Role of ceftazidime dose regimen on the selection of resistant Enterobacter cloacae in the intestinal flora of rats treated for an experimental pulmonary infection.

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 beta-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 >or= 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.

Reproductive and hormonal factors in male and female colon cancer.

We analysed data from a case-control study in the Netherlands in order to investigate whether reproductive events and hormonal factors are similarly related to colon cancer risk in men and women after adjustment for dietary factors. In total, 232 colon cancer cases (102 women, 130 men) and 259 controls (123 women, 136 men) were interviewed about life style, medical conditions and usual dietary patterns, using a structured dietary history technique. In women, age at first childbirth was positively associated with colon cancer risk (odds ratio (OR) age > or = 26 vs < 26 years, 1.7; 95% confidence interval (CI), 0.9-3.3). Women with three or more children were at reduced risk compared with women with one or two children (OR, 0.6; 95% CI, 0.3-1.1). When women had had their first child after the age of 26 years, parity was observed to be important (for one or two children vs > or = three children: OR, 2.8; 95% CI, 1.1-7.0). For men, opposite but non-significant associations were found. Adjustment for dietary patterns and other risk factors did not change the estimates markedly. Of the hormonal factors, late age at menarche decreased risk (OR, 0.5; 95% CI, 0.3-0.9) while late age at natural menopause slightly increased risk. Our study provides additional support for the role of reproductive status in the aetiology of colon cancer in women, independently of dietary factors.