Improving the Drug Development Pipeline for Mycobacteria: Modelling Antibiotic Exposure in the Hollow Fibre Infection Model.

Zahra Sadouki,Frank Kloprogge,Priya Solanki,Arundhati Maitra,Timothy D. McHugh

doi:10.3390/antibiotics10121515

Abstract

Mycobacterial infections are difficult to treat, requiring a combination of drugs and lengthy treatment times, thereby presenting a substantial burden to both the patient and health services worldwide. The limited treatment options available are under threat due to the emergence of antibiotic resistance in the pathogen, hence necessitating the development of new treatment regimens. Drug development processes are lengthy, resource intensive, and high-risk, which have contributed to market failure as demonstrated by pharmaceutical companies limiting their antimicrobial drug discovery programmes. Pre-clinical protocols evaluating treatment regimens that can mimic in vivo PK/PD attributes can underpin the drug development process. The hollow fibre infection model (HFIM) allows for the pathogen to be exposed to a single or a combination of agents at concentrations achieved in vivo–in plasma or at infection sites. Samples taken from the HFIM, depending on the analyses performed, provide information on the rate of bacterial killing and the emergence of resistance. Thereby, the HFIM is an effective means to investigate the efficacy of a drug combination. Although applicable to a wide variety of infections, the complexity of anti-mycobacterial drug discovery makes the information available from the HFIM invaluable as explored in this review.

Highlights

The genus Mycobacterium contains several important human and animal pathogens in addition to environmental species
In the case of amikacin, the CMAX-to-MIC ratio is the best predictor for M. tuberculosis killing and this index can be used for individualising therapy where resources allow for it
Srivastava et al reported that drug combinations of fluoroquinolones (800 mg of moxifloxacin) with increased doses of rifampicin (3 times the standard dose) and pyrazinamide result in rapid killing of M. tuberculosis H37Ra with no significant toxicity as demonstrated by the liver organoid model developed in the hollow fibre system [70]

Summary

Introduction

The genus Mycobacterium contains several important human and animal pathogens in addition to environmental species. Unlike in animal experiments, repeated sampling from the hollow fibre cartridge of the bacterial culture can be performed Plating these samples on to media containing high concentrations of drugs can provide information on whether the given treatment enhances or suppresses the emergence of resistance. HFIM experiments with MAC infected monocytes or macrophages treated with azithromycin and ethambutol with or without rifampicin showed poor kill rates and emergence of acquired resistance within 7 days of treatment [41,42]. Tigecycline, a minocycline derivative, effectively clears extra- and intra-cellular M. tuberculosis as evidenced through HFIM experiments [45] It mirrored early bactericidal activity of isoniazid while suppressing regrowth of bacteria throughout the course of the experiment. In the case of amikacin, the CMAX-to-MIC ratio is the best predictor for M. tuberculosis killing and this index can be used for individualising therapy where resources allow for it

Application of HFIM in Dose and Dosing Interval Selection

Application of HFIM in Evaluating Combination Therapy

Findings

Discussion