title: Comparison of ampicillin-sulbactam regimens simulating 1.5- and 3.0-gram doses to humans in treatment of Escherichia coli bacteremia in mice.
abstract: A mouse model of bacteremia was used to compare the efficacies of 1.5- and 3.0-g intravenous doses of ampicillin-sulbactam. Seven strains of Escherichia coli producing various levels of TEM-1 beta-lactamase were used as the challenge isolates. These strains included six clinical isolates (MICs from 2/1 micrograms/ml [with 2 and 1 microgram/ml being the respective concentrations of ampicillin and sulbactam] to 32/16 micrograms/ml) with similar degrees of virulence in mice and a laboratory genetic transformant (E. coli AFE) which hyperproduces TEM-1 (MIC = 128/64 micrograms/ml). Human pharmacokinetics were simulated by injecting mice subcutaneously twice (1 h apart) with ampicillin-sulbactam at concentrations of 40 mg/kg of body weight (1.5 g) and 80 mg/kg (3.0 g). Against two clinical isolates for which ampicillin-sulbactam MICs were < or = 8/4 micrograms/ml, no difference was observed in either the rate or level of killing between the two doses, and both doses were 100% protective against lethal infection. Against the four clinical isolates for which ampicillin-sulbactam MICs were between 16/8 and 32/16 micrograms/ml, a slight delay in killing was noted with three of the strains. This delay was followed by a rapid 2- to 3-log drop in the level of bacteremia, and both doses of ampicillin-sulbactam were 100% protective against lethal septicemia. With strain AFE, no killing was observed with the 40-mg/kg dose compared with a 2-log killing with the 80-mg/kg dose. This difference in killing correlated with a decreased protective efficacy of the 40-mg/kg dose. These data suggest that the 1.5-g preparation of ampicillin-sulbactam is as effective as the 3.0-g dose in the treatment of experimentally induced E. coli bacteremia, as long as ampicillin-sulbactam MICs are 32/16 micrograms/ml or less.
authors.affiliation: Department of Medical Microbiology, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Lister
authors.forename: C C
authors.initials: CC
authors.lastname: Sanders
mesh_terms: D000667:Ampicillin / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D016470:Bacteremia / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination / Q000627:therapeutic use*; D004927:Escherichia coli Infections / Q000188:drug therapy*; D008297:Male; D051379:Mice; D013407:Sulbactam / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: C035444:sultamicillin; D000667:Ampicillin; D013407:Sulbactam