Song Jae-Hoon
Samsung Medical Center, Sungkyunkwan University Asian-Pacific Research Foundation for Infectious Diseases (ARFID), Seoul, Korea.
Int J Infect Dis. 2003 Mar;7 Suppl 1:S1-4. doi: 10.1016/s1201-9712(03)90064-6.
Antimicrobial agents are generally evaluated in preclinical studies assessing in vitro activity, animal models demonstrating in vivo bacteriologic efficacy, and clinical trials primarily investigating safety and clinical efficacy. However, large sample sizes are required to detect any differences in outcomes between antimicrobials in clinical trials, and, generally, studies are powered to show only clinical equivalence. In addition, diagnosis is often based on clinical symptoms, rather than microbiological evidence of bacterial infection, and the patients most likely to have resistant pathogens are often excluded. Clinical efficacy can be achieved in some bacterial infections in which antimicrobials are suboptimal or even not prescribed. However, bacterial eradication maximizes clinical efficacy and may also reduce the development and spread of resistant organisms. The goal of antimicrobial therapy is, therefore, to eradicate bacteria at the site of infection. Bacterial eradication is not usually assessed as a primary endpoint within the limits of currently recommended clinical trial design. However, pharmacokinetic (PK) (serum concentration profiles, penetration to site of infection) and pharmacodynamic (PD) (susceptibility, concentration- versus time-dependent killing, post-antimicrobial effects) criteria can be used to predict bacteriologic efficacy. PK/PD predictions should be confirmed during all phases of antimicrobial development and throughout clinical use in response to changing patterns of resistance. A clear rationale for dose recommendations can be determined preclinically based on PK/PD parameters, and correlated with efficacy, safety and resistance endpoints in clinical trials. The duration of treatment and dose should be the shortest that will reliably eradicate the pathogen(s), and that is safe and well tolerated. Currently available agents vary significantly in their ability to achieve PK/PD parameters necessary for bacteriologic eradication. Recommendations for appropriate antimicrobial therapy should be based on PK/PD parameters, with the aim of achieving the maximum potential for eradication of both existing and emerging resistant pathogens.
抗菌药物通常在临床前研究中进行评估，这些研究包括评估体外活性、证明体内细菌学疗效的动物模型，以及主要研究安全性和临床疗效的临床试验。然而，在临床试验中需要大样本量才能检测出抗菌药物之间在疗效上的任何差异，而且一般来说，研究的目的仅在于显示临床等效性。此外，诊断通常基于临床症状，而非细菌感染的微生物学证据，而且最有可能携带耐药病原体的患者往往被排除在外。在一些细菌感染中，即使抗菌药物并非最佳选择甚至未使用抗菌药物，也能实现临床疗效。然而，细菌清除可使临床疗效最大化，还可能减少耐药菌的产生和传播。因此，抗菌治疗的目标是根除感染部位的细菌。在目前推荐的临床试验设计范围内，细菌清除通常不作为主要终点进行评估。然而，药代动力学（PK）（血清浓度曲线、感染部位的渗透情况）和药效学（PD）（敏感性、浓度-时间依赖性杀菌作用、抗菌后效应）标准可用于预测细菌学疗效。在抗菌药物研发的各个阶段以及整个临床使用过程中，应根据耐药模式的变化，通过PK/PD预测来确认疗效。基于PK/PD参数，可在临床前确定明确的剂量推荐依据，并将其与临床试验中的疗效、安全性和耐药终点相关联。治疗持续时间和剂量应是能可靠根除病原体的最短时间，且安全并耐受性良好。目前可用的药物在实现细菌学根除所需的PK/PD参数的能力方面差异显著。适当的抗菌治疗建议应基于PK/PD参数，目的是最大程度地根除现有和新出现的耐药病原体。
