What the Clinical Microbiologist Should Know About Pharmacokinetics/Pharmacodynamics in the Era of Emerging Multidrug Resistance: Focusing on β-Lactam/β-Lactamase Inhibitor Combinations

Abstract

As a class, β-lactamase inhibitors have proved successful in extending the clinical utility of β-lactam antibiotics by circumventing β-lactamase-mediated resistance. However, the rapid evolution of these β-lactamases calls for a critical reevaluation of the relationships between susceptibility, drug exposures, and bacterial response. The existing paradigm for in vitro susceptibility testing and development of β-lactam/β-lactamase inhibitor combinations may not optimally facilitate clinical use. Thus, alternative approaches for pairing these combinations and evaluating in vitro susceptibility are needed to provide better guidance to clinicians.

Keywords: Combination therapy; Gram-negative bacteria; Optimal dosing; Pharmacokinetics/pharmacodynamics; Susceptibility testing.

Figure 1

Different Hypothetical Pharmacodynamic Profiles of a β-lactamase Inhibitor A hypothetical β-lactamase inhibitor is known to have the following therapeutic concentration range with a standard dosing regimen: C_max = 32 mg/L (inverted triangle) and C_min = 2 mg/L (upright triangle). When used in combination with a β-lactam, various response profiles (i.e., MIC reduction) can be anticipated for bacteria expressing different β-lactamase(s): Black - minimal change in susceptibility (inactive inhibitor) Green - dramatic reduction in susceptibility below C_min, minimal change over the therapeutic range (ideal active inhibitor) Gold - moderate reduction in susceptibility below C_min, minimal change over the therapeutic range (active inhibitor rendered ineffective by other non-enzymatic resistance mechanisms) Purple - gradual reduction in susceptibility over the therapeutic range (typical active inhibitor) Pink - minimal change in susceptibility over the therapeutic range but gradual reduction above the therapeutic range (potentially active inhibitor with more aggressive dosing)

Figure 2

Pharmacokinetic/Pharmacodynamic Indices for Killing Activity of Antibiotics PK/PD indices used to characterize the killing activity of various antibiotics: C_max/MIC – peak concentration divided by MIC AUC/MIC - the area under the concentration-time curve divided by the MIC %fT>MIC - the percentage of free-time above MIC In all cases, the MIC (red dashed line) is expected to remain unchanged over time

Figure 3

Depiction of MIC as Function of Inhibitor Concentration and Estimation of %fT>MICi Piperacillin MICs for a clinical isolate were determined in the presence of tazobactam concentrations ranging from 0–256 mg/L and modeled using the sigmoid inhibitory E_max model (Figure 3a) to generate isolate-specific model paramater estimates. A free (unbound) tazobactam pharmacokinetic profile associated with a 0.5 g dose delivered every 8 h was then simulated (Figure 3b) and integrated with the E_max model parameter estimates to simulate a theoretical instantaneous MIC (MICi) profile (Figure 3c). In contrast to the common approch, the MICi profile (red dashed line) reflected changing pathogen susceptibility as the inhibitor concentration fluctuated over time. Finally, a simulated unbound piperacillin pharmacokinetic profile associated with a 4 g dose every 8 h was superimposed on the theoretical MICi profile (Figure 3d). The %fT>MICi was then estimated as the duration of the dosing interval over which the piperacillin concentration exceed the MICi (fT>MICi = 39.6% in Figure 3d).