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.