Abstract

Objectives: Liver transplant recipients are more susceptible to vancomycin-resistant enterococci colonization than healthy individuals. We investigated the prevalence of vancomycin-resistant enterococci colonization and its effect on the outcomes of liver transplant recipients.
Materials and Methods: Patients who had undergone primary liver transplant at the Shiraz Organ Transplant Center from 2015 to 2017 were enrolled in this study. Demographic characteristics, laboratory test results, duration of stay in the intensive care unit, total duration of hospital stay, and clinical outcome data were extracted from the Shiraz Organ Transplant Center database. Posttransplant outcomes such as graft rejection, mortality, hospital stay, and kidney function tests were included for the first 90 days after transplant.
Results: A total of 753 liver transplant recipients (470 males and 283 females) were included in this study. Vancomycin-resistant enterococci colonization was identified in 51 patients (6.8%) after transplant at the time of intensive care unit admission. Our study found no significant difference between outcomes for patients with vancomycin-resistant enterococci colonization and outcomes for patients without colonization, including graft rejection, mortality, hospital stay, and kidney function tests.
Conclusions: Our study revealed that asymptomatic vancomycin-resistant enterococci colonization in
liver transplant patients has no adverse effect on
the duration of posttransplant hospital stay, early mortality rate, graft rejection rate, or kidney function compared with noncolonized patients.

Key words : Asymptomatic, Graft Rejection, Mortality, Transplantation

Introduction

One of the major concerns in health care-associated infections is vancomycin-resistant enterococci (VRE). Colonization and infection with this microorganism have been increasing for more than 10 years. Liver transplant recipients are more susceptible to VRE colonization because of their life-threatening condition, long-duration stays in hospital and intensive care unit (ICU), organ dysfunction, invasive devices and procedures, and consequently greater risk for morbidity and mortality. Vancomycin-resistant enterococci colonization rates (3%-55%) and attributable mortality rates (50%-82%) have been reported among liver transplant recipients.^1-3

A prospective study was conducted on 142 liver transplant recipients in Korea that compared patient outcomes at the time of transplant and after transplant. Vancomycin-resistant enterococci colo­nization was reported in 37 patients (22.8%) at the time of transplant and 21 patients (20%) after transplant. Although liver recipients who were colonized with VRE after transplant had higher rates of infection-related mortality than the patients who were colonized before transplant, the difference was not significant, and the graft rejection rate was not significant between the 2 groups. Long ICU stay was reported to be a risk factor for VRE colonization.⁴

Patel and colleagues reported a frequency of gastrointestinal VRE colonization of 3.4% and 55% before and after liver transplant, respectively. Those patients with postoperative complications and ICU admission early after transplant were more susceptible to VRE infections.⁵ Another study reported that the risk of VRE infection was higher among rectal carriers of VRE before and after transplant. The prevalence of VRE colonization on admission was 30.1% among 91 patients in a US liver transplant surgical ICU in California.⁶

Hand and Patel reported that antibiotic use, length of hospitalization, and environmental conta­mination were the risk factors for VRE acquisition.⁷

Each center has its own admission strategy for control of vancomycin-resistant enterococci infection. One standard precautionary regimen consists of contact precautions, intensified disinfection strategies, use of personal protective equipment, and active surveillance.⁸

We perform routine active surveillance cultures and a protocol for VRE colonization for liver transplant recipients at the Shiraz Organ Transplant Center.We do not administrate antibiotics for clinical asymptomatic liver transplant recipients with positive colonization in our center. Therefore, we decided to find out the effect of VRE colonization and this approach on the outcomes of liver transplant recipients.

Materials and Methods

We conducted a retrospective cohort study at the Shiraz Organ Transplant Center from August 23, 2015, to August 23, 2017. A total of 753 patients who had undergone primary liver transplant were enrolled in this study. Every recipient received a liver from a deceased donor except for 24 patients who were less than 16 years old and received a liver from a parent.

In accordance with our protocol for VRE prevention and management, perirectal and perianal swab samples were collected immediately after liver transplant whenever the patients were transferred to the liver transplant ICU.

Demographic characteristics, laboratory test results, durations of ICU stay and total hospital stay, and factors associated with clinical outcomes such as mortality rate, kidney function, and graft rejection were extracted from the Shiraz Organ Transplant Center database. Posttransplant outcomes were included for the first 90 days after transplant. Graft rejection was diagnosed by liver biopsy.

This study was approved by the Ethics Committee of the Shiraz University of Medical Sciences (IR.SUMS.MED.REC. 1396.s167). The data were analyzed with SPSS software (version 18). The chi-square test, the Fisher exact test, and a t test was performed for categorical variables, and P < .05 was considered statistically significant.

Specimen collection and surveillance culture
The specimens were collected by trained nurses according to the Infection Control Committee protocol. Briefly, each swab was carefully introduced in the anal sphincter region (1-5 cm) and gently rotated. Then, the swab was immersed in saline solution (0.9%, 5 mL) and transported to the microbiology laboratory. In the laboratory, the diluted fecal samples were cultured in blood agar media and incubated at 35 °C to 37 °C for 24 to 72 hours. If enterococci colonies developed to confirm the species, then the sample was transferred to bile media and 6% saline. After confirmation of the enterococci colony, the plates were examined for vancomycin resistance with BBL Sensi-Disc antimicrobial susceptibility test discs according to standards of the Clinical and Laboratory Standards Institute.

Results

A total of 753 liver transplant recipients (470 males and 283 females) were enrolled in our study. The mean age of the patients was 37.03 ± 17.41 years. Of the 753 patients, 627 patients had chronic liver failure (89.2%) and 81 patients had acute liver failure (11.3%). Of 753 liver transplant recipients, 91 patients (12.1%) had been admitted to the hospital before transplant (7.6 ± 2.8 days).

A total of 51 patients with VRE colonization (6.8%) were identified after transplant at the time of admission to the transplant ICU. There were 10 VRE-colonized patients who had a history of hospital admission before transplant and 41 patients who had no history of such admission. No statistically significant difference was seen between these 2 groups (P = .11).

Mean total days of hospital stay after transplant, including ICU plus ward admission days, was
11.15 ± 4.63 days for VRE patients and 11.72 ± 7.17 for non-VRE patients (P = .3). In addition, the mean days of admission in ICU showed no statistically significant difference (5.98 ± 3.86 vs 5.81 ± 4.18 days, respectively; P = .79). Three VRE patients and 30 non-VRE patients required reoperation in the first month (P = .6).

No statistically significant difference was seen in the rate of retransplant in VRE patients compared with non-VRE patients (0 vs 7 cases; P = .46). During the first month, 6 cases of acute graft rejection were found in VRE patients and 64 cases of acute graft rejection were reported in the non-VRE patients without statistically significant difference (P = .5). After 3 months, 1 and 36 cases of acute graft rejection were found in VRE and non-VRE patients, respectively, with no statistically significant difference (P = .3).

Serum creatinine level in the first month was 0.93 ± 0.34 mg/dL in patients with VRE and 1.01 ± 0.59 mg/dL in patients without VRE. After 3 months, the creatinine level was 1 ± 0.21 mg/dL in patients with VRE and 1.05 ± 0.57 mg/dL in patients without VRE. No statistically significant difference was seen in the serum creatinine level in patients with VRE versus patients without VRE at these time intervals (P = .402 and 0.587, respectively).

In the first month of transplant, 3 patients in the VRE group and 65 patients in the non-VRE group died, and there was no statistically significant difference in the mortality rate in the VRE group compared with the non-VRE group (P = .6). The extension of the follow-up period to 3 months showed no statistically significant difference in the mortality rate of the VRE group compared with the non-VRE group (3 vs 78 cases; P = .24).

Discussion

The clinical and epidemiological outcomes of liver transplant recipients that experienced pretransplant VRE colonization is not described well until now.³

Liver transplant recipients, as well as other solid-organ transplant recipients, are prone to VRE infection; therefore, active surveillance for VRE colonization in high epidemic regions and during outbreaks is recommended, but antibiotic therapy is not suggested for VRE-colonized patients.^9,10 Liver transplant candidates have well-known risk factors for VRE colonization such as central venous catheterization and rifaximin use, so these patients require more attention.^2,11

We perform routine active surveillance cultures to detect VRE colonization in all liver transplant recipients as soon as they enter the transplant ICU at our institution. We do not administer antibiotics for clinically asymptomatic liver transplant recipients with positive VRE colonization in our center. Our study found that the prevalence of VRE colonization was 6.8% in the early phase of liver transplant. A review article and a meta-analysis reported variable frequencies of VRE colonization rate before and after solid-organ transplant (0%-18% vs 14%-44%, respectively).^12,13

The original studies among patients who had undergone pretransplant VRE surveillance reported different prevalence of pretransplant VRE colonization ranging from 3% to 49%.^2,4,11,14-16 The wide range of pretransplant VRE colonization rate could be the result of variable prevalence of VRE around the world, with the highest rate in the United States and the lowest in rate in Canada and a worldwide prevalence of 10.3%.¹⁷

Vancomycin-resistant enterococci colonization did not affect the outcomes of our patients. Our study found no significant difference between outcomes in patients with and without VRE colonization, including graft rejection, mortality, hospital stay, and kidney function test. These results support our transplant center protocol, which recommends no treatment for asymptomatic VRE colonization.

Hospital stay
O’Driscoll and Crank reported longer ICU and hospital stays among VRE-infected patients compared with those without VRE infection.¹⁷ Two other studies reported that VRE-colonized patients before transplant had significantly longer ICU and hospital stays after transplant.^3,16 However, we found no significant difference in total hospital stay in VRE patients compared with non-VRE patients.

Mortality
There is some controversy with regard to VRE colonization and mortality rate. Russel and colleagues reported higher rates of infection and death among VRE-colonized liver transplant recipients and candidates.¹⁵ The comparison of mortality rate based on VRE acquisition time showed VRE colonization after liver transplant was higher than before transplant.⁴ Another study did not identify VRE infection as the associated risk factor for mortality; rather, other factors, especially patients’ medical status, were more important.¹⁸

Results of the Swiss Transplant Cohort Study showed that development of VRE infection from colonization was infrequent, and enterococcal infection did not result in a higher rate of mortality.¹⁹ Our result supports the recent findings; that is, no significant difference in the mortality rate of VRE colonization and noncolonized patients was observed.

Renal function
Liver transplant patients are more susceptible to alterations in renal function due to variable hemodynamic status and side effects of different kinds of medications.^20-22 The results of our study did not show any significant difference in serum creatinine level among patients who were colonized with VRE and patients who were not colonized in the first and third months of follow-up. Although another study showed VRE colonization is clearly associated with acute kidney injury in patients undergoing liver transplant.²³

Graft rejection
A study reported that graft rejection rate was also not significantly different among VRE-colonized patients at pretransplant and posttransplant time and not significantly different compared with noncolonized patients.¹⁶ However, one study by Belga and colleagues reported that VRE-colonized patients experienced graft dysfunction.²⁴ Our study found no significant difference in the rate of acute graft rejection between VRE colonization and noncolonized patients.

Although VRE infection after liver transplant is known to be a major cause of morbidity and mortality, the pretransplant colonization has a limited role in this effect, and infection after VRE colonization is rare.^2,19

If colonization occurs, then it will usually persist for months, and there is no practical method to resolve it.²⁵ A cohort study of patients who were VRE carriers by Davido and colleagues showed that almost half of the cohort population experienced spontaneous decolonization after 3 months.²⁶ On the other hand, treatment options for VRE colonization are limited and are associated with significant adverse effects and greater drug resistance. Linezolid, which is known as a drug of choice for VRE strains, has side effects of cytopenia and neuropathy²⁷ that may have adverse effects on the posttransplant course. The strengths of our study include its cohort design and high sample size (753 liver transplant patients).

Conclusions

The results of our study revealed that asymptomatic VRE colonization in liver transplant patients has no adverse effect on the duration of posttransplant hospital stay, early mortality rate, graft rejection rate, and kidney function compared with noncolonized patients. These findings support the observational strategy in asymptomatic VRE-colonized transplanted patients rather than antibiotic therapy, which has extra cost and adverse effects.

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