A drug interaction between fusidic acid and a combination of ritonavir and saquinavir.

Abstract

A 32-year-old male infected with the human immunodeficiency virus (HIV) was seen for acute onset of nausea, fatigue, arthralgias, vertigo and jaundice. At that time, he was being treated twice daily with ritonavir 400 mg, saquinavir 400 mg and stavudine 40 mg for 3 months. Fusidic acid (Fucidin®) 500 mg three times daily had been started 1 week earlier for a scalp furuncle. On examination he was ill-appearing but was afebrile with stable vital signs. Examination was significant only for jaundice. Figure 1 indicates the patient’s laboratory values, plasma drug concentrations, and time courses of drug therapy. The patient was admitted to hospital with a possible diagnosis of fusidic acid toxicity. Fusidic acid therapy was stopped and hydration was initiated. Plasma drug concentrations, laboratory values and time course of drug therapy. While in hospital viral causes of hepatitis were excluded. His plasma concentration of fusidic acid 16 h after his last dose was 195 µg ml−1 (expected level < 100 µg ml−1[1]), and ritonavir and saquinavir plasma concentrations were 19.3 and 11.2 µg ml−1, respectively, between 5 and 10 h after the doses (observed range of maximum concentrations [2, 3]: ritonavir: 4–12 µg ml−1, saquinavir: 1–4 µg ml−1). The patient improved after 24 h and was discharged. Four days later he returned with nausea, weakness, jaundice and a further increase in liver function tests. All medications were discontinued and his liver function tests improved. Drug analysis revealed a fusidic acid concentration of 132 µg ml−1 (6 days post), and ritonavir and saquinavir levels of 43.4 and 16.3 µg ml−1, respectively, between 3 and 10 h after the doses. On day 45 (39 days since starting fusidic acid), ritonavir, saquinavir and stavudine were restarted. The following month, his liver function tests were normal and his plasma viral load was suppressed ( Figure 1). A follow-up plasma analysis (day 122) demonstrated no fusidic acid present, and ritonavir and saquinavir plasma concentrations were within the expected ranges. Oral administration of standard doses of fusidic acid, 500 mg three times daily, is well tolerated, but adverse reactions to the drug include gastrointestinal upset, reversible jaundice, anorexia, lethargy, vertigo and arthralgias. Maximum plasma concentrations occur 2 -3 h after the dose in healthy volunteers. Fusidic acid is eliminated primarily by biliary excretion of various conjugative and cytochrome P450 (CYP) oxidative metabolites [4]. Fusidic acid has demonstrated inhibition of CYP3A4 isoforms in vitro[unpublished data]. Fusidic acid displays nonlinear pharmacokinetics with an elimination half-life ranging from 6–14 h [4, 5]. The initial plasma sample in this patient was collected during the elimination phase of fusidic acid, and the concentration (195 µg ml−1) was about twice the peak levels observed in patients with cholestasis who had received fusidic acid 500 mg three times daily intravenously over 2 h for 4 days [1]. In our patient, the fusidic acid concentration decreased only 32% over 4.5 days, suggesting a first order elimination half-life of 8 days. The high concentrations and prolonged elimination of fusidic acid may have been caused by ritonavir and saquinavir inhibiting fusidic acid metabolism through CYP [6] or Phase II conjugation. Concurrently, fusidic acid appears to have inhibited the metabolism of both ritonavir and saquinavir as suggested by their elevated concentrations (43.2 and 16.3 µg ml−1) during fusidic acid administration, which normalized after fusidic acid was discontinued. Ritonavir and saquinavir are common causes of gastrointestinal upset, and have also been responsible for cases of hepatitis [7]. In the current case, ritonavir and saquinavir were previously well-tolerated, but vertigo, anorexia, jaundice and paresthesias were observed after addition of fusidic acid. These effects may have resulted from protease inhibitor or fusidic acid administration. This case demonstrates that plasma concentrations of both protease inhibitors, ritonavir and saquinavir, as well as fusidic acid, may be significantly elevated when these agents are administered in combination, possibly from mutual inhibition of metabolism. Therefore we recommend that coadministration of fusidic acid with either of these two drugs be avoided.