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 (CT) 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 CT. 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.

中文翻译：

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重新审视棋盘以了解 β-内酰胺/β-内酰胺酶抑制剂组合的开发

采用系统滴定（例如连续两倍稀释）的二维“棋盘”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作用。棋盘上的最低抑菌浓度 (MIC) 是抗生素效力相同的等有效点。 β-内酰胺和 β-内酰胺酶抑制剂组合的棋盘 MIC 曲线表示用于假设的“思想实验”，并揭示了可以改进当前实践的方法。由于不同类型的反应（即独立性与加性性与一种有效药物；相互作用与非相互作用）产生不同的 MIC 曲线，因此不应不加区别地汇集来自不同菌株/分离株的数据，因为汇集数据集的组成将影响任何推导的药代动力学/药效学（PK/PD）指数。由于 β-内酰胺酶抑制剂阈值浓度 (CT) 参数是 β-内酰胺伴侣给药方案的函数，因此不可能基于 CT 得出通用的 PK/PD 指数目标。替代敏感性测试方法代表棋盘格的不同平面；对于所有 β-内酰胺和 β-内酰胺酶抑制剂组合，固定比率方法不太容易出现偏差。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 指数是不合适的。