In vitro efficacy of relebactam versus avibactam against Mycobacterium abscessus complex

James Harrison,John A Weaver,Maya Desai,Jonathan A.G Cox

doi:10.1016/j.tcsw.2021.100064

Abstract

Infections resulting from Mycobacterium abscessus are increasing in prevalence worldwide, with the greatest risk posed to patients with underlying respiratory conditions. Treatment for infections is difficult due to wide ranging intrinsic antimicrobial resistance, which is compounded by the existence of a range of subspecies within the M. abscessus complex, each with varying additional antimicrobial resistance profiles. Previously, the use of β-lactam/β-lactamase inhibitors within a combination therapy has been proposed as an effective treatment option for pulmonary M. abscessus infections. Here, we assess the in vitro efficacy of two non-β-lactam based inhibitors, relebactam and avibactam, as agents against M. abscessus with their respective partner drugs imipenem and ceftazidime, as well as in triplicate combinations with additional β-lactam antibiotics against the M. abscessus complex. We have shown that the commercially available ratio of imipenem to relebactam is the appropriate ratio for bactericidal activity against M. abscessus, whereas the ratio between ceftazidime and avibactam is redundant, due to inactivity of ceftazidime to inhibit the bacteria. We have identified that the use of imipenem and meropenem alongside either relebactam or avibactam yield low minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) for each M. abscessus subspecies, which are within the therapeutically achievable concentration ranges within the epithelial lining fluid of the lungs. We propose the implementation of imipenem with relebactam in place of stand-alone imipenem into the current treatment regime, alongside meropenem, as a future front-line treatment option for M. abscessus complex infections.

Highlights

Mycobacterium abscessus is an opportunistic human pathogen that is an increasing global health threat, capable of causing pulmonary disease or skin and soft tissue infections
High morbidity due to M. abscessus infection can be attributed to the difficulty in treatment with antimicrobials, largely in part due to the multiple antibiotic resis tance mechanisms employed by the pathogen (Lopeman et al, 2019)
The β-lactam/β-lactamase inhibitor combinations of IMI/REL and CAZ/AVI are pre-formulated at 2:1 and 4:1 ratios respectively (Vazquez et al, 2012, Lucasti et al, 2016). Since these formulations were created to treat infections other than those caused by M. abscessus, we investigated the role of differing β-lactam/β-lactamase inhibitor ra tios against this organism in vitro

Summary

Introduction

Mycobacterium abscessus is an opportunistic human pathogen that is an increasing global health threat, capable of causing pulmonary disease or skin and soft tissue infections. The prolonged treatment regime consists of a combination therapy of amikacin, tigecycline and imipenem, as well as clarithromycin or azi thromycin (if susceptible) for one month. This is followed up with a combination of clofazimine, linezolid, minocycline, moxifloxacin or cotrimoxaole alongside nebulised amikacin, (dependent upon isolate sus ceptibility profiling) for 12-months (Haworth et al, 2017, Chen et al, 2019). Bolletii is the rarest (Adekambi et al, 2006, Tortoli et al, 2016, Minias et al, 2020) Both of these subspecies contain a functional erm(41) gene encoding for inducible macrolide resistance. It is an important consideration to identify subspecies susceptibilities to the front line treatment options, and any drug discovery efforts to combat M. abscessus

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