Comparative dose-effect relations at several dosing intervals for beta-lactam, aminoglycoside and quinolone antibiotics against gram-negative bacilli in murine thigh-infection and pneumonitis models.
Relatively few animal studies have investigated the influence of dosing regimens on the efficacy of antibiotics possessing different pharmacodynamic characteristics. We evaluated the impact of dosing interval on the relative efficacy and potency of beta-lactams, aminoglycosides, and ciprofloxacin against Pseudomonas aeruginosa. Escherichia coli, and Klebsiella pneumoniae in murine pneumonitis and thigh-infection models. We used a sigmoid dose-response model to determine the maximal bactericidal effect at 24 hours (Emax) and the total dose required to achieve 50% of Emax (P50) at several dosing intervals. P50S (a measure of drug potency, in mg/kg/day) for beta-lactams increased 14- to 73-fold with longer intervals in both models. Dosing interval had little impact on P50S for aminoglycosides or ciprofloxacin. Emax varied among drugs but displayed no dependence on dosing interval. This method of analysis allows comparison of efficacy and dependence of potency on dosing regimen among different classes of antibiotics.
Leggett
J E
JE
Department of Medicine, Wm. S. Middleton Veterans Hospital, Madison, Wisconsin.
Ebert
S
S
Fantin
B
B
Craig
W A
WA
D042462:4-Quinolones; D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004755:Enterobacteriaceae / Q000187:drug effects; D004756:Enterobacteriaceae Infections / Q000188:drug therapy; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D016018:Least-Squares Analysis; D051379:Mice; D008813:Mice, Inbred ICR; D011014:Pneumonia / Q000188:drug therapy; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013047:Specific Pathogen-Free Organisms; D047090:beta-Lactams
D042462:4-Quinolones; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D047090:beta-Lactams