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Objectives: The use of cephalosporins combined with clavulanate for the treatment of ESBL-harbouring Enterobacteriaceae has been scarcely described. We aimed to describe the effect of different concentrations of clavulanate in the MIC of cefixime and ceftibuten of ESBL-producing Escherichia coli and Klebsiella pneumoniae. Methods: ESBL-producing E. coli and K. pneumoniae isolates were studied. Fixed concentrations of cefixime and ceftibuten (ranges of 32–0.25 and 64–0.5 ng/ml, respectively) were used. Combinations of cefixime/clavulanate and ceftibuten/clavulanate in different ratios (1:0, 1:1, 2:1, 4:1, 8:1, 16:1, 32:1) were tested. MIC were determined by broth microdilution. Results: A total of 6 ESBL-producing E. coli, 6 ESBL-producing K. pneumoniae and 2 control E. coli were tested. When different quantities of clavulanate were added to cefixime and ceftibuten, greater than two-fold decreases in the MIC were observed. When testing the 1:1 cefixime/clavulanate ratio, 10/12 isolates were susceptible. When the ratios 2:1, 4:1, 8:1 and 16:1 were tested, susceptibility was noted for 9/12, 8/12, 4/12 and 5/12 isolates, respectively. Only 2/12 K. pneumoniae isolates were susceptible when the ratio 32:1 was tested. When testing ceftibuten/clavulanate, all isolates remained susceptible across all experiments. Conclusions: Clavulanic acid has a favourable effect in reducing the MIC of cefixime and ceftibuten in isolates of ESBL-producing E. coli and K. pneumoniae. Combining clavulanate with ceftibuten or cefixime could be a useful treatment strategy.

Ceftibuten, C15H14N4O6S2, with the systematic name (6R,7R)-7-{[(Z)-2-(2-amino-1,3-thiazol-4-yl)-4-carboxybut-2-enoyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, is a third generation, orally administered cephalosporin antibiotic with broad antimicrobial activity and stability against extended spectrum β-lactamases. Ceftibuten can exist in various hydration states and to better understand the location of the water molecules of crystallization and their effect on the structure, the crystal structures of anhydrous (I) and hydrated (II) ceftibuten were determined and both occur as zwitterions with proton transfer from the carboxylate group adjacent to the β-lactam ring to the N atom of the thiazole ring. The β-lactam ring in (I) is almost planar but the equivalent grouping in (II) is slightly buckled. In the extended structure of (I), O—H...O and N—H...O hydrogen bonds link the molecules into a three-dimensional network. In (II), O—H...Oc, N—H...Oc, O—H...Ow, N—H...Ow and Ow—H...Ow (c = ceftibuten, w = water) hydrogen bonds link the components into a three-dimensional network. A large void space is present within the anhydrous crystal structure that can accommodate between two and three molecules of water.

Ledaborbactam (formerly VNRX-5236), a bicyclic boronate β-lactamase inhibitor with activity against class A, C, and D β-lactamases, is under development as an orally bioavailable etzadroxil prodrug (VNRX-7145) in combination with ceftibuten for the treatment of urinary tract infections. At ceftibuten breakpoints of ≤1 mg/L (EUCAST) and ≤8 mg/L (CLSI), 92.5% and 99.0%, respectively, of 200 carbapenem-resistant Klebsiella pneumoniae isolates, predominantly K. pneumoniae carbapenemase producing, were susceptible to ceftibuten-ledaborbactam (ledaborbactam tested at a fixed concentration of 4 mg/L) compared to 4.5% and 30.5%, respectively, to ceftibuten alone.

Objectives: The use of cephalosporins combined with clavulanate for the treatment of ESBL-harbouring Enterobacteriaceae has been scarcely described. We aimed to describe the effect of different concentrations of clavulanate in the MIC of cefixime and ceftibuten of ESBL-producing Escherichia coli and Klebsiella pneumoniae., Methods: ESBL-producing E. coli and K. pneumoniae isolates were studied. Fixed concentrations of cefixime and ceftibuten (ranges of 32-0.25 and 64-0.5 ng/ml, respectively) were used. Combinations of cefixime/clavulanate and ceftibuten/clavulanate in different ratios (1:0, 1:1, 2:1, 4:1, 8:1, 16:1, 32:1) were tested. MIC were determined by broth microdilution., Results: A total of 6 ESBL-producing E. coli, 6 ESBL-producing K. pneumoniae and 2 control E. coli were tested. When different quantities of clavulanate were added to cefixime and ceftibuten, greater than two-fold decreases in the MIC were observed. When testing the 1:1 cefixime/clavulanate ratio, 10/12 isolates were susceptible. When the ratios 2:1, 4:1, 8:1 and 16:1 were tested, susceptibility was noted for 9/12, 8/12, 4/12 and 5/12 isolates, respectively. Only 2/12 K. pneumoniae isolates were susceptible when the ratio 32:1 was tested. When testing ceftibuten/clavulanate, all isolates remained susceptible across all experiments., Conclusions: Clavulanic acid has a favourable effect in reducing the MIC of cefixime and ceftibuten in isolates of ESBL-producing E. coli and K. pneumoniae. Combining clavulanate with ceftibuten or cefixime could be a useful treatment strategy., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests. The authors did not receive direct payments from the sponsor., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Ceftibuten, C15H14N4O6S2, with the systematic name (6R,7R)-7-{[(Z)-2-(2-amino-1,3-thia­zol-4-yl)-4-carb­oxy­but-2-eno­yl]amino}-8-oxo-5-thia-1-aza­bicyclo­[4.2.0]oct-2-ene-2-carb­oxy­lic acid, is a third generation, orally administered cephalosporin anti­biotic with broad anti­microbial activity and stability against extended spectrum β-lactamases. Ceftibuten can exist in various hydration states and to better understand the location of the water mol­ecules of crystallization and their effect on the structure, the crystal structures of anhydrous (I) and hydrated (II) ceftibuten were determined and both occur as zwitterions with proton transfer from the carboxyl­ate group adjacent to the β-lactam ring to the N atom of the thia­zole ring. The β-lactam ring in (I) is almost planar but the equivalent grouping in (II) is slightly buckled. In the extended structure of (I), O—HO and N—HO hydrogen bonds link the mol­ecules into a three-dimensional network. In (II), O—HOc, N—HOc, O—HOw, N—HOw and Ow—HOw (c = ceftibuten, w = water) hydrogen bonds link the components into a three-dimensional network. A large void space is present within the anhydrous crystal structure that can accommodate between two and three mol­ecules of water. [ABSTRACT FROM AUTHOR]

The treatment of urinary tract infections (UTIs) has been complicated by the emergence of multidrug-resistant, β-lactamase-expressing pathogens. As a result of the limited treatment options, patients often require hospitalization and intravenous therapy. In essence, a strong unmet need for oral antibiotics, active against extended-spectrum β-lactamase (ESBL) uropathogens has emerged. Oral carbapenems (tebipenem and sulopenem) and oral cephalosporin/β-lactamase inhibitor combinations are in various stages of clinical development for the treatment of uncomplicated and complicated UTI. Tebipenem, if approved, will be the first oral treatment for complicated UTI while sulopenem will be for uncomplicated UTI. The β-lactamase inhibitors ETX0282, VNRX7145, ARX1796, and QPX7728 are combined with cefpodoxime proxetil or ceftibuten that achieve favorable exposures in urine compared to other uropathogen-active oral cephalosporins. The combination ceftibuten-QPX7728 has potential broad-spectrum coverage against carbapenemase producers including metallo β-lactamase producers. Other novel combinations, namely cefpodoxime/ETX0282, ceftibuten/VNRX-7145, and ceftibuten/ARX1796, have also demonstrated excellent activity against Klebsiella pneumoniae carbapanemase (KPC) and OXA-48-like producers. All these agents, upon their arrival for commercial use, would strengthen the outpatient therapy. [ABSTRACT FROM AUTHOR]

There are challenges in developing dispersible tablets with a high drug loading of a waterinsoluble drug having flexibility, either as dispersible in water or as dispersible in the oral cavity before swallowing with overall acceptability. Overall acceptability is determined by the characteristics of the drug product and user acceptance. This study aimed to design and optimise the flexible dispersible tablets design using a model drug, namely ceftibuten with the drug loading of about 72%w/w of targeted tablet weight, in a statistically significant manner using design-expert software. The significant effects of screened input parameters on target responses were characterised based on the half-normal plot for the magnitude of effects, pareto chart for standardised effects, and variance analysis for the statistically significant model. The characterised design was optimised using the response surface method (RSM). The optimised target response was statistically confirmed based on the extent of statistical significance (very significant <0.01, significant <0.05 but >0.01). Among the input factors studied, crospovidone concentration shows a statistically very significant effect (<0.0001) on target response namely in vitro disintegration time, in vivo disintegration time, and overall acceptability of intended flexible dispersible tablet design. The outcome of designed and evaluated flexible dispersible tablets (FDT) using design-expert software demonstrated its ability to predict the design space with a statistical significance, which maximises the robust product characteristics and overall user acceptance. [ABSTRACT FROM AUTHOR]

ObjectiveAntibiotic use rates have declined dramatically since the 1990s. We aimed to determine if, when, and at what level the decline in antibiotic-dispensing rates ended and which diagnoses contributed to the trends.MethodsAntibiotic dispensings and diagnoses were obtained from 2 health insurers for 3- to

AbstractObjective: We aimed to investigate the incidence and characteristics of acute prostatitis after transrectal prostate biopsy in men whom were given prophylactic ceftibuten combined with gentamicin.Material and Methods: We analyzed the retrospective data from 245 patients who underwent transrectal ultrasound (TRUS) guided prostate biopsy over a 2 year period. Men in which acute prostatitis occured after the procedure were investigated. All patients received 400 mg ceftibuten orally once daily for 5 days, beginning 12 and 2 hours before biopsy; combined with single dose 160 mg gentamicin intramuscularly just before the procedure. All biopsies were performed as outpatient procedures. Results: Of the 245 cases, acute prostatitis developed in 2 (0,8%). Escherichia Coli that was positive for extended spectrum β-lactamase activity was isolated both from blood and urine in 1 case. The bacteria detected in urine and blood cultures were resistant to ciprofloxacin, levofloxacin, gentamicin, cefepime, ceftriaxone and cefuroxime. However, no bacteria was isolated either from blood or urine in the other case. Both patients had acute prostatitis after the first biopsy. Conclusion: Prophylactic ceftibuten combined with single dose gentamicin seems effective in preventing acute bacterial prostatitis after TRUS-guided prostate biopsy. Due to increasing rate of quinolone resistance among the world, alternative prophylaxis regimens including cephalosporins such as ceftibuten should be considered in men undergoing prostate biopsy. Prospective randomized trials with larger series may give more conclusive data.

This was a phase I, randomized, double-blind, placebo-controlled, ascending single- and multiple-dose study of oral ceftibuten to describe the pharmacokinetics (PK) of cis- ceftibuten (administered form) and trans- ceftibuten (metabolite), and to describe safety and tolerability at higher than licensed doses. Subjects received single 400, 600, or 800 mg doses of ceftibuten on Days 1 and 4, followed by 7 days of twice-daily dosing from Days 4 to 10. Non-compartmental methods were used to describe parent drug and metabolite PK in plasma and urine. Dose proportionality was examined using C max , AUC 0-12 , and AUC 0-INF . Accumulation was calculated as the ratio of AUC 0-12 on Days 4 and 10. Adverse events (AEs) were monitored throughout the study. Following single ascending doses, mean cis ceftibuten trans- ceftibuten C -ceftibuten urinary recovery accounted for 64.3%-86.9% of the administered dose over 48 h. Following multiple ascending doses, mean max were 17.6, 24.1, and 28.1 mg/L, and 1.1, 1.5, and 2.2 mg/L, respectively; cis ceftibuten cis - and trans- -ceftibuten urinary recovery accounted for 72.2%-96.4% of the administered dose at steady state. The exposure of C max ceftibuten increased proportionally with increasing doses. cis -ceftibuten urinary recovery accounted for 72.2%-96.4% of the administered dose at steady state. The exposure of cis- ceftibuten accumulation factor was 1.14-1.19 and 1.28-1.32. The most common gastrointestinal treatment emergent AEs were mild and resolved without intervention. Ceftibuten was well tolerated. Dose proportionality and accumulation of trans- ceftibuten increased proportionally with increasing doses. Cis -ceftibuten were observed. These results support the ongoing development of ceftibuten at doses up to 800 mg twice-daily. (The study was registered at ClinicalTrials.gov under the identifier NCT03939429.).trans- ceftibuten accumulation factor was 1.14-1.19 and 1.28-1.32. The most common gastrointestinal treatment emergent AEs were mild and resolved without intervention. Ceftibuten was well tolerated. Dose proportionality and accumulation of cis - and trans -ceftibuten were observed. These results support the ongoing development of ceftibuten at doses up to 800 mg twice-daily. (The study was registered at ClinicalTrials.gov under the identifier NCT03939429.)., Competing Interests: Elizabeth E. Morgan, Michael N. Dudley, Jeffery S. Loutit, and David C. Griffith are all employees of Qpex Biopharma.

Acute tonsillitis (AT) (from Latin tonsillae - tonsils; Russian synonym - "angina" (Engl. sore throat), from Latin ango - clasp, squeeze, strangle) is an acute infectious disease which is locally manifested in acute inflammation of components of the pharyngeal lymphatic ring, often the tonsils. The term angina (in Russian means sore throat) has been known since ancient times; today it is associated with various pathological conditions in the oropharynx with common symptoms but different etiology and course.

Objective. Objectives. To investigate etiology and in vitro susceptibility of the most common pathogens causing community-acquired urinary tract infections (UTIs) in Russia. Materials and Methods. A total of 182 uropathogens isolated from urine samples of patients with communityacquired UTI were collected in Russia during 2013–2014 and included in the study. Results. Among the identified microorganisms the most prevalent uropathogens were Enterobacteriaceae (87,9%) and E. coli (68,1%). Drugs active against more than 90% of all Enterobacteriaceae isolates were fosfomycin (98,1%) and ceftibuten (93,1%). Susceptibility rates to other tested β-lactams were at the range of 63,7% — 81,9%. Fluoroquinolones, nitrofurantoin and co-trimoxazole were active against 75% — 84% of all Enterobacteriaceae isolates. Out of tested antibiotics the most active against E. coli were again fosfomycin (99%), nitrofurantoin (98%) and ceftibuten (95%). Susceptibility of E. coli isolates to fluoroquinolones (ciprofloxacin and norfloxacin) was 78% and 81%, respectively. Susceptibility of E. coli to co-trimoxazole was 73%. Conclusions. Higher susceptibility rates of all Enterobacteriaceae and E. coli alone to fosfomycin and ceftibuten shown in this study enable the use of these antimicrobials in treatment of community-acquired UTI in Russia.

The impact of β-lactamases on susceptibility to oral penems/carbapenems (tebipenem, sulopenem, and faropenem) and other carbapenem molecules was evaluated in Escherichia coli , alone and in combination with avibactam or taniborbactam β-lactamase inhibitors. Tebipenem and sulopenem exhibited a similar spectrum of activity compared to the intravenous carbapenems and displayed lower MIC values than ceftibuten-avibactam against E. coli producing extended-spectrum β-lactamases or AmpC enzymes. Combined with taniborbactam, tebipenem and sulopenem exhibited low MIC values against almost all tested recombinant E. coli , including metallo-β-lactamase producers., Competing Interests: The authors declare no conflict of interest.

Acute tonsillopharyngitis is one of the most common community-acquired infections. Up to 20–30 % cases of this disease in childhood are caused by the group A -hemolytic streptococcus and required systemic antibacterial treatment in order to arrest symptoms and localization of the infectious focus as well as to prevent purulent complications (acute rheumatic fever etc.). Despite the well-known total perceptibility of the group A -hemolytic streptococcus to penicillin in vitro, the cases of recurrent clinical course due to the lack of eradication of the causative agent during the initial penicillin therapy or re-infection are common. The analysis of both causes of clinical and/or bacteriological inefficacy of the treatment and the ways to overcome these problems, including with the help of alternative antibacterial drugs, are discussed in the article.

Extended-spectrum-beta-lactamase (ESBL)-producing Enterobacterales as a cause of community-acquired uncomplicated urinary tract infection (UTI) is on the rise. Currently, there are minimal oral treatment options. New combinations of existing oral third-generation cephalosporins paired with clavulanate may overcome resistance mechanisms seen in these emerging uropathogens. Ceftriaxone-resistant Escherichia coli and Klebsiella pneumoniae containing CTX-M-type ESBLs or AmpC, in addition to narrow-spectrum OXA and SHV enzymes, were selected from blood culture isolates obtained from the MERINO trial. Minimum inhibitory concentration (MIC) values of third-generation cephalosporins (cefpodoxime, ceftibuten, cefixime, cefdinir), both with and without clavulanate, were determined. One hundred and one isolates were used with ESBL, AmpC and narrow-spectrum OXA genes (e.g. OXA-1, OXA-10) present in 84, 15 and 35 isolates, respectively. Susceptibility to oral third-generation cephalosporins alone was very poor. Addition of 2 mg/L clavulanate reduced the MIC 50 values (cefpodoxime MIC 50 2 mg/L, ceftibuten MIC 50 2 mg/L, cefixime MIC 50 2 mg/L, cefdinir MIC 50 4 mg/L) and restored susceptibility (33%, 49%, 40% and 21% susceptible, respectively) in a substantial number of isolates. This finding was less pronounced in isolates co-harbouring AmpC. In-vitro activity of these new combinations may be limited in real-world Enterobacterales isolates co-harbouring multiple antimicrobial resistance genes. Pharmacokinetic/pharmacodynamic data would be useful for further evaluation of their activity., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Ceftibuten/ARX-1796 (avibactam prodrug) is a novel oral antibacterial combination in early clinical development for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis. ARX-1796 is the novel avibactam prodrug being combined with ceftibuten for oral dosing that is converted to active avibactam in vivo . A Clinical and Laboratory Standards Institute (CLSI) M23 (2018) tier 2 broth microdilution quality control (QC) study was conducted with ceftibuten-avibactam to establish MIC QC ranges. Ceftibuten-avibactam broth microdilution QC ranges were approved for Escherichia coli ATCC 25922 (0.016/4 to 0.12/4 μg/mL), E. coli NCTC 13353 (0.03/4 to 0.12/4 μg/mL), Klebsiella pneumoniae ATCC 700603 (0.06/4 to 0.25/4 μg/mL), K. pneumoniae ATCC BAA-1705 (0.03/4 to 0.25/4 μg/mL), and K. pneumoniae ATCC BAA-2814 (0.12/4 to 0.5/4 μg/mL) by the CLSI Subcommittee on Antimicrobial Susceptibility Testing in January 2022. Approved ceftibuten-avibactam QC ranges will support future clinical development, device manufacturers, and routine patient care., Competing Interests: The authors declare a conflict of interest. The studies were performed by JMI Laboratories and supported by Pfizer, Inc. M.D.H., K.A.F., H.S.S., and M.C. are employees of JMI Laboratories, which was a paid consultant to Pfizer in connection with the development of this manuscript. G.G.S. is an employee of Pfizer, Inc. JMI Laboratories contracted to perform services in 2021 for AbbVie Inc., Affinity Biosensors, AimMax Therapeutics, Inc., Alterity Therapeutics, Amicrobe, Inc., Arietis Pharma, Armata Pharmaceuticals, Inc., Astrellas Pharma Inc., Basilea Pharmaceutica AG, Becton, Dickinson and Company (BD), bioMérieux, Inc., Boost Biomes, Brass Dome Ventures Ltd., Bravos Biosciences, Bugworks Research Inc., Centers for Disease Control and Prevention, Cerba Research, Cidara Therapeutics, Cipla Ltd., ContraFect Corp., CXC7, DiamondV, Enveda Biosciences, Fedora Pharmaceuticals, Inc., Fimbrion Therapeutics, First Light Diagnostics, Forge Therapeutics, Inc., Fox Chase Cancer Center, GlaxoSmithKline plc (GSK), Harvard University, Institute for Clinical Pharmacodynamics (ICPD), International Health Management Associates (IHMA), Inc., Iterum Therapeutics plc, Janssen Research & Development, Johnson & Johnson, Kaleido Biosciences, Inc., Laboratory Specialists, Inc. (LSI), Meiji Seika Pharma Co., Ltd., Melinta Therapeutics, Menarini Group, Merck & Co., Inc., MicuRx Pharmaceuticals Inc., Mutabilis, Nabriva Therapeutics, National Institutes of Health, Novome Biotechnologies, Omnix Medical Ltd., Paratek Pharma, Pattern Bioscience, Pfizer Inc., Prokaryotics Inc., Pulmocide Ltd., QPEX Biopharma, Inc., Roche Holding AG, Roivant Sciences, SeLux Diagnostics, Inc., Shionogi Inc., Sinovent Pharmaceuticals, Inc., SNIPR Biome ApS, Spero Therapeutics, Summit Therapeutics, Inc., T2 Biosystems, TenNor Therapeutics, Thermo Fisher Scientific, University of Southern California, University of Wisconsin, USCAST, U.S. Food and Drug Administration, Venatorx Pharmaceutics, Inc., Weill Cornell Medicine, and Wockhardt Ltd.

Tonsillopharyngitis is a common multietiological infectious disease, more often caused by streptococci infection. The development and adoption of oral III generation cephalosporins into clinical practice significantly widened the possibilities of treatment of inflammatoryinfectious diseases, including tonsillopharyngitis. One of the III generation cephalosporins is Ceftibuten (Cedax) — a drug with b-lactam properties, which inhibits bacterial peptidoglycan synthesis. It has relatively long post-antibiotic effect, characterized by high activity in point of majority of enterobacteria, and is very stable to destructive action of -lactamases. It also can be accumulated in tissues, providing high concentration of active substance in inflammation nidus. The therapeutic dose of the drug for adults is 400 mg/day. Ceftibuten is recommended and effectively used in pediatric practice in treatment of tonsillopharyngitis and otitis.

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 (MIC 50/90 , 0.03/0.06 mg/L) was fourfold more potent than ceftazidime-avibactam (MIC 50/90 , 0.12/0.25 mg/L) based on MIC 50/90 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., (© 2023. The Author(s).)

We used 73 group B Streptococcus with reduced penicillin susceptibility (PRGBS) isolates and determined more rational cutoff values of previously developed disk diffusion method for detecting PRGBS using oxacillin, ceftizoxime, and ceftibuten disks. Using the novel cutoff values, the three disks showed high sensitivity and specificity, which were above 90.0%., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Ceftibuten is an established, oral, third-generation cephalosporin in early clinical development in combination with an oral prodrug of avibactam for the treatment of complicated urinary tract infections, including acute pyelonephritis. We evaluated the in vitro activity of ceftibuten-avibactam against 1,165 Enterobacterales isolates selected from the 2016-2020 ATLAS global surveillance program based upon their β-lactamase genotype, β-lactam-susceptible phenotype, species identification, and specimen source (95.8% urine). MICs were determined by CLSI broth microdilution. Avibactam was tested at a fixed concentration of 4 μg/mL. Molecular methods were used to identify β-lactamase genes. Ceftibuten-avibactam inhibited 90% (MIC 90 ) of ESBL-producing ( n = 645), KPC-producing ( n = 60), chromosomal AmpC-positive ( n = 100), OXA-48-like-producing ( n = 50), and acquired AmpC-producing ( n = 110) isolates at concentrations of 0.12, 0.5, 1, 2, and 4 μg/mL, respectively. At concentrations of ≤1 and ≤8 μg/mL, ceftibuten-avibactam inhibited 98.4 and 99.2% of ESBL-positive isolates; 96.7 and 100% of KPC-positive isolates; 91.0 and 99.0% of chromosomal AmpC-positive isolates; 86.0 and 96.0% of OXA-48-like-positive isolates; and 85.5 and 91.8% of acquired AmpC-positive isolates. Against ESBL-producing, KPC-producing, chromosomal AmpC-positive, OXA-48-like-producing, and acquired AmpC-producing isolates, ceftibuten-avibactam was 256-, 128-, >64-, >32-, and > 16-fold more potent than ceftibuten alone. The potency of ceftibuten-avibactam was 4-fold greater than ceftazidime-avibactam against ESBL-producing (ceftibuten-avibactam MIC 90 , 0.12 μg/mL; ceftazidime-avibactam MIC 90 , 0.5 μg/mL) and KPC-producing (0.5 μg/mL; 2 μg/mL) isolates, equivalent to ceftazidime-avibactam (MIC 90 , 2 μg/mL) against OXA-48-like-producing isolates, 2-fold less active than ceftazidime-avibactam (1 μg/mL; 0.5 μg/mL) against chromosomal AmpC-positive isolates, and 4-fold less active than ceftazidime-avibactam (4 μg/mL; 1 μg/mL) against acquired AmpC-producing isolates. Continued development of ceftibuten-avibactam appears justified.

Objectives: Oral β-lactam treatment options for MDR Enterobacterales are lacking. Ledaborbactam (formerly VNRX-5236) is a novel orally bioavailable β-lactamase inhibitor that restores ceftibuten activity against Ambler Class A-, C- and D-producing Enterobacterales. We assessed the ledaborbactam exposure needed to produce bacteriostasis against ceftibuten-resistant Enterobacterales in the presence of humanized ceftibuten exposures in the neutropenic murine thigh infection model., Methods: Twelve ceftibuten-resistant clinical isolates (six Klebsiella pneumoniae, five Escherichia coli and one Enterobacter cloacae) were utilized. Ceftibuten/ledaborbactam MICs ranged from 0.12 to 2 mg/L (ledaborbactam fixed at 4 mg/L). A ceftibuten murine dosing regimen mimicking ceftibuten 600 mg q12h human exposure was developed and administered alone and in combination with escalating exposures of ledaborbactam. The log10 cfu/thigh change at 24 h relative to 0 h controls was plotted against ledaborbactam fAUC0-24/MIC and the Hill equation was used to determine exposures associated with bacteriostasis., Results: The mean ± SD 0 h bacterial burden was 5.96 ± 0.24 log10 cfu/thigh. Robust growth (3.12 ± 0.93 log10 cfu/thigh) was achieved in untreated control mice. Growth of 2.51 ± 1.09 log10 cfu/thigh was observed after administration of humanized ceftibuten monotherapy. Individual isolate exposure-response relationships were strong (mean ± SD R2 = 0.82 ± 0.15). The median ledaborbactam fAUC0-24/MIC associated with stasis was 3.59 among individual isolates and 6.92 in the composite model., Conclusions: Ledaborbactam fAUC0-24/MIC exposures for stasis were quantified with a ceftibuten human-simulated regimen against β-lactamase-producing Enterobacterales. This study supports the continued development of oral ceftibuten/ledaborbactam etzadroxil (formerly ceftibuten/VNRX-7145)., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)