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Bactericidal activity, killing rate and post-antibiotic effect in the serum of patients with urinary tract infection receiving netilmicin 6 mg/kg once daily in comparison with 2 mg/kg TID

par Van Der Auwera, Philippe
Référence Journal of Drug Development, 1, SUPPL. 3, page (25-33)
Publication Publié, 1988

Article révisé par les pairs

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Résumé :

During an ongoing randomized, prospective study comparing the efficacy and safety of netilmicin given once or thrice daily for the treatment of urinary tract infections in cancer patients, serum bactericidal titers against a variety of Gram-negative bacilli including E. coli, E. cloacae, S. marcescens, K. pneumoniae and P. aeruginosa were studied. The rate of killing in serum and the duration of post-antibiotic effect (PAE) were also investigated. The following mean serum netilmicin concentrations were obtained on day 1 after 6 mg/kg as a single i.v. dose (group 1) at time, 0, 30 minutes, 1, 2 and 6 hours, respectively: 28, 21, 17, 12 and 7 mg/l; and after 2 mg/kg (group 2) at the same times: 8, 5, 5, 3 and 1.5 mg/l. Accumulation was seen on day 5 in the TID group with a 10% increase in the serum concentrations. Median serum bactericidal titers (% of the sera with a titer ≥8) in samples collected 6 hours after administration were: 8-32 (64-96%) against Enterobacteriaceae and <2 (8%) against P. aeruginosa in group 1; 2-8 (25-85%) against Enterobacteriaceae and <2 (0%) against P. aeruginosa in group 2. An excellent correlation (Spearman, p <0.001) was found between expected and measured serum bactericidal activities. The rate of killing in serum was rapid (2-3 log in 2 hours against P. aeruginosa; 3-5 log in 2 hours against the Enterobacteriaceae) and correlated with the serum concentration of netilmicin. The killing rates observed for Enterobacteriaceae were high and did not differ whether netilmicin was given OD or TID. Against P. aeruginosa and S. marcescens, the OD administration resulted in a higher killing rate than the TID administration. In Mueller-Hinton broth not supplemented with calcium and magnesium ions, the killing rate of P. aeruginosa was ≥1 log/h faster than in the supplemented medium, however, regrowth occurred after 24 hours of incubation in half of the tests whether the medium was supplemented or not. The duration of the PAE depended on the strain and the serum concentration of netilmicin. Pre-exposure of bacteria to netilmicin increased the killing by human polymorphonuclear leukocytes without affecting phagocytosis. The clinical significance of these observations remains to be adequately studied in prospective comparative clinical trials.