title: In Vitro Activity of β-Lactams in Combination with β-Lactamase Inhibitors against Multidrug-Resistant Mycobacterium tuberculosis Isolates.
abstract: The combination of β-lactams and β-lactamase inhibitors has been shown to have potent in vitro activity against multidrug-resistant tuberculosis (MDR-TB) isolates. In order to identify the most potent β-lactam-β-lactamase inhibitor combination against MDR-TB, we selected nine β-lactams and three β-lactamase inhibitors, which belong to different subgroups. A total of 121 MDR-TB strains were included in this study. Out of the β-lactams used herein, biapenem was the most effective against MDR-TB and had an MIC50 value of 8 μg/ml. However, after the addition of clavulanate or sulbactam, meropenem exhibited the most potent anti-MDR-TB activity with an MIC50 value of 4 μg/ml. For meropenem, 76 (62.8%), 41 (33.9%), and 22 (18.2%) of the 121 MDR-TB strains were subjected to a synergistic effect when the drug was combined with sulbactam, tazobactam, or clavulanate, respectively. Further statistical analysis revealed that significantly more strains experienced a synergistic effect when exposed to the combination of meropenem with sulbactam than when exposed to meropenem in combination with tazobactam or clavulanate, respectively (P < 0.01). In addition, a total of 10.7% (13/121) of isolates harbored mutations in the blaC gene, with two different nucleotide substitutions: AGT333AGG and ATC786ATT. For the strains with a Ser111Arg substitution in BlaC, a better synergistic effect was observed in the meropenem-clavulanate and in the amoxicillin-clavulanate combinations than that in a synonymous single nucleotide polymorphism (SNP) group. In conclusion, our findings demonstrate that the combination of meropenem and sulbactam shows the most potent activity against MDR-TB isolates. In addition, the Ser111Arg substitution of BlaC may be associated with an increased susceptibility of MDR-TB isolates to meropenem and amoxicillin in the presence of clavulanate.
authors.affiliation: Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: National Center for Tuberculosis Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Beijing Pediatric Research Institute, Beijing Children's Hospital affiliated to Capital Medical University, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: National Center for Tuberculosis Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China pangyu@chinatb.org.
authors.forename: Yu
authors.initials: Y
authors.lastname: Pang
mesh_terms: D000658:Amoxicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019818:Clavulanic Acid / Q000494:pharmacology; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification; D013407:Sulbactam / Q000494:pharmacology*; D013845:Thienamycins / Q000494:pharmacology*; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology; D001618:beta-Lactamases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D013845:Thienamycins; D019818:Clavulanic Acid; D000658:Amoxicillin; D001618:beta-Lactamases; D000077731:Meropenem; D013407:Sulbactam