title: Anti-anaerobic activity of a new β-lactamase inhibitor NXL104 in combination with β-lactams and metronidazole.
abstract: NXL104 is a new β-lactamase inhibitor (BLI) that inhibits class A and class C β-lactamase enzymes. In this study, the activity of NXL104 in combination with the third-generation cephalosporins ceftazidime (CAZ) and ceftriaxone (CRO) or with piperacillin (PIP) was evaluated against 316 anaerobic bacteria. Minimum inhibitory concentrations (MICs) were determined using an agar dilution method. The BLIs NXL104 or tazobactam (TAZ) were added to the β-lactams at a fixed concentration of 4 mg/L. A triple combination of NXL104 with an 8:1 ratio of CAZ and metronidazole (MTZ) was also tested. The activities of CAZ, CRO and PIP in combination with NXL104 were enhanced against many of the bacteria. MIC(50) values (MIC for 50% of the organisms) for CAZ+NXL104 were 8-16-fold lower than those of CAZ against Gram-negative anaerobes. Antibiotic resistance rates against all anaerobic strains were: CAZ, 37.7%; CRO, 31%; CAZ+NXL104, 15.2%; CRO+NXL104, 5.4%; and MTZ, 4.1%. No resistant strains could be observed with PIP+TAZ, PIP+NXL104 or the triple combination MTZ+CAZ+NXL104. In conclusion, the triple combination of MTZ+CAZ+NXL104 demonstrated potent antibacterial activity against anaerobes representing most clinical species. It appears appropriate for the treatment of polymicrobial infections, since CAZ+NXL104 also exhibits potent activity against β-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa. It is currently being tested in phase 2 clinical trials for the treatment of complicated intra-abdominal infections.
authors.affiliation: Faculty of Pharmacy, Université of Lille 2, Lille, France. luc.dubreuil@univ-lille2.fr
authors.forename: L J
authors.initials: LJ
authors.lastname: Dubreuil
authors.forename: S
authors.initials: S
authors.lastname: Mahieux
authors.forename: C
authors.initials: C
authors.lastname: Neut
authors.forename: C
authors.initials: C
authors.lastname: Miossec
authors.forename: J
authors.initials: J
authors.lastname: Pace
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001421:Bacteria, Anaerobic / Q000187:drug effects* / Q000201:enzymology; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D006089:Gram-Negative Anaerobic Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008795:Metronidazole / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D065093:beta-Lactamase Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D065093:beta-Lactamase Inhibitors; D008795:Metronidazole; C543519:avibactam