Noreddin Ayman M, Roberts Danielle, Nichol Kim, Wierzbowski Aleksandra, Hoban Daryl J, Zhanel George G
Department of Medical Microbiology, Faculty of Medicine, University of Manitoba. Departments of Clinical Microbiology. Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada.
Antimicrob Agents Chemother. 2002 Dec;46(12):4029-34. doi: 10.1128/AAC.46.12.4029-4034.2002.
The association between macrolide resistance mechanisms and clinical outcomes remains understudied. The present study, using an in vitro pharmacodynamic model, assessed clarithromycin (CLR) activity against mef(A)-positive and erm(B)-negative Streptococcus pneumoniae isolates by simulating free-drug concentrations in serum and both total (protein-bound and free) and free drug in epithelial lining fluid (ELF). Five mef(A)-positive and erm(B)-negative strains, one mef(A)-negative and erm(B)-positive strain, and a control [mef(A)-negative and erm(B)-negative] strain of S. pneumoniae were tested. CLR was modeled using a one-compartment model, simulating a dosage of 500 mg, per os, twice a day (in serum, free-drug C(p) maximum of 2 micro g/ml, t(1/2) of 6 h; in ELF, C(ELF(total)) maximum of 35 micro g/ml, t(1/2) of 6 h; C(ELF(free)) maximum of 14 micro g/ml, t(1/2) of 6 h). Starting inocula were 10(6) CFU/ml in Mueller-Hinton broth with 2% lysed horse blood. With sampling at 0, 4, 8, 12, 20, and 24 h, the extent of bacterial killing was assessed. Achieving CLR T/MIC values of > or =90% (AUC(0-24)/MIC ratio, > or =61) resulted in bacterial eradication, while T>MIC values of 40 to 56% (AUC(0-24)/MIC ratios of > or =30.5 to 38) resulted in a 1.2 to 2.0 log(10) CFU/ml decrease at 24 h compared to that for the initial inoculum. CLR T/MIC values of < or =8% (AUC(0-24)/MIC ratio, < or =17.3) resulted in a static effect or bacterial regrowth. The high drug concentrations in ELF that were obtained clinically with CLR may explain the lack of clinical failures with mef(A)-producing S. pneumoniae strains, with MICs up to 8 micro g/ml. However, mef(A) isolates for which MICs are > or =16 micro g/ml along with erm(B) may result in bacteriological failures.
大环内酯类耐药机制与临床结局之间的关联仍未得到充分研究。本研究使用体外药效学模型，通过模拟血清中的游离药物浓度以及上皮衬液（ELF）中的总药物（蛋白结合型和游离型）和游离药物浓度，评估了克拉霉素（CLR）对携带mef(A)且erm(B)阴性的肺炎链球菌分离株的活性。对5株携带mef(A)且erm(B)阴性的菌株、1株mef(A)阴性且erm(B)阳性的菌株以及1株对照菌株（mef(A)阴性且erm(B)阴性）的肺炎链球菌进行了测试。使用单室模型对CLR进行建模，模拟口服剂量为500 mg，每日两次（在血清中，游离药物C(p)最大值为2 μg/ml，t(1/2)为6小时；在ELF中，C(ELF(total))最大值为35 μg/ml，t(1/2)为6小时；C(ELF(free))最大值为14 μg/ml，t(1/2)为6小时）。起始接种物浓度为在含2%裂解马血的Mueller-Hinton肉汤中10(6) CFU/ml。在0、4、8、12、20和24小时进行采样，评估细菌杀灭程度。CLR的T/MIC值≥90%（AUC(0 - 24)/MIC比值≥61）可导致细菌根除，而T>MIC值为40%至56%（AUC(0 - 24)/MIC比值≥30.5至38）时，与初始接种物相比，24小时时细菌数量减少1.2至2.0 log(10) CFU/ml。CLR的T/MIC值≤8%（AUC(0 - 24)/MIC比值≤17.3）会导致细菌生长停滞或再生长。临床上使用CLR时在ELF中获得的高药物浓度可能解释了对于MIC高达8 μg/ml的携带mef(A)的肺炎链球菌菌株缺乏临床治疗失败的情况。然而，对于MIC≥16 μg/ml且同时携带erm(B)的mef(A)分离株可能会导致细菌学治疗失败。
