Cethromycin-mediated protection against the plague pathogen Yersinia pestis in a rat model of infection and comparison with levofloxacin

Jason A. Rosenzweig, Sheri M. Brackman, Michelle L. Kirtley, Jian Sha, Tatiana E. Erova, Linsey A. Yeager, Johnny Peterson, Ze Qi Xu, Ashok Chopra

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The Gram-negative plague bacterium, Yersinia pestis, has historically been regarded as one of the deadliest pathogens known to mankind, having caused three major pandemics. After being transmitted by the bite of an infected flea arthropod vector, Y. pestis can cause three forms of human plague: bubonic, septicemic, and pneumonic, with the latter two having very high mortality rates. With increased threats of bioterrorism, it is likely that a multidrug-resistant Y. pestis strain would be employed, and, as such, conventional antibiotics typically used to treat Y. pestis (e.g., streptomycin, tetracycline, and gentamicin) would be ineffective. In this study, cethromycin (a ketolide antibiotic which inhibits bacterial protein synthesis and is currently in clinical trials for respiratory tract infections) was evaluated for antiplague activity in a rat model of pneumonic infection and compared with levofloxacin, which operates via inhibition of bacterial topoisomerase and DNA gyrase. Following a respiratory challenge of 24 to 30 times the 50% lethal dose of the highly virulent Y. pestis CO92 strain, 70 mg of cethromycin per kg of body weight (orally administered twice daily 24 h postinfection for a period of 7 days) provided complete protection to animals against mortality without any toxic effects. Further, no detectable plague bacilli were cultured from infected animals' blood and spleens following cethromycin treatment. The antibiotic was most effective when administered to rats 24 h postinfection, as the animals succumbed to infection if treatment was further delayed. All cethromycin-treated survivors tolerated 2 subsequent exposures to even higher lethal Y. pestis doses without further antibiotic treatment, which was related, in part, to the development of specific antibodies to the capsular and low-calcium-response V antigens of Y. pestis. These data demonstrate that cethromycin is a potent antiplague drug that can be used to treat pneumonic plague.

Original languageEnglish (US)
Pages (from-to)5034-5042
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume55
Issue number11
DOIs
StatePublished - Nov 2011

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cethromycin
Yersinia pestis
Levofloxacin
Plague
Infection
Anti-Bacterial Agents
Arthropod Vectors
Ketolides
DNA Gyrase
Bioterrorism
Siphonaptera
Bacterial DNA
Bacterial Proteins
Mortality
Poisons
Lethal Dose 50
Pandemics
Streptomycin
Bites and Stings
Gentamicins

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Cethromycin-mediated protection against the plague pathogen Yersinia pestis in a rat model of infection and comparison with levofloxacin. / Rosenzweig, Jason A.; Brackman, Sheri M.; Kirtley, Michelle L.; Sha, Jian; Erova, Tatiana E.; Yeager, Linsey A.; Peterson, Johnny; Xu, Ze Qi; Chopra, Ashok.

In: Antimicrobial Agents and Chemotherapy, Vol. 55, No. 11, 11.2011, p. 5034-5042.

Research output: Contribution to journalArticle

Rosenzweig, Jason A. ; Brackman, Sheri M. ; Kirtley, Michelle L. ; Sha, Jian ; Erova, Tatiana E. ; Yeager, Linsey A. ; Peterson, Johnny ; Xu, Ze Qi ; Chopra, Ashok. / Cethromycin-mediated protection against the plague pathogen Yersinia pestis in a rat model of infection and comparison with levofloxacin. In: Antimicrobial Agents and Chemotherapy. 2011 ; Vol. 55, No. 11. pp. 5034-5042.
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