Novel
rifamycins (new chemical entities [NCEs]) having MICs of 0.002 to 0.03 microg/ml against Staphylococcus aureus and retaining some activity against
rifampin-resistant mutants were tested for in vivo efficacy against susceptible and
rifampin-resistant strains of S. aureus.
Rifalazil and
rifampin had a 50% effective dose (ED50) of 0.06 mg/kg of
body weight when administered as a single intravenous (i.v.) dose in a murine
septicemia model against a susceptible strain of S. aureus. The majority of NCEs showed efficacy at a lower i.v. dose (0.003 to 0.06 mg/kg). In addition, half of the NCEs tested for oral efficacy had ED50s in the range of 0.015 to 0.13 mg/kg, i.e., lower or equivalent to the oral ED50s of
rifampin and
rifalazil. NCEs were also tested in the
septicemia model against a
rifampin-resistant strain of S. aureus. Twenty-four of 169 NCEs were efficacious when administered as a single oral dose of 80 mg/kg. These NCEs were examined in the murine thigh
infection model against a susceptible strain of S. aureus. Several NCEs dosed by
intraperitoneal injection at 0.06 mg/kg caused a significant difference in bacterial titer compared with placebo-treated animals. No NCEs showed efficacy in the thigh model against a highly
rifampin-resistant strain. However, several NCEs showed an effect when tested against a partially
rifampin-resistant strain. The NCEs having a 25-hydroxyl moiety were more effective as a group than their 25-O-acetyl counterparts. These model systems defined candidate NCEs as components of potential combination
therapies to treat systemic
infections or as monotherapeutic agents for topical applications.