Efficacy of mecillinam against clinical multidrug-resistant Escherichia coli in a murine urinary tract infection model

Abstract

Pivmecillinam, a pro-drug of mecillinam, has been used extensively in Scandinavia for the treatment of acute lower urinary tract infections (UTIs) caused by Enterobacterales. It is still an attractive first-line drug for the empirical treatment of UTIs owing to the low prevalence of resistance as well as its favourable impact on the intestinal microbiota as a pro-drug and good in vitro efficacy against extended-spectrum β-lactamase (ESBL)- and plasmid-mediated AmpC β-lactamase-producing <i>Escherichia coli</i>. However, optimal dosing of pivmecillinam as well as its in vivo efficacy against UTIs caused by multidrug-resistant (MDR) broad-spectrum β-lactamase-producing <i>E. coli</i> has not been thoroughly studied. In this study, the efficacy of two mimicked human dosing regimens of pivmecillinam (200 mg and 400 mg three times daily) against clinical <i>E. coli</i> strains, including isolates producing ESBLs (CTX-M-14 and CTX-M-15), plasmid-mediated AmpCs (CMY-4 and CMY-6) and carbapenemases (NDM-1 and VIM-29), in a murine UTI model was compared. Both dosing regimens reduced the number of CFU/mL in urine for all strains, including mecillinam-resistant strains. Combining the effect for all six strains showed no significant differences in effect between doses for all three fluids/organs, but for each dose there was a highly significant effect in urine, kidney and bladder compared with vehicle-treated mice. Overall, this highlights the need for further studies to elucidate the role of mecillinam in the treatment of infections caused by MDR <i>E. coli</i> producing broad-spectrum β-lactamases, including specific carbapenemases.