Ethambutol optimal clinical dose and susceptibility breakpoint identification by use of a novel pharmacokinetic-pharmacodynamic model of disseminated intracellular Mycobacterium avium.
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 dose-effect 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 pharmacokinetic-pharmacodynamic 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 >or=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.
Division of Infectious Diseases, UT Southwestern Medical Center, Dallas, TX 75390-9113, USA.
Devyani
D
Deshpande
Shashikant
S
Srivastava
Claudia
C
Meek
Richard
R
Leff
Tawanda
T
Gumbo
D000995:Antitubercular Agents / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004352:Drug Resistance, Microbial; D004977:Ethambutol / Q000493:pharmacokinetics*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000382:microbiology*; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009010:Monte Carlo Method; D009162:Mycobacterium avium / Q000187:drug effects* / Q000254:growth & development; D015270:Mycobacterium avium-intracellulare Infection / Q000188:drug therapy* / Q000382:microbiology
D000995:Antitubercular Agents; D004977:Ethambutol