Omadacycline efficacy in the hollow fibre system model of pulmonary Mycobacterium avium complex and potency at clinically attainable doses.
J Antimicrob Chemother
; 77(6): 1694-1705, 2022 05 29.
Article
em En
| MEDLINE
| ID: mdl-35257162
ABSTRACT
OBJECTIVES:
The standard of care (SOC) for the treatment of pulmonary Mycobacterium avium complex (MAC) disease (clarithromycin, rifabutin, and ethambutol) achieves sustained sputum conversion rates of only 54%. Thus, new treatments should be prioritized.METHODS:
We identified the omadacycline MIC against one laboratory MAC strain and calculated drug half life in solution, which we compared with measured MAC doubling times. Next, we performed an omadacycline hollow fibre system model of intracellular MAC (HFS-MAC) exposure-effect study, as well as the three-drug SOC, using pharmacokinetics achieved in patient lung lesions. Data was analysed using bacterial kill slopes (γ-slopes) and inhibitory sigmoid Emax bacterial burden versus exposure analyses. Monte Carlo experiments (MCE) were used to identify the optimal omadacycline clinical dose.RESULTS:
Omadacycline concentration declined in solution with a half-life of 27.7â h versus a MAC doubling time of 16.3â h, leading to artefactually high MICs. Exposures mediating 80% of maximal effect changed up to 8-fold depending on sampling day with bacterial burden versus exposure analyses, while γ-slope-based analyses gave a single robust estimate. The highest omadacycline monotherapy γ-slope was -0.114 (95% CI -0.141 to -0.087) (r2â=â0.98) versus -0.114 (95% CI -0.133 to -0.094) (r2â=â0.99) with the SOC. MCEs demonstrated that 450â mg of omadacycline given orally on the first 2â days followed by 300â mg daily would achieve the AUC0-24 target of 39.67â mg·h/L.CONCLUSIONS:
Omadacycline may be a potential treatment option for pulmonary MAC, possibly as a back-bone treatment for a new MAC regimen and warrants future study in treatment of this disease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Complexo Mycobacterium avium
/
Infecção por Mycobacterium avium-intracellulare
Limite:
Humans
Idioma:
En
Revista:
J Antimicrob Chemother
Ano de publicação:
2022
Tipo de documento:
Article