Current and Emerging Treatment Options for Multidrug Resistant Escherichia coli Urosepsis: A Review

Abstract

Escherichia coli is a versatile commensal and pathogenic member of the human microflora. As the primary causative pathogen in urosepsis, E. coli places an immense burden on healthcare systems worldwide. To further exacerbate the issue, multi drug resistance (MDR) has spread rapidly through E. coli populations, making infections more troublesome and costlier to treat. This paper aimed to review the literature concerning the development of MDR in uropathogenic E. coli (UPEC) and explore the existing evidence of current and emerging treatment strategies. While some MDR strains maybe treated with β-lactam-β-lactamase inhibitor combinations as well as cephalosporins, cephamycin, temocillin and fosfomycin, current treatment strategies for many MDR UPEC strains are reliant on carbapenems. Carbapenem overreliance may contribute to the alarming dissemination of carbapenem-resistance amongst some UPEC communities, which has ushered in a new age of difficult to treat infections. Alternative treatment options for carbapenem resistant UPEC may include novel β-lactam-β-lactamase or carbapenemase inhibitor combinations, cefiderocol, polymyxins, tigecycline, aminoglycosides or fosfomycin. For metallo-β-lactamase producing strains (e.g., NDM, IMP-4), combinations of cefazidime-avibacam with aztreonam have been used. Additionally, the emergence of new antimicrobials brings new hope to the treatment of such infections. However, continued research is required to successfully bring these into the clinic for the treatment of MDR E. coli urosepsis.

A review of the mechanisms that confer antibiotic resistance in pathotypes of E. coli

“…Taniborbactam, which contains boronic acid, is a β -lactamase inhibitor that effectively inhibits AmpC, ESBL such as CTX-M and SHV and carbapenemases such as MBLs (VIM and NDM but not IMP) and serine- β -lactamases, such as OXA-48 and KPC-2. Therefore, it blocks class A, class B, class C and class D β -lactamases, which is a feature not presented by other b-lactamase inhibitors ( Walker et al., 2022 ). As the medication forms a covalent bond with the serine residue at the enzyme-mediated hydrolysis site, serine β -lactamase is inhibited.…”

“…Currently, antibiotics such as cefiderocol, colistin, fosfomycin, nitrofurantoin, and tigecycline can successfully treat UPEC strains that are resistant to carbapenem. Different nations have different levels of antimicrobial agent resistance ( Figure 5 ) ( Walker et al., 2022 ).…”

“…The FDA approved cefiderocol, a new type of cephalosporin antibiotic that acts as a siderophore, on November 14, 2019 for treating complicated UTIs in adults. Studies have demonstrated its effectiveness against carbapenem-resistant UPEC strains that belong to all Ambler classes, including those that produce ESBL, AmpC, KPC, and NDM-1 ( El-Lababidi and Rizk, 2020 ; Walker et al., 2022 ).…”

Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics

“…Rapid treatment of BSI with an effective antibiotic greatly improves outcome, so when BSI is suspected, patients are usually prescribed antibiotics before microbiological confirmation of the causative organism and its antibiotic susceptibility, which can take several days (3). The antibiotics of choice tend to be β-lactams, usually the penicillin/penicillinase inhibitor combination piperacillin/tazobactam, or possibly a third-generation cephalosporin (3GC) (4). β-lactam resistance in E. coli is primarily due to β-lactamase enzymes such as CTX-M-15 (3GC resistance) (5) or OXA-1 (piperacillin/tazobactam resistance) (6).…”

“…β-lactam resistance in E. coli is primarily due to β-lactamase enzymes such as CTX-M-15 (3GC resistance) (5) or OXA-1 (piperacillin/tazobactam resistance) (6). Where β-lactams cannot be used, aminoglycoside antibiotics, either amikacin or gentamicin, are the usual alternative (4). In E. coli , resistance to these agents is predominantly due to aminoglycoside acetyltransferase (AAC) enzymes of the AAC(6’)-I (amikacin resistance) or AAC(3)-II (gentamicin resistance) types.…”