Inclusion Criteria:
1. Provide written informed consent prior to any study related procedures not part of normal medical care. If permitted by local country and institution-specific guidelines, surrogate consent/use of a legally authorized representative may be provided. Alternatively, the decision can be made according to the procedure permitted by local law and institutional Standard Operating Procedures. If a patient regains consciousness while in the study and, per the Investigator's judgment, the patient is able to read, assess, understand, and make his/her own decision to participate in the study, the patient may agree to continue participation. In such cases, the patient must be reconsented.
2. Male or female patients, ≥ 18 and ≤ 82 years of age at the time of signing informed consent.
3. A confirmed diagnosis of HABP or VABP requiring treatment with IV antibiotics in the judgment of the Investigator.
4. High probability of a pneumonia (HABP or VABP) due to ABC as a single pathogen, or member of a polymicrobial infection based on evidence from RDT from a sample collected within 48 hours prior to randomization, AND one of the following:
1. Has received no more than 48 hours of potentially active antimicrobial treatment against CRABC prior to the first dose of study drug; OR
2. Is clinically failing prior treatment regimens (i.e., clinical deterioration or failure to improve after at least 48 hours of antibiotic treatment).
5. An APACHE II \< 30 or qSOFA score ≥ 2 at Screening.
6. Women of childbearing potential must have a negative highly sensitive urine or serum pregnancy test before randomization. Participating women of childbearing potential must be willing to consistently use one highly effective method of contraception from Screening until at least 30 days after administration of the last dose of study drug.
7. Diagnosed with HABP or VABP
Exclusion Criteria:
1. For Part A only, patients with an infection known to be resistant to colistin, with a known intolerance to polymyxins, or taking any drug that prevents them from receiving polymyxins.
2. Evidence of active concurrent pneumonia requiring additional antimicrobial treatment caused by, e.g., Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, Pneumocystitis jiroveci, Aspergillus spp, respiratory syncytial virus, influenza and parainfluenza viruses, Middle East respiratory syndrome coronavirus, mycobacteria, mucormycosis.
3. Any of the following health conditions:
1. Pulmonary disease that precludes evaluation of a therapeutic response.
2. Pleural empyema (exception: acceptable if drainage occurs within 24 hours of Screening and patient is expected to be treated in ≤ 14 days).
3. Solid organ transplant within 6 months prior to randomization.
4. Evidence of deep seated infection, e.g., Gram-negative osteomyelitis, or meningitis requiring prolonged therapy.
5. Acute infective endocarditis due to Gram-positive bacteria that requires urgent treatment/emergent indication of surgery, or patients in whom surgery is contraindicated due to prohibitive risk for surgery due to comorbidities.
6. Surgical wound infections requiring further surgical management e.g., wound closure, drain removal.
7. Peritonitis.
8. Irremovable implantable device or line thought to be the source of the ABC infection.
9. Known or suspected neuropathy or neuromuscular disease.
10. Human immunodeficiency virus infection.
11. Chronic immunosuppression due to drugs and/or underlying disease
4. Bronchial obstruction or a history of post obstructive pneumonia (this does not exclude patients with pneumonia who have an underlying chronic obstructive pulmonary disease).
5. Patients classified under futility of care, as determined by the medical team, indicating a lack of potential for benefit from intervention or patients who are permanent residents of long-term care facilities and have been assessed by the clinical team as receiving palliative or comfort-focused care.
6. Sustained shock with persisting hypotension requiring vasopressors to maintain mean arterial pressure ≥ 65 mmHg
7. Diagnosis of ventilator-associated tracheobronchitis.
8. Inability to provide proper respiratory specimens for culture.
9. Received more than 48 hours of potentially active treatment against CRABC prior to the first dose of study drug.
10. Known or suspected allergy to polymyxin, rifabutin, colistin, ampicillin/sulbactam, meropenem or their excipients.
11. Acute graft-versus-host disease (Grade ≥ 3).
12. Requirement for continuing treatment with probenecid, methotrexate, ganciclovir, valproic acid, or divalproex sodium during the study.
13. Requirement at the time of randomization for any reason, or likely to require during the patient's participation in the study (from randomization through the EoS Visit), for additional systemic Gram-negative antimicrobial therapy potentially active toward CRABC.
14. Expected survival \< 72 hours or a Do Not Resuscitate Order.
15. Burns \> 40% of total body surface area.
16. Presence of neutropenia (absolute neutrophil count \< 1500/mm3) obtained from a local laboratory at Screening, or anticipated neutropenia with absolute neutrophil count \< 1500 cells/mm3.
17. Severe renal disease defined as an estimated glomerular filtration rate (eGFR) as per Modification of Diet in Renal Disease (MDRD) formula (MDRD eGFR) \< 30 mL/min/1.73 m2, or requirement for peritoneal dialysis, hemodialysis, hemofiltration, or a urine output \< 20 mL/hour over a 24 hour period.
18. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3× upper limit of normal (ULN) AND total bilirubin \> 2×ULN at Screening (using local laboratory values); or Child Pugh Class C in patients with chronic liver function impairment. Evidence of significant hepatic disease or dysfunction, including known acute viral hepatitis, hepatic cirrhosis, hepatic failure, chronic ascites, or hepatic encephalopathy.
Note: Patients with AST or ALT up to 5×ULN are eligible if these elevations are acute and are documented as being directly related to the infectious process being treated.
19. Investigator's opinion of clinically significant ECG finding such as new ischemic changes, infarct, or ventricular arrhythmia with immediate potential for a fatal outcome, bradycardia not corrected by pacemaker or medication, or, prior to the current infection, a history of New York Heart Association Class IV cardiac failure defined as severe limitations - experiences symptoms even while at rest, mostly bedbound patients, within 1 year.
20. Abnormal QT interval corrected for heart rate by Fridericia formula (QTcF): \> 500 ms confirmed with repeat ECG.
21. Stroke (ischemic or intracerebral hemorrhage) within 10 days prior to randomization or expected survival from stroke \< 28 days or Glasgow Coma Scale score 3 with no hope of improvement.
22. Women who are pregnant or nursing.
23. Patients who are currently enrolled in or have not yet completed, in the last 30 days or 5 half lives, whichever is longer, another investigational device or drug study or those who are receiving other investigational agents.
24. Unable or not willing, in the opinion of the Investigator, to comply with all study protocol.
