Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Lime Walk Building, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom.
Antimicrob Agents Chemother. 2013 Jun;57(6):2451-6. doi: 10.1128/AAC.01386-12. Epub 2013 Mar 4.
An in vitro single-compartment dilutional pharmacokinetic model was used to study the pharmacodynamics of ceftaroline against Staphylococcus aureus (both methicillin-susceptible S. aureus [MSSA] and methicillin-resistant S. aureus [MRSA]). Mean serum free concentrations of ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) dosed in humans at 600 mg every 12 h (q12h) were simulated, and activities against 12 S. aureus strains (3 MSSA strains and 9 MRSA strains, 3 of which had a vancomycin-intermediate phenotype) were determined. Ceftaroline produced 2.5- to 4.0-log10-unit reductions in viable counts by 24 h with all strains and a 0.5- to 4.0-log-unit drop in counts at 96 h. The antibacterial effect could not be related to the strain MIC across the ceftaroline MIC range from 0.12 to 2.0 μg/ml. In dose-ranging studies, the cumulative percentage of a 24-h period that the free drug concentration exceeded the MIC under steady-state pharmacokinetic conditions (fT(MIC)) of 24.5% ± 8.9% was associated with a 24-h bacteriostatic effect, one of 27.8% ± 9.5% was associated with a -1-log-unit drop, and one of 32.1% ± 8.1% was associated with a -2-log-unit drop. The MSSA and MRSA strains had similar fT(MIC) values. fT(MIC) values increased with increasing duration of exposure up to 96 h. Changes in ceftaroline population analysis profiles were related to fT(MIC). fT(MIC)s of <50% were associated with growth on 4× MIC recovery plates at 96 h of drug exposure. These data support the use of ceftaroline fosamil at doses of 600 mg q12h to treat S. aureus strains with MICs of ≤ 2 μg/ml. An fT(MIC) of 25 to 30% would make a suitable pharmacodynamic index target, but fTMIC values of ≥ 50% are needed to suppress the emergence of resistance and require clinical evaluation.
采用体外单室稀释药代动力学模型研究头孢洛林对金黄色葡萄球菌（包括甲氧西林敏感金黄色葡萄球菌 [MSSA] 和甲氧西林耐药金黄色葡萄球菌 [MRSA]）的药效学。模拟了人体中每 12 小时（q12h）给予 600 毫克头孢洛林（前药头孢洛林磷酸酯的活性代谢物）的血清游离浓度，并测定了 12 株金黄色葡萄球菌菌株（3 株 MSSA 菌株和 9 株 MRSA 菌株，其中 3 株具有中间表型的万古霉素）的活性。所有菌株在 24 小时内，头孢洛林可使活菌计数减少 2.5-4.0 对数单位，在 96 小时时，计数减少 0.5-4.0 对数单位。抗菌效果与头孢洛林 MIC 范围内（0.12-2.0μg/ml）的菌株 MIC 无关。在剂量范围研究中，在稳态药代动力学条件下，游离药物浓度超过 MIC 的 24 小时累积百分比（fT（MIC））为 24.5%±8.9%，与 24 小时抑菌作用相关；27.8%±9.5%与 1 对数单位下降相关；32.1%±8.1%与 2 对数单位下降相关。MSSA 和 MRSA 菌株的 fT（MIC）值相似。fT（MIC）值随暴露时间的增加而增加，最高可达 96 小时。头孢洛林群体分析谱的变化与 fT（MIC）有关。fT（MIC）＜50%与 96 小时药物暴露时在 4×MIC 恢复平板上的生长有关。这些数据支持使用头孢洛林磷酸酯 600mg q12h 剂量治疗 MICs≤2μg/ml 的金黄色葡萄球菌菌株。fT（MIC）为 25-30%可能是合适的药效学指标靶标，但需要 fTMIC 值≥50%以抑制耐药性的出现，需要临床评价。
