Torrico M, Aguilar L, González N, Giménez M J, Echeverría O, Cafini F, Sevillano D, Alou L, Coronel P, Prieto J
Microbiology Department, School of Medicine, University Complutense, Avda Complutense s/n, 28040, Madrid, Spain.
Antimicrob Agents Chemother. 2007 Oct;51(10):3699-706. doi: 10.1128/AAC.01530-06. Epub 2007 Jul 30.
The aim of this study was to explore bactericidal activity of total and free serum simulated concentrations after the oral administration of cefditoren (400 mg, twice daily [bid]) versus the oral administration of amoxicillin-clavulanic acid extended release formulation (2,000/125 mg bid) against Haemophilus influenzae. A computerized pharmacodynamic simulation was performed, and colony counts and beta-lactamase activity were determined over 48 h. Three strains were used: ampicillin-susceptible, beta-lactamase-negative ampicillin-resistant (BLNAR) (also resistant to amoxicillin-clavulanic acid) and beta-lactamase-positive amoxicillin-clavulanic acid-resistant (BLPACR) strains, with cefditoren MICs of < or =0.12 microg/ml and amoxicillin-clavulanic acid MICs of 2, 8, and 8 microg/ml, respectively. Against the ampicillin-susceptible and BLNAR strains, bactericidal activity (> or =3 log(10) reduction) was obtained from 6 h on with either total and free cefditoren or amoxicillin-clavulanic acid. Against the BLPACR strain, free cefditoren showed bactericidal activity from 8 h on. In amoxicillin-clavulanic acid simulations the increase in colony counts from 4 h on occurred in parallel with the increase in beta-lactamase activity for the BLPACR strain. Since both BLNAR and BLPACR strains exhibited the same MIC, this was due to the significantly lower (P < or = 0.012) amoxicillin concentrations from 4 h on in simulations with beta-lactamase positive versus negative strains, thus decreasing the time above MIC (T>MIC). From a pharmacodynamic point of view, the theoretical amoxicillin T>MIC against strains with elevated ampicillin/amoxicillin-clavulanic acid MICs should be considered with caution since the presence of beta-lactamase inactivates the antibiotic, thus rendering inaccurate theoretical calculations. The experimental bactericidal activity of cefditoren is maintained over the dosing interval regardless of the presence of a mutation in the ftsI gene or beta-lactamase production.
本研究旨在探讨口服头孢妥仑（400mg，每日两次）与口服阿莫西林 - 克拉维酸缓释制剂（2000/125mg bid）后，血清总浓度和游离浓度模拟值对流感嗜血杆菌的杀菌活性。进行了计算机化药效学模拟，并在48小时内测定菌落计数和β - 内酰胺酶活性。使用了三株菌株：氨苄西林敏感株、β - 内酰胺酶阴性氨苄西林耐药（BLNAR）株（也对阿莫西林 - 克拉维酸耐药）和β - 内酰胺酶阳性阿莫西林 - 克拉维酸耐药（BLPACR）株，头孢妥仑的MIC分别≤0.12μg/ml，阿莫西林 - 克拉维酸的MIC分别为2、8和8μg/ml。对于氨苄西林敏感株和BLNAR株，头孢妥仑总浓度和游离浓度以及阿莫西林 - 克拉维酸在6小时后均获得了杀菌活性（≥3 log₁₀减少）。对于BLPACR株，游离头孢妥仑从8小时起显示出杀菌活性。在阿莫西林 - 克拉维酸模拟中，BLPACR株从4小时起菌落计数增加与β - 内酰胺酶活性增加同时发生。由于BLNAR株和BLPACR株表现出相同的MIC，这是因为在β - 内酰胺酶阳性菌株与阴性菌株的模拟中，从4小时起阿莫西林浓度显著降低（P≤0.012），从而缩短了高于MIC的时间（T＞MIC）。从药效学角度来看，对于氨苄西林/阿莫西林 - 克拉维酸MIC升高的菌株，理论上的阿莫西林T＞MIC应谨慎考虑，因为β - 内酰胺酶的存在会使抗生素失活，从而使理论计算不准确。无论ftsI基因是否发生突变或是否产生β - 内酰胺酶，头孢妥仑在给药间隔期间均保持实验性杀菌活性。
