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Acta Crystallographica. Section E,... Apr 2022Ceftibuten, CHNOS, with the systematic name...
Ceftibuten, CHNOS, with the systematic name (6,7)-7-{[()-2-(2-amino-1,3-thia-zol-4-yl)-4-carb-oxy-but-2-eno-yl]amino}-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carb-oxy-lic acid, is a third generation, orally administered cephalosporin anti-biotic with broad anti-microbial activity and stability against extended spectrum β-lactamases. Ceftibuten can exist in various hydration states and to better understand the location of the water mol-ecules 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 carboxyl-ate group adjacent to the β-lactam ring to the N atom of the thia-zole 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 mol-ecules into a three-dimensional network. In (II), O-H⋯O, N-H⋯O, O-H⋯O, N-H⋯O and O-H⋯O (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 mol-ecules of water.
PubMed: 35492283
DOI: 10.1107/S2056989022002110 -
The Journal of Antimicrobial... Dec 2022Oral β-lactam treatment options for MDR Enterobacterales are lacking. Ledaborbactam (formerly VNRX-5236) is a novel orally bioavailable β-lactamase inhibitor that...
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).
Topics: Animals; Mice; Humans; Ceftibuten; beta-Lactamase Inhibitors; Anti-Bacterial Agents; Lactams; Klebsiella pneumoniae; Escherichia coli; Microbial Sensitivity Tests; beta-Lactamases
PubMed: 36272135
DOI: 10.1093/jac/dkac359 -
Antimicrobial Agents and Chemotherapy Nov 2022Ceftibuten-ledaborbactam etzadroxil is a cephalosporin-boronate β-lactamase inhibitor prodrug combination under development as an oral treatment for complicated urinary...
Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-β-Lactamase-Positive Clinical Isolates of from a 2018-2020 Global Surveillance Collection.
Ceftibuten-ledaborbactam etzadroxil is a cephalosporin-boronate β-lactamase inhibitor prodrug combination under development as an oral treatment for complicated urinary tract infections caused by multidrug-resistant (MDR) producing serine β-lactamases (Ambler class A, C, and D). , 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 activity against phenotypic and genotypic subsets from a 2018-2020 global culture collection of 3,889 clinical isolates of , including MDR organisms, extended-spectrum-β-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. β-Lactamase genes were characterized by PCR followed by Sanger sequencing or whole-genome sequencing for selected β-lactam-resistant isolate subsets. At ≤1 μg/mL, ceftibuten-ledaborbactam (MIC, 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-β-lactamase negative), ceftibuten-ledaborbactam inhibited 96.3% of CTX-M-9 group (MIC, 0.25 μg/mL), 91.5% of CTX-M-1 group (MIC, 0.5 μg/mL), and 88.2% of SHV-positive (MIC, 2 μg/mL) isolates at ≤1 μg/mL. Against specific serine carbapenemase genotype-positive isolates, ceftibuten-ledaborbactam inhibited 85.9% of KPC-positive (MIC, 2 μg/mL) and 82.9% of OXA-48-group-positive (MIC, 2 μg/mL) isolates at ≤1 μg/mL. Continued development of ceftibuten-ledaborbactam appears warranted.
Topics: Ceftibuten; Anti-Bacterial Agents; beta-Lactamases; Microbial Sensitivity Tests; Serine; Azabicyclo Compounds
PubMed: 36286518
DOI: 10.1128/aac.00934-22 -
Antimicrobial Agents and Chemotherapy Jan 2024This was a phase I, randomized, double-blind, placebo-controlled, ascending single- and multiple-dose study of oral ceftibuten to describe the pharmacokinetics (PK) of... (Randomized Controlled Trial)
Randomized Controlled Trial
A phase I, randomized, double-blind, placebo-controlled, ascending single- and multiple-dose study of the pharmacokinetics, safety, and tolerability of oral ceftibuten in healthy adult subjects.
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 ceftibuten (administered form) and 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 , AUC, and AUC. Accumulation was calculated as the ratio of AUC on Days 4 and 10. Adverse events (AEs) were monitored throughout the study. Following single ascending doses, mean - and ceftibuten were 17.6, 24.1, and 28.1 mg/L, and 1.1, 1.5, and 2.2 mg/L, respectively; -ceftibuten urinary recovery accounted for 64.3%-86.9% of the administered dose over 48 h. Following multiple ascending doses, mean - and ceftibuten were 21.7, 28.1, and 38.8 mg/L, and 1.4, 1.9, and 2.8 mg/L, respectively; -ceftibuten urinary recovery accounted for 72.2%-96.4% of the administered dose at steady state. The exposure of and ceftibuten increased proportionally with increasing doses. - and 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 - and -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.).
Topics: Adult; Humans; Ceftibuten; Area Under Curve; Double-Blind Method; Healthy Volunteers; Administration, Oral; Dose-Response Relationship, Drug
PubMed: 38059635
DOI: 10.1128/aac.01099-23 -
PLoS Computational Biology Jun 2022The rate of modern drug discovery using experimental screening methods still lags behind the rate at which pathogens mutate, underscoring the need for fast and accurate...
The rate of modern drug discovery using experimental screening methods still lags behind the rate at which pathogens mutate, underscoring the need for fast and accurate predictive simulations of protein evolution. Multidrug-resistant bacteria evade our defenses by expressing a series of proteins, the most famous of which is the 29-kilodalton enzyme, TEM β-lactamase. Considering these challenges, we applied a covalent docking heuristic to measure the effects of all possible alanine 237 substitutions in TEM due to this codon's importance for catalysis and effects on the binding affinities of commercially-available β-lactam compounds. In addition to the usual mutations that reduce substrate binding due to steric hindrance, we identified two distinctive specificity-shifting TEM mutations, Ala237Arg and Ala237Lys, and their respective modes of action. Notably, we discovered and verified through minimum inhibitory concentration assays that, while these mutations and their bulkier side chains lead to steric clashes that curtail ampicillin binding, these same groups foster salt bridges with the negatively-charged side-chain of the cephalosporin cefixime, widely used in the clinic to treat multi-resistant bacterial infections. To measure the stability of these unexpected interactions, we used molecular dynamics simulations and found the binding modes to be stable despite the application of biasing forces. Finally, we found that both TEM mutants also bind strongly to other drugs containing negatively-charged R-groups, such as carumonam and ceftibuten. As with cefixime, this increased binding affinity stems from a salt bridge between the compounds' negative moieties and the positively-charged side chain of the arginine or lysine, suggesting a shared mechanism. In addition to reaffirming the power of using simulations as molecular microscopes, our results can guide the rational design of next-generation β-lactam antibiotics and bring the community closer to retaking the lead against the recurrent threat of multidrug-resistant pathogens.
Topics: Anti-Bacterial Agents; Cefixime; Molecular Dynamics Simulation; Mutation; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams
PubMed: 35759512
DOI: 10.1371/journal.pcbi.1009944 -
Diagnostic Microbiology and Infectious... Jun 2022Ceftibuten is an oral cephalosporin approved by the US Food and Drug Administration in 1995 that is in early clinical development to be combined with an oral prodrug of...
Ceftibuten is an oral cephalosporin approved by the US Food and Drug Administration in 1995 that is in early clinical development to be combined with an oral prodrug of avibactam. We evaluated the activity of ceftibuten-avibactam against molecularly characterized Enterobacterales that produced clinically relevant β-lactamases and assessed the best avibactam concentration to be combined with ceftibuten for susceptibility testing. Resistance mechanisms were evaluated by whole genome sequencing. MIC values were determined by broth microdilution of ceftibuten, avibactam, and ceftibuten combined with fixed concentrations (2, 4, and 8 mg/L) and ratios (1:1 and 2:1) of avibactam. The organism collection (n = 71) included Enterobacterales producing ESBLs, KPC, metallo-β-lactamases, AmpC, K-1, OXA-48, and SME, as well as isolates with porin alterations. The ceftibuten-avibactam combination that best separated isolates with β-lactamases inhibited by avibactam from isolates with resistance mechanisms that are not affected by avibactam was the combination with avibactam at a fixed concentration of 4 mg/L.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Ceftibuten; Drug Combinations; Humans; Microbial Sensitivity Tests; beta-Lactamases
PubMed: 35390644
DOI: 10.1016/j.diagmicrobio.2022.115673 -
Pediatrics and Neonatology Dec 2014"Round pneumonia" or "spherical pneumonia" is a well-characterized clinical entity that seems to be less addressed by pediatricians in Taiwan. We herein report the case...
"Round pneumonia" or "spherical pneumonia" is a well-characterized clinical entity that seems to be less addressed by pediatricians in Taiwan. We herein report the case of a 7-year-old boy who presented with prolonged fever, cough, and chest X-rays showing a well-demarcated round mass measuring 5.9 × 5.6 × 4.3 cm in the left lower lung field, findings which were typical for round pneumonia. The urinary pneumococcal antigen test was positive, and serum anti-Mycoplasma pneumoniae antibody titer measurement using a microparticle agglutination method was 1:160 (+). After oral administration of antibiotics including azithromycin and amoxicillin/clavulanate, which was subsequently replaced by ceftibuten due to moderate diarrhea, the fever subsided 2 days later and the round patch had completely resolved on the 18th day after the diagnosis. Recent evidence suggests treating classical round pneumonia with antibiotics first and waiving unwarranted advanced imaging studies, while alternative etiologies such as abscesses, tuberculosis, nonbacterial infections, congenital malformations, or neoplasms should still be considered in patients with atypical features or poor treatment response.
Topics: Anti-Bacterial Agents; Azithromycin; Child; Humans; Male; Pneumonia, Bacterial; Pneumonia, Mycoplasma; Pneumonia, Pneumococcal; Taiwan
PubMed: 23597522
DOI: 10.1016/j.pedneo.2013.01.014 -
Antibiotics (Basel, Switzerland) Feb 2021Efforts to develop and pair novel oral β-lactamase inhibitors with existing β-lactam agents to treat extended spectrum β-lactamase (ESBL) and carbapenemase-producing...
Efforts to develop and pair novel oral β-lactamase inhibitors with existing β-lactam agents to treat extended spectrum β-lactamase (ESBL) and carbapenemase-producing Enterobacterales are gaining ground. Ceftibuten is an oral third-generation cephalosporin capable of achieving high urine concentrations; however, there are no robust data describing its pharmacodynamic profile. This study characterizes ceftibuten pharmacokinetics and pharmacodynamics in a neutropenic murine thigh infection model. Enterobacterales isolates expressing no known clinically-relevant enzymatic resistance ( = 7) or harboring an ESBL ( = 2) were evaluated. The ceftibuten minimum inhibitory concentrations (MICs) were 0.03-4 mg/L. Nine ceftibuten regimens, including a human-simulated regimen (HSR) equivalent to clinical ceftibuten doses of 300 mg taken orally every 8 h, were utilized to achieve various T > MICs. A sigmoidal E model was fitted to T > MIC vs. change in log CFU/thigh to determine the requirements for net stasis and 1-log CFU/thigh bacterial burden reduction. The growth of the 0 h and 24 h control groups was 5.97 ± 0.37 and 8.51 ± 0.84 log CFU/thigh, respectively. Ceftibuten HSR resulted in a -0.49 to -1.43 log CFU/thigh bacterial burden reduction at 24 h across the isolates. Stasis and 1-log CFU/thigh reduction were achieved with a T > MIC of 39% and 67% respectively. The T > MIC targets identified can be used to guide ceftibuten dosage selection to optimize the likelihood of clinical efficacy.
PubMed: 33669512
DOI: 10.3390/antibiotics10020201 -
Antimicrobial Agents and Chemotherapy Jan 2022Ceftibuten/VNRX-7145 is a cephalosporin/boronate β-lactamase inhibitor combination under development as an oral treatment for complicated urinary tract infections...
Ceftibuten/VNRX-7145 is a cephalosporin/boronate β-lactamase inhibitor combination under development as an oral treatment for complicated urinary tract infections caused by producing serine β-lactamases (Ambler class A, C, and D). , VNRX-7145 (VNRX-5236 etzadroxil) is cleaved to the active inhibitor, VNRX-5236. We assessed the activity of ceftibuten/VNRX-5236 against 1,066 urinary isolates of from a 2014-2016 global culture collection. Each isolate tested was preselected to possess a multidrug-resistant (MDR) phenotype that included nonsusceptibility 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) at 2 μg/ml; MICs for ESBL- (= 566), serine carbapenemase- (= 116), and acquired AmpC-positive (= 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, 2 μg/ml) was similar (within one doubling-dilution) to intravenous-only agents ceftazidime-avibactam (MIC 2 μg/ml) and meropenem-vaborbactam (MIC 1 μg/ml). Continued investigation of ceftibuten/VNRX-5236 is warranted.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Ceftibuten; Humans; Microbial Sensitivity Tests; Urinary Tract Infections; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 34662183
DOI: 10.1128/AAC.01304-21