Bentley Darren J
Certara Drug Development Solutions, Certara Level 2-Acero, 1 Concourse Way, Sheffield S1 2BJ, UK.
Antibiotics (Basel). 2024 Apr 7;13(4):337. doi: 10.3390/antibiotics13040337.
A two-dimensional "checkerboard" array employing systematic titration (e.g., serial two-fold dilutions) is a well-established in vitro method for exploring the antibacterial effects of novel drug combinations. Minimum inhibitory concentrations (MICs) on the checkerboard are isoeffective points at which the antibiotic potency is the same. Representations of checkerboard MIC curves for a β-lactam and β-lactamase inhibitor combination are used in hypothetical "thought experiments" and reveal the ways in which current practices can be improved. Because different types of response (i.e., independence vs. additivity vs. one effective agent; interaction vs. noninteraction) produce different MIC curves, data from different strains/isolates should not be pooled indiscriminately, as the composition of a pooled dataset will influence any derived pharmacokinetic/pharmacodynamic (PK/PD) index. Because the β-lactamase inhibitor threshold concentration (C) parameter is a function of the β-lactam partner dosing regimen, it is not possible to derive a universal PK/PD index target based on C. Alternative susceptibility testing methods represent different planes through the checkerboard; a fixed ratio method is less prone to bias for all β-lactam and β-lactamase inhibitor combinations. Susceptibility test MICs will often not reflect the sensitivity of the strain/isolate to the β-lactamase inhibitor, so the use of these MICs to normalize PK/PD indices is inappropriate.
采用系统滴定法（如连续两倍稀释法）的二维“棋盘格”阵列是一种成熟的体外方法，用于探索新型药物组合的抗菌效果。棋盘格上的最低抑菌浓度（MIC）是抗生素效力相同的等效点。β-内酰胺类与β-内酰胺酶抑制剂组合的棋盘格MIC曲线表示法用于假设的“思维实验”，并揭示了当前做法可改进的方式。由于不同类型的反应（即独立性与相加性与单一有效药物；相互作用与非相互作用）会产生不同的MIC曲线，来自不同菌株/分离株的数据不应随意合并，因为合并数据集的组成会影响任何推导的药代动力学/药效学（PK/PD）指标。由于β-内酰胺酶抑制剂阈值浓度（C）参数是β-内酰胺类药物给药方案的函数，因此不可能基于C得出通用的PK/PD指标目标。替代药敏试验方法代表穿过棋盘格的不同平面；固定比例法对所有β-内酰胺类与β-内酰胺酶抑制剂组合的偏差较小。药敏试验MIC通常不能反映菌株/分离株对β-内酰胺酶抑制剂的敏感性，因此使用这些MIC来标准化PK/PD指标是不合适的。
