for mortality in the studied group of patients. The issue of whether infections due to multidrug-resistant Gram-negative bacteria are associated with increased mortality is controversial;24,25 however, recent data show that attributable mortality is associated with these infections.26
Unfortunately, the presence of enterobacteria with ESBL activity in a variety of environments (patients, animals and food) probably constitutes an important event that is sometimes associated with the development of further mechanisms of resistance, including carbapenem resistance.27 In addition, molecular mechanisms enhance this potential.28,29 Crosstalk between strains of enterobacteria of the same and different species makes the dissemination of multidrug resistance even worse.30,31
On the basis of the results of our study, the all-cause in-hospital mortality was not statistically different between cases with CRKp and matched controls with CSKp. Despite the lack of attributable mortality to CRKp infections, at least in the relatively small sample size of our study and in the context of the empirical treatment our patients received, i.e. common use of polymyxins,32–34 one has to acknowledge that emerging CRKp infections constitute a significant evolution of antimicrobial resistance. Judicious use of antibiotics complementary to strict infection control measures seems to be mandatory in order to minimize or at least delay the widespread presence of multiresistant bacteria.
Our study has limitations. First, we should acknowledge that the number of patients included in this study is relatively small, although this is a common problem in studies assessing risk factors of infections because of multidrug-resistant microorganisms.35 Secondly, molecular epidemiology investigations using PFGE patterns and PCR for resistance genes and sequencing of PCR products were not performed in our study; thus details on the kind of carbapenemase are not available. The importance of identifying each specific carbapenemase must be acknowledged, as the MICs vary with the type of carbapenemase and may have an impact on treatment results. However, we thought that we should present our experience with this emerging type of infection and designed this retrospective study to assess possible risk factors for the development of CRKp infections and describe the outcome of patients with such infections.
In conclusion, this matched case–control study identified previous exposure to fluoroquinolones and antipseudomonal penicillins as independent risk factors for acquisition of infections due to CRKp. Hospital mortality in the general setting of patients with CRKp infections in this study was not different from that of patients with CSKp infections.
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None.
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None to declare.
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Acknowledgements |
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We thank Alex Spanos for his help in the statistical analysis of the data.
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