Eagye Kathryn J, Kuti Joseph L, Dowzicky Michael, Nicolau David P
Center for Anti-In fective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
Wyeth Research, Collegeville, Pennsylvania, USA.
Clin Ther. 2007 May;29(5):889-899. doi: 10.1016/j.clinthera.2007.05.018.
Inappropriate antibiotic therapy (ie, the selection of an empiric agent without activity against the responsible pathogen) of secondary peritonitis may result in poor patient outcomes. The selection of an appropriate agent can be challenging because of the emerging resistance of target organisms to commonly prescribed antibiotics.
The aim of this study was to perform a pharmacodynamic analysis, using recent global surveillance data, of commonly prescribed antibiotic agents and a newer agent, tigecycline, indicated in 2005 for the treatment of complicated intra-abdominal infections, to determine their probability for achieving microbiologic success against aerobic bacteria associated with secondary peritonitis.
A 2-compartment model was constructed using pharmacokinetic data from critically ill patients and global surveillance data on MIC distributions for microorganisms encountered in secondary peritonitis. A Monte Carlo simulation of the modeled data was performed to determine drug-appropriate pharmacodynamic end points, including free-drug time above the MIC, steady-state concentration above the MIC, and AUC/MIC ratios. A cumulative fraction of response (CFR) against aerobic bacteria involved in secondary peritonitis was calculated for cefepime, ceftazidime, ceftriaxone, imipenem, levofloxacin, pip eracillin/tazobactam, and tigecycline. A CFR > or =90% was considered microbiologic success. The following treatment regimens, administered as 30-minute N infusions, were examined: cefepime 1 and 2 g q12h, ceftazidime 1 and 2 g q8h, ceftriaxone 1 and 2 g q24h, imipenem 500 mg q6h, levofloxacin 750 mg q24h, pip eracillin/tazobactam 3.375 g q6h, and tigecycline 50 mg q12h, after a loading dose of 100 mg.
A CFR > or =90% against nonenterococcal bacteria was predicted for imipenem 500 mg q6h (96.8%), cefepime 2 and 1 g q12h (95.3% and 92.4%, respectively), ceftazidime 2 g q8h (94.2%), and piperacillin/tazobactam 3.375 g q6h (91.2%). A CFR of 84.5% was predicted for tigecycline 50 mg q12h. Ceftriaxone and levofloxacin were predicted to have a CFR <80%. When enterococci were included in the model, the predicted CFRs for imipenem, piperacillin/tazobactam, and tigecycline were 93.4%, 88.4%, and 86.7%, respectively.
: MIC distribution and pathogen prevalence strongly influence the likelihood of microbiological success in secondary peritonitis; therefore, decisions regarding empiric therapy should consider local epidemiology. Using current global data, the following regimens are adequate choices if Enterococcus is not targeted: Combination therapy (with metronidazole) using cefepime 1 g or 2 g q12h, or ceftazidime 2 g q8h; or monotherapy with imipenem 500 mg q6h or piperacillin-tazobactam 3.375 g q6h. When Enterococcus is included in the epidemiologic mix, imipenem, piperacillin/tazobactam, and tigecycline all appear to be viable monotherapeutic choices.
继发性腹膜炎的不恰当抗生素治疗（即选择对致病病原体无活性的经验性用药）可能导致患者预后不良。由于目标微生物对常用抗生素的耐药性不断出现，选择合适的药物具有挑战性。
本研究旨在利用近期全球监测数据，对常用抗生素和2005年被批准用于治疗复杂性腹腔内感染的新型药物替加环素进行药效学分析，以确定它们对与继发性腹膜炎相关的需氧菌实现微生物学治愈的可能性。
利用重症患者的药代动力学数据和继发性腹膜炎中所遇到微生物的全球监测MIC分布数据构建二室模型。对模拟数据进行蒙特卡洛模拟，以确定合适的药效学终点，包括高于MIC的游离药物时间、高于MIC的稳态浓度以及AUC/MIC比值。计算头孢吡肟、头孢他啶、头孢曲松、亚胺培南、左氧氟沙星、哌拉西林/他唑巴坦和替加环素针对继发性腹膜炎中需氧菌的累积反应分数（CFR）。CFR≥90%被视为微生物学治愈。研究了以下以30分钟静脉输注给药的治疗方案：头孢吡肟1克和2克，每12小时一次；头孢他啶1克和2克，每8小时一次；头孢曲松1克和2克，每24小时一次；亚胺培南500毫克，每6小时一次；左氧氟沙星750毫克，每24小时一次；哌拉西林/他唑巴坦3.375克，每6小时一次；替加环素50毫克，每12小时一次，负荷剂量为10毫克。
预测亚胺培南500毫克每6小时一次（96.8%）、头孢吡肟2克和1克每12小时一次（分别为95.3%和92.4%）、头孢他啶2克每8小时一次（94.2%）以及哌拉西林/他唑巴坦3.375克每6小时一次（91.2%）对非肠球菌的CFR≥90%。预测替加环素50毫克每12小时一次的CFR为84.5%。预测头孢曲松和左氧氟沙星的CFR<80%。当模型中纳入肠球菌时，预测亚胺培南、哌拉西林/他唑巴坦和替加环素的CFR分别为93.4%、88.4%和86.7%。
MIC分布和病原体流行情况强烈影响继发性腹膜炎微生物学治愈的可能性；因此，经验性治疗的决策应考虑当地的流行病学情况。根据当前全球数据，如果不将肠球菌作为目标，以下方案是合适的选择：联合治疗（联合甲硝唑）使用头孢吡肟1克或2克每12小时一次或者头孢他啶2克每8小时一次；或者亚胺培南500毫克每6小时一次或哌拉西林 - 他唑巴坦3.375克每6小时一次进行单药治疗。当流行病学组合中包括肠球菌时，亚胺培南、哌拉西林/他唑巴坦和替加环素似乎都是可行的单药治疗选择。
