Azithromycin Dose To Maximize Efficacy and Suppress Acquired Drug Resistance in Pulmonary Mycobacterium avium Disease
Azithromycin Dose To Maximize Efficacy and Suppress Acquired Drug Resistance in Pulmonary Mycobacterium avium Disease
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DOI：
10.1128/aac.02854-15
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发表时间：
2016-04-01
影响因子：
4.9
通讯作者：
Gumbo, Tawanda
中科院分区：
文献类型：
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作者：
Deshpande, Devyani;Pasipanodya, Jotam G.;Gumbo, Tawanda
鸟分枝杆菌复合体现在是美国慢性肺炎的主要分枝杆菌病因。大环内酯类和乙胺丁醇是治疗肺部疾病的主要药物。然而，治疗结果仍然很差，空洞性疾病的微生物治愈率为4%。阿奇霉素的治疗剂量大多是从用于治疗其他细菌性肺炎的剂量中借用的;没有正式的肺支原体剂量反应研究。禽流感和最佳剂量尚不清楚。我们利用群体药代动力学和药代动力学/药效学衍生的阿奇霉素暴露与最佳微生物杀灭或耐药性抑制相关，对每日0.5至10 g阿奇霉素剂量的10，000例患者进行剂量效应研究的Monte Carlo模拟。目前推荐的剂量500 mg/天在0%的患者中达到了目标暴露量。仅通过每天8 g的极高剂量，分别在87%和54%的患者中实现了与最佳杀灭和耐药性抑制相关的暴露。阿奇霉素敏感性断点是MIC为16 mg/L，高于该断点，患者在8 g/天的极高剂量下治疗失败，这表明临界浓度为32 mg/L，比目前使用的敏感性断点256 mg/L低8倍。如果使用每天500毫克的标准剂量，那么临界浓度将下降到2毫克/升，比256毫克/升低128倍。将耐药分离株误分类为敏感株可以解释当前剂量的高失败率。
Mycobacterium avium complex is now the leading mycobacterial cause of chronic pneumonia in the United States. Macrolides and ethambutol form the backbone of the regimen used in the treatment of pulmonary disease. However, therapy outcomes remain poor, with microbial cure rates of 4% in cavitary disease. The treatment dose of azithromycin has mostly been borrowed from that used to treat other bacterial pneumonias; there are no formal dose-response studies in pulmonary M. avium disease and the optimal dose is unclear. We utilized population pharmacokinetics and pharmacokinetics/pharmacodynamics-derived azithromycin exposures associated with optimal microbial kill or resistance suppression to perform 10,000 patient Monte Carlo simulations of dose effect studies for daily azithromycin doses of 0.5 to 10 g. The currently recommended dose of 500 mg per day achieved the target exposures in 0% of patients. Exposures associated with optimal kill and resistance suppression were achieved in 87 and 54% of patients, respectively, only by the very high dose of 8 g per day. The azithromycin susceptibility breakpoint above which patients failed therapy on the very high doses of 8 g per day was an MIC of 16 mg/liter, suggesting a critical concentration of 32 mg/liter, which is 8-fold lower than the currently used susceptibility breakpoint of 256 mg/liter. If the standard dose of 500 mg a day were used, then the critical concentration would fall to 2 mg/liter, 128-fold lower than 256 mg/liter. The misclassification of resistant isolates as susceptible could explain the high failure rates of current doses.