Abstract
Objective:
To identify risk factors associated with carbapenem-resistant Klebsiella pneumoniae (CRKP) infection/colonization and death and to investigate the resistance and homology of CRKP.
Methods:
A retrospective 1:1 case–control study was conducted at Changhai Hospital, China, from January 2010 to December 2011.The study population included 30 patients with CRKP infection/colonization and 30 matched patients with carbapenem-susceptible K. pneumoniae (CSKP) infection/colonization at the same site. Homology analysis was conducted by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). Potential resistance genes were detected by PCR.
Results:
Independent risk factors for CRKP infection/colonization were admission to exposure to glycopeptides [Odds ratio (OR): 43.84, 95% confidence interval (CI): 1.73–1111.91, P = 0.020], cefoperazone plus sulbactam (OR: 49.56, 95% CI: 1.42–1726.72, P = 0.030) and tracheostomy (OR: 677.82, 95% CI: 2.76–1667, P = 0.020). Age (OR: 1.07, 95% CI: 1.00–1.14, P = 0.04), renal dysfunction (OR: 17.63, 95% CI: 2.34–132.87, P = 0.005) and exposure to cefoperazone plus sulbactam (OR: 8.87, 95% CI: 1.29–61.07, P = 0.026) were independent risk factors for the death of patients with K. pneumoniae infection/colonization. Older age (OR: 1.16, 95% CI: 1.01–1.39, P = 0.011) was an independent risk factor for the death of patients with CRKP infection/colonization. Thirty CRKP strains were all KPC-2-producing resistant strains with genotype of ST-11.
Conclusion:
Exposure to glycopeptides, cefoperazone plus sulbactam and tracheostomy were independent risk factors for CRKP infection/colonization, and older age was an independent risk factor for CRKP infection/colonization caused death.
Keywords: Carbapenem-resistant Klebsiella pneumoniae, Mortality, Risk factors, Antimicrobial resistance
Introduction
Klebsiella pneumoniae (K. pneumoniae) is one of the pathogens responsible for hospital-acquired infections including pneumonia, septicaemia, urinary tract and lower biliary tract infections and hepatic abscess, especially in immunocompromised people.1–3 Carbapenems are often used to treat infection/colonization caused by K. pneumoniae producing extended-spectrum beta-lactamases (ESBLs).4 However, the increasing prevalence of antibiotic-resistant bacteria, including carbapenem-resistant K. pneumoniae (CRKP), has become a potentially pathogenic and fatal factor.5 Mortality of the patients infected with CRKP seems to be higher compared to the patients infected with carbapenem-susceptible K. pneumoniae (CSKP).6
Carbapenem-resistant K. pneumoniae was first reported in 1997 and very rare in the world at that time.7 A novel carbapenem-hydrolyzing beta-lactamase named KPC-1 was isolated from a carbapenem-resistant strain of K. pneumoniae in 2001.8 Currently, the epidemic outbreaks of KPC-producing strains have been reported in many countries and regions.9–11K. pneumoniae is commonly present in intensive care unit (ICU) as a species of Enterobacteriaceae, which is most prone to producing the enzyme associated with carbapenem resistance.12 As treatment regimens suitable for CRKP infection/colonization are limited, epidemiological and microbiological studies on carbapenem-resistant Gramme-negative bacteria appear to be particularly important.
Identifying risk factors for the development of CRKP acquisition is important for treatment options, and consequently, a number of risk factors for CRKP infection/colonization have been revealed in some retrospective clinical studies.4,12–14 However, the conclusions were not always consistent among these studies. Antibiotic exposure was considered an independent factor for CRKP infection/colonization in some studies,12 but not in all.6,13 Other independent factors were prior ICU stay, renal disease, diabetes mellitus, solid tumour, tracheostomy, endoscopy, urinary catheter insertion and antipseudomonal penicillin use.4,6,12–15
In order to improve empirical therapy efficacy, we identified risk factors correlated with CRKP infection/colonization and mortality caused by K. pneumoniae. In addition, microbiological features of the strains were also detected.
Methods
Subjects and study design
This retrospective study was performed at Shanghai Changhai Hospital of China, a tertiary-care teaching hospital with 2000 beds. Patients with hospital-acquired K. pneumoniae infection/colonization (positive K. pneumoniae culture 48 hours after admission) from January 2010 to December 2011 were included in this study.
Patients inclusion criteria were hospital stay ≥ 7 days; age >18 years; no prior K. pneumoniae infection/colonization before the current admission; with the same site of infection/colonization for CRKP and CSKP. Carbapenem-susceptible K. pneumoniae -infected patients were with a difference in age of ± 5 years and K. pneumoniae culture time of ± 3 days compared with CRKP-infected patients. If several potential patients of the CSKP group met the qualification, only one was randomly selected.
Data collection
Data collection was performed by reviewing medical and microbiological data and recording: clinical departments where strains were isolated, patients age, gender, comorbidities such as lung disease, cardiac insufficiency, renal insufficiency, diabetes mellitus and hypoalbuminaemia, treatments before obtaining the positive culture such as mechanical ventilation, invasive procedures (deep venous catheterization, indwelling gastric tube, indwelling urethral catheter and tracheostomy), hospitalization (length of ICU staying, APCHE II score), antibiotic administration 3 months prior to the current hospitalization and during the current hospitalization until the positive culture for K. pneumoniae was obtained such as fluoroquinolones, first-generation cephalosporins, second-generation cephalosporins, third-generation cephalosporins, cefoperazone plus sulbactam, carbapenems (imipenem or meropenem), amikacin, glycopeptides (vancomycin, teicoplanin) and the clinical outcomes. Among them, hypoproteinemia was defined as plasma albumin < 30 g/l; lung diseases included chronic obstructive pulmonary disease, chronic bronchitis, and respiratory failure; inclusion criteria for cardiac dysfunction were brain natriuretic factor or peptide (BNP)>400 pg/ml or previously conformed cardiac dysfunction. All antimicrobial agents included in the statistics were those used for at least 48 hours before K. pneumoniae infection/colonization.
Statistical analysis
All statistical analyses were performed using statistical software SPSS 18.0 (SPSS Inc., Chicago, IL, USA). All data were expressed as mean ± standard deviation for continuous variables or percent for categorical variables. In analysis of risk factors for CRKP infection/colonization and mortality, univariate logistic regression analysis was performed. To identify the independent risk factors, variables with P < 0.05 in the univariate analysis were included in multivariate logistic regression model and analyzed using backward stepwise regression. Odds ratio (OR) and 95% confidence interval (CI) were also calculated. For all statistical analyses, P < 0.05 indicated statistical significance.
Resistance mechanism and homology analysis of CRKP
Imipenem susceptibility of the strains was determined by metallo-beta-lactamases (MBLs) Etest.16 The Hodge test was used when resistance to one of the carbapenems was demonstrated.17 The minimum inhibitory concentration (MIC) ≥ 16 μg/ml was used as the standard of CRKP strains.18,19
The strain genotyping was performed using multilocus sequence typing (MLST) method. Seven housekeeping genes (rpoB, gapA, mdh, pgi, pho E, infB and tonB) were, respectively, amplified. The products were sequenced and aligned to obtain ST genotyping of the strains at http://www.Pasteur.fr/cgi-bin/genopole/PF8/mlstdbnet.pl?page = allseq&file = klebs_profiles.xml. The potential resistance genes (NDM-1, CTX and KPC) were obtained by PCR amplification. The genomic DNA of the K. pneumoniae strains was digested using XbaI restriction endonuclease. The obtained fragments were separated using pulsed-field gel electrophoresis (PFGE). Pulsed-field gel electrophoresis was performed with a contour-clamped homogeneous electric field DRII apparatus from Bio-Rad Laboratories (Richmond, CA, USA). The chromosomal DNA was digested overnight with XbaI (Takara, Dalian, China). DNA was electrophoresed in 1.2% agarose at 6 V/cm for 24 hours; the pulse time was increased from 5 to 40 seconds. The results were analyzed using the software of Bio-Rad Quantity one. The PFGE types were analyzed according to the criteria defined by Tenover et al.20
Results
Thirty CRKP strains were separately derived from emergency department (nine strains), department of burn injury (six strains), osteology (three strains), neurology (one strain), neurosurgery (three strains), thoracic surgery (three strains), general surgery (three strains), department of gastroenterology (one strain) and pneumology (one strain). The specimens were collected from sputum (17 strains), wound secretions (6 strains), urine (3 strains), blood (2 strains), and drainage fluid (2 strains). The specimen collection departments and sites in CSKP group were in one-to-one correspondence with those in CRKP group.
Risk factors for CRKP infection/colonization: a clinical case–control study
Several factors were found to be associated with CRKP infection/colonization, including prior exposure to cefoperazone plus sulbactam, carbapenems or glycopeptide, deep venous catheterization, tracheostomy, indwelling urethral catheter, indwelling gastric tube, higher APCHE II score, ICU stay, and longer ICU length of stay (P < 0.05) (Table 1). Among them, prior exposure to glycopeptide (OR: 43.84, 95% CI: 1.73–1111.91, P = 0.02) or cefoperazone plus sulbactam administration (OR: 49.56, 95% CI: 1.42–1726.72, P = 0.03), deep venous catheterization (OR: 46.88, 95% CI: 0.52–4238.09, P = 0.09) and tracheotomy (OR: 677.82, 95% CI: 2.76–1667, P = 0.020) were independent risk factors for CRKP infection/colonization (Table 1).
Table 1. Analysis of risk factors for patients infected with CRKP.
| Variables | Univariate analysis | Multivariate analysis | ||||
| Risk factors | CRKP (n = 30) | CSKP (n = 30) | OR (95% CI) | P-value | OR (95% CI) | P-value |
| Age (years) | 59·8 ± 17·5 | 60·6 ± 17·2 | 0·86 (0·97–1·03) | 0·856 | ||
| Male, n (%) | 25 (83·3) | 5 (76·7) | 0·66 (0·18–2·4) | 0·52 | ||
| Concomitant diseases, n (%) | ||||||
| Lung disease | 15 (50·0) | 10 (33·3) | 2·0 (0·71–5·67) | 0·193 | ||
| Cardiac dysfunction | 8 (26·7) | 8 (26·7) | 1·00 (0·32–3·14) | 1 | ||
| Renal dysfunction | 12 (40·0) | 7 (23·3) | 2·19 (0·72–6·69) | 0·169 | ||
| Diabetes | 5 (16·7) | 4 (13·3) | 1·30 (0·31–5·40) | 0·718 | ||
| Hypoalbuminaemia | 18 (60) | 13 (43·3) | 1·96 (0·70–5·48) | 0·199 | ||
| Tumour | 5 (16·7) | 11 (36·7) | 0·35 (0·10–1·16) | 0·086 | ||
| Antibiotics application before Klebsiella pneumoniae infection, n (%) | ||||||
| Fluoroquinolone | 19 (63·3) | 12 (40) | 2·6 (0·91–7·30) | 0·073 | ||
| 2nd generation cephalosporins | 9 (30) | 12 (40) | 0·64 (0·22–1·87) | 0·418 | ||
| 3rd generation cephalosporins | 7 (23·3) | 7 (23·3) | 1·00 (0·30–3·30) | 1 | ||
| Amikacin | 6 (20) | 1 (3·3) | 7·30 (0·82–64·5) | 0·076 | ||
| Carbapenem | 20 (66·7) | 7 (23·3) | 6·57 (2·10–20·48) | 0·001 | 4·62 (0·25–84·05) | 0·3 |
| Cefoperazone plus sulbactam | 15 (50) | 5 (16·7) | 5·0 (1·51–16·60) | 0·008 | 49·56 (1·42–1726·72) | 0·03 |
| Tazocin | 4 (13·3) | 5 (16·7) | 0·77 (0·19–3·19) | 0·718 | ||
| Glycopeptides | 17 (56·7) | 4 (13·3) | 8·5 (2·37–30·46) | 0·001 | 43·84 (1·73–1111·91) | 0·02 |
| Invasive procedures, n (%) | ||||||
| Deep venous catheterization | 27 (90) | 17 (56·7) | 6·88 (1·71–27·8) | 0·007 | 46·88 (0·52–4238·09) | 0·09 |
| Tracheotomy | 26 (86·7) | 13 (43·3) | 8·5 (2·37–30·46) | 0·001 | 677·82 (2·76–1667) | 0·02 |
| Indwelling urethral catheter | 26 (86·7) | 19 (63·3) | 3·76 (1·04–13·64) | 0·044 | 0·11 (0·01–4·96) | 0·26 |
| Indwelling gastric tube | 25 (83·3) | 16 (53·3) | 4·37 (1·32–14·50) | 0·016 | 0·05 (0·01–2·32) | 0·13 |
| APCHE2 score | 22·9 ± 8·1 | 17·2 ± 7·4 | 1·10 (1·02-1·18) | 0·01 | 1·01 (0·83-1·23) | 0·92 |
| Hospital stay (days) | 33·8 ± 30·8 | 18·0 ± 23·4 | 1·03 (1·00–1·06) | 0·054 | ||
| ICU stay (days) | 25 (83·3) | 18 (60) | 3·33 (0·99–11·14) | 0·048 | 0·54 (0·02–14·66) | 0·72 |
| Hospital stay before bacteraemia (days) | 33·8 ± 30·8 | 13·2 ± 27·4 | 1·03 (1·01–1·06) | 0·02 | 1·09 (0·98–1·2) | 0·1 |
| Outcomes | ||||||
| Death | 10 (33·3) | 5 (16·7) | ||||
| Improvement | 20 (66·7) | 25 (83·3) | ||||
CRKP: carbapenem-resistant Klebsiella pneumonia; CSKP: carbapenem-sensitive Klebsiella; OR: odds ratio; CI: confidence interval; ICU: intensive care unit.
The variables screened in univariate analysis with P < 0·05 were included in the multivariate logistic regression analysis after repeated verification of the fitted model.
Clinical cohort study on mortality: patients who survived versus those died from K. pneumoniae infection/colonization
Among the enrolled 60 patients with K. pneumoniae infection or colonization, 15 (25%) patients died. Univariate analysis indicated that older age, lung diseases, cardiac dysfunction, renal dysfunction, exposure to cefoperazone plus sulbactam and longer ICU length of stay were associated with the death of the K. pneumoniae-infected/colonized patients (P < 0.05) (Table 2). Multivariate analysis showed that older age (OR: 1.07, 95% CI: 1.00–1.14, P = 0.04), renal dysfunction (OR: 17.63, 95% CI: 2.34–132.87, P = 0.005) and exposure to cefoperazone plus sulbactam (OR: 8.87, 95% CI: 1.29–61.07, P = 0.026) were independent risk factors associated with K. pneumonia infection/colonization induced death (Table 2).
Table 2. Analysis of risk factors associated with Klebsiella pneumoniae infection/colonization induced death.
| Variables | Univariate analysis | Multivariate analysis | ||||
| Risk factors | Death (n = 15) | Survival (n = 45) | OR (95% CI) | P-value | OR (95% CI) | P-value |
| Age (years) | 71·3 ± 13·8 | 56·5 ± 16·8 | 1·07 (1·02–1·12) | 0·007 | 1·07 (1·00–1·14) | 0·04 |
| Male, n (%) | 11 (73·3) | 37 (82·2) | 0·59 (0·15–2·35) | 0·459 | ||
| Concomitant diseases, n (%) | ||||||
| Lung disease | 10 (66·7) | 15 (33·3) | 4 (1·16–13·82) | 0·028 | ||
| Cardiac dysfunction | 7 (46·7) | 9 (20) | 3·5 (1–12·22) | 0·049 | 1·05 (0·16–6·7) | 0·96 |
| Renal dysfunction | 10 (66·7) | 9 (20) | 8 (2·18–29·31) | 0·002 | 17·63 (2·34–132·87) | 0·005 |
| Liver dysfunction | 1 (6·7) | 1 (2·2) | 3·14 (0·18–53·59) | 0·429 | ||
| Diabetes | 2 (13·3) | 7 (15·6) | 0·84 (0·15–4·54) | 0·835 | ||
| Hypoalbuminaemia | 9 (60) | 22 (48·9) | 1·57 (0·48–5·14) | 0·458 | ||
| Tumour | 4 (26·7) | 12 (26·7) | 1 (0·27–3·75) | 1 | ||
| Antibiotics application before K. pneumoniae infection, n (%) | ||||||
| Fluoroquinolone | 11 (73·3) | 20 (44·4) | 3·44 (0·95–12·45) | 0·06 | ||
| 2nd generation cephalosporins | 4 (26·7) | 17 (37·8) | 0·6 (0·16–2·18) | 0·437 | ||
| 3rd generation cephalosporins | 6 (40) | 8 (17·8) | 3·08 (0·85–11·14) | 0·086 | ||
| Amikacin | 2 (13·3) | 5 (11·1) | 1·23 (0·21–7·12) | 0·817 | ||
| Carbapenem | 9 (60) | 18 (40) | 2·25 (0·68–7·42) | 0·183 | ||
| Cefoperazone plus sulbactam | 9 (60) | 11 (24·4) | 4·64 (1·35–15·97) | 0·015 | 8·87 (1·29–61·07) | 0·026 |
| Tazocin | 3 (20) | 6 (13·3) | 1·62 (0·35–7·5) | 0·534 | ||
| Glycopeptides | 5 (33·3) | 16 (35·6) | 0·91 (0·26–3·12) | 0·876 | ||
| Invasive procedures, n (%) | ||||||
| Deep venous catheterization | 13 (86·7) | 31 (68·9) | 2·94 (0·58–14·79) | 0·192 | ||
| Tracheotomy | 12 (80) | 27 (60) | 2·67 (0·66–10·8) | 0·69 | ||
| Indwelling urethral catheter | 12 (80) | 33 (73·3) | 1·45 (0·35–6·06) | 0·607 | ||
| Indwelling gastric tube | 12 (80) | 29 (64·4) | 2·21 (0·54–8·99) | 0·269 | ||
| Surgery | 4 (26·7) | 24 (53·3) | 0·32 (0·09–1·15) | 0·081 | ||
| APCHE2 score | 30·7 ± 4·3 | 16·5 ± 5·7 | 10·67 (0·87–130·64) | 0·064 | ||
| ICU stay (days) | 13 (86·7) | 30 (66·7) | 3·25 (0·65–16·3) | 0·152 | ||
| Hospital stay before bacteraemia, days | 41 ± 41·2 | 18 ± 24·5 | 1·02 (1·00–1·04) | 0·031 | 1·01 (0·98–1·03) | 0·48 |
OR: odds ratio; CI: confidence interval; ICU: intensive care unit.
The variables screened in univariate analysis with P < 0·05 were included in the multivariate logistic regression analysis after repeated verification of the fitted model.
Clinical cohort study on mortality: patients who survived versus those died from CRKP infection/colonization
Ten of the 30 patients with CRKP infection/colonization died. Univariate analysis indicated that the factors such as older age, renal dysfunction and exposure to cefoperazone plus sulbactam were associated with death (P < 0.05) (Table 3). Among them, only older age (OR: 1.16, 95% CI: 1.01–1.39, P = 0.011) was the independent risk factor for death of patients with CRKP infection/colonization (Table 3).
Table 3. Analysis of risk factors associated with CRKP infection/colonization induced death.
| Variables | Univariate analysis | Multivariate analysis | ||||
| Risk factors | Death (n = 10) | Survival (n = 20) | OR (95% CI) | P-value | OR (95% CI) | P-value |
| Age (years) | 73·6 ± 11·1 | 52·9 ± 16·0 | 1·11 (1·03–1·20) | 0·009 | 1·16 (1·01–1·39) | 0·011 |
| Male, n (%) | 7 (70) | 18 (90) | 0·26 (0·04–1·9) | 0·18 | ||
| Concomitant diseases, n (%) | ||||||
| Renal dysfunction | 7 (70) | 5 (25) | 7 (1·29–37·91) | 0·024 | 185·69 (0·91–37 797·14) | 0·054 |
| Antibiotics application before K. pneumoniae infection, n (%) | ||||||
| Cefoperazone plus sulbactam | 8 (80) | 7 (35) | 7·43 (1·23–45·01) | 0·029 | 319·05 (0·68–149 157·23) | 0·07 |
CRKP: carbapenem-resistant Klebsiella pneumonia; OR: odds ratio; CI: confidence interval; ICU: intensive care unit.
The variables screened in univariate analysis with P < 0·05 were included in the multivariate logistic regression analysis after repeated verification of the fitted model.
Resistance mechanism and homology analysis of CRKP
All of the 30 imipenem-resistant CRKP strains (MIC ≥ 16 μg/ml) were multiresistant (susceptibility to polymyxin was not measured). The main resistance mechanism of the 30 CRKP strains was attributed to KPC production. The genotypes of all strains were ST-11 (Fig. 1).
Figure 1.
Pulsed-field gel electrophoresis (PFGE) patterns of carbapenem-resistant Klebsiella pneumoniae (CRKP). The fourth lane indicated ESBL+CSKP (ATCC 700603), and the others indicated CRKP strains.
Discussion
Since the reports on CRKP, treating K. pneumoniae infection/colonization using carbapenems has been challenged. To improve empirical therapy efficacy, we studied the risk factors for CRKP infection/colonization. Our investigation indicates that CRKP infection/colonization was associated with various factors such as ICU stay, prior antibiotic use and invasive procedures. Exposure to glycopeptides or cefoperazone plus sulbactam as well as tracheotomy were independent risk factors for CRKP infection/colonization; age, renal insufficiency and cefoperazone plus sulbactam administration were independent risk factors for death of K. pneumoniae-infected patients; older age was an independent risk factor for death of patients with CRKP infection/colonization. These findings suggested that the clinicians should place emphasis on the appropriate antibiotic use and aseptic invasive procedures.
Our study suggested that ICU staying and longer length of ICU stay before K. pneumoniae infection/colonization were associated with CRKP infection/colonization, which was consistent with the studies conducted by Gregory et al.21 and Schwaber et al.22 Most patients admitted to the ICU have relatively serious complications. Furthermore, the airborne and contact transmission of resistant bacteria in the ICU environment may lead to nosocomial infection/colonization. The patients with prolonged ICU stay may undergo more invasive procedures and may be treated with a longer duration of antibiotics use or with broad spectrum antibiotics. All the above factors can lead to the emergence of carbapenems-resistant bacteria.
Carbapenems administration has been proven to be an independent risk factor for carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter baumannii infection/colonization.23,24 Our study suggested that carbapenems administration prior to K. pneumoniae infection was also associated with CRKP infection, which was consistent with many previous retrospective clinical studies.22,25–29 The fluoroquinolones or quinolones utilization was also an independent risk factor for CRKP infection/colonization29 and death.26,30 Laboratory evidences indicated that plasmid-encoded quinolone resistance determinant gene causing low-level fluoroquinolone resistance was located on K. pneumoniae plasmids encoding KPC gene (especially blaKPC-2 and qnrB4). However, the present study as well as the studies conducted by Gregory et al.,21 Kwalk et al.25 and Wu et al.31 failed to prove the correlation between fluoroquinolones use and CRKP infection/colonization. This might be due to the fact that quinolones abuse in some regions had resulted in non-significant difference in the clinical studies.
We also found that glycopeptide or cefoperazone plus sulbactam administration were risk factors for CRKP infection/colonization, which was consistent with the previous finding.31 Long-term application of glycopeptides would significantly inhibit the growth of Gramme-positive bacteria and thus lead to more frequent mutations and drug resistance of Gramme-negative bacteria. However, cefoperazone plus sulbactam administration could not be explained by this possible mechanism. Further microbiological researches remain to be performed.
Our studies suggested that tracheotomy was an independent risk factor associated with CRKP infection/colonization. Frequent invasive operations and tube indwelling may cause respiratory tract or gastrointestinal mucosal injury easily. The mucosal barrier injury will cause further decline in the body resistance and increase in probabilities of bacterial colonization or infection/colonization.
Besides, this study concluded that older age, concomitant disease (renal insufficiency) and application of cefoperazone plus sulbactam were independent risk factors for death caused by K. pneumoniae infection/colonization. Advanced age, severe underlining diseases and inadequate antibiotic treatment would reduce the immunity, which increased the risk of infection/colonization and even death.
Most of the present clinical studies focus on the risk factors for acquisition of CRKP, but few reports combined the mechanisms of resistance. The risk factors and sensitivity of antibiotic agent of CRKP may not differ with different mechanisms of resistance, so microbiological detection of K. pneumoniae was particularly included in our study. Analysis on the genotypes and homogeneity of the strains suggested that KPC-2 was the main factor causing antibiotic resistance in CRKP strains. Some researchers also indicated that the resistance mechanisms of 53% CRKP strains were due to KPC-2 producing.24,32–34 In addition to producing KPC enzyme, the CRKP resistance mechanisms also included the loss of outer membrane proteins and production of beta-lactam-hydrolyzing enzymes.35
Our study also has some limitations. First, we should acknowledge that the sample size was not large enough, which might lead to errors in statistical analysis and the omission of some other risk factors. Second, there was not an established criterion for differentiating infection from colonization of K. pneumoniae in the study. In addition, this study was only conducted in one tertiary-care teaching hospital. Prospective, multicenter clinical trials are expected to be performed.
Conclusion
This retrospective study indicated that exposure to glycopeptides or cefoperazone plus sulbactam, as well as tracheostomy, were independent risk factors for severe infection/colonization caused by CRKP. These findings may provide some recommendation for the diagnosis and treatment of patients infected with KPC-producing CRKP strains in Shanghai, China.
Disclaimer Statements
Contributors All listed authors participated meaningfully in the study and have seen and approved the final manuscript.
Funding This study was supported by research grants from the Important National Science and Technology Specific Projects (NO.2013ZX10003009).
Conflicts of interest We declare that we have no conflicts of interest.
Ethics approval This retrospective study was performed in Shanghai Changhai Hospital of China.
References
- 1.Han SH. Review of hepatic abscess from Klebsiella pneumoniae An association with diabetes mellitus and septic endophthalmitis. West J Med. 1995;162:220–4. [PMC free article] [PubMed] [Google Scholar]
- 2.Ahmad TA, Haroun M, Hussein AA, El Ashry el SH, El-Sayed LH. Development of a new trend conjugate vaccine for the prevention of Klebsiella pneumoniae. Infect Dis Rep. 2012;4:e33. doi: 10.4081/idr.2012.e33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Neuhauser MM, Weinstein RA, Rydman R, Danziger LH, Karam G, Quinn JP. Antibiotic resistance among gram-negative bacilli in us intensive care units: implications for fluoroquinolone use. JAMA. 2003;289:885–8. doi: 10.1001/jama.289.7.885. [DOI] [PubMed] [Google Scholar]
- 4.Orsi GB, Garcia-Fernandez A, Giordano A, Venditti C, Bencardino A, Gianfreda R et al. Risk factors and clinical significance of ertapenem-resistant Klebsiella pneumoniae in hospitalised patients. J Hosp Infect. 2011;78:54–8. doi: 10.1016/j.jhin.2011.01.014. [DOI] [PubMed] [Google Scholar]
- 5.Won SY, Munoz-Price LS, Lolans K, Hota B, Weinstein RA, Hayden MK. Emergence and rapid regional spread of Klebsiella pneumoniae carbapenemase-producing enterobacteriaceae. Clin Infect Dis. 2011;53:532–40. doi: 10.1093/cid/cir482. [DOI] [PubMed] [Google Scholar]
- 6.Hussein K, Raz-Pasteur A, Finkelstein R, Neuberger A, Shachor-Meyouhas Y, Oren I et al. Impact of carbapenem resistance on the outcome of patients' hospital-acquired bacteraemia caused by Klebsiella pneumoniae. J Hosp Infect. 2013;83:307–13. doi: 10.1016/j.jhin.2012.10.012. [DOI] [PubMed] [Google Scholar]
- 7.MacKenzie FM, Forbes KJ, Dorai-John T, Amyes SG, Gould IM. Emergence of a carbapenem-resistant Klebsiella pneumoniae. Lancet. 1997;350:783. doi: 10.1016/s0140-6736(05)62567-6. [DOI] [PubMed] [Google Scholar]
- 8.Yigit H, Queenan AM, Anderson GJ, Domenech-Sanchez A, Biddle JW, Steward CD et al. Novel carbapenem-hydrolyzing beta-lactamase, kpc-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob Agents Chemother. 2001;45:1151–61. doi: 10.1128/AAC.45.4.1151-1161.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Kitchel B, Rasheed JK, Patel JB, Srinivasan A, Navon-Venezia S, Carmeli Y et al. Molecular epidemiology of kpc-producing Klebsiella pneumoniae isolates in the united states: clonal expansion of multilocus sequence type 258. Antimicrob Agents Chemother. 2009;53:3365–70. doi: 10.1128/AAC.00126-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Rogers BA, Aminzadeh Z, Hayashi Y, Paterson DL. Country-to-country transfer of patients and the risk of multi-resistant bacterial infection. Clin Infect Dis. 2011;53:49–56. doi: 10.1093/cid/cir273. [DOI] [PubMed] [Google Scholar]
- 11.Jean S-S, Hsueh P-R. High burden of antimicrobial resistance in asia. Int J Antimicrob Agents. 2011;37:291–5. doi: 10.1016/j.ijantimicag.2011.01.009. [DOI] [PubMed] [Google Scholar]
- 12.Kofteridis DP, Valachis A, Dimopoulou D, Maraki S, Christidou A, Mantadakis E et al. Risk factors for carbapenem-resistant Klebsiella pneumoniae infection/colonization: a case-case-control study. J Infect Chemother. 2014;20:293–7. doi: 10.1016/j.jiac.2013.11.007. [DOI] [PubMed] [Google Scholar]
- 13.Borer A, Saidel-Odes L, Eskira S, Nativ R, Riesenberg K, Livshiz-Riven I et al. Risk factors for developing clinical infection with carbapenem-resistant Klebsiella pneumoniae in hospital patients initially only colonized with carbapenem-resistant K pneumoniae. Am J Infect Control. 2012;40:421–5. doi: 10.1016/j.ajic.2011.05.022. [DOI] [PubMed] [Google Scholar]
- 14.Nguyen M, Eschenauer GA, Bryan M, O'Neil K, Furuya EY, Della-Latta P et al. Carbapenem-resistant Klebsiella pneumoniae bacteremia: factors correlated with clinical and microbiologic outcomes. Diagn Microbiol Infect Dis. 2010;67:180–4. doi: 10.1016/j.diagmicrobio.2010.02.001. [DOI] [PubMed] [Google Scholar]
- 15.Orsi GB, Venditti M. Carbapenem-resistant Klebsiella pneumoniae transmission associated to endoscopy. Am J Infect Control. 2013;41:849–50. doi: 10.1016/j.ajic.2013.01.036. [DOI] [PubMed] [Google Scholar]
- 16.Kotlovsky T, Shalginov R, Austin L, Sprecher H. Rapid detection of bla KPC-positive Klebsiella pneumoniae in a clinical setting. Eur J Clin Microbiol Infect Dis. 2009;28:309–11. doi: 10.1007/s10096-008-0615-2. [DOI] [PubMed] [Google Scholar]
- 17.Anderson K, Lonsway D, Rasheed J, Biddle J, Jensen B, McDougal L et al. Evaluation of methods to identify the Klebsiella pneumoniae carbapenemase in enterobacteriaceae. J Clin Microbiol. 2007;45:2723–5. doi: 10.1128/JCM.00015-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Wikler MA. Performance standards for antimicrobial susceptibility testing: seventeenth informational supplement. Wayne, PA: Clinical and Laboratory Standards Institute; 2007. [Google Scholar]
- 19.Cockerill FR. Performance standards for antimicrobial susceptibility testing: twenty-first informational supplement. Wayne, PA: Clinical and Laboratory Standards Institute (CLSI); 2011. [Google Scholar]
- 20.Tenover FC, Kalsi RK, Williams PP, Carey RB, Stocker S, Lonsway D et al. Carbapenem resistance in Klebsiella pneumoniae not detected by automated susceptibility testing. Emer Infect Dis. 2006;12:1209. doi: 10.3201/eid1208.060291. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Gregory CJ, Llata E, Stine N, Gould C, Santiago LM, Vazquez GJ et al. Outbreak of carbapenem-resistant Klebsiella pneumoniae in puerto rico associated with a novel carbapenemase variant. Infect Control Hosp Epidemiol. 2010;31:476–84. doi: 10.1086/651670. [DOI] [PubMed] [Google Scholar]
- 22.Schwaber MJ, Klarfeld-Lidji S, Navon-Venezia S, Schwartz D, Leavitt A, Carmeli Y. Predictors of carbapenem-resistant Klebsiella pneumoniae acquisition among hospitalized adults and effect of acquisition on mortality. Antimicrob Agents Chemother. 2008;52:1028–33. doi: 10.1128/AAC.01020-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Zavascki AP, Cruz RP, Goldani LZ. Risk factors for imipenem-resistant Pseudomonas aeruginosa: a comparative analysis of two case-control studies in hospitalized patients. J Hosp Infect. 2005;59:96–101. doi: 10.1016/j.jhin.2004.09.007. [DOI] [PubMed] [Google Scholar]
- 24.Lee SO, Kim NJ, Choi SH, Hyong Kim T, Chung JW, Woo JH et al. Risk factors for acquisition of imipenem-resistant Acinetobacter baumannii: a case-control study. Antimicrob Agents. Chemother. 2004;48:224–8. doi: 10.1128/AAC.48.1.224-228.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Kwak YG, Choi SH, Choo EJ, Chung JW, Jeong JY, Kim NJ et al. Risk factors for the acquisition of carbapenem-resistant Klebsiella pneumoniae among hospitalized patients. Microb Drug Resist. 2005;11:165–9. doi: 10.1089/mdr.2005.11.165. [DOI] [PubMed] [Google Scholar]
- 26.Gasink LB, Edelstein PH, Lautenbach E, Synnestvedt M, Fishman NO. Risk factors and clinical impact of Klebsiella pneumoniae carbapenemase-producing K. Pneumoniae. Infect Control Hosp Epidemiol. 2009;30:1180–5. doi: 10.1086/648451. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Patel G, Huprikar S, Factor SH, Jenkins SG, Calfee DP. Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies. Infect Control Hosp Epidemiol. 2008;29:1099–106. doi: 10.1086/592412. [DOI] [PubMed] [Google Scholar]
- 28.Orsi G, Bencardino A, Vena A, Carattoli A, Venditti C, Falcone M et al. Patient risk factors for outer membrane permeability and KPC-producing carbapenem-resistant Klebsiella pneumoniae isolation: results of a double case – control study. Infection. 2013;41:61–7. doi: 10.1007/s15010-012-0354-2. [DOI] [PubMed] [Google Scholar]
- 29.Gomez Rueda V, Zuleta Tobon JJ. Risk factors for infection with carbapenem-resistant Klebsiella pneumoniae: a case-case-control study. Colomb Med (Cali). 2014;45:54–60. [PMC free article] [PubMed] [Google Scholar]
- 30.Falagas ME, Rafailidis PI, Kofteridis D, Virtzili S, Chelvatzoglou FC, Papaioannou V et al. Risk factors of carbapenem-resistant Klebsiella pneumoniae infections: a matched case control study. J Antimicrob Chemother. 2007;60:1124–30. doi: 10.1093/jac/dkm356. [DOI] [PubMed] [Google Scholar]
- 31.Wu D, Cai J, Liu J. Risk factors for the acquisition of nosocomial infection with carbapenem-resistant Klebsiella pneumoniae. South Med J. 2011;104:106–10. doi: 10.1097/SMJ.0b013e318206063d. [DOI] [PubMed] [Google Scholar]
- 32.Deshpande LM, Fritsche TR, Moet GJ, Biedenbach DJ, Jones RN. Antimicrobial resistance and molecular epidemiology of vancomycin-resistant enterococci from north america and europe: a report from the sentry antimicrobial surveillance program. Diagn Microbiol Infect Dis. 2007;58:163–70. doi: 10.1016/j.diagmicrobio.2006.12.022. [DOI] [PubMed] [Google Scholar]
- 33.Meakins S, Fisher IS, Berghold C, Gerner-Smidt P, Tschape H, Cormican M et al. Antimicrobial drug resistance in human nontyphoidal salmonella isolates in europe 2000-2004: a report from the enter-net international surveillance network. Microb Drug Resist. 2008;14:31–5. doi: 10.1089/mdr.2008.0777. [DOI] [PubMed] [Google Scholar]
- 34.Mavroidi A, Neonakis I, Liakopoulos A, Papaioannou A, Ntala M, Tryposkiadis F et al. Detection of citrobacter koseri carrying beta-lactamase KPC-2 in a hospitalised patient, Greece. Euro Surveill. 2011;16:2011. [PubMed] [Google Scholar]
- 35.Landman D, Bratu S, Quale J. Contribution of ompk36 to carbapenem susceptibility in KPC-producing. Klebsiella pneumoniae J Med Microbiol. 2009;58:1303–8. doi: 10.1099/jmm.0.012575-0. [DOI] [PMC free article] [PubMed] [Google Scholar]