Sevillano David, Aguilar Lorenzo, Alou Luis, Giménez María-José, González Natalia, Torrico Martha, Cafini Fabio, Fenoll Asunción, Coronel Pilar, Prieto José
Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain.
PLoS One. 2008 Jul 23;3(7):e2717. doi: 10.1371/journal.pone.0002717.
Although protein binding is a reversible phenomenon, it is assumed that antibacterial activity is exclusively exerted by the free (unbound) fraction of antibiotics.
METHODOLOGY/PRINCIPAL FINDINGS: Activity of cefditoren, a highly protein bound 3(rd) generation cephalosporin, over 24h after an oral 400 mg cefditoren-pivoxil bid regimen was studied against six S. pneumoniae strains (penicillin/cefditoren MICs; microg/ml): S1 (0.12/0.25), S2 (0.25/0.25), S3 and S4 (0.5/0.5), S5 (1/0.5) and S6 (4/0.5). A computerized pharmacodynamic simulation with media consisting in 75% human serum and 25% broth (mean albumin concentrations = 4.85+/-0.12 g/dL) was performed. Protein binding was measured. The cumulative percentage of a 24h-period that drug concentrations exceeded the MIC for total (T > MIC) and unbound concentrations (fT > MIC), expressed as percentage of the dosing interval, were determined. Protein binding was 87.1%. Bactericidal activity (> or = 99.9% initial inocula reduction) was obtained against strains S1 and S2 at 24h (T > MIC = 77.6%, fT > MIC = 23.7%). With T > MIC of 61.6% (fT > MIC = 1.7%), reductions against S3 and S4 ranged from 90% to 97% at 12h and 24h; against S5, reduction was 45.1% at 12h and up to 85.0% at 24h; and against S6, reduction was 91.8% at 12h, but due to regrowth of 52.9% at 24h. Cefditoren physiological concentrations exerted antibacterial activity against strains exhibiting MICs of 0.25 and 0.5 microg/ml under protein binding conditions similar to those in humans.
CONCLUSIONS/SIGNIFICANCE: The results of this study suggest that, from the pharmacodynamic perspective, the presence of physiological albumin concentrations may not preclude antipneumococcal activity of highly bound cephalosporins as cefditoren.
尽管蛋白质结合是一种可逆现象，但一般认为抗生素的抗菌活性仅由游离（未结合）部分发挥。
方法/主要发现：研究了口服400mg头孢妥仑匹酯每日两次方案24小时后，高度蛋白结合的第三代头孢菌素头孢妥仑针对六种肺炎链球菌菌株（青霉素/头孢妥仑MICs；μg/ml）的活性：S1（0.12/0.25）、S2（0.25/0.25）、S3和S4（0.5/0.5）、S5（1/0.5）和S6（4/0.5）。使用由75%人血清和25%肉汤（平均白蛋白浓度 = 4.85±0.12g/dL）组成的培养基进行计算机化药效学模拟。测量蛋白质结合情况。确定了24小时期间药物浓度超过总浓度（T＞MIC）和未结合浓度（fT＞MIC）的MIC的累积百分比，以给药间隔的百分比表示。蛋白质结合率为87.1%。在24小时时对S1和S2菌株获得了杀菌活性（初始接种物减少≥99.9%）（T＞MIC = 77.6%，fT＞MIC = 23.7%）。T＞MIC为61.6%（fT＞MIC = 1.7%）时，在12小时和24小时对S3和S4的减少率为90%至97%；对S5，在12小时时减少率为45.1%，在24小时时高达85.0%；对S6，在12小时时减少率为91.8%，但在24小时时有52.9%的再生长。在与人体相似的蛋白质结合条件下，头孢妥仑的生理浓度对MIC为0.25和0.5μg/ml的菌株具有抗菌活性。
结论/意义：本研究结果表明，从药效学角度来看，生理白蛋白浓度的存在可能并不排除像头孢妥仑这样高度结合的头孢菌素的抗肺炎球菌活性。
