VRE have emerged as important nosocomial pathogens in bloodstream, urinary tract, and wound infections over the past 2 decades and will remain so for the foreseeable future . Importantly, immunocompromised patients appear to be at high risk for VRE colonization or infection and show poor prognosis [20,21]. The present study described the clinical features and outcomes of liver transplant recipients with VRE infection in detail. Association of an inadequate dose of daptomycin with death was a key finding from the study. Our findings are consistent with those reported in previous series [9-12]. These findings may help solidify our understanding of the clinical features of VRE infection among liver transplant recipients.
Vancomycin resistance is independently associated with increased mortality among patients with enterococcal bloodstream infections . Importantly, an overall in-hospital mortality rate of 18.2% was observed among all included liver transplant recipients with VRE colonization or infection in the present study. For subjects who developed VRE infection in the early post-liver transplant period, their in-hospital mortality rate increased to 23%. Moreover, 15% of these patients died within 30 days after development of VRE infection. Previous studies have indicated that the crude mortality rate of VRE infection among liver transplant recipients ranged from 23% to 82% [9,10,12,22-24]. Excluding the data from an era before the availability of effective antibiotic treatment for VRE infection, the observed mortality rates for VRE bacteremia are still unacceptably high in this patient population (33% to 56%) [10,25]. Some previous studies and our report indicate that VRE infection in liver transplant recipients serves as an indicator for is associated with increased mortality. Thus, implementation of appropriate preventive strategies and timely identification of VRE infection in these patients is vital to avoid preventable mortality and morbidity.
Appropriate antimicrobial therapy is crucial in reducing the mortality in patients with VRE infection. Limited effective antimicrobial agents are available to treat VRE infection . Linezolid and daptomycin as are the two most commonly used agents for treatment of VRE infection . Linezolid is a bacteriostatic antibiotic that is approved for the use in VRE infection . Safety concerns limit the use of linezolid, particularly in cirrhotic patients with thrombocytopenia . Additionally, a study including 644 patients with VRE bacteremia noted that treatment with linezolid was associated with significantly higher treatment failure when compared with daptomycin . Daptomycin is a concentration-dependent bactericidal agent. It has been shown to exert rapid bactericidal activity against enterococci . Daptomycin dosage for staphylococcal bacteremia is 6 mg/kg intravenously once daily . Many clinicians are using similar doses of daptomycin for treatment of VRE infection. In the setting of enterococcal bloodstream infections, Britt et al. revealed that high-dose daptomycin (≥10 mg/kg) was associated with reduced 30-day mortality when compared with the standard-dose (6 mg/kg) . In a study involving 112 patients, Chuang et al. reported that daptomycin regimens with higher doses (≥9 mg/kg) were associated with lower mortality than those with standard (<7 mg/kg) doses . Nonetheless, most of these studies have presented data regarding daptomycin therapeutic dosages for VRE infection in the general patient population rather than in liver transplant patients. We found an association between higher daptomycin dose and survival in liver transplant recipients with VRE infection. Daptomycin dose ≥8 mg/kg was associated with significantly better patient survival than a dose <8 mg/kg. Survivors received higher median daptomycin dose than non-survivors (8.7 mg/kg vs. 7.8 mg/kg). The present study expands the previous ﬁndings about the importance of daptomycin therapeutic dosage for the treatment of VRE infection in liver transplant patients. To the best of our knowledge, this is the first study that reported the impact of daptomycin dosage for treatment of VRE infection in liver transplant recipients. Our findings highlight the urgent need for clinicians’ awareness regarding optimal daptomycin dosage for the treatment of VRE infection in liver transplant recipients.
Although enterococci are less virulent than many other bacteria, delayed antibiotic therapy for patients with VRE infection is associated with poor clinical outcomes . In the present study, delays in initiating the antimicrobial therapy against VRE did not contribute significantly to increased mortality. Remarkably, only 1 patient in our study received effective antimicrobial therapy within 48 hours after the onset of VRE infection. This finding should be considered with caution while interpreting the data, as it may lead to bias in the results of the present study. Larger prospective studies are required to elucidate whether the delay in the treatment of VRE infection affects the outcome in liver transplant recipients.
Data regarding the influence of VRE infection on clinical endpoints other than mortality are lacking. We observed that two-thirds of the non-survivors in the early post-transplant period developed VRE bloodstream infection and primary graft failure. The association between VRE bacteremia and primary graft failure is unclear. Multiple factors have been studied as risk factors for graft failure including optimum donor selection; vascular, biliary, and immunological complications; and bacterial infection [32,33]. We agree with the suggestions from other studies that VRE infection may have contributed to graft failure in liver transplant recipients [10-12]. On the other hand, the greater number of graft failure in non-surviving patients in this study can be partly explained by the poor general condition including relatively higher Model for End-stage Liver Disease scores at the time of transplantation compared to survivors, although this difference did not reach statistical significance (Table 2).
Pre-transplant VRE colonization or infection could contribute to a higher incidence of VRE infection at the time of organ transplantation. In a prospective surveillance study involving 22 patients with VRE colonization before liver transplantation, 7 (32%) developed clinical VRE infection post-transplantation . In a study of 61 patients who underwent pre-transplant VRE surveillance, 44% of the patients exhibited VRE colonization after liver transplantation . In the present study, 2 patients experienced VRE infection prior to the transplantation. Notably, none of them had VRE colonization or infection after transplantation. Additionally, 13 patients developed VRE infection within 60 days after liver transplantation, but none of them had a history of VRE colonization prior to the transplantation. This finding is inconsistent with previously published findings that suggested that VRE colonization in patients was associated with post-transplant VRE infection. The possible explanation for this discrepancy could be that the number of events in our study were not high enough to detect the effect of pre-transplant colonization on post-transplant infection. Additionally, in the present study, the incidence of VRE colonization/infection was 5.1% among patients admitted to liver transplant surgical intensive care unit, which is lower compared to findings in earlier studies from other countries [23,34]. Although hospital-wide routine active surveillance for VRE was not performed at our institution, poorer outcomes associated with acquisition of VRE infection after transplantation in our study and in earlier reports highlight the importance of infection-control measures including contact precautions, usage of personal protective equipment, and appropriate disinfection strategies to prevent nosocomial acquisition of VRE, especially in the post-transplantation period.
The present study has several limitations. This was a retrospective study and suffered from the limitations of this design. The statistical power was quite low due to the small number of cases studied. Due to the limited sample size, we could not compare the treatment outcomes between daptomycin and linezolid in liver transplant recipients.