#Less Is More: Now Trending for Surgical Antibacterial Prophylaxis in Liver Transplantation (2019)

Potential conflict of interest: Nothing to report. See Article on Page 1043 Surgical antibacterial prophylaxis (SAP) is recommended for the prevention of surgical site infection (SSI).1 Perioperative antibacterials are thought to prevent SSI by decreasing the bacterial burden at the surgical site, which may facilitate healing.1 SAP should be administered within 60 minutes prior to the surgical incision to ensure adequate concentrations in serum and tissues. It should be redosed based on the half‐life of the drug vis‐à‐vis the length of procedure and then be administered for the shortest effective duration to avoid the adverse effects of antibacterial use. National and international SSI prevention guidelines do not recommend extending SAP after closure of the surgical incision.1 Antimicrobial stewardship to enhance patient safety and outcomes in solid organ transplantation (SOT) is gaining attention.3 SAP is routinely indicated in liver transplantation (LT), but its use warrants attention because published data for SAP in this setting are limited with existing guidelines making little or no mention of transplant‐specific procedures. This results in significant interinstitutional variation in the choice of SAP agent and duration.4 On the basis of the published literature demonstrating high SSI rates after LT and the perception that extended SAP will minimize risks, continuing SAP after LT is a common practice, although no studies have validated it. We applaud Berry et al. for exploring this topic in a pilot study published in this issue of Liver Transplantation.5 This was a single‐center, open‐label, randomized controlled study comparing SSI rates in 2 SAP groups: short antibiotics (SAs) and extended antibiotics (EAs) with 51 first‐time, nonhospitalized LT candidates enrolled in each group. Patients in both groups received 1 dose of intravenous antibacterials 30 minutes prior to incision. Standard prophylaxis of renally adjusted intravenous piperacillin/tazobactam (P/T) was redosed 4 hours into the transplant procedure. Patients with reported beta‐lactam allergies received 1 intravenous dose of vancomycin and ciprofloxacin prior to incision. In the SA group, SAP was limited to preoperative and intraoperative administration. In the EA group, SAP was continued for 72 hours from the initial dose. After excluding participants whose transplant was delayed or canceled, 48 and 49 patients were analyzed in the SA and EA groups, respectively. Baseline characteristics and transplant indications in both groups were similar. Protocol deviations occurred in 19% (9/48) of patients in the SA group with SAP extending into the postoperative period and in 6% (3/49) in the EA group with SAP limited to intraoperative dosing only. Although the authors hypothesized a lower SSI rate in the EA group, no differences were observed in the primary outcome of 30‐day SSI rates in both intention‐to‐treat (19% versus 27%; P = 0.39) and per‐protocol (23% versus 24%; P = 0.87) analyses. Similarly, there were no significant differences in multiple secondary outcomes, including nosocomial infection and mortality within 30 days and graft loss and rejection at the end of follow‐up. Importantly, this is one of the first studies to use the desirability of outcome ranking (DOOR) and the response adjusted for duration of antibiotic risk (RADAR) tool to evaluate antimicrobial use and outcomes in SOT recipients. Although there are limitations to this calculation, the DOOR/RADAR score estimated a 63% (95% confidence interval, 53%‐73%) probability of a desirable outcome in the SA group in comparison to the EA group. To our knowledge, this is the first study to evaluate the duration of SAP in LT and is a significant step in defining optimal antibacterial strategies in this population. However, there are limitations that highlight the need for further investigations. Excluding pre‐LT patients hospitalized at the time of transplantation may limit real‐world applicability of these results because hospitalization at the time of LT is common and may present unique risks in the posttransplant setting. Additionally, an important acknowledged limitation is the statistical underpowering of this study. Future studies must carefully select power thresholds for adequate detection of more nuanced outcome differences. Similarly, the small sample size makes it difficult to detect significant differences in complications of antibacterial use though small but similar rates of vancomycin‐resistant Enterococcus and Clostridium difficile infections were seen in both groups. The EA group actually received more days of treatment antibiotics (median, 12 versus 7 days; P = 0.03) used for suspected or proven infection. Although questions remain regarding drug choice, this trial was not intended to detect the influence of different antibiotics on outcomes. Although the investigators used P/T for standard prophylaxis, other agents with varying spectrums of antimicrobial activity have been previously studied.4 Antibiotic selection should consider institutional microbial epidemiology and may need to be individualized for patients colonized with multidrug‐resistant organisms. Reported penicillin allergies have been associated with SSI in non‐SOT recipients and are thought to reflect the use of non–beta‐lactam antibiotics for SAP.6 Although this small pilot study does not provide any insights about the association of penicillin allergies with SSI in LT recipients, we believe it is important to identify true penicillin allergies prior to LT. Even in the context of a clinical trial, SAP was extended into the postoperative period in many patients in the SA arm, which likely highlights the false perception of ongoing infection risk used to justify extended prophylaxis in LT recipients. The majority of studies that have compared short and long durations of antibacterial treatment for a variety of indications demonstrate no improvement in outcomes with longer durations. Unlike the authors, we hypothesize that the same holds true for SAP even in LT recipients. Accordingly, we have a very positive outlook of the “negative” findings in this study, which validate the ongoing pursuit of antimicrobial stewardship in LT. Though these concepts are not new,7 these data will bring more attention to the “less is more” approach even in vulnerable LT recipients. We believe the results of this pilot study underscore the need for a larger multicenter study to define the optimal duration of SAP and potentially confirm that extended SAP is not needed in LT.