Antimicrobial activity of ceftibuten-avibactam against a global collection of Enterobacterales from patients with urinary tract infections (2021)

Abstract

We evaluated the in vitro activity of ceftibuten-avibactam against Enterobacterales causing urinary tract infection (UTI). A total of 3216 isolates (1/patient) were consecutively collected from patients with UTI in 72 hospitals from 25 countries in 2021 then susceptibility tested by CLSI broth microdilution. Ceftibuten-susceptible breakpoints currently published by EUCAST (≤ 1 mg/L) and CLSI (≤ 8 mg/L) were applied to ceftibuten-avibactam for comparison. The most active agents were ceftibuten-avibactam (98.4%/99.6% inhibited at ≤ 1/ ≤ 8 mg/L), ceftazidime-avibactam (99.6% susceptible [S]), amikacin (99.1%S), and meropenem (98.2%S). Ceftibuten-avibactam (MIC50/90, 0.03/0.06 mg/L) was fourfold more potent than ceftazidime-avibactam (MIC50/90, 0.12/0.25 mg/L) based on MIC50/90 values. The most active oral agents were ceftibuten (89.3%S; 79.5% inhibited at ≤ 1 mg/L), levofloxacin (75.4%S), and trimethoprim-sulfamethoxazole (TMP-SMX; 73.4%S). Ceftibuten-avibactam inhibited 97.6% of isolates with an extended-spectrum β-lactamase phenotype, 92.1% of multidrug-resistant isolates, and 73.7% of carbapenem-resistant Enterobacterales (CRE) at ≤ 1 mg/L. The second most active oral agent against CRE was TMP-SMX (24.6%S). Ceftazidime-avibactam was active against 77.2% of CRE isolates. In conclusion, ceftibuten-avibactam was highly active against a large collection of contemporary Enterobacterales isolated from patients with UTI and exhibited a similar spectrum to ceftazidime-avibactam. Ceftibuten-avibactam may represent a valuable option for oral treatment of UTI caused by multidrug-resistant Enterobacterales.

Antibacterial Prodrugs to Overcome Bacterial Antimicrobial Resistance

“…The addition of the β-lactamase inhibitor avibactam (24, Figure 8) leads to the broadening of the spectrum of Gram-negative pathogens that are susceptible to the drug, including β-lactamase-producing Enterobacterales [27,29,30]. A study carried out by Sader et al [30] determined MIC50 and MIC90 values of 0.03 and 0.06 µg/mL, respectively, for the ceftibuten-avibactam combination against 3216 Enterobacterales. Rifabutin (25, Figure 9) is a semisynthetic product from the rifamycins class of antibiotics that, in addition to its antituberculosis properties, has recently shown potent activity against A. baumannii strains in vitro and in vivo.…”

“…Ceftibuten ( 23 , Figure 8 ), an orally active 3rd generation cephalosporin, is already approved for the treatment of infections caused by H. influenzae , H. parainfluenzae , M. catarrhalis , and penicillin-susceptible S. pneumoniae , having already shown clinical efficiency in the treatment of uncomplicated UTIs. The addition of the β -lactamase inhibitor avibactam ( 24 , Figure 8 ) leads to the broadening of the spectrum of Gram-negative pathogens that are susceptible to the drug, including β -lactamase-producing Enterobacterales [ 27 , 29 , 30 ]. A study carried out by Sader et al [ 30 ] determined MIC 50 and MIC 90 values of 0.03 and 0.06 µg/mL, respectively, for the ceftibuten-avibactam combination against 3216 Enterobacterales.…”

“…The addition of the β -lactamase inhibitor avibactam ( 24 , Figure 8 ) leads to the broadening of the spectrum of Gram-negative pathogens that are susceptible to the drug, including β -lactamase-producing Enterobacterales [ 27 , 29 , 30 ]. A study carried out by Sader et al [ 30 ] determined MIC 50 and MIC 90 values of 0.03 and 0.06 µg/mL, respectively, for the ceftibuten-avibactam combination against 3216 Enterobacterales.…”

“… Structure of TBP-PI-HBR ( 22 ), ceftibuten ( 23 ), and avibactam ( 24 ) [ 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. …”

Determination of MIC Quality Control Ranges for Ceftibuten-Avibactam (Fixed 4 μg/mL), a Novel β-Lactam/β-Lactamase Inhibitor Combination

“…The effectiveness of cephalosporins, including ceftibuten, against Enterobacterales isolates has diminished due to the emergence and spread of ESBL- and carbapenemase (KPC and OXA-48)-producing isolates. Ceftibuten/ARX-1796 (avibactam prodrug) is a new orally active antibacterial combination in early clinical development possessing potent in vitro activity against ESBL-, KPC-, OXA-48-, and AmpC-producing Enterobacterales isolates, including those causing urinary tract infections ( 9 – 11 ; H. S. Sader, C. G. Carvalhaes, M. D. Huband, R. E. Mendes, and M. Castanheira, 12 ). ARX-1796 is the novel prodrug of avibactam being combined with ceftibuten for oral dosing that is converted to active avibactam in vivo .…”