Pharmacokinetics of Rifampin and Clarithromycin in Patients Treated for Mycobacterium ulcerans Infection

Abstract

In a randomized controlled trial in Ghana, treatment of Mycobacterium ulcerans infection with streptomycin (SM)-rifampin (RIF) for 8 weeks was compared with treatment with SM-RIF for 4 weeks followed by treatment with RIF-clarithromycin (CLA) for 4 weeks. The extent of the interaction of RIF and CLA combined on the pharmacokinetics of the two compounds is unknown in this population and was therefore studied in a subset of patients. Patients received CLA at a dose of 7.5 mg/kg of body weight once daily, rounded to the nearest 125 mg. RIF was administered at a dose of 10 mg/kg, rounded to the nearest 150 mg. SM was given at a dose of 15 mg/kg once daily as an intramuscular injection. Plasma samples were drawn at steady state and analyzed by liquid chromatography-tandem mass spectroscopy. Although many antimycobacterial agents appeared to be effective against Mycobacterium ulcerans infections in in vitro and in animal models (4,11,27,30), clinical evidence of the effectiveness of antimicrobial treatment was predominantly based on a small study conducted with patients in Ghana (15). Conceivably, using antimycobacterial agents results not only in preventing bacilli from replicating and killing microorganisms but also in halting the production of the toxin mycolactone (36). This toxin that causes the tissue damage is produced by enzymes encoded by the pMUM001 plasmid (33). Current WHO recommendations suggest 8 or more weeks of treatment with rifampin (RIF) plus streptomycin (SM) for all clinical forms of active Buruli ulcer disease (BUD). Daily injections with streptomycin are problematic, as most patients live in remote areas with limited health care facilities. Proper hygiene with these injections, as well as intrinsic ototoxicity and renal toxicity, is a concern. Therefore, an oral treatment schedule is urgently needed to reduce the number of injections and to improve the tolerability and safety of the proposed regimen. Pregnant women might also benefit from treatment without aminoglycosides. This problem was addressed by comparing 8 weeks of SM (15 mg/kg of body weight) and RIF (10 mg/kg) treatment (8SR arm) and 4 weeks of streptomycin and rifampin treatment followed by 4 weeks of RIF plus clarithromycin (CLA; 7.5 mg/kg) treatment (4SR/4CR arm) in a randomized controlled trial (the BURULICO trial) (26). CLA was chosen for inclusion in the treatment regimen because of in vitro data suggesting that this drug is active against M. ulcerans, for which the MICs range from Ͻ0.125 to 2.0 mg/liter (30). In a pharmacokinetic (PK) study with adults who received doses of 500 mg twice daily, plasma CLA concentrations (5) were well above the MIC for most M. ulcerans isolates.The clinical effectiveness of macrolides is only partly explained by pharmacokinetics, because these drugs typically accumulate in inflammatory cells, especially macrophages, at the site of infection (1). Although M. ulcerans infection has long been regarded a predominantly extracellular infection (20), evidence has emerged from animal models that M. ulcera...

Comparison of Two Assays for Molecular Determination of Rifampin Resistance in Clinical Samples from Patients with Buruli Ulcer Disease

“…Standardized antimycobacterial treatment consists of rifampin (RMP) and streptomycin administered for 8 weeks. An oral regimen combining RMP and clarithromycin is currently under clinical evaluation (1)(2)(3). Notwithstanding the efficiency of chemotherapy, treatment failures and various types of secondary lesions have been reported, suggesting the need for customized clinical management strategies (4)(5)(6).…”

Increasing Experience with Primary Oral Medical Therapy for Mycobacterium ulcerans Disease in an Australian Cohort

“…Wallace and others demonstrated for patients with Mycobacterium avium complex infection treated with RC that the mean serum level of clarithromycin given as a single agent was 5.4 Ϯ 2.1 g/ml but that this decreased substantially, to 0.7 Ϯ 0.6 g/ml, in patients receiving rifampin with clarithromycin (16). The pharmacokinetics of the RC combination (with clarithromycin dosed at 7.5 mg/kg/ day) for M. ulcerans infection were studied, and the results indicated that the median concentration of clarithromycin was above the MIC for M. ulcerans but that the concentration of 4-hydroxyclarithromycin was not (17). The authors of that study therefore recommended that clarithromycin should be dosed at 7.5 mg/kg twice daily (or 15 mg/kg daily in an extended-release formulation) to ensure higher levels of exposure to clarithromycin and an increase in the time above the MIC compared to those achieved with a dose of 7.5 mg/kg once daily (17).…”

“…The pharmacokinetics of the RC combination (with clarithromycin dosed at 7.5 mg/kg/ day) for M. ulcerans infection were studied, and the results indicated that the median concentration of clarithromycin was above the MIC for M. ulcerans but that the concentration of 4-hydroxyclarithromycin was not (17). The authors of that study therefore recommended that clarithromycin should be dosed at 7.5 mg/kg twice daily (or 15 mg/kg daily in an extended-release formulation) to ensure higher levels of exposure to clarithromycin and an increase in the time above the MIC compared to those achieved with a dose of 7.5 mg/kg once daily (17). We concur with this recommendation in order to avoid subtherapeutic treatment with clarithromycin, and hence secondary rifampin resistance development as may occur when rifampin monotherapy is used (18).…”

Evaluation of macrolides for possible use against multidrug-resistantMycobacterium tuberculosis

“…Some semi-synthetic macrolides have already shown efficacy against, and are part of standard therapy against, many nontuberculous mycobacteria [13], such as Mycobacterium leprae [14][15][16], Mycobacterium ulcerans [17,18] and Mycobacterium avium [19,20]. As stated in the WHO guidelines, little is known about the effectiveness of macrolides against M. tuberculosis [4].…”