Dataset Information

In Vitro and Intracellular Activity of Imipenem Combined with Rifabutin and Avibactam against Mycobacterium abscessus.

ABSTRACT: Repurposing drugs may be useful as an add-on in the treatment of Mycobacterium abscessus pulmonary infections, which are particularly difficult to cure. M. abscessus naturally produces a ?-lactamase, BlaMAb, which is inhibited by avibactam. The recommended regimens include imipenem, which is hydrolyzed by BlaMAb and used without any ?-lactamase inhibitor. Here, we determine whether the addition of rifabutin improves the activity of imipenem alone or in combination with avibactam against M. abscessus CIP104536. Rifabutin at 16 ?g/ml was only bacteriostatic (MIC of 4 ?g/ml) and was moderately synergistic in combination with imipenem (fractional inhibitory concentration [FIC] index of 0.38). Addition of rifabutin (16 ?g/ml) moderately increased killing by a low (8 ?g/ml) but not by a high (32 ?g/ml) concentration of imipenem. Addition of avibactam (4 ?g/ml) did not further increase killing by the former combination. In infected macrophages, rifabutin (16 ?g/ml) increased the activity of imipenem at 8 and 32 ?g/ml, achieving 3- and 100-fold reductions in the numbers of intracellular bacteria, respectively. Avibactam (16 ?g/ml) improved killing by imipenem at 8 ?g/ml. A 5-fold killing was obtained for a triple combination comprising avibactam (16 ?g/ml) and therapeutically achievable doses of imipenem (8 ?g/ml) and rifabutin (1 ?g/ml). These results indicate that the imipenem-rifabutin combination should be further considered for the treatment of M. abscessus pulmonary infections in cystic fibrosis patients and that addition of a ?-lactamase inhibitor might improve its efficacy. Mechanistically, the impact of BlaMAb inhibition by avibactam on antibiotic activity was assessed by comparing CIP104536 and a ?-lactamase-deficient derivative.

SUBMITTER: Le Run E

PROVIDER: S-EPMC6105861 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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In Vitro and Intracellular Activity of Imipenem Combined with Rifabutin and Avibactam against Mycobacterium abscessus.

Le Run Eva E Arthur Michel M Mainardi Jean-Luc JL

Antimicrobial agents and chemotherapy 20180727 8

Repurposing drugs may be useful as an add-on in the treatment of Mycobacterium abscessus pulmonary infections, which are particularly difficult to cure. M. abscessus naturally produces a β-lactamase, BlaMAb, which is inhibited by avibactam. The recommended regimens include imipenem, which is hydrolyzed by BlaMAb and used without any β-lactamase inhibitor. Here, we determine whether the addition of rifabutin improves the activity of imipenem alone or in combina ...[more]

PMID: 29866869

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Project description:The role of novel β-lactam/β-lactamase inhibitor combinations in ceftazidime-nonsusceptible (CAZ-NS) and imipenem-nonsusceptible (IPM-NS) Pseudomonas aeruginosa has not been fully elucidated. This study evaluated the in vitro activity of novel β-lactam/β-lactamase inhibitor combinations against Pseudomonas aeruginosa clinical isolates, determined how avibactam restored ceftazidime activity, and compared the activity of ceftazidime-avibactam (CZA) and imipenem-relebactam (IMR) against KPC-producing P. aeruginosa. Similar high susceptibility rates for CZA, IMR, and ceftolozane-tazobactam (88.9% to 89.8%) were found for 596 P. aeruginosa clinical isolates from 11 hospitals in China, and a higher susceptibility rate to ceftazidime than imipenem was observed (73.5% versus 63.1%). For CAZ-NS and IPM-NS isolates, susceptibility rates for CZA, ceftolozane-tazobactam, and IMR were 61.5% (75/122), 54.9% (67/122), and 51.6% (63/122), respectively. For CAZ-NS, IPM-NS but CZA-susceptible isolates, 34.7% (26/75) harbored acquired β-lactamases with KPC-2 predominant (n = 19), and 45.3% (34/75) presented overexpression of chromosomal β-lactamase ampC. Among 22 isolates carrying KPC-2 carbapenemase alone, susceptibility rates to CZA and IMR were 86.4% (19/22) and 9.1% (2/22), respectively. Notably, 95% (19/20) of IMR-nonsusceptible isolates had an inactivating mutation of oprD gene. In conclusion, CZA, ceftolozane-tazobactam, and IMR exhibit high activity against P. aeruginosa, and CZA is more active than IMR against CAZ-NS and IPM-NS isolates as well as KPC-producing P. aeruginosa. Avibactam overcomes ceftazidime resistance engendered by KPC-2 enzyme and overexpressed AmpC. IMPORTANCE The emergence of antimicrobial resistance poses a particular challenge globally, and the concept of P. aeruginosa with "difficult-to-treat" resistance (DTR-P. aeruginosa) was proposed. Here, P. aeruginosa clinical isolates were highly susceptible to three β-lactamase inhibitor combinations, CZA, IMR, and ceftolozane-tazobactam. The combination of KPC-2 enzyme and nonfunctional porin OprD contributed to IMR resistance in P. aeruginosa, and CZA was more active than IMR in fighting against KPC-2-producing P. aeruginosa. CZA also showed good activity against CAZ-NS and IPM-NS P. aeruginosa, primarily by inhibiting KPC-2 enzyme and overproduced AmpC, supporting the clinical use of CZA in the treatment of infections caused by DTR-P. aeruginosa.

Dataset Information

In Vitro and Intracellular Activity of Imipenem Combined with Rifabutin and Avibactam against Mycobacterium abscessus.

Publications

<i>In Vitro</i> and Intracellular Activity of Imipenem Combined with Rifabutin and Avibactam against Mycobacterium abscessus.

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