Old antibiotics as alternative treatment options for urinary tract infections caused by ESBL-, AmpC- and carbapenemase-producing Escherichia coli

Abstract

Multidrug-resistant (MDR) bacteria, including Escherichia coli, producing extended-spectrum β-lactamase (ESBL), AmpC or carbapenemases, are acknowledged among the most significant global health threats. Growing rates of MDR E.coli can lead to an increase in the use of reserve antimicrobials. Re-introducing “old antimicrobials” could offer a timely solution. This work aimed at evaluating the role of fosfomycin, mecillinam, temocillin, and nitrofurantoin as the treatment options for urinary tract infections (UTIs) caused by MDR ESBL-, AmpC-, and carbapenemase-producing E. coli. In paper 1, we investigated the susceptibility patterns among a Norwegian nationwide collection of ESBL-producing E. coli from 2010-2011. A high proportion of isolates (91-100%) was sensitive to fosfomycin, mecillinam, temocillin, and nitrofurantoin and had low co-resistance. This is comparable to amikacin and carbapenems (95-100%). In contrast, high levels of resistance were observed to broad-spectrum β-lactams such as 3rd generation cephalosporins and aztreonam (67-100%). Moreover, we observed a high proportion of resistance for trimethoprim-sulfamethoxazole (71%), gentamicin (40%), tobramycin (50%), and ciprofloxacin (74%) and co-resistance among them (36% for three and 40% for two drug classes). In papers 2 and 3, we further studied fosfomycin and mecillinam, respectively, in a murine UTI model. For fosfomycin, we performed the pharmacokinetic/pharmacodynamic (PK/PD) analysis and tested in vivo efficacy against MDR plasmid-mediated AmpC-/ESBL-/carbapenemase-producing clinical E. coli isolates. The optimal PK/PD index, based on fosfomycin bloodstream levels, was Cmax, followed by AUC/MIC0–72. Fosfomycin reduced the CFU/ml in urine, bladder, and kidneys of all susceptible MDR strains, except for one harboring fosA. In paper 3, two mecillinam dosing regimens were calculated. We aimed to mimic human PK for pivmecillinam dosing regimens of 200 mg and 400 mg TID. For both doses, mecillinam reduced the urinary CFU-counts for all strains except one ESBL-producer at 400 mg TID. Efficacy was shown against carbapenemase-producers, including NDM-1 (mecillinam MIC 2 mg/L) and VIM-29 (mecillinam MIC 64 mg/L). The present works suggest old drugs to be promising alternatives to reserve drugs against UTIs caused by MDR E. coli.