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Synergistic and bactericidal activities of mecillinam, amoxicillin and clavulanic acid combinations against extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli in 24-h time-kill experiments
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
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2019 (English)In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 53, no 1, p. 74-79Article in journal (Refereed) Published
Abstract [en]

This study aimed to evaluate the potential synergistic and bactericidal effects of mecillinam in combination with amoxicillin and clavulanic acid against extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. Eight clinical E. coli isolates with varying susceptibility to mecillinam [minimum inhibitory concentrations (MICs) of 0.125 mg/L to >256 mg/L] and high-level resistance to amoxicillin (MICs > 256 mg/L) were used. Whole-genome sequencing was performed to determine the presence of beta-lactamase genes and mutations in the cysB gene. The activities of single drugs and the combinations of two or three drugs were tested in 24-h time-kill experiments. Population analysis was performed for two strains before and after experiments. Only one strain had a mutation in the cysB gene resulting in an amino acid substitution. With the two-drug combinations, initial killing was observed both with mecillinam and amoxicillin when combined with clavulanic acid. Synergy was observed with mecillinam and clavulanic acid against one strain and with amoxicillin and clavulanic acid against three strains. However, following significant re-growth, a bactericidal effect was found only with amoxicillin and clavulanic acid against two strains. Pre-existing subpopulations with elevated mecillinam MICs were detected before experiments and were selected with mecillinam alone or in two-drug combinations. In contrast, the three-drug combination showed enhanced activity with synergy against six strains, a bactericidal effect against all eight strains, and suppression of resistance during 24-h antibiotic exposure. This combination may be of clinical interest in the treatment of urinary tract infections caused by ESBL-producing E. coli.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV , 2019. Vol. 53, no 1, p. 74-79
Keywords [en]
Amdinocillin, Mecillinam, Synergy, Extended-spectrum beta-lactamase, ESBL, Urinary tract infection
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-375234DOI: 10.1016/j.ijantimicag.2018.09.011ISI: 000455090800012PubMedID: 30236958OAI: oai:DiVA.org:uu-375234DiVA, id: diva2:1283622
Available from: 2019-01-29 Created: 2019-01-29 Last updated: 2019-01-29Bibliographically approved

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Shams, AydaMontelin, HannaLagerbäck, PernillaTängdén, Thomas

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