Early Tacrolimus C0/D Ratio and Subsequent Proven Invasive Fungal Disease After Liver Transplantation with Routine...

Invasive fungal disease (IFD) may occur despite routine early echinocandin prophylaxis after liver transplantation, but the relationship between early tacrolimus exposure metrics and subsequent proven IFD remains uncertain. We evaluated whether early tacrolimus trough concentration and the concentration-to-dose (C0/D) ratio were associated with subsequent proven IFD in this prophylaxis-treated cohort.

In a two-center retrospective cohort of adult liver transplant recipients receiving routine postoperative caspofungin for 5 days, tacrolimus exposure was summarized as the patient-level median trough concentration and C0/D ratio during postoperative days (PODs) 3-10. Inpatient fungal outcomes were classified as no fungal infection, probable/possible IFD, or proven IFD according to consensus criteria. Multinomial logistic regression adjusted for prespecified demographics, illness severity, immunosuppression, and center; exposure quartiles and restricted cubic splines assessed dose-response and nonlinearity. Exploratory sensitivity analyses examined severity-adjusted associations, apparent discrimination, and incremental area under the receiver operating characteristic curve (AUC).

Among 164 recipients, 25 (15.2%) developed proven IFD and 18 (11.0%) probable/possible IFD; proven cases were predominantly mould infections, including Aspergillus spp. and Mucorales. Higher tacrolimus trough concentrations were associated with proven IFD (per 5 ng/mL: adjusted odds ratio [aOR], 4.84; 95% confidence interval [CI], 2.20-10.66) but not with probable/possible IFD. The C0/D ratio showed a stronger and more consistent association with proven IFD than trough concentration alone. In exploratory analyses, the apparent AUC of C0/D was 0.802 (95% CI, 0.682-0.903); adding log(C0/D) to a clinical severity panel increased the apparent AUC from 0.902 to 0.928 (ΔAUC, 0.026; 95% bootstrap CI, -0.034 to 0.087).

A higher tacrolimus C0/D ratio was associated with subsequent proven IFD in recipients receiving routine early echinocandin prophylaxis. These hypothesis-generating findings do not establish causality, an actionable C0/D threshold, or a management strategy, and require prospective external validation before clinical implementation.