title: Evaluation of imipenem for prophylaxis and therapy of Yersinia pestis delivered by aerosol in a mouse model of pneumonic plague.
abstract: It has been previously shown that mice subjected to an aerosol exposure to Yersinia pestis and treated with β-lactam antibiotics after a delay of 42 h died at an accelerated rate compared to controls. It was hypothesized that endotoxin release in antibiotic-treated mice accounted for the accelerated death rate in the mice exposed to aerosol Y. pestis. Imipenem, a β-lactam antibiotic, binds to penicillin binding protein 2 with the highest affinity and produces rounded cells. The binding of imipenem causes cells to lyse quickly and thereby to release less free endotoxin. Two imipenem regimens producing fractions of time that the concentration of free, unbound drug was above the MIC (fT>MIC) of approximately 25% (6/24 h) and 40% (9.5/24 h) were evaluated. In the postexposure prophylaxis study, the 40% and 25% regimens produced 90% and 40% survivorship, respectively. In the 42-h treatment study, both regimens demonstrated a 40 to 50% survivorship at therapy cessation and some deaths thereafter, resulting in a 30% survivorship. As this was an improvement over the results with other β-lactams, a comparison of both endotoxin and cytokine levels in mice treated with imipenem and ceftazidime (a β-lactam previously demonstrated to accelerate death in mice during treatment) was performed and supported the original hypotheses; however, the levels observed in animals treated with ciprofloxacin (included as an unrelated antibiotic that is also bactericidal but should cause little lysis due to a different mode of action) were elevated and significantly (7-fold) higher than those with ceftazidime.
authors.affiliation: Institute for Innovative Therapeutics, University of Florida Research and Academic Center, Orlando, Florida, USA hsheine@ufl.edu.
authors.forename: Henry S
authors.initials: HS
authors.lastname: Heine
authors.affiliation: Institute for Innovative Therapeutics, University of Florida Research and Academic Center, Orlando, Florida, USA.
authors.forename: Arnold
authors.initials: A
authors.lastname: Louie
authors.affiliation: University of Wyoming, Laramie, Wyoming, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Adamovicz
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Ft. Detrick, Maryland, USA.
authors.forename: Kei
authors.initials: K
authors.lastname: Amemiya
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Ft. Detrick, Maryland, USA.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Fast
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Ft. Detrick, Maryland, USA.
authors.forename: Lynda
authors.initials: L
authors.lastname: Miller
authors.affiliation: Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Opal
authors.affiliation: Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: John
authors.initials: J
authors.lastname: Palardy
authors.affiliation: Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: Nicolas A
authors.initials: NA
authors.lastname: Parejo
authors.affiliation: Institute of Biomedical and Pharmaceutical Research, Nurnberg-Heroldsburg, Germany Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Duisburg-Essen, Germany.
authors.forename: Fritz
authors.initials: F
authors.lastname: Sörgel
authors.affiliation: Institute of Biomedical and Pharmaceutical Research, Nurnberg-Heroldsburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Kinzig-Schippers
authors.affiliation: Institute for Innovative Therapeutics, University of Florida Research and Academic Center, Orlando, Florida, USA.
authors.forename: George L
authors.initials: GL
authors.lastname: Drusano
mesh_terms: D000336:Aerosols; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002442:Ceftazidime / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002939:Ciprofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000032:analysis; D005260:Female; D015378:Imipenem / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010930:Plague / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D016019:Survival Analysis; D015010:Yersinia pestis / Q000187:drug effects*
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D016207:Cytokines; D004731:Endotoxins; D002939:Ciprofloxacin; D015378:Imipenem; D002442:Ceftazidime