What is the role of daptomycin for vancomycin-resistant Enterococcus (VRE) prophylaxis in liver transplant recipients?

Introduction
Liver transplant (LT) recipients are particularly vulnerable to infections, with studies showing infection rates approaching 80% within the first year after transplant.1 Among these, infections caused by vancomycin-resistant Enterococcus (VRE), especially E. faecium, are increasingly common and pose significant concern.2 VRE infections are associated with high mortality, and their risk is amplified by the immunosuppression, prolonged hospital stays, and repeated invasive procedures that often accompany LT. Notably, perioperative VRE colonization rates among solid organ transplant (SOT) recipients have been reported to range from approximately 12% to 17%, with LT recipients experiencing the highest rates. Colonization before surgery is predictive of subsequent infection, and in LT recipients, VRE colonization has been linked with 1-year mortality rates as high as 60%.2,3

Multiple factors contribute to the risk of VRE colonization and infection in LT recipients.2,3 Pre-transplant risk factors include hospitalization, procedures such as paracentesis or endoscopic retrograde cholangiopancreatography (ERCP), and the use of anti-anaerobic antibiotics.2 Post-transplant risk factors include continued exposure to anti-anaerobic antibiotics, reoperation, high Model for End-stage Liver Disease (MELD) scores, donor cytomegalovirus (CMV) seropositivity, biliary complications, intraoperative transfusion, and the need for renal replacement therapy (RRT).2,3

One proposed strategy to reduce VRE infection in LT recipients involves the use of perioperative prophylaxis with daptomycin in LT recipients colonized with VRE.1,2 Daptomycin is a lipopeptide antibiotic with potent activity against Gram-positive organisms, and is bactericidal against VRE.2

Clinical evidence for daptomycin prophylaxis
Two cohort studies have investigated the use of daptomycin in high-risk LT recipients colonized with VRE.3,4 First, a comparative retrospective cohort by Mak et al (2023) conducted at a single center in the U.S. evaluated 36 VRE-colonized LT recipients between 2018 and 2022, comparing outcomes between those who received prophylaxis with daptomycin (n=19) and those who did not (n=17).3 Colonization was determined prior to LT via a VRE rectal swab screen or a positive VRE culture (eg, urine). All patients received standard perioperative prophylaxis (ie, piperacillin-tazobactam). In the daptomycin group, daptomycin 6 mg/kg was administered once preoperatively and once postoperatively. The primary outcomes were VRE infection at 14 and 90 days post-transplant.

At baseline, the median MELD score was 35 in the daptomycin group and 38 in the no daptomycin group, with approximately half of all patients in both groups having received RRT prior to LT.3 Results demonstrate that the daptomycin group had significantly fewer VRE infections within 14 days post-LT (0% vs. 24% [n=4], p=0.04), though differences were not statistically significant at 90 days (15.8% [n=3] vs. 29.4% [n=5], p=0.43). Of the 8 patients with post-LT VRE infection, all but 1 had bloodstream infections. The average daptomycin dose was 6.03 mg/kg based on total body weight and 7.1 mg/kg based on personalized body weight. All post-transplant VRE isolates remained susceptible to daptomycin.

Perioperative risk factors for VRE infection were generally well balanced between daptomycin and no daptomycin groups, including no statistically differences in intraoperative transfusion requirements (10 vs 7 units; p=0.226), CMV donor positivity (11 vs 6 patients; p=0.202), incidence of hemorrhage (1 patient each), use of renal replacement therapy (15 vs 13 patients; p>0.99), occurrence of biliary leak or stricture (1 patient each), or transplant reoperation or other complications (2 vs 1 patient; p>0.99).3 The median duration of operation was longer in the daptomycin group (median, 11 vs 8.5 hours; p=0.027). Longer intensive care unit (ICU) stays were also seen in the daptomycin group (median, 8 vs. 7 days; p=0.039), but the difference did not reach statistical significance for overall duration of hospital stay (median, 14 vs 11 days; p=0.104). There were no significant differences between groups in the rates of ICU readmission, acute rejection, or 90-day mortality.

Another retrospective single-center study by Sarwar et al (2020) evaluated 27 VRE-colonized LT recipients from 2013 to 2019, of whom 25 received perioperative daptomycin prophylaxis in addition to standard antimicrobial prophylaxis with piperacillin/tazobactam. Screening for VRE was done via rectal swab.4 Daptomycin 6 mg/kg was administered preoperatively, then every 12 hours intraoperatively and every 24 hours postoperatively for 48 hours, adjusted for renal function. Prophylaxis was extended to 5 days in cases of hepatic artery or portal vein thrombosis, significant postoperative bleeding, Roux-en-Y hepaticojejunostomy, biliary leak, bowel perforation, or acute hepatic failure. At baseline, 12% of participants had a prior VRE infection. The median duration of daptomycin prophylaxis was 3 days (range, 1 to 7). Among those receiving daptomycin, 72% had 2 or more post-transplant VRE infection risk factors; the most common were RRT (60%), hemorrhage (32%), CMV donor seropositivity (32%), and reoperation (24%). No VRE-related infections occurred within 90 days among daptomycin recipients, whereas both participants who did not receive daptomycin developed early VRE bacteremia.

An additional study from China was published, with only the abstract available in English.5 While details are limited, this study suggests that the use of daptomycin for prophylaxis in patients undergoing LT may prevent infections due to Gram-positive cocci.

Clinical guidelines and practical considerations
A 2019 guideline from the American Society of Transplantation (AST) focused on intra-abdominal infection in SOT recipients states that empiric antimicrobial therapy should be individualized in consideration of the pathogens with which the patient is known to be colonized, potential side effect profile, drug interactions, and the site-specific antibiogram.1 The guideline makes the following recommendation in regards to the use of VRE prophylaxis in colonized SOT recipients:

“Empiric therapy against VRE is not recommended except in hemodynamically unstable patients who are colonized with VRE or those who fail to improve despite otherwise broad‐spectrum antibiotic therapy, particularly liver transplant recipients (weak, very low).”

Daptomycin is listed among preferred agents for prophylaxis in patients colonized by VRE, alongside linezolid and tedizolid.1 Tigecycline is also listed, but its use is discouraged due to poor clinical outcomes and tolerability. The guideline does acknowledge that indications for empiric anti-VRE therapy should be better defined.

Since the 2019 guideline, more recent evidence from the aforementioned cohort studies by Mak et al (2023) and Sarwar et al (2020) supports that perioperative daptomycin prophylaxis may be beneficial in LT recipients colonized with VRE.1,3,4 In both studies, daptomycin was administered intravenously at a dose of 6 mg/kg preoperatively, followed by one or more postoperative doses, with adjustments made for renal function and body weight. The typical duration of prophylaxis ranged from 48 to 72 hours, though extended courses up to several days were employed in patients with additional post-transplant complications. These studies demonstrated reduced early postoperative VRE infection rates among patients who received daptomycin, particularly within the first 90 days post-transplant.

Conclusion
Daptomycin has demonstrated favorable outcomes when used as part of perioperative prophylactic regimens in VRE-colonized LT recipients who have additional risk factors for VRE infection.1,3,4 However, optimal dosing strategies, approaches to risk stratification, and the long-term effects on antimicrobial resistance patterns and the individual microbiome warrant further investigation.1,2

References

  1. Haidar G, Green M; American Society of Transplantation Infectious Diseases Community of Practice. Intra-abdominal infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13595. doi:10.1111/ctr.13595
  2. Nellore A, Huprikar S; AST ID Community of Practice. Vancomycin-resistant Enterococcus in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13549. doi:10.1111/ctr.13549
  3. Mak JT, Ha S, Perloff S, Knorr JP. Perioperative daptomycin for prophylaxis of vancomycin-resistant Enterococcus infection in colonized liver transplant recipients. Transpl Infect Dis. 2024;26(1):e14186. doi:10.1111/tid.14186
  4. Sarwar S, Koff A, Malinis M, Azar MM. Daptomycin perioperative prophylaxis for the prevention of vancomycin-resistant Enterococcus infection in colonized liver transplant recipients. Transpl Infect Dis. 2020;22(3):e13280. doi:10.1111/tid.13280
  5. Wu X, Wu L, Shu L, Xie C, Wan Q. Characteristics of Gram-positive cocci infection and the therapeutic effect after liver transplantation. Published May 2023. Accessed July 1, 2025. https://pubmed.ncbi.nlm.nih.gov/37539573/

Prepared by:
Kathy Sarna, PharmD, BCPS
Clinical Assistant Professor
Retzky College of Pharmacy

September 2025

The information presented is current as of July 1, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.