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Abstract
PurposeTacrolimus and everolimus are widely used to prevent allograft rejection. Both are metabolized by the hepatic cytochrome P450 (CYP) enzyme CYP3A4 and are substrate for P-glycoprotein (P-gp). Drugs influencing the activity or expression of CYP enzymes and P-gp can cause clinically relevant changes in the metabolism of immunosuppressants. Several case reports have reported that flucloxacillin appeared to decrease levels of drugs metabolized by CYP3A4 and P-gp. The magnitude of this decrease has not been reported yet.MethodsIn this single-center retrospective cohort study, we compared the tacrolimus and everolimus blood trough levels (corrected for the dose) before, during, and after flucloxacillin treatment in eleven transplant patients (tacrolimus n = 11 patients, everolimus n = 1 patient, flucloxacillin n = 11 patients).ResultsThe median tacrolimus blood trough level decreased by 37.5% (interquartile range, IQR 26.4–49.7%) during flucloxacillin treatment. After discontinuation of flucloxacillin, the tacrolimus blood trough levels increased by a median of 33.7% (IQR 22.5–51.4%). A Wilcoxon signed-rank test showed statistically significantly lower tacrolimus trough levels during treatment with flucloxacillin compared with before (p = 0.009) and after flucloxacillin treatment (p = 0.010). In the only available case with concomitant everolimus and flucloxacillin treatment, the same pattern was observed.ConclusionsFlucloxacillin decreases tacrolimus trough levels, possibly through a CYP3A4 and/or P-gp-inducing effect. It is strongly recommended to closely monitor tacrolimus and everolimus trough levels during flucloxacillin treatment and up to 2 weeks after discontinuation of flucloxacillin.
Highlights
The calcineurin inhibitor tacrolimus and the mammalian target of rapamycin inhibitor everolimus are widely used in organ transplantation to prevent allograft rejection [1]
These findings suggest that flucloxacillin might be a CYP3A4 inducer
While conducting this study, we found a case series of 4 adult heart transplant patients reporting a decrease in tacrolimus (n = 4) and everolimus (n = 1) blood trough levels during flucloxacillin treatment [12]
Summary
The calcineurin inhibitor tacrolimus and the mammalian target of rapamycin (mTOR) inhibitor everolimus are widely used in organ transplantation to prevent allograft rejection [1]. Because both immunosuppressants have a narrow therapeutic window and show great inter- and intraindividual variability in pharmacokinetics, frequent monitoring of blood drug levels is required [2]. Transplant patients are at increased risk for bacterial infections and flucloxacillin is a relatively frequently used antibiotic.
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