In Vitro Activity of Ceftibuten/VNRX-5236 against Urinary Tract Infection Isolates of Antimicrobial-Resistant Enterobacterales

Abstract

Ceftibuten/VNRX-7145 is a cephalosporin/boronate β-lactamase inhibitor combination under development as an oral treatment for complicated urinary tract infections caused by Enterobacterales producing serine β-lactamases (Ambler class A, C and D). In vivo , VNRX-7145 (VNRX-5236 etzadroxil) is cleaved to the active inhibitor, VNRX-5236. We assessed the in vitro activity of ceftibuten/VNRX-5236 against 1,066 urinary isolates of Enterobacterales from a 2014-2016 global culture collection. Each isolate tested was pre-selected to possess a multidrug-resistant (MDR) phenotype that included non-susceptibility to amoxicillin-clavulanate and resistance to levofloxacin. MICs were determined by CLSI broth microdilution. VNRX-5236 was tested at a fixed concentration of 4 μg/ml. Ceftibuten/VNRX-5236 inhibited 90% of all isolates tested (MIC 90 ) at 2 μg/ml; MIC 90 s for ESBL- ( n =566), serine carbapenemase- ( n =116), and acquired AmpC-positive ( n =58) isolate subsets were ≤0.25, >32, and 8 μg/ml, respectively. At concentrations of ≤1, ≤2, and ≤4 μg/ml, ceftibuten/VNRX-5236 inhibited 89.1, 91.7, and 93.1% of all isolates tested; 96.5, 97.7, and 98.4% of ESBL-positive isolates; 75.9, 81.9, and 81.9% of serine carbapenemase-positive isolates; and 70.7, 81.0, and 87.9% of acquired AmpC-positive isolates. Ceftibuten/VNRX-5236 at concentrations of ≤1, ≤2, and ≤4 μg/ml inhibited 85-89, 89-91, and 91-92% of isolates that were not susceptible (defined by CLSI and EUCAST breakpoint criteria) to nitrofurantoin, trimethoprim-sulfamethoxazole, and/or fosfomycin, (as part of their MDR phenotype), oral agents commonly prescribed to treat uncomplicated urinary tract infections. The potency of ceftibuten/VNRX-5236 (MIC 90 , 2 μg/ml) was similar (within one doubling-dilution) to intravenous-only agents ceftazidime-avibactam (MIC 90 2 μg/ml) and meropenem-vaborbactam (MIC 90 1 μg/ml). Continued investigation of ceftibuten/VNRX-5236 is warranted.

Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-β-Lactamase-Positive Clinical Isolates of Enterobacterales from a 2018–2020 Global Surveillance Collection

“…Our study of recent isolates collected globally demonstrated that ceftibuten-ledaborbactam possesses potent in vitro activity (>88% of isolates were inhibited at 1 μg/mL) against ESBL-positive (CTX-M-1 group-, CTX-M-9 group-, and SHV-positive) isolates of Enterobacterales , confirming earlier reports ( 12 , 13 , 19 ). For molecularly defined ESBL-positive isolates, ceftibuten-ledaborbactam (MIC 90 , 0.25 to 2 μg/mL), imipenem (MIC 90 , 0.25 to 1 μg/mL), and meropenem (MIC 90 , 0.12 to 0.25 μg/mL) had low MICs (≤1 μg/mL) and comparable in vitro activities ( Table 2 ).…”

“…Ceftibuten-ledaborbactam at 1 μg/mL inhibited 89.7% of MDR isolates, compared to susceptibilities of 86.5% for imipenem-relebactam, 84.6% for meropenem, and 77.6% for imipenem. Previous studies have also reported that ceftibuten-ledaborbactam demonstrated similar potency in vitro compared to carbapenems (meropenem) and current β-lactam/β-lactamase inhibitors (meropenem-vaborbactam and ceftazidime-avibactam) against MDR Enterobacterales ( 12 , 19 ). In one recent study of 205 challenge set isolates of Enterobacterales , Mendes et al reported that ceftibuten-ledaborbactam MICs (MIC 50 , 0.12 μg/mL; MIC 90 , 1 μg/mL) were 2- to 4-fold lower than for ceftazidime-avibactam (MIC 50 , 0.5 μg/mL; MIC 90 , 2 μg/mL) ( 13 ).…”

“…Mendes et al reported ceftibuten-ledaborbactam MIC 90 s of 0.5 and 1 μg/mL, respectively, for 50 KPC-positive and 52 OXA-48-like-positive isolates of Enterobacterales ; 92.0% of KPC-positive isolates and 94.0% of OXA-48-like-positive isolates were inhibited by ceftibuten-ledaborbactam at a concentration of ≤1 μg/mL ( 13 ). Another earlier study showed that although ceftibuten-ledaborbactam was active against OXA-48/OXA-48-like producers in isolation or in isolates also producing an ESBL, MICs were elevated against isolates coproducing OXA-48 group and CMY or OXA-48 group and DHA ( 12 ). Overexpression of an ESBL (CTX-M-15) or KPC (KPC-2 or KPC-3) in isogenic strains of E. coli did not significantly increase ceftibuten-ledaborbactam MICs, while the overexpression of an AmpC β-lactamase (P99 or CMY-42) increased MICs from 0.25 μg/mL (control) to 4 μg/mL ( 20 ).…”

“…Ledaborbactam covalently and reversibly binds and inhibits the active site serine of Ambler class A, C, and D β-lactamases ( 7 – 10 ). Ceftibuten-ledaborbactam has shown potent inhibitory activity against challenge sets of MDR Enterobacterales expressing serine β-lactamases (Ambler class A, C, and D), including those that hydrolyze carbapenems such as KPCs and OXAs ( 11 – 13 ). Ledaborbactam alone lacks antibacterial activity ( 11 ).…”

Carbapenemase Inhibitors: Updates on Developments in 2021

“…The combination of CTB/VNRX-7154 showed similar potency level to ceftazidime-avibactam (IV) and meropenem-avibactam against Enterobacterales- producing SBLs, in in vitro studies. This combination offers an alternative path to treatment since it is readily orally available [ 55 ].…”