Health Condition 1: A499- Bacterial infection, unspecified Health Condition 2: K650- Generalized (acute) peritonitis Health Condition 3: J159- Unspecified bacterial pneumonia Health Condition 4: N390- Urinary tract infection, site notspecified
Conditions
Interventions
Intervention1: Aztreonam-Avibactam (ATM-AVI): ATM-AVI doses (loading, extended loading and maintenance) and the dosing frequency of the
maintenance dose are dependent on renal function. Subjects will
Colistin (or polymixin B if colistin not available /accessible)
Fosfomycin
Meropenem
Tigecycline. If the chosen BAT does not provide adequate anaerobic coverage for cIAI subjects
MTZ is to be administered as a co therapy. BAT dose, frequency, dose adjustments with renal impairment wil
Sponsors
Pfizer Limited
Pfizer Limited
Eligibility
Inclusion criteria
Inclusion criteria: Inclusion Criteria All Subjects 1. Subject must be >=18 years of age. 2. Evidence of a personally signed and dated informed consent document indicating that the subject or a legally acceptable representative has been informed of all pertinent aspects of the study. 3. Subjects must have a confirmed diagnosis of serious bacterial infection, specifically cIAI, HAP/VAP, cUTI, or BSI requiring administration of IV antibacterial therapy. 4. Subjects must have an MBL- positive Gram- negative bacteria (an Enterobacteriaceae and/or Stenotrophomonas maltophilia for which the imipenem or meropenem MIC is >= 4 μg/mL), that was isolated from an appropriate specimen obtained within 5 days prior to screening. 5. Female subject of childbearing potential must have a negative serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL. 6. Subjects who have received appropriate prior systemic antibiotic[s] for a carbapenem nonsusceptible pathogen must meet the following criteria (Note: antibiotic[s] is considered appropriate if microbiological susceptibility test results show that all carbapenem non-susceptible pathogens are susceptible to the systemic antibiotic[s] received): 1. Worsening or lack of improvement of objective symptoms or signs of infection after at least 48 hours of antibacterial therapy Note: Symptomatic subjects (see inclusion criteria 3 and 4) with an isolated causative pathogen that was not susceptible to the prior systemic therapy are eligible for this trial. 7. Subject must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Additional Inclusion Criteria- cIAI Subjects 1. Subject must have a specimen obtained from an abdominal source during a surgical intervention within 5 days prior to screening from which a study qualifying pathogen was isolated upon culture. Surgical intervention includes open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery. 2. The subject has at least 1 of the following diagnosed during the surgical intervention: Cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wall; Diverticular disease with perforation or abscess; Appendiceal perforation or peri-appendiceal abscess; Acute gastric or duodenal perforations, only if operated on >24 hours after diagnosis; Traumatic perforation of the intestines, only if operated on >12 hours after diagnosis; Other secondary peritonitis (not primary/ spontaneous bacterial peritonitis associated with cirrhosis or chronic ascites); Intra abdominal abscess (including of the liver and spleen provided that there is extension beyond the organ with evidence of intra peritoneal involvement). 3. Subject has at least 1 of the following signs / symptoms from each of the following 2 groups: Group A: Evidence of systemic inflammatory response: Documented fever (defined as body temperature >=38°C) or hypothermia (with a rectal core body temperature Elevated white blood cells (WBC) ( >12000 cells/μL); Systolic blood pressure (SBP) SBP decrease of >40 mmHg;
Exclusion criteria
Exclusion criteria: Exclusion Criteria All Subjects 1. Subject has an Acute Physiology and Chronic Health Evaluation (APACHE) II score >30. 2. Subjects unlikely to respond to up to 14 days of study treatment. 3. History of serious allergic reaction (anaphylaxis, angioedema, bronchospasm, hypersensitivity) to any systemic antibacterial allowed per protocol. 4. Subject has previously been treated with ATM-AVI Subject with known Clostridium difficile associated diarrhea. 5. Subjects with perinephric infection. 6. Colonization with an MBL-producing Gram-negative bacteria without signs or symptoms. 7. Estimated CrCL 8. Hepatic disease as indicated by ALT or AST >3 x ULN at Screening. Exception: AST and/or ALT up to 5 x ULN if these elevations are acute and directly related to the infectious process. 9. Bilirubin greater than 2 X ULN, unless related to the acute infection or due to known Gilberts disease. 10. Alkaline phosphatase (ALP) >3 x ULN. Exception: up to 11. Absolute neutrophil count Additional Exclusion Criteria - cIAI Subjects 1. Subject has infections limited to the hollow viscous, such as simple cholecystitis, gangrenous cholecystitis without rupture, and simple appendicitis, or has acute suppurative cholangitis, infected necrotizing pancreatitis, or pancreatic abscess. 2. Subject has abdominal wall abscess or small bowel obstruction without perforation or ischemic bowel without perforation. 3. Subject has a cIAI managed by staged abdominal repair (STAR), or "open abdomen" technique, or marsupialization. This criterion is intended to exclude subjects in whom the abdomen is left open,particularly those for whom re operation is planned. 4. Subject who has prior liver, pancreas or small bowel transplant. Additional Exclusion Criteria - HAP/VAP Subjects 1. APACHE II score abscess, pleural empyema, or post obstructive pneumonia. 3. Subject is a recipient of a lung or heart transplant. 4. Subjects with myasthenia gravis. Additional exclusion criteria - cUTI Subjects 1. Subjects with suspected or confirmed complete obstruction of any portion of the urinary tract, perinephric or intrarenal abscess, or prostatitis, or history of any illness that, in the opinion of the investigator, may confound the results of the study or pose additional risk in administering the study therapy to the subject. 2. Subjects with renal transplantation. 3. Subjects with a permanent urinary diversion (eg, with ileal loops, cutaneous ureterostomy or vesicoureteral reflux). 4. Subjects who are likely to receive ongoing antibacterial drug prophylaxis after treatment of cUTI (eg, subjects with vesico-ureteric reflux). 5. Any recent history of trauma to the pelvis or urinary tract. 6. Subjects with uncomplicated urinary tract infections (generally female subjects with urinary frequency, urgency, or pain or discomfort without systemic symptoms or signs of infection). Additional exclusion criteria - BSI Subjects 1. Subject has a prosthetic cardiac valve or synthetic endovascular graft. 2. Subject has a suspected or documented medical condition with well
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Proportion of subjects with clinical cure in the microbiological Intent-To-Treat (micro-ITT) analysis setTimepoint: Up to 31 days | — |
Secondary
| Measure | Time frame |
|---|---|
| Incidence and severity of adverse eventsTimepoint: from first dose up to 48 days;Incidence of abnormalities in physical examinationTimepoint: from first dose up to 48 days;Incidence of clinical laboratory abnormalitiesTimepoint: from first dose up to 48 days;Incidence of ECG abnormalitiesTimepoint: from first dose up to 48 days;Incidence of vital sign abnormalitiesTimepoint: from first dose up to 48 days;Proportion of subjects who died on or before 28 days in the Intent-To-Treat (ITT) and micro-ITT analysis setsTimepoint: from randomization up to 31 days;Proportion of subjects with a favorable per pathogen microbiological response in the micro ITT and ME analysis setsTimepoint: Time Frame: within 24 hours after the completion of the last infusion of IV study treatment and up to 31 days;Proportion of subjects with a favorable per subject microbiological response in the micro ITT and ME analysis setsTimepoint: within 24 hours after the completion of the last infusion of IV study treatment and up to 31 days;Proportion of subjects with clinical cure in the micro-ITT and ME analysis setsTimepoint: within 24 hours after the completion of the last infusion of IV study treatment;Proportion of subjects with clinical cure in the Microbiologically Evaluable (ME) analysis setTimepoint: up to 31 days | — |
Countries
Argentina, China, Greece, India, Malaysia, Mexico, Peru, Philippines, Romania, Russian Federation, Taiwan, United States of America
Contacts
Public ContactDr Seema Pai
Pfizer Limited
Outcome results
None listed