Ethambutol Optimal Clinical Dose and Susceptibility Breakpoint Identification by Use of a Novel Pharmacokinetic-Pharmacodynamic Model of Disseminated Intracellular Mycobacterium avium

Abstract

Ethambutol, together with a macrolide, is the backbone for treatment of disseminated Mycobacterium avium disease. However, at the standard dose of 15 mg/kg of body weight/day, ethambutol efficacy is limited. In addition, susceptibility breakpoints have consistently failed to predict clinical outcome. We performed doseeffect studies with extracellular M. avium as well as with bacilli within human macrophages. The maximal kill rate (E max ) for ethambutol against extracellular bacilli was 5.54 log 10 CFU/ml, compared to 0.67 log 10 CFU/ml for intracellular M. avium, after 7 days of exposure. Thus, extracellular assays demonstrated high efficacy. We created a hollow-fiber system model of intracellular M. avium and performed microbial pharmacokineticpharmacodynamic studies using pharmacokinetics similar to those of ethambutol for humans. The E max in the systems was 0.79 log 10 CFU/ml with 7 days of daily therapy, so the kill rates approximated those encountered in patients treated with ethambutol monotherapy. Ratio of peak concentration to MIC (C max /MIC) was linked to microbial kill rate. The C max /MIC ratio needed to achieve the 90% effective concentration (EC 90 ) in serum was 1.23, with a calculated intramacrophage C max /MIC ratio of 13. In 10,000 patient Monte Carlo simulations, doses of 15, 50, and 75 mg/kg achieved the EC 90 in 35.50%, 76.81%, and 86.12% of patients, respectively. Therefore, ethambutol doses of >50 mg/kg twice a week would be predicted to be better than current doses of 15 mg/kg for treatment of disseminated M. avium disease. New susceptibility breakpoints and critical concentrations of 1 to 2 mg/liter were identified for the determination of ethambutol-resistant M. avium in Middlebrook broth. Given that the modal MIC of clinical isolates is around 2 mg/liter, most isolates should be considered ethambutol resistant.Bacteria of the Mycobacterium avium complex (MAC) are not only a cause of important opportunistic infections in patients with AIDS and cancer but also an important cause of pulmonary disease in "immunocompetent" patients (5,17,26,31). In immunocompromised patients, disseminated disease is common and lethal (8, 10). Current therapy is based on a backbone of ethambutol, concurrent with either azithromycin or clarithromycin, administered for many months to several years (17,18). This therapy fails in up to half of patients and therefore still needs to be optimized.The first test used to examine the therapeutic potential of ethambutol, as for all other antibiotics, is MIC determination. With this test, it is hoped that discrimination can be made as to whether ethambutol should be used in the patient from whom M. avium was isolated. Unfortunately, susceptibility studies have failed to predict the effectiveness of ethambutol in patients with disseminated M. avium disease in the past (5, 34, 39). We hypothesize that part of the problem has been an arbitrarily chosen susceptibility breakpoint, which did not take into account population pharmacokinetics and microbial pharmacokinetics-ph...

A Multilaboratory, Multicountry Study To Determine MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testing of Selected First-Line Antituberculosis Drugs, Second-Line Injectables, Fluoroquinolones, Clofazimine, and Linezolid

“…One important consideration in this regard is that PK/PD data determined in serum cannot always be used to predict susceptibility of an intracellular mycobacterium. For example, reduced moxifloxacin and ethambutol efficacy within macrophages has been shown against Staphylococcus aureus and Mycobacterium avium (18)(19)(20)(21).…”

Moxifloxacin Pharmacokinetics/Pharmacodynamics and Optimal Dose and Susceptibility Breakpoint Identification for Treatment of Disseminated Mycobacterium avium Infection

“…Our PK/PD model was designed to fulfill these criteria. We have demonstrated elsewhere (15) that, in this model, weekly microbial kill rates for 15 mg/kg/day ethambutol monotherapy mirror those in patients, so that the PK/PD relationships derived in this model likely have clinical meaning.…”

“…To our knowledge no moxifloxacin PK/PD studies have ever been performed for the treatment of MAC infection. We have developed an in vitro PK/PD model of intracellular M. avium infection (15) in which a bacillary burden similar to that encountered in patients with disseminated disease was exposed to the same moxifloxacin concentration-time profiles encountered in the serum of patients. This disease model was utilized to identify the relationship between moxifloxacin exposure and microbial kill.…”

Azithromycin Dose To Maximize Efficacy and Suppress Acquired Drug Resistance in Pulmonary Mycobacterium avium Disease

“…In that study, the MIC 50 was 8 mg/liter, and (12,26). These experiments have been used to identify optimal doses for treatment of MAC in the past (7,27). Here, we specifically implemented these methods, taking into account the intracellular nature of MAC and expected intracellular pulmonary penetration of azithromycin.…”

“…In PK/PD studies in the hollow-fiber system model of MAC (HFS-MAC), the maximal kill by ethambutol was limited, with monotherapy at maximal doses achieving bacterial burden higher than at the start of treatment (7). Indeed, it is believed that most microbial kill achieved by the regimen is derived from macrolides, so that when there is resistance to the macrolide, therapy fails (8,9).…”