Mortality Associated With Carbapenem- Resistant Klebsiella pneumoniae Infections in Liver Transplant Recipients

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1 LIVER TRANSPLANTATION 18: , 2012 ORIGINAL ARTICLE Mortality Associated With Carbapenem- Resistant Klebsiella pneumoniae Infections in Liver Transplant Recipients Jayant S. Kalpoe, 1,2 Edith Sonnenberg, 1 Stephanie H. Factor, 1 Juan del Rio Martin, 3 Thomas Schiano, 1 Gopi Patel, 1 and Shirish Huprikar 1 1 Department of Medicine, Mount Sinai Medical Center, New York, NY; 2 Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands; and 3 Liver Transplant Program, Mutual Aid Hospital, San Juan, Puerto Rico Resistant bacterial infections are important causes of morbidity and mortality after liver transplantation (LT). This was a retrospective cohort study evaluating the outcomes associated with carbapenem-resistant Klebsiella pneumoniae (CRKP) infections after LT. In a cohort of 175 consecutive LT recipients, 91 infection episodes were observed in 61 patients (35%). The mortality rate 1 year after LT was 18% (32/175). Enterococcus (43%) and Klebsiella species (37%) were the most frequently isolated bacteria. CRKP infections occurred in 14 patients, and 10 of these patients (71%) died. Seven of these deaths occurred within 30 days of the CRKP infection. The median time to the onset of CRKP infections was 12 days (range ¼ days) after LT. The survival rate was significantly lower for patients with a CRKP infection versus patients without a CRKP infection (29% versus 86%, log-rank P < 0.001). In a multivariate analysis, the only pre-lt and post-lt clinical variables significantly associated with death were a Model for End-Stage Liver Disease score 30 (hazard ratio ¼ 3.4, P ¼ 0.04) and a post-lt CRKP infection (hazard ratio ¼ 4.9, P ¼ 0.007). In conclusion, the outcomes associated with CRKP infections in LT recipients are poor. Because the optimal treatment strategies for CRKP infections remain undefined, improved preventive strategies are needed to curtail the devastating impact of CRKP in LT recipients. Liver Transpl 18: , VC 2012 AASLD. Received September 5, 2011; accepted December 16, Bacterial infections remain the most common infectious complication after liver transplantation (LT), and they frequently occur within the first 2 months after LT. 1,2 s account for 19% to 30% of all major infections after LT, 3-5 and the mortality rate approaches 36% for these patients. 5,6 In recent years, an increased frequency of bloodstream infections due to gram-negative bacteria (specifically Klebsiella pneumoniae) has been reported for LT recipients. 5,7 Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a threat to hospitalized patients worldwide 8 and is associated with significant mortality. 9,10 We conducted a retrospective cohort study to determine the prevalence of and outcomes associated with bacterial infections after LT. Our primary aim was to determine the outcomes associated with CRKP infections in LT recipients. PATIENTS AND METHODS Study Population The study was approved by the institutional review board of the Mount Sinai School of Medicine. The cohort included adult patients who underwent Abbreviations: CRE, carbapenem-resistant Enterobacteriaceae; CRKP, carbapenem-resistant Klebsiella pneumoniae; ESBL, extended-spectrum b-lactamase; KPC, Klebsiella pneumoniae carbapenemase; LT, liver transplantation; MDR, multidrug-resistant; MELD, Model for End-Stage Liver Disease; UTI, urinary tract infection. Address reprint requests to Shirish Huprikar, M.D., Department of Medicine, Mount Sinai Medical Center, 1 Gustave L. Levy Place, Box 1090, New York, NY Telephone: ; FAX: ; shirish.huprikar@mssm.edu DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2012 American Association for the Study of Liver Diseases.

2 LIVER TRANSPLANTATION, Vol. 18, No. 4, 2012 KALPOE ET AL. 469 TABLE 1. Demographic and Baseline Clinical Data for the LT Recipients Characteristic All Patients (n ¼ 175) Yes (n ¼ 14) No (n ¼ 161) P Value Recipient age Years [median (range)] 55 (23-78) 57 (52-71) 55 (23-78) 0.05 >50 years [n (%)] 131 (75) 14 (100) 117 (73) 0.02 Male [n (%)] 142 (81) 9 (64) 133 (83) 0.15 Race/ethnicity [n (%)] White 82 (47) 5 (36) 77 (48) 0.32 Hispanic 43 (25) 6 (43) 37 (23) Asian 22 (13) 0 22 (14) Black 17 (10) 2 (14) 15 (9) Other 11 (6) 1 (7) 10 (6) Underlying liver disease [n (%)]* Hepatitis C virus 79 (45) 6 (43) 73 (45) 0.86 Hepatocellular carcinoma 71 (41) 5 (36) 66 (41) 0.78 Alcoholic liver disease 40 (23) 3 (21) 37 (23) 0.89 Hepatitis B virus 21 (12) 0 21 (13) 0.22 Other 50 (29) 6 (43) 44 (27) 0.23 Comorbid condition [n (%)]* Ascites 106 (61) 11 (79) 95 (59) 0.25 Esophageal varices 97 (55) 9 (64) 88 (55) 0.58 Encephalopathy 77 (44) 8 (57) 69 (43) 0.40 Spontaneous bacterial peritonitis 34 (19) 3 (21) 31 (19) 0.74 Comorbid disease* Hypertension 64 (37) 8 (57) 56 (35) 0.15 Diabetes mellitus 55 (31) 8 (57) 47 (29) 0.04 Chronic kidney disease 11 (6) 4 (29) 7 (4) Coronary artery disease 17 (10) 2 (14) 15 (9) 0.63 Human immunodeficiency virus 3 (2) 0 3 (2) >0.99 MELD score [median (range)] 21 (6-45) 27 (8-37) 19 (6-45) 0.10 MELD score ranges [n (%)] (34) 2 (14) 58 (36) (40) 5 (36) 65 (40) (26) 7 (50) 38 (24) Patient location before LT [n (%)] Home 129 (74) 8 (57) 121 (75) 0.20 Hospital 46 (26) 6 (43) 40 (25) *Some patients had more than 1 disease or condition. Post-LT CRKP Infection Within 1 Year deceased or living donor LT between January 1, 2005 and October 1, 2006 at Mount Sinai Hospital in New York City. Patients younger than 18 years and patients undergoing re-lt were excluded. The standard perioperative antibacterial prophylaxis consisted of ampicillin and sulbactam for 48 hours. The immunosuppression consisted of induction with daclizumab and corticosteroids and then maintenance with a corticosteroid taper and tacrolimus with or without mycophenolate mofetil. All patients received Mycostatin troches, trimethoprim and sulfamethoxazole, and valganciclovir for 3 months after LT. Definitions A bacterial infection episode was defined as the presence of a bacterial pathogen from a sterile site (eg, blood, peritoneal fluid, cerebrospinal fluid, or pleural fluid) in combination with clinical signs and symptoms of infection. A bloodstream infection was defined as the presence of Staphylococcus aureus, Streptococcus species, Enterococcus species, or any gram-negative bacteria in 1 or more blood cultures or as the presence of other bacteria in 2 sets of blood cultures or in 1 blood culture plus another sterile site culture. was defined as the presence of positive peritoneal fluid cultures. Intra-abdominal infections included surgical site infections, cholangitis, abscesses, and infected bilomas. Pneumonia and urinary tract infections (UTIs) were not included in our study because the currently accepted definitions could not be applied on account of the limitations of the available clinical data. Data Collection Medical records were reviewed from 1 year before LT until 1 year after LT. The following pre-lt information

3 470 KALPOE ET AL. LIVER TRANSPLANTATION, April 2012 was collected: demographic data (sex, age, and race), etiology of liver disease, clinical manifestations of liver disease, natural Model for End-Stage Liver Disease (MELD) score, comorbid medical conditions, laboratory data, cytomegalovirus serological status, pre-lt infections, and location before LT (ie, home versus hospital). The following post-lt information was collected: characteristics of transplant surgery (operative time, blood product requirements, immunosuppression regimen, and antimicrobial prophylaxis), episodes of rejection and cytomegalovirus disease, reoperation or re-lt, total days of hospitalization, and death within 1 year after LT. All episodes of post-lt bacterial infections were identified, and the following information was collected for each episode: infection type, bacterial pathogen, timing after LT, and therapy. Statistical Analysis A Kaplan-Meier analysis was performed to determine the impact of post-lt bacterial infections and CRKP infections on survival. Cox proportional hazard models were built to identify those factors independently associated with survival after transplantation. In one model, the evaluated exposures were post-lt infections in general. In another model, the evaluated exposures were specific bacterial pathogens so that the significance of CRKP infections could be determined. Possible confounders included the following: demographic characteristics (age, sex, and race), MELD score, underlying liver disease (hepatitis B, hepatitis C, hepatocellular carcinoma, fulminant hepatic failure, and alcohol-related disease), comorbid diseases (coronary artery disease, diabetes, chronic kidney disease, human immunodeficiency virus, and hypertension), cirrhotic conditions (ascites, a history of esophageal variceal bleeding, and a history of spontaneous bacterial peritonitis), combined liver-kidney transplantation, hospitalization before LT, and pre-lt infections. Computer-assisted forward, backward, and stepwise regression identified those factors independently associated with survival after transplantation. A P value 0.05 was considered statistically significant. All statistical calculations were performed with SPSS 18 (SPSS, Somers, NY). RESULTS Patient Characteristics The study cohort consisted of 175 LT recipients. The baseline demographics and the clinical characteristics are outlined in Table 1. The median MELD score was 21 (range ¼ 6-45), and the majority of the patients (74%) had a natural MELD score < 30. Hepatitis C virus infections and alcoholic liver disease were the most common etiologies of liver failure. All patients had multiple comorbid medical conditions, and concurrent hepatocellular carcinoma was common. Patients with CRKP infections were slightly older, were more likely to have diabetes or chronic kidney TABLE 2. Summary of Post-LT Infections Characteristic n (%) Infected patients 61/175 (35) Infection episodes 91 Type of infection (n ¼ 91)* 61 (67) 45 (49) Intra-abdominal infection 35 (38) Other 5 (5) Episodes associated with pathogens (n ¼ 91) 1 pathogen 63 (69) 2 pathogens 20 (22) >2 pathogens 8 (9) Isolated pathogens (n ¼ 91)* Gram-negative 63 (69) Klebsiella (all) 34 (37) Susceptible 6 (7) ESBL (carbapenem-susceptible) 11 (12) CRKP 17 (19) Other Enterobacteriaceae 15 (16) Pseudomonas aeruginosa 14 (15) Gram-positive 51 (56) Enterococcus species 39 (43) Vancomycin-resistant Enterococcus 21 (23) Susceptible 18 (20) S. aureus 12 (13) Methicillin-resistant S. aureus 8 (9) Methicillin-susceptible S. aureus 4 (4) Other 11 (12) *More than 1 type of infection or pathogen could be associated with an infection episode. Includes nonabdominal abscesses [skin (3), brain (1), and nasal (1)]. Includes Streptococcus species (n ¼ 4), coagulasenegative Staphylococcus species (n ¼ 3), Fusobacterium species (n ¼ 1), and Acinetobacter species (n ¼ 3). disease, and were more likely to have a MELD score 30. Post-LT Outcomes Within 1 year of LT, 32 patients (18%) died. The median length of the hospital stay after LT was 21 days (range ¼ days). Overall, 91 bacterial infection episodes were observed in 61 patients (35%; Table 2). s were present for 61 of the infection episodes (67%) in 34 patients, peritonitis was present for 45 episodes (49%) in 26 patients, and intra-abdominal infections were present for 35 episodes (38%) in 20 patients. Sixty-three of the infection episodes (69%) were associated with 1 pathogen, 20 (22%) were associated with 2 pathogens, and 8 (9%) were associated with more than 2 pathogens. Gramnegative bacteria were isolated in 63 episodes (69%), and gram-positive bacteria were isolated in 51 episodes (56%). The most frequently isolated bacteria were Enterococcus (39/91 or 43%) and Klebsiella species (34/91 or 37%). CRKP and extended-spectrum

4 LIVER TRANSPLANTATION, Vol. 18, No. 4, 2012 KALPOE ET AL. 471 TABLE 3. Summary of the Clinical Characteristics of CRKP Infections Age Time From LT to Infection Antimicrobial Quartile Sex (Years) (Days) Infection Type Therapy (Days) Outcome 1 Male 53 5 Cefepime (2) Died 6 days after LT 1 Male 53 4 Liver abscess Polymyxin B (42) Died 84 days after LT Muscle abscess Gentamicin (43) 2 Male 52 1 Surgical site infection Polymyxin B (59) Survived 2 Female Abdominal abscess Polymyxin B (25) Died 38 days after LT 2 Female Polymyxin B (3) Died 358 days after LT Tigecycline (13) 2 Male Surgical site infection Tigecycline (7) Survived 3 Female Tigecycline (8) Died 29 days after LT 3 Female Surgical site infection Polymyxin B (37) Survived Abdominal abscess 3 Male Liver abscess Polymyxin B (16) Died 29 days after LT 3 Male Liver abscess Polymyxin B (10) Died 30 days after LT Abdominal abscess Tigecycline (3) 3 Male 55 7 Abdominal abscess Tigecycline (23) Died 331 days after LT 4 Male Polymyxin B (1) Died 128 days after LT 4 Female Abdominal abscess Polymyxin B (11) Survived Tigecycline (11) 4 Male Liver abscess Polymyxin (4) Died 17 days after LT Tigecycline (4) b-lactamase (ESBL) producing, carbapenem-susceptible K. pneumoniae represented the overwhelming majority of Klebsiella isolates (28/34). Vancomycin-resistant Enterococcus represented the majority of Enterococcus isolates (21/39). Multidrug-resistant (MDR) Enterobacteriaceae, including ESBL-producing carbapenem-susceptible Enterobacteriaceae and CRKP, were isolated in 23 of the 61 patients (38%) with post-lt bacterial infections. CRKP infections occurred in 14 patients (23%; Table 3). One patient had 3 CRKP infection episodes, and another patient had 2 episodes. The median interval from LT to the CRKP infection was 12 days (range ¼ days), and 93% of the CRKP infections (13/14) occurred within 1 month after LT. CRKP bloodstream infections were present in 86% of the patients with CRKP infections (12/14). CRKP intraabdominal infections or peritonitis was present in 79% of these patients (11/14). Nine of 11 patients with CRKP intra-abdominal infections or peritonitis also had CRKP bloodstream infections. Ten of the 14 patients with CRKP infections (71%) died; 7 died within 30 days of the infection. The median time from infection to death was 15.5 days (range ¼ days). CRKP infections were identified in all quartiles of the study period (Table 3). Risk Factors Associated With Post-LT Mortality According to the Kaplan-Meier analysis, the survival rate was significantly lower for patients with an infection within 1 year of LT versus patients without post- LT bacterial infections (67% versus 90%, log-rank P < 0.001; Fig. 1A). The 1-year survival rate was significantly lower for patients with a CRKP infection versus patients without a CRKP infection (29% versus 86%, log-rank P < 0.001; Fig. 1B). In the Cox proportional hazards models, post-lt infections were not independently associated with death (data not shown). The only pre-lt and post-lt variables independently associated with death 1 year after LT were a MELD score 30 (hazard ratio ¼ 3.4, P ¼ 0.04) and a CRKP

5 472 KALPOE ET AL. LIVER TRANSPLANTATION, April 2012 Figure 1. Survival rates associated with infections. (A) A Kaplan-Meier analysis demonstrated reduced survival for LT recipients with infections versus LT recipients without infections (67% versus 90%, log-rank P < 0.001). (B) A Kaplan-Meier analysis demonstrated reduced survival for LT recipients with CRKP infections versus LT recipients without CRKP infections (29% versus 86%, log-rank P < 0.001). infection after LT (hazard ratio ¼ 4.9, P ¼ 0.007; Table 4). DISCUSSION To the best of our knowledge, this is the first study specifically describing the incidence of and poor outcomes associated with CRKP infections in a cohort of LT recipients. CRKP infections were observed in nearly 25% of the patients with bacterial infections after LT, and this resulted in a 5-fold increased risk of death. This was the only post-lt clinical variable independently associated with mortality. Previous studies have demonstrated the emergence of gram-negative bacterial infections in LT recipients and the morbidity associated with them. 11 In a cohort study of 475 LT recipients, Shi et al. 11 reported that greater mortality was associated with MDR gram-negative bacterial infections, which were observed in more than 50% of the patients. However, 90% of the Enterobacteriaceae in that study were carbapenem-susceptible. Linares et al. 7 recently reported that 53% of the K. pneumoniae isolates in their solid organ transplant population were ESBL-producing strains; however, none were reported to be carbapenem-resistant. Similarly, Klebsiella species were the most common gram-negative bacteria in our study, but only 50% were carbapenem-susceptible. The extremely poor outcomes observed in our LT cohort with CRKP infections are consistent with the published reports. In a review of 12 reported cases of carbapenem-resistant Enterobacteriaceae (CRE) in solid organ transplant recipients, 6 of the 7 LT recipients with carbapenem-resistant Klebsiella died. 15 The association between CRKP and mortality has been previously described in studies not limited to transplant patients. In a case-control study, we previously described higher mortality rates for hospitalized patients with CRKP versus patients with carbapenemsusceptible Klebsiella (48% versus 20%, P < 0.001). The transplant recipient status was demonstrated to be an independent risk factor for CRKP infections. 9 Another retrospective cohort study reported that a hospital mortality rate of 60% was associated with CRKP infections in a heterogeneous patient population that included transplant recipients (42% of the patients). 10 Controlled studies for guiding the clinical management of CRKP and other MDR gram-negative bacterial infections are lacking. Previous studies have suggested that the efficacy of currently available antibacterial agents is poor, but adjunctive procedures such as catheter removal and abscess drainage are essential. 9,10 Prospective randomized controlled trials for the treatment of CRKP infections with currently available antibacterial agents are likely not feasible. However, a well-designed, collaborative prospective cohort study involving major transplant centers could be valuable in determining the risk factors, preventive strategies, and possible therapeutic strategies associated with favorable outcomes in the management of CRKP infections. Prevention is perhaps the most important strategy for minimizing the morbidity and mortality associated with CRKP and other MDR bacterial infections. Casecontrol studies have suggested that antimicrobial exposure is associated with the acquisition of CRKP. 9 Prudent antimicrobial use remains important in the prevention of MDR bacterial infections. Prolonged antibacterial courses are not recommended in most

6 LIVER TRANSPLANTATION, Vol. 18, No. 4, 2012 KALPOE ET AL. 473 TABLE 4. Univariate and Multivariate Cox Proportional Hazards Analyses of Pre-LT and Post-LT Factors Associated With 1-Year Mortality After Transplantation Univariate Analysis Hazard Ratio Multivariate Analysis Hazard Ratio Risk Factor (95% Confidence Interval) P Value (95% Confidence Interval) P Value Age > 51 years 1.9 ( ) 0.19 Male sex 0.6 ( ) 0.14 Underlying liver disease Hepatitis C virus 1.4 ( ) 0.34 Hepatocellular carcinoma 1.0 ( ) 0.95 Alcoholic liver disease 1.4 ( ) 0.44 Hepatitis B virus 0.2 ( ) 0.13 Manifestation of liver disease Ascites 1.7 ( ) 0.16 Esophageal varices 0.8 ( ) 0.54 Encephalopathy 1.3 ( ) 0.43 Spontaneous bacterial peritonitis 1.0 ( ) 0.93 Comorbid disease Hypertension 1.2 ( ) 0.61 Diabetes mellitus 1.0 ( ) >0.99 End-stage renal disease 1.0 ( ) >0.99 Coronary artery disease 0.3 ( ) 0.22 Human immunodeficiency virus 4.5 ( ) 0.61 MELD score ( ) (1.1-11) 0.04 Combined liver-kidney recipient 1.5 ( ) 0.70 Pre-LT hospitalization 1.7 ( ) 0.13 Bacteria causing post-lt infection CRKP 7.1 ( ) < ( ) ESBL-producing K. pneumoniae 3.3 ( ) Other susceptible gram-negative rods 2.4 ( ) 0.04 Pseudomonas species 3.2 ( ) 0.01 Vancomycin-resistant Enterococcus 2.3 ( ) 0.05 Methicillin-resistant S. aureus 1.4 ( ) 0.70 Other susceptible gram-positive cocci 1.6 ( ) 0.36 Pre-LT infection within 365 days 1.6 ( ) 0.22 situations and likely only increase the risks of toxicity and/or resistance. Infection control strategies are also important for the prevention of bacterial infections. Singh et al. 16 described a robust reduction in S. aureus infections in LT recipients with an aggressive infection control strategy that included (1) active surveillance for detecting nasal and rectal carriage, (2) cohorting and strict contact isolation precautions, and (3) decolonization with nasal mupirocin. Notably, an outbreak of CRE in Israel was not controlled by local measures and was contained only after a centrally coordinated, nationwide intervention strategy was implemented. 17 Only 1 patient in our study was known to be colonized with CRKP before LT (data not shown). However, surveillance was not routinely performed throughout the study period, and it is possible that other patients were colonized before LT. During the study period, contact isolation was required for all patients who were colonized or infected with any CRE. Active surveillance for detecting rectal carriage of CRE is now performed in high-prevalence areas such as intensive care units. It has also been considered for hospitalized LT candidates and recipients to allow for the early implementation of appropriate infection control measures to prevent horizontal transmission and to identify patients at greater risk for infection. Although active surveillance studies have demonstrated high attack rates among CRKP-colonized individuals, 18 colonization with CRKP is presently not considered an absolute contraindication to LT. Perioperative antibacterial prophylaxis is adjusted at our hospital according to our knowledge of the susceptibilities of colonizing strains so that we can potentially minimize the perioperative infection risk. We acknowledge that data supporting this strategy are lacking, and further studies are needed to validate these approaches and determine the significance of colonization with CRKP or other CRE before LT. There are limitations to this study. First, we were unable to include pneumonia and UTIs in this study and may have underestimated the number of infection episodes and the number of patients with infections. Because respiratory and urinary tract bacterial isolates are frequent colonizers in hospitalized patients, it is necessary to apply strict definitions of pneumonia and UTIs to distinguish infections from colonization. However, we were unable to apply strict definitions

7 474 KALPOE ET AL. LIVER TRANSPLANTATION, April 2012 because of missing data essential to these definitions. Notably, CRKP grew in the urine and/or respiratory cultures of 6 patients in our cohort in the setting of prolonged hospitalizations, and they often had proven infections due to other pathogens. Most urine cultures in our study were taken in the setting of an indwelling catheter, which often reflects colonization. Symptoms were frequently not documented, and urinalysis either was not performed or was negative. Most respiratory cultures in our study were for patients who underwent tracheostomy, and chest X-rays either were not performed or were difficult to interpret because of poor technique. We believe that the integrity of our data would have compromised by misclassification bias if we had attempted to include UTIs and pneumonia. We acknowledge, however, that the results of our study may not apply to LT recipients with CRKP pneumonia or UTIs. Second, because our data come from a single-center experience with LT recipients in an area endemic for CRKP, our findings may not be relevant to other patient populations in other clinical settings. However, the morbidity described with CRKP infections in the literature published to date suggests that our findings are not unique. 19,20 Third, it is possible that other unmeasured factors associated with the severity of illness may have contributed to the outcomes observed in our study. Finally, although most analyzed isolates of CRKP from our hospital have demonstrated Klebsiella pneumoniae carbapenemase (KPC) production (KPC-2 or KPC-3), the mechanisms of carbapenem resistance in the CRKP infections in this study are not fully described. However, it is not clear that knowledge of the mechanisms of carbapenem resistance affects the clinical response to antimicrobials or clinical outcomes. In conclusion, our study demonstrates that CRKP infections are associated with significant mortality in LT recipients. Further studies are needed to explore the evolving epidemiology and outcomes associated with CRKP infections and effective strategies for preventing and treating CRKP infections in LT patients and other organ transplant patients. REFERENCES 1. Huprikar S. Update in infectious diseases in liver transplant recipients. Clin Liver Dis 2007;11: Blair JE, Kusne S. Bacterial, mycobacterial, and protozoal infections after liver transplantation part I. Liver Transpl 2005;11: Singh N, Gayowski T, Wagener M, Yu VL. Infectious complications in liver transplant recipients on tacrolimus. Prospective analysis of 88 consecutive liver transplants. Transplantation 1994;58: Wagener MM, Yu VL. Bacteremia in transplant recipients: a prospective study of demographics, etiologic agents, risk factors, and outcomes. 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