Zidebactam-Cefepime + Metronidazole Safety Study

Overseen By Alena Jandourek, MD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Wockhardt

Must not be taking: NSAIDs, Sucralfate, others

Disqualifiers: Cardiovascular, CNS, Respiratory, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to assess the safety and tolerability of a combination of two antibiotics, Zidebactam-Cefepime, administered alone or with metronidazole. The focus is on understanding how these drugs behave in the body both separately and together. Healthy adults without major health issues or surgeries in the past six months may qualify for this study. Participants will receive different treatments with breaks in between to observe how the body processes the drugs. As a Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

Yes, you will need to stop taking most prescription medications, except for certain contraceptives and hormone therapies, at least 14 days before the study. Over-the-counter medications and supplements should be stopped 7 days before the study, with some exceptions for low-dose acetaminophen.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that cefepime-zidebactam is generally safe for treating difficult bacterial infections. One study demonstrated that this combination effectively targeted resistant Pseudomonas aeruginosa, a challenging bacteria, without major safety concerns. Another study also identified it as a safe option for similar infections.

Metronidazole, another treatment in this trial, is already widely used and approved for various infections. It is usually well-tolerated, though some individuals might experience mild side effects like nausea or headaches.

This trial is in its early stages (Phase 1), so researchers are focusing on safety. While complete safety data for zidebactam-cefepime is still being collected, existing evidence and metronidazole's known safety record suggest these treatments are likely to be well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Zidebactam-Cefepime with Metronidazole because it offers a unique approach to tackling hard-to-treat bacterial infections. Unlike standard antibiotics, which often face resistance issues, Zidebactam enhances the effectiveness of Cefepime by inhibiting bacterial enzymes that usually degrade these drugs. This combination could potentially overcome antibiotic resistance, making it a powerful tool against infections that are currently difficult to treat with existing options. Additionally, Metronidazole targets anaerobic bacteria, complementing the broad-spectrum capabilities of Zidebactam-Cefepime. This multi-pronged attack could lead to more effective treatment outcomes for patients.

What evidence suggests that this trial's treatments could be effective?

This trial will evaluate the effectiveness of Zidebactam-Cefepime in treating difficult bacterial infections. Studies have shown that combining zidebactam with cefepime effectively targets infections caused by Pseudomonas aeruginosa, which often resist other antibiotics. Research indicates that zidebactam enhances cefepime's ability to bypass the bacteria's defenses, boosting the antibiotic's effectiveness. Specifically, patients with serious infections have improved with this treatment. Known for its strong action against hard-to-treat bacteria, the evidence supports its potential effectiveness in managing challenging infections. ^{1 4 6 7 8}

Are You a Good Fit for This Trial?

This trial is for healthy adult men and women who can participate in a study to test the safety of new drug combinations. Participants will receive single doses of Zidebactam-Cefepime (ZID-FEP) and Metronidazole, both alone and together, with breaks in between treatments.

Inclusion Criteria

Body mass index of 18 to 31 kg/m2 (inclusive)

Subjects voluntarily consented to participate in this study and who have signed and dated the informed consent form

Resting supine blood pressure of 90 to 139 (systolic)/50 to 89 (diastolic) mmHg and a resting pulse rate of 40 to 100 beats per minute

Exclusion Criteria

I have a history of bleeding disorders.

History of Clostridium difficile induced diarrhea or infection within 1 year before screening

Consumed more than 28 units of alcohol per week at any time in the 6 months before study drug administration (1 unit of alcohol is equivalent to 8 ounces of beer, 4 ounces of wine, or 1 ounce of spirits) or history of active alcoholism and/or drug/chemical abuse within the last 3 to 5 years

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive single doses of ZID-FEP and metronidazole alone or in combination over 3 treatment periods with a 48-hour washout period between each

1 week

3 visits (in-person)

Follow-up

Participants are monitored for safety and pharmacokinetics after treatment

1 week

3 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Metronidazole
• Zidebactam-Cefepime

Trial Overview The study is testing how safe ZID-FEP combined with Metronidazole is and how these drugs behave in the body when given separately or together. It's a Phase I trial where each participant receives three different treatments across separate periods.

How Is the Trial Designed?

Group I: Zidebactam Cefepime Experimental Treatment 3 Interventions

Zidebactam Cefepime 3gm Vial

Who Is Running the Clinical Trial?

Wockhardt

Lead Sponsor

Trials

36

Recruited

3,500+

Eric Solutions LLC

Collaborator

Trials

2

Recruited

50+

Published Research Related to This Trial

Cefepime (Maxipime) is highly effective against a wide range of bacteria commonly involved in surgical infections, making it a strong choice for treating severe infections in surgical patients, as demonstrated in a study of 30 patients.

The study supports using Cefepime as a monotherapy for most cases, but it can be combined with other antibiotics like aminoglycosides or metronidazole for severe or complicated infections, enhancing its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cefepime (Maxipime) treatment efficacy in surgical patients ]. Simion, L., Bratucu, E., Straja, D., et al.[2018]

WCK 5222, a combination of cefepime and zidebactam, demonstrated strong in vitro activity against a wide range of Gram-negative bacteria, including 99.9% effectiveness against Enterobacteriaceae and significant efficacy against carbapenem-resistant strains.

The combination was particularly effective with lower minimum inhibitory concentration (MIC) values compared to cefepime alone, indicating its potential as a powerful treatment option for multidrug-resistant bacterial infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

WCK 5222 (Cefepime-Zidebactam) Antimicrobial Activity against Clinical Isolates of Gram-Negative Bacteria Collected Worldwide in 2015. Sader, HS., Castanheira, M., Huband, M., et al.[2023]

Cefepime combined with zidebactam (WCK 5222) demonstrated strong in vitro activity against various Gram-negative bacteria, including those producing clinically significant β-lactamases, with lower minimum inhibitory concentrations (MICs) than when each drug was used alone, indicating a synergistic effect.

This combination was particularly effective against Enterobacteriaceae and Pseudomonas aeruginosa, suggesting it could be a promising treatment option for infections caused by resistant strains, where current treatment options are limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

WCK 5222 (cefepime/zidebactam) antimicrobial activity tested against Gram-negative organisms producing clinically relevant β-lactamases. Sader, HS., Rhomberg, PR., Flamm, RK., et al.[2018]

Cefepime/zidebactam (WCK 5222) demonstrated effective in vitro activity against Enterobacteriaceae producing both metallo-β-lactamase and serine-β-lactamase, with minimum inhibitory concentrations significantly lower than the susceptible-dose dependent breakpoint.

In a comparison of treatment regimens, the combination of aztreonam and ceftazidime/avibactam showed significantly greater potency than meropenem/vaborbactam against these resistant strains, suggesting it may be the preferred option for treating infections caused by these bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the in vitro activity of WCK 5222 (cefepime/zidebactam) and currently available combination therapies against single- and double-carbapenemase producing Enterobacteriaceae: Expanding the zone of hope. Avery, LM., Mullane, EM., Nicolau, DP.[2020]

Cefepime/zidebactam has demonstrated significant efficacy against carbapenem-resistant Gram-negative infections, showing effective minimum inhibitory concentrations (MIC50/90) of 0.5/2 mg/L against Enterobacterales, including those producing metallo-β-lactamases, in a study of 563 isolates from Greek hospitals.

The effectiveness of cefepime/zidebactam against multi-drug-resistant bacteria is attributed to its novel β-lactam-enhancer mechanism, making it a promising treatment option where other antibiotics, like colistin, show limited activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro activity of cefepime/zidebactam (WCK 5222) against recent Gram-negative isolates collected from high resistance settings of Greek hospitals. Bhagwat, SS., Legakis, NJ., Skalidis, T., et al.[2021]

Cefepime/zidebactam demonstrated effective in vitro activity against multidrug-resistant Klebsiella pneumoniae isolates, with minimum inhibitory concentrations (MICs) consistently at or below 4 mg/L, indicating its potential as a treatment option.

The antibiotic successfully overcomes both enzymatic and non-enzymatic resistance mechanisms, including the presence of carbapenemase genes and mutations in outer membrane proteins that typically hinder the effectiveness of carbapenems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of β-lactam plus β-lactam-enhancer combination cefepime/zidebactam against Klebsiella pneumoniae harbouring defective OmpK35/36 porins and carbapenemases. Joshi, P., Shrivastava, R., Bhagwat, S., et al.[2021]

Cefepime-zidebactam is a promising new antibiotic currently in phase 3 trials, showing effectiveness against various antibiotic-resistant Gram-negative infections due to its unique mechanism that enhances β-lactam activity.

In a specific case, cefepime-zidebactam successfully treated a severe infection caused by a highly resistant strain of Pseudomonas aeruginosa in a patient with acute T-cell leukemia, highlighting its potential as a salvage therapy for difficult-to-treat infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Use of Cefepime-Zidebactam (WCK 5222) as a Salvage Therapy for the Treatment of Disseminated Extensively Drug-Resistant New Delhi Metallo-β-Lactamase-Producing Pseudomonas aeruginosa Infection in an Adult Patient with Acute T-Cell Leukemia. Tirlangi, PK., Wanve, BS., Dubbudu, RR., et al.[2023]

Cefepime combined with zidebactam showed strong effectiveness against over 99% of common Gram-negative bacteria like E. coli and K. pneumoniae, with minimal resistance observed in most cases.

While cefepime/zidebactam was effective against many Pseudomonas aeruginosa isolates, its activity was reduced in carbapenem-resistant strains and significantly lower against Acinetobacter baumannii, indicating the need for further studies on its efficacy in these tougher cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of cefepime/zidebactam (WCK 5222) against Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii endemic to New York City medical centres. Khan, Z., Iregui, A., Landman, D., et al.[2020]

Cefepime demonstrated effective antibacterial activity against Enterobacter species with reduced susceptibility to other beta-lactam antibiotics, as all 17 infections in the study responded positively to treatment.

The study, involving 16 patients with various infections, showed that cefepime led to the eradication of bacteria in 88.2% of cases, with no emergence of resistance, highlighting its potential as a reliable treatment option for resistant infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of cefepime in the treatment of infections due to multiply resistant Enterobacter species. Sanders, WE., Tenney, JH., Kessler, RE.[2019]

Cefepime is a fourth-generation cephalosporin that has shown effective clinical and bacteriological responses in treating moderate to severe pneumonia, comparable to other antibiotics like ceftazidime and ceftriaxone, based on randomized clinical trials.

It is generally well tolerated with mild to moderate side effects, such as rash and diarrhea, making it a suitable option for empiric treatment of pneumonia, especially in cases resistant to other antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cefepime: a review of its use in the management of hospitalized patients with pneumonia. Chapman, TM., Perry, CM.[2019]

In a trial involving 70 patients with various infections, cefepime demonstrated a high efficacy rate, with 98% of clinically evaluable patients showing satisfactory responses and 95% of pathogens eradicated.

Cefepime was well tolerated, with only minor adverse effects reported, indicating its safety for use in treating infections caused by a wide range of bacteria, including S. aureus and P. aeruginosa.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open trial of cefepime (BMY 28142) for infections in hospitalized patients. Oster, S., Edelstein, H., Cassano, K., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11858600/

β-Lactam/β-Lactamase Inhibitor Combination Antibiotics ... Cefepime/zidebactam has been reported to be effective in treating patients with extensively drug-resistant Pseudomonas aeruginosa infections ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S221371652500164X

Successful use of cefepime/zidebactam in deep-seated ... Short Communication. Successful use of cefepime/zidebactam in deep-seated infections due to extensively drug-resistant Pseudomonas aeruginosa: A case series.

3. journals.asm.org journals.asm.org/doi/10.1128/aac.00233-19

In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) against ... WCK 5222 demonstrated enhanced efficacy over zidebactam alone in the majority of isolates up to an MIC of 32 μg/ml, a finding attributed to the ...

4. jmilabs.com jmilabs.com/data/posters/2022.JAC_.Sader_.10.1093-21-WRC-02-M1.pdf

Antimicrobial activity of cefepime/zidebactam (WCK 5222), ... Cefepime/zidebactam was tested at a 1:1 ratio. Results: Cefepime/zidebactam was highly active against Enterobacterales (MIC50/90 0.03/0.25 mg/L; ...

5. academic.oup.com academic.oup.com/jacamr/article/7/4/dlaf129/8204463

Cefepime-zidebactam therapy for extensively drug-resistant ... Antimicrobial therapy with cefepime-zidebactam along with source control allowed successful liver transplantation in a patient with cefiderocol- ...

6. cdn.caymanchem.com cdn.caymanchem.com/cdn/insert/30701.pdf

PRODUCT INFORMATION SAFETY DATA. This material should be considered hazardous until further information becomes available. Do not ingest, inhale, get in eyes, on skin, ...

7. journals.asm.org journals.asm.org/doi/10.1128/aac.00500-23

Successful Use of Cefepime-Zidebactam (WCK 5222) as a ... In summary, cefepime-zidebactam appears to be a safe option for the treatment of XDR P. aeruginosa infections, with broader coverage of ...

8. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/57/NCT05645757/Prot_001.pdf

A PHASE I, RANDOMIZED, DOUBLE-BLIND, PLACEBO No placebo subjects are included in standalone ZID cohorts, since adequate safety data for higher doses of ZID alone in comparison with placebo ...