title: Comparison of the effect of cefepime with four cephalosporins against pneumococci with various susceptibilities to penicillin, in vitro and in the mouse peritonitis model.
abstract: The purpose of this study was to compare the effect, both in vitro and in vivo, of cefepime with those of four other cephalosporins, namely ceftriaxone, cefotaxime, cefuroxime and cephalothin, against penicillin-resistant pneumococci. One hundred pneumococcal strains, 31 penicillin-susceptible, 30 penicillin-intermediate-resistant and 39 penicillin-resistant pneumococci, were used in MIC studies. Time-kill experiments were carried out for four strains. In the mouse peritonitis model, the dose that gave protection to 50% of mice challenged with a lethal dose of pneumococci (ED50) was determined for three pneumococci and five cephalosporins. The MICs of all five cephalosporins and penicillin correlated significantly with each other. In vitro, the most potent cephalosporins against pneumococci were cefotaxime, ceftriaxone and cefepime, followed by cefuroxime and cephalothin. In time-kill experiments, carried out for four pneumococci, no differences were found in the killing effect of these five cephalosporins in relation to MICs. In the mouse peritonitis model, there was no significant correlation between log(MIC) and log(ED50) for the five cephalosporins against three pneumococci (Spearman's rho = 0.39, P = 0.16). However, if the values for cefepime against the three pneumococci were excluded, there was a significant correlation for the remaining four cephalosporins (Spearman's rho = 0.62, P = 0.04). For all three pneumococci, the ED50s of cefepime were lower than expected from the MICs. It was not possible to explain this beneficial difference in the effect of cefepime in terms of in-vitro bactericidal activities, serum protein binding or pharmacodynamic parameters.
authors.affiliation: Department of Research and Development, Statens Serum Institut, Copenhagen-S, Denmark.
authors.forename: J D
authors.initials: JD
authors.lastname: Knudsen
authors.forename: K
authors.initials: K
authors.lastname: Fuursted
authors.forename: N
authors.initials: N
authors.lastname: Frimodt-Møller
authors.forename: F
authors.initials: F
authors.lastname: Espersen
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D000077723:Cefepime; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D051379:Mice; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D010403:Penicillin Resistance / Q000502:physiology*; D010538:Peritonitis / Q000188:drug therapy* / Q000382:microbiology*; D011008:Pneumococcal Infections / Q000188:drug therapy* / Q000382:microbiology*; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D013997:Time Factors
chemical_list: D001798:Blood Proteins; D002511:Cephalosporins; D000077723:Cefepime