Asunto(s)
Antibacterianos/farmacología , Fluoroquinolonas , Indoles , Mycobacterium/efectos de los fármacos , Nocardia/efectos de los fármacos , Quinolonas , Pruebas de Sensibilidad Microbiana , Mycobacterium/aislamiento & purificación , Nocardia/aislamiento & purificación , Especificidad de la EspecieRESUMEN
The recent emergence of methicillin-resistant Staphylococcus aureus (MRSA) with decreased susceptibility to vancomycin has intensified the search for alternative therapies for the treatment of infections caused by this organism. One approach has been to identify a beta-lactam with improved affinity for PBP 2a, the target enzyme responsible for methicillin resistance in staphylococci. BMS-247243 is such a candidate, with MICs that inhibit 90% of isolates tested (MIC(90)s) of 4, 2, and 8 microg/ml for methicillin-resistant strains of S. aureus, S. epidermidis, and S. haemolyticus, respectively, as determined on plates with Mueller-Hinton agar and 2% NaCl. The BMS-247243 MICs for MRSA were minimally affected by the susceptibility testing conditions (inoculum size, prolonged incubation, addition of salt to the test medium) or by staphylococcal beta-lactamases. BMS-247243 MIC(90)s for methicillin-susceptible staphylococcal species ranged from < or = 0.25 to 1 microg/ml. The BMS-247243 MIC(90) for beta-lactamase-producing S. aureus strains was fourfold higher than that for beta-lactamase-nonproducing strains. BMS-247243 is hydrolyzed by staphylococcal beta-lactamases at 4.5 to 26.2% of the rates measured for cephaloridine. The affinity of BMS-247243 for PBP 2a was >100-fold better than that of methicillin or cefotaxime. BMS-247243 is bactericidal for MRSA, killing the bacteria twice as fast as vancomycin. These in vitro activities of BMS-247243 correlated with its in vivo efficacy against infections in animals, including the neutropenic murine thigh and rabbit endocarditis models involving MRSA strains. In conclusion, BMS-247243 has in vitro and in vivo activities against methicillin-resistant staphylococci and thus may prove to be useful in the treatment of infections caused by these multidrug-resistant organisms.
Asunto(s)
Proteínas Bacterianas , Proteínas Portadoras , Resistencia a la Meticilina/fisiología , Morfolinas/farmacología , Morfolinas/uso terapéutico , Muramoilpentapéptido Carboxipeptidasa , Piridinas/farmacología , Piridinas/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Animales , Antibacterianos/uso terapéutico , Ciclofosfamida/farmacología , Endocarditis Bacteriana/tratamiento farmacológico , Endocarditis Bacteriana/microbiología , Hexosiltransferasas/genética , Hexosiltransferasas/metabolismo , Hidrólisis , Terapia de Inmunosupresión , Inmunosupresores/farmacología , Cinética , Resistencia a la Meticilina/genética , Ratones , Pruebas de Sensibilidad Microbiana , Morfolinas/metabolismo , Complejos Multienzimáticos/genética , Complejos Multienzimáticos/metabolismo , Músculo Esquelético/microbiología , Proteínas de Unión a las Penicilinas , Peptidil Transferasas/genética , Peptidil Transferasas/metabolismo , Unión Proteica , Piridinas/metabolismo , Conejos , Infecciones Estafilocócicas/microbiología , Vancomicina/uso terapéuticoRESUMEN
BMS-247243, a novel cephalosporin inhibitory for methicillin-resistant staphylococci, primarily has activity against gram-positive bacteria. The activities of BMS-247243, cefotaxime, and ceftriaxone against streptococci and Streptococcus pneumoniae were similar. BMS-247243 inhibits Enterococcus faecalis but not Enterococcus faecium. BMS-247243 also inhibits many inherently vancomycin-resistant species (Leuconstoc, Lactobacillus, Pediococcus) and anaerobic gram-positive bacteria.
Asunto(s)
Cefalosporinas/farmacología , Bacterias Grampositivas/efectos de los fármacos , Morfolinas/farmacología , Piridinas/farmacología , Animales , Bacterias/efectos de los fármacos , Farmacorresistencia Microbiana , Femenino , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Terapia de Inmunosupresión , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Resistencia a las Penicilinas , Infecciones Neumocócicas/tratamiento farmacológico , Infecciones Neumocócicas/microbiología , Factores de TiempoRESUMEN
The quinolones differ in their mechanisms of bacterial killing. The rate of bacterial killing by quinolones can be influenced by the addition of bacterial protein or RNA synthesis inhibitors, and the growth phase of the bacterium. In this study, we compared the killing activities of gatifloxacin, trovafloxacin, ciprofloxacin and norfloxacin against staphylococci, pneumococci and Escherichia coli. Gatifloxacin killing of these organisms occurred regardless of the metabolic state of the microbes. Unlike the comparator quinolones, gatifloxacin killing was not influenced by the addition of bacterial protein or RNA synthesis inhibitors. Gatifloxacin was able to kill non-dividing staphylococcal and E. coli cells.