Possible Interaction Between Intravenous Azithromycin and Oral Cyclosporine

Abstract

A 42-year-old man who had received a cadaveric kidney transplant 9 years earlier was admitted to the hospital with pneumonia. His oral cyclosporine dosage for the past 2 years was stabilized at 100 mg twice/day; his cyclosporine whole blood trough levels 15 days earlier and on the day he was admitted were both 178 ng/ml. The patient was treated with intravenous ceftriaxone and intravenous azithromycin and continued to receive the same dosage of oral cyclosporine. On hospital day 3, his cyclosporine trough level rose to 400 ng/ml and his dosage was reduced by 50%. Trough levels were 181 ng/ml and 175 ng/ml on hospital days 6 and 9, respectively On hospital day 9, the patient stopped receiving azithromycin. On hospital day 14, his cyclosporine trough level dropped to 76 ng/ml, and his cyclosporine dosage was increased back to 100 mg twice/day. The dosage produced trough levels consistent with those before he had been admitted. The patient was discharged on day 20, and a follow-up cyclosporine trough level determined 3 weeks later was 175 ng/ml. Administration of azithromycin may have caused the increased cyclosporine concentrations in this patient through p-glycoprotein inhibition and/or competition for biliary excretion. Azithromycin's interference may be inferred by the increase in cyclosporine levels after administration of this drug and the decrease in cyclosporine levels after its discontinuation-both consistent with the pharmacokinetic properties of cyclosporine. Ceftriaxone and acute-phase reactant activation during infection, however, also may have interfered with the patient's cyclosporine elimination. Azithromycin generally is considered unlikely to interact with cyclosporine. Nonetheless, practitioners should be aware of this possibility and should monitor cyclosporine levels closely, especially in critically ill patients who have other complications.

Evaluation of azithromycin in systemic and toothpaste forms for the treatment of ciclosporin‐associated gingival overgrowth in dogs

“…Previous studies have reported that macrolide antibiotics, including erythromycin and clarithromycin, increase blood levels of CsA in humans and rats . This interaction is thought to be related to the inhibitory effect of macrolide antibiotics on cytochrome P450 .…”

“…In vitro and in vivo studies in rats and humans have shown that azalides do not significantly inhibit hepatic microsomal enzymes or produce enzyme–metabolite complexes, and therefore it was thought that AZI should not result in increased CsA blood levels in these species . However, human case reports have documented increased CsA levels during concurrent administration with both oral and intravenous azithromycin . It has been hypothesized that the potential increase in CsA levels may result from AZI inhibiting the P‐glycoprotein efflux pump and/or competing with CsA for biliary excretion .…”

Azithromycin is associated with increased survival in lung transplant recipients with bronchiolitis obliterans syndrome

“…[28] Macrolides have been described to increased levels of certain immunosuppressive medications including cyclosporine, which may contribute to its beneficial effect on BOS. [29] Patients in our study on cyclosporine or tacrolimus did routinely have levels monitored to ensure they remained in normal range. We do not have data to directly address what the effect of azithromycin was on these drug levels in our cohorts, however, a previous study using azithromycin in lung transplant recipients did not show that azithromycin dramatically changed cyclosporine or tacrolimus levels.…”

Influence of P-Glycoprotein Inhibitors on Accumulationof Macrolides in J774 MurineMacrophages

“…In parallel, erythromycin and azithromycin are capable of inhibiting the transport of various substrates of the P-glycoprotein in epithelial cells in vitro as well as in vivo (9,12,13,23,30,31,39). Yet, little is known about the role of efflux transporters in the handling of macrolides by macrophages, in which these drugs are known to accumulate in large amounts (2,3,20,24).…”