VRE in cirrhotic patients

Vancomycin resistant enterococci (VRE) have emerged as a worldwide concern especially in patients hospitalized in the Intensive Care Unit setting and in those who are immunocompromised [1]. Among liver transplant recipients, the most common bacterial pathogens include Enterococcus species and Enterobacteriaceae species [1]. As fluoroquinolones have increasingly been in use for prophylaxis in spontaneous bacterial peritonitis (SBP), there has been an increasing trend towards more gram-positive bacterial infections compared to gram-negative organisms [2]. Patients with cirrhosis who are awaiting liver transplant or have received liver transplants, are at an increased risk of colonization and infection with VRE [3]. Several studies involving liver transplant recipients have shown increased morbidity and mortality in patients with VRE infection and colonization compared to those without VRE [1, 3, 4].

Fewer studies have evaluated the impact of VRE colonization and infection in liver transplant candidates prior to transplantation. McNeil et al. found that liver transplant candidates colonized with VRE before transplantation had greater morbidity, significantly longer time in the ICU after transplantation and longer post-operative hospital stays, but not greater mortality compared with non-colonized candidates [5]. This study did not compare outcomes of VRE-infected patients with patients infected with other organisms. In addition to SBP prophylaxis, cirrhotic patients with recurrent hepatic encephalopathy are commonly prescribed rifaximin, a non-absorbable antibiotic that decreases the rate of relapse of encephalopathy [6]. The impact of SBP prophylactic antibiotic use on VRE infection in cirrhotic patients has not been evaluated.

A retrospective, chart review study was performed involving all cirrhotic patients admitted to the Hepatology Service at Keck Hospital of the University of Southern California from January 2010 through December 2014. The goals of this study were: [1] to examine the risk factors that predispose cirrhotic patients to VRE infection compared to cirrhotic patients infected with gram-negative organisms and uninfected patients; and [2] to use VRE infection status as an exposure variable to compare the subsequent outcomes, including 30-day and 1-year mortality, length of hospital stay, and length of ICU stay, of VRE-infected cirrhotic patients to other cirrhotic patients infected with gram-negative organisms and uninfected patients.

VRE infection is a significant cause of morbidity in patients with end stage liver disease [1]. The continued spread of multi-drug resistant bacteria leads to limited treatment options and potential for significant negative impact on patients. It has been well documented that VRE colonization and infection in orthotopic liver transplant (OLT) recipients results in increased morbidity, as defined by longer ICU stay, and mortality [3, 5, 7‐9]. Studies have shown that VRE colonization in cirrhotics is associated with increased risk of subsequent infection and death [5, 10]. However, there is a deficit of literature addressing the outcomes of cirrhotic patients prior to transplantation who are infected with VRE and the risk factors associated with acquisition of VRE infection.

In this ethnically diverse retrospective study, VRE infected and non-infected populations significantly differed with respect to gender, race and disease severity indices. The majority of the VRE infected subjects were female, Hispanic race and had higher Child Pugh and MELD scores compared to those who were infected with other organisms (non-VRE) or had sterile cultures.

Female gender and Hispanic race have not previously been shown to be risk factors for VRE acquisition in cirrhotic patients. The reasoning for why women and Hispanics are at increased risk was not evidently clear. It is possible that the occurrence is due in part to a high Hispanic population in southern California leading to an overall increased prevalence of the disease. As many VRE cultures were collected from urine, one could predict a female predominance given incidence of urinary tract infection being more common in females [11].

In the univariate analysis compared to uninfected individuals, the use of SBP prophylaxis was found to be a risk factor for the acquisition of VRE infection as was the use of rifaximin, a non-absorbable antibiotic used to treat hepatic encephalopathy [6]. When all antibiotics were evaluated together, the use of any antibiotic (either for SBP or hepatic encephalopathy prophylaxis) was found to be a risk factor for VRE infection, compared to uninfected individuals. VRE colonization is associated with antibiotic usage, in particular prolonged fluoroquinolone use in cirrhotic patients, and has been associated with increased risk of gram-positive infections [2, 8]. Hagen et al. evaluated the role that pre-transplant antibiotics, in particular SBP prophylaxis, had with VRE colonization rates [12]. Cirrhotic patients with moderate illness (median MELD 11) had VRE rectal swab cultures and completed screening questionnaires to determine antibiotic exposure during the 3 months prior to study enrollment. Only 3.4% of the participants were colonized with VRE, and 17% had taken SBP prophylaxis (specific antibiotics were not mentioned) during the prior 3 months, showing no correlation of SBP prophylaxis on VRE colonization. Not all participants had cultures collected at other sites to indicate actual VRE infection, and of the few reported, most were actually not colonized with VRE. As such, the authors suggest that pre-transplant colonization with VRE plays a minor role in post-transplant morbidity and mortality attributed to the VRE infection [12]. Thus, it appears that measures aimed at reducing VRE colonization should be directed to more critically ill patients with higher MELD scores. This is not a practice we do at our hospital to routinely check rectal swabs. Another study found the use of SBP prophylaxis with fluoroquinolones in cirrhotics was more predictive of infection with antibiotic resistant bacterial organism, notably VRE [13]. Interestingly, this same study did not find a significant risk of antibiotic resistant bacterial infection with the use of non-absorbed antibiotics such as rifaximin. Another study showed that the use of the non-absorbed antibiotic, neomycin, was associated with VRE colonization [5]. These findings are in contrast with our results, as ours showed that rifaximin use was associated with increased risk of infection with VRE. This is an interesting result given the characteristics of rifaximin as having an estimated bioavailability in the blood after oral administration of less than 0.4%. When in anaerobic environment such as the colon, rifaximin reduces plasmid transfer, which is important in transfer of bacterial resistance [7]. With guidelines now recommending rifaximin as the first line treatment for hepatic encephalopathy, this raises concern for potential increases in development of bacterial resistance in a time when rifaximin use will only continue to intensify [6].

Lastly, our analysis showed that any dialysis (HD, PD or CRRT) was associated with increased risk of VRE infection (Table 3) compared both the gram negative and uninfected individuals. While dialysis may be considered a surrogate for the overall severity of illness among those patients with VRE infection, the strong positive association of VRE infection with dialysis remained after adjustment for disease severity measured as the Child Pugh score in multivariate analysis (Table 3).

All of the patients were followed for 1 year after the identified positive or negative culture to document subsequent transplantation. It was interesting to note that the majority of all patients in the study actually did not go on to receive any type of transplantation at our study center.

Multiple studies have shown that VRE infection in liver transplant recipients results in longer hospital stay and mortality [3, 5, 7‐9]. Similarly, we show that VRE infection in cirrhotics pre-transplantation have longer mean ICU and mean total hospital stay in addition to increased one-year mortality compared to those cirrhotics without VRE infection (Table 4). This was true even after adjustment for sex, race and ethnicity, but was reduced to non-significant levels with adjustment for severity indices (Child Pugh and MELD scores). It is unclear whether VRE infection serves as an independent risk factor for increased mortality or if it is an indicator for patients with more severe illnesses and thus at a higher risk for death. Nonetheless, identification of VRE should prompt timely therapy and implementation of appropriate preventive strategies.

Limitations to our study include the retrospective study data acquisition comprised of chart review, and sampling from a single referral center. Furthermore, some follow up may be incomplete in a few subjects in regards to mortality, as continued care is not always done at our facility if patients do not go on to transplant. Our data may be incomplete in regards to specific details of the medical history and prior antibiotics obtained from outside hospitals, as our institution is a referral center so not all records were available or accessible for the patient during the chart review. While this study employed a small patient sample with subsequent reduction in statistical power, it is still the largest series of cirrhotics analyzed with VRE. This is one of the first studies that showed the effect of female gender and Hispanic ethnicity on VRE. There will need to be further studies completed in order to further elucidate the role of cirrhosis and VRE on outcomes particularly after liver transplantation.

Hispanic ethnicity and female gender in this study was associated with VRE infection in cirrhotic patients admitted to Keck Medical Center of the University of Southern California. Due to the morbidity associated with VRE infection it is important to be aware of these risk factors and further studies into these infections.