RESUMEN
Mycobacterium abscessus is responsible for difficult-to-treat chronic pulmonary infections in humans. Current regimens, including parenteral administrations of cefoxitin (FOX) in combination with amikacin and clarithromycin, raise compliance problems and are frequently associated with high failure and development of resistance. Aerosol delivery of FOX could be an interesting alternative. FOX was administered to healthy rats by intravenous bolus or intratracheal nebulization, and concentrations were determined in plasma and epithelial lining fluid (ELF) by liquid chromatography-tandem mass spectrometry. After intrapulmonary administration, the FOX area under the curve within ELF was 1,147 times higher than that in plasma, indicating that this route of administration offers a biopharmaceutical advantage over intravenous administration. FOX antimicrobial activity was investigated using time-kill curves combined with a pharmacokinetic/pharmacodynamic (PK/PD) type modeling approach in order to account for its in vitro instability that precludes precise determination of MIC. Time-kill data were adequately described by a model including in vitro degradation, a sensitive (S) and a resistant (R) bacteria subpopulation, logistic growth, and a maximal inhibition-type growth inhibition effect of FOX. Median inhibitory concentrations were estimated at 16.2 and 252 mg/liter for the S and R subpopulations, respectively. These findings suggest that parenteral FOX dosing regimens used in patients for the treatment of M. abscessus are not sufficient to reduce the bacterial burden and that FOX nebulization offers a potential advantage that needs to be further investigated.
Asunto(s)
Antibacterianos/farmacología , Cefoxitina/farmacocinética , Cefoxitina/uso terapéutico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Mycobacterium abscessus/efectos de los fármacos , Administración Intravenosa/métodos , Animales , Antibacterianos/farmacocinética , Claritromicina/farmacocinética , Claritromicina/uso terapéutico , Masculino , Pruebas de Sensibilidad Microbiana/métodos , Infecciones por Mycobacterium no Tuberculosas/microbiología , Ratas , Ratas Sprague-Dawley , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/microbiologíaRESUMEN
Amikacin and gentamicin pharmacokinetic behaviors after nebulization were determined by comparing plasma and pulmonary epithelial lining fluid (ELF) concentrations in rats after intratracheal and intravenous administrations. ELF areas under concentration-time curve were 874 and 162 times higher after nebulization than after intravenous administration for amikacin and gentamicin, respectively. Even if both molecules appear to be good candidates for nebulization, these results demonstrate a much higher targeting advantage of nebulization for amikacin than for gentamicin.
