Your browser doesn't support javascript.

Biblioteca Virtual em Saúde

Brasil

Home > Pesquisa > ()
Imprimir Exportar

Formato de exportação:

Exportar

Email
Adicionar mais destinatários
| |

Minocycline treatment for pulmonary Mycobacterium avium complex disease based on pharmacokinetics/pharmacodynamics and Bayesian framework mathematical models.

Ruth, Mike M; Magombedze, Gesham; Gumbo, Tawanda; Bendet, Paula; Sangen, Jasper J N; Zweijpfenning, Sanne; Hoefsloot, Wouter; Pennings, Lian; Koeken, Valerie A C M; Wertheim, Heiman F L; Lee, Pooi S; van Ingen, Jakko; Deshpande, Devyani.
J Antimicrob Chemother; 74(7): 1952-1961, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31039251

OBJECTIVES:

Our aim was to identify the pharmacokinetic/pharmacodynamic parameters of minocycline in the hollow-fibre system (HFS) model of pulmonary Mycobacterium avium complex (MAC) and to identify the optimal clinical dose.

METHODS:

Minocycline MICs for 55 MAC clinical isolates from the Netherlands were determined. We also co-incubated primary isolated macrophages infected with MAC with minocycline. Next, we performed a 28 day HFS-MAC model dose-response study in which we mimicked pulmonary concentration-time profiles achieved in patients. The HFS-MAC model was sampled at intervals to determine the minocycline pharmacokinetics and MAC burden. We identified the AUC0-24/MIC ratios associated with 1.0 log10 cfu/mL kill below day 0 (stasis), defined as a bactericidal effect. We then performed 10000 Monte Carlo experiments to identify the optimal dose for a bactericidal effect in patients.

RESULTS:

The MIC for 50% and 90% of cumulative clinical isolates was 8 and 64 mg/L, respectively. Minocycline decreased MAC bacterial burden below stasis in primary isolated macrophages. In the HFS-MAC model, minocycline achieved a microbial kill of 3.6 log10 cfu/mL below stasis. The AUC0-24/MIC exposure associated with a bactericidal effect was 59. Monte Carlo experiments identified a minocycline susceptibility MIC breakpoint of 16 mg/L. At this proposed breakpoint, the clinical dose of 200 mg/day achieved the bactericidal effect exposure target in ∼50% of patients, while 400 mg/day achieved this in 73.6% of patients, in Monte Carlo experiments.

CONCLUSIONS:

Minocycline at a dose of 400 mg/day is expected to be bactericidal. We propose a clinical trial for validation.
Selo DaSilva