Case series of immunosuppressant drug interactions with flucloxacillin in heart transplant recipients

Abstract

Background After heart transplantation, the International Society for Heart and Lung Transplantation (ISHLT) recommends calcineurin inhibitor (CNI)‐based immunosuppressant therapy with mycophenolate or a mammalian target of rapamycin (mTOR) inhibitor. Both CNIs and mTOR inhibitors are extensively metabolised by the cytochrome P450 enzyme pathway and are substrates of P‐glycoprotein (PGP), making drug interactions with these therapies an important consideration. Herein we report four cases of probable drug interactions between tacrolimus and everolimus with flucloxacillin in orthotopic heart transplant recipients. The effects were subtherapeutic immunosuppressant concentrations and cellular rejection. Clinical details All four heart transplant recipients received intravenous (IV) flucloxacillin for methicillin‐sensitive Staphylococcus aureus infections in conjunction with immunosuppression regimens containing everolimus and/or tacrolimus. Despite tacrolimus and everolimus dose adjustments, Grade 2R rejection was diagnosed in all four patients in association with subtherapeutic immunosuppressant concentrations. Outcomes A considerable increase in tacrolimus and everolimus trough concentrations was observed following cessation of IV flucloxacillin. The rise in concentrations occurred despite no change in or dose reductions of immunosuppressants. A possible mechanism for the interaction is via pregnane X receptor activation. Conclusion These cases provide support that flucloxacillin significantly reduces tacrolimus and everolimus trough concentrations in heart transplant recipients. Dosage adjustments and close monitoring of drug concentrations or consideration of alternative antimicrobial therapy is required to avoid episodes of rejection or adverse events upon commencing and ceasing flucloxacillin therapy.

Flucloxacillin decreases tacrolimus blood trough levels: a single-center retrospective cohort study

“…Our findings are in line with the findings of the case series by Gellatly et al [12], showing a decrease of tacrolimus trough levels during flucloxacillin treatment in 4 adult heart transplant patients. The additional value of our study is that we were able to quantify the change in trough levels by correcting the tacrolimus blood trough levels for the prescribed dose.…”

“…However, literature considering this effect is inconsistent and mentions that the interaction might only be relevant in specific CYP3A5 genotypes [29,30]. Therefore, we conclude, in accordance with Gellatly et al, that the potential impact of steroid use is minimal, if at all present [12].…”

“…A comprehensive PubMed database search for drug-drug interaction between flucloxacillin and tacrolimus or everolimus led to no results. Later, 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]. In their study, Gellatly et al hypothesize that this is caused by the CYP3A4-inducing properties of flucloxacillin [12].…”

“…In our study, nine out of eleven patients used steroids and some had dose changes during the study period (data not shown). It has been previously hypothesized that steroids such as prednisolone can increase the tacrolimus dose requirement [12]. However, literature considering this effect is inconsistent and mentions that the interaction might only be relevant in specific CYP3A5 genotypes [29,30].…”