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  • Title: In vivo selection of a complex mutant TEM (CMT) from an inhibitor-resistant TEM (IRT) during ceftazidime therapy.
    Author: Jacquier H, Marcadé G, Raffoux E, Dombret H, Woerther PL, Donay JL, Arlet G, Cambau E.
    Journal: J Antimicrob Chemother; 2013 Dec; 68(12):2792-6. PubMed ID: 23861309.
    Abstract:
    OBJECTIVES: A relapse from Escherichia coli bloodstream infection was observed in a patient with acute leukaemia treated with ceftazidime for 7 days for febrile neutropenia. Whereas the original E. coli isolate was resistant to β-lactam/β-lactamase inhibitor combinations (EC1), the relapse E. coli isolate showed a similar phenotype but with resistance extended to ceftazidime (EC2). We investigated the molecular mechanisms of β-lactam resistance and sought if EC2 could have been selected in vivo from EC1. METHODS: EC1 and EC2 isolates were compared for antibiotic MICs, plasmid content, genotyping, β-lactamase genes and their environment. Both isolates were conjugated with E. coli JW4111ΔampC and MICs determined for transconjugants. In addition, ceftazidime-resistant mutants were selected in vitro from EC1. RESULTS: EC1 and EC2 showed identical patterns for genotyping and resistance plasmids. PCR sequencing of blaTEM in EC1 showed the mutations M69L and N276D corresponding to TEM-35, also called inhibitor-resistant TEM (IRT)-4. In EC2, the TEM allele showed an additional mutation, R164S, known to confer resistance to ceftazidime. The combination of these three mutations was previously reported in TEM-158, described as the complex mutant TEM (CMT)-9, associated with resistance to β-lactamase inhibitors and third-generation cephalosporins. In vitro selection of ceftazidime-resistant mutants from EC1 yielded six different CMT alleles, including TEM-158 containing the R164S mutation. CONCLUSIONS: This first known report of in vivo selection of CMT from IRT, reproduced in vitro, shows how the evolution of β-lactamase enzymes is easily driven by antibiotic pressure, even during a short antibiotic therapy.
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