In vitro efficacy of relebactam versus avibactam against Mycobacterium abscessus complex

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.

Contemporary Pharmacotherapies for Nontuberculosis Mycobacterial Infections: A Narrative Review

“…Although the currently available dose/ratio of imipenem/relebactam was optimized, no combination of ceftazidime/avibactam was effective. However, triple-combination imipenem, relebactam, and meropenem resulted in the lowest MICs and minimum bactericidal concentrations for all three subspecies [ 89 ]. Other studies have shown that the addition of ampicillin to imipenem/relebactam, and to a lesser extent to ceftazidime/avibactam, can result in lower Mabs MICs [ 89 , 90 ].…”

“…However, triple-combination imipenem, relebactam, and meropenem resulted in the lowest MICs and minimum bactericidal concentrations for all three subspecies [ 89 ]. Other studies have shown that the addition of ampicillin to imipenem/relebactam, and to a lesser extent to ceftazidime/avibactam, can result in lower Mabs MICs [ 89 , 90 ]. Currently, all three β-lactamase inhibitors are available only in coformulations with β-lactams: imipenem/cilastatin with relebactam, ceftazidime with avibactam, and meropenem with vaborbactam.…”

Drug Repurposing for the Treatment of Mycobacterium abscessus Infections

“…49 The success of these dual combinations has facilitated investigations of even further complexity, with triple combinations also showing great promise. Successful examples include the following: durlobactam and amoxicillin with either imipenem or cefuroxime 45 ; meropenem and imipenem with avibactam or relebactam 54 ; and imipenem, relebactam and amoxicillin. 55 The possibility for different combinations is therefore extensive and provides an optimistic view for the future of M. abscessus treatment, allowing us to simultaneously increase drug susceptibility and reduce dose requirements to ultimately lessen the treatment burden caused by their side effects.…”