Strongly Bactericidal All-Oral β-Lactam Combinations for the Treatment of Mycobacterium abscessus Lung Disease

Abstract

Bioactive forms of oral β-lactams were screened in vitro against Mycobacterium abscessus with and without the bioactive form of the oral β-lactamase inhibitor avibactam ARX1796. Sulopenem was equally active without avibactam, while tebipenem, cefuroxime, and amoxicillin required avibactam for optimal activity.

Activity of Oral Tebipenem-Avibactam in a Mouse Model of Mycobacterium abscessus Lung Infection

“…Two β-lactams, imipenem (IPM) and cefoxitin (FOX), used to treat M. abscessus lung disease, are administered by the intravenous route and show modest in vitro activity at 20 to 50 μM, limiting their clinical utility ( 12 ). In contrast to IPM and FOX, the β-lactam tebipenem (TBP) in combination with the β-lactamase inhibitor avibactam (AVI) exhibits an attractive, low micromolar MIC and pronounced bactericidal activity in vitro ( 13 – 16 ). However, both TBP and AVI show limited oral bioavailability ( 17 , 18 ), reducing their clinical attractiveness.…”

“… M. abscessus K21 belongs to the subspecies abscessus , forms rough colonies, and harbors the C28 sequevar of erm41 ; it is thus macrolide sensitive ( 23 ). The MIC of TBP (in the presence of 4 μg/mL AVI) against isolate K21 was 4 μM ( 16 ). To determine the appropriate dosing, the plasma concentration-time profile of TBP-PI and AVI-ARX administered orally to CD1 mice (Charles River Laboratories) was determined by liquid chromatography coupled with tandem mass spectrometry.…”

“…Clarithromycin was administered orally once daily as a positive control at 250 mg/kg, as described previously ( 24 ). We typically employ clarithromycin as a positive control in our drug discovery projects ( 16 , 23 ), as this is the macrolide recommended for macrolide drug susceptibility testing ( 25 ). However, the macrolide azithromycin is preferred clinically due to its improved tolerability, fewer drug-drug interactions, and equal efficacy ( 26 , 27 ).…”

“…(A) Plasma concentration-time profile of TBP, the active component of TBP-PI, and AVI, the active component of AVI-ARX, following a single oral dose of 400 mg/kg TBP-PI (EC/13222; GlaxoSmithKline, Tres Cantos, Madrid, Spain) and 200 mg/kg AVI-AXR (catalog number HY-132987; MedChemExpress) in CD1 mice. The red dotted line shows the MIC of TBP (4 μM; 1.5 μg/mL) in the presence of 4 μg/mL AVI (indicated by the black dotted line) against M. abscessus K21 ( 16 ). (B) Efficacy of TBP-PI plus AVI-ARX (TPB/AVI) and clarithromycin (CLR) control in an NOD SCID mouse model.…”

“…One limitation of this study is the small fraction of the dosing interval during which the concentration of AVI-ARX was higher than 4 μg/mL following a single daily dose, i.e., from days 7 to 10 in the efficacy study. This concentration is clinically relevant and protects TBP against the major β-lactamase activity in M. abscessus ( 16 , 29 ). Therefore, we may have slightly underestimated the efficacy of tebipenem.…”