A Study to Determine the Efficacy, Safety and Tolerability of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) Versus Meropenem (MER) ± Colistin (COL) for the Treatment of Serious Infections Due to Gram Negative Bacteria.

All subjects:

1. Male or female from 18 years of age

2. Provision of informed consent

3. Confirmed diagnosis of HAP/VAP or cIAI requiring iv antibiotic treatment

4. Female patients are authorized to participate in this clinical study if criteria concerning pregnancy avoidance stated in the protocol are met and negative pregnancy test

Additional for cIAI:

1. Diagnosis of cIAI, EITHER:

Intra-operative/postoperative enrolment with visual confirmation of cIAI. OR Preoperative enrollment with evidence of systemic inflammatory response, physical and radiological findings consistent with cIAI; confirmation of cIAI at time of surgery within 24 hours of study entry

2. Surgical intervention within 24 hours (before or after) the administration of the first dose of study drug

Additional for HAP/VAP:

1. Onset symptoms \> 48h after admission to or \<7 days after discharge from an inpatient care facility

2. New or worsening infiltrate on CXR or CT scan

3. Clinical signs and symptoms and laboratory findings consistent with HAP/VAP

4. Respiratory specimen obtained for Gram stain and culture following onset of symptoms and prior to randomisation

10. Patient has a total bilirubin \>2 × ULN, unless isolated hyperbilirubinemia is directly related to infectious process or due to known Gilbert's disease

12. Absolute neutrophil count \<500/mm3

13. Pregnant or breastfeeding or if of child bearing potential, not using a medically accepted effective method of birth control.

14. Any other condition that may confound the results of the study or pose additional risks to the subject

15. Unlikely to comply with protocol

16. History of epilepsy or seizure disorders excluding febrile seizures of childhood

Additional for cIAI

1. Diagnosis of abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation; traumatic bowel perforation with surgery within 12 hours of diagnosis; perforation of gastroduodenal ulcer with surgery \< 24 hours of diagnosis primary etiology is not likely to be infectious

2. Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess

3. Prior liver, pancreas or small-bowel transplant

4. Staged abdominal repair (STAR), open abdomen technique or marsupialisation

Additional for HAP/VAP

1. APACHE II score \< 10

2. Known or high likelihood of Gram-positive monomicrobial infection

3. Lung abscess, pleural empyema, post-obstructive pneumonia

4. Lung or heart transplant

5. Myasthenia gravis

What this study is about