Freie Universitaet Berlin, Institute of Pharmacy, Department of Clinical Pharmacy and Biochemistry, Berlin, Germany.
Graduate Research Training Program PharMetrX, Berlin/Potsdam, Germany.
Antimicrob Agents Chemother. 2022 Jun 21;66(6):e0230221. doi: 10.1128/aac.02302-21. Epub 2022 May 23.
The objectives of this study were the identification in (morbidly) obese and nonobese patients of (i) the most appropriate body size descriptor for fosfomycin dose adjustments and (ii) adequacy of the currently employed dosing regimens. Plasma and target site (interstitial fluid of subcutaneous adipose tissue) concentrations after fosfomycin administration (8 g) to 30 surgery patients (15 obese/15 nonobese) were obtained from a prospective clinical trial. After characterization of plasma and microdialysis-derived target site pharmacokinetics via population analysis, short-term infusions of fosfomycin 3 to 4 times daily were simulated. The adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target attainment (PTA) analysis based on the unbound drug-related targets of an %T (the fraction of time that unbound fosfomycin concentrations exceed the MIC during 24 h) of 70 and an AUC/MIC (the area under the concentration-time curve from 0 to 24 h for the unbound fraction of fosfomycin relative to the MIC) of 40.8 to 83.3. Lean body weight, fat mass, and creatinine clearance calculated via adjusted body weight (ABW) (CLCR) of all patients (body mass index [BMI] = 20.1 to 52.0 kg/m) explained a considerable proportion of between-patient pharmacokinetic variability (up to 31.0% relative reduction). The steady-state unbound target site/plasma concentration ratio was 26.3% lower in (morbidly) obese than nonobese patients. For infections with fosfomycin-susceptible pathogens (MIC ≤ 16 mg/L), intermittent "high-dosage" intravenous (i.v.) fosfomycin (8 g, three times daily) was sufficient to treat patients with a CLCR of <130 mL/min, irrespective of the pharmacokinetic/pharmacodynamic indices considered. For infections by Pseudomonas aeruginosa with a MIC of 32 mg/L, when the index AUC/MIC is applied, fosfomycin might represent a promising treatment option in obese and nonobese patients, especially in combination therapy to complement β-lactams, in which carbapenem-resistant P. aeruginosa is critical. In conclusion, fosfomycin showed excellent target site penetration in obese and nonobese patients. Dosing should be guided by renal function rather than obesity status. (This study has been registered in the EU Clinical Trials Register under EudraCT no. 2012-004383-22.).
(i) 确定最适合调整磷霉素剂量的身体大小描述符；(ii) 评估目前使用的给药方案是否充分。从一项前瞻性临床试验中获得了 30 名手术患者（15 名肥胖/15 名非肥胖）接受磷霉素（8 克）给药后的血浆和靶位（皮下脂肪组织间质液）浓度。通过群体分析对血浆和微透析衍生的靶位药代动力学进行表征后，模拟了每日 3 至 4 次短时间输注磷霉素。通过基于游离药物相关目标的药代动力学/药效学目标达到率（PTA）分析评估治疗的充分性，该目标为 %T（24 小时内游离磷霉素浓度超过 MIC 的时间分数）的 70 和 AUC/MIC（游离磷霉素的浓度-时间曲线下面积相对于 MIC 为 40.8 至 83.3）。所有患者（体重指数 [BMI]为 20.1 至 52.0 kg/m）的瘦体重、脂肪量和肌酐清除率通过调整体重（ABW）（CLCR）计算，解释了患者间药代动力学变异性的相当大比例（相对减少高达 31.0%）。与非肥胖患者相比，肥胖（病态肥胖）患者的稳态游离靶位/血浆浓度比降低了 26.3%。对于对磷霉素敏感的病原体（MIC≤16mg/L）引起的感染，间歇性“高剂量”静脉（i.v.）磷霉素（8 克，每日 3 次）足以治疗 CLCR<130 mL/min 的患者，无论考虑何种药代动力学/药效学指数。对于 MIC 为 32mg/L 的铜绿假单胞菌感染，当应用 AUC/MIC 指数时，磷霉素可能成为肥胖和非肥胖患者的一种有前途的治疗选择，尤其是在与β-内酰胺联合治疗中，其中耐碳青霉烯类铜绿假单胞菌是关键。总之，磷霉素在肥胖和非肥胖患者中显示出极好的靶位穿透性。应根据肾功能而不是肥胖状况来指导剂量。（本研究已在欧盟临床试验注册中心注册，注册号为 EudraCT no. 2012-004383-22。）
