Goessens W H F, Mouton J W, ten Kate M T, Bijl A J, Ott A, Bakker-Woudenberg I A J M
Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
J Antimicrob Chemother. 2007 Mar;59(3):507-16. doi: 10.1093/jac/dkl529. Epub 2007 Feb 8.
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.
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 beta-lactamase activity under cefoxitin-induced and non-induced conditions.
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 >or= 128 mg/L) were characterized as stable derepressed mutants.
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.
在大鼠肺炎克雷伯菌引起的肺部感染治疗期间，研究头孢他啶剂量增加和给药频率对肠道中耐头孢他啶阴沟肠杆菌选择的影响。
肺部感染大鼠（每组10只）在肺部细菌接种24小时后开始接受治疗，给予头孢他啶剂量为每天3.1至400mg/kg，给药频率为每6、12或24小时一次，持续18天。通过在含（6.4mg/L）和不含头孢他啶的琼脂平板上培养新鲜粪便标本，在第0、8、15、22、29、36和43天监测肠道阴沟肠杆菌耐药性的出现。评估每种给药方案感染大鼠的药效学指标和突变选择窗（MSW）内的时间。通过在头孢西丁诱导和非诱导条件下测定β-内酰胺酶活性来鉴定耐头孢他啶阴沟肠杆菌突变体。
观察到肠道中对头孢他啶敏感的阴沟肠杆菌减少，并且在第8、15和22天与fAUC/MIC以及在第8、15、22、29和36天与fCmax呈显著相关。与每12小时或每24小时给药的动物相比，更多每天每6小时接受12 - 25mg/kg和50 - 100mg/kg头孢他啶治疗的大鼠被耐头孢他啶阴沟肠杆菌突变体定植。在第15、36和43天，被耐头孢他啶阴沟肠杆菌突变体定植的大鼠比例与头孢他啶血浆浓度在MSW范围内的时间相关。仅在第15天，fCmax与被耐头孢他啶阴沟肠杆菌定植的大鼠显著减少之间存在相关性。耐头孢他啶阴沟肠杆菌突变体（MIC≥128mg/L）被鉴定为稳定的去阻遏突变体。
当大鼠每6小时接受中等剂量（每天12 - 25或50 - 100mg/kg）头孢他啶治疗时，尤其会出现被稳定的去阻遏耐头孢他啶阴沟肠杆菌突变体定植的情况。耐药性的出现与MSW内的时间相关。
