title: Azithromycin Dose To Maximize Efficacy and Suppress Acquired Drug Resistance in Pulmonary Mycobacterium avium Disease.
abstract: Mycobacterium aviumcomplex is now the leading mycobacterial cause of chronic pneumonia in the United States. Macrolides and ethambutol form the backbone of the regimen used in the treatment of pulmonary disease. However, therapy outcomes remain poor, with microbial cure rates of 4% in cavitary disease. The treatment dose of azithromycin has mostly been borrowed from that used to treat other bacterial pneumonias; there are no formal dose-response studies in pulmonaryM. aviumdisease and the optimal dose is unclear. We utilized population pharmacokinetics and pharmacokinetics/pharmacodynamics-derived azithromycin exposures associated with optimal microbial kill or resistance suppression to perform 10,000 patient Monte Carlo simulations of dose effect studies for daily azithromycin doses of 0.5 to 10 g. The currently recommended dose of 500 mg per day achieved the target exposures in 0% of patients. Exposures associated with optimal kill and resistance suppression were achieved in 87 and 54% of patients, respectively, only by the very high dose of 8 g per day. The azithromycin susceptibility breakpoint above which patients failed therapy on the very high doses of 8 g per day was an MIC of 16 mg/liter, suggesting a critical concentration of 32 mg/liter, which is 8-fold lower than the currently used susceptibility breakpoint of 256 mg/liter. If the standard dose of 500 mg a day were used, then the critical concentration would fall to 2 mg/liter, 128-fold lower than 256 mg/liter. The misclassification of resistant isolates as susceptible could explain the high failure rates of current doses.
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA.
authors.forename: Devyani
authors.initials: D
authors.lastname: Deshpande
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA.
authors.forename: Jotam G
authors.initials: JG
authors.lastname: Pasipanodya
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA Department of Medicine, University of Cape Town, Observatory, South Africa tawanda.gumbo@baylorhealth.edu.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
mesh_terms: D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D017963:Azithromycin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003198:Computer Simulation; D054796:Drug Dosage Calculations; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D009010:Monte Carlo Method; D015269:Mycobacterium avium Complex / Q000187:drug effects / Q000254:growth & development; D015270:Mycobacterium avium-intracellulare Infection / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D017963:Azithromycin
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