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Multicenter Study
. 2021 Oct 11;76(11):2839-2846.
doi: 10.1093/jac/dkab289.

Clavulanate combinations with mecillinam, cefixime or cefpodoxime against ESBL-producing Enterobacterales frequently associated with blaOXA-1 in a paediatric population with febrile urinary tract infections

André Birgy  1   2 , Fouad Madhi  3   4   5 , Camille Jung  3   6 , Corinne Levy  4   6   7 , Aurélie Cointe  1   2 , Philippe Bidet  1   2 , Claire Amaris Hobson  1 , Stéphane Bechet  7 , Elsa Sobral  7 , Hoang Vuthien  8 , Agnès Ferroni  9 , Saïd Aberrane  10 , Gaëlle Cuzon  11   12   13   14 , Laetitia Beraud  15 , Vincent Gajdos  16   17 , Elise Launay  18 , Didier Pinquier  19 , Hervé Haas  20 , Marie Desmarest  21 , Marie-Aliette Dommergues  4   22 , Robert Cohen  4   5   6   7   23 , Stéphane Bonacorsi  1   2 ; Group of the National Observatory of Urinary tract Infection due to ESBL-producing Enterobacteriaceae in children
Collaborators, Affiliations
Multicenter Study

Clavulanate combinations with mecillinam, cefixime or cefpodoxime against ESBL-producing Enterobacterales frequently associated with blaOXA-1 in a paediatric population with febrile urinary tract infections

André Birgy et al. J Antimicrob Chemother. .

Abstract

Objectives: Oral treatment of febrile urinary tract infections (FUTIs) can be impaired by MDR Enterobacterales often combining ESBL and inhibitor-resistant genes. We studied the impact of β-lactamases and Enterobacterales' genotypes on the cefixime, cefpodoxime and mecillinam ± amoxicillin/clavulanate MICs.

Materials and methods: In this multicentric study, we included 251 previously whole-genome-sequenced ESBL-producing Enterobacterales, isolated in French children with FUTIs. The MICs of cefixime, cefpodoxime, mecillinam alone and combined with amoxicillin/clavulanate were determined and analysed with respect to genomic data. We focused especially on the isolates' ST and their type of β-lactamases. Clinical outcomes of patients who received cefixime + amoxicillin/clavulanate were also analysed.

Results: All isolates were cefixime and cefpodoxime resistant. Disparities depending on blaCTX-M variants were observed for cefixime. The addition of amoxicillin/clavulanate restored susceptibility for cefixime and cefpodoxime in 97.2% (MIC50/90 of 0.38/0.75 mg/L) and 55.4% (MIC50/90 of 1/2 mg/L) of isolates, respectively, whatever the ST, the blaCTX-M variants or the association with inhibitor-resistant β-lactamases (34.2%). All isolates were susceptible to mecillinam + amoxicillin/clavulanate with MIC50/90 of 0.19/0.25 mg/L, respectively. Neither therapeutic failure nor any subsequent positive control urine culture were reported for patients who received cefixime + amoxicillin/clavulanate as an oral relay therapy (n = 54).

Conclusions: Despite the frequent association of ESBL genes with inhibitor-resistant β-lactamases, the cefixime + amoxicillin/clavulanate MICs remain low. The in vivo efficacy of this combination was satisfying even when first-line treatment was ineffective. Considering the MIC distributions and pharmacokinetic parameters, mecillinam + amoxicillin/clavulanate should also be an alternative to consider when treating FUTIs in children.

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