1. Provision of informed consent prior to any study-specific procedures.
2. Male or female from 18 to 90 years of age inclusive.
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 (presence of pus
within the abdominal cavity) of an intra-abdominal infection associated with
peritonitis. Surgical intervention includes open laparotomy, percutaneous drainage of
an abscess, or laparoscopic surgery. Specimens from the surgical intervention must be
sent for culture. Patients who undergo a surgical procedure with complete fascial
closure are appropriate for the trial. The skin incision may be left open for purposes
of wound management as long as complete fascial closure is accomplished. The patient
has at least 1 of the following diagnosed during the surgical intervention:
1. Cholecystitis with gangrenous rupture or perforation or progression of the
infection beyond the gallbladder wall
2. Diverticular disease with perforation or abscess
3. Appendiceal perforation or peri-appendiceal abscess
4. Acute gastric or duodenal perforations, only if operated on >24 hours after
diagnosis
5. Traumatic perforation of the intestines, only if operated on >12 hours after
diagnosis (f) Secondary peritonitis (but not spontaneous bacterial peritonitis
associated with cirrhosis and chronic ascites)
(g) Intra abdominal abscess (including of liver or spleen provided that there is
extension beyond the organ with evidence of intraperitoneal involvement) OR
Preoperative enrollment where the following clinical criteria are met with
confirmation of infection by surgical intervention within 24 hours of entry:
1. Requirement for surgical intervention, defined per protocol as open laparotomy,
percutaneous drainage of an abscess, or laparoscopic surgery
2. Evidence of systemic inflammatory response, with at least one of the following:
- Fever (defined as body temperature >38°C) or hypothermia with a core body
temperature
- Elevated white blood cells (>12000 cells/μL)
- Systolic blood pressure
systolic blood pressure decrease of >40 mmHg Increased heart rate ( >90 bpm)
and respiratory rate (>20 breaths/min)
- Hypoxemia (defined as oxygen saturation
- Altered mental status.
3. Physical findings consistent with intra-abdominal infection, such as:
- Abdominal pain and/or tenderness, with or without rebound
- Localized or diffuse abdominal wall rigidity
- Abdominal mass.
4. Supportive radiologic imaging findings of intra-abdominal infection such as
perforated intraperitoneal abscess detected on computed tomography scan, magnetic
resonance image, or ultrasound.
5. Specimens from the surgical intervention will be sent for culture for isolation
of both aerobic and anaerobic bacteria.
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 while assuming the organism is known to be sensitive to ATM-AVI.
- 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
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 investigation study containing AVI
3. Patient has participated or intends to participate in any other clinical study that
involves the administration of an investigational medication at the time of
presentation, during the course of the study, or during the 30 days prior to study
start.
4. Patient has a history of serious allergy, hypersensitivity (eg, anaphylaxis), or any
serious reaction to aztreonam, carbapenem, monobactam or other ?-lactam antibiotics,
avibactam, nitroimidazoles or metronidazole, or any of the excipients of the
respective (investigational) medicinal products to be administered during the study
5. Patient has a 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 (these are considered situations of peritoneal soiling before infection
has become established); another intra-abdominal process in which the primary etiology
is not likely to be infectious
6. Patient has a simple cholecystitis, gangrenous cholecystitis without rupture, simple
appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis,
pancreatic abscess or ischaemic/necrotic intestine without perforation
7. Patient has a cIAI managed by staged abdominal repair (STAR), open abdomen technique
or any situation where infection source control is not likely to be achieved or in
whom the abdomen is left open, particularly those for whom re-operation is planned, or
those unlikely to solely respond to antimicrobial therapy
8. At screening, if it is known the patient has an infection due to a pathogen that is
unlikely to respond to ATM-AVI plus metronidazole treatment
9. Patient has a rapidly progressive (expected to die in
including acute hepatic failure, respiratory failure or septic shock with a high risk
of mortality due to other causes than cIAI
10. Patient has received systemic antibacterial agents within the 72- hour period prior to
study entry, unless either of the following pertains:
1. Patient has a new infection (not considered a treatment failure) and the
following is met:
- Patient received no more than 24 hours within the 72 hour period prior to study
entry
2. Patient is considered to have failed the previous treatment regimen
11. Patient has a concurrent infection that may interfere with the evaluation of clinical
cure for the study therapy
12. Patient needs effective concomitant systemic antibacterials (oral, IV, or
intramuscular) or antifungals in addition to the investigational product and
metronidazole
13. Patient has creatinine clearance ?50 ml/min. Note: following review of PK and safety
data from the first 10 enrolled patients, and the confirmation of a provisional dose
schedule, patients with a creatinine clearance of 31 - 50 mL/min may be included.
14. Patient has had acute hepatitis in the prior 6 months, chronic hepatitis, cirrhosis
(any Child-Pugh class), acute hepatic failure, or acute decompensation of chronic
hepatic failure
15. Presence of hepatic disease as indicated by aspartate aminotransferase (AST) or
alanine transaminase (ALT) >3 × upper limit of normal (ULN) at Screening. Patients
with AST and/or ALT >3 × ULN and
not accompanied by a total bilirubin ? 2xULN and documented by the investigator as
being directly related to the infectious process being treated
16. Patient has a total bilirubin >3 × ULN, unless isolated hyperbilirubinemia is directly
related to the acute infection or due to known Gilbert's disease
17. Alkaline phosphatase (ALP) >3 × ULN. Patients with values >3 × ULN and
eligible if this value is acute and directly related to the infectious process being
treated.
18. Patients with an immunocompromising illness
19. Known active Clostridium difficile associated diarrhoea
20. Any other condition that, in the opinion of the investigator, may confound the results
of the study or pose additional risks
21. Patient with a do not resuscitate order
22. Patient has an absolute neutrophil count
23. Patient has a hematocrit
24. Patient has a platelet count are permitted if the reduction is historically stable
25. Patient is currently receiving treatment with probenecid.
26. Patient is pregnant or breastfeeding or if of child bearing potential,
27. Patient is unlikely to comply with protocol,
28. Patient is currently receiving anti-convulsant therapy to prevent recurrence of a past
history of seizures.
29. Patient has a prior liver, pancreas or small-bowel transplant.