RESUMEN
JNJ-Q2, a novel fluorinated 4-quinolone, was evaluated for its antibacterial potency by broth and agar microdilution MIC methods in studies focused on skin and respiratory tract pathogens, including strains exhibiting contemporary fluoroquinolone resistance phenotypes. Against a set of 118 recent clinical isolates of Streptococcus pneumoniae, including fluoroquinolone-resistant variants bearing multiple DNA topoisomerase target mutations, an MIC(90) value for JNJ-Q2 of 0.12 microg/ml was determined, indicating that it was 32-fold more potent than moxifloxacin. Against a collection of 345 recently collected methicillin-resistant Staphylococcus aureus (MRSA) isolates, including 256 ciprofloxacin-resistant strains, the JNJ-Q2 MIC(90) value was 0.25 microg/ml, similarly indicating that it was 32-fold more potent than moxifloxacin. The activities of JNJ-Q2 against Gram-negative pathogens were generally comparable to those of moxifloxacin. In further studies, JNJ-Q2 exhibited bactericidal activities at 2x and 4x MIC levels against clinical isolates of S. pneumoniae and MRSA with various fluoroquinolone susceptibilities, and its activities were enhanced over those of moxifloxacin. In these studies, the activity exhibited against strains bearing gyrA, parC, or gyrA plus parC mutations was indicative of the relatively balanced (equipotent) activity of JNJ-Q2 against the DNA topoisomerase target enzymes. Finally, determination of the relative rates or frequencies of the spontaneous development of resistance to JNJ-Q2 at 2x and 4x MICs in S. pneumoniae, MRSA, and Escherichia coli were indicative of a lower potential for resistance development than that for current fluoroquinolones. In conclusion, JNJ-Q2 exhibits a range of antibacterial activities in vitro that is supportive of its further evaluation as a potential new agent for the treatment of skin and respiratory tract infections.
Asunto(s)
Antibacterianos/farmacología , Fluoroquinolonas/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Antibacterianos/química , Ciprofloxacina/farmacología , Diseño de Fármacos , Farmacorresistencia Bacteriana/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Fluoroquinolonas/químicaRESUMEN
In phase 3 clinical trials for ceftobiprole treatment of complicated skin and skin structure infections, 1,219 gram-positive and 276 gram-negative aerobic baseline pathogens were identified. Ceftobiprole inhibited all staphylococcal isolates, including methicillin-resistant strains, at MICs of =4 mug/ml. Against Enterobacteriaceae and Pseudomonas aeruginosa isolates, the potency of ceftobiprole was similar to that of cefepime.
Asunto(s)
Antibacterianos/farmacología , Cefalosporinas/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Enfermedades Cutáneas Bacterianas/microbiología , Enterobacteriaceae/clasificación , Enterobacteriaceae/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/microbiología , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus/clasificación , Staphylococcus/efectos de los fármacosRESUMEN
Meticillin-resistant Staphylococcus aureus (MRSA) isolates from two worldwide ceftobiprole Phase 3 clinical trials for the treatment of complicated skin and skin-structure infections were characterised by clonality, staphylococcal cassette chromosome mec (SCCmec) type and the presence of Panton-Valentine leukocidin (PVL). PVL was predominantly found in US isolates (196/231 vs. 13/110 non-US isolates). SCCmec type IV was the most common (253/329) owing to the predominance of clone USA300 in isolates from the USA (197/226). In Europe, SCCmec type III was the most prevalent (30/74). Ceftobiprole minimum inhibitory concentrations (MICs) ranged from 0.25 microg/mL to 4 microg/mL, with MICs Asunto(s)
Antibacterianos/uso terapéutico
, Cefalosporinas/uso terapéutico
, Staphylococcus aureus Resistente a Meticilina/clasificación
, Staphylococcus aureus Resistente a Meticilina/genética
, Infecciones Cutáneas Estafilocócicas/tratamiento farmacológico
, Infecciones Cutáneas Estafilocócicas/microbiología
, Técnicas de Tipificación Bacteriana/métodos
, Análisis por Conglomerados
, Dermatoglifia del ADN/métodos
, ADN Bacteriano/genética
, Europa (Continente)
, Genotipo
, Humanos
, Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos
, Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación
, Pruebas de Sensibilidad Microbiana
, Estados Unidos
RESUMEN
We evaluated the effect of optimized doses and dosing schedules of metronidazole, tetracycline, and bismuth-metronidazole-tetracycline (BMT) triple therapy with only 1 day of dosing on Helicobacter pylori SS1 titers in a mouse model. A reduction of bacterial titers was observable with 22.5 and 112.5 mg of metronidazole per kg of body weight (as well as BMT) given twice daily and four times daily (QID). Two hundred milligrams of tetracycline per kilogram, given QID, resulted in only a slight reduction of H. pylori titers in the stomach. We argue that optimization of doses based on antimicrobial drug levels in the animal and shortened (1 or 2 days) drug administration can be used to facilitate early evaluation of putative anti-H. pylori drug candidates in lieu of using human doses and extended schedules (7 to 14 days), as can be deduced from the results seen with these antimicrobial agents.