Determine the PK and Safety and Tolerability of ATM-AVI for the Treatment of cIAIs in Hospitalized Adults (REJUVENATE)
Condition: Complicated Intra-Abdominal Infections, cIAIs
MeSH terms: Infections; Intraabdominal Infections
Intervention: ATM-AVI; Metronidazole
Intervention description: Cohort 1:
(Creatinine clearance > 50 mL/min)6500mg ATM/1777mg AVI on day 1 followed by total daily dose of 6000mg ATM/1640mg AVI
Cohorts 2 and 3:
(Creatinine clearance > 50 mL/min) As above, or: 6500 mg ATM/2167 mg on Day 1 followed by a total daily dose of 6000 mg ATM/2000 m AVI
(Creatinine clearance 31 - 50 mL/min) 4250 mg ATM/1162 mg AVI on Day 1 followed by total daily dose 3000 mg ATM/820 mg AVI, or:
4250 mg ATM/1417 mg AVI on Day 1 followed by total daily dose 3000 mg ATM/1000 mg AVI; Metronidazole 500mg infused over 1 hour every 8 hours
Intervention MeSH terms: Metronidazole
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 40.0
Sex: All
Minimum age: 18 Years
Maximum age: 90 Years
Healthy volunteers: No
Keywords: cIAIs in hospitalized adults

Summary:

      Determine the PK and safety and tolerability of aztreonam-avibactam (ATM-AVI) in the
      treatment of hospitalized adults with cIAI
    

Eligibility criteria:

        Inclusion Criteria:

          1. Provision of informed consent

          2. Male or female from 18 to 90 years

          3. Female patients are authorized to participate in this clinical study if criteria
             concerning pregnancy avoidance stated in the protocol are met

          4. 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

          5. Patients who failed prior antibacterial treatment for their current cIAI can be
             enrolled but must:

               -  Have a known or suspected pathogen causing cIAI that is resistant to the prior
                  therapy

               -  Require surgical intervention.

          6. Patient must have or will have a surgical intervention within 24 hours (before or
             after) the administration of the first dose of study drug

        Exclusion criteria:

          1. Involvement in the planning and/or conduct of the study

          2. Patient has been previously enrolled in this study, previously treated with ATM-AVI or
             previously participated in an investigational study containing AVI

          3. Patient has participated or intends to participate in any other clinical study that
             involves the administration of a study drug during the course of the study, or during
             the 30 days prior to study start.

          4. History of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious
             reaction to aztreonam, carbapenem,monobactam or other β-lactam antibiotics, avibactam,
             nitroimidazoles or metronidazole, or any of the excipients of the study drugs

          5. 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 within 24 hours of
             diagnosis primary etiology is not likely to be infectious

          6. Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis,
             acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess
             or ischaemic/necrotic intestine without perforation

          7. Staged abdominal repair (STAR), open abdomen technique or where infection source
             control is not likely to be achieved; unlikely to solely respond to antimicrobial
             therapy

          8. Infection due to a pathogen that is unlikely to respond to ATM-AVI plus metronidazole

          9. Rapidly progressive or terminal illness

         10. Systemic antibacterial agents received within the 72- hour period prior to study
             entry, unless:

               1. A new infection and no more than 24 hours of prior antibiotic treatment received
                  within the 72 hour period prior to study entry or

               2. Patient is considered to have failed the previous treatment

         11. Concurrent infection that may interfere with the evaluation of clinical cure for the
             study therapy

         12. requirement for effective concomitant systemic antibacterials or antifungals

         13. Creatinine clearance ≤30 ml/min or requirement for renal replacement therapy

         14. Acute hepatitis in the prior 6 months, chronic hepatitis, cirrhosis, acute hepatic
             failure, or acute decompensation of chronic hepatic failure

         15. Hepatic disease as indicated by AST or ALT >3 × ULN. Patients with AST and/or ALT >3 ×
             ULN and < 5 × ULN are eligible if acute, not accompanied by a total bilirubin ≥ 2xULN
             and documented by the investigator as being directly related to cIAI.

         16. Patient has a total bilirubin >3 × ULN, unless isolated hyperbilirubinemia is directly
             related to cIAI or due to known Gilbert's disease

         17. ALP >3 × ULN. Patients with values >3 × ULN and <5 x ULN are eligible if acute and
             directly related to the infectious process being treated.

         18. Immunocompromising illness

         19. Active Clostridium difficile associated diarrhoea

         20. Any other condition that may confound the results of the study or pose additional
             risks

         21. Do not resuscitate order

         22. Absolute neutrophil count <1000/μL

         23. Hematocrit <25% or hemoglobin <8 gm/dL.

         24. Platelet count <75,000/μL.

         25. Currently receiving probenecid.

         26. Pregnant or breastfeeding or if of child bearing potential, not using a medically
             accepted effective method of birth control.

         27. Unlikely to comply with protocol,

         28. Currently receiving anti-convulsant therapy to prevent recurrence of a past history of
             seizures.

         29. Prior liver, pancreas or small-bowel transplant.