The Pharmacokinetics and Pharmacodynamics of Pulmonary Mycobacterium avium Complex Disease Treatment
- 15 September 2012
- journal article
- research article
- Published by American Thoracic Society in American Journal of Respiratory and Critical Care Medicine
- Vol. 186 (6), 559-565
- https://doi.org/10.1164/rccm.201204-0682oc
Abstract
Rationale: Currently recommended multidrug treatment regimens for Mycobacterium avium complex (MAC) lung disease yield limited cure rates. This results, in part, from incomplete understanding of the pharmacokinetics and pharmacodynamics of the drugs. Objectives: To study pharmacokinetics, pharmacodynamics, and drug interactions of multidrug treatment regimens in a large cohort of patients with MAC lung disease. Methods: We retrospectively collected pharmacokinetic data of all patients treated for MAC lung disease in the Adult Care Unit at National Jewish Health, Denver, Colorado, in the January 2006 to January 2010 period; we retrospectively calculated areas under the time-concentration curve (AUC). Minimum inhibitory concentrations (MIC) of their MAC isolates were retrieved for pharmacodynamic calculations. Measurements and Main Results: We included 531 pharmacokinetic analyses, performed for 481 patients (84% females; mean age, 63 yr; mean body mass index, 21.6). Peak serum concentrations (Cmax) below target range were frequent for ethambutol (48% of patients); clarithromycin (56%); and azithromycin (35%). Concurrent administration of rifampicin led to 68%, 23%, and 10% decreases in Cmax of clarithromycin, azithromycin, and moxifloxacin. Cmax/MIC or AUC/MIC ratios associated with bactericidal activity were seldom met; 57% of patients achieved target ratios for ethambutol, versus 42% for clarithromycin, 19% for amikacin, 18% for rifampicin, and 11% for moxifloxacin. Conclusions: Currently recommended regimens for MAC lung disease yield important pharmacologic interactions and low concentrations of key drugs including macrolides. Pharmacodynamic indices for rifampicin, clarithromycin, amikacin, and moxifloxacin are seldom met. This may partly explain the poor outcomes of currently recommended treatment regimens. Trials of new drugs and new dosing strategies are needed.Keywords
This publication has 34 references indexed in Scilit:
- Pulmonary Nontuberculous Mycobacterial Disease Prevalence and Clinical FeaturesAmerican Journal of Respiratory and Critical Care Medicine, 2010
- Ethambutol Optimal Clinical Dose and Susceptibility Breakpoint Identification by Use of a Novel Pharmacokinetic-Pharmacodynamic Model of Disseminated Intracellular Mycobacterium aviumAntimicrobial Agents and Chemotherapy, 2010
- Proposal to elevate Mycobacterium avium complex ITS sequevar MAC-Q to Mycobacterium vulneris sp. nov.International Journal of Systematic and Evolutionary Microbiology, 2009
- Clinical relevance of non-tuberculous mycobacteria isolated in the Nijmegen-Arnhem region, The NetherlandsThorax, 2009
- An Official ATS/IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial DiseasesAmerican Journal of Respiratory and Critical Care Medicine, 2007
- Factors Related to Response to Intermittent Treatment of Mycobacterium avium Complex Lung DiseaseAmerican Journal of Respiratory and Critical Care Medicine, 2006
- Pharmacokinetics-Pharmacodynamics of Rifampin in an Aerosol Infection Model of TuberculosisAntimicrobial Agents and Chemotherapy, 2003
- Evaluation of the MicroSeq System for Identification of Mycobacteria by 16S Ribosomal DNA Sequencing and Its Integration into a Routine Clinical Mycobacteriology LaboratoryJournal of Clinical Microbiology, 2003
- Laboratory diagnosis of nontuberculous mycobacteriaClinics in Chest Medicine, 2002
- USING THERAPEUTIC DRUG MONITORING TO DOSE THE ANTIMYCOBACTERIAL DRUGSClinics in Chest Medicine, 1997