RESTORE-IMI 2: Imipenem/Relebactam/Cilastatin Versus Piperacillin/Tazobactam for Treatment of Participants With Bacterial Pneumonia (MK-7655A-014)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02493764
• Collaborator: (none)
• Enrollment: 537
• Arms: 2
• Actual Duration (Months): 40.3

Study Details

Study Description

Brief Summary

This study aims to compare treatment with a fixed-dose combination (FDC) of imipenem/relebactam/cilastatin (IMI/REL) with a FDC of piperacillin/tazobactam (PIP/TAZ) in participants with hospital-acquired or ventilator-associated bacterial pneumonia (HABP or VAPB, respectively). The primary hypothesis is that IMI/REL is non-inferior to PIP/TAZ in the incidence rate of all-cause mortality.

Condition or Disease	Intervention/Treatment	Phase
Bacterial Pneumonia	Drug: Imipenem; Drug: Relebactam; Drug: Cilastatin; Drug: Piperacillin; Drug: Tazobactam; Drug: Linezolid	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 537 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-Blind, Active Comparator-Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Piperacillin/Tazobactam in Subjects With Hospital-Acquired Bacterial Pneumonia or Ventilator-Associated Bacterial Pneumonia
• Actual Study Start Date: Nov 24, 2015
• Actual Primary Completion Date: Apr 3, 2019
• Actual Study Completion Date: Apr 3, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IMI/REL Imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered intravenously (IV) every 6 hours for a minimum of 7 days, up to 14 days. At study entry open label linezolid 600 mg will also be administered by IV every 12 hours for up to 14 days.	Drug: Imipenem; Imipenem 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days; Drug: Relebactam; Relebactam 250 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days; Drug: Cilastatin; Cilastatin 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days; Drug: Linezolid; Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days
Active Comparator: PIP/TAZ Piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At study entry open label linezolid 600 mg will also be administered by IV every 12 hours for up to 14 days.	Drug: Piperacillin; Piperacillin 4000 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days; Drug: Tazobactam; Tazobactam 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days; Drug: Linezolid; Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With All-cause Mortality (ACM) Through Day 28 in the Modified Intention-to-treat (MITT) Population [Up to 28 days]

   The percentage of participants in the MITT population with mortality due to any cause from randomization through Day 28 was determined for each arm.

Secondary Outcome Measures

1. Percentage of Participants in the MITT Population With a Favorable Clinical Response (FCR) at Early Follow-up (EFU) Visit [Up to 16 days after end of therapy (up to 30 days)]

   The percentage of participants with a FCR at EFU was determined for each arm. Favorable clinical response at EFU was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required).

2. Percentage of Participants With ≥1 Adverse Event (AE) [Up to 30 days]

   An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

3. Percentage of Participants Discontinuing Study Therapy Due to an AE [Up to 14 days]

   An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

4. Percentage of Participants With ACM in the Microbiological Modified Intention-to-treat (mMITT) Population [Up to 28 days]

   The percentage of participants in the mMITT population with mortality due to any cause from randomization through Day 28 was determined for each arm.

5. Percentage of Participants With ACM at EFU in the MITT Population [Up to 16 days after end of therapy (up to 30 days)]

   The percentage of participants in the MITT population with mortality due to any cause from randomization through EFU was determined for each arm.

6. Percentage of Participants With ACM at EFU in the mMITT Population [Up to 16 days after end of therapy (up to 30 days)]

   The percentage of participants in the mMITT population with mortality due to any cause from randomization through EFU was determined for each arm.

7. Percentage of Participants in the Clinically Evaluable (CE) Population With a FCR at On-therapy Visit 1 (OTX1) [Day 3] [Day 3 (OTX1)]

   The percentage of participants with a FCR at OTX1 was determined for each arm. Favorable clinical response at OTX1 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).

8. Percentage of Participants in the CE Population With a FCR at OTX2 (Day 6) [Day 6 (OTX2)]

   The percentage of participants with a FCR at OTX2 was determined for each arm. Favorable clinical response at OTX2 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).

9. Percentage of Participants in the CE Population With a FCR at OTX3 (Day 10) [Day 10 (OTX3)]

   The percentage of participants with a FCR at OTX3 was determined for each arm. Favorable clinical response at OTX3 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).

10. Percentage of Participants in the CE Population With a FCR at EOT Visit [From Day 7 to Day 14]

    The percentage of participants with a FCR at EOT was determined for each arm. Favorable clinical response at EOT was defined as either "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required) or "improved" (the majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"] and no additional antibiotics are required).

11. Percentage of Participants in the CE Population With a FCR at Day 28 [Day 28]

    The percentage of participants with a FCR at Day 28 was determined for each arm. Favorable clinical response at Day 28 was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required).

12. Percentage of Participants in the CE Population With a FCR at EFU Visit [Up to 16 days after end of therapy (up to Day 30)]

    The percentage of participants with a FCR at EFU was determined for each arm. Favorable clinical response at EFU was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required).

13. Percentage of Participants in the MITT Population With a FCR at OTX1 (Day 3) [Day 3 (OTX1)]

    The percentage of participants with a FCR at OTX1 was determined for each arm. Favorable clinical response at OTX1 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).

14. Percentage of Participants in the MITT Population With a FCR at OTX2 (Day 6) [Day 6 (OTX2)]

    The percentage of participants with a FCR at OTX2 was determined for each arm. Favorable clinical response at OTX2 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).

15. Percentage of Participants in the MITT Population With a FCR at OTX3 (Day 10) [Day 10 (OTX3)]

    The percentage of participants with a FCR at OTX3 was determined for each arm. Favorable clinical response at OTX3 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).

16. Percentage of Participants in the MITT Population With a FCR at EOT [From Day 7 to Day 14]

    The percentage of participants with a FCR at EOT was determined for each arm. Favorable clinical response at EOT was defined as either "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required) or "improved" (the majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"] and no additional antibiotics are required).

17. Percentage of Participants in the MITT Population With a FCR at Day 28 [Day 28]

    The percentage of participants with a FCR at Day 28 was determined for each arm. Favorable clinical response at Day 28 was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required).

18. Percentage of Participants in the mMITT Population With a Favorable Microbiological Response (FMR) at End of Treatment (EOT) Visit [From Day 7 to Day 14]

    The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved).

19. Percentage of Participants in the mMITT Population With a FMR at EFU Visit [Up to 16 days after end of therapy (up to Day 30)]

    The percentage of participants with a FMR at EFU was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EFU showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved).

20. Percentage of Participants in the Microbiologically Evaluable (ME) Population With a FMR at EOT Visit [From Day 7 to Day 14]

    The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved).

21. Percentage of Participants in the ME Population With a FMR at EFU Visit [Up to 16 days after end of therapy (up to Day 30)]

    The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Requires treatment with IV antibiotic therapy for hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP)

• Fulfills clinical and radiographic criteria, with onset of criteria occurring after more than 48 hours of hospitalization or within 7 days after discharge from a hospital (for HABP); or at least 48 hours after mechanical ventilation (for VABP)

• Has an adequate baseline lower respiratory tract specimen obtained for Gram stain and culture

• Has an infection known or thought to be caused by microorganisms susceptible to the IV study therapy

• Agrees to allow any bacterial isolates obtained from protocol-required specimens related to the current infection to be provided to the Central Microbiology Reference Laboratory for study-related microbiological testing, long term storage, and other future testing

• Is not of reproductive potential; or if of reproductive potential agrees to avoid impregnating a partner or avoid becoming pregnant, by practicing abstinence or using acceptable contraception

Exclusion Criteria:

• Has a baseline lower respiratory tract specimen Gram stain that shows the presence of Gram-positive cocci only

• Has confirmed or suspected community-acquired bacterial pneumonia (CABP)

• Has confirmed or suspected pneumonia of viral, fungal or parasitic origin

• Has HABP/VABP caused by an obstructive process, including lung cancer or other known obstruction

• Has a carcinoid tumor or carcinoid syndrome

• Has active immunosuppression defined as either receiving immunosuppressive medications or having a medical condition associated with immunodeficiency

• Is expected to survive for less than 72 hours

• Has a concurrent condition or infection that would preclude evaluation of therapeutic response

• Has received effective antibacterial drug therapy for the index infection of HABP/VABP for more than 24 hours continuously, during the previous 72 hours

• Has a history of serious allergy, hypersensitivity or a serious reaction to any penicillin or beta-lactamase inhibitors

• Female is pregnant, expecting to conceive, is breastfeeding or plans to breastfeed

• Has a history of seizure disorder requiring ongoing prior treatment with anti-convulsive therapy within the last 3 years

• Anticipates treatment with the following: valproic acid or divalproex sodium, serotonin re-uptake inhibitors, tricyclic antidepressants, or serotonin receptor antagonists, meperidine, buspirone, concomitant systemic antibacterial agents, antifungal or antiviral therapy for the index infection of HABP/VABP

• Is currently undergoing hemodialysis or peritoneal dialysis

• Is currently participating in, has participated in during the previous 30 days, or anticipates to participate in any other clinical study involving the administration of experimental medication

• Has previously participated in this study

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 6, 2018

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02493764
• Other Study ID Numbers: 7655A-014; 2015-000246-34; 163240; MK-7655A-014
• First Posted: Jul 9, 2015
• Last Update Posted: Apr 16, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Pneumonia; Pneumonia, Bacterial; Tazobactam; Linezolid; Piperacillin; Imipenem; Relebactam; Cilastatin

Study Results

Participant Flow

Recruitment Details	Adult male and female participants requiring intravenous (IV) therapy for hospital-acquired bacterial pneumonia (HABP) or ventilator-assisted bacterial pneumonia (VABP) were recruited at 120 study centers in 28 countries.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a fixed dose combination (FDC) administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until methicillin-resistant Staphylococcus aureus (MRSA) was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Period Title: Overall Study
STARTED	268	269
COMPLETED	185	187
NOT COMPLETED	83	82

Baseline Characteristics

Arm/Group Title	IMI/REL	PIP/TAZ	Total
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Total of all reporting groups
Overall Participants	268	269	537
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.4 (17.0)	58.9 (18.4)	59.7 (17.7)
Sex: Female, Male (Count of Participants)
Female	86 32.1%	78 29%	164 30.5%
Male	182 67.9%	191 71%	373 69.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	56 20.9%	55 20.4%	111 20.7%
Not Hispanic or Latino	209 78%	205 76.2%	414 77.1%
Unknown or Not Reported	3 1.1%	9 3.3%	12 2.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	5 1.9%	8 3%	13 2.4%
Asian	42 15.7%	37 13.8%	79 14.7%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.4%	1 0.2%
Black or African American	4 1.5%	6 2.2%	10 1.9%
White	208 77.6%	209 77.7%	417 77.7%
More than one race	9 3.4%	7 2.6%	16 3%
Unknown or Not Reported	0 0%	1 0.4%	1 0.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With All-cause Mortality (ACM) Through Day 28 in the Modified Intention-to-treat (MITT) Population
Description	The percentage of participants in the MITT population with mortality due to any cause from randomization through Day 28 was determined for each arm.
Time Frame	Up to 28 days

Outcome Measure Data

Analysis Population Description

The MITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci on Gram stain of the baseline lower respiratory tract (LRT) specimen.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	264	267
Number [Percentage of participants]	15.9 5.9%	21.3 7.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in all-cause mortality
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was declared when the upper bound of the 2-sided 95% confidence interval (CI) for the difference in mortality (IMI/REL minus PIP/TAZ) was < 10 percentage points.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 1 sided
	Comments	A one-sided alpha level of 0.025 was used to declare significance.
Method of Estimation	Estimation Parameter	Adjusted difference in ACM
	Estimated Value	-5.3
	Confidence Interval	(2-Sided) 95%; -11.9 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

2. Secondary Outcome

Title	Percentage of Participants in the MITT Population With a Favorable Clinical Response (FCR) at Early Follow-up (EFU) Visit
Description	The percentage of participants with a FCR at EFU was determined for each arm. Favorable clinical response at EFU was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required).
Time Frame	Up to 16 days after end of therapy (up to 30 days)

Outcome Measure Data

Analysis Population Description

The MITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci on Gram stain of the baseline LRT specimen.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	264	267
Number [Percentage of participants]	61.0 22.8%	55.8 20.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in FCR
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was declared when the lower bound of the 2-sided 95% CI for the difference in FCR (IMI/REL minus PIP/TAZ) was > 12.5 percentage points.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 1 sided
	Comments	A one-sided alpha level of 0.025 was used to declare significance.
Method of Estimation	Estimation Parameter	Adjusted difference in FCR
	Estimated Value	5.0
	Confidence Interval	(2-Sided) 95%; -3.2 to 13.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

3. Secondary Outcome

Title	Percentage of Participants With ≥1 Adverse Event (AE)
Description	An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time Frame	Up to 30 days

Outcome Measure Data

Analysis Population Description

All participants who received ≥1 dose of study therapy are included.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	266	269
Number [Percentage of participants]	85.0 31.7%	86.6 32.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments
	Type of Statistical Test	Other
	Comments	Difference in % with AE vs PIP/TAZ
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in % with AE
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 95%; -7.7 to 4.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants Discontinuing Study Therapy Due to an AE
Description	An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time Frame	Up to 14 days

Outcome Measure Data

Analysis Population Description

All participants who received ≥1 dose of study therapy are included.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	266	269
Number [Percentage of participants]	5.6 2.1%	8.2 3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments
	Type of Statistical Test	Other
	Comments	Difference in % discontinuing vs PIP/TAZ
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in % discontinuing
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -7.1 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants With ACM in the Microbiological Modified Intention-to-treat (mMITT) Population
Description	The percentage of participants in the mMITT population with mortality due to any cause from randomization through Day 28 was determined for each arm.
Time Frame	Up to 28 days

Outcome Measure Data

Analysis Population Description

The mMITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci only on baseline Gram stain and who have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	215	218
Number [Percentage of participants]	16.7 6.2%	20.2 7.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in all-cause mortality
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in ACM
	Estimated Value	-3.5
	Confidence Interval	(2-Sided) 95%; -10.9 to 3.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

6. Secondary Outcome

Title	Percentage of Participants With ACM at EFU in the MITT Population
Description	The percentage of participants in the MITT population with mortality due to any cause from randomization through EFU was determined for each arm.
Time Frame	Up to 16 days after end of therapy (up to 30 days)

Outcome Measure Data

Analysis Population Description

The MITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci on Gram stain of the baseline specimen.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	264	267
Number [Percentage of participants]	14.8 5.5%	19.5 7.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in all-cause mortality
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was declared when the upper bound of the 2-sided 95% CI for the difference in mortality (IMI/REL minus PIP/TAZ) was ≥ 10 percentage points.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in ACM
	Estimated Value	-4.6
	Confidence Interval	(2-Sided) 95%; -11.0 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

7. Secondary Outcome

Title	Percentage of Participants With ACM at EFU in the mMITT Population
Description	The percentage of participants in the mMITT population with mortality due to any cause from randomization through EFU was determined for each arm.
Time Frame	Up to 16 days after end of therapy (up to 30 days)

Outcome Measure Data

Analysis Population Description

The mMITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci only on baseline Gram stain and who have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	215	218
Number [Percentage of participants]	15.3 5.7%	18.3 6.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in all-cause mortality
	Type of Statistical Test	Other
	Comments	Adjusted difference in ACM
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in ACM
	Estimated Value	-3.1
	Confidence Interval	(2-Sided) 95%; -10.2 to 3.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

8. Secondary Outcome

Title	Percentage of Participants in the Clinically Evaluable (CE) Population With a FCR at On-therapy Visit 1 (OTX1) [Day 3]
Description	The percentage of participants with a FCR at OTX1 was determined for each arm. Favorable clinical response at OTX1 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).
Time Frame	Day 3 (OTX1)

Outcome Measure Data

Analysis Population Description

The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 3 clinical response data.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	171	165
Number [Percentage of participants]	70.8 26.4%	72.8 27.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable clinical response
	Type of Statistical Test	Other
	Comments	Difference in FCR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FCR
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 95%; -11.3 to 7.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

9. Secondary Outcome

Title	Percentage of Participants in the CE Population With a FCR at OTX2 (Day 6)
Description	The percentage of participants with a FCR at OTX2 was determined for each arm. Favorable clinical response at OTX2 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).
Time Frame	Day 6 (OTX2)

Outcome Measure Data

Analysis Population Description

The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 6 clinical response data.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	171	165
Number [Percentage of participants]	85.5 31.9%	87.8 32.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable clinical response
	Type of Statistical Test	Other
	Comments	Difference in FCR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FCR
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -9.8 to 5.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

10. Secondary Outcome

Title	Percentage of Participants in the CE Population With a FCR at OTX3 (Day 10)
Description	The percentage of participants with a FCR at OTX3 was determined for each arm. Favorable clinical response at OTX3 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).
Time Frame	Day 10 (OTX3)

Outcome Measure Data

Analysis Population Description

The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 10 clinical response data.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	171	165
Number [Percentage of participants]	89.6 33.4%	83.6 31.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable clinical response
	Type of Statistical Test	Other
	Comments	Difference in favorable clinical response
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FCR
	Estimated Value	6.6
	Confidence Interval	(2-Sided) 95%; -4.6 to 18.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

11. Secondary Outcome

Title	Percentage of Participants in the CE Population With a FCR at EOT Visit
Description	The percentage of participants with a FCR at EOT was determined for each arm. Favorable clinical response at EOT was defined as either "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required) or "improved" (the majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"] and no additional antibiotics are required).
Time Frame	From Day 7 to Day 14

Outcome Measure Data

Analysis Population Description

The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have EOT clinical response data.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	171	165
Number [Percentage of participants]	84.7 31.6%	85.3 31.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable clinical response
	Type of Statistical Test	Other
	Comments	Difference in FCR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FCR
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -8.1 to 7.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

12. Secondary Outcome

Title	Percentage of Participants in the CE Population With a FCR at Day 28
Description	The percentage of participants with a FCR at Day 28 was determined for each arm. Favorable clinical response at Day 28 was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required).
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 28 clinical response data.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	147	144
Number [Percentage of participants]	70.5 26.3%	75.6 28.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable clinical response
	Type of Statistical Test	Other
	Comments	Difference in FCR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FCR
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 95%; -14.3 to 7.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

13. Secondary Outcome

Title	Percentage of Participants in the CE Population With a FCR at EFU Visit
Description	The percentage of participants with a FCR at EFU was determined for each arm. Favorable clinical response at EFU was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required).
Time Frame	Up to 16 days after end of therapy (up to Day 30)

Outcome Measure Data

Analysis Population Description

The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have EFU clinical response data.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	147	144
Number [Percentage of participants]	74.3 27.7%	79.4 29.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable clinical response
	Type of Statistical Test	Other
	Comments	Difference in FCR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FCR
	Estimated Value	-3.7
	Confidence Interval	(2-Sided) 95%; -13.6 to 6.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

14. Secondary Outcome

Title	Percentage of Participants in the MITT Population With a FCR at OTX1 (Day 3)
Description	The percentage of participants with a FCR at OTX1 was determined for each arm. Favorable clinical response at OTX1 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).
Time Frame	Day 3 (OTX1)

Outcome Measure Data

Analysis Population Description

The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 3 data.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	264	267
Number [Percentage of participants]	68.0 25.4%	64.7 24.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable clinical response
	Type of Statistical Test	Other
	Comments	Difference in FCR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FCR
	Estimated Value	3.5
	Confidence Interval	(2-Sided) 95%; -4.6 to 11.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

15. Secondary Outcome

Title	Percentage of Participants in the MITT Population With a FCR at OTX2 (Day 6)
Description	The percentage of participants with a FCR at OTX2 was determined for each arm. Favorable clinical response at OTX2 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).
Time Frame	Day 6 (OTX2)

Outcome Measure Data

Analysis Population Description

The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 6 data.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	264	267
Number [Percentage of participants]	83.5 31.2%	83.1 30.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable clinical response
	Type of Statistical Test	Other
	Comments	Difference in FCR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FCR
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -6.3 to 7.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

16. Secondary Outcome

Title	Percentage of Participants in the MITT Population With a FCR at OTX3 (Day 10)
Description	The percentage of participants with a FCR at OTX3 was determined for each arm. Favorable clinical response at OTX3 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).
Time Frame	Day 10 (OTX3)

Outcome Measure Data

Analysis Population Description

The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 10 data.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	264	267
Number [Percentage of participants]	83.5 31.2%	80.4 29.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable clinical response
	Type of Statistical Test	Other
	Comments	Difference in FCR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FCR
	Estimated Value	3.4
	Confidence Interval	(2-Sided) 95%; -7.1 to 14.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

17. Secondary Outcome

Title	Percentage of Participants in the MITT Population With a FCR at EOT
Description	The percentage of participants with a FCR at EOT was determined for each arm. Favorable clinical response at EOT was defined as either "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required) or "improved" (the majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"] and no additional antibiotics are required).
Time Frame	From Day 7 to Day 14

Outcome Measure Data

Analysis Population Description

The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have EOT data.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	264	267
Number [Percentage of participants]	74.2 27.7%	69.7 25.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable clinical response
	Type of Statistical Test	Other
	Comments	Difference in FCR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FCR
	Estimated Value	4.4
	Confidence Interval	(2-Sided) 95%; -3.1 to 12.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

18. Secondary Outcome

Title	Percentage of Participants in the MITT Population With a FCR at Day 28
Description	The percentage of participants with a FCR at Day 28 was determined for each arm. Favorable clinical response at Day 28 was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required).
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 28 data.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	264	267
Number [Percentage of participants]	51.9 19.4%	50.6 18.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable clinical response
	Type of Statistical Test	Other
	Comments	Difference in FCR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FCR
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; -7.2 to 9.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

19. Secondary Outcome

Title	Percentage of Participants in the mMITT Population With a Favorable Microbiological Response (FMR) at End of Treatment (EOT) Visit
Description	The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved).
Time Frame	From Day 7 to Day 14

Outcome Measure Data

Analysis Population Description

The mMITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci only on baseline Gram stain, have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity, and have EOT data.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	215	218
Number [Percentage of participants]	77.2 28.8%	67.9 25.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable microbiological response
	Type of Statistical Test	Other
	Comments	Difference in FMR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FMR
	Estimated Value	9.7
	Confidence Interval	(2-Sided) 95%; 1.6 to 17.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

20. Secondary Outcome

Title	Percentage of Participants in the mMITT Population With a FMR at EFU Visit
Description	The percentage of participants with a FMR at EFU was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EFU showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved).
Time Frame	Up to 16 days after end of therapy (up to Day 30)

Outcome Measure Data

Analysis Population Description

The mMITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci only on baseline Gram stain, have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity, and have EFU data.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	215	218
Number [Percentage of participants]	67.9 25.3%	61.9 23%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable microbiological response
	Type of Statistical Test	Other
	Comments	Difference in FMR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FMR
	Estimated Value	6.2
	Confidence Interval	(2-Sided) 95%; -2.7 to 15.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

21. Secondary Outcome

Title	Percentage of Participants in the Microbiologically Evaluable (ME) Population With a FMR at EOT Visit
Description	The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved).
Time Frame	From Day 7 to Day 14

Outcome Measure Data

Analysis Population Description

The ME population is all randomized participants with ≥1 dose of study therapy; not only gram-positive cocci on baseline Gram stain; IMI/REL-sensitive baseline pathogen as cause of HABP/VABP; met entry criteria; no protocol deviations; received minimum duration of IV therapy; have microbiological EOT data and LRT culture available.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	140	133
Number [Percentage of participants]	87.1 32.5%	85.5 31.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable microbiological response
	Type of Statistical Test	Other
	Comments	Difference in FMR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FMR
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; -5.5 to 11.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

22. Secondary Outcome

Title	Percentage of Participants in the ME Population With a FMR at EFU Visit
Description	The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved).
Time Frame	Up to 16 days after end of therapy (up to Day 30)

Outcome Measure Data

Analysis Population Description

The ME population is all randomized participants with ≥1 dose of study therapy; not only gram-positive cocci on baseline Gram stain; IMI/REL-sensitive baseline pathogen as cause of HABP/VABP; met entry criteria; no protocol deviations; received minimum duration of IV therapy; have microbiological EFU data and LRT culture available.

Arm/Group Title	IMI/REL	PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.	Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Measure Participants	121	117
Number [Percentage of participants]	89.9 33.5%	86.4 32.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMI/REL, PIP/TAZ
	Comments	Adjusted difference in favorable microbiological response
	Type of Statistical Test	Other
	Comments	Difference in FMR
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in FMR
	Estimated Value	4.7
	Confidence Interval	(2-Sided) 95%; -4.0 to 14.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.

Adverse Events

Time Frame	Up to 30 days
Adverse Event Reporting Description	An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. All randomized participants who received ≥1 dose of IV study therapy are included in the analysis.
Arm/Group Title	IMI/REL		PIP/TAZ
Arm/Group Description	Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.		Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
All Cause Mortality
	IMI/REL		PIP/TAZ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/266 (16.5%)		58/269 (21.6%)
Serious Adverse Events
	IMI/REL		PIP/TAZ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/266 (26.7%)		86/269 (32%)
Blood and lymphatic system disorders
Splenic lesion	0/266 (0%)	0	1/269 (0.4%)	1
Thrombocytopenia	1/266 (0.4%)	1	0/269 (0%)	0
Cardiac disorders
Acute myocardial infarction	0/266 (0%)	0	1/269 (0.4%)	1
Atrial fibrillation	1/266 (0.4%)	1	2/269 (0.7%)	2
Atrioventricular block complete	1/266 (0.4%)	1	0/269 (0%)	0
Bradycardia	1/266 (0.4%)	1	1/269 (0.4%)	1
Cardiac arrest	10/266 (3.8%)	12	7/269 (2.6%)	9
Cardiac failure	2/266 (0.8%)	2	2/269 (0.7%)	2
Cardiac failure acute	1/266 (0.4%)	1	1/269 (0.4%)	1
Cardiac failure congestive	1/266 (0.4%)	1	0/269 (0%)	0
Cardio-respiratory arrest	1/266 (0.4%)	1	2/269 (0.7%)	2
Cardiopulmonary failure	2/266 (0.8%)	2	2/269 (0.7%)	2
Cardiovascular insufficiency	3/266 (1.1%)	3	4/269 (1.5%)	4
Myocardial infarction	0/266 (0%)	0	1/269 (0.4%)	1
Supraventricular tachycardia	0/266 (0%)	0	1/269 (0.4%)	1
Tachyarrhythmia	1/266 (0.4%)	1	0/269 (0%)	0
Gastrointestinal disorders
Colitis ischaemic	1/266 (0.4%)	1	1/269 (0.4%)	1
Diarrhoea	0/266 (0%)	0	1/269 (0.4%)	1
Duodenal ulcer perforation	1/266 (0.4%)	1	0/269 (0%)	0
Gastrointestinal haemorrhage	0/266 (0%)	0	1/269 (0.4%)	1
Intestinal ischaemia	0/266 (0%)	0	1/269 (0.4%)	1
Intestinal ulcer	1/266 (0.4%)	1	0/269 (0%)	0
Large intestine perforation	0/266 (0%)	0	1/269 (0.4%)	1
Mesenteric vein thrombosis	0/266 (0%)	0	1/269 (0.4%)	1
Small intestinal perforation	0/266 (0%)	0	1/269 (0.4%)	1
General disorders
Brain death	0/266 (0%)	0	1/269 (0.4%)	1
Death	1/266 (0.4%)	1	1/269 (0.4%)	1
Multiple organ dysfunction syndrome	1/266 (0.4%)	1	6/269 (2.2%)	6
Vascular stent thrombosis	0/266 (0%)	0	1/269 (0.4%)	1
Hepatobiliary disorders
Hypertransaminasaemia	0/266 (0%)	0	2/269 (0.7%)	2
Ischaemic hepatitis	0/266 (0%)	0	1/269 (0.4%)	1
Infections and infestations
Bacteraemia	1/266 (0.4%)	1	0/269 (0%)	0
Brain abscess	0/266 (0%)	0	1/269 (0.4%)	1
Bronchitis	1/266 (0.4%)	1	0/269 (0%)	0
Carbuncle	0/266 (0%)	0	1/269 (0.4%)	1
Endocarditis	1/266 (0.4%)	1	0/269 (0%)	0
Endocarditis bacterial	0/266 (0%)	0	1/269 (0.4%)	1
Fungaemia	0/266 (0%)	0	1/269 (0.4%)	1
Infectious pleural effusion	0/266 (0%)	0	1/269 (0.4%)	1
Intervertebral discitis	1/266 (0.4%)	1	0/269 (0%)	0
Lung abscess	1/266 (0.4%)	1	1/269 (0.4%)	1
Meningitis	1/266 (0.4%)	1	1/269 (0.4%)	1
Neurological infection	0/266 (0%)	0	1/269 (0.4%)	1
Peritonitis	1/266 (0.4%)	1	0/269 (0%)	0
Pneumonia	6/266 (2.3%)	6	3/269 (1.1%)	3
Pneumonia acinetobacter	1/266 (0.4%)	1	1/269 (0.4%)	1
Pneumonia staphylococcal	1/266 (0.4%)	1	0/269 (0%)	0
Post procedural sepsis	0/266 (0%)	0	1/269 (0.4%)	1
Sepsis	3/266 (1.1%)	3	3/269 (1.1%)	3
Septic shock	7/266 (2.6%)	7	4/269 (1.5%)	4
Skin infection	1/266 (0.4%)	1	0/269 (0%)	0
Spinal cord infection	1/266 (0.4%)	1	0/269 (0%)	0
Tracheitis	0/266 (0%)	0	1/269 (0.4%)	1
Tuberculosis	1/266 (0.4%)	1	0/269 (0%)	0
Urinary tract infection	1/266 (0.4%)	1	0/269 (0%)	0
Wound infection staphylococcal	0/266 (0%)	0	1/269 (0.4%)	1
Injury, poisoning and procedural complications
Endotracheal intubation complication	0/266 (0%)	0	1/269 (0.4%)	1
Implant tissue necrosis	1/266 (0.4%)	1	0/269 (0%)	0
Spinal shock	0/266 (0%)	0	1/269 (0.4%)	1
Splenic rupture	1/266 (0.4%)	1	0/269 (0%)	0
Subdural haematoma	1/266 (0.4%)	1	0/269 (0%)	0
Traumatic haemothorax	1/266 (0.4%)	1	0/269 (0%)	0
Wound complication	0/266 (0%)	0	1/269 (0.4%)	2
Wound evisceration	0/266 (0%)	0	1/269 (0.4%)	1
Investigations
Alanine aminotransferase increased	3/266 (1.1%)	3	1/269 (0.4%)	1
Aspartate aminotransferase increased	2/266 (0.8%)	2	1/269 (0.4%)	1
Hepatic enzyme increased	0/266 (0%)	0	1/269 (0.4%)	1
Metabolism and nutrition disorders
Diabetic ketoacidosis	0/266 (0%)	0	1/269 (0.4%)	1
Hyperkalaemia	0/266 (0%)	0	1/269 (0.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer	0/266 (0%)	0	2/269 (0.7%)	2
Nervous system disorders
Basilar artery thrombosis	0/266 (0%)	0	1/269 (0.4%)	1
Brain dislocation syndrome	1/266 (0.4%)	1	3/269 (1.1%)	3
Brain oedema	0/266 (0%)	0	3/269 (1.1%)	3
Cerebral infarction	0/266 (0%)	0	1/269 (0.4%)	1
Cerebrovascular accident	1/266 (0.4%)	1	1/269 (0.4%)	1
Coma	1/266 (0.4%)	1	0/269 (0%)	0
Generalised tonic-clonic seizure	0/266 (0%)	0	1/269 (0.4%)	1
Haemorrhage intracranial	1/266 (0.4%)	1	0/269 (0%)	0
Haemorrhagic stroke	1/266 (0.4%)	1	3/269 (1.1%)	3
Hydrocephalus	0/266 (0%)	0	1/269 (0.4%)	1
Intracranial pressure increased	0/266 (0%)	0	1/269 (0.4%)	1
Ischaemic stroke	1/266 (0.4%)	1	1/269 (0.4%)	1
Lethargy	1/266 (0.4%)	1	0/269 (0%)	0
Seizure	0/266 (0%)	0	1/269 (0.4%)	2
Subarachnoid haemorrhage	0/266 (0%)	0	1/269 (0.4%)	1
Renal and urinary disorders
Acute kidney injury	0/266 (0%)	0	8/269 (3%)	8
Renal failure	2/266 (0.8%)	2	1/269 (0.4%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/266 (0.4%)	1	0/269 (0%)	0
Acute respiratory failure	2/266 (0.8%)	2	1/269 (0.4%)	1
Aspiration	1/266 (0.4%)	1	0/269 (0%)	0
Atelectasis	1/266 (0.4%)	1	0/269 (0%)	0
Haemothorax	0/266 (0%)	0	1/269 (0.4%)	1
Hydrothorax	2/266 (0.8%)	2	0/269 (0%)	0
Pleural effusion	0/266 (0%)	0	1/269 (0.4%)	1
Pleural fibrosis	1/266 (0.4%)	1	0/269 (0%)	0
Pneumonia aspiration	4/266 (1.5%)	4	0/269 (0%)	0
Pneumothorax	1/266 (0.4%)	1	2/269 (0.7%)	2
Pneumothorax spontaneous	2/266 (0.8%)	2	0/269 (0%)	0
Pulmonary congestion	0/266 (0%)	0	1/269 (0.4%)	1
Pulmonary embolism	0/266 (0%)	0	2/269 (0.7%)	2
Pulmonary hypertension	1/266 (0.4%)	1	0/269 (0%)	0
Respiratory depression	1/266 (0.4%)	1	0/269 (0%)	0
Respiratory distress	0/266 (0%)	0	1/269 (0.4%)	1
Respiratory failure	2/266 (0.8%)	3	3/269 (1.1%)	3
Skin and subcutaneous tissue disorders
Decubitus ulcer	1/266 (0.4%)	1	0/269 (0%)	0
Vascular disorders
Circulatory collapse	3/266 (1.1%)	3	2/269 (0.7%)	2
Haematoma	1/266 (0.4%)	1	0/269 (0%)	0
Haemodynamic instability	0/266 (0%)	0	1/269 (0.4%)	1
Hypovolaemic shock	0/266 (0%)	0	1/269 (0.4%)	1
Shock haemorrhagic	0/266 (0%)	0	1/269 (0.4%)	1
Other (Not Including Serious) Adverse Events
	IMI/REL		PIP/TAZ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	98/266 (36.8%)		105/269 (39%)
Blood and lymphatic system disorders
Anaemia	28/266 (10.5%)	30	27/269 (10%)	28
Gastrointestinal disorders
Diarrhoea	21/266 (7.9%)	22	29/269 (10.8%)	32
General disorders
Pyrexia	11/266 (4.1%)	19	20/269 (7.4%)	29
Investigations
Alanine aminotransferase increased	23/266 (8.6%)	25	18/269 (6.7%)	18
Aspartate aminotransferase increased	29/266 (10.9%)	31	19/269 (7.1%)	19
Metabolism and nutrition disorders
Hypokalaemia	18/266 (6.8%)	19	24/269 (8.9%)	25
Hyponatraemia	14/266 (5.3%)	15	3/269 (1.1%)	3
Respiratory, thoracic and mediastinal disorders
Hydrothorax	11/266 (4.1%)	11	14/269 (5.2%)	17

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation.