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. (REVISIT)
Complicated Intra-abdominal Infection, Hosptial Acquired Pneumonia, Ventilator Associated Pneumonia
About this trial
This is an interventional treatment trial for Complicated Intra-abdominal Infection focused on measuring Complicated intra-abdominal infection, Hosptial acquired pneumonia, Ventilator associated pneumonia, Gram negative infections, Metallo-beta lactamase, Multi drug resistant pathogens
Eligibility Criteria
Inclusion Criteria:
All subjects:
- Male or female from 18 years of age
- Provision of informed consent
- Confirmed diagnosis of HAP/VAP or cIAI requiring iv antibiotic treatment
- 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:
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
- Surgical intervention within 24 hours (before or after) the administration of the first dose of study drug
Additional for HAP/VAP:
- Onset symptoms > 48h after admission to or <7 days after discharge from an inpatient care facility
- New or worsening infiltrate on CXR or CT scan
- Clinical signs and symptoms and laboratory findings consistent with HAP/VAP
- Respiratory specimen obtained for Gram stain and culture following onset of symptoms and prior to randomisation
Exclusion criteria:
All subjects:
- APACHE II score > 30
- Confirmed or suspected infection caused by Gram-negative species not expected to respond to study drug, or Gram-positive species
- Receipt of >24 hr systemic antibiotic within 48h prior to randomisation (exception in case of treatment failure)
- 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
- Known Clostridium difficle associated diarrhoea
- Requirement for effective concomitant systemic antibacterials or antifungals
- Creatinine clearance ≤15 ml/min or requirement or expectation for renal replacement therapy
- Acute hepatitis, cirrhosis, acute hepatic failure, chronic hepatic failure
- Hepatic disease as indicated by AST or ALT >3 × ULN. Patients with AST and/or ALT up to 5 × ULN are eligible if acute and documented by the investigator as being directly related infectious process
- Patient has a total bilirubin >2 × ULN, unless isolated hyperbilirubinemia is directly related to infectious process or due to known Gilbert's disease
- 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
- Absolute neutrophil count <500/mm3
- Pregnant or breastfeeding or if of child bearing potential, not using a medically accepted effective method of birth control.
- Any other condition that may confound the results of the study or pose additional risks to the subject
- Unlikely to comply with protocol
- History of epilepsy or seizure disorders excluding febrile seizures of childhood
Additional for cIAI
- 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
- Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess
- Prior liver, pancreas or small-bowel transplant
- Staged abdominal repair (STAR), open abdomen technique or marsupialisation
Additional for HAP/VAP
- APACHE II score < 10
- Known or high likelihood of Gram-positive monomicrobial infection
- Lung abscess, pleural empyema, post-obstructive pneumonia
- Lung or heart transplant
- Myasthenia gravis
Sites / Locations
- Banner University Medical Center - Tucson
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Harbor-UCLA Medical Center
- Southern Illinois University School of Medicine
- Memorial Medical Center
- Sanatorio Britanico
- Sanatorio Servicios Medicos SM
- Hospital San Roque
- University Hospital Alexandrovska, Clinic of Anesthesiology and Intensive Care
- University Hospital Queen Joanna ISUL, Clinic of Surgery
- University Multiprofile Hospital for Active Treatment ''Prof.Dr Stoyan Kirkovich''AD
- Peking University Third Hospital
- Zhangzhou Municipal Hospital of Fujian Province
- ZhuJiang Hospital of Southern Medical University
- The First Affiliated Hospital of Shantou University Medical College
- The Second People's Hospital of Shenzhen
- Nanning First People's Hospital
- Affiliated Hospital of Guilin Medical University
- Changsha Third Hospital
- Hunan Province People's Hospital
- Baotou Central Hospital
- Jiangyin People's Hospital
- Affiliated Hospital of Jiangsu University
- Huashan Hospital Fudan University
- Shanghai Pulmonary Hospital
- The First people's Hospital of Kunming
- The First Affiliated Hospital of College of Medicine, Zhejiang University
- Taizhou Hospital of Zhejiang Province
- Lishui People's Hospital
- Quzhou People's Hospital
- Peking University People's Hospital
- Jiangyin People's Hospital
- Tianjin Union Medical Center
- Klinicka bolnica Merkur
- Klinicki bolnicki centar Rijeka
- University Hospital Centre Osijek
- General Hospital "Dr. Josip Bencevic" Slavonski Brod
- Clinical Hospital Dubrava
- Fakultni nemocnice Brno
- Krajska zdravotni, a.s. - Nemocnice Decin, o.z.
- Lekarna Nemocnice Decin, Krajska zdravotni, a.s.- Nemocnice Decin, o.z.
- Public Hospital Kolin, a.s.
- Nemocnice Kyjov, prispevkova organizace
- Fakultni nemocnice Kralovske Vinohrady
- General Hospital of Athens "Evangelismos"
- General and Chest Diseases Hospital "Sotiria"
- General Hospital of Athens "Laiko"
- University General Hospital "ATTIKON"
- University General Hospital of Heraklion
- University General Hospital of Larissa
- Koutlimbaneio and Triantafylleio General Hospital of Larissa
- King George Hospital
- Victoria Hospital, Bangalore Medical College and Research Institute
- M S Ramaiah Medical College and Hospitals
- Kasturba Medical College and Hospital
- JSS Hospital
- Amrita Institute of Medical Sciences & Research Centre
- Government Medical College, Kozhikode
- Deenanath Mangeshkar Hospital And Research Centre
- Sahyadri Super Speciality Hospital
- Sahyadri Super Specialty Hospital
- S.R. Kalla Memorial Gastro & General Hospital
- Apollo Hospitals
- King George's Medical University
- Dayanand Medical College and Hospital
- Sahyadri Clinical Research & Development Center
- Sahyadri Specialty Hospital
- Assuta Ashdod University Hospital
- Rambam Health Care Campus
- Hadassah Medical Organization, Hadassah Medical Center, Ein-Karem
- Rabin Medical Center, Beilinson Hospital
- Tel Aviv Sourasky Medical Center
- The Chaim Sheba Medical Center
- Shamir Medical Center, Infectious Diseases Unit
- Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
- Azienda Ospedaliero-Universitaria Ospedali Riuniti
- Azienda Ospedaliero Universitaria di Modena
- Farmacia Ospedaliera - Direzione Assistenza Farmaceutica
- SC di Radiologia - Azienda Ospedaliera Universitaria di Modena
- Azienda Ospedaliero-Universitaria Pisana Ospedale Cisanello
- UO Radiognastostica 2 Azienda Ospedaliero-Universitaria Pisana Ospedale Cisanello
- UO Farmaceutica Azienda Ospedaliero-Universitaria Pisana
- Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Presidio Ospedaliero Universitario Santa
- Gachon University Gil Medical Center - Infectious Disease
- Seoul National University Hospital
- The Catholic University of Korea, Eunpyeong St. Mary's Hospital
- Hallym University Kangnam Sacred Heart Hospital
- Hospital Seberang Jaya
- Hospital Sultanah Nur Zahirah
- University Malaya Medical Centre
- Hospital Civil Fray Antonio Alcalde
- Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
- De La Salle Medical and Health Sciences Institute
- Baguio General Hospital and Medical Center
- Davao Doctors Hospital
- St. Paul's Hospital of Iloilo, Inc.
- West Visayas State University Medical Center
- Makati Medical Center
- Philippine General Hospital, Central Intensive Care Unit
- Asian Hospital and Medical Center
- Quirino Memorial Medical Center
- St. Luke's Medical Center
- Institutul National de Boli Infectioase "Prof. Dr. Matei Bals"
- Spitalul Clinic de Boli Infectioase si tropicale "Dr. Victor Babes"
- Spitalul Clinic de Boli Infectioase Cluj-Napoca
- Spitalul Clinic de Boli Infectioase "Sf. Parascheva" Iasi
- Spitalul Clinic Judetean de Urgenta "Pius Brinzeu"
- Private Healthcare Institution "Clinical Hospital 'Russian Railroad Medicine, Chelyabinsk'"
- State Budgetary Healthcare Institution "Regional Clinical Hospital No. 2" of the Ministry of Health
- GBUZ of Novosibirsk region "City Clinical Hospital # 2"
- State autonomous institution of healthcare of the Perm Region" City clinical hospital #4"
- FGBOU VO "The First St. Petersburg state medical university n. a. I.P. Pavlova"
- OGBUZ "Smolensk Regional Clinical Hospital"
- FSBEI of HE "Smolensk State Medical University" of the Ministry of Health of the RF
- Scientific Research Institute of Antimicrobial Chemotherapy
- Hospital Universitari Germans Trias i Pujol
- Hospital Universitario Mutua de Terrassa
- Complejo Hospitalario Universitario de Vigo. Area Sanitaria de Vigo. Hospital Alvaro Cunqueiro
- Parc de Salut Mar- Hospital del Mar
- Hospital de la Santa Creu i Sant Pau
- Hospital Universitario Reina Sofia
- Hospital Universitario Ramon y Cajal
- Hospital Regional Universitario de Malaga
- Hospital Universitario Virgen Macarena
- Hospital Universitario Virgen del Rocio
- Hospital Universitari i Politecnic la Fe
- Hospital Universitario Miguel Servet
- National Taiwan University Hospital Yun-Lin Branch
- Kaohsiung Medical University Chung-Ho Memorial Hospital
- Kaohsiung Veterans General Hospital
- Taichung Veterans General Hospital
- National Taiwan University Hospital
- Taipei Municipal Wanfang Hospital
- Faculty of Medicine Siriraj Hospital
- Srinagarind Hospital, Division of Infectious Disease and Tropical Medicine
- Bamrasnaradura Infectious Disease Institute (BIDI)
- Songklanagarind Hospital, Prince of Songkla University
- Hacettepe Universitesi Tip Fakultesi
- Ankara University Faculty of Medicine
- T.C. Saglik Bakanligi Ankara Sehir Hastanesi
- Acibadem Atakent Hospital
- Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi
- Ege University Faculty of Medicine
- Kocaeli University Medical Faculty
- Karadeniz Technical University Medical Faculty Farabi Hospital
- OKU "Chernivetska oblasna klinichna likarnia", khirurhichne viddilennia
- KZ "Dnipropetrovska oblasna klinichna likarnia im. I.I. Mechnykova", viddilennia khirurhii №2
- Komunalnyi zaklad "Miska klinichna likarnia No.4" Dniprovskoi miskoi rady, viddilennia profpatolohii
- Oblasna klinichna likarnia, viddilennia anesteziolohii ta intensyvnoi terapii
- Ivano-Frankivska tsentralna miska klin likarnia, viddilennia khirurhii,
- DU "Instytut zahalnoi ta nevidkladnoi khirurhii imeni V.T. Zaitseva Natsionalnoi akademii medychnykh
- Kyivska miska klinichna likarnia No. 3, khirurhichne viddilennia
- Kyivska miska klinichna likarnia #4, khirurhichne viddilennia #1
- Komunalne nekomertsiine pidpryiemstvo Lvivskoi oblasnoi rady Lvivska oblasna klinichna likarnia
- Odeska klinichna likarnia na zaliznychnomu transporti filii "Tsentr okhorony zdorovia" aktsionernoho
- Komunalne pidpryiemstvo "1-a miska klinichna likarnia Poltavskoi miskoi rady",
- Vinnytska oblasna klinichna likarnia im. M.I. Pyrohova
Arms of the Study
Arm 1
Arm 2
Experimental
Active Comparator
Aztreonam-Avibactam ± Metronidazole
Meropenem ± Colistin
All patients randomised to this arm will receive ATM-AVI; all patients with cIAI will receive MTZ for anaerobic cover
All patients randomised to this arm will receive MER; addition of COL will be at investigator's discretion in line with local practice