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.

Inclusion Criteria:

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 criteriaconcerning pregnancy avoidance stated in the protocol are met and negative pregnancytest

Additional for cIAI:

1. Diagnosis of cIAI, EITHER: Intra-operative/postoperative enrolment with visual confirmation of cIAI. ORPreoperative enrollment with evidence of systemic inflammatory response, physicaland radiological findings consistent with cIAI; confirmation of cIAI at time ofsurgery within 24 hours of study entry

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

Additional for HAP/VAP:

1. Onset symptoms > 48h after admission to or <7 days after discharge from an inpatientcare 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 symptomsand prior to randomisation

Exclusion criteria:

All subjects:

1. APACHE II score > 30

2. Confirmed or suspected infection caused by Gram-negative species not expected torespond to study drug, or Gram-positive species

3. Receipt of >24 hr systemic antibiotic within 48h prior to randomisation (exceptionin case of treatment failure)

4. History of serious allergy, hypersensitivity (eg, anaphylaxis), or any seriousreaction to aztreonam, carbapenem,monobactam or other β-lactam antibiotics,avibactam, nitroimidazoles or metronidazole, or any of the excipients of the studydrugs

5. Known Clostridium difficle associated diarrhoea

6. Requirement for effective concomitant systemic antibacterials or antifungals

7. Creatinine clearance ≤15 ml/min or requirement or expectation for renal replacementtherapy

8. Acute hepatitis, cirrhosis, acute hepatic failure, chronic hepatic failure

9. Hepatic disease as indicated by AST or ALT >3 × ULN. Patients with AST and/or ALT upto 5 × ULN are eligible if acute and documented by the investigator as beingdirectly related infectious process

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

11. ALP >3 × ULN. Patients with values >3 × ULN and <5 x ULN are eligible if acute anddirectly related to the infectious process being treated

12. Absolute neutrophil count <500/mm3

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

14. Any other condition that may confound the results of the study or pose additionalrisks 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 boweldisease without perforation; traumatic bowel perforation with surgery within 12hours of diagnosis; perforation of gastroduodenal ulcer with surgery < 24 hours ofdiagnosis 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