Revisiting the Checkerboard to Inform Development of β-Lactam/β-Lactamase Inhibitor Combinations

Abstract

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.