2021•Journal of Antimicrobial ChemotherapyRequires access
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, Fouad Madhi, Camille Jung, Corinne Lévy, Aurélie Cointe, Philippe Bidet, Claire Amaris Hobson, Stéphane Béchet, Elsa Sobral, Hoang Vu-Thien, Agnès Ferroni, Saïd Aberrane, Gaëlle Cuzon, Laëtitia Beraud, Vincent Gajdos, Elise Launay, Didier Pinquier, Hervé Haas, Marie Desmarest, Marie‐Aliette Dommergues, Robert W. Cohen, Stéphane Bonacorsi, the Group of the National Observatory of Urinary tract Infection due to ESBL-producing Enterobacteriaceae in children, M. N. Adam, Marleèe Amara, Isabelle Andriantahina, Abdelmalek Belgaid, Sandra Biscardi, Sophie Boyer, Catherine Branger, Isabelle Breant, Jack Breuil, J. Caillon, Emmanuel Cixous, Bogdan Cojocaru, Irina Craiu, Marion Decobert, Rodrigue Dessein, Florence Doucet‐Populaire, François Dubos, Sarah Ducrocq, Anne Farges-Berth, Cécile Farrugia, Alain Fiacre, Aurélien Galerne, Hélène Garrec, Emilie Georget, E. Grimprel, Laure Hees, Franck Labbee, A. Pitsch, Isabelle Poilane, Valérie Sivadon‐Tardy, Valérie Soussan-Banini, Benoit Starck, Sandra Timsit, Philippe Traore, Anne Vachée, Olivier Vignaud
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.