Shrivastava Avneesh, Boorgula Gunavanthi D, Singh Sanjay, Stiles Danaleigh, McShane Pamela J, Devine Megan, Gumbo Tawanda, Srivastava Shashikant
Division of Infectious Diseases, Department of Medicine, University of Texas at Tyler School of Medicine, Tyler, Texas, USA.
Undergraduate Medical Education, University of Texas at Tyler School of Medicine, Tyler, Texas, USA.
Microbiol Spectr. 2025 Sep 10:e0149225. doi: 10.1128/spectrum.01492-25.
Despite the long therapy duration, the treatment outcomes for 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 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.
