Methods
Study Design and Patients
We performed a retrospective study of consecutive adult patients undergoing liver transplantation at the University of Pittsburgh Medical Center (UPMC) between November 1, 2008 and December 1, 2012 to compare IFI rates in patients receiving either targeted or universal antifungal prophylaxis. Patients were excluded if they underwent multivisceral transplantation or dual transplant with lung(s) or heart, had an IFI at the time of transplant, died on the day of transplant or if the transplant was performed at an outside institution. The University of Pittsburgh Institutional Review Board approved the study.
Antifungal Prophylaxis
Patients were divided into two groups, based on antifungal prophylaxis regimen. The universal prophylaxis group consisted of patients transplanted between November 1, 2008 and October 31, 2010, during which the standard practice was VORI 200 mg oral twice daily for all patients. VORI was started within 1 day of transplant and continued for the duration of the immediate posttransplant ICU stay. In November 2010, we instituted our tiered, targeted approach to antifungal prophylaxis (Figure 1). The targeted prophylaxis group consisted of patients transplanted between November 1, 2010 and December 1, 2012.
Definitions
IFIs were defined according to EORTC/MSG criteria; superficial fungal infections, mucocutaneous candidiasis and Candida colonization were not included. Death was attributed to IFI if there was ongoing positive fungal culture or infectious process at the time of death. Compliance with prophylaxis algorithms was defined by the use of the recommended agent. As there was a 3-month roll-out for the change in antifungal prophylaxis strategy, compliance in the targeted prophylaxis group was assessed after this period. The primary outcome of this study was the development of IFI within 100 days of transplantation. The secondary outcomes were attributable mortality for IFI, all-cause mortality at 100 days, compliance with antifungal prophylaxis algorithms and toxicity of VORI.
Immunosuppressive Regimen and Prophylaxis
The standard immunosuppression during the study period consisted of methylprednisolone at the time of transplant followed postoperatively by tacrolimus, mycophenolate and prednisone. For patients with underlying renal insufficiency (SCr > 1.5 mg/dL), an early calcineurin-sparing regimen consisting of basiliximab induction followed by steroid taper and mycophenolate was used. Peri-operative antibacterial prophylaxis consisted of ampicillin–sulbactam for 72 h; for patients allergic to β-lactam agents, aztreonam and vancomycin were recommended. Beginning in May 2011, patients known to be colonized with vancomycin-resistant Enterococcus received tigecycline for prophylaxis. Throughout the study period, trimethoprim/sulfamethoxazole was given for 1 year posttransplant. Prior to November 2011, preemptive valganciclovir was administered to all LT recipients with cytomegalovirus (CMV) viremia, regardless of donor and recipient serology status; all other patients received acyclovir prophylaxis for the first month posttransplant. After November 2011, CMV seronegative recipients of livers from seropositive donors received universal prophylaxis with valganciclovir for 6 months; other patients received preemptive valganciclovir.
Statistical Analysis
Instat Software (Graphpad Software Inc., San Diego, CA) was used. Comparisons of dichotomous and continuous variables were performed using Fisher's exact test and Mann–Whitney U test, respectively. To identify risk factors for IFIs, variables suggested by univariate analysis (p ≤ 0.05) were entered into a multivariate logistic regression model; the type of antifungal prophylaxis (targeted vs. universal) was included in the model to address its impact on IFI. Stata/SE 12.1 (StataCorp LP, College Station, TX) was used to compute p-values, odds ratios and 95% confidence intervals. Kaplan–Meier curves were used to calculate event-free survival; curves were compared by log-rank test. Significance was defined as p-value ≤0.05 (two-tailed).