Cappelletty D M, Rybak M J
Department of Pharmacy Services, Detroit Receiving Hospital/University Health Center, Michigan 48201, USA.
Antimicrob Agents Chemother. 1996 May;40(5):1148-52. doi: 10.1128/AAC.40.5.1148.
We examined the bactericidal activities of penicillin, cefprozil, cefixime, cefaclor, and loracarbef against three clinical isolates of Streptococcus pneumoniae which were susceptible, moderately susceptible, and resistant to penicillin. An in vitro two-compartment glass infection model was used to simulate human pharmacokinetics in the presence of bacteria. Also, changes in organism susceptibility and development of resistant subpopulations were evaluated. Simulated pediatric dosage regimens and target peak concentrations in the central compartment were as follows: penicillin V-potassium, 26 mg/kg of body weight every 6 h (q6h) and 14 micrograms/ml; cefaclor, 13.4 mg/kg q8h and 16 micrograms/ml; loracarbef, 15 mg/kg q12h and 19 micrograms/ml; cefprozil, 15 mg/kg q12h and 11 micrograms/ml; and cefixime, 8mg/kg q24h and 4 micrograms/ml. Targeted half-lives of each agent were 1 h for penicillin, cefaclor, and loracarbef; 1.3 h for cefprozil; and 3.5 h for cefixime. Growth controls were performed at two different pump rates, 0.8 and 2.0 ml/min (half-lives = 3.5 and 1 h, respectively). Each isolate demonstrated autolysis at the lower rate which was attributed to a decreased supply of fresh nutrients available to the organisms in the infection compartment. Against the susceptible isolate, the time to 99.9% killing was statistically significant between penicillin V-potassium and both cefaclor and cefixime (P < 0.029). Loracarbef never achieved a 99.9% reduction in the inoculum. At 48 h penicillin, cefprozil, and cefaclor were equivalent in extent of killing. Against the intermediately resistant isolate, cefprozil was superior to all other regimens with respect to rate of killing (P < 0.013) and extent of killing at 24 h (P < 0.0003). At 48 h penicillin, cefprozil, and cefaclor were equivalent in extent of killing. All of the regimens exhibited inferior activity against this penicillin-resistant isolate. A 99.9% kill was never obtained with any of the regimens, nor was there an appreciable decrease in the colony counts. In conclusion, it appears that cefprozil, penicillin, and cefaclor are effective therapies against sensitive and even intermediately sensitive isolates of S. pneumoniae. However, none of the oral therapies appear to be of any benefit against penicillin-resistant isolates. The in vitro model may be an effective tool in evaluating other multiple-dose therapies against this fastidious organism, since the continual supply of fresh medium maintains the viability of S. pneumoniae with minimal stationary-phase autolysis.
我们检测了青霉素、头孢丙烯、头孢克肟、头孢克洛和氯碳头孢对三株临床分离的肺炎链球菌的杀菌活性，这三株菌分别对青霉素敏感、中度敏感和耐药。采用体外双室玻璃感染模型在有细菌存在的情况下模拟人体药代动力学。此外，还评估了微生物敏感性的变化和耐药亚群的形成。模拟的儿科给药方案和中央室的目标峰浓度如下：青霉素V钾，每6小时（q6h）26mg/kg体重，目标峰浓度14μg/ml；头孢克洛，每8小时13.4mg/kg，目标峰浓度16μg/ml；氯碳头孢，每12小时15mg/kg，目标峰浓度19μg/ml；头孢丙烯，每12小时15mg/kg，目标峰浓度11μg/ml；头孢克肟，每24小时8mg/kg，目标峰浓度4μg/ml。每种药物的目标半衰期分别为：青霉素、头孢克洛和氯碳头孢1小时；头孢丙烯1.3小时；头孢克肟3.5小时。生长对照在两种不同的泵速下进行，分别为0.8和2.0ml/min（半衰期分别为3.5和1小时）。每种分离株在较低泵速下均表现出自溶，这归因于感染室中生物体可获得的新鲜营养物质供应减少。对于敏感分离株，青霉素V钾与头孢克洛和头孢克肟之间达到99.9%杀灭率的时间具有统计学显著差异（P<0.029）。氯碳头孢从未使接种物减少99.9%。在48小时时，青霉素、头孢丙烯和头孢克洛的杀菌程度相当。对于中度耐药分离株，头孢丙烯在杀菌速率（P<0.013）和24小时时的杀菌程度（P<0.0003）方面优于所有其他方案。在48小时时，青霉素、头孢丙烯和头孢克洛的杀菌程度相当。所有方案对这种耐青霉素分离株的活性均较差。任何一种方案均未实现99.9%的杀灭率，菌落计数也没有明显下降。总之，头孢丙烯、青霉素和头孢克洛似乎是治疗敏感甚至中度敏感肺炎链球菌分离株的有效疗法。然而，对于耐青霉素分离株，似乎没有一种口服疗法有任何益处。体外模型可能是评估针对这种苛求菌的其他多剂量疗法的有效工具，因为新鲜培养基的持续供应可维持肺炎链球菌的活力，且静止期自溶最小。
