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
Authors: Birgy André , Madhi Fouad , Jung Camille , Levy Corinne , Cointe Aurélie , Bidet Philippe , Hobson Claire Amaris , Bechet Stéphane , Sobral Elsa , Vuthien Hoang , Ferroni Agnès , Aberrane Saïd , Cuzon Gaëlle , Beraud Laetitia , Gajdos Vincent , Launay Elise , Pinquier Didier , Haas Hervé , Desmarest Marie , Dommergues Marie-Aliette , Cohen Robert , Bonacorsi Stéphane ,   the Group of the National Observatory of Urinary tract Infection due to ESBL-producing Enterobacteriaceae in children, Adam Marie-Noëlle , Amara Marleèe , Andriantahina Isabelle , Belgaid Abdelmalek , Biscardi Sandra , Boyer Sophie , Branger Catherine , Breant Isabelle , Breuil Jack , Caillon Jocelyne , Cixous Emmanuel , Cojocaru Bogdan , Craiu Irina , Decobert Marion , Dessein Rodrigue , Doucet-Populaire Florence , Dubos François , Ducrocq Sarah , Farges-Berth Anne , Farrugia Cécile , Fiacre Alain , Galerne Aurélien , Garrec Hélène , Georget Emilie , Grimprel Emmanuel , Hees Laure , Labbee Franck , Pitsch Aurélia , Poilane Isabelle , Sivadon-Tardy Valérie , Soussan-Banini Valérie , Starck Benoit , Timsit Sandra , Traore Philippe , Vachee Anne , Vignaud Olivier 
Published: July 2021

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.