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

Ceftibuten-ledaborbactam etzadroxil is a cephalosporin-boronate ß-lactamase inhibitor prodrug combination under development as an oral treatment for complicated urinary tract infections caused by multidrug-resistant (MDR) Enterobacterales producing serine ß-lactamases (Ambler class A, C, and D). In vivo, ledaborbactam etzadroxil (formerly VNRX-7145) is cleaved to the active inhibitor ledaborbactam (formerly VNRX-5236). To more completely define the breadth of ceftibuten-ledaborbactam's activity against important antimicrobial-resistant pathogens, we assessed its in vitro activity against phenotypic and genotypic subsets from a 2018-2020 global culture collection of 3,889 clinical isolates of Enterobacterales, including MDR organisms, extended-spectrum-ß-lactamase (ESBL)-positive organisms, and organisms that are nonsusceptible and resistant to other antimicrobials. MICs were determined by CLSI broth microdilution and interpreted using both CLSI and EUCAST breakpoints. Ledaborbactam was tested at a fixed concentration of 4 µg/mL. ß-Lactamase genes were characterized by PCR followed by Sanger sequencing or whole-genome sequencing for selected ß-lactam-resistant isolate subsets. At ≤1 µg/mL, ceftibuten-ledaborbactam (MIC90, 0.25 µg/mL) inhibited 89.7% of MDR isolates, 98.3% of isolates with a presumptive ESBL-positive phenotype, and 92.6% of trimethoprim-sulfamethoxazole-nonsusceptible, 91.7% of levofloxacin-nonsusceptible, 88.1% of amoxicillin-clavulanate-nonsusceptible, 85.7% of ceftibuten-resistant (MIC >1 µg/mL), and 54.1% of carbapenem-nonsusceptible isolates. Against specific ESBL genotype-positive isolates (AmpC negative, serine carbapenemase negative, and metallo-ß-lactamase negative), ceftibuten-ledaborbactam inhibited 96.3% of CTX-M-9 group (MIC90, 0.25 µg/mL), 91.5% of CTX-M-1 group (MIC90, 0.5 µg/mL), and 88.2% of SHV-positive (MIC90, 2 µg/mL) isolates at ≤1 µg/mL. Against specific serine carbapenemase genotype-positive isolates, ceftibuten-ledaborbactam inhibited 85.9% of KPC-positive (MIC90, 2 µg/mL) and 82.9% of OXA-48-group-positive (MIC90, 2 µg/mL) isolates at ≤1 µg/mL. Continued development of ceftibuten-ledaborbactam appears warranted.

In Vivo Pharmacodynamic Profile of Ceftibuten-Clavulanate Combination against Extended-Spectrum-ß-Lactamase-Producing Enterobacteriaceae in the Murine Thigh Infection Model.

Ceftibuten-clavulanate (CTB-CLA) is a novel ß-lactam-ß-lactamase combination with potential utility for the management of urinary tract infections caused by extended-spectrum-ß-lactamase (ESBL)-producing organisms. We examined the pharmacodynamics of the combination against 25 Enterobacteriaceae expressing ß-lactamases (CTX-M, TEM, and SHV wild types and SHV-ESBL) in the murine thigh infection model. MIC values of CTB and CTB-CLA ranged from 1 to >32 mg/liter and 0.125 to 8 mg/liter, respectively. Human-simulated regimens of CTB and CLA equivalent to clinical doses of 400 mg orally (p.o.) every 8 h (q8h) and 187 mg q8h, respectively, were developed. CLA dose fractionation studies were undertaken to characterize the driver of efficacy. CLA dose-ranging studies were undertaken to assess the activity of the CTB human-simulated regimen in combination with escalating CLA exposures. The relationships between the percentage of the dosing interval during which the free CLA plasma concentrations remained above a threshold concentration (%fT>CT ) and the change in log10 CFU per thigh at 24 h were examined across different threshold concentrations. Additionally, the efficacy of a human-simulated regimen of CTB-CLA was assessed against isolates with various susceptibilities to the combination. The pharmacokinetic/pharmacodynamic index that best correlated with the efficacy of the combination was %fT > threshold CLA plasma concentration of 0.5 mg/liter. The plasma %fT>0.5 mg/liter associated with the static endpoint was 20.59%. For isolates with CTB-CLA MICs of ≤4 mg/liter, stasis was achieved with a human-simulated regimen of CTB-CLA against 20/22 isolates (90.9%), while for isolates with MICs of 8 mg/liter, only 1/3 tested isolates (33.3%) displayed stasis. Results suggest a susceptibility breakpoint of 4 mg/liter for CTB-CLA. These data support the consideration of the CTB-CLA combination for the treatment of urinary tract infections due to ESBL-producing Enterobacteriaceae.

Ceftibuten plus amoxicillin-clavulanic acid for oral treatment of urinary tract infections with ESBL producing E. coli and K. pneumoniae: a retrospective observational case-series.

This study aimed to evaluate the clinical and bacteriological effect of oral treatment with ceftibuten plus amoxicillin-clavulanic acid in patients with a urinary tract infection (UTI) caused by an extended-spectrum ß-lactamase (ESBL)-producing micro-organism. In this retrospective observational case-series, oral treatment with ceftibuten 400 mg QD plus amoxicillin-clavulanic acid 625 mg TID for 14 days was evaluated in ten patients with pyelonephritis caused by an ESBL-positive micro-organism resistant to ciprofloxacin and co-trimoxazole. Presence of ESBL genes was confirmed using PCR and micro-array. EUCAST breakpoints were used for susceptibility testing. Ten patients (five women) were evaluated in 2016 and 2017. Six patients were from outpatient hospital care, and four from primary care. Urinary cultures yielded seven E. coli and three K. pneumoniae ESBL-positive isolates. Using Vitek-2, all isolates were resistant to cefotaxime, and resistant (n = 7) or intermediately susceptible (n = 3) to ceftazidime. With disc diffusion, all isolates were susceptible to ceftibuten (zones 25-32 mm), while with MIC test strips eight of ten isolates were resistant to ceftibuten (MICs 0.5-4 mg/L). An amoxicillin-clavulanic acid disc next to the ceftibuten disc extended the ceftibuten zone by 2-8 mm. All patients experienced clinical cure. Bacteriological cure (absence of pretreatment micro-organism in the first follow-up culture obtained within 3 months after treatment) was observed in all eight patients with follow-up cultures. This case-series shows that the synergistic combination of ceftibuten plus amoxicillin-clavulanic acid may be an option for oral treatment of UTIs caused by ESBL producing E. coli or K. pneumoniae.