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Antimicrobial Agents and Chemotherapy, November 2006, p. 3658-3664, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.01087-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Efficacy of Novel Rifamycin Derivatives against Rifamycin-Sensitive and -Resistant Staphylococcus aureus Isolates in Murine Models of Infection{triangledown}

David M. Rothstein,1* Ronald S. Farquhar,1,{dagger} Klari Sirokman,2,3 Karen L. Sondergaard,2,3 Charles Hazlett,2,3,{ddagger} Angelia A. Doye,2,3 Judith K. Gwathmey,2,3 Steve Mullin,1,§ John van Duzer,1 and Christopher K. Murphy1

ActivBiotics, Inc., 110 Hartwell Avenue, Lexington, Massachusetts 02421,1 Gwathmey, Inc., 763 Building E, Concord Avenue, Cambridge, Massachusetts 01238,2 Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 022153

Received 19 August 2005/ Returned for modification 31 January 2006/ Accepted 21 August 2006

Novel rifamycins (new chemical entities [NCEs]) having MICs of 0.002 to 0.03 µg/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.

* Corresponding author. Mailing address: ActivBiotics, Inc., 110 Hartwell Ave., Lexington, MA 02421. Phone: (781) 372 4822. Fax: (781) 274-9129. E-mail: drothstein{at}activbiotics.com.

{triangledown} Published ahead of print on 28 August 2006.

{dagger} Present address: Charles River Laboratories, Worcester, MA.

{ddagger} Present address: 145 Forest Street, Franklin, MA 02038.

§ Present address: Novartis Institutes for Biomedical Research, Inc., Infectious Disease, 100 Technology Sq., Cambridge, MA 02139.

Antimicrobial Agents and Chemotherapy, November 2006, p. 3658-3664, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.01087-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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