Outcomes Following Macrolide Use in Kidney Transplant Recipients

Abstract

Background: Calcineurin inhibitors (CNI; cyclosporine, tacrolimus) are critical for kidney transplant immunosuppression, but have multiple potential drug interactions, such as with macrolide antibiotics. Macrolide antibiotics (clarithromycin, erythromycin, and azithromycin) are often used to treat atypical infections. Clarithromycin and erythromycin inhibit CNI metabolism and increase the risk of CNI nephrotoxicity, while azithromycin does not. Objective: To determine the frequency of CNI-macrolide co-prescriptions, the proportion who receive post-prescription monitoring, and the risk of adverse drug events in kidney transplant recipients. Design: Retrospective cohort study. Setting: We used linked health care databases in Alberta, Canada. Patients: We included 293 adult kidney transplant recipients from 2008-2015 who were co-prescribed a CNI and macrolide. Measurements: The primary outcome was a composite of all-cause hospitalization, acute kidney injury (creatinine increase ≥0.3 mg/dL or 1.5 times baseline), or death within 30 days of the macrolide prescription. Methods: We identified CNI-macrolide co-prescriptions and compared outcomes in those who received clarithromycin/erythromycin versus azithromycin. We used a linear mixed-effects model to examine the mean change in serum creatinine and estimated glomerular filtration rate (eGFR). Results: Of the 293 recipients who were co-prescribed a CNI and a macrolide, 38% (n = 112) were prescribed clarithromycin/erythromycin while 62% (n = 181) were prescribed azithromycin. Compared with azithromycin users, clarithromycin/erythromycin users were less likely to have outpatient serum creatinine monitoring post-prescription (56% vs 69%, P = .03). There was no significant difference in the primary outcome between the 2 groups (17% vs 11%, P = .11); however, the risk of all-cause hospitalization was higher in the clarithromycin/erythromycin group (10% vs 3%, P = .02). The mean decrement in eGFR was significantly greater in the clarithromycin/erythromycin versus azithromycin group (−5.4 vs −1.9 mL/min/1.73 m 2 , P < .05). Limitations: We did not have CNI levels to correlate with the timing of CNI-macrolide co-prescriptions. We also did not have information regarding the indications for macrolide prescriptions. Conclusion: Clarithromycin and erythromycin were frequently co-prescribed in kidney transplant recipients on CNIs despite known drug interactions. Clarithromycin/erythromycin use was associated with a higher risk of hospitalization compared with azithromycin users. Safer prescribing practices in kidney transplant recipients are warranted.

Adverse events with quetiapine and clarithromycin coprescription: A population‐based retrospective cohort study

“…These results support that a clinically significant adverse drug interaction exists between clarithromycin and quetiapine in a predominantly elderly population. This is in keeping with previous work which has clearly shown that CYP3A4 inhibitor drug interactions have clinically significant adverse effects with a wide range of common medications including calcium channel blockers, 21,23 statins, 22 and calcineurin inhibitors 38 …”

Mycobacterium haemophilum skin and soft tissue infection in a kidney transplant recipient: A case report and summary of the literature

“…10,11 Drug-drug interactions are one of the caveats challenging clini- In a retrospective study linking healthcare databases across Canada, there was no significant difference observed in allograft dysfunction between kidney transplant recipients who received clarithromycin and azithromycin. 13 In our case, we informed transplant nephrologists of these potential effects and levels of immunosuppressants…”

Signal of safety due to adverse drug reactions induced by tacrolimus with or without azithromycin

“…However, AZM is metabolized by different pathways, so the impact of CYP3A4 inhibitory and drug‐drug interactions are small 4 . When macrolide antibiotics are administered to patients using calcineurin inhibitors, including TAC, the mean decrease in estimated glomerular filtration rate has been reported to be significantly smaller in the AZM group than in the CAM and EM groups 17 . In addition, CAMs are listed as “strong inhibitors” of P450s, while EMs are listed as “moderate inhibitors” in the Drug Development and Drug Interactions document prepared by the FDA 18 .…”

“…4 When macrolide antibiotics are administered to patients using calcineurin inhibitors, including TAC, the mean decrease in estimated glomerular filtration rate has been reported to be significantly smaller in the AZM group than in the CAM and EM groups. 17 In addition, CAMs are listed as "strong inhibitors" of P450s, while…”