JAC Advance Access originally published online on February 8, 2007
Journal of Antimicrobial Chemotherapy 2007 59(3):507-516; doi:10.1093/jac/dkl529
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Role of ceftazidime dose regimen on the selection of resistant Enterobacter cloacae in the intestinal flora of rats treated for an experimental pulmonary infection
1 Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands 2 Department of Medical Microbiology & Infectious Diseases, Canisius Wilhelmina Ziekenhuis, Nijmegen, The Netherlands
Received 8 September 2006; returned 28 October 2006; revised 6 December 2006; accepted 6 December 2006
* Corresponding author. Tel: + 31-10-463-6171; Fax: + 31-10-463-3875; E-mail: w.goessens{at}erasmusmc.nl
Objectives: The effect of ceftazidime dosing increments and frequency of dosing on the selection of ceftazidime-resistant Enterobacter cloacae in the intestine was studied in rats, during treatment of a pulmonary infection caused by Klebsiella pneumoniae.
Methods: Rats with pulmonary infection (n = 10 per group) received therapy with doses of ceftazidime at 3.1 to 400 mg/kg per day at a frequency of every 6,12 or 24 h for 18 days, starting 24 h after bacterial inoculation of the lung. Emergence of resistance in intestinal E. cloacae was monitored by culturing fresh stool specimens at days 0, 8, 15, 22, 29, 36 and 43 on agar plates with (6.4 mg/L) and without ceftazidime. Pharmacodynamic indices and time within the mutant selection window (MSW) were assessed in infected rats for each regimen. Ceftazidime-resistant E. cloacae mutants were characterized by determination of the ß-lactamase activity under cefoxitin-induced and non-induced conditions.
Results: A reduction of intestinal ceftazidime-susceptible E. cloacae was observed and showed a significant correlation with the fAUC/MIC at days 8, 15 and 22 and with the fCmax on days 8, 15, 22, 29 and 36. More rats treated with 12–25 and 50–100 mg/kg per day every 6 h were found colonized with ceftazidime-resistant E. cloacae mutants than animals treated every 12 h or every 24 h. The proportion of rats colonized with ceftazidime-resistant E. cloacae mutants at days 15, 36 and 43 correlated with the time during which ceftazidime plasma concentrations were within the boundaries of the MSW. Only at day 15 was a correlation demonstrated between the fCmax and significantly fewer rats colonized with ceftazidime-resistant E. cloacae. Ceftazidime-resistant E. cloacae mutants (MIC 
128 mg/L) were characterized as stable derepressed mutants.
Conclusions: Colonization with stable derepressed ceftazidime-resistant E. cloacae mutants particularly occurred when rats were exposed to moderate doses of ceftazidime (12–25 or 50–100 mg/kg per day) administered every 6 h. Emergence of resistance was correlated with time within the MSW.
Keywords: PK/PD indices , mutation prevention concentration , mutant selection window , collateral damage
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