Fallon Renee M, Kuti Joseph L, Doern Gary V, Girotto Jennifer E, Nicolau David P
Department of Pharmacy Services, Maine Medical Center, Portland, Maine, USA.
Paediatr Drugs. 2008;10(5):329-35. doi: 10.2165/00148581-200810050-00006.
To determine the probability of oral beta-lactam regimens achieving bactericidal pharmacodynamic exposure against pathogens causing acute otitis media (AOM) given contemporary prevalence and resistance rates.
A 5000-patient Monte Carlo simulation was used to recreate steady-state concentration-time profiles for oral drug administration regimens of amoxicillin, amoxicillin/clavulanic acid, cefpodoxime, cefprozil, ceftibuten, and cefuroxime in a population of 12.5-month-old children. The percent of simulated children in whom free drug concentrations above the minimum inhibitory concentration (MIC) for 50% of the drug administration interval (50% fT>MIC) were achieved was determined; 180 middle ear fluid isolates (56 Haemophilus influenzae and 124 Streptococcus pneumoniae) collected during the 2004 Global Respiratory Antimicrobial Surveillance Project (GRASP) were used. The cumulative fraction of response (CFR) was calculated and weighted against the prevalence of organisms causing AOM extrapolated from the literature. The contribution of a 'Pollyanna phenomenon' for each organism was also incorporated to estimate clinical effectiveness.
Against S. pneumoniae isolates, amoxicillin 30 mg/kg every 8 hours (84.7%) achieved the greatest CFR followed by amoxicillin/clavulanic acid and the other amoxicillin-based regimens. Against H. influenzae isolates, cefpodoxime, ceftibuten, and amoxicillin/clavulanic acid each achieved a CFR of >90%. When weighted by the prevalence of AOM-causing pathogens, CFR was highest for cefpodoxime (87.5%), amoxicillin/clavulanic acid (85.7%), and amoxicillin 30 mg/kg every 8 hours (70.8%). The contribution of a 'Pollyanna phenomenon' increased the probability of clinical effectiveness for all agents, with amoxicillin/clavulanic acid (90.2%) and cefpodoxime (90.1%) having the highest weighted CFR.
Based on the recent epidemiologic and resistance profiles of S. pneumoniae and H. influenzae, amoxicillin/clavulanic acid (45 mg/kg every 12 hours) and cefpodoxime (5 mg/kg every 12 hours) provide the greatest likelihood of achieving optimal pharmacodynamic exposures empirically in children with AOM.
根据当代病原体流行率和耐药率，确定口服β-内酰胺类治疗方案对引起急性中耳炎（AOM）的病原体实现杀菌性药效学暴露的概率。
采用5000例患者的蒙特卡洛模拟，在12.5个月大的儿童群体中重建阿莫西林、阿莫西林/克拉维酸、头孢泊肟、头孢丙烯、头孢布烯和头孢呋辛口服给药方案的稳态浓度-时间曲线。确定模拟儿童中在50%的给药间隔（50% fT>MIC）内游离药物浓度高于最低抑菌浓度（MIC）的百分比；使用2004年全球呼吸道抗菌药物监测项目（GRASP）期间收集的180株中耳积液分离株（56株流感嗜血杆菌和124株肺炎链球菌）。计算累积反应分数（CFR），并根据从文献中推断出的引起AOM的病原体流行率进行加权。还纳入了每种病原体的“盲目乐观现象”的贡献，以估计临床有效性。
对于肺炎链球菌分离株，每8小时一次30mg/kg阿莫西林（84.7%）的CFR最高，其次是阿莫西林/克拉维酸和其他基于阿莫西林的治疗方案。对于流感嗜血杆菌分离株，头孢泊肟、头孢布烯和阿莫西林/克拉维酸的CFR均>90%。根据引起AOM的病原体流行率加权后，头孢泊肟（87.5%）、阿莫西林/克拉维酸（85.7%）和每8小时一次30mg/kg阿莫西林（70.8%）的CFR最高。“盲目乐观现象”的贡献增加了所有药物临床有效性的概率，阿莫西林/克拉维酸（90.2%）和头孢泊肟（90.1%）的加权CFR最高。
根据肺炎链球菌和流感嗜血杆菌最近的流行病学和耐药情况，阿莫西林/克拉维酸（每12小时45mg/kg）和头孢泊肟（每12小时5mg/kg）在AOM儿童中凭经验实现最佳药效学暴露的可能性最大。
