title: Comparative antibiotic dose-effect relations at several dosing intervals in murine pneumonitis and thigh-infection models.
abstract: Animal studies that compare antibiotics have used only a limited number of doses administered at intervals chosen without regard for their pharmacodynamic effects of pharmacokinetic profiles. We compared the relative efficacy and potency of three beta-lactams and two aminoglycosides in lung and thigh-infection models in neutropenic mice by defining the maximum attainable antimicrobial effect at 24 h (Emax) and the total dose required to reach 50% of maximum effect (P50) at several dosing intervals. For beta-lactams, Emaxs were similar, whereas P50s increased 10- to 50-fold with longer intervals in both models. Aminoglycosides were significantly more bactericidal in the lung than in the thigh, and dosing interval had little impact on P50s in either model. Recognizing the variable impact of dosing interval on efficacy for different classes of antibiotics is mandatory for the proper design and interpretation of comparative trials.
authors.affiliation: Medical Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.
authors.forename: J E
authors.initials: JE
authors.lastname: Leggett
authors.forename: B
authors.initials: B
authors.lastname: Fantin
authors.forename: S
authors.initials: S
authors.lastname: Ebert
authors.forename: K
authors.initials: K
authors.lastname: Totsuka
authors.forename: B
authors.initials: B
authors.lastname: Vogelman
authors.forename: W
authors.initials: W
authors.lastname: Calame
authors.forename: H
authors.initials: H
authors.lastname: Mattie
authors.forename: W A
authors.initials: WA
authors.lastname: Craig
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002437:Cefazolin / Q000627:therapeutic use; D002442:Ceftazidime / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005839:Gentamicins / Q000627:therapeutic use; D015378:Imipenem / Q000627:therapeutic use; D007710:Klebsiella Infections / Q000188:drug therapy*; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000254:growth & development*; D008168:Lung / Q000382:microbiology; D051379:Mice; D008813:Mice, Inbred ICR; D009132:Muscles / Q000382:microbiology*; D011014:Pneumonia / Q000188:drug therapy*
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D015378:Imipenem; D002442:Ceftazidime; D002437:Cefazolin