Evaluation of the pharmacokinetics–pharmacodynamics of fusidic acid against Staphylococcus aureus and Streptococcus pyogenes using in vitro infection models: implications for dose selection

Abstract

The pharmacokinetics–pharmacodynamics (PK-PD) of fusidic acid were investigated against methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pyogenes using in vitro infection models. Front-loaded and non–front-loaded fusidic acid dosing regimens were evaluated over 48 h using a 1-compartment infection model and over 240 h using a hollow fiber infection model (HFIM). All dosing regimens demonstrated initial decreases in bacterial density against both isolates in both in vitro models. A mechanism-based PK-PD model was developed to describe the effect of the concentration–time course of fusidic acid on the time course of MRSA in the in vitro infection model. With the use of this model and Monte Carlo simulation to evaluate the effect of different dosing regimens against MRSA, front-loaded [≥1200 mg every 12 h (Q12) × 2 doses followed by ≥600 mg Q12 h] compared to non–front-loaded (600 mg Q12 h) dosing regimens demonstrated better activity. HFIM data confirmed the effect of the front-loaded dosing regimens over 48 h and also demonstrated the suppression of growth of the total population and resistant subpopulations for MRSA over 96 and 120 h, respectively, associated with these dosing regimens.

Introduction

Fusidic acid, administered as sodium fusidate, is an oral antibiotic with in vitro activity against Staphylococcus aureus and Streptococcus pyogenes (Castanheira et al., 2010, Rhomberg et al., 2009), the primary pathogens associated with skin and skin-structure infections. It is currently being developed in the United States for the treatment of acute bacterial skin and skin-structure infections (ABSSSI).

In vitro infection models, such as the 1-compartment and hollow fiber infection models (HFIM), can provide valuable information regarding the pharmacokinetics–pharmacodynamics (PK-PD) of antimicrobial agents. These models are especially useful in discriminating among candidate dosing regimens, particularly in the circumstance where the pharmacokinetic (PK) profile in patients is difficult to mimic in an animal infection model. Such is the case with fusidic acid, where the apparent half-life after an oral dose of 550 mg in healthy volunteers is 14.5 h (Bulitta et al., 2009b) as compared to the very short apparent half-life in mice (i.e., less than a few minutes) (Degenhardt et al., 2009). This magnitude of difference in half-life, which would require the administration of multiple doses per hour in mice to mimic exposures in patients, is logistically challenging. In such cases, the use of in vitro infection models, which allow for any concentration–time profile of interest to be mimicked, provides the opportunity to effectively evaluate the PK-PD of an antibacterial agent. PK-PD targets associated with efficacy can then be identified based on analyses of such data. With the use of Monte Carlo simulation (MCS), together with PK-PD targets from non-clinical infection models and PK parameters from a population PK model based on data from healthy subjects, potential dosing regimens for future clinical trials can be evaluated (Bhavnani et al., 2005, Drusano et al., 2001). This process, which is described in the Food and Drug Administration (FDA) draft guidance for industry for the development of drugs for the treatment of patients with ABSSSI (US Department of Health and Human Services, Food and Drug Administration & Center for Drug Evaluation and Research (CDER), 2010), represents the current paradigm for supporting clinical trial dose selection for antibacterial agents.

The objectives of this study were 3-fold. The first objective was to evaluate the PK-PD of fusidic acid against methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pyogenes over 48 h using data from a 1-compartment infection model. As part of this objective and using the data for MRSA, a mechanism-based PK-PD model to describe the relationship between the concentration–time course of fusidic acid and bacterial growth and death was developed. The second objective was to use this mechanism-based PK-PD model, a previously developed population PK model and MCS to evaluate the effect of several different fusidic acid dosing regimens on the bacterial density of MRSA to support phase 2 dose selection. The last objective of this study was to use a HFIM to confirm the effect of selected fusidic acid dosing regimens over a 10-day period of study. The impact of fusidic acid on the change in bacterial burden and suppression of resistance of MRSA and Streptococcus pyogenes was evaluated in this system.