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Efficacy of novel rifamycin derivatives against rifamycin-sensitive and -resistant Staphylococcus aureus isolates in murine models of infection.

Abstract
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.
AuthorsDavid M Rothstein, Ronald S Farquhar, Klari Sirokman, Karen L Sondergaard, Charles Hazlett, Angelia A Doye, Judith K Gwathmey, Steve Mullin, John van Duzer, Christopher K Murphy
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 50 Issue 11 Pg. 3658-64 (Nov 2006) ISSN: 0066-4804 [Print] United States
PMID16940074 (Publication Type: Journal Article)
Chemical References
  • Anti-Bacterial Agents
  • Rifamycins
Topics
  • Administration, Oral
  • Animals
  • Anti-Bacterial Agents (administration & dosage, pharmacology, therapeutic use)
  • Chemistry, Pharmaceutical
  • Drug Resistance, Bacterial
  • Mice
  • Microbial Sensitivity Tests
  • Muscle, Skeletal (microbiology)
  • Mutation
  • Neutropenia (complications)
  • Rifamycins (administration & dosage, pharmacology, therapeutic use)
  • Sepsis (drug therapy, microbiology)
  • Staphylococcal Infections (microbiology)
  • Staphylococcus aureus (drug effects, genetics)
  • Structure-Activity Relationship

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