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 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...

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Main Authors: Rothstein, David M. , Farquhar, Ronald S., Sirokman, Klari, Sondergaard, Karen L., Hazlett, Charles, Doye, Angelia A., Gwathmey, Judith K., Mullin, Steve, van Duzer, John, Murphy, Christopher K.
Format: Artigo
Sprog:English
Udgivet: American Society for Microbiology 2006
Fag:
Experimental Therapeutics
Online adgang:https://ncbi.nlm.nih.gov/pmc/articles/PMC1635239/
https://ncbi.nlm.nih.gov/pubmed/16940074
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1128/AAC.01087-05
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spelling pubmed-16352392007-03-01 Efficacy of Novel Rifamycin Derivatives against Rifamycin-Sensitive and -Resistant Staphylococcus aureus Isolates in Murine Models of Infection Rothstein, David M.  Farquhar, Ronald S. Sirokman, Klari Sondergaard, Karen L. Hazlett, Charles Doye, Angelia A. Gwathmey, Judith K. Mullin, Steve van Duzer, John Murphy, Christopher K. Antimicrob Agents Chemother Experimental Therapeutics 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 (ED(50)) 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 ED(50)s in the range of 0.015 to 0.13 mg/kg, i.e., lower or equivalent to the oral ED(50)s 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. American Society for Microbiology 2006-11 2006-08-28 /pmc/articles/PMC1635239/ /pubmed/16940074 http://dx.doi.org/10.1128/AAC.01087-05 Text en Copyright © 2006, American Society for Microbiology
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Experimental Therapeutics
spellingShingle Experimental Therapeutics
Rothstein, David M. 
Farquhar, Ronald S.
Sirokman, Klari
Sondergaard, Karen L.
Hazlett, Charles
Doye, Angelia A.
Gwathmey, Judith K.
Mullin, Steve
van Duzer, John
Murphy, Christopher K.
Efficacy of Novel Rifamycin Derivatives against Rifamycin-Sensitive and -Resistant Staphylococcus aureus Isolates in Murine Models of Infection
description 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 (ED(50)) 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 ED(50)s in the range of 0.015 to 0.13 mg/kg, i.e., lower or equivalent to the oral ED(50)s 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.
author Rothstein, David M. 
Farquhar, Ronald S.
Sirokman, Klari
Sondergaard, Karen L.
Hazlett, Charles
Doye, Angelia A.
Gwathmey, Judith K.
Mullin, Steve
van Duzer, John
Murphy, Christopher K.
author_facet Rothstein, David M. 
Farquhar, Ronald S.
Sirokman, Klari
Sondergaard, Karen L.
Hazlett, Charles
Doye, Angelia A.
Gwathmey, Judith K.
Mullin, Steve
van Duzer, John
Murphy, Christopher K.
author_sort Rothstein, David M. 
title Efficacy of Novel Rifamycin Derivatives against Rifamycin-Sensitive and -Resistant Staphylococcus aureus Isolates in Murine Models of Infection
title_short Efficacy of Novel Rifamycin Derivatives against Rifamycin-Sensitive and -Resistant Staphylococcus aureus Isolates in Murine Models of Infection
title_full Efficacy of Novel Rifamycin Derivatives against Rifamycin-Sensitive and -Resistant Staphylococcus aureus Isolates in Murine Models of Infection
title_fullStr Efficacy of Novel Rifamycin Derivatives against Rifamycin-Sensitive and -Resistant Staphylococcus aureus Isolates in Murine Models of Infection
title_full_unstemmed Efficacy of Novel Rifamycin Derivatives against Rifamycin-Sensitive and -Resistant Staphylococcus aureus Isolates in Murine Models of Infection
title_sort efficacy of novel rifamycin derivatives against rifamycin-sensitive and -resistant staphylococcus aureus isolates in murine models of infection
publisher American Society for Microbiology
publisher_facet American Society for Microbiology
publishDate 2006
url https://ncbi.nlm.nih.gov/pmc/articles/PMC1635239/
https://ncbi.nlm.nih.gov/pubmed/16940074
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1128/AAC.01087-05
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