Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
J Antimicrob Chemother. 2013 Mar;68(3):648-58. doi: 10.1093/jac/dks442. Epub 2012 Nov 27.
Ceftaroline fosamil is approved for treatment of acute bacterial skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus (MRSA). We examined the activity of its active metabolite (ceftaroline) against intracellular forms of S. aureus in comparison with vancomycin, daptomycin and linezolid.
Two methicillin-susceptible S. aureus (MSSA) and 11 MRSA strains with ceftaroline MICs from 0.125 to 2 mg/L [two strains vancomycin- and one strain linezolid-resistant (EUCAST interpretative criteria); VISA and cfr+] were investigated. The activity was measured in broth and after phagocytosis by THP-1 monocytes in concentration-dependent experiments (24 h of incubation) to determine: (i) relative potencies (EC(50)) and static concentrations (C(s)) (mg/L and × MIC); and (ii) relative activities at human C(max) (E(C)(max)) and maximal relative efficacies (E(max)) (change in log(10) cfu compared with initial inoculum). Ceftaroline stability and cellular accumulation (at 24 h) were measured by mass spectrometry.
Ceftaroline showed similar activities in broth and in monocytes compared with vancomycin, daptomycin and linezolid, with no impact of resistance mechanisms to vancomycin or linezolid. For all four antibiotics, intracellular E(C)(max) and E(max) were considerably lower than in broth (∼0.5 log(10) versus 4-5 log(10) cfu decrease), but the EC(50) and C(s) showed comparatively little change (all values between ∼0.3 and ∼6× MIC). The mean cellular to extracellular ceftaroline concentration ratios (20 mg/L; 24 h) were 0.66 ± 0.05 and 0.90 ± 0.36 in uninfected and infected cells, respectively.
In vitro, ceftaroline controls the growth of intracellular MRSA to an extent similar to that of vancomycin, linezolid and daptomycin for strains with a ceftaroline MIC ≤ 2 mg/L.
头孢洛林酯氨丁三醇已获批准用于治疗耐甲氧西林金黄色葡萄球菌（MRSA）引起的急性细菌性皮肤和皮肤结构感染。我们研究了其活性代谢物（头孢洛林）对金黄色葡萄球菌细胞内形式的作用，并与万古霉素、达托霉素和利奈唑胺进行了比较。
我们研究了 2 株甲氧西林敏感金黄色葡萄球菌（MSSA）和 11 株头孢洛林 MIC 为 0.125 至 2mg/L 的 MRSA 菌株[2 株万古霉素耐药和 1 株利奈唑胺耐药（EUCAST 解释标准）；VISA 和 cfr+]。在浓度依赖性实验（孵育 24 小时）中，通过肉汤和 THP-1 单核细胞吞噬作用来测量活性，以确定：（i）相对效力（EC50）和静态浓度（C（s））（mg/L 和×MIC）；以及（ii）在人 C（max）（E（C）（max））和最大相对功效（E（max））时的相对活性（与初始接种物相比的 log10cfu 变化）。通过质谱法测量头孢洛林的稳定性和细胞内积累（24 小时）。
与万古霉素、达托霉素和利奈唑胺相比，头孢洛林在肉汤和单核细胞中的活性相似，对万古霉素或利奈唑胺的耐药机制没有影响。对于所有四种抗生素，细胞内 E（C）（max）和 E（max）均明显低于肉汤（约 0.5log10 与 4-5log10cfu 减少），但 EC50 和 C（s）变化不大（所有值在约 0.3 至约 6×MIC 之间）。20mg/L（24 小时）时，未感染和感染细胞中外头孢洛林的细胞内/细胞外浓度比分别为 0.66±0.05 和 0.90±0.36。
在体外，对于头孢洛林 MIC≤2mg/L 的菌株，头孢洛林控制细胞内 MRSA 生长的程度与万古霉素、利奈唑胺和达托霉素相似。
