Oral cephalosporin and β-lactamase inhibitor combinations for ESBL-producing Enterobacteriaceae urinary tract infections

Abstract

ESBL-producing Enterobacteriaceae as uropathogens have given rise to a sizeable amount of global morbidity. Community and hospital surveillance studies continue to report increasing proportions of these organisms as causes of urinary tract infection (UTI). Due to limited treatment options and the presence of cross-resistance amongst oral antibiotics of different classes, patients often require IV therapy, thereby increasing healthcare costs and reducing the effectiveness of delivering healthcare. Oral cephalosporin antibiotics are well known for their ability to achieve high urinary concentrations, in addition to achieving clinical success for treatment of uncomplicated UTI with a drug-susceptible pathogen. Novel cephalosporin/β-lactamase inhibitor combinations have been developed and demonstrate good in vitro activity against ESBL-producing isolates. A pooled analysis of in vitro activity of existing oral cephalosporin/clavulanate combinations in ESBL-producing Enterobacteriaceae has shown MIC50s of 0.5–1, 0.125–1 and 0.25 mg/L for cefpodoxime, ceftibuten and cefixime, respectively. A novel cyclic boronic acid β-lactamase inhibitor, QPX7728, was able to produce MIC50 values of 0.5 and ≤0.06 mg/L when paired with cefpodoxime and ceftibuten, respectively. Other novel combinations, cefpodoxime/ETX0282 and ceftibuten/VNRX7145, have also demonstrated excellent activity against ESBL producers. Clinical trials are now awaited.

Nitrofurantoin Combined With Amikacin: A Promising Alternative Strategy for Combating MDR Uropathogenic Escherichia coli

“…Combinations of antibiotics are commonly used in medicine to broaden the antimicrobial spectrum and generate synergistic effects and this therapy has proven effective against MDR bacteria (Gomara and Ramon-Garcia, 2019). For example, the use of oral cephalosporin and b-lactamase inhibitor combinations for ESBL-producing Enterobacteriaceae UTI (Stewart et al, 2020).…”

Bicyclic Boronate β‐Lactamase Inhibitors: The Present Hope against Deadly Bacterial Pathogens

“…ETX0282 ( 14) in combination with cefpodoxime proxetil, which is a prodrug of cefpodoxime approved for the treatment of antibiotic-resistant Enterobacteriaceae urinary tract infection, is a promising oral therapy for infections caused by ESBLproducing and carbapenem-resistant Enterobacteriaceae. [103][104][105][106] Undoubtedly, the broad-spectrum of activity of durlobactam (13) and ETX0282 ( 14)-or its active form ETX1317 (15)-represents a huge advance in restoring the efficacy of carbapenems in infections caused by the WHO priority pathogens. However, like avibactam these compounds are also inefficient against metallo--lactamases (Table 1).…”

Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections

“…clavulanic acid) which is certainly a better combination than amoxicillin ? clavulanic acid [58]. Entasis seems to be the first company that ventured into discovering a prodrug of diazabicyclooctane with good oral bioavailability.…”

“…The combination of amoxicillin and clavulanic acid is generally not preferred for UTI for two reasons: (1) the concentration of intact clavulanic acid eliminated in the urine is low and (2) clavulanic acid is not an inhibitor of class C (and also an inducer) and OXA-1 enzymes commonly associated with ESBL uropathogens [ 57 ]. Combining clavulanic acid with an oral cephalosporin was attempted (ceftibuten + clavulanic acid) which is certainly a better combination than amoxicillin + clavulanic acid [ 58 ]. Entasis seems to be the first company that ventured into discovering a prodrug of diazabicyclooctane with good oral bioavailability.…”