<i>In Vitro</i> Activity of <i>β</i>-Lactams in Combination with <i>β</i>-Lactamase Inhibitors against <i>Mycobacterium tuberculosis</i> Clinical Isolates

Objectives Evaluating the activity of nineteen β -lactams in combination with different β -lactamase inhibitors to determine the most potent combination against Mycobacterium tuberculosis (MTB) in vitro . Methods Drug activity was examined by drug susceptibility test with 122 clinical isolates from China. Mutations of blaC and drug targets ldt Mt1 , ldt Mt2 , dacB2, and crfA were analyzed by nucleotide sequencing. Results Tebipenem (TBM) in combination with clavulanate (CLA) exhibited the highest anti-TB activity. The MIC of β -lactam antibiotics was reduced most evidently in the presence of CLA, compared to avibactam (AVI) and sulbactam (SUB). Eight polymorphism sites were identified in blaC , which were not associated with β -lactams resistance. Interestingly, one strain carrying G514A mutation in blaC was highly susceptible to β -lactams regardless of the presence of inhibitors. The transpeptidase encoding genes, ldt Mt1 , ldt Mt2 , and dacB2 , harboured three mutations, two mutations, and one mutation, respectively, but no correlation was found between these mutations and drug resistance. Conclusion The activity of β -lactams against MTB and different synergetic effect of β -lactamase inhibitors were indicated. TBM/CLA exhibited the most activity and has a great prospect in developing novel anti-TB regimen; however, further clinical research is warranted. Moreover, the resistance to the β -lactam antibiotics might not be conferred by single target mutation in MTB and requires further studies.