Efficacy and Safety of CAZ-AVI in the Treatment of Infections Due to Carbapenem-resistant G- Pathogens in Chinese Adults

Clinical cure was defined as improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e, complicated intra-abdominal infection \[cIAI\], complicated urinary-tract infection \[cUTI\], hospital-acquired pneumonia/ventilator-associated pneumonia \[HAP/VAP\] or bloodstream infection \[BSI\]) after study treatment. Also, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response was assessed by the independent adjudication committee. 95 percent (%) confidence interval (CI) was calculated using Jeffrey's method.

Time frame: At TOC visit (From Day 21 up to Day 24)

Population: mMITT analysis set (subset of ITT analysis set) included all participants who met minimum disease requirements and received any amount of study therapy, had at least 1 carbapenem-resistant Gram-negative pathogen in an adequate initial/pre-study culture. Participants with inherently resistant pathogens (monomicrobial infections due to any Acinetobacter species) were excluded from mMITT analysis set.

Number of participants who discontinued the study due to adverse events were reported in this outcome measure. Discontinuations from study due to TEAEs included all participants with an AE record indicating that the AE caused permanent discontinuation from the study. Permanent discontinuations from any study intervention due to TEAEs included participants with an AE record indicating that action taken with study treatment was drug withdrawn but AE did not cause the participant to be discontinued from study.

Time frame: From start of study treatment on Day 1 up to 32 days after the last dose of study intervention (Up to 46 days)

Population: Safety analysis set included all participants who took any study intervention. Participants were analyzed according to the product they actually received.

Potentially clinically significant criteria included Bilirubin(mg/dL): \>2.0\*ULN and Chg \>150% increase (inc).Aspartate Aminotransferase,Alanine Aminotransferase(Units/Liter\[U/L\]):\>3.0\*ULN and Chg \>200% inc.Alkaline Phosphatase(U/L):\<0.5\*LLN and Chg \>80% decrease (dec),\> 2.0\*ULN and Chg \>100% inc.Protein,Albumin(g/dL):\<0.5\*LLN and Chg \>50% dec,\>1.5\*ULN and Chg \>50% inc.Blood Urea Nitrogen(mg/dL):\<0.2\*LLN and Chg \>100% dec, \>3.0\*ULN and Chg \>200% inc.Creatinine(mg/dL):\>2.0\*ULN and Chg \>100% inc.Sodium(milliequivalent\[mEq\]/L):\<0.85\*LLN and Chg \>10% dec, \>1.1\*ULN and Chg \>10% inc.Potassium,Chloride(mEq/L):\<0.8\*LLN and Chg \>20% dec, \>1.2\*ULN and Chg \>20% inc.Calcium(mg/dL):\<0.7\*LLN and Chg \>30% dec,\> 1.3\*ULN and Chg \>30% inc.Bicarbonate(mEq/L):\<0.7\*LLN and Chg \>40% dec, \>1.3\*ULN and Chg \>40% inc.Glucose(mg/dL):\<0.6\*LLN and Chg \>40% dec, \>3.0\*ULN and Chg \>200% inc.Number of participants with potentially clinically significant values for any clinical chemistry parameters were reported.

Time frame: From first dose of study treatment (Day 1) until TOC (Up to Day 24)

Population: Safety analysis set included all participants who took any study intervention. Participants were analyzed according to the product they actually received. Here, 'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure.

Potentially clinically significant hematology parameters included Hemoglobin (gram/deciliter), Hematocrit (%), Erythrocytes (10\^12/Liter \[L\]): value \< 0.8\*lower limit of normal (LLN) and change (Chg) \> 20% decrease, value \> 1.3\*upper limit of normal (ULN) and Chg \> 30% increase. Platelets (10\^9/L): Value \< 0.65\*LLN and Chg \> 50% decrease, Value \> 1.5\*ULN and Chg \> 100% increase. Leukocytes (10\^9/L): Value \< 0.65\*LLN and Chg \> 60% decrease, Value \> 1.6\*ULN and Chg \> 100% increase. Lymphocytes (10\^9/L): Value \< 0.25\*LLN and Chg \> 75% decrease, Value \> 1.5\*ULN and Chg \> 100% increase. Neutrophils (10\^9/L): Value \< 0.65\*LLN and Chg \> 75% decrease, Value \> 1.6\*ULN and Chg \> 100% increase. Basophils (10\^9/L), Eosinophils (10\^9/L), Monocytes (10\^9/L): Value \> 4.0\*ULN and Chg \> 300% increase. Number of participants with potentially clinically significant values for any hematology parameters were reported in this outcome measure.

Time frame: From first dose of study treatment (Day 1) until TOC (Up to Day 24)

Population: Safety analysis set included all participants who took any study intervention. Participants were analyzed according to the product they actually received. Here, 'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure.

An adverse event (AE) was any untoward medical occurrence in a study participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment-emergent adverse event (TEAE) was any AE that started after the study intervention start date and time.

Time frame: From start of study treatment on Day 1 up to 32 days after the last dose of study intervention (Up to 46 days)

Population: Safety analysis set included all participants who took any study intervention. Participants were analyzed according to the product they actually received.

Percentage of participants who died due to any cause up to Day 28 was reported in this outcome measure. The 95% CI was calculated using the Jeffrey's method.

Time frame: From first dose of study intervention (Day 1) up to Day 28

Population: Intent-to-Treat (ITT) Analysis Set included all participants randomly assigned to study intervention and who took at least one dose of study intervention.

Clinical cure was defined as improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response was assessed by the independent adjudication committee. 95% CI was calculated using Jeffrey's method.

Time frame: At EOT visit (up to 24 hours after the last infusion on Day 14)

Population: mMITT analysis set (subset of ITT analysis set) included all participants who met minimum disease requirements and received any amount of study therapy, had at least 1 carbapenem-resistant Gram-negative pathogen in an adequate initial/pre-study culture. Participants with inherently resistant pathogens (monomicrobial infections due to any Acinetobacter species) were excluded from the mMITT analysis set.

Clinical cure: improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also, for cIAI participants, no unplanned drainage or surgical intervention was necessary since initial procedure. 95% CI based on Jeffrey's method. ME analysis set (sub-set of mMITT): participants who received 3 days of study intervention, or received study intervention for \>=48 hours with \>= 80% compliance, or for \<48 hours before discontinuation due to adverse event, no concomitant antibiotics against baseline carbapenem-resistant gram negative pathogens between first dose and TOC (excluding participants with failed study therapy requiring additional antibiotics), had baseline organisms genetically confirmed by central microbiological testing, no indeterminate clinical outcome at EOT or TOC visits, no important protocol deviations that affect assessment of efficacy.

Time frame: At EOT visit (up to 24 hours after the last infusion on Day 14)

Population: ME analysis set was evaluated.

Clinical cure: improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for index infection (i.e. cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also, for cIAI participants, no unplanned drainage or surgical intervention was necessary since initial procedure. 95% CI based on Jeffrey's method. ME analysis set (sub-set of mMITT): participants who received 3 days of study intervention, or received study intervention for \>=48 hours with \>= 80% compliance, or for \<48 hours before discontinuation due to adverse event, no concomitant antibiotics against baseline carbapenem-resistant gram negative pathogens between first dose and TOC (excluding participants with failed study therapy requiring additional antibiotics), had baseline organisms genetically confirmed by central microbiological testing, no indeterminate clinical outcome at end of treatment (EOT) or TOC visits, no important protocol deviations that affect assessment of efficacy.

Time frame: At TOC visit (From Day 21 up to Day 24)

Population: ME analysis set was evaluated.

Favorable microbiological response=eradication: absence (or urine quantification \<10\^3 CFU/mL for cUTI participants) of causative pathogen from appropriately obtained specimen at site of infection or presumed eradication: repeat culture of specimens were not performed/clinically indicated in participant who had clinical cure (specific to cIAI,HAP/VAP participants). 95% CI was calculated using Jeffrey's method. ME analysis set: participants received 3 days of study intervention,or received study intervention for \>= 48 hours with \>=80% compliance or for \<48 hours before discontinuation due to adverse event, no concomitant antibiotics against baseline carbapenem-resistant gram negative pathogens between first dose and TOC (excluding participants with failed study therapy requiring additional antibiotics), had baseline organisms confirmed by central microbiological testing, no indeterminate clinical outcome at EOT/TOC, no important protocol deviations that affect assessment of efficacy.

Time frame: At EOT visit (Up to 24 hours after last infusion on Day 14)

Population: ME analysis set was evaluated.

Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification \<10\^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). 95% CI was calculated using Jeffrey's method.

Time frame: At EOT visit (Up to 24 hours after last infusion on Day 14)

Population: mMITT analysis set (subset of ITT analysis set) included all participants who met minimum disease requirements and received any amount of study therapy, had at least 1 carbapenem-resistant Gram-negative pathogen in an adequate initial/pre-study culture. Participants with inherently resistant pathogens (monomicrobial infections due to any Acinetobacter species) were excluded from the mMITT analysis set.

Favorable microbiological response=eradication: absence (or urine quantification \<10\^3 CFU/mL for cUTI participants) of causative pathogen from appropriately obtained specimen at site of infection or presumed eradication: repeat culture of specimens were not performed/clinically indicated in participant who had clinical cure (specific to cIAI,HAP/VAP participants). 95% CI was calculated using Jeffrey's method. ME analysis set: participants received 3 days of study intervention,or received study intervention for \>= 48 hours with \>=80% compliance or for \<48 hours before discontinuation due to adverse event, no concomitant antibiotics against baseline carbapenem-resistant gram negative pathogens between first dose and TOC (excluding participants with failed study therapy requiring additional antibiotics), had baseline organisms confirmed by central microbiological testing, no indeterminate clinical outcome at EOT/TOC, no important protocol deviations that affect assessment of efficacy.

Time frame: At TOC visit (From Day 21 up to Day 24)

Population: ME analysis set was evaluated.

Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification \<10\^3 colony forming units per milliliter \[CFU/mL\] for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/ clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). 95% CI was calculated using Jeffrey's method.

Time frame: At TOC visit (From Day 21 up to Day 24)

Population: mMITT analysis set (subset of ITT analysis set) included all participants who met minimum disease requirements and received any amount of study therapy, had at least 1 carbapenem-resistant Gram-negative pathogen in an adequate initial/pre-study culture. Participants with inherently resistant pathogens (monomicrobial infections due to any Acinetobacter species) were excluded from the mMITT analysis set.

Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification \<10\^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). 95% CI was calculated using Jeffrey's method.

Time frame: At EOT visit (Up to 24 hours after last infusion on Day 14)

Population: mMITT analysis set: all participants who met minimum disease requirements, received any amount of study therapy, had at least 1 carbapenem-resistant Gram-negative pathogen in an adequate initial/pre-study culture. Participants with inherently resistant pathogens were excluded. All participants reported under 'Overall Number of Participants Analyzed' contributed data to table but may not have evaluable data for every row. 'Number Analyzed' =number of participants evaluable for the specified rows.

Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification \<10\^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). 95% CI was calculated using Jeffrey's method.

Time frame: At TOC visit (From Day 21 up to Day 24)

Population: mMITT analysis set: all participants who met minimum disease requirements, received any amount of study therapy, had at least 1 carbapenem-resistant Gram-negative pathogen in an adequate initial/pre-study culture. Participants with inherently resistant pathogens were excluded. All participants reported under 'Overall Number of Participants Analyzed' contributed data to table but may not have evaluable data for every row. 'Number Analyzed' =number of participants evaluable for the specified rows.