Efficacy of novel rifamycin derivatives against rifamycin-sensitive and -resistant Staphylococcus aureus isolates in murine models of infection.
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.
Rothstein
David M
DM
ActivBiotics, Inc., 110 Hartwell Ave., Lexington, MA 02421, USA. drothstein@activbiotics.com
Farquhar
Ronald S
RS
Sirokman
Klari
K
Sondergaard
Karen L
KL
Hazlett
Charles
C
Doye
Angelia A
AA
Gwathmey
Judith K
JK
Mullin
Steve
S
van Duzer
John
J
Murphy
Christopher K
CK
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002626:Chemistry, Pharmaceutical; D024881:Drug Resistance, Bacterial; D051379:Mice; D008826:Microbial Sensitivity Tests; D018482:Muscle, Skeletal / Q000382:microbiology; D009154:Mutation; D009503:Neutropenia / Q000150:complications; D012294:Rifamycins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D013203:Staphylococcal Infections / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D012294:Rifamycins