Empiric treatment of nosocomial spontaneous bacterial peritonitis: One size does not fit all
Authors: Michael G. Ison
Journal: Hepatology (2016)

See article on page XXXX Potential conflict of interest: Nothing to report. Patients with cirrhosis have an increased risk of developing bacterial infections, particularly spontaneous bacterial peritonitis (SBP). SBP is defined as an ascitic fluid infection without an evident intra‐abdominal surgically treatable source. Patients with SBP present with signs and symptoms of infection, including fever, abdominal pain, and altered mental status, in addition to an ascitic fluid absolute polymorphonuclear leukocyte count ≥250 cells/μL; cultures of ascites fluid are positive for bacteria in about half of patients when cultures are obtained.1 Such infections are associated with an increased risk of mortality. SBP can be classified into community‐acquired (SBP <72 hours after hospital admission without use of antibiotics within 7 days of presentation), health care‐associated (extensive exposure to the health care setting and/or receipt of antibiotics within 7 days of presentation), and nosocomial infection (onset of signs and symptoms of SBP ≥72 hours after hospital admission). Community‐acquired SBP typically develops by seeding of the ascites fluid with bacteria from the gastrointestinal tract, such as Escherichia coli and Klebsiella, although streptococcal and staphylococcal infections can also occur.1 Current guidelines suggest that initial empiric therapy for community‐acquired SBP be an intravenous third‐generation cephalosporin, although an oral fluoquinolone can be used in patients without prior exposure to quinolones, vomiting, shock, grade 2 or higher hepatic encephalopathy, or serum creatinine >3 mg/dL.1 Patients with extensive health care exposure may be at increased risk for colonization and infection with multidrug‐resistant bacteria. Emerging data, predominantly from Europe, suggest that multidrug‐resistant bacteria are increasingly responsible for SBP in patients who are receiving fluoquinolone prophylaxis, in patients with frequent contact with the health care system, and in patients who develop nosocomial SBP. In one study of SBP in patients on fluoquinolone prophylaxis, 18% of culture‐confirmed infections were due to multidrug‐resistant bacteria.4 SBP caused by resistant bacteria were rare in one recent study from Spain on community‐acquired infections (7%) but far more common in patients with frequent contact with the health care system (22%) and those with nosocomially acquired infection (41%).5 Resistance can result in failure to respond to initial empiric therapy with a third‐generation cephalosporin in 33%‐75% of cases, and such failure to respond is associated with reduced survival.3 As a result, a panel of European experts have recently recommended using broader‐spectrum antibiotics with nosocomial SBP.3 Unfortunately, the optimal therapy for such patients is generally based on expert opinion given the paucity of prospective studies in the contemporary era. In this edition of hepatology, investigators from the University of Padua conducted a randomized, controlled trial of ceftazadmine (2 g every 8 hours or renally adjusted dose; C group) versus meopenem (1 g every 8 hours or renally adjusted dose) plus daptomycin (6 mg/kg daily or renally adjusted dose) (M/D group) for the empiric treatment of nosocomial SBP; standard supportive therapy and albumin were given to all patients as well.6 The study was designed to enroll about 30 patients in each arm but was stopped after enrolling about half the goal (15 M/D group and 16 C group) at the time of interim analysis. The groups were generally similar, although the M/D group was slightly more likely to have a higher Child‐Pugh score. Patients in the M/D group were more likely to resolve infection (86.7% versus 25%, P < 0.001); reasons for failure were failure to reduce polymorphonuclear cell count ≥25% at 48 hours (seven in the C group versus one in the M/D group), isolation of resistant bacteria to assigned treatment (four in the C group), and failure to have a polymorphonuclear cell count of <250 cells/μL at the end of 7 days of therapy. Nonresponders were more likely to have received norfloxacin prophylaxis. Overall, there was no difference in 30‐day or 90‐day transplant‐free survival between the groups (86.7% versus 81.3% 30‐day and 79.4% versus 68.8% 90‐day for M/D and C groups, respectively). Multivariate modeling found that ineffective first‐line treatment (hazard ratio = 20.6), development of acute kidney injury during hospitalization (hazard ratio = 23.2), and baseline mean arterial pressure (hazard ratio = 0.92) were independent predictors of 90‐day transplant‐free survival. Based on these findings, the authors conclude that the meropenem/daptomycin combination should be the preferred regimen for the management of nosocomial SBP, consistent with European expert opinion.3 But digging deeper into the data, it is clear that one size does not fit all for the approach to empiric therapy for nosocomial SBP. The choice of antibiotics by the investigators was based upon data from their center suggesting a high rate of multidrug‐resistant gram‐negative rods, enterococci, and Staphylococcus aureus. From their experience, culture‐positive nosocomial SBP was caused by gram‐negative rods 48% of the time (the most commonly isolated gram‐negative rods were E. coli [25%] and Pseudomonas aeruginosa [10%]), Enterococcus 24% of the time, and Staphylococcus 19% of the time. Of the gram‐negatives, 100% were susceptible to carbapenems but only 60% were susceptible to cephalosporins and 40% to fluoquinolones. Most of the staphylococci (75%) were methicillin‐susceptible, and only 20% of the enterococci were resistant to vancomycin.6 Based on these data, vancomycin would have been a reasonable empiric gram‐positive agent for most of the gram‐positive infections. Rates of cephalosporin susceptibility may vary significantly from center to center, as will the rates of extended‐spectrum β‐lactamase and other multidrug‐resistant bacteria. Likewise, vancomycin‐resistant Enterococcus is likely to be more common in many centers than it was in Padua. As such, tailored empiric therapy may be more appropriate based on the local susceptibility patterns and therefore may diverge from the regimen used in this study. The greatest concern with broad use of carbapenems is induction of β‐lactamases and enhanced susceptibility to acquisition of bacteria that are resistant to the class of antibiotics. The authors in this study did not present data on the emergence of resistance in patients treated with either regimen. Longer‐term studies of the impact of expanded use of broader antibiotics would be needed to inform the risk of resistance emergence and acquisition in treated patients. Studies have clearly correlated increased use of broad‐spectrum antibiotics with increased burden of resistant bacteria in patients seeking health care.7 Conversely, careful restriction of antibiotics has likewise been demonstrated to reduce the incidence of resistance.9 As a result, future studies should attempt to identify the individuals at greatest risk of resistance and the impact of expanded use of broad therapy on resistance. Lastly, while there was a higher rate of overall response, predominantly early response, with the use of the broader meropenem/daptomycin therapy, there was no clear impact on 30‐day and 90‐day transplant‐free survival. This finding speaks most strongly for the need to consider a more graded approach to such patients. The data suggest that close monitoring of individuals with a third‐generation cephalosporin as empiric therapy for all forms of SBP, including nosocomial infections, may be a highly reasonable approach. Selection of a cephalosporin with Pseudomonas coverage would be appropriate for centers with high rates of pseudomonal nosocomial SBP, whereas narrower‐spectrum cephalosporins may be appropriate at centers with low rates of Pseudomonas. Broader therapy could then be considered for patients who fail to respond, have severe systemic inflammatory response syndrome on presentation, or develop systemic inflammatory response syndrome despite therapy. Such an approach, for the data presented by this study, suggests that escalation of therapy may be needed in many patients; but such an approach is not associated with increased mortality. Alternatively, studies could identify patients for whom broader‐spectrum therapy would be appropriate empirically. One obvious risk factor that might suggest a need for broader early therapy would be colonization with multidrug‐resistant bacteria. The authors in this study did not present data on colonization in their patients, so this risk factor cannot be assessed. Future studies should be conducted to see if enhanced screening of patients with cirrhosis helps to identify patients at higher risk of developing SBP due to resistant bacteria. The fact that resistant bacteria were more commonly identified in patients receiving fluoroquinolone‐based prophylaxis may suggest that this population, in particular, requires especially close monitoring for acquisition of resistant flora. While this study begins to provide evidence that broad empiric therapy for nosocomial SBP may be appropriate, one size definitely does not fit all. The epidemiology of infections is rapidly changing at any individual center. Each center should develop the infrastructure to monitor the epidemiology and outcomes of SBP in their patients with cirrhosis, with stratification by community‐onset, health care‐associated, and nosocomial SBP. This will require careful collaboration between the hepatology team, the infectious diseases team, and the microbiology laboratory and will need to be constantly monitored for changing patterns. This study and future studies will help to inform the specific risk factors that inform when broader therapy should be used empirically to treat subsets of patients with SBP and the impact of such an approach on resistance and patient outcomes. With more studies and better local data, the optimal approach can be tailored for each individual hospital.