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Commentary on Risk Factors and Impact of Perioperative Prophylaxis on the Risk of Extended-spectrum β-Lactamase-producing Enterobacteriaceae-related Infection Among Carriers Following Liver Transplantation

Galvin, Zita MB, BCh (BAO), MRCPI, MD1,2

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doi: 10.1097/TP.0000000000003232
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Infections are one of the principal causes of morbidity and mortality in liver transplant recipients (LTRs).1 Over the past 2 decades, there has been a significant increase in the number of documented antimicrobial-resistant bacteria among solid organ transplant (SOT) recipients.2 LTRs are at particular risk for multidrug-resistant (MDR) Gram-negative bacteria, including extended spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E), because of both pretransplant and posttransplant factors, including frequent and prolonged hospitalizations, use of broad-spectrum antibiotics, use of spontaneous bacterial peritonitis (SBP) prophylaxis, and the need for invasive procedures.3,4 Additional risk factors for ESBL-related infections among LTRs include Model for End-Stage Liver Disease score (>25) and the need for a second operation.5 ESBL-E are associated with high mortality rates among LTRs. Anesi et al6 recently demonstrated an approximate 2.5-fold increased risk of graft failure or death within 60 days of an ESBL-E bacteremia among SOT recipients compared with those with non-ESBL-E bacteremia.

To prevent ESBL-E outbreaks in SOT units, many general precautions are widely accepted including strict hand hygiene, minimized use and meticulous care of indwelling devices, and contact isolation precautions in patients with known pathogen colonization and/or infection (although in regions of endemicity, the role of contact precautions is unclear).7 Intestinal decolonization among SOT recipients with known ESBL-E carriage is not recommended, and studies have reported that this approach could actually potentiate the emergence of MDR organisms.8 Another prevention strategy is the use of targeted perioperative antimicrobial prophylaxis regimens in the liver transplant population with MDR organism colonization.5 This approach is not universally practiced, and American Society of Transplantation has recently suggested that the role of targeted ESBL-E perioperative prophylaxis remains undefined.9 Other studies suggest that instead of altering prophylaxis regimes, programs should devise empirical treatment regimens that are directed at the most common pathogens and take into account specific risk factors.10

In this issue of the journal, Logre et al11 present a clinical tool to improve the judicious use of carbapenems for suspected ESBL-E infection following liver transplant (LT), in patients with pre-LT ESBL-E carriage. This topic is of significant clinical interest and, if externally validated, it could help to rationalize the empirical treatment of suspected ESBL-E infections in ESBL-E carriers. This is a retrospective analysis of prospectively collected data from a large monocentric liver transplant program. The authors analyze the incidence and risk factors of/for post-LT infections with ESBL-E organisms. They report that 39% patients colonized with ESBL-E pre-LT developed an ESBL-E infection in the post-LT period compared with 3.5% of noncolonized patients (median = 11 d). In multivariate analysis, K klebsiellapneumoniae carriage, model for end stage liver disease ≥25, preoperative SBP prophylaxis, and antimicrobial exposure during the month before LT were independent predictors of ESBL-E infection. Based on these variables, the authors constructed a colonization to infection risk score that can stratify ESBL-E carriers into different categories according to their risk of developing an ESBL-E-related infection. Prescribers can use these categories to help rationalize the use of carbapenems, for example, in ESBL-E carriers with ≥2 points, the risk of ESBL-E-related infection is >60%, therefore justifying the empirical prescription of carbapenems as first-line therapy. They also report that perioperative antimicrobial prophylaxis targeting colonizing ESBL-E was associated with a reduced risk of post-LT ESBL-E infections.

As mentioned above, there are multiple risk factors for the development of ESBL-E infections, of which ESBL-E carriage is one. Given the complexity and vulnerability of LTRs, there is a tendency to prescribe carbapenems as first-line agents to target ESBL-E in cases of suspected infection in a known carrier. However, the likelihood of ESBL-E carriers developing ESBL-E infections can be as low as 10% in some intensive care unit populations, indicating a poor positive predictive value. Therefore, empirical carbapenem usage in colonized patients could contribute to the development of further drug-resistant pathogens. There are currently no guidelines specifically addressing the management of suspected MDR infections in LTR. The authors have constructed an easy-to-calculate risk score, colonization to infection, to identify carriers at highest risk for ESBL-E infections, thus helping to spare carbapenem use and rationalize the use of broad-spectrum antibiotics.

Factors such as prolonged hospital admission pre-LT, reoperation post-LT, surgical blood loss, and bile leaks have been reported to increase the risk of post-LT infections, none of which was significant in this cohort. The greatest limitation of this monocentric study is the lack of an external validation cohort. Prediction models perform better on data on which the model was constructed and external validation is essential before implementing prediction models into clinical practice. Another point of controversy is the author’s suggestion that effective perioperative prophylaxis targeting the ESBL-E colonizing isolate may protect against post-LT ESBL-E infections. It is important to note that the sample size is very small, only 11 patients in the inactive antimicrobial group, a point that is also acknowledged by the authors. Additional studies are needed to validate or contradict this hypothesis. There is a need for structured formal recommendations for antimicrobial prophylaxis in transplantation, particularly in those patients who are colonized with an MDR organism pretransplantation.

Difficult-to-treat bacterial infections are increasingly more common and are a significant threat to successful organ transplantation. Further studies are needed to confirm the findings in this study and would also help to inform antimicrobial stewardship initiatives to limit the spread and evolution of MDR pathogens, especially in the setting of organ transplantation.

REFERENCES

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9. Pouch SM, Patel G; AST Infectious Diseases Community of Practice. Multidrug-resistant Gram-negative bacterial infections in solid organ transplant recipients-guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019; 33:e13594
10. Viehman JA, Clancy CJ, Clarke L, et al. Surgical site infections after liver transplantation: emergence of multidrug-resistant bacteria and implications for prophylaxis and treatment strategies. Transplantation. 2016; 100:2107–2114
11. Logre E, Bert F, Khoy-Ear L, et al. Risk factors and impact of perioperative prophylaxis on the risk of Extended-spectrum B-lactamase producing enterobacteriaceae-related infection among carriers following liver transplantation. Transplantation. 2020
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