ArticleAntimicrobial agents and chemotherapy2010
Ethambutol optimal clinical dose and susceptibility breakpoint identification by use of a novel pharmacokinetic-pharmacodynamic model of disseminated intracellular Mycobacterium avium.
Article in Antimicrobial agents and chemotherapy, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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39 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
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- Ethambutol pharmacokinetic variability is linked to body mass in overweight, obese, and extremely obese people.Antimicrobial agents and chemotherapy · 2012Trial
- Falling short: Inadequate target attainment in guideline-based therapy of nontuberculous mycobacterial disease.medRxiv : the preprint server for health sciences · 2026Article
- Novel regimens for treatment ofbioRxiv : the preprint server for biology · 2026Article
- Rifamycin-, macrolide-, and ethambutol-free combinations to treatThe international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease · 2026Article
- Preclinical pharmacokinetics/pharmacodynamics studies defining the role of ethambutol inAntimicrobial agents and chemotherapy · 2026Article
- Pharmacodynamic evidence for tedizolid use inIJTLD open · 2026Article
- Tigecycline pharmacodynamics in the hollow fiber system ofbioRxiv : the preprint server for biology · 2025Article
- Tigecycline pharmacodynamics in the hollow fiber system ofFrontiers in pharmacology · 2025Article
- Non-Tuberculous Mycobacteria: Single Center Analyses of Risk Factors, Management and Mortality Outcomes of Adults with HIV.Diagnostics (Basel, Switzerland) · 2024Article
- Ceftriaxone Efficacy for Mycobacterium avium Complex Lung Disease in the Hollow Fiber and Translation to Sustained Sputum Culture Conversion in Patients.The Journal of infectious diseases · 2024Article
- Antibacterial action of penicillin againstIJTLD open · 2024Article
- Sarecycline pharmacokinetics/pharmacodynamics in the hollow-fibre model of Mycobacterium avium complex: so near and yet so far.The Journal of antimicrobial chemotherapy · 2024Article
- Correlation of drug exposure and bacterial susceptibility with treatment response forBMJ open · 2023Article
- Structural Determinants of Indole-2-carboxamides: Identification of Lead Acetamides with Pan Antimycobacterial Activity.Journal of medicinal chemistry · 2023Article
- Towards Improved Management of Tuberculous Bloodstream Infections: Pharmacokinetic Considerations with Suggestions for Better Treatment Outcomes.Antibiotics (Basel, Switzerland) · 2022Article
- Omadacycline efficacy in the hollow fibre system model of pulmonary Mycobacterium avium complex and potency at clinically attainable doses.The Journal of antimicrobial chemotherapy · 2022Article
- Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Drug Treatment of Non-Tuberculous Mycobacteria in Cystic Fibrosis.Clinical pharmacokinetics · 2021Review
- Therapeutic Drug Monitoring in Non-Tuberculosis Mycobacteria Infections.Clinical pharmacokinetics · 2021Review
- Comparison of Rifamycins for Efficacy AgainstFrontiers in pharmacology · 2021Article
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5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 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.
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