Sulbactam-durlobactam improves cephalosporin and carbapenem susceptibility and time-kill effect against Mycobacterium...

Despite the long therapy duration, the treatment outcomes for Mycobacterium abscessus lung disease (MAB-LD) are very poor. β-Lactams are among the recommended drugs for the treatment of MAB-LD; however, they are prone to hydrolysis by MAB β-lactamase enzymes. Therefore, β-lactamase inhibitors have been developed to overcome this problem. Here, we performed minimum inhibitory concentration studies with a reference MAB strain (ATCC19977) and a collection of 63 clinical isolates for penicillin, cephalosporin, and carbapenems alone or in combination with β-lactamase inhibitors, sulbactam/durlobactam (Sul/Dur). There was an average 64-fold (range: 19 to 103) reduction in drugs MIC in the presence of 4 mg/L Sul/Dur (1:1 ratio). The fold reduction in MICs was as follows: amoxicillin 94, ceftriaxone 103, cefuroxime 69, cefdinir 19, cefalexin 74, imipenem 23, meropenem 37, tebipenem 89, and faropenem 74. The Sul/Dur combination also improved the kill effect of the tested β-lactams by multiple folds as follows: amoxicillin 12.6, ceftriaxone 2,872, cefuroxime 135.5, cefdinir 26.5, cefalexin 1,030, imipenem and meropenem 14, and faropenem 5.5. Since imipenem is already included in the MAB-LD treatment recommendations and ceftriaxone achieves very high lung concentration, we propose to first test these drugs with Sul/Dur as a double β-lactam-β-lactamase backbone regimen to advance the therapy for MAB-LD.IMPORTANCEβ-Lactams are among the recommended drugs for the treatment of Mycobacterium abscessus lung disease (MAB-LD); however, they are prone to hydrolysis by MAB β-lactamase enzymes. We show that sulbactam/durlobactam (Sul/Dur) can improve the kill effect of several β-lactam antibiotics that, otherwise, due to observed high minimum inhibitory concentration, deem ineffective. Based on our findings, we propose imipenem that is already included in the MAB-LD treatment recommendations and ceftriaxone that achieves very high lung concentration, to test with Sul/Dur as a double β-lactam-β-lactamase backbone regimen to advance the therapy for MAB-LD.