Cefepime-Zidebactam Versus Ceftazidime-Avibactam With or Without Colistin for Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia

This is a Phase 3, randomized, double-blind, multicenter, comparative study evaluating cefepime-zidebactam (FEP-ZID) versus ceftazidime-avibactam (CAZ-AVI) with or without colistin in the treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). Trial participants will be randomized in a 1:1 ratio to receive either FEP-ZID or CAZ-AVI with or without colistin for 7 to 14 days. Colistin will be added to the CAZ-AVI regimen (or matching saline to the FEP-ZID regimen, to maintain blinding) for participants with a baseline pathogen presumed or confirmed to be CAZ-AVI-resistant. All trial participants will also receive linezolid for coverage of methicillin-resistant staphylococci for at least the first 3 days of treatment. The primary objectives are to assess 14-day all-cause mortality between treatment groups and to assess the safety and tolerability of FEP-ZID relative to CAZ-AVI with or without colistin. Secondary objectives include 28-day all-cause mortality, clinical and microbiological outcomes at End-of-Treatment (EOT) and Test-of-Cure (TOC), sustained clinical cure at Late Follow-up (LFU), superinfection and new infection rates, and pharmacokinetic (PK) characterization of FEP and ZID.

Inclusion Criteria: 1. Male or female ≥18 years of age. 2. Provide signed written informed consent prior to any study specific procedures. A legally acceptable representative may provide consent provided this is permitted by national law and ethical considerations as well as institution-specific guidelines (proxy consent). In participants in clinical course compatible with an emergency situation and not able to provide consent while a legally acceptable representative is not available, a deferred consent framework for emergency research may be applied if permitted by national law and ethical considerations as well as institution-specific guidelines. 3. Have at least one of the following new-onset or worsening signs within 24 hours prior to randomization: * Fever (oral, tympanic, temporal, or rectal temperature \>38 °C \[\>100.4 °F\]) * Hypothermia (rectal/core temperature \48 hours if discharged within the last 7 days). 2. New or worsening infiltrate consistent with pneumonia on X-ray or chest CT obtained at least 48 hours or more after hospital admission. 3. New onset or acute worsening pulmonary symptoms or signs, such as cough, dyspnea, tachypnea, (e.g., respiratory rate greater than 25 breaths per minute), hypoxemia, expectorated sputum production, and/or requirement for mechanical ventilation. 5\. If a female of childbearing potential, must have a negative urine or serum pregnancy test (β-human chorionic gonadotropin) during their hospitalization and must agree to use one of the following highly effective methods of contraception through TOC: * Surgical sterilization (defined as bilateral oophorectomy or bilateral salpingectomy, but excluding bilateral tubal occlusion) * Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal) * Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable) * Intrauterine device * Intrauterine hormone-releasing system * Sexual intercourse with only vasectomized partners, or * Abstinence, defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the trial participant * Post-menopausal (as defined in the note below) Note: a female is considered to be of childbearing potential unless post-menopausal for more than 1 year of spontaneous amenorrhea or permanently surgically sterilized (bilateral oophorectomy, salpingectomy, hysterectomy, tubal ligation). A high follicle stimulation hormone level in the post-menopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. 6.If male, trial participant must agree to use an acceptable barrier method of birth control (i.e., condom) with female partner(s) of childbearing potential who are using one of the contraceptive methods described above in Inclusion Criterion 5, and must not donate sperm from Screening through TOC. Exclusion Criteria: 1. History of serious or significant hypersensitivity or allergic reaction (e.g., anaphylaxis, urticaria, other significant reaction) to any β-lactam antibiotic or to the excipient L-arginine; avibactam or avibactam-containing-product; linezolid; or colistin. 2. Current pneumonia due to Stenotrophomonas or Burkholderia species identified on culture prior to randomization. 3. Known or suspected community-acquired, viral, fungal (including Pnuemocystis jirovecii), mycobacterial (including tuberculous), or parasitic pneumonia. 4. Diagnosed or suspected to have atypical pneumonia (including Legionella pneumophilia) or a positive test result on the BPP for an atypical organism. 5. Current pneumonia known or suspected to be caused by an organism that is resistant to FEP-ZID or to both CAZ-AVI and colistin. 6. Diagnosed with COVID-19 or positive test for SARS-CoV-2 virus within the past 2 weeks. 7. Any of the following conditions or diagnoses: * Cystic fibrosis or similar conditions (e.g., non-cystic fibrosis bronchiectasis) * Lung abscess * Pleural empyema * Lung cancer or metastases to the lungs or other known causes of pulmonary obstruction * Penetrating chest trauma * Definitive diagnosis of aspiration pneumonia * Any other infection outside of the lung that requires systemic antibacterial therapy 8. Current treatment with a monoamine oxidase inhibitor (MAOI) or having received a MAOI within the past 2 weeks prior to randomization, or need for such treatment during the study treatment period. 9. Current receipt of curariform muscle relaxants (e.g., tubocurarine) or other drugs potentiating the neuromuscular blocking effect (e.g., ether, succinylcholine, gallamine, decamethonium and sodium citrate), or need for such treatment during the study treatment period. 10. Receipt of CAZ-AVI or FEP-ZID within 30 days prior to enrolment for treatment of any infection. 11. Receipt of potentially effective systemic or inhaled antibacterial therapy for more than 48 hours within 72 hours prior to randomization, with the exception of either of the following: * Receipt of \>48 hours of prior antibiotic therapy and in the investigator's opinion, failed that prior antibiotic therapy (i.e., worsening signs and symptoms) or * Documented to have a gram-negative pathogen that is non-susceptible to the prior therapy administered for the pneumonia 12. Pneumonia caused by sole gram-positive pathogen(s) if known based on culture report or BPP result. 13. Expected survival \30. 15. History of epilepsy or seizure disorder requiring current treatment with anti-seizure medication. 16. Women who are pregnant or nursing. 17. Participants CRRT (e.g., continuous venovenous hemofiltration, continuous venovenous hemodialysis, or continuous venovenous hemodiafiltration) as there is no available data on dosing of FEP-ZID for those on CRRT at this time. 18. Participants with a CrCl \2 times the upper limit of normal (unless elevated indirect bilirubin due to known Gilbert's syndrome), or alanine aminotransferase ≥5 × upper limit of normal, or known to meet Child-Pugh class C criteria for liver insufficiency. 20. On extracorporeal membrane oxygenation (ECMO) or expected to receive ECMO within 72 hours. 21. Current neutropenia defined as \