Development of resistance during ceftazidime and cefepime therapy in a murine peritonitis model

Abstract

Resistance emerging after ceftazidime or cefepime therapy was investigated in a peritonitis model. Mice were given a peritoneal challenge (10* cfu plus talcum) and treated by either antibiotic (50 mg/kg/dose, which produced similar antibiotic concentrations in peritoneal fluid in both cases). After one or three doses, resistance never developed in Serratia marcescens or Citrobacter freiouiii infections. After Enterobacter cloacae and Pseudomonas aeruginosa challenge, ceftazidime selected more resistance (21/36 cases) than did cefepime (1/36 cases). In mice challenged with resistant strains selected by ceftazidime therapy, cefepime (six doses) successfully treated 7/18 E. cloacae infections but 0/18 P. aeruginosa infections; ceftazidime was never effective. Neither cefepime nor ceftazidime cured mice infected with the resistant strain selected by cefepime. MICs were poor predictors of further emergence of resistance in mice inoculated with strains classified as susceptible, but antibiotic-containing agar gradients plated with a high inoculum (10* cfu) allowed better prediction. In selected clinical situations, cefepime may be preferable because it may be associated with less frequent emergence of resistance.

Comparative Study of the Effects of Ceftizoxime, Piperacillin, and Piperacillin-Tazobactam Concentrations on Antibacterial Activity and Selection of Antibiotic-Resistant Mutants of Enterobacter cloacae and Bacteroides fragilis In Vitro and In Vivo in Mixed-Infection Abscesses

“…expanded-spectrum cephalosporin therapy in comparison to treatment with a ␤-lactam-␤-lactamase inhibitor combination (19,21,23,28,32). Furthermore, the resistant mutants selected during therapy comprised a heterogeneous population of not just stably derepressed mutants, as previously reported, but also mutants with resistance mechanisms other than ␤-lactamase production (4,17,34).…”

Effect of Dosing and Dosing Frequency on the Efficacy of Ceftizoxime and the Emergence of Ceftizoxime Resistance during the Early Development of Murine Abscesses Caused by Bacteroides fragilis and Enterobacter cloacae Mixed Infection

“…Enterobacter strains can be involved in such infections (9,31). We acknowledge that the PDI values reported here were obtained from experiments using a single E. cloacae-cephalosporin combination and that this preferential selection may not be common to all Enterobacter/Enterobacteriaceae strains (25,30). Indeed, none of the dosing regimens increased the frequency with which CZX-resistant strains of B. fragilis were isolated from the abscesses (30).…”

“…While the ratio of the area under the concentrationtime curve (AUC) at 24 h to MIC of Ն100 (10,33,36) or a peak-to-MIC ratio of 8 to 10 (3, 8) may significantly reduce the emergence of resistant subpopulations during treatment with fluoroquinolones and aminoglycosides, it has been reported that these indices do not appear to play an important role in the suppression of resistance during ␤-lactam therapy (33). However, recent findings have indicated the importance of a high-dose, short-elimination half-life regimen to minimize the emergence of cephalosporin-resistant Escherichia coli strains (25).…”

“…In our quest to find dosing regimens that will prevent the emergence of resistance, perhaps higher doses given less frequently may be more beneficial (11a, 24). Alternatively, the use of antibiotics with enhanced activity against resistant mutants, for example, cefepime (17,25,30), may be more advantageous in the treatment of infections involving "high-risk" strains.…”

Regulation of Rab5 GTPase activity during Pseudomonas aeruginosa-macrophage interaction

“…Often these drugs are administered in combination with aminoglycosides as a regimen for treatment of serious pseudomonal infections. Unfortunately, for each of these agents, emergence of resistance, causing treatment failure has been described during therapy (Quinn, Dudek et al 1986;Milatovic and Braveny 1987;Pechere and Vladoianu 1992;Cometta, Baumgartner et al 1994;Fink, Snydman et al 1994). Clinically significant antibiotic resistance has arisen against virtually every antibiotic developed .…”