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.

A Phase 3 Prospective, Randomized, Multicenter, Open Label, Central Assessor Blinded, Parallel Group, Comparative Study To Determine The Efficacy, Safety And Tolerability Of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) Versus Meropenem±Colistin (MER±COL) For The Treatment Of Serious Infections Due To Gram Negative Bacteria, Including Metallo Β Lactamase (MBL) - Producing Multidrug Resistant Pathogens, For Which There Are Limited Or No Treatment Options

• ATM-AVI (Drug): (Creatinine clearance > 50 mL/min) 6500 mg ATM/2167 mg (loading dose, extended loading dose and maintenance dose) by iv infusion on Day 1 followed by a total daily dose of 6000 mg ATM/2000 mg AVI (Creatinine clearance 31 - 50 mL/min) 4250 mg ATM/1417 mg AVI on Day 1 (loading dose, extended loading dose, maintenance dose) followed by total daily dose 3000 mg ATM/1000 mg AVI (Creatinine clearance 16 - 30 mL/min) 2700 mg ATM/900 mg AVI on Day 1 (loading dose, extended loading dose maintenance dose), followed by total daily dose 2025 mg ATM/675 mg AVI
• MTZ (Drug): For cIAI only; 500 mg/100 mL metronidazole iv infusion over 1hr q8h
• MER (Drug): Where pathogen initially not suspected of being MER-resistant: (Creatinine clearance > 50 mL/min) 1000 mg meropenem by 30 min iv infusion q8h (Creatinine clearance 26 - 50 mL/min) 1000mg meropenem by 30 min iv infusion q12h (Creatinine clearance 16 - 25 mL/min) 500 mg meropenem by 30 min iv infusion q12h Where pathogen initially suspected of being MER-resistant (Creatinine clearance > 50 mL/min) 2000 mg meropenem by 180 min iv infusion q8h (Creatinine clearance 26 - 50 mL/min) 2000 mg meropenem by 180 min iv infusion q12h (Creatinine clearance 16 - 25 mL/min) 1000 mg meropenem by 180 min iv infusion q12h
• COL (Drug): Loading dose 9 million IU by 30 -60 min iv infusion (6 million IU where weight < 60 kg) followed by one of the following maintenance doses: (Creatinine clearance > 50 mL/min) after a 12h interval, commence maintenance dosing 9 million IU daily in 2 or 3 divided doses by 30 -60 min iv infusions. (Creatinine clearance 31 - 50 mL/min) After a 24 hr interval, commence maintenance dosing of 6 million IU daily in 2 divided doses by 30 -60 min iv infusion (Creatinine clearance 21 - 30 mL/min) After a 24 hr interval, commence maintenance dosing 5 million IU daily in 2 divided doses by 30 -60 min iv infusion (Creatinine clearance 16 - 20 mL/min) after a 24 hr interval, commence maintenance dosing 4 million IU daily in 2 divided doses by 30 -60 min iv infusion

Primary outcomes

• Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit: Intent-To-Treat (ITT) Analysis Set [At TOC visit (Day 28)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% confidence interval (CI) was based on Jeffrey's method.
• Percentage of Participants With Clinical Cure at TOC Visit: Clinically Evaluable (CE) Analysis Set [At TOC visit (Day 28)]: Clinical cure = improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method. CE analysis set:all participants in ITT analysis set; met criteria for cIAI, or HAP/VAP; received at least 48 hours of study treatment or <48 hours of treatment before discontinuing study drug due to AE; no concomitant antibiotics for any baseline pathogens between first dose and TOC (except protocol-allowed antibiotics); no prior antibiotics other than allowed per protocol; no important protocol deviations; no clinical outcome of indeterminate at TOC; no monomicrobial infections due to non-eligible pathogens and did not have only Gram-positive pathogens.

Secondary outcomes

• Percentage of Participants With Clinical Cure at TOC Visit: Microbiological Intent-To-Treat (Micro-ITT) Analysis Set [At TOC visit (Day 28)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method.
• Percentage of Participants With Clinical Cure at TOC Visit: Microbiologically Evaluable (ME) Analysis Set [At TOC visit (Day 28)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method.
• Percentage of Participants With Clinical Cure at TOC Visit by Type of Infection: ITT Analysis Set [At TOC visit (Day 28)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method.
• Percentage of Participants With Clinical Cure at TOC Visit by Type of Infection: CE Analysis Set [At TOC visit (Day 28)]: Clinical cure = improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method. CE analysis set:all participants in ITT analysis set; met criteria for cIAI, or HAP/VAP; received at least 48 hours of study treatment or <48 hours of treatment before discontinuing study drug due to AE; no concomitant antibiotics for any baseline pathogens between first dose and TOC (except protocol-allowed antibiotics); no prior antibiotics other than allowed per protocol; no important protocol deviations; no clinical outcome of indeterminate at TOC; no monomicrobial infections due to non-eligible pathogens and did not have only Gram-positive pathogens.
• Percentage of Participants With Clinical Cure in Participants With Metallo-beta-lactamase (MBL) Positive Pathogen at TOC Visit: Micro-ITT Analysis Set [At TOC visit (Day 28)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee.
• Percentage of Participants With Clinical Cure in Participants With MBL Positive Pathogen at TOC Visit: ME Analysis Set [At TOC visit (Day 28)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee.
• Percentage of Participants With Favorable Per-Participant Microbiological Response at TOC Visit: Micro- ITT Analysis Set [At TOC visit day (28)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure.
• Percentage of Participants With Favorable Per-Participant Microbiological Response at TOC Visit: ME Analysis Set [At TOC Visit (Day 28)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure.
• Percentage of Participants Who Died on or Before 28 Days After Randomization: ITT Analysis Set [From randomization up to 28 days]: Percentage of participants who died on or before 28 days after randomization is reported in this outcome measure.
• Percentage of Participants Who Died on or Before 28 Days After Randomization: Micro-ITT Analysis Set [From randomization up to 28 days]: Percentage of participants who died on or before 28 days after randomization is reported in this outcome measure.
• Plasma Concentration of Aztreonam [Anytime between 25 to 30 minutes, 3.25 to 3.5 hours, 5.5 to 6.5 hours, 7.5 to 8.5 hours post start of infusion on Day 1; 2.75 to 3 hours, 3.5 to 4.5 hours, 5 to 6 and 7 to 8 hours post start of infusion on Day 4]: Plasma concentration for aztreonam according to renal function (augmented, normal and mild, moderate and severe is presented in this outcome measure. Augmented = Creatinine clearance (CrCL) > 150 milliliters per minute (mL/min); Normal \& Mild = CrCL > 50 to <=150 mL/min; Moderate = CrCL > 30 to ≤ 50 mL/min; Severe = CrCL > 15 to ≤ 30 mL/min.
• Plasma Concentration of Avibactam [Anytime between 25 to 30 minutes, 3.25 to 3.5 hours, 5.5 to 6.5 hours, 7.5 to 8.5 hours post start of infusion on Day 1; 2.75 to 3 hours, 3.5 to 4.5 hours, 5 to 6 and 7 to 8 hours post start of infusion on Day 4]: Plasma concentration for avibactam according to renal function (augmented, normal and mild, moderate and severe is presented in this outcome measure. Augmented = CrCL > 150 mL/min; Normal \& Mild = CrCL > 50 to <=150 mL/min; Moderate = CrCL > 30 to ≤ 50 mL/min; Severe = CrCL > 15 to ≤ 30 mL/min.
• Maximum Plasma Concentration for a Dosing Interval at Steady-State (Cmax, ss) According to Clinical Response by Infection Type at TOC: Aztreonam [At TOC (Day 28)]: Population PK predicted maximum plasma concentration for a dosing interval at steady-state (Cmax,ss) for participants who received aztreonam-avibactam in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Clinical response categories included, clinical cure=improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Failure was defined as participants who met any of the following criteria like death (after receiving at least 48 hours of study treatment) and participants who received treatment with further antibiotics for the index infection. Indeterminate was defined as death (after receiving less than 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
• Percentage of Time That Free Plasma Concentrations Are Above the Minimum Inhibitory Concentration Over a Dosing Interval (%fT>MIC Aztreonam (ATM) of 8 mg/L) According to Clinical Response by Infection Type at TOC: Aztreonam [At TOC (Day 28)]: Population PK predicted (%fT>MIC ATM of 8 mg/L) for participants who received aztreonam-avibactam in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Clinical response categories included, clinical cure=improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Failure was defined as participants who met any of the following criteria like death (after receiving at least 48 hours of study treatment) and participants who received treatment with further antibiotics for the index infection. Indeterminate was defined as death (after receiving less than 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
• Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss ) According to Clinical Response by Infection Type at TOC: Aztreonam [0 to 24 hours at TOC (Day 28)]: Population PK predicted (AUC24,ss) for participants who received aztreonam-avibactam in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Clinical response categories included, clinical cure=improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Failure was defined as participants who met any of the following criteria like death (after receiving at least 48 hours of study treatment) and participants who received treatment with further antibiotics for the index infection. Indeterminate was defined as death (after receiving less than 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
• Maximum Plasma Concentration for a Dosing Interval at Steady-state (Cmax,ss) According to Microbiological Response by Infection Type at TOC: Aztreonam [At TOC (Day 28)]: Population PK predicted (Cmax,ss) for participants who received ATM-AVI in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Microbiological response included Favorable =baseline pathogens for participant had a favorable outcome. Eradication: Absence of causative pathogen from an appropriately obtained specimen at site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Unfavorable=persistence, persistence with increasing MIC, or presumed persistence. Persistence= Causative organism still present from appropriately obtained specimen at site of infection. Presumed persistence= Participant assessed as a clinical failure and repeat culture of specimens were not performed/clinically indicated. Indeterminate = death (after receiving < 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
• Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss) According to Microbiological Response by Infection Type at TOC: Aztreonam [0 to 24 hours at TOC (Day 28)]: Population PK predicted (AUC24,ss) for participants who received ATM-AVI in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Microbiological response included Favorable =baseline pathogens for participant had a favorable outcome. Eradication: Absence of causative pathogen from an appropriately obtained specimen at site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Unfavorable=persistence, persistence with increasing MIC, or presumed persistence. Persistence= Causative organism still present from appropriately obtained specimen at site of infection. Presumed persistence= Participant assessed as a clinical failure and repeat culture of specimens were not performed/clinically indicated. Indeterminate = death (after receiving < 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
• Percentage of Time That Free Plasma Concentrations Are Above the Minimum Inhibitory Concentration Over a Dosing Interval (%fT>MIC Aztreonam (ATM) of 8 mg/L) According to Microbiological Response by Infection Type at TOC: Aztreonam [At TOC (Day 28)]: Population PK predicted (%fT>MIC ATM of 8 mg/L) for participants who received ATM-AVI in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Microbiological response included Favorable =baseline pathogens for participant had a favorable outcome. Eradication: Absence of causative pathogen from an appropriately obtained specimen at site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Unfavorable=persistence, persistence with increasing MIC, or presumed persistence. Persistence= Causative organism still present from appropriately obtained specimen at site of infection. Presumed persistence= Participant assessed as a clinical failure and repeat culture of specimens were not performed/clinically indicated. Indeterminate = death (after receiving < 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
• Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss) According to Clinical Response by Infection Type at TOC: Avibactam [0 to 24 hours at TOC (Day 28)]: Population PK predicted (AUC24,ss) for participants who received aztreonam-avibactam in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Clinical response categories included, clinical cure=improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Failure was defined as participants who met any of the following criteria like death (after receiving at least 48 hours of study treatment) and participants who received treatment with further antibiotics for the index infection. Indeterminate was defined as death (after receiving less than 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
• Maximum Plasma Concentration for a Dosing Interval at Steady-state (Cmax,ss ) According to Clinical Response by Infection Type at TOC: Avibactam [At TOC (Day 28)]: Population PK predicted (Cmax,ss) for participants who received aztreonam-avibactam in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Clinical response categories included, clinical cure=improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Failure was defined as participants who met any of the following criteria like death (after receiving at least 48 hours of study treatment) and participants who received treatment with further antibiotics for the index infection. Indeterminate was defined as death (after receiving less than 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
• Percent of Time That Free Plasma Concentrations Are Above the Threshold Concentration Over a Dosing Interval (%fT>CT of 2.5mg/L) According to Clinical Response by Infection Type at TOC: Avibactam [At TOC (Day 28)]: Population PK predicted (%fT>CT of 2.5mg/L) for participants who received aztreonam-avibactam in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Clinical response categories included, clinical cure=improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Failure was defined as participants who met any of the following criteria like death (after receiving at least 48 hours of study treatment) and participants who received treatment with further antibiotics for the index infection. Indeterminate was defined as death (after receiving less than 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
• Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss) According to Microbiological Response by Infection Type at TOC: Avibactam [0 to 24 hours At TOC (Day 28)]: Population PK predicted (AUC24,ss) for participants who received ATM-AVI in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Microbiological response included Favorable =baseline pathogens for participant had a favorable outcome. Eradication: Absence of causative pathogen from an appropriately obtained specimen at site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Unfavorable=persistence, persistence with increasing MIC, or presumed persistence. Persistence= Causative organism still present from appropriately obtained specimen at site of infection. Presumed persistence= Participant assessed as a clinical failure and repeat culture of specimens were not performed/clinically indicated. Indeterminate = death (after receiving<48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
• Maximum Plasma Concentration for a Dosing Interval at Steady-state (Cmax,ss (mg/L)) According to Microbiological Response by Infection Type at TOC: Avibactam [At TOC (Day 28)]: Population PK predicted (Cmax,ss (mg/L)) for participants who received ATM-AVI in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Microbiological response included Favorable =baseline pathogens for participant had a favorable outcome. Eradication: Absence of causative pathogen from an appropriately obtained specimen at site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Unfavorable=persistence, persistence with increasing MIC, or presumed persistence. Persistence= Causative organism still present from appropriately obtained specimen at site of infection. Presumed persistence= Participant assessed as a clinical failure and repeat culture of specimens were not performed/clinically indicated. Indeterminate = death (after receiving<48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
• Percent of Time That Free Plasma Concentrations Are Above the Threshold Concentration Over a Dosing Interval; (%fT>CT of 2.5 mg/L) According to Microbiological Response by Infection Type at TOC: Avibactam [At TOC (Day 28)]: Population PK predicted (%fT>CT of 2.5 mg/L) for participants who received ATM-AVI in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Microbiological response included Favorable =baseline pathogens for participant had a favorable outcome. Eradication: Absence of causative pathogen from an appropriately obtained specimen at site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Unfavorable=persistence, persistence with increasing MIC, or presumed persistence. Persistence= Causative organism still present from appropriately obtained specimen at site of infection. Presumed persistence= Participant assessed as a clinical failure and repeat culture of specimens were not performed/clinically indicated. Indeterminate = death (after receiving < 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
• Number of Participants With Adverse Events (AEs) and Serious AEs [From start of study treatment until end of late follow-up (Up to Day 45)]: An adverse event (AE) was any untoward medical occurrence in a study participant administered medicinal product,; the event need not necessarily have a causal relationship with product treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital abnormal/birth defect or considered an important medical event.
• Number of Participants With Potentially Clinically Significant Hematology Abnormalities [From start of study treatment until TOC visit (Up to Day 28)]: Criteria for potential clinically significant hematology results were as follows: hemoglobin, hematocrit and erythrocyte <0.7*lower limit of normal \[LLN\] and >30% decrease from Baseline (DFB); >1.3*upper limit of normal (ULN) and >30% increase from Baseline (IFB). Platelet count <0.65*LLN and > 50% decrease from baseline; > 1.5 * ULN and > 100% increase from baseline. leukocyte: < 0.65* LLN and > 60% decrease from baseline; > 1.5* ULN and 100% increase from baseline. Neutrophils/leukocytes < 0.65 * LLN and >75% decrease from baseline; > 1.6*ULN and > 100% increase from baseline. Lymphocytes/leukocytes < 0.25* LLN and > 75% decrease from baseline;> 1.5* ULN and > 100% increase from baseline, Eosinophils/leukocytes, Monocytes/leukocytes, Basophils/leukocytes > 4.0* ULN and > 300% increase from baseline.
• Number of Participants With Potentially Clinically Significant Clinical Chemistry Abnormalities [From start of study treatment until At TOC visit (Up to Day 28)]: Albumin < 0.5* LLN and> 50% decrease from baseline (DFB);> 1.5 * ULN and> 50% increase from baseline (IFB). Alkaline phosphatase < 0.5 * LLN and> 80% DFB;> 3.0 * ULN and> 100%. Alanine and Aspartate aminotransferase > 3.0 * ULN and> 100% IFB. Bicarbonate < 0.7 * LLN and > 40% DFB;> 1.3 * ULN and> 40% IFB. Blood urea nitrogen < 0.2 * LLN and > 100% DFB; > 3.0 * ULN and > 200% IFB. Calcium < 0.7 * LLN and > 30% DFB;> 1.3 * ULN and> 30% IFB. Chloride < 0.8 * LLN >and 20% DFB; > 1.2 * ULN and > 20% IFB. Creatinine > 2.0 * ULN and> 100% IFB; Glucose < 0.6 * LLN and> 40% DFB; > 3.0 * ULN and> 200% IFB. Potassium < 0.8 * LLN and > 20% DFB; > 1.2 * ULN and> 20% IFB. Sodium < 0.85 * LLN and> 10% DFB;> 1.1 * ULN and >10% IFB. Bilirubin > 1.5 * ULN and > 100% IFB.; Direct bilirubin > 2.0 * ULN and > 150% IFB.
• Number of Participants With Abnormalities in Vital Signs [From start of study treatment until TOC visit (Up to Day 28)]: Vitals signs, included blood pressure and, heart rate. Blood pressure (BP) and heart rate were measured using a semiautomatic BP recording device with the participant in a supine position after at least 10 minutes of rest. Criteria for abnormalities included: Systolic BP (millimeters of mercury \[mmHg\]): value more than (>) 150 and increase from baseline more than equal (>= 30) or value less than (<) 90 and decrease from baseline >= 30; DBP: value > 100 and increase from baseline >=20 or Value < 50 and decrease from baseline >= 20; Heart Rate (beats per minute \[BPM\]): value < 40 or > 120.
• Number of Participants With Abnormal Physical Examination Finding [Screening, End of treatment (up to 24 hours post infusion on Day 14) and Test of Cure (Day 28)]: A complete physical examination was performed and included an assessment of the following: general appearance including site of infection, skin, head and throat (head, eyes, ears, nose, and throat), lymph nodes, lungs, cardiovascular (CV), abdomen, musculoskeletal, and neurological systems.
• Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings [Baseline (latest non-missing value before start of treatment) and Day 3]: Standard 12-lead ECGs were recorded with the participants in the supine position after the participant had rested in this position for 10 minutes. Clinically significant findings were based on investigators assessment.

Other outcomes

• Percentage of Participants With Clinical Cure at End of Treatment (EOT) Visit: ITT Analysis Set [At EOT visit (Within 24 hours after last infusion on Day 14)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method.
• Percentage of Participants With Clinical Cure at EOT Visit: Micro-ITT Analysis Set [At EOT visit (Within 24 hours after last infusion on Day 14)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method.
• Percentage of Participants With Clinical Cure at EOT Visit: CE Analysis Set [At EOT visit (Within 24 hours after last infusion on Day 14)]: Clinical cure = improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method. CE analysis set: all participants in ITT analysis set; met criteria for cIAI, or HAP/VAP; received at least 48 hours of study treatment or <48 hours of treatment before discontinuing study drug due to AE; no concomitant antibiotics for any baseline pathogens between first dose and TOC (except protocol-allowed antibiotics); no prior antibiotics other than allowed per protocol; no important protocol deviations; no clinical outcome of indeterminate at TOC; no monomicrobial infections due to non-eligible pathogens and did not have only Gram-positive pathogens.
• Percentage of Participants With Clinical Cure at EOT Visit: ME Analysis Set [At EOT visit (Within 24 hours after last infusion on Day 14)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method.
• Percentage of Participants With Clinical Cure by Type of Infection at EOT Visit: ITT Analysis Set [At EOT visit (Within 24 hours after last infusion on Day 14)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method.
• Percentage of Participants With Clinical Cure by Type of Infection at EOT Visit: CE Analysis Set [At EOT visit (Within 24 hours after last infusion on Day 24)]: Clinical cure = improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method. CE analysis set: all participants in ITT analysis set; met criteria for cIAI, or HAP/VAP; received at least 48 hours of study treatment or <48 hours of treatment before discontinuing study drug due to AE; no concomitant antibiotics for any baseline pathogens between first dose and TOC (except protocol-allowed antibiotics); no prior antibiotics other than allowed per protocol; no important protocol deviations; no clinical outcome of indeterminate at TOC; no monomicrobial infections due to non-eligible pathogens and did not have only Gram-positive pathogens.
• Percentage of Participants With Clinical Cure by Pathogen Resistance Type at EOT Visit: Micro-ITT Analysis Set [At EOT visit (Within 24 hours after last infusion on Day 14)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. Percentage of participants with clinical cure by pathogen resistance type (ATM non-susceptible and Meropenem non-susceptible based on European Committee on Antimicrobial Susceptibility Testing \[EUCAST\] criteria and Clinical and Laboratory Standards Institute \[CLSI\] criteria, Extended spectrum beta-lactamases \[ESBL\]-positive, Carbapenemase-positive, Serene Carbapenemase and Metallo-beta-lactamase-positive) is reported in this outcome measure.
• Percentage of Participants With Clinical Cure by Pathogen Resistance Type at TOC Visit: Micro-ITT Analysis Set [At TOC (Day 28)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. Percentage of participants with clinical cure by pathogen resistance type (ATM non-susceptible and Meropenem non-susceptible based on EUCAST criteria and CLSI criteria, ESBL-positive, Carbapenemase-positive, Serene Carbapenemase and Metallo-beta-lactamase-positive) is reported in this outcome measure.
• Percentage of Participants With Clinical Cure by Pathogen Resistance Type at EOT Visit: ME Analysis Set [At EOT (Within 24 hours after last infusion on Day 14)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. Percentage of participants with clinical cure by pathogen resistance type (ATM non-susceptible and Meropenem non-susceptible based on EUCAST criteria and CLSI criteria, ESBL-positive, Carbapenemase-positive, Serene Carbapenemase and Metallo-beta-lactamase-positive) is reported in this outcome measure.
• Percentage of Participants With Clinical Cure by Pathogen Resistance Type at TOC Visit: ME Analysis Set [At TOC visit (Day 28)]: Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. Percentage of participants with clinical cure by pathogen resistance type (ATM non-susceptible and Meropenem non-susceptible based on EUCAST criteria and CLSI criteria, ESBL-positive, Carbapenemase-positive, Serene Carbapenemase and Metallo-beta-lactamase-positive) is reported in this outcome measure.
• Percentage of Participants With Favorable Per Participant Microbiological Response at EOT Visit: Micro-ITT Analysis Set [At EOT visit (Within 24 hours after last infusion on Day 14)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure.
• Percentage of Participants With Favorable Per Participant Microbiological Response at EOT Visit : ME Analysis Set [At EOT visit (Within 24 hours after last infusion on Day 14)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure.
• Number of Participants With Favorable Microbiological Response Per-Pathogen at EOT Visit: Micro-ITT Analysis Set [At EOT (Within 24 hours after last infusion on Day 14)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Only those pathogens are reported which had more than or equal to 10 isolates for either treatment group.
• Number of Participants With Favorable Microbiological Response Per-Pathogen at at TOC Visit: Micro-ITT Analysis Set [At TOC visit (Day 28)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Only those pathogens are reported which had more than or equal to 10 isolates for either treatment group.
• Number of Participants With Favorable Microbiological Response Per-Pathogen at EOT Visit: ME Analysis Set [At EOT (Within 24 hours after last infusion on Day 14)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Only those pathogens are reported which had more than or equal to 10 isolates for either treatment group.
• Number of Participants With Favorable Microbiological Response Per-Pathogen at TOC Visit: ME Analysis Set [At TOC visit (Day 28)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Only those pathogens are reported which had more than or equal to 10 isolates for either treatment group.
• Percentage of Participants With Favorable Per-Participant Microbiological Response by Pathogen Resistance Type at EOT Visit: Micro-ITT Analysis Set [At EOT (Within 24 hours after last infusion on Day 14)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Percentage of participants with favorable microbiological response by pathogen resistance type (ATM non-susceptible and Meropenem non-susceptible based on EUCAST criteria and CLSI criteria, ESBL-positive, Carbapenemase-positive, Serene Carbapenemase and Metallo-beta-lactamase-positive) is reported in this outcome measure.
• Percentage of Participants With Favorable Per-Participant Microbiological Response by Pathogen Resistance Type at TOC Visit: Micro-ITT Analysis Set [At TOC visit (Day 28)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Percentage of participants with favorable microbiological response by pathogen resistance type (ATM non-susceptible and Meropenem non-susceptible based on EUCAST criteria and CLSI criteria, ESBL-positive, Carbapenemase-positive, Serene Carbapenemase and Metallo-beta-lactamase-positive) is reported in this outcome measure.
• Percentage of Participants With Favorable Per-Participant Microbiological Response by Pathogen Resistance Type at EOT Visit: ME Analysis Set [At EOT (Within 24 hours after last infusion on Day 14)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Percentage of participants with favorable microbiological response by pathogen resistance type (ATM non-susceptible, Meropenem non-susceptible based on EUCAST criteria and CLSI criteria, ESBL-positive, Carbapenemase-positive, Serene Carbapenemase and Metallo-beta-lactamase-positive) is reported in this outcome measure.
• Percentage of Participants With Favorable Per-Participant Microbiological Response by Pathogen Resistance Type at TOC Visit: ME Analysis Set [At TOC visit (Day 28)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Percentage of participants with favorable microbiological response by pathogen resistance type (ATM non-susceptible, Meropenem non-susceptible based on EUCAST criteria and CLSI criteria, ESBL-positive, Carbapenemase-positive, Serene Carbapenemase and Metallo-beta-lactamase-positive) is reported in this outcome measure.
• Percentage of Participants With Favorable Per-Pathogen Microbiological Response by Pathogen Resistance Type at EOT Visit: Micro-ITT Analysis Set [At EOT (Within 24 hours after last infusion on Day 14)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Percentage of participants with favorable per-pathogen microbiological response by pathogen resistance type (ATM non-susceptible, Meropenem non-susceptible based on EUCAST criteria and CLSI criteria, ESBL-positive, Carbapenemase-positive, Serene Carbapenemase and Metallo-beta-lactamase-positive) is reported in this outcome measure.
• Percentage of Participants With Favorable Per-Pathogen Microbiological Response by Pathogen Resistance Type at TOC Visit: Micro-ITT Analysis Set [At TOC visit (Day 28)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Percentage of participants with favorable per-pathogen microbiological response by pathogen resistance type (ATM non-susceptible, Meropenem non-susceptible based on EUCAST criteria and CLSI criteria, ESBL-positive, Carbapenemase-positive, Serene Carbapenemase and Metallo-beta-lactamase-positive) is reported in this outcome measure.
• Percentage of Participants With Favorable Per-Pathogen Microbiological Response by Pathogen Resistance Type at EOT Visit: ME Analysis Set [At EOT (Within 24 hours after last infusion on Day 14)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Percentage of participants with favorable per-pathogen microbiological response by pathogen resistance type (ATM non-susceptible, Meropenem non-susceptible based on EUCAST criteria and CLSI criteria, ESBL-positive, Carbapenemase-positive, Serene Carbapenemase and Metallo-beta-lactamase-positive) is reported in this outcome measure.
• Percentage of Participants With Favorable Per-Pathogen Microbiological Response by Pathogen Resistance Type at TOC Visit: ME Analysis Set [At TOC visit (Day 28)]: Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Percentage of participants with favorable per-pathogen microbiological response by pathogen resistance type (ATM non-susceptible, Meropenem non-susceptible based on EUCAST criteria and CLSI criteria, ESBL-positive, Carbapenemase-positive, Serene Carbapenemase and Metallo-beta-lactamase-positive) is reported in this outcome measure.
• Number of Participants According to Total Score for the Composite Endpoint of Symptom-Based Objective Clinical Measures: ITT Analysis Set [Up to Day 28]
• Number of Participants According to Total Score for the Composite Endpoint of Symptom-Based Objective Clinical Measures: CE Analysis Set [Up to Day 28]: CE analysis set: all participants in ITT analysis set; met criteria for cIAI, or HAP/VAP; received at least 48 hours of study treatment or <48 hours of treatment before discontinuing study drug due to AE; no concomitant antibiotics for any baseline pathogens between first dose and TOC (except protocol-allowed antibiotics); no prior antibiotics other than allowed per protocol; no important protocol deviations; no clinical outcome of indeterminate at TOC; no monomicrobial infections due to non-eligible pathogens and did not have only Gram-positive pathogens.
• Percentage of Participants Who Died on or Before 14 Days From Randomization: ITT Analysis Set [From randomization up to 14 days]: Percentage of participants who died on or before 14 days from randomization is reported in this outcome measure.
• Total Length of Hospital Stay up to TOC Visit: ITT Analysis Set [From randomization up to Day 28]: The total length of hospital stay was defined as the total number of calendar days on which the participant was in the hospital from the date of randomization up to and including the specified time point of TOC.
• Total Length of Hospital Stay up to TOC Visit: CE Analysis Set [From randomization up to Day 28]: The total length of hospital stay was defined as the total number of calendar days on which the participant was in the hospital from the date of randomization up to and including the specified time point of TOC. CE analysis set: all participants in ITT analysis set; met criteria for cIAI, or HAP/VAP; received at least 48 hours of study treatment or <48 hours of treatment before discontinuing study drug due to AE; no concomitant antibiotics for any baseline pathogens between first dose and TOC (except protocol-allowed antibiotics); no prior antibiotics other than allowed per protocol; no important protocol deviations; no clinical outcome of indeterminate at TOC; no monomicrobial infections due to non-eligible pathogens and did not have only Gram-positive pathogens.
• Duration of Study Treatment [From first dose of study treatment until last dose of treatment (Up to 14 days)]: The duration of therapy in calendar days were calculated as follows: Date of last dose of study drug - date of first dose of study drug +1.
• Length of Intensive Care Unit (ICU) Stay: ITT Analysis Set [From randomization until TOC visit (Up to Day 28)]: The total length of ICU stay was defined as the total number of calendar days on which the participant was in ICU for the period from date of randomization until the TOC visit.
• Length of Intensive Care Unit (ICU) Stay: CE Analysis Set [From randomization until TOC visit (Up to Day 28)]: The total length of ICU stay was defined as the total number of calendar days on which the participant was in ICU for the period from date of randomization until the TOC visit. CE analysis set: all participants in ITT analysis set; met criteria for cIAI, or HAP/VAP; received at least 48 hours of study treatment or <48 hours of treatment before discontinuing study drug due to AE; no concomitant antibiotics for any baseline pathogens between first dose and TOC (except protocol-allowed antibiotics); no prior antibiotics other than allowed per protocol; no important protocol deviations; no clinical outcome of indeterminate at TOC; no monomicrobial infections due to non-eligible pathogens and did not have only Gram-positive pathogens.
• Number of Participants Admitted to the ICU: ITT Analysis Set [From randomization until TOC visit (Up to Day 28)]: Number of participants admitted to the ICU up to TOC were reported in this outcome measure.
• Number of Participants Admitted to the ICU: CE Analysis Set [From randomization until TOC visit (Up to Day 28)]: The number of participants admitted to the ICU were reported in this outcome measure. CE analysis set: all participants in ITT analysis set; met criteria for cIAI, or HAP/VAP; received at least 48 hours of study treatment or <48 hours of treatment before discontinuing study drug due to AE; no concomitant antibiotics for any baseline pathogens between first dose and TOC (except protocol-allowed antibiotics); no prior antibiotics other than allowed per protocol; no important protocol deviations; no clinical outcome of indeterminate at TOC; no monomicrobial infections due to non-eligible pathogens and did not have only Gram-positive pathogens.
• Number of Participants With Mechanical Ventilation: ITT Analysis Set [From randomization until TOC visit (Up to Day 28)]: Number of participants with mechanical ventilation were reported in this outcome measure.
• Number of Participants With Mechanical Ventilation: CE Analysis Set [From randomization until TOC visit (Up to Day 28)]: Number of participants with mechanical ventilation were reported in this outcome measure. CE analysis set: all participants in ITT analysis set; met criteria for cIAI, or HAP/VAP; received at least 48 hours of study treatment or <48 hours of treatment before discontinuing study drug due to AE; no concomitant antibiotics for any baseline pathogens between first dose and TOC (except protocol-allowed antibiotics); no prior antibiotics other than allowed per protocol; no important protocol deviations; no clinical outcome of indeterminate at TOC; no monomicrobial infections due to non-eligible pathogens and did not have only Gram-positive pathogens.
• Duration of Mechanical Ventilation in HAP/VAP Participants: ITT Analysis Set [From randomization until TOC visit (Up to Day 28)]: Duration of mechanical ventilation was defined as the total number of calendar days on which the participant required mechanical ventilation from the date of randomization up to TOC.
• Duration of Mechanical Ventilation in HAP/VAP Participants: CE Analysis Set [From randomization until TOC visit (Up to Day 28)]: Duration of mechanical ventilation was defined as the total number of calendar days on which the participant required mechanical ventilation from the date of randomization up to TOC. CE analysis set: all participants in ITT analysis set; met criteria for cIAI, or HAP/VAP; received at least 48 hours of study treatment or <48 hours of treatment before discontinuing study drug due to AE; no concomitant antibiotics for any baseline pathogens between first dose and TOC (except protocol-allowed antibiotics); no prior antibiotics other than allowed per protocol; no important protocol deviations; no clinical outcome of indeterminate at TOC; no monomicrobial infections due to non-eligible pathogens and did not have only Gram-positive pathogens.
• Number of Participants With Unplanned Surgical Interventions in Complicated Intra-abdominal Infections (cIAI) Participants: ITT Analysis Set [From randomization until TOC visit (Up to Day 28)]: Unplanned surgical interventions was defined as those occurring after the initial qualifying surgical intervention and prior to the TOC visit. Number of cIAI participants with unplanned surgical intervention according to clinical response categories of cure and failure is reported in this outcome measure.
• Number of Participants With Unplanned Surgical Interventions in cIAI Participants: CE Analysis Set [From randomization until TOC visit (Up to Day 28)]: Unplanned surgical interventions was defined as those occurring after the initial qualifying surgical intervention and prior to the TOC visit. Number of cIAI participants with unplanned surgical intervention according to clinical response categories of cure and failure is reported in this outcome measure.

Sex: All, ages: 18 Years to any

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 criteria concerning pregnancy avoidance stated in the protocol are met and negative pregnancy test

Additional for cIAI:

1. 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
2. Surgical intervention within 24 hours (before or after) the administration of the first dose of study drug

Additional for HAP/VAP:

1. Onset symptoms > 48h after admission to or <7 days after discharge from an inpatient care 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 symptoms and prior to randomisation

Exclusion criteria:

All subjects:

1. APACHE II score > 30
2. Confirmed or suspected infection caused by Gram-negative species not expected to respond to study drug, or Gram-positive species
3. Receipt of >24 hr systemic antibiotic within 48h prior to randomisation (exception in case of treatment failure)
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. 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 replacement therapy
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 up to 5 × ULN are eligible if acute and documented by the investigator as being directly related infectious process
10. Patient has a total bilirubin >2 × ULN, unless isolated hyperbilirubinemia is directly 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 and directly 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 medically accepted effective method of birth control.
14. Any other condition that may confound the results of the study or pose additional risks 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 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
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

Participant flow

Outcome results

• Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit: Intent-To-Treat (ITT) Analysis Set (Primary), Number, Percentage of participants: Aztreonam-avibactam ± Metronidazole 68.4 (62.8 to 73.7); Meropenem± Colistimethate 65.7 (57.6 to 73.2)
• Percentage of Participants With Clinical Cure at TOC Visit: Clinically Evaluable (CE) Analysis Set (Primary), Number, Percentage of participants: Aztreonam-avibactam ± Metronidazole 77.0 (71.0 to 82.3); Meropenem± Colistimethate 74.3 (65.3 to 81.9)
• Percentage of Participants With Clinical Cure at TOC Visit: Microbiological Intent-To-Treat (Micro-ITT) Analysis Set (Secondary), Number, Percentage of participants: Aztreonam-avibactam ± Metronidazole 72.9 (66.0 to 79.0); Meropenem± Colistimethate 72.3 (62.7 to 80.6)
• Percentage of Participants With Clinical Cure at TOC Visit: Microbiologically Evaluable (ME) Analysis Set (Secondary), Number, Percentage of participants: Aztreonam-avibactam ± Metronidazole 78.5 (71.4 to 84.5); Meropenem± Colistimethate 75.9 (65.7 to 84.3)
• Percentage of Participants With Clinical Cure at TOC Visit by Type of Infection: ITT Analysis Set (Secondary), Number, Percentage of participants: Aztreonam-avibactam ± Metronidazole 76.4 (70.3 to 81.8); Meropenem± Colistimethate 74.0 (65.0 to 81.7)
• Percentage of Participants With Clinical Cure at TOC Visit by Type of Infection: CE Analysis Set (Secondary), Number, Percentage of participants: Aztreonam-avibactam ± Metronidazole 85.1 (79.2 to 89.9); Meropenem± Colistimethate 79.5 (69.9 to 87.1)
• Percentage of Participants With Clinical Cure in Participants With Metallo-beta-lactamase (MBL) Positive Pathogen at TOC Visit: Micro-ITT Analysis Set (Secondary), Number, Percentage of participants: Aztreonam-avibactam ± Metronidazole 28.6; Meropenem± Colistimethate 66.7
• Percentage of Participants With Clinical Cure in Participants With MBL Positive Pathogen at TOC Visit: ME Analysis Set (Secondary), Number, Percentage of participants: Aztreonam-avibactam ± Metronidazole 50.0; Meropenem± Colistimethate 0
• Percentage of Participants With Favorable Per-Participant Microbiological Response at TOC Visit: Micro- ITT Analysis Set (Secondary), Number, Percentage of participants: Aztreonam-avibactam ± Metronidazole 75.7; Meropenem± Colistimethate 73.9
• Percentage of Participants With Favorable Per-Participant Microbiological Response at TOC Visit: ME Analysis Set (Secondary), Number, Percentage of participants: Aztreonam-avibactam ± Metronidazole 77.2; Meropenem± Colistimethate 75.9
• Percentage of Participants Who Died on or Before 28 Days After Randomization: ITT Analysis Set (Secondary), Number, Percentage of participants: Aztreonam-avibactam ± Metronidazole 4.3; Meropenem± Colistimethate 7.1
• Percentage of Participants Who Died on or Before 28 Days After Randomization: Micro-ITT Analysis Set (Secondary), Number, Percenatge of participants: Aztreonam-avibactam ± Metronidazole 2.8; Meropenem± Colistimethate 6.4
• Plasma Concentration of Aztreonam (Secondary), Geometric mean, Milligram/Liter: Aztreonam-avibactam ± Metronidazole 43.3 +/- 339.08
• Plasma Concentration of Avibactam (Secondary), Geometric mean, Milligram/Liter: Aztreonam-avibactam ± Metronidazole 10.77 +/- 353.86
• Maximum Plasma Concentration for a Dosing Interval at Steady-State (Cmax, ss) According to Clinical Response by Infection Type at TOC: Aztreonam (Secondary), Geometric mean, Milligram per liter (mg/L): Aztreonam- Avibactam 52.47 +/- 37.49
• Percentage of Time That Free Plasma Concentrations Are Above the Minimum Inhibitory Concentration Over a Dosing Interval (%fT>MIC Aztreonam (ATM) of 8 mg/L) According to Clinical Response by Infection Type at TOC: Aztreonam (Secondary), Geometric mean, Percentage of time: Aztreonam- Avibactam 90.4 +/- 41.9
• Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss ) According to Clinical Response by Infection Type at TOC: Aztreonam (Secondary), Geometric mean, Milligram*hours per liter (mg*h/L): Aztreonam- Avibactam 816.18 +/- 41.83
• Maximum Plasma Concentration for a Dosing Interval at Steady-state (Cmax,ss) According to Microbiological Response by Infection Type at TOC: Aztreonam (Secondary), Geometric mean, Milligram per liter (mg/L): Aztreonam- Avibactam 53.26 +/- 34.03
• Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss) According to Microbiological Response by Infection Type at TOC: Aztreonam (Secondary), Geometric mean, Milligram*hours per liter: Aztreonam- Avibactam 830.23 +/- 38.42
• Percentage of Time That Free Plasma Concentrations Are Above the Minimum Inhibitory Concentration Over a Dosing Interval (%fT>MIC Aztreonam (ATM) of 8 mg/L) According to Microbiological Response by Infection Type at TOC: Aztreonam (Secondary), Geometric mean, Percentage of time: Aztreonam- Avibactam 92.57 +/- 17.66
• 52 more outcome measures not shown.

Adverse events

Time frame: All-cause mortality: From signing of informed consent until end of late follow up visit (Day 45); non-SAEs and SAEs: From start of study treatment until end of late follow-up visit (Up to Day 45).

Serious adverse events by term

17 more terms not shown.

Other adverse events by term

57 more sites not listed.

• Results publication: Raber SR, Xie R, Rogers H, Soto E, Arhin FF, Stone GG, Leister-Tebbe H, Chow JW. Microbiological, Clinical, and Pharmacokinetic/Pharmacodynamic Data to Support EUCAST Aztreonam-Avibactam Minimum Inhibitory Concentration Susceptibility Breakpoints Against Enterobacterales. Infect Dis Ther. 2026 Jan;15(1):183-195. doi: 10.1007/s40121-025-01267-3. Epub 2025 Nov 21. PMID 41269522
• Results publication: Xie R, Rogers H, Chow JW, Soto E, Raber SR. Population pharmacokinetic/pharmacodynamic modeling to optimize aztreonam-avibactam dose regimens for adult patients. Antimicrob Agents Chemother. 2025 Aug 6;69(8):e0195024. doi: 10.1128/aac.01950-24. Epub 2025 Jun 18. PMID 40530972
• Results publication: Carmeli Y, Cisneros JM, Paul M, Daikos GL, Wang M, Torre-Cisneros J, Singer G, Titov I, Gumenchuk I, Zhao Y, Jimenez-Rodriguez RM, Liang L, Chen G, Pyptiuk O, Aksoy F, Rogers H, Wible M, Arhin FF, Luckey A, Leaney JL, Pypstra R, Chow JW; COMBACTE-CARE consortium REVISIT study group. Aztreonam-avibactam versus meropenem for the treatment of serious infections caused by Gram-negative bacteria (REVISIT): a descriptive, multinational, open-label, phase 3, randomised trial. Lancet Infect Dis. 2025 Feb;25(2):218-230. doi: 10.1016/S1473-3099(24)00499-7. Epub 2024 Oct 7. PMID 39389071
• Results publication: Das S, Riccobene T, Carrothers TJ, Wright JG, MacPherson M, Cristinacce A, McFadyen L, Xie R, Luckey A, Raber S. Dose selection for aztreonam-avibactam, including adjustments for renal impairment, for Phase IIa and Phase III evaluation. Eur J Clin Pharmacol. 2024 Apr;80(4):529-543. doi: 10.1007/s00228-023-03609-x. Epub 2024 Jan 22. PMID 38252170

• Study Protocol (PDF, 2022-05-18)
• Statistical Analysis Plan (PDF, 2020-06-25)

• Pfizer CT.gov Call Center, Study director, Pfizer

NIH grants: 2017