LIVER TRANSPLANTATION 20:856–863, 2014
ORIGINAL ARTICLE
Etiology and Mortality of Spontaneous Bacterial Peritonitis in Liver Transplant Recipients: A Cohort Study rez-Cameo,1 Vıctor Vargas,1 Lluıs Castells,1 Itxarone Bilbao,2 Isabel Campos-Varela,1 Cristina Pe 3 Albert Pahissa,3 and Oscar Len3 Joan Gavalda, 1 Liver Unit, Department of Internal Medicine, 2Department of Hepatobiliopancreatic Surgery and Transplantation, and 3Department of Infectious Diseases, Vall d’Hebron Hospital, Barcelona, Spain
Spontaneous bacterial peritonitis (SBP) in liver transplantation (LT) recipients who progress to cirrhosis has received little attention. We investigated the adequacy of empirical treatment with third-generation cephalosporins for SBP in this population and the impact of transplantation on the evolution of the infection. We performed a cohort study with 138 SBP episodes: 19 in LT patients and 119 in non-LT patients. The etiology of SBP was identified for 73.7% of the episodes in LT patients and for 38.7% of the episodes in non-LT patients (P 5 0.004). The main microorganisms in recipients were Escherichia coli (35.7%) and Streptococcus pneumoniae (21.4%). The etiologies did not differ in non-LT patients. The cephalosporin sensitivity was similar in the 2 groups (85.7% versus 78.4%, P 5 0.7). LT recipients developed renal failure (57.9% versus 25.2%, P 5 0.004) and encephalopathy (42.1% versus 22%, P 5 0.08) more often than non-LT patients, and the mortality rates during episodes (52.6% versus 13.4%, P < 0.001) and at 6 months (70.6% versus 34.7%, P 5 0.005) were higher. According to a multivariate analysis, the mortality-associated risk factors at diagnosis were a Model for End-Stage Liver Disease (MELD) score > 18 odds ratio (OR) 5 6.1 and being an LT recipient (OR 5 4.45). At 6 months, the risk factors for mortality were a MELD score > 18 (OR 5 3.08), being an LT recipient (OR 5 3.47), a known etiology (OR 5 2.08), and the presence of C 2014 AASLD. hepatocellular carcinoma (OR 5 3.73). Liver Transpl 20:856-863, 2014. V Received January 14, 2014; accepted April 3, 2014. The treatment of choice for end-stage cirrhosis is liver transplantation (LT). Nonetheless, the recurrence of the primary disease, the development of liver cirrhosis (especially in patients with hepatitis C virus, in whom reinfection almost always occurs), and associated complications are common causes of late graft loss and have an impact on morbidity and mortality.1-4 It is well recognized that spontaneous bacterial peritonitis (SBP) is associated with a high mortality rate (approximately 20%) in patients with cirrhosis,5-7 and
the first SBP episode predicts a significant decrease in survival, even in the short term, with 1-year survival rates ranging from 28.5% to 93%.8-13 Nonantipseudomonal third-generation cephalosporins (3CP) are the treatment of choice for SBP,5,6,10 but several recent studies have reported that bacterial resistance to 3CP has reached a disturbing level of 43%.6,14 Nosocomial and health care–related infections are often associated with multidrug-resistant microorganisms such as Enterobacteriaceae producing extended-spectrum beta-
Abbreviations: 3CP, third-generation cephalosporin; CI, confidence interval; ESBL, extended-spectrum beta-lactamase; GPC, gram-positive cocci; HIV, human immunodeficiency virus; HR, hazard ratio; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; OR, odds ratio; SBP, spontaneous bacterial peritonitis. No grants or financial support was used to perform this study. The authors of this article have no conflicts of interest to disclose as described by Liver Transplantation. Preliminary data from this study were presented at the European Association for the Study of the Liver Monothematic Conference on Bacterial Infections in Cirrhosis (Barcelona, Spain, May 2013). rez-Cameo, M.D., Liver Unit, Department of Internal Medicine, Vall d’Hebron Hospital, Passeig de la Vall Address reprint requests to Cristina Pe d’Hebron 119-129, 08035 Barcelona, Spain. Telephone: 134 934893000/932740000; FAX: 134 932746068; E-mail:
[email protected] DOI 10.1002/lt.23889 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
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lactamases (ESBLs), methicillin-resistant Staphylococcus aureus, and some species of Enterococcus.6,11,13,15,16 Other risk factors for the development of SBP by ESBL enterobacteria are previous antibiotic treatments15,16 and a previous history of SBP.17 The use of quinolones for SBP prophylaxis involves a change in the intestinal flora with an increase in gram-positive cocci (GPCs).6,14,15 In light of these factors, some authors have proposed a change in empirical antibiotic therapy, with drugs such as piperacillin-tazobactam or carbapenems used in select at-risk groups (eg, patients with hospital-acquired SBP, patients with prior antibiotic treatment or prophylaxis, and patients undergoing invasive procedures).6,10,11,13-15 LT recipients carry many of these risk factors, but data are lacking on the epidemiology of SBP in this population. The aim of this study was to compare the etiologies of SBP and the suitability of current empirical treatments with 3CP in patients who develop cirrhosis after LT and nontransplant patients with cirrhosis. We also studied the influence of transplantation on mortality during SBP episodes and at the 6-month follow-up.
PATIENTS AND METHODS Study Design A retrospective cohort study was conducted at Vall d’Hebron Hospital (Barcelona, Spain), a 1000-bed teaching hospital at which LT has been performed more than 1000 times since 1988. We selected all patients treated in emergency/hospitalization areas from November 2009 to April 2011 (both inclusive) after we had reviewed medical charts of both patients with cirrhosis and LT recipients at our center. The study received a priori approval by the appropriate institutional review committee. For the purposes of this study, we compared patients with cirrhosis who had undergone LT and patients with cirrhosis who had not undergone transplantation. Data were collected from both groups for the following: demographics (age and sex), medical history, characteristics of cirrhosis (including the cause), liver function [Child and (MELD) scores], and complications. For transplant patients, data related to immunosuppressive treatments were also collected. Clinical and laboratory information, microbiological findings (culture results, causal microorganisms, and susceptibility testing), and administered treatments (empirical and etiological antibiotic therapies) were also compiled. The use of albumin as an additional treatment was recorded. Finally, we collected information on complications and deaths during SBP episodes and at the 6-month follow-up.
Definitions SBP was defined as a polymorphonuclear leukocyte count greater than 250 cells/mL in ascitic fluid. Episodes were included regardless of whether the ascites culture was positive or negative.5,11 Renal failure as a condition before SBP was defined as a plasma creatinine value higher than 1.5 mg/dL,
as described previously.18 Renal failure as a complication during the follow-up was defined as an increase in the plasma creatinine value greater than 0.3 mg/dL, as described in international guidelines.19 The ChildPugh scale and the MELD score were calculated as reported previously.20-22 SBP was considered to have a nosocomial origin when the diagnosis was made after the first 48 hours of hospitalization or within 8 days after hospital discharge. In the study of mortality and its causes, cirrhosisrelated death was established when SBP, cirrhosis, ascites decompensation, renal failure, hepatic encephalopathy, gastrointestinal bleeding, or liver failure was the essential cause of death. Death during an episode of SBP was established when the patient did not achieve a clinical or analytical cure and died before a resolution of the infection.
Statistical Analyses Frequencies and percentages were calculated for categorical variables, and the means for continuous variables were determined after the verification of normality with the Kolmogorov-Smirnov test. Subsequently, a bivariate analysis was performed with the chi-square test with correction via Fisher’s exact test for categorical variables and with the Student t test for continuous variables with a normal distribution. Continuous variables that were not normally distributed were compared with nonparametric tests (Mann-Whitney). A multivariate logistic regression analysis incorporating all episodes was performed to identify independent risk factors for death during SBP episodes. In the 6-month mortality study, we included only the last episode of each patient. Previous SBP episodes from the same patient collected during the study period were included in the variable number of previous SBP episodes. Kaplan-Meier curves were constructed to evaluate survival probabilities and were compared with the Cox proportional hazards test. Variables showing statistically significant differences in the univariate analysis were then tested in multivariate models. Models were performed in a sequential fashion: they were begun with the variable most strongly associated with mortality and were continued until no other variable reached significance or changed the hazard ratios (HRs) of variables already in the model. In addition, clinically relevant factors with P values < 0.1 that were considered potential confounders on the basis of experience and data in the literature were forced into the multivariate model so that we could investigate their effects. Statistical significance was set at 5% (P < 0.05). All statistical analyses were performed with IBM SPSS Statistics for Windows 19.0 (IBM Corp., Armonk, NY)
RESULTS Characteristics of Patients and Episodes We reviewed 169 episodes of SBP. Nineteen of these episodes were excluded because they were ultimately
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TABLE 1. Baseline Characteristics of the Study Cohort Characteristic
LT (n 5 19)
Non-LT (n 5 119)
P Value
8 (42.1) 64 (15)
74 (62.2) 60 (24)
0.09 0.79
17 (89.5) 0 1 (5.3) 1 (5.3) 0 0 1 (5.3)
61 (51.3) 3 (2.5) 46 (38.7) 0 3 (2.5) 6 (5) 27 (22.7)
0.002 0.004 0.12
0 7 (36.8) 10 (52.6) 2 (10.5) 28 (20) 6 (31.6) 4 (21.1) 13 (68.4) 4 (21.1) 8 (42.1) 0 2 (10.5) 2 (10.5) 6 (31.6) 8 (42.1)
7 (5.9) 41 (34.5) 67 (56.3) 4 (3.4) 19 (10) 45 (37.8) 40 (33.6) 82 (68.9) 8 (6.7) 42 (35.3) 9 (7.6) 22 (18.5) 0 21 (17.6) 31 (26.1)
0.8 0.7 0.04 0.6 0.27 0.96 0.06 0.56 0.21 0.52 0.2 0.14
Sex: male [n (%)] Age (years)* Etiology of cirrhosis [n (%)] Hepatitis C virus Hepatitis B virus Alcoholic Primary biliary cirrhosis Autoimmune Other causes Alcohol consumption [n (%)] Child-Pugh stage [n (%)] A B C Not calculated MELD score* Previous hepatic encephalopathy [n (%)] Previous gastrointestinal bleeding [n (%)] Previous ascites [n (%)] Renal failure [n (%)] Diabetes mellitus [n (%)] HIV infection [n (%)] Hepatocellular carcinoma [n (%)] Previous corticosteroid treatment [n (%)] Previous antibiotic treatment: 30 days [n (%)] Prophylactic antibiotic [n (%)] *The data are presented as medians and interquartile ranges.
found to be cases of secondary peritonitis, and 12 were excluded because of diagnostic coding errors (they were not SBP cases). Thus, 138 episodes of SBP were analyzed in patients with cirrhosis: 19 episodes in 18 LT recipients and 119 episodes in 104 nonrecipients. The median MELD score was 28 for the LT recipients and 19 for the non-LT patients (P 5 0.04). For a significantly larger percentage of LT patients versus non-LT patients, the cause of cirrhosis was a hepatitis C virus infection (89.5% versus 51.3%, P 5 0.002). None of the LT patients included in this study had fibrosing cholestatic hepatitis C virus. Only 1 LT patient was receiving interferon treatment when SBP presented. There were no significant differences between the 2 groups with respect to complications occurring during the course of the cirrhosis or other background variables. Seventeen LT patients had previously undergone FibroScan and/or liver biopsy confirming the presence of cirrhosis, and the other 2 transplant recipients fulfilled clinical, biochemical, and echographic criteria. Baseline characteristics are shown in Table 1. The main immunosuppressive regimen for the LT recipients consisted of tacrolimus administered either as monotherapy (9 patients or 47.4%) or with corticosteroids (2 patients or 10.5%). The median tacrolimus serum level was 3.3 ng/mL (range 5 2.0-7.5 ng/mL). Other immunosuppressive regimens included monotherapy with mycophenolate (2 patients or 10.5%),
everolimus (1 patient or 5.3%), cyclosporine (1 patient or 5.3%), or rapamycin (1 patient or 5.3%). Finally, different combinations of previous drugs were used in 3 LT recipients (15.8%). In 2 cases, the dose of the immunosuppressive drugs was reduced during the SBP episode; in 1 case, the immunosuppressive regimen was stopped; and in another case, the regimen was changed from tacrolimus to everolimus because of veno-occlusive disease. No episodes of rejection were documented afterward.
Microbiology of Episodes The cause of SBP was identified for a higher percentage of episodes in LT patients versus non-LT patients (73.7% versus 38.7%, P 5 0.004) by ascitic fluid culture (72.2% versus 26.9%, P < 0.001) or blood culture (Table 2). Nosocomial infections were similar for the 2 groups (36.8% for LT recipients versus 26.1% for non-LT patients, P < 0.32; Table 3). The etiology of SBP episodes is shown in Table 2. The most frequent isolate in recipient episodes was Escherichia coli (5 episodes or 35.7%), which was followed by Streptococcus pneumoniae. No episodes were caused by gram-positive bacilli in this group, whereas 3 episodes were recorded for the nontransplant patients. Nonetheless, there were no significant differences in the microorganism distributions of the 2 groups (Table 2). E. coli ESBLs accounted for only 1
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TABLE 2. Microbiology and Antibiotic Sensitivity Characteristic Positive ascitic fluid culture [n/N (%)] Positive blood culture [n/N (%)] Antibiotic susceptibility pattern [n (%)] Known etiology [n (%)] Microorganism identified [n (%)] E. coli Other gram-negative bacilli Pseudomonas aeruginosa Klebsiella pneumoniae Enterobacter aerogenes Enterobacter cloacae Citrobacter braakii Serratia marcescens Streptococcus pneumoniae Other GPCs Staphylococcus aureus Staphylococcus epidermidis Staphylococcus capitis Streptococcus agalactiae Enterococcus faecium Other Enterococcus Streptococcus bovis Streptococcus sanguinis Streptococcus gordonii Other Streptococcus viridans Gram-positive bacilli Antibiotic susceptibility pattern [n/N (%)] Amoxicillin plus clavulanic acid Piperacillin plus tazobactam Quinolones Ceftriaxone/cefotaxime Carbapenem Multidrug-resistant microorganism: E. coli ESBL [n/N (%)]
LT (n 5 19) 13/18 5/16 13 14
(72.2) (31.2) (68.4) (73.7)
Non-LT (n 5 119) 29/108 22/84 40 46
P Value
(26.9) (26.2) (33.6) (38.7)
0.99 >0.99 0.7 -
10/13 (76.9) 7/8 (87.5) 9/12 (75) 12/14 (85.7) 9/9 (100) 0/14
23/33 (69.7) 16/21 (76.2) 26/35 (74.3) 29/37 (78.4) 21/21 (100) 1/37 (2.7)
0.7 0.6 >0.99 0.7 -
episode in a non-LT patient, and there were no episodes caused by resistant gram-positive microorganisms such as methicillin-resistant S. aureus and vancomycin-resistant Enterococcus.
between the groups in their susceptibility to 3CP (85.7% versus 78.4%, P 5 0.7) or the other antibiotics tested (Table 2). The use of albumin for renal failure prophylaxis was similar in the 2 groups (Table 3).
SBP Characteristics and Antibiotic Treatment
Complications and Mortality Analysis
LT recipients with SBP presented with abdominal pain (73.7% versus 42.8%, P 5 0.01) and hepatic encephalopathy (73.7% versus 41.2%, P 5 0.008) more often than non-LT patients. Other characteristics of episodes are shown in Table 3. Empirical antibiotic therapy with 3CP was given for 73.7% of the episodes in LT recipients and for 84.9% of the episodes in non-LT patients (P 5 0.2). Empirical treatment was maintained throughout episodes for 73.7% of the LT recipients and for 70.6% of the nonLT patients (P 5 0.7). Antibiotic treatment was changed for etiological reasons for 4 episodes in LT recipients (21.1%) and for 18 episodes in non-LT patients (15.1%). A therapy change was made to 3CP for 3 of the 4 recipient episodes. For episodes in nonLT patients, there were 6 changes to 3CP and 5 changes to quinolones. No differences were found
Transplant patients with cirrhosis had a higher percentage of complications in the form of renal failure (57.9% versus 25.2%, P 5 0.004) and hepatic encephalopathy (42.1% versus 22%, P 5 0.08) in comparison with nontransplant patients (Table 3), and they presented with higher mortality rates during episodes (52.6% versus 13.4%, P < 0.001) and at 6 months (70.6% versus 34.7%, P 5 0.005; Fig. 1). Ten LT recipients died during SBP episodes, and 2 died during the 6-month follow-up. All deaths were cirrhosisrelated. Six LT recipients died because of hepatic failure (50%), 5 died because of sepsis (41.7%), and the last patient died because of gastrointestinal bleeding (8.3%). In the multivariate analysis of risk factors for death during episodes, a statistically significant association was found with a MELD score >18 at the time of the
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TABLE 3. Characteristics of Episodes Characteristic Kind of episode [n (%)] Positive ascitic fluid culture Negative ascitic fluid culture Nosocomial acquisition [n (%)] Time from transplant to SBP (months)* Clinical data Abdominal pain [n (%)] Encephalopathy [n (%)] Diarrhea [n (%)] Ascitic decompensation [n (%)] Gastrointestinal bleeding [n (%)] Temperature ( C)† Initial paracentesis: neutrophils in ascites (number/mm3)† Blood analysis† Platelets (number/mm3) Bilirubin (mg/dL) Prothrombin time (%) Initial creatinine (mg/dL) Final creatinine (mg/dL) Empirical antibiotic treatment [n (%)] Amoxicillin 1 clavulanic acid Piperacillin 1 tazobactam Cephalosporin Quinolones Carbapenem Albumin administration [n/N (%)] Antibiotic treatment duration (days)† Complications [n (%)] Encephalopathy Renal failure Death [n (%)] During episode At 6-month follow-up
LT (n 5 19)
Non-LT (n 5 119)
P Value
13 (68.4) 6 (31.6) 7 (36.8) 64 (8–166)
29 (24.4) 90 (75.6) 31 (26.1) -
0.99 >0.99 >0.99 0.08 0.02
66,200 (35,100) 4.66 (9.51) 37 (42) 1.7 (1.77) 1.39 (1.4)
10,100 (72,000) 2.55 (3.2) 55 (24) 1.0 (0.87) 0.99 (0.49)
0.03 0.046 0.02 0.06 0.04
1 (5.3) 3 (15.8) 14 (73.7) 0 0 16/17 (94) 8 (6)
7 (5.9) 2 (1.7) 101 (84.9) 4 (3.4) 3 (2.5) 90/113 (80) 8 (6)
>0.99 0.02 0.2 0.2 0.27
8 (42.1) 11 (57.9)
26 (21.9) 30 (25.2)
0.08 0.004
10 (52.6) 12/17 (70.6)
16 (13.4) 35/101 (34.7)
18 and being an LT recipient (Table 5). In the 6-month mortality study, the independent risk factors for death were being an LT recipient, a MELD score > 18 at diagnosis, the identification of the causal agent, and the presence of hepatocellular carcinoma (Table 6).
DISCUSSION
Figure 1.
Survival analysis (Kaplan-Meier)
This study was designed to investigate whether there were etiological differences in SBP episodes suffered by patients with cirrhosis who had undergone LT and
patients who had not. The ultimate goal was determining whether a different empirical antibiotic treatment should be given to LT patients. Furthermore, we
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TABLE 4. Analysis of Mortality During an SBP Episode Bivariate Analysis
Multivariate Analysis
Risk Factor for Mortality
P Value
OR
95% CI
P Value
OR
95% CI
MELD score > 18 Known etiology Complications Renal insufficiency Hepatic encephalopathy