Xeruborbactam + Ceftibuten for Bacterial Infection
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Qpex Biopharma, Inc.
No Placebo Group
Trial Summary
What is the purpose of this trial?A Phase 1, open-label, single-dose study to determine the safety and pharmacokinetics of ORAvance (ceftibuten/xeruborbactam oral prodrug \[QPX7831\]) in participants with renal impairment
Do I have to stop taking my current medications to join the trial?
The trial protocol does not specify if you must stop taking your current medications. However, you cannot use medications that affect the elimination of serum creatinine or compete with renal tubular secretion within 30 days before the trial or during it. Also, certain over-the-counter and prescription drugs, like antacids, are prohibited 7 days before the trial starts.
What data supports the effectiveness of the drug Xeruborbactam + Ceftibuten for bacterial infections?
Ceftibuten, one of the components of the drug, has been shown to be effective in treating respiratory and urinary tract infections, with a high rate of clinical cure and bacterial eradication. Additionally, similar combinations like ceftibuten-ledaborbactam have shown strong activity against drug-resistant bacteria, suggesting potential effectiveness for the new combination.
12345Is the combination of Xeruborbactam and Ceftibuten safe for humans?
Ceftibuten has been shown to be generally safe in humans, with mild to moderate side effects like stomach upset occurring in 5 to 10% of patients. In studies, adverse effects such as diarrhea and slight liver enzyme changes were noted but resolved quickly after treatment.
12467What makes the drug Xeruborbactam + Ceftibuten unique for treating bacterial infections?
This drug combination is unique because it combines ceftibuten, an oral antibiotic effective against many resistant bacteria, with xeruborbactam, a prodrug that enhances its activity against multidrug-resistant bacteria, particularly those producing specific enzymes (beta-lactamases) that usually make them resistant to other antibiotics.
13489Eligibility Criteria
This trial is for adults aged 18-80 with renal impairment (eGFR < 90 mL/min) who can sign consent and follow the study protocol. Men must use contraception or abstain from sex, while women need to be postmenopausal, surgically sterile, or using birth control. Participants should have a stable pulse rate and not consume alcohol before dosing.Inclusion Criteria
I am between 18 and 80 years old.
I am a woman who cannot have children, either due to menopause or sterilization.
My BMI is between 18.5 and 40.
My kidney function is reduced, with an eGFR below 90 mL/min.
Participant Groups
The study tests the safety and how the body processes ORAvance, a combination of ceftibuten/xeruborbactam oral prodrug (QPX7831), in those with kidney issues. It's an open-label Phase 1 trial where everyone gets a single dose of the drug to see how it works.
1Treatment groups
Experimental Treatment
Group I: Open Label, Single Dose Combination of Ceftibuten & Xeruborbactam oral prodrugExperimental Treatment2 Interventions
24 pts will be enrolled with varying degrees of RI as well as 8 participants with normal renal function (NRF). 8 participants will be enrolled in each group (G) based on estimated glomerular function rate (eGFR) at screening:
* G1: Mild RI (eGFR 60 to 90 mL/min/1.73m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration equation \[CKP-EPI\]) adjusted for the participant's body surface \[BSA\])
* G2: Moderate RI (eGFR 30 to \< 60 mL/min/1.73m2 calculated using the CKD-EPI equation adjusted for the participant's BSA)
* G3: Severe RI (eGFR \< 30 mL/min/1.73m2 calculated using the CKD-EPI equation) not receiving dialysis therapy
* G4: Healthy participants with NRF matched to patients in Groups 1, 2 and 3 based on age, gender and BMI All pts will receive a single dose of ceftibuten \& QPX7831 on Day 1. Pts will remain in the clinic until completion of the post-dose procedures on Day 8. Participants will be contacted by phone between Days 10-12 for follow-up.
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
University of Miami Clinical PharmacologyMiami, FL
Orlando Clinical Research CenterOrlando, FL
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Who is running the clinical trial?
Qpex Biopharma, Inc.Lead Sponsor
Biomedical Advanced Research and Development AuthorityCollaborator
Shionogi Inc.Industry Sponsor
References
Ceftibuten: a new expanded-spectrum oral cephalosporin. [2019]To review the antimicrobial activity, pharmacokinetics, clinical efficacy, and tolerability of ceftibuten, a new expanded-spectrum oral cephalosporin.
[Effectiveness of ceftibuten++ in the sequential therapy of respiratory and urinary tract infections]. [2018]A prospective, comparative, multicentre trial was performed to study the efficacy and safety of ceftibuten in respiratory and complicated urinary tract infections. Patients (n = 152) requiring parenteral 2nd or 3rd generation cephalosporine therapy were randomly assigned to continue parenteral therapy (Group A) or to receive oral ceftibuten 400 mg, or 9 mg/kgbw/day (Group B) from the 3.-5. days on. The patients, whose conditions have not improved significantly at day 3-5, were omitted from the study, so the number of evaluated patients was 131. In Group A, out of 59 patients 51 were clinically cured, the bacteriological eradication rate was 47/54. In Group B, out of 72 patients 67 were cured and 62 out of 66 pathogens were eradicated. The cost of step-down therapy was 44.3% less than the parenteral one. No adverse effect was observed that could surely be attributed to ceftibuten. According to these data, ceftibuten can be used in step-down therapy in respiratory and urinary tract infections requiring parenteral therapy at first and that offers a safe and less expensive therapeutic approach.
Ceftibuten: minimal inhibitory concentrations, postantibiotic effect and beta-lactamase stability--a rationale for dosing programs. [2018]Ceftibuten, a new orally absorbed cephalosporin with a novel side chain, has broad in vitro activity against most of the important respiratory pathogens including Streptococcus pneumoniae and both beta-lactamase-negative and beta-lactamase-positive Haemophilus influenzae and Moraxella (Branhamella) catarrhalis. Furthermore it has high activity against Enterobacteriaceae, which contain classic TEM-1 beta-lactamases and those containing the new extended spectrum beta-lactamases, which hydrolyze parenteral third generation cephalosporins. Studies have shown that ceftibuten has a postantibiotic effect comparable to that of other beta-lactams against S. pneumoniae, H. influenzae and M. catarrhalis. Blood levels achieved after a single 400-mg dose given once daily or 9 mg/kg/day taken once daily for children yield blood levels and postantibiotic inhibition for the majority of a dosing period. The in vitro and pharmacokinetic data can be correlated to provide reasonable dosing programs for the new oral cephalosporins.
Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-β-Lactamase-Positive Clinical Isolates of Enterobacterales from a 2018-2020 Global Surveillance Collection. [2022]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) Enterobacterales producing serine β-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-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 (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-β-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 Vitro Activity of Ceftibuten-Avibactam against β-Lactamase-Positive Enterobacterales from the ATLAS Global Surveillance Program. [2023]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% (MIC90) 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 MIC90, 0.12 μg/mL; ceftazidime-avibactam MIC90, 0.5 μg/mL) and KPC-producing (0.5 μg/mL; 2 μg/mL) isolates, equivalent to ceftazidime-avibactam (MIC90, 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.
Ceftibuten. A review of its antibacterial activity, pharmacokinetic properties and clinical efficacy. [2018]Ceftibuten is an orally active third generation cephalosporin which has a broad spectrum of in vitro antibacterial activity, encompassing the majority of Gram-negative pathogens and streptococci, and which shows greater stability than several other cephalosporins against bacteria producing extended-spectrum beta-lactamases. In clinical studies, ceftibuten (generally 400 mg/day in adults or 9 mg/kg/day in children, administered once daily) was effective in the treatment of acute uncomplicated or complicated urinary tract infections, demonstrating an efficacy similar to that of cefaclor (1500 mg/day), and similar or superior to that of cotrimoxazole (trimethoprim/sulfamethoxazole; 8/40 mg/kg/day) in children. The majority of patients with acute or chronic lower respiratory tract infections responded to treatment with ceftibuten, and response rates were similar to those achieved with cefaclor (750 or 1500 mg/day). Ceftibuten 9 mg/kg/day was at least as effective as cefaclor and as effective as amoxicillin/clavulanic acid (both 40 mg/kg/day) in children with acute otitis media, and was superior to phenoxymethylpenicillin (penicillin V; 25 mg/kg/day) in children and adolescents with streptococcal pharyngitis or scarlet fever caused by Group A beta-haemolytic streptococci. Ceftibuten was well tolerated in most patients, with adverse events (mostly mild to moderate gastrointestinal disturbances) generally occurring in 5 to 10% of patients. Thus, ceftibuten, with a once- or twice-daily oral dosage regimen, good tolerability profile and activity against a wide range of bacterial organisms, offers a promising alternative to other agents (including cefaclor, cotrimoxazole, amoxicillin/clavulanic acid, bacampicillin and phenoxymethylpenicillin) for the treatment of patients with urogenital and respiratory tract infections. Its place in therapy will be more clearly defined following further large comparative trials, in which it is likely to prove most useful in patients with infections caused by beta-lactamase-producing pathogens.
Comparative study of ceftibuten and cefixime in the treatment of complicated urinary tract infections. [2018]Between August 1996 and May 1998, a total of 62 patients who had complicated urinary tract infections treated at the Taipei Veterans General Hospital were enrolled into this study. This prospective, randomized, open-labeled trial aimed at comparing the efficacy and safety of ceftibuten and cefixime, prescribed each at a dose of 200 mg twice daily, in treating complicated urinary tract infection. Seventeen patients were later excluded from the analysis because of resistant pathogens (7 patients), uncomplicated urinary tract infection (6), initial culture negative for bacteria (3), and infective endocarditis (1). The remaining 45 patients were categorized into ceftibuten (n=23; mean age, 71.3 years) and cefixime (n=22; mean age, 62.8 years) treatment groups. No significant difference in demographic data and clinical characteristics was found between the 2 groups. The clinical efficacy rate (78.3% vs 77.3%, p=0.9) and bacteriological eradication rate (52.2% vs 63.6%, p=0.08) were similar between the ceftibuten and the cefixime group. Adverse effects caused by ceftibuten treatment included diarrhea and slight elevation of the serum level of liver transaminase in 2 (6.5%) patients. Those caused by cefixime treatment included slight elevation of serum level of liver transaminase in 2 (6.5%) patients and skin rash in 1 (3.2%) patient. All of these adverse effects resolved quickly after the regimen had been completed, and no patient discontinued the regimen because of the adverse effects. The results suggest that oral administration of ceftibuten 200 mg twice daily is as effective and safe as oral administration of cefixime 200 mg twice daily in the treatment of complicated urinary tract infections.
Ceftibuten and bactericidal kinetics. Comparative in vitro activity against Enterobacteriaceae producing extended spectrum beta-lactamases. [2019]Ceftibuten, compared to cefixime, cefetamet, cefpodoxime, loracarbef, cefprozil, cefuroxime, cefaclor, and cefadroxil, was the most active oral cephalosporin derivative against Enterobacteriaceae producing plasmid-encoded broad spectrum beta-lactamases. In a pharmacodynamic model, ceftibuten was bactericidal for Haemophilus influenzae and Streptococcus pneumoniae at concentrations simulating human serum levels following 200 mg, p.o., b.i.d.
Antimicrobial effects of the combination of ceftibuten and an orally absorbed penem SCH 29482. [2019]Ceftibuten is a new beta-lactamase-stable 3-aminothiazolyl cephalosporin that lacks activity against staphylococci and group-B streptococci. We determined the effect of the combination of ceftibuten with SCH 29482, an orally absorbed penem. The combination of the two agents was additive for 25% or indifferent for 57% of the Gram-positive species, Haemophilus, and Moraxella tested with a mean fractional inhibitory concentration (FIC) index of 0.75. The combination of ceftibuten and SCH 29482 was also indifferent for Bacteroides fragilis and other Bacteroides species, all of which were inhibited by less than or equal to micrograms/ml of SCH 29482. Antagonism of the combination was found for 80% of Serratia marcescens and for 30% of Citrobacter freundii and Enterobacter cloacae. Overall, the combination of ceftibuten and SCH 29482 at concentrations that can be achieved in serum after ingestion of 400 and 50 micrograms/ml, respectively, provided antibacterial activity against most Gram-positive aerobic and anaerobic species that cause upper respiratory, intraabdominal, and urinary infections.