Inhibition activity of Nocardia farcinica β-lactamase FAR IFM10152 by avibactam.

Nocardia farcinica, one of the most frequent pathogenic species responsible for nocardiosis, is characterized by frequent brain involvement and resistance to beta-lactams mediated by a class A beta-lactamase. Kinetic parameters for hydrolysis of various p-lactams by FAR(IFM10152) from strain IFM 10152 were determined by spectrophotometry revealing a high catalytic activity (k(cat)/K-m) for amoxicillin, aztreonam, and nitrocefin. For cephems, k(cat)/K-m was lower but remained greater than 10 4 M s(-1). A low catalytic activity was observed for meropenem, imipenem, and ceftazidime hydrolysis. FAR(IFM10152) inhibition by avibactam and clavulanate was compared using nitrocefin as a reporter substrate. FAR(IFM10152) was efficaciously inhibited by avibactam with a carbamoylation rate constant (k(2)/K-i) of (1.7 +/- 0.3) x 10(4) M-1 s(-1). The 50% effective concentrations (EC(50)s) of avibactam and clavulanate were 0.060 +/- 0.007 mu M and 0.28 +/- 0.06 mu M, respectively. Amoxicillin, cefotaxime, imipenem, and meropenem MICs were measured for ten clinical strains in the presence of avibactam and clavulanate. At 4 mu g/ml, avibactam and clavulanate restored amoxicillin susceptibility in all but one of the tested strains but had no effect on the MICs of cefotaxime, imipenem, and meropenem. At 0.4 mu g/ml, amoxicillin susceptibility (MIC <= 8 mu g/ml) was restored for 9 out of 10 strains by avibactam but only for 4 out of 10 strains by clavulanate. Together, these results indicate that avibactam was at least as potent as clavulanate, suggesting that the amoxicillin-avibactam combination could be considered as an option for the rescue treatment of N. farcinice infections if clavulanate cannot be used.