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Clinical Trial Results:
A Phase III, Randomized, Multicenter, Double-Blind, Double-Dummy, Parallel-Group, Comparative Study to Determine the Efficacy, Safety, and Tolerability of Ceftazidime-Avibactam (CAZ-AVI, formerly CAZ104) Versus Doripenem Followed by Appropriate Oral Therapy in the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis, With a Gram-Negative Pathogen in Hospitalized Adults

Summary
EudraCT number	2011-005722-21
Trial protocol	GR DE CZ ES IT BG PL GB
Global end of trial date	21 Jul 2015

Results information
Results version number	v1(current)
This version publication date	05 Feb 2016
First version publication date	05 Feb 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

D4280C00004

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

AstraZeneca AB

Sponsor organisation address

S-151 85, Södertälje, Sweden,

Public contact

Nel Moore, AstraZeneca AB, +44 7884115907, Nell.Moore@astrazeneca.com

Scientific contact

Leanne Gasink, AstraZeneca AB, +1 302-299-2237, Leanne.Gasink@astrazeneca.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

04 Sep 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

21 Aug 2014

Global end of trial reached?

Yes

Global end of trial date

21 Jul 2015

Was the trial ended prematurely?

Main objective of the trial

To assess the noninferiority of ceftazidime-avibactam (CAZ-AVI, formerly CAZ104) compared with doripenem with respect to the following FDA coprimary endpoints and EU primary endpoint in the microbiological modified intent-to-treat (mMITT) analysis set: FDA Primary Objective (Coprimary Endpoints): Symptomatic resolution (or return to premorbid state) of UTI-specific symptoms except flank pain (frequency/urgency/dysuria/suprapubic pain) and resolution of, or improvement in, flank pain based on the patient-reported symptom assessment response at the Day 5 visit. Both per-patient favourable microbiological response and symptomatic resolution (or return to premorbid state) of all UTI-specific symptoms (frequency/urgency/dysuria/suprapubic pain/flank pain) based on the patient-reported symptom assessment response at the Test of Cure (TOC) visit. EU Primary Objective: Per patient favourable microbiological response at the TOC visit.

Protection of trial subjects

The study will be performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with the International Conference on Harmonisation (ICH) harmonised tripartite guideline E6(R1): Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples.

Background therapy

Evidence for comparator

Actual start date of recruitment

10 Oct 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 77

Country: Number of subjects enrolled

Croatia: 53

Country: Number of subjects enrolled

Czech Republic: 10

Country: Number of subjects enrolled

Hungary: 5

Country: Number of subjects enrolled

Poland: 47

Country: Number of subjects enrolled

Romania: 154

Country: Number of subjects enrolled

Russian Federation: 184

Country: Number of subjects enrolled

Serbia: 8

Country: Number of subjects enrolled

Slovakia: 22

Country: Number of subjects enrolled

Turkey: 4

Country: Number of subjects enrolled

Ukraine: 215

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

Greece: 2

Country: Number of subjects enrolled

Italy: 2

Country: Number of subjects enrolled

Portugal: 1

Country: Number of subjects enrolled

Spain: 33

Country: Number of subjects enrolled

United States: 6

Country: Number of subjects enrolled

Argentina: 15

Country: Number of subjects enrolled

Brazil: 10

Country: Number of subjects enrolled

Israel: 6

Country: Number of subjects enrolled

Korea, Republic of: 17

Country: Number of subjects enrolled

Mexico: 29

Country: Number of subjects enrolled

Peru: 61

Country: Number of subjects enrolled

Taiwan: 14

Country: Number of subjects enrolled

Japan: 55

Worldwide total number of subjects

1033

EEA total number of subjects

409

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

710

From 65 to 84 years

313

85 years and over

Subject disposition

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Recruitment details

A total of 1033 patients were randomized in 133 centers in 25 countries. The first patient was randomized on 10OCT2012 and the last patient was randomized on 30JUN2014. A total of 5 patients in the CAZ-AVI arm and 8 patients in Doripenem arm were randomized but did not receive study drug.

Screening details

None

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

CAZ-AVI

Arm description

Ceftazidime-avibactam treatment group

Arm type

Experimental

Investigational medicinal product name

Ceftazidime-avibactam

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Sterile crystalline powder, 2000 mg ceftazidime and 500 mg avibactam

Doripenem

Arm description

Doripenem treatment group

Arm type

Active comparator

Investigational medicinal product name

Doripenem

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Sterile powder, 500 mg

Number of subjects in period 1	CAZ-AVI	Doripenem
Started	516	517
Completed	473	476
Not completed	43	41
Consent withdrawn by subject	12	12
Other Eligibility criteria	11	9
Lost to follow-up	20	20

Baseline characteristics

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Reporting group title

CAZ-AVI

Reporting group description

Ceftazidime-avibactam treatment group

Reporting group title

Doripenem

Reporting group description

Doripenem treatment group

Reporting group values	CAZ-AVI	Doripenem	Total
Number of subjects	516	517	1033
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	357	353	710
From 65-84 years	153	160	313
85 years and over	6	4	10
Age Continuous \|
Units: Years
arithmetic mean (standard deviation)	51.6 ± 19.82	52.3 ± 18.89	-
Gender, Male/Female
Units: Participants
Female	353	364	717
Male	163	153	316
Age, Customized
Units: Subjects
18-45	195	175	370
46-64	162	178	340
65-74	80	100	180
75-90	79	64	143

End points

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Reporting group title

CAZ-AVI

Reporting group description

Ceftazidime-avibactam treatment group

Reporting group title

Doripenem

Reporting group description

Doripenem treatment group

Primary: Patient-reported symptomatic response at day 5 (mMITT analysis set): non-inferiority hypothesis test

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End point title

Patient-reported symptomatic response at day 5 (mMITT analysis set): non-inferiority hypothesis test

End point description

Proportion of patients with symptomatic resolution (or return to premorbid state) of UTI-specific symptoms except flank pain (frequency/urgency/dysuria/suprapubic pain) with resolution of or improvement in flank pain based on the patient-reported symptom assessment response at the Day 5 visit in the mMITT analysis set. The sponsor will conclude noninferiority if the lower limit of the 95% CI of difference (corresponding to a 97.5% 1-sided lower bound) is greater than -12.5% for both FDA coprimary outcome variables (symptomatic resolution at day 5 or favorable combined response at test of cure (TOC)).

End point type

Primary

End point timeframe

At Day 5 visit. Day 5 visit is based on 24 hour periods from the first dose date and time.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participants
number (not applicable)
Symptomatic resolution	276	276
Symptom persistence	103	124
Indeterminate	14	17
Symptomatic resolution rate	70.2	66.2

Non-inferiority hypothesis test

Statistical analysis description

H0: Difference (CAZ-AVI treatment group minus Doripenem treatment group) of symptomatic resolution rates ≤ -12.5%

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

810

Analysis specification

Pre-specified

Analysis type

^[1]

Method

Unstratified Miettinen & Nurminen method

Parameter type

Difference of symp resolution rates

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2.39

upper limit

10.42

Notes
[1] - -12.5%

Primary: Combined patient-reported symptomatic and microbiological response at TOC (mMITT analysis set): non-inferiority hypothesis test

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End point title

Combined patient-reported symptomatic and microbiological response at TOC (mMITT analysis set): non-inferiority hypothesis test

End point description

Proportion of patients with both a favorable per patient microbiological response and symptomatic resolution (or return to premorbid state) of all UTI-specific symptoms (frequency/urgency/dysuria/suprapubic pain/flank pain) based on the patient-reported symptom assessment response at the TOC visit in the mMITT analysis set. The sponsor will conclude noninferiority if the lower limit of the 95% CI of difference (corresponding to a 97.5% 1-sided lower bound) is greater than -12.5% for both FDA coprimary outcome variables (symptomatic resolution at day 5 or favorable combined response at test of cure (TOC)).

End point type

Primary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participants
number (not applicable)
Favorable	280	269
Unfavorable	81	109
Indeterminate	32	39
Favorable response rate	71.2	64.5

Non-inferiority hypothesis test

Statistical analysis description

H0: Difference (CAZ-AVI treatment group minus Doripenem treatment group) of favorable combined response rates ≤ -12.5%

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

810

Analysis specification

Pre-specified

Analysis type

^[2]

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of favorable combined resp rates

Point estimate

6.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

13.12

Notes
[2] - -12.5%

Primary: Per-patient microbiological response at TOC (mMITT analysis set): non-inferiority hypothesis test

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End point title

Per-patient microbiological response at TOC (mMITT analysis set): non-inferiority hypothesis test

End point description

Proportion of patients with a favorable per patient microbiological response at TOC. The primary efficacy outcome variable for ROW is the proportion of patients with a favorable per-patient microbiological response at the TOC visit in the mMITT analysis set.

End point type

Primary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participants
number (not applicable)
Favorable	304	296
Unfavorable	58	83
Indeterminate	31	38
Favorable response rate	77.4	71

Non-inferiority hypothesis test

Statistical analysis description

H0: Difference (CAZ-AVI treatment group minus Doripenem treatment group) of favorable response rates ≤ -12.5%

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

810

Analysis specification

Pre-specified

Analysis type

^[3]

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of favorable response rates

Point estimate

6.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.33

upper limit

12.36

Notes
[3] - -12.5%

Secondary: Per-patient microbiological response at EOT (IV) (mMITT analysis set)

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End point title

Per-patient microbiological response at EOT (IV) (mMITT analysis set)

End point description

Proportion of patients with a favorable per-patient microbiological response at EOT (IV)

End point type

Secondary

End point timeframe

At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participants
number (not applicable)
Favorable	374	395
Unfavorable	1	3
Indeterminate	18	19
Favorable response rate	95.2	94.7

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of favorable response rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

810

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of favorable response rates

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2.7

upper limit

3.56

Secondary: Per-patient microbiological response at LFU (mMITT analysis set)

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End point title

Per-patient microbiological response at LFU (mMITT analysis set)

End point description

Proportion of patients with a favorable per patient microbiological response at LFU

End point type

Secondary

End point timeframe

At LFU visit. LFU visit is 45 to 52 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participants
number (not applicable)
Favorable	268	254
Unfavorable	83	125
Indeterminate	42	38
Favorable response rate	68.2	60.9

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of favorable response rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

810

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of favorable response rates

Point estimate

7.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.68

upper limit

13.81

Secondary: Per-patient microbiological response at EOT (IV) (ME at EOT (IV) analysis set)

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End point title

Per-patient microbiological response at EOT (IV) (ME at EOT (IV) analysis set)

End point description

Proportion of patients with a favorable per-patient microbiological response at EOT (IV)

End point type

Secondary

End point timeframe

At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	325	361
Units: Participants
number (not applicable)
Favorable	324	359
Unfavorable	1	2
Favorable response rate	99.7	99.4

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of favorable response rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

686

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of favorable response rates

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.21

upper limit

1.72

Secondary: Per-patient microbiological response at TOC (ME at TOC analysis set)

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End point title

Per-patient microbiological response at TOC (ME at TOC analysis set)

End point description

Proportion of patients with a favorable per patient microbiological response at TOC

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	286	298
Units: Participants
number (not applicable)
Favorable	241	225
Unfavorable	45	73
Favorable response rate	84.3	75.5

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of favorable response rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

584

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of favorable response rates

Point estimate

8.8

Confidence interval

level

95%

sides

2-sided

lower limit

2.27

upper limit

15.24

Secondary: Per-patient microbiological response at LFU (ME at LFU analysis set)

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End point title

Per-patient microbiological response at LFU (ME at LFU analysis set)

End point description

Proportion of patients with a favorable per patient microbiological response at LFU

End point type

Secondary

End point timeframe

At LFU visit. LFU visit is 45 to 52 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	245	262
Units: Participants
number (not applicable)
Favorable	182	166
Unfavorable	63	96
Favorable response rate	74.3	63.4

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of favorable response rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

507

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of favorable response rates

Point estimate

10.9

Confidence interval

level

95%

sides

2-sided

lower limit

2.86

upper limit

18.85

Secondary: Per-patient microbiological response at EOT (IV) (Extended ME at EOT (IV) analysis set)

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End point title

Per-patient microbiological response at EOT (IV) (Extended ME at EOT (IV) analysis set)

End point description

Proportion of patients with a favorable per-patient microbiological response at EOT (IV)

End point type

Secondary

End point timeframe

At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	336	371
Units: Participants
number (not applicable)
Favorable	335	369
Favorable response rate	99.7	99.5
Unfavorable	1	2

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of favorable response rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

707

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of favorable response rates

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.17

upper limit

1.68

Secondary: Per-patient microbiological response at TOC (Extended ME at TOC analysis set)

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End point title

Per-patient microbiological response at TOC (Extended ME at TOC analysis set)

End point description

Proportion of patients with a favorable per patient microbiological response at TOC

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	292	311
Units: Participants
number (not applicable)
Favorable	243	236
Favorable response rate	83.2	75.9
Unfavorable	49	75

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of favorable response rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

603

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of favorable response rates

Point estimate

7.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.88

upper limit

13.74

Secondary: Per-patient microbiological response at LFU (Extended ME at LFU analysis set)

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End point title

Per-patient microbiological response at LFU (Extended ME at LFU analysis set)

End point description

Proportion of patients with a favorable per patient microbiological response at LFU

End point type

Secondary

End point timeframe

At LFU visit. LFU visit is 45 to 52 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	251	272
Units: Participants
number (not applicable)
Favorable	184	173
Favorable response rate	73.3	63.6
Unfavorable	67	99

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of favorable response rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

523

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of favorable response rates

Point estimate

9.7

Confidence interval

level

95%

sides

2-sided

lower limit

1.72

upper limit

17.55

Secondary: Investigator determined clinical response at EOT (IV) (mMITT analysis set)

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End point title

Investigator determined clinical response at EOT (IV) (mMITT analysis set)

End point description

Proportion of patients with a clinical cure at EOT (IV). The investigator should consider the entirety of the patient’s clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient’s clinical response.

End point type

Secondary

End point timeframe

At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participants
number (not applicable)
Clinical cure	378	407
Clinical cure rate	96.2	97.6
Clinical failure	5	5
Indeterminate	10	5

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

810

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clinical cure rates

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.07

upper limit

1.02

Secondary: Investigator determined clinical response at TOC (mMITT analysis set)

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End point title

Investigator determined clinical response at TOC (mMITT analysis set)

End point description

Proportion of patients with a clinical cure at TOC. The investigator should consider the entirety of the patient’s clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient’s clinical response.

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participants
number (not applicable)
Clinical cure	355	377
Clinical cure rate	90.3	90.4
Clinical failure	11	24
Indeterminate	27	16

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

810

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clinical cure rates

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-4.23

upper limit

4.03

Secondary: Investigator determined clinical response at LFU (mMITT analysis set)

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End point title

Investigator determined clinical response at LFU (mMITT analysis set)

End point description

Proportion of patients with a clinical cure at LFU. The investigator should consider the entirety of the patient’s clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient’s clinical response.

End point type

Secondary

End point timeframe

At LFU visit. LFU visit is 45 to 52 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participants
number (not applicable)
Clinical cure	335	350
Clinical cure rate	85.2	83.9
Clinical failure	23	39
Indeterminate	35	28

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

810

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clinical cure rates

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-3.71

upper limit

6.3

Secondary: Investigator determined clinical response at EOT (IV) (ME at EOT (IV) analysis set)

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End point title

Investigator determined clinical response at EOT (IV) (ME at EOT (IV) analysis set)

End point description

End point type

Secondary

End point timeframe

At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	325	361
Units: Participants
number (not applicable)
Clinical cure	318	358
Clinical cure rate	97.8	99.2
Clinical failure	4	2
Indeterminate	3	1

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

686

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clinical cure rates

Point estimate

-1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-3.64

upper limit

0.55

Secondary: Investigator determined clinical response at TOC (ME at TOC analysis set)

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End point title

Investigator determined clinical response at TOC (ME at TOC analysis set)

End point description

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	286	298
Units: Participants
number (not applicable)
Clinical cure	277	285
Clinical cure rate	96.9	95.6
Clinical failure	4	13
Indeterminate	5	0

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

584

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clinical cure rates

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.03

upper limit

4.56

Secondary: Investigator determined clinical response at LFU (ME at LFU analysis set)

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End point title

Investigator determined clinical response at LFU (ME at LFU analysis set)

End point description

End point type

Secondary

End point timeframe

At LFU visit. LFU visit is 45 to 52 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	245	262
Units: Participants
number (not applicable)
Clinical cure	226	236
Clinical cure rate	92.2	90.1
Clinical failure	15	24
Indeterminate	4	2

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

507

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clinical cure rates

Point estimate

2.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.9

upper limit

7.24

Secondary: Investigator determined clinical response at EOT (IV) (Extended ME at EOT (IV) analysis set)

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End point title

Investigator determined clinical response at EOT (IV) (Extended ME at EOT (IV) analysis set)

End point description

End point type

Secondary

End point timeframe

At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	336	371
Units: Participants
number (not applicable)
Clinical cure	327	368
Clinical cure rate	97.3	99.2
Clinical failure	4	2
Indeterminate	5	1

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

707

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clinical cure rates

Point estimate

-1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-4.3

upper limit

0.04

Secondary: Investigator determined clinical response at TOC (Extended ME at TOC analysis set)

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End point title

Investigator determined clinical response at TOC (Extended ME at TOC analysis set)

End point description

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	292	311
Units: Participants
number (not applicable)
Clinical cure	283	298
Clinical cure rate	96.9	95.8
Clinical failure	4	13
Indeterminate	5	0

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

603

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clinical cure rates

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-2.07

upper limit

4.32

Secondary: Investigator determined clinical response at LFU (Extended ME at LFU analysis set)

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End point title

Investigator determined clinical response at LFU (Extended ME at LFU analysis set)

End point description

End point type

Secondary

End point timeframe

At LFU visit. LFU visit is 45 to 52 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	251	272
Units: Participants
number (not applicable)
Clinical cure	232	246
Clinical cure rate	92.4	90.4
Clinical failure	15	24
Indeterminate	4	2

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

523

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clinical cure rates

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2.94

upper limit

6.91

Secondary: Investigator determined clinical response at EOT (IV) (CE at EOT (IV) analysis set)

Top of page

End point title

Investigator determined clinical response at EOT (IV) (CE at EOT (IV) analysis set)

End point description

End point type

Secondary

End point timeframe

At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	350	391
Units: Participants
number (not applicable)
Clinical cure	346	387
Clinical cure rate	98.9	99
Clinical failure	4	4

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

741

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clinical cure rates

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.99

upper limit

1.61

Secondary: Investigator determined clinical response at TOC (CE at TOC analysis set)

Top of page

End point title

Investigator determined clinical response at TOC (CE at TOC analysis set)

End point description

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	297	330
Units: Participants
number (not applicable)
Clinical cure	289	309
Clinical cure rate	97.3	93.6
Clinical failure	8	21

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

627

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clinical cure rates

Point estimate

3.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.41

upper limit

7.16

Secondary: Investigator determined clinical response at LFU (CE at LFU analysis set)

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End point title

Investigator determined clinical response at LFU (CE at LFU analysis set)

End point description

End point type

Secondary

End point timeframe

At LFU visit. LFU visit is 45 to 52 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	254	287
Units: Participants
number (not applicable)
Clinical cure	235	254
Clinical cure rate	92.5	88.5
Clinical failure	19	33

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

541

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clinical cure rates

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

9.05

Secondary: Investigator determined clinical response at TOC for patients infected by ceftazidime-resistant Gram-negative pathogen (mMITT analysis set)

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End point title

Investigator determined clinical response at TOC for patients infected by ceftazidime-resistant Gram-negative pathogen (mMITT analysis set)

End point description

Clinical cure at the TOC visit for patients infected with a ceftazidime resistant pathogen in the mMITT analysis set. Includes patients infected by at least one ceftazidime-resistant Gram-negative pathogen.

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participants
number (not applicable)
All patients - Clinical cure (n=75, 84)	67	75
All patients - Clinical cure rate	89.3	89.3
Escherichia coli patients - Clin cure (n=36, 37)	33	31
Klebsiella pneumoniae patients-Clin cure(n=18,30)	17	28
Pseudomonas aeruginosa patients- Clin cure(n=7,6)	5	6
Enterobacter cloacae patients-Clin cure(n=7,6)	5	5
Proteus mirabilis patients - Clin cure (n=2, 5)	2	5

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates in All patients with a ceftazidime-resistant Gram-negative pathogen

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

810

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clin cure rates in All patients

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-10.4

upper limit

10.1

Secondary: Investigator determined clinical response at TOC for patients infected by ceftazidime-resistant Gram-negative pathogen (ME at TOC analysis set)

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End point title

Investigator determined clinical response at TOC for patients infected by ceftazidime-resistant Gram-negative pathogen (ME at TOC analysis set)

End point description

Clinical cure at the TOC visit for patients infected with a ceftazidime resistant pathogen in the ME at TOC analysis set. Includes patients infected by at least one ceftazidime-resistant Gram-negative pathogen.

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	286	298
Units: Participants
number (not applicable)
All patients - Clinical cure (n=48, 57)	47	55
All patients - Clinical cure rate	97.9	96.5
Escherichia coli patients-Clin cure (n=23,27)	22	25
Klebsiella pneumoniae patients-Clin cure(n=14,22)	14	22
Pseudomonas aeruginosa patients-Clin cure(n=1, 2)	1	2
Enterobacter cloacae patients-Clin cure(n=5,5)	5	5
Proteus mirabilis patients - Clin cure (n=0, 2)	0	2

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates in All patients with a ceftazidime-resistant Gram-negative pathogen

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

584

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clin cure rates in All patients

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-7.8

upper limit

10.2

Secondary: Investigator determined clinical response at TOC for patients infected by ceftazidime-resistant Gram-negative pathogen (Extended ME at TOC analysis set)

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End point title

Investigator determined clinical response at TOC for patients infected by ceftazidime-resistant Gram-negative pathogen (Extended ME at TOC analysis set)

End point description

Clinical cure at the TOC visit for patients infected with a ceftazidime resistant pathogen in the Extended ME at TOC analysis set. Includes patients infected by at least one ceftazidime-resistant Gram-negative pathogen.

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	292	311
Units: Participants
number (not applicable)
All patients - Clinical cure (n=51, 63)	50	61
All patients - Clinical cure rate	98	96.8
Escherichia coli patients - Clin cure (n=23, 27)	22	25
Klebsiella pneumoniae patients-Clin cure(n=15,23)	15	23
Pseudomonas aeruginosa patients-Clin cure(n=3,6)	3	6
Enterobacter cloacae patients-Clin cure(n=5,5)	5	5
Proteus mirabilis patients - Clin cure (n=0, 2)	0	2

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of clinical cure rates in All patients with a ceftazidime-resistant Gram-negative pathogen

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

603

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of clin cure rates in All patients

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-7.5

upper limit

9.2

Secondary: Per-patient microbiological response at TOC in patients infected by ceftazidime-resistant Gram-negative pathogen (mMITT analysis set)

Top of page

End point title

Per-patient microbiological response at TOC in patients infected by ceftazidime-resistant Gram-negative pathogen (mMITT analysis set)

End point description

Favorable per-patient microbiological response at the TOC visit for patients infected with a ceftazidime resistant pathogen in the mMITT analysis set.

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	75	84
Units: Participants
number (not applicable)
Favorable	47	51
Favorable response rate	62.7	60.7
Unfavorable	19	27
Indeterminate	9	6

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of favorable response rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

159

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of favorable response rates

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-13.18

upper limit

16.89

Secondary: Per-patient microbiological response at TOC in patients infected by ceftazidime-resistant Gram-negative pathogen (ME at TOC analysis set)

Top of page

End point title

Per-patient microbiological response at TOC in patients infected by ceftazidime-resistant Gram-negative pathogen (ME at TOC analysis set)

End point description

Favorable per-patient microbiological response at the TOC visit for patients infected with a ceftazidime resistant pathogen in the ME at TOC analysis set.

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	48	57
Units: Participants
number (not applicable)
Favorable	35	37
Favorable response rate	72.9	64.9
Unfavorable	13	20

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of favorable response rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of favorable response rates

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-10.03

upper limit

25.21

Secondary: Per-patient microbiological response at TOC in patients infected by ceftazidime-resistant Gram-negative pathogen (Extended ME at TOC analysis set)

Top of page

End point title

Per-patient microbiological response at TOC in patients infected by ceftazidime-resistant Gram-negative pathogen (Extended ME at TOC analysis set)

End point description

Favorable per-patient microbiological response at the TOC visit for patients infected with a ceftazidime resistant pathogen in the Extended ME at TOC analysis set.

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	51	63
Units: Participants
number (not applicable)
Favorable	37	41
Favorable response rate	72.5	65.1
Unfavorable	14	22

Confidence interval

Statistical analysis description

Confidence interval of the difference (CAZ-AVI treatment group minus Doripenem treatment group) of favorable response rates

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

114

Analysis specification

Pre-specified

Analysis type

Method

Unstratified Miettinen & Nurminen method

Parameter type

Diff of favorable response rates

Point estimate

7.5

Confidence interval

level

95%

sides

2-sided

lower limit

-9.91

upper limit

24.01

Secondary: Time to first defervescence while on IV study therapy (mMITT analysis set)

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End point title

Time to first defervescence while on IV study therapy (mMITT analysis set)

End point description

Time to first defervescence while on IV study therapy in patients in the mMITT analysis set who have fever at study entry.

End point type

Secondary

End point timeframe

Time to first defervescence is defined as the time (in days) from the first dose of IV study therapy to first absence of fever, which is temperature ≤ 37.8 C in a 24-hour period.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participants
number (not applicable)
Number of patients with fever (>38°C) at baseline	157	150
Number afebrile at the time of the last obs	155	143
Number censored at the time of the last obs	2	7
Median time (days) to defervescence	2	3

Analysis of time to first defervescence

Statistical analysis description

H0: No difference in time to first defervescence between treatment groups

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

810

Analysis specification

Pre-specified

Analysis type

P-value

= 0.038

Method

Logrank

Confidence interval

Secondary: Time to first defervescence while on IV study therapy (ME at TOC analysis set)

Top of page

End point title

Time to first defervescence while on IV study therapy (ME at TOC analysis set)

End point description

Time to first defervescence while on IV study therapy in patients in the ME at TOC analysis set who have fever at study entry.

End point type

Secondary

End point timeframe

Time to first defervescence is defined as the time (in days) from the first dose of IV study therapy to first absence of fever, which is temperature ≤ 37.8 C in a 24-hour period.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	286	298
Units: Participants
number (not applicable)
Number of patients with fever (>38°C) at baseline	124	108
Number afebrile at the time of the last obs	124	105
Number censored at the time of the last obs	0	3
Median time (days) to defervescence	3	3

Analysis of time to first defervescence

Statistical analysis description

H0: No difference in time to first defervescence between treatment groups

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

584

Analysis specification

Pre-specified

Analysis type

P-value

= 0.129

Method

Logrank

Confidence interval

Secondary: Time to first defervescence while on IV study therapy (Extended ME at TOC analysis set)

Top of page

End point title

Time to first defervescence while on IV study therapy (Extended ME at TOC analysis set)

End point description

Time to first defervescence while on IV study therapy in patients in the Extended ME at TOC analysis set who have fever at study entry.

End point type

Secondary

End point timeframe

Time to first defervescence is defined as the time (in days) from the first dose of IV study therapy to first absence of fever, which is temperature ≤ 37.8 C in a 24-hour period.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	292	311
Units: Participants
number (not applicable)
Number of patients with fever (>38°C) at baseline	124	111
Number afebrile at the time of the last obs	124	108
Number censored at the time of the last obs	0	3
Median time (days) to defervescence	3	3

Analysis of time to first defervescence

Statistical analysis description

H0: No difference in time to first defervescence between treatment groups

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

603

Analysis specification

Pre-specified

Analysis type

P-value

= 0.08

Method

Logrank

Confidence interval

Secondary: Time to first defervescence while on IV study therapy (CE at TOC analysis set)

Top of page

End point title

Time to first defervescence while on IV study therapy (CE at TOC analysis set)

End point description

Time to first defervescence while on IV study therapy in patients in the CE at TOC analysis set who have fever at study entry.

End point type

Secondary

End point timeframe

Time to first defervescence is defined as the time (in days) from the first dose of IV study therapy to first absence of fever, which is temperature ≤ 37.8 C in a 24-hour period.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	297	330
Units: Participants
number (not applicable)
Number of patients with fever (>38°C) at baseline	123	118
Number afebrile at the time of the last obs	122	113
Number censored at the time of the last obs	1	5
Median time (days) to defervescence	3	3

Analysis of time to first defervescence

Statistical analysis description

H0: No difference in time to first defervescence between treatment groups

Comparison groups

CAZ-AVI v Doripenem

Number of subjects included in analysis

627

Analysis specification

Pre-specified

Analysis type

P-value

= 0.155

Method

Logrank

Confidence interval

Secondary: Per-pathogen microbiological response at EOT (IV) for baseline pathogen (mMITT analysis set)

Top of page

End point title

Per-pathogen microbiological response at EOT (IV) for baseline pathogen (mMITT analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the mMITT analysis set

End point type

Secondary

End point timeframe

At EOT IV visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participant
Escherichia coli - Favorable (n=292, 306)	280	293
Klebsiella pneumoniae - Favorable (n=44, 56)	41	51
Proteus mirabilis - Favorable (n=17, 13)	16	11
Enterobacter cloacae - Favorable (n= 11,13)	9	13
Pseudomonas aeruginosa - Favorable (n=18, 20)	17	18

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at TOC for baseline pathogen (mMITT analysis set)

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End point title

Per-pathogen microbiological response at TOC for baseline pathogen (mMITT analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the TOC visit in the mMITT analysis set

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participant
Escherichia coli - Favorable (n=292, 306)	229	220
Klebsiella pneumoniae - Favorable (n=44, 56)	33	35
Proteus mirabilis - Favorable (n=17, 13)	16	9
Enterobacter cloacae - Favorable (n= 11,13)	6	9
Pseudomonas aeruginosa - Favorable (n=18, 20)	12	15

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at LFU for baseline pathogen (mMITT analysis set)

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End point title

Per-pathogen microbiological response at LFU for baseline pathogen (mMITT analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the LFU visit in the mMITT analysis set

End point type

Secondary

End point timeframe

At LFU visit. LFU visit is 45 to 52 days from Randomization

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participant
Escherichia coli - Favorable (n=292, 306)	198	189
Klebsiella pneumoniae - Favorable (n=44, 56)	32	30
Proteus mirabilis - Favorable (n=17, 13)	16	6
Enterobacter cloacae - Favorable (n= 11,13)	6	9
Pseudomonas aeruginosa - Favorable (n=18, 20)	9	13

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at EOT (IV) for baseline pathogen (Extended ME at EOT (IV) analysis set)

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End point title

Per-pathogen microbiological response at EOT (IV) for baseline pathogen (Extended ME at EOT (IV) analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the Extended ME at EOT (IV) analysis set

End point type

Secondary

End point timeframe

At EOT IV visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	336	371
Units: Participant
Escherichia coli - Favorable (n=250, 274)	250	274
Klebsiella pneumoniae - Favorable (n=34, 49)	34	48
Proteus mirabilis - Favorable (n=13, 11)	13	11
Enterobacter cloacae - Favorable (n= 9, 12)	9	12
Pseudomonas aeruginosa - Favorable (n=18, 18)	17	17

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at TOC for baseline pathogen (Extended ME at TOC analysis set)

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End point title

Per-pathogen microbiological response at TOC for baseline pathogen (Extended ME at TOC analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the TOC visit in the Extended ME at TOC analysis set

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	292	311
Units: Participant
Escherichia coli - Favorable (n=214, 226)	180	176
Klebsiella pneumoniae - Favorable (n=32, 42)	26	29
Proteus mirabilis - Favorable (n=14, 7)	14	4
Enterobacter cloacae - Favorable (n= 7, 11)	5	8
Pseudomonas aeruginosa - Favorable (n=13, 18)	8	13

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at LFU for baseline pathogen (Extended ME at LFU analysis set)

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End point title

Per-pathogen microbiological response at LFU for baseline pathogen (Extended ME at LFU analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the LFU visit in the Extended ME at LFU analysis set

End point type

Secondary

End point timeframe

At LFU visit. LFU visit is 45 to 52 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	251	272
Units: Participant
Escherichia coli - Favorable (n=179, 198)	129	131
Klebsiella pneumoniae - Favorable (n=31, 36)	24	19
Proteus mirabilis - Favorable (n=11,5)	11	1
Enterobacter cloacae - Favorable (n= 7, 11)	5	8
Pseudomonas aeruginosa - Favorable (n=12, 16)	7	9

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at EOT (IV) for baseline pathogen (ME at EOT (IV) analysis set)

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End point title

Per-pathogen microbiological response at EOT (IV) for baseline pathogen (ME at EOT (IV) analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the ME at EOT (IV) analysis set

End point type

Secondary

End point timeframe

At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	325	361
Units: Participant
Escherichia coli - Favorable (n=249, 270)	249	270
Klebsiella pneumoniae - Favorable (n=33, 48)	33	47
Proteus mirabilis - Favorable (n=13,11)	13	11
Enterobacter cloacae - Favorable (n= 9, 12)	9	12
Pseudomonas aeruginosa - Favorable (n=10, 15)	9	14

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at TOC for baseline pathogen (ME at TOC analysis set)

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End point title

Per-pathogen microbiological response at TOC for baseline pathogen (ME at TOC analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the TOC visit in the ME at TOC analysis set

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	286	298
Units: Participant
Escherichia coli - Favorable (n=214, 221)	180	171
Klebsiella pneumoniae - Favorable (n=31, 41)	25	28
Proteus mirabilis - Favorable (n=14, 7)	14	4
Enterobacter cloacae - Favorable (n= 7, 11)	5	8
Pseudomonas aeruginosa - Favorable (n=9, 13)	7	9

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at LFU for baseline pathogen (ME at LFU analysis set)

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End point title

Per-pathogen microbiological response at LFU for baseline pathogen (ME at LFU analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the LFU visit in the ME at LFU analysis set

End point type

Secondary

End point timeframe

At LFU visit. LFU visit is 45 to 52 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	245	262
Units: Participant
Escherichia coli - Favorable (n=179, 194)	129	127
Klebsiella pneumoniae - Favorable (n=30, 35)	23	18
Proteus mirabilis - Favorable (n=11,5)	11	1
Enterobacter cloacae - Favorable (n= 7, 11)	5	8
Pseudomonas aeruginosa - Favorable (n=8, 13)	6	8

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at EOT (IV) for blood only (mMITT analysis set)

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End point title

Per-pathogen microbiological response at EOT (IV) for blood only (mMITT analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the mMITT analysis set for blood only

End point type

Secondary

End point timeframe

At EOT IV visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participant
Escherichia coli - Favorable (n=32, 28)	31	28
Klebsiella pneumoniae - Favorable (n=4, 2)	2	2
Proteus mirabilis - Favorable (n=1, 0)	1	0
Pseudomonas aeruginosa - Favorable (n=1, 2)	1	2

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at TOC for blood only (mMITT analysis set)

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End point title

Per-pathogen microbiological response at TOC for blood only (mMITT analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the TOC visit in the mMITT analysis set for blood only

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participant
Escherichia coli - Favorable (n=32, 28)	31	28
Klebsiella pneumoniae - Favorable (n=4, 2)	3	2
Proteus mirabilis - Favorable (n=1, 0)	1	0
Pseudomonas aeruginosa - Favorable (n=1, 2)	1	2

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at LFU for blood only (mMITT analysis set)

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End point title

Per-pathogen microbiological response at LFU for blood only (mMITT analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the LFU visit in the mMITT analysis set for blood only

End point type

Secondary

End point timeframe

At LFU visit. LFU visit is 45 to 52 days from Randomization

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participant
Escherichia coli - Favorable (n=32, 28)	29	27
Klebsiella pneumoniae - Favorable (n=4, 2)	3	2
Proteus mirabilis - Favorable (n=1, 0)	1	0
Pseudomonas aeruginosa - Favorable (n=1, 2)	1	2

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at EOT (IV) for blood only (Extended ME at EOT (IV) analysis set)

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End point title

Per-pathogen microbiological response at EOT (IV) for blood only (Extended ME at EOT (IV) analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the Extended ME at EOT (IV) analysis set for blood only

End point type

Secondary

End point timeframe

At EOT IV visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	336	371
Units: Participant
Escherichia coli - Favorable (n=26, 24)	26	24
Klebsiella pneumoniae - Favorable (n=2, 1)	1	1
Proteus mirabilis - Favorable (n=1, 0)	1	0
Pseudomonas aeruginosa - Favorable (n=1, 2)	1	2

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at TOC for blood only (Extended ME at TOC analysis set)

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End point title

Per-pathogen microbiological response at TOC for blood only (Extended ME at TOC analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the TOC visit in the Extended ME at TOC analysis set for blood only

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	292	311
Units: Participant
Escherichia coli - Favorable (n=22, 20)	22	20
Klebsiella pneumoniae - Favorable (n=2, 2)	2	2
Proteus mirabilis - Favorable (n=1, 0)	1	0
Pseudomonas aeruginosa - Favorable (n=0, 1)	0	1

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at LFU for blood only (Extended ME at LFU analysis set)

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End point title

Per-pathogen microbiological response at LFU for blood only (Extended ME at LFU analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the LFU visit in the Extended ME at LFU analysis set for blood only

End point type

Secondary

End point timeframe

At LFU visit. LFU visit is 45 to 52 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	251	272
Units: Participant
Escherichia coli - Favorable (n=19, 18)	19	17
Klebsiella pneumoniae - Favorable (n=2, 1)	2	1
Proteus mirabilis - Favorable (n=1, 0)	1	0
Pseudomonas aeruginosa - Favorable (n=0, 1)	0	1

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at EOT (IV) for blood only (ME at EOT (IV) analysis set)

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End point title

Per-pathogen microbiological response at EOT (IV) for blood only (ME at EOT (IV) analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the ME at EOT (IV) analysis set for blood only

End point type

Secondary

End point timeframe

At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	325	361
Units: Participant
Escherichia coli - Favorable (n=26, 24)	26	24
Klebsiella pneumoniae - Favorable (n=2, 1)	1	1
Proteus mirabilis - Favorable (n=1, 0)	1	0
Pseudomonas aeruginosa - Favorable (n=1, 2)	1	2

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at TOC for blood only (ME at TOC analysis set)

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End point title

Per-pathogen microbiological response at TOC for blood only (ME at TOC analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the TOC visit in the ME at TOC analysis set for blood only

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	286	298
Units: Participant
Escherichia coli - Favorable (n=22, 20)	22	20
Klebsiella pneumoniae - Favorable (n=2, 2)	2	2
Proteus mirabilis - Favorable (n=1, 0)	1	0
Pseudomonas aeruginosa - Favorable (n=0, 1)	0	1

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at LFU for blood only (ME at LFU analysis set)

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End point title

Per-pathogen microbiological response at LFU for blood only (ME at LFU analysis set)

End point description

Number of favorable per-pathogen microbiological responses at the LFU visit in the ME at LFU analysis set for blood only

End point type

Secondary

End point timeframe

At LFU visit. LFU visit is 45 to 52 days from Randomization.

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	245	262
Units: Participant
Escherichia coli - Favorable (n=19, 18)	19	17
Klebsiella pneumoniae - Favorable (n=2, 1)	2	1
Proteus mirabilis - Favorable (n=1, 0)	1	0
Pseudomonas aeruginosa - Favorable (n=0, 1)	0	1

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at TOC by CAZ AVI MIC for baseline pathogen (mMITT analysis set)

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End point title

Per-pathogen microbiological response at TOC by CAZ AVI MIC for baseline pathogen (mMITT analysis set)

End point description

Per pathogen microbiological response at TOC by CAZ-AVI MIC for baseline pathogen in the mMITT analysis set

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participant
E. coli (MIC: <=0.008) - Favorable (n=5, 6)	3	5
E. coli (MIC: 0.015) - Favorable (n=8, 7)	8	6
E. coli (MIC: 0.03) - Favorable (n=28, 35)	24	23
E. coli (MIC: 0.06) - Favorable (n=123, 139)	103	111
E. coli (MIC: 0.12) - Favorable (n=90, 81)	67	54
E. coli (MIC: 0.25) - Favorable (n=28, 25)	18	13
E. coli (MIC: 0.5) - Favorable (n=5, 6)	4	2
E. coli (MIC: 1) - Favorable (n=3, 0)	1	0
E. coli (MIC: 2) - Favorable (n=1, 0)	1	0
E. coli (MIC: 4) - Favorable (n=0, 0)	0	0
E. coli (MIC: 8) - Favorable (n=0, 0)	0	0
E. coli (MIC: 16) - Favorable (n=0, 0)	0	0
E. coli (MIC: 32) - Favorable (n=0, 0)	0	0
E. coli (MIC: >32) - Favorable (n=0, 0)	0	0
Kleb.pneumoniae (MIC: <=0.008)-Favorable(n=0, 0)	0	0
Kleb. pneumoniae (MIC: 0.015) -Favorable (n=1, 0)	1	0
Kleb. pneumoniae (MIC: 0.03) - Favorable (n=1, 2)	1	2
Kleb. pneumoniae (MIC: 0.06) - Favorable (n=9, 8)	7	8
Kleb.pneumoniae (MIC: 0.12) -Favorable(n=11, 10)	9	7
Kleb. pneumoniae (MIC: 0.25) - Favorable(n=4, 10)	1	3
Kleb. pneumoniae (MIC: 0.5) - Favorable (n=8, 16)	6	11
Kleb. pneumoniae (MIC: 1) - Favorable (n=8, 5)	6	3
Kleb. pneumoniae (MIC: 2) - Favorable (n= 2, 4)	2	0
Kleb. pneumoniae (MIC: 4) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: 8) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: 16) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: 32) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: >32) - Favorable (n=0, 1)	0	1
Proteus mirabilis (MIC:<=0.008)- Favorable(n=0,0)	0	0
Proteus mirabilis (MIC: 0.015)- Favorable (n=1,1)	1	0
Proteus mirabilis (MIC: 0.03)- Favorable(n=10, 5)	10	3
Proteus mirabilis (MIC: 0.06)- Favorable (n=6,6)	5	5
Proteus mirabilis (MIC: 0.12)- Favorable (n=0,0)	0	0
Proteus mirabilis (MIC: 0.25)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 0.5)- Favorable (n=0,1)	0	1
Proteus mirabilis (MIC: 1)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 2)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 4)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 8)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 16)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 32)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: >32)- Favorable (n=0, 0)	0	0
Entero. cloacae (MIC: <=0.008)- Favorable(n= 0,0)	0	0
Entero. cloacae (MIC: 0.015)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 0.03)- Favorable (n= 1,0)	1	0
Entero. cloacae (MIC: 0.06)- Favorable (n= 0, 1)	0	1
Entero. cloacae (MIC: 0.12)- Favorable (n= 3,2)	2	2
Entero. cloacae (MIC: 0.25)- Favorable (n= 1,4)	0	1
Entero. cloacae (MIC: 0.5)- Favorable (n= 1,1)	0	1
Entero. cloacae (MIC: 1)- Favorable (n= 2,5)	1	4
Entero. cloacae (MIC: 2)- Favorable (n= 1,0)	1	0
Entero. cloacae (MIC: 4)- Favorable (n= 2,0)	1	0
Entero. cloacae (MIC: 8)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 16)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 32)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: >32)- Favorable (n= 0,0)	0	0
P.aeruginosa (MIC: <=0.008) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.015) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.03) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.06) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.12) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.25) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.5) - Favorable (n=0,2)	0	2
P.aeruginosa (MIC: 1) - Favorable (n=1,4)	1	2
P.aeruginosa (MIC: 2) - Favorable (n=5,5)	5	5
P.aeruginosa (MIC: 4) - Favorable (n=7,6)	3	4
P.aeruginosa (MIC: 8) - Favorable (n=2,2)	1	1
P.aeruginosa (MIC: 16) - Favorable (n=1,1)	0	1
P.aeruginosa (MIC: 32) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: >32) - Favorable (n=2,0)	2	0

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at TOC by CAZ AVI MIC for baseline pathogen (Extended ME at TOC analysis set)

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End point title

Per-pathogen microbiological response at TOC by CAZ AVI MIC for baseline pathogen (Extended ME at TOC analysis set)

End point description

Per pathogen microbiological response at TOC by CAZ-AVI MIC for baseline pathogen in the Extended ME at TOC analysis set

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	292	311
Units: Participant
E. coli (MIC: <=0.008) - Favorable (n=4,4)	2	4
E. coli (MIC: 0.015) - Favorable (n=5, 6)	5	5
E. coli (MIC: 0.03) - Favorable (n=18, 21)	17	17
E. coli (MIC: 0.06) - Favorable (n=95, 111)	83	94
E. coli (MIC: 0.12) - Favorable (n=68, 54)	56	40
E. coli (MIC: 0.25) - Favorable (n=19, 18)	13	8
E. coli (MIC: 0.5) - Favorable (n=2, 5)	2	2
E. coli (MIC: 1) - Favorable (n=2, 0)	1	0
E. coli (MIC: 2) - Favorable (n=1, 0)	1	0
E. coli (MIC: 4) - Favorable (n=0, 0)	0	0
E. coli (MIC: 8) - Favorable (n=0, 0)	0	0
E. coli (MIC: 16) - Favorable (n=0, 0)	0	0
E. coli (MIC: 32) - Favorable (n=0, 0)	0	0
E. coli (MIC: >32) - Favorable (n=0, 0)	0	0
Kleb.pneumoniae (MIC: <=0.008)-Favorable(n=0, 0)	0	0
Kleb. pneumoniae (MIC: 0.015) - Favorable(n=1, 0)	1	0
Kleb. pneumoniae (MIC: 0.03) - Favorable (n=1, 2)	1	2
Kleb. pneumoniae (MIC: 0.06) - Favorable (n=5, 7)	4	7
Kleb.pneumoniae (MIC: 0.12) -Favorable(n=8, 9)	7	6
Kleb. pneumoniae (MIC: 0.25) - Favorable (n=3, 7)	1	2
Kleb. pneumoniae (MIC: 0.5) - Favorable (n=6, 11)	4	8
Kleb. pneumoniae (MIC: 1) - Favorable (n=6, 4)	6	3
Kleb. pneumoniae (MIC: 2) - Favorable (n= 2, 1)	2	0
Kleb. pneumoniae (MIC: 4) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: 8) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: 16) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: 32) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: >32) - Favorable (n=0, 1)	0	1
Proteus mirabilis (MIC:<=0.008)- Favorable(n=0,0)	0	0
Proteus mirabilis (MIC: 0.015)- Favorable (n=1,0)	1	0
Proteus mirabilis (MIC: 0.03)- Favorable (n=9, 2)	9	0
Proteus mirabilis (MIC: 0.06)- Favorable (n=4,5)	4	4
Proteus mirabilis (MIC: 0.12)- Favorable (n=0,0)	0	0
Proteus mirabilis (MIC: 0.25)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 0.5)- Favorable (n=0,0)	0	0
Proteus mirabilis (MIC: 1)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 2)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 4)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 8)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 16)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 32)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: >32)- Favorable (n=0, 0)	0	0
Entero. cloacae (MIC: <=0.008)- Favorable(n= 0,0)	0	0
Entero. cloacae (MIC: 0.015)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 0.03)- Favorable (n= 1,0)	1	0
Entero. cloacae (MIC: 0.06)- Favorable (n= 0, 1)	0	1
Entero. cloacae (MIC: 0.12)- Favorable (n= 1,2)	1	2
Entero. cloacae (MIC: 0.25)- Favorable (n= 0,3)	0	0
Entero. cloacae (MIC: 0.5)- Favorable (n= 1,1)	0	1
Entero. cloacae (MIC: 1)- Favorable (n= 1,4)	1	4
Entero. cloacae (MIC: 2)- Favorable (n= 1,0)	1	0
Entero. cloacae (MIC: 4)- Favorable (n= 2,0)	1	0
Entero. cloacae (MIC: 8)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 16)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 32)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: >32)- Favorable (n= 0,0)	0	0
P.aeruginosa (MIC: <=0.008) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.015) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.03) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.06) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.12) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.25) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.5) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 1) - Favorable (n=1,4)	1	2
P.aeruginosa (MIC: 2) - Favorable (n=4,5)	4	5
P.aeruginosa (MIC: 4) - Favorable (n=5,6)	1	4
P.aeruginosa (MIC: 8) - Favorable (n=2,2)	1	1
P.aeruginosa (MIC: 16) - Favorable (n=0,1)	0	1
P.aeruginosa (MIC: 32) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: >32) - Favorable (n=1,0)	1	0

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at TOC by CAZ AVI MIC for baseline pathogen (ME at TOC analysis set)

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End point title

Per-pathogen microbiological response at TOC by CAZ AVI MIC for baseline pathogen (ME at TOC analysis set)

End point description

Per pathogen microbiological response at TOC by CAZ-AVI MIC for baseline pathogen in the ME at TOC analysis set

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	286	298
Units: Participant
E. coli (MIC: <=0.008) - Favorable (n=4,4)	2	4
E. coli (MIC: 0.015) - Favorable (n=5, 6)	5	5
E. coli (MIC: 0.03) - Favorable (n=18, 21)	17	17
E. coli (MIC: 0.06) - Favorable (n=95, 111)	83	94
E. coli (MIC: 0.12) - Favorable (n=68, 54)	56	40
E. coli (MIC: 0.25) - Favorable (n=19, 18)	13	8
E. coli (MIC: 0.5) - Favorable (n=2, 5)	2	2
E. coli (MIC: 1) - Favorable (n=2, 0)	1	0
E. coli (MIC: 2) - Favorable (n=1, 0)	1	0
E. coli (MIC: 4) - Favorable (n=0, 0)	0	0
E. coli (MIC: 8) - Favorable (n=0, 0)	0	0
E. coli (MIC: 16) - Favorable (n=0, 0)	0	0
E. coli (MIC: 32) - Favorable (n=0, 0)	0	0
E. coli (MIC: >32) - Favorable (n=0, 0)	0	0
Kleb.pneumoniae (MIC: <=0.008)-Favorable(n=0, 0)	0	0
Kleb. pneumoniae (MIC: 0.015) -Favorable (n=1, 0)	1	0
Kleb. pneumoniae (MIC: 0.03) - Favorable (n=1, 2)	1	2
Kleb. pneumoniae (MIC: 0.06) - Favorable (n=5, 7)	4	7
Kleb.pneumoniae (MIC: 0.12) -Favorable(n=8, 9)	7	6
Kleb. pneumoniae (MIC: 0.25) - Favorable (n=3, 7)	1	2
Kleb. pneumoniae (MIC: 0.5) - Favorable (n=6, 11)	4	8
Kleb. pneumoniae (MIC: 1) - Favorable (n=5, 4)	5	3
Kleb. pneumoniae (MIC: 2) - Favorable (n= 2, 1)	2	0
Kleb. pneumoniae (MIC: 4) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: 8) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: 16) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: 32) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: >32) - Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC:<=0.008)- Favorable(n=0,0)	0	0
Proteus mirabilis (MIC: 0.015)- Favorable (n=1,0)	1	0
Proteus mirabilis (MIC: 0.03)- Favorable (n=9, 2)	9	0
Proteus mirabilis (MIC: 0.06)- Favorable (n=4,5)	4	4
Proteus mirabilis (MIC: 0.12)- Favorable (n=0,0)	0	0
Proteus mirabilis (MIC: 0.25)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 0.5)- Favorable (n=0,0)	0	0
Proteus mirabilis (MIC: 1)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 2)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 4)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 8)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 16)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 32)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: >32)- Favorable (n=0, 0)	0	0
Entero. cloacae (MIC: <=0.008)- Favorable(n= 0,0)	0	0
Entero. cloacae (MIC: 0.015)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 0.03)- Favorable (n= 1,0)	1	0
Entero. cloacae (MIC: 0.06)- Favorable (n= 0, 1)	0	1
Entero. cloacae (MIC: 0.12)- Favorable (n= 1,2)	1	2
Entero. cloacae (MIC: 0.25)- Favorable (n= 0,3)	0	0
Entero. cloacae (MIC: 0.5)- Favorable (n= 1,1)	0	1
Entero. cloacae (MIC: 1)- Favorable (n= 1,4)	1	4
Entero. cloacae (MIC: 2)- Favorable (n= 1,0)	1	0
Entero. cloacae (MIC: 4)- Favorable (n= 2,0)	1	0
Entero. cloacae (MIC: 8)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 16)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 32)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: >32)- Favorable (n= 0,0)	0	0
P.aeruginosa (MIC: <=0.008) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.015) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.03) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.06) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.12) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.25) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.5) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 1) - Favorable (n=1,4)	1	2
P.aeruginosa (MIC: 2) - Favorable (n=4,4)	4	4
P.aeruginosa (MIC: 4) - Favorable (n=3,4)	1	3
P.aeruginosa (MIC: 8) - Favorable (n=1,1)	1	0
P.aeruginosa (MIC: 16) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 32) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: >32) - Favorable (n=0,0)	0	0

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen (mMITT analysis set)

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End point title

Per-pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen (mMITT analysis set)

End point description

Per pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen in the mMITT analysis set

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	393	417
Units: Participant
E. coli (MIC: <=0.008) - Favorable (n=1, 3)	1	3
E. coli (MIC: 0.015) - Favorable (n=160, 160)	127	119
E. coli (MIC: 0.03) - Favorable (n=112, 123)	89	86
E. coli (MIC: 0.06) - Favorable (n=14, 10)	10	4
E. coli (MIC: 0.12) - Favorable (n=3, 3)	1	2
E. coli (MIC: 0.25) - Favorable (n=1, 0)	1	0
E. coli (MIC: 0.5) - Favorable (n=0,0)	0	0
E. coli (MIC: 1) - Favorable (n=0, 0)	0	0
E. coli (MIC: 2) - Favorable (n=0, 0)	0	0
E. coli (MIC: 4) - Favorable (n=0, 0)	0	0
E. coli (MIC: 8) - Favorable (n=0, 0)	0	0
E. coli (MIC: 16) - Favorable (n=0, 0)	0	0
E. coli (MIC: >16) - Favorable (n=0, 0)	0	0
Kleb.pneumoniae (MIC: <=0.008)-Favorable(n=0, 0)	0	0
Kleb. pneumoniae (MIC: 0.015) - Favorable(n=1, 3)	1	2
Kleb. pneumoniae (MIC: 0.03)-Favorable (n=22, 27)	16	21
Kleb. pneumoniae (MIC: 0.06)- Favorable(n=11, 16)	10	7
Kleb.pneumoniae (MIC: 0.12) -Favorable(n=4,4)	2	2
Kleb. pneumoniae (MIC: 0.25) - Favorable (n=2,3)	1	2
Kleb. pneumoniae (MIC: 0.5) - Favorable (n=2, 1)	1	0
Kleb. pneumoniae (MIC: 1) - Favorable (n=1, 0)	1	0
Kleb. pneumoniae (MIC: 2) - Favorable (n= 0, 0)	0	0
Kleb. pneumoniae (MIC: 4) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: 8) - Favorable (n=0, 1)	0	1
Kleb. pneumoniae (MIC: 16) - Favorable (n=0, 1)	0	0
Kleb. pneumoniae (MIC: >16) - Favorable (n=1, 0)	1	0
Proteus mirabilis (MIC:<=0.008)- Favorable(n=0,0)	0	0
Proteus mirabilis (MIC: 0.015)- Favorable (n=0,0)	0	0
Proteus mirabilis (MIC: 0.03)- Favorable (n=1, 0)	1	0
Proteus mirabilis (MIC: 0.06)- Favorable (n=2,2)	2	1
Proteus mirabilis (MIC: 0.12)- Favorable (n=6,5)	5	4
Proteus mirabilis (MIC: 0.25)- Favorable (n=6, 4)	6	2
Proteus mirabilis (MIC: 0.5)- Favorable (n=2,2)	2	2
Proteus mirabilis (MIC: 1)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 2)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 4)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 8)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 16)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: >16)- Favorable (n=0, 0)	0	0
Entero. cloacae (MIC: <=0.008)- Favorable(n= 0,0)	0	0
Entero. cloacae (MIC: 0.015)- Favorable (n= 3,1)	2	1
Entero. cloacae (MIC: 0.03)- Favorable (n= 1,5)	1	2
Entero. cloacae (MIC: 0.06)- Favorable (n= 3, 1)	1	1
Entero. cloacae (MIC: 0.12)- Favorable (n= 0, 4)	0	4
Entero. cloacae (MIC: 0.25)- Favorable (n= 0,1)	0	0
Entero. cloacae (MIC: 0.5)- Favorable (n= 4,0)	2	0
Entero. cloacae (MIC: 1)- Favorable (n= 0,1)	0	1
Entero. cloacae (MIC: 2)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 4)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 8)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 16)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: >16)- Favorable (n= 0,0)	0	0
P.aeruginosa (MIC: <=0.008) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.015) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.03) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.06) - Favorable (n=2,3)	2	3
P.aeruginosa (MIC: 0.12) - Favorable (n=2,2)	1	2
P.aeruginosa (MIC: 0.25) - Favorable (n=2,5)	2	2
P.aeruginosa (MIC: 0.5) - Favorable (n=2,1)	2	1
P.aeruginosa (MIC: 1) - Favorable (n=1,4)	0	3
P.aeruginosa (MIC: 2) - Favorable (n=1,0)	1	0
P.aeruginosa (MIC: 4) - Favorable (n=2,2)	1	1
P.aeruginosa (MIC: 8) - Favorable (n=2,1)	1	1
P.aeruginosa (MIC: 16) - Favorable (n=2,1)	0	1
P.aeruginosa (MIC: >16) - Favorable (n=2,1)	2	1

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen (Extended ME at TOC analysis set)

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End point title

Per-pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen (Extended ME at TOC analysis set)

End point description

Per pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen in the Extended ME at TOC analysis set

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	292	311
Units: Participant
E. coli (MIC: <=0.008) - Favorable (n=1,1)	1	1
E. coli (MIC: 0.015) - Favorable (n=122, 119)	106	95
E. coli (MIC: 0.03) - Favorable (n=79, 89)	64	70
E. coli (MIC: 0.06) - Favorable (n=10, 8)	7	3
E. coli (MIC: 0.12) - Favorable (n=1, 2)	1	1
E. coli (MIC: 0.25) - Favorable (n=1, 0)	1	0
E. coli (MIC: 0.5) - Favorable (n=0, 0)	0	0
E. coli (MIC: 1) - Favorable (n=0, 0)	0	0
E. coli (MIC: 2) - Favorable (n=0, 0)	0	0
E. coli (MIC: 4) - Favorable (n=0, 0)	0	0
E. coli (MIC: 8) - Favorable (n=0, 0)	0	0
E. coli (MIC: 16) - Favorable (n=0, 0)	0	0
E. coli (MIC: >16) - Favorable (n=0, 0)	0	0
Kleb.pneumoniae (MIC: <=0.008)-Favorable(n=0, 0)	0	0
Kleb. pneumoniae (MIC: 0.015) - Favorable(n=1, 2)	1	1
Kleb. pneumoniae (MIC:0.03) - Favorable(n=15, 23)	12	18
Kleb. pneumoniae (MIC: 0.06) - Favorable(n=8, 12)	7	6
Kleb.pneumoniae (MIC: 0.12) -Favorable(n=3, 2)	2	2
Kleb. pneumoniae (MIC: 0.25) - Favorable (n=2, 2)	1	1
Kleb. pneumoniae (MIC: 0.5) - Favorable (n=1, 0)	1	0
Kleb. pneumoniae (MIC: 1) - Favorable (n=1, 0)	1	0
Kleb. pneumoniae (MIC: 2) - Favorable (n= 0,0)	0	0
Kleb. pneumoniae (MIC: 4) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: 8) - Favorable (n=0, 1)	0	1
Kleb. pneumoniae (MIC: 16) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: >16) - Favorable (n=1, 0)	1	0
Proteus mirabilis (MIC:<=0.008)- Favorable(n=0,0)	0	0
Proteus mirabilis (MIC: 0.015)- Favorable (n=0,0)	0	0
Proteus mirabilis (MIC: 0.03)- Favorable (n=1,0)	1	0
Proteus mirabilis (MIC: 0.06)- Favorable (n=2,2)	2	1
Proteus mirabilis (MIC: 0.12)- Favorable (n=4,2)	4	2
Proteus mirabilis (MIC: 0.25)- Favorable (n=6, 3)	6	1
Proteus mirabilis (MIC: 0.5)- Favorable (n=1,0)	1	0
Proteus mirabilis (MIC: 1)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 2)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 4)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 8)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 16)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: >16)- Favorable (n=0, 0)	0	0
Entero. cloacae (MIC: <=0.008)- Favorable(n= 0,0)	0	0
Entero. cloacae (MIC: 0.015)- Favorable (n= 1,1)	1	1
Entero. cloacae (MIC: 0.03)- Favorable (n= 1,4)	1	1
Entero. cloacae (MIC: 0.06)- Favorable (n= 2, 1)	1	1
Entero. cloacae (MIC: 0.12)- Favorable (n= 0,4)	0	4
Entero. cloacae (MIC: 0.25)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 0.5)- Favorable (n= 3,0)	2	0
Entero. cloacae (MIC: 1)- Favorable (n= 0,1)	0	1
Entero. cloacae (MIC: 2)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 4)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 8)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 16)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: >16)- Favorable (n= 0,0)	0	0
P.aeruginosa (MIC: <=0.008) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.015) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.03) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.06) - Favorable (n=2,3)	2	3
P.aeruginosa (MIC: 0.12) - Favorable (n=1,2)	0	2
P.aeruginosa (MIC: 0.25) - Favorable (n=2,4)	2	1
P.aeruginosa (MIC: 0.5) - Favorable (n=2,1)	2	1
P.aeruginosa (MIC: 1) - Favorable (n=1,3)	0	2
P.aeruginosa (MIC: 2) - Favorable (n=1,0)	1	0
P.aeruginosa (MIC: 4) - Favorable (n=0,2)	0	1
P.aeruginosa (MIC: 8) - Favorable (n=1,1)	0	1
P.aeruginosa (MIC: 16) - Favorable (n=2,1)	0	1
P.aeruginosa (MIC: >16) - Favorable (n=1,1)	1	1

No statistical analyses for this end point

Secondary: Per-pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen (ME at TOC analysis set)

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End point title

Per-pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen (ME at TOC analysis set)

End point description

Per pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen in the ME at TOC analysis set

End point type

Secondary

End point timeframe

At TOC visit. TOC visit is 21 to 25 days from Randomization

End point values	CAZ-AVI	Doripenem
Number of subjects analysed	286	298
Units: Participant
E. coli (MIC: <=0.008) - Favorable (n=1,1)	1	1
E. coli (MIC: 0.015) - Favorable (n=122, 119)	106	95
E. coli (MIC: 0.03) - Favorable (n=79, 89)	64	70
E. coli (MIC: 0.06) - Favorable (n=10, 8)	7	3
E. coli (MIC: 0.12) - Favorable (n=1,2)	1	1
E. coli (MIC: 0.25) - Favorable (n=1,0)	1	0
E. coli (MIC: 0.5) - Favorable (n=0,0)	0	0
E. coli (MIC: 1) - Favorable (n=0, 0)	0	0
E. coli (MIC: 2) - Favorable (n=0, 0)	0	0
E. coli (MIC: 4) - Favorable (n=0, 0)	0	0
E. coli (MIC: 8) - Favorable (n=0, 0)	0	0
E. coli (MIC: 16) - Favorable (n=0, 0)	0	0
E. coli (MIC: >16) - Favorable (n=0, 0)	0	0
Kleb.pneumoniae (MIC: <=0.008)-Favorable(n=0, 0)	0	0
Kleb. pneumoniae (MIC: 0.015) - Favorable(n=1, 2)	1	1
Kleb. pneumoniae (MIC:0.03) - Favorable(n=15, 23)	12	18
Kleb. pneumoniae (MIC: 0.06) - Favorable(n=8, 12)	7	6
Kleb.pneumoniae (MIC: 0.12) -Favorable(n=3,2)	2	2
Kleb. pneumoniae (MIC: 0.25) - Favorable (n=2, 2)	1	1
Kleb. pneumoniae (MIC: 0.5) - Favorable (n=1,0)	1	0
Kleb. pneumoniae (MIC: 1) - Favorable (n=1, 0)	1	0
Kleb. pneumoniae (MIC: 2) - Favorable (n= 0,0)	0	0
Kleb. pneumoniae (MIC: 4) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: 8) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: 16) - Favorable (n=0, 0)	0	0
Kleb. pneumoniae (MIC: >16) - Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC:<=0.008)- Favorable(n=0,0)	0	0
Proteus mirabilis (MIC: 0.015)- Favorable (n=0,0)	0	0
Proteus mirabilis (MIC: 0.03)- Favorable (n=1, 0)	1	0
Proteus mirabilis (MIC: 0.06)- Favorable (n=2,2)	2	1
Proteus mirabilis (MIC: 0.12)- Favorable (n=4,2)	4	2
Proteus mirabilis (MIC: 0.25)- Favorable (n=6, 3)	6	1
Proteus mirabilis (MIC: 0.5)- Favorable (n=1,0)	1	0
Proteus mirabilis (MIC: 1)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 2)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 4)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 8)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: 16)- Favorable (n=0, 0)	0	0
Proteus mirabilis (MIC: >16)- Favorable (n=0, 0)	0	0
Entero. cloacae (MIC: <=0.008)- Favorable(n= 0,0)	0	0
Entero. cloacae (MIC: 0.015)- Favorable (n= 1,1)	1	1
Entero. cloacae (MIC: 0.03)- Favorable (n= 1,4)	1	1
Entero. cloacae (MIC: 0.06)- Favorable (n= 2, 1)	1	1
Entero. cloacae (MIC: 0.12)- Favorable (n= 0,4)	0	4
Entero. cloacae (MIC: 0.25)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 0.5)- Favorable (n= 3,0)	2	0
Entero. cloacae (MIC: 1)- Favorable (n= 0,1)	0	1
Entero. cloacae (MIC: 2)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 4)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 8)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: 16)- Favorable (n= 0,0)	0	0
Entero. cloacae (MIC: >16)- Favorable (n= 0,0)	0	0
P.aeruginosa (MIC: <=0.008) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.015) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.03) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 0.06) - Favorable (n=2,3)	2	3
P.aeruginosa (MIC: 0.12) - Favorable (n=1,2)	0	2
P.aeruginosa (MIC: 0.25) - Favorable (n=2,4)	2	1
P.aeruginosa (MIC: 0.5) - Favorable (n=2,1)	2	1
P.aeruginosa (MIC: 1) - Favorable (n=1,3)	0	2
P.aeruginosa (MIC: 2) - Favorable (n=1,0)	1	0
P.aeruginosa (MIC: 4) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 8) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: 16) - Favorable (n=0,0)	0	0
P.aeruginosa (MIC: >16) - Favorable (n=0,0)	0	0

No statistical analyses for this end point

Secondary: Plasma concentrations for ceftazidime within 15 minutes before/after dose (PK analysis set)

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End point title

Plasma concentrations for ceftazidime within 15 minutes before/after dose (PK analysis set) ^[4]

End point description

Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.

End point type

Secondary

End point timeframe

within 15 minutes before/after dose

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The marketed treatment ‘Doripenem’ has been selected as the comparator in this protocol. However, the PK profile has already been established for the marketed treatment ‘Doripenem’. Therefore, the PK analysis is only performed on the investigational product ‘CAZ-AVI’ in this protocol.

End point values	CAZ-AVI
Number of subjects analysed	480
Units: Participant
geometric mean (full range (min-max))	65481.2 (1260 to 3190000)

No statistical analyses for this end point

Secondary: Plasma concentrations for ceftazidime between 30 to 90 minutes after dose(PK analysis set)

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End point title

Plasma concentrations for ceftazidime between 30 to 90 minutes after dose(PK analysis set) ^[5]

End point description

Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.

End point type

Secondary

End point timeframe

Between 30 to 90 minutes after dose

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The marketed treatment ‘Doripenem’ has been selected as the comparator in this protocol. However, the PK profile has already been established for the marketed treatment ‘Doripenem’. Therefore, the PK analysis is only performed on the investigational product ‘CAZ-AVI’ in this protocol.

End point values	CAZ-AVI
Number of subjects analysed	483
Units: Participant
geometric mean (full range (min-max))	47575.1 (749 to 414000)

No statistical analyses for this end point

Secondary: Plasma concentrations for avibactam within 15 minutes before/after dose (PK analysis set)

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End point title

Plasma concentrations for avibactam within 15 minutes before/after dose (PK analysis set) ^[6]

End point description

Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.

End point type

Secondary

End point timeframe

within 15 minutes before/after dose

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The marketed treatment ‘Doripenem’ has been selected as the comparator in this protocol. However, the PK profile has already been established for the marketed treatment ‘Doripenem’. Therefore, the PK analysis is only performed on the investigational product ‘CAZ-AVI’ in this protocol.

End point values	CAZ-AVI
Number of subjects analysed	489
Units: Participant
geometric mean (full range (min-max))	9307.3 (125 to 1780000)

No statistical analyses for this end point

Secondary: Plasma concentrations for ceftazidime between 300 to 360 minutes after dose(PK analysis set)

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End point title

Plasma concentrations for ceftazidime between 300 to 360 minutes after dose(PK analysis set) ^[7]

End point description

Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.

End point type

Secondary

End point timeframe

Between 300 to 360 minutes after dose

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The marketed treatment ‘Doripenem’ has been selected as the comparator in this protocol. However, the PK profile has already been established for the marketed treatment ‘Doripenem’. Therefore, the PK analysis is only performed on the investigational product ‘CAZ-AVI’ in this protocol.

End point values	CAZ-AVI
Number of subjects analysed	481
Units: Participant
geometric mean (full range (min-max))	16959.6 (156 to 1640000)

No statistical analyses for this end point

Secondary: Plasma concentrations for avibactam between 30 to 90 minutes after dose(PK analysis set)

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End point title

Plasma concentrations for avibactam between 30 to 90 minutes after dose(PK analysis set) ^[8]

End point description

Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.

End point type

Secondary

End point timeframe

Between 30 to 90 minutes after dose

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The marketed treatment ‘Doripenem’ has been selected as the comparator in this protocol. However, the PK profile has already been established for the marketed treatment ‘Doripenem’. Therefore, the PK analysis is only performed on the investigational product ‘CAZ-AVI’ in this protocol.

End point values	CAZ-AVI
Number of subjects analysed	490
Units: Participant
geometric mean (full range (min-max))	6587.2 (113 to 105000)

No statistical analyses for this end point

Secondary: Plasma concentrations for avibactam between 300 to 360 minutes after dose(PK analysis set)

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End point title

Plasma concentrations for avibactam between 300 to 360 minutes after dose(PK analysis set) ^[9]

End point description

Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.

End point type

Secondary

End point timeframe

Between 300 to 360 minutes after dose

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The marketed treatment ‘Doripenem’ has been selected as the comparator in this protocol. However, the PK profile has already been established for the marketed treatment ‘Doripenem’. Therefore, the PK analysis is only performed on the investigational product ‘CAZ-AVI’ in this protocol.

End point values	CAZ-AVI
Number of subjects analysed	488
Units: Participant
geometric mean (full range (min-max))	1883.2 (26 to 336000)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Includes the AEs with an onset date and time on or after the date and time of first dose and up to and including the late follow-up (LFU) visit

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Doripenem

Reporting group description

Doripenem treatment group

Reporting group title

CAZ-AVI

Reporting group description

Ceftazidime-avibactam treatment group

Serious adverse events	Doripenem	CAZ-AVI
Total subjects affected by serious adverse events
subjects affected / exposed	12 / 509 (2.36%)	21 / 511 (4.11%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 509 (0.20%)	0 / 511 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Post procedural haemorrhage
subjects affected / exposed	1 / 509 (0.20%)	0 / 511 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural haemorrhage
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	1 / 509 (0.20%)	0 / 511 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Thrombophlebitis superficial
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 509 (0.00%)	2 / 511 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	1 / 509 (0.20%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 509 (0.20%)	0 / 511 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery aneurysm
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Hypoglycaemic seizure
subjects affected / exposed	1 / 509 (0.20%)	0 / 511 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tension headache
subjects affected / exposed	1 / 509 (0.20%)	0 / 511 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 509 (0.20%)	0 / 511 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterovesical fistula
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Retroperitoneal haematoma
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	1 / 509 (0.20%)	0 / 511 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperventilation
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Calculus ureteric
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 509 (0.00%)	3 / 511 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure chronic
subjects affected / exposed	1 / 509 (0.20%)	0 / 511 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Spinal pain
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 509 (0.20%)	0 / 511 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic hepatitis C
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 509 (0.00%)	1 / 511 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Orchitis
subjects affected / exposed	1 / 509 (0.20%)	0 / 511 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 509 (0.20%)	0 / 511 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 509 (0.20%)	0 / 511 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	Doripenem	CAZ-AVI
Total subjects affected by non serious adverse events
subjects affected / exposed	57 / 509 (11.20%)	67 / 511 (13.11%)
Nervous system disorders
Headache
subjects affected / exposed	40 / 509 (7.86%)	38 / 511 (7.44%)
occurrences all number	41	41
Gastrointestinal disorders
Constipation
subjects affected / exposed	7 / 509 (1.38%)	11 / 511 (2.15%)
occurrences all number	8	11
Diarrhoea
subjects affected / exposed	6 / 509 (1.18%)	13 / 511 (2.54%)
occurrences all number	6	14
Nausea
subjects affected / exposed	10 / 509 (1.96%)	15 / 511 (2.94%)
occurrences all number	10	16

More information

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Were there any global substantial amendments to the protocol? Yes

09 Aug 2013

Combined the 2 protocols (D4280C00002 and D4280C00004) into a single study database

09 Aug 2013

All data analyses based on data from the combined studies (D4280C00002 and D4280C00004)

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Patient-reported symptomatic response at day 5 (mMITT analysis set): non-inferiority hypothesis test

Primary: Patient-reported symptomatic response at day 5 (mMITT analysis set): non-inferiority hypothesis test

Primary: Combined patient-reported symptomatic and microbiological response at TOC (mMITT analysis set): non-inferiority hypothesis test

Primary: Combined patient-reported symptomatic and microbiological response at TOC (mMITT analysis set): non-inferiority hypothesis test

Primary: Per-patient microbiological response at TOC (mMITT analysis set): non-inferiority hypothesis test

Primary: Per-patient microbiological response at TOC (mMITT analysis set): non-inferiority hypothesis test

Secondary: Per-patient microbiological response at EOT (IV) (mMITT analysis set)

Secondary: Per-patient microbiological response at EOT (IV) (mMITT analysis set)

Secondary: Per-patient microbiological response at LFU (mMITT analysis set)

Secondary: Per-patient microbiological response at LFU (mMITT analysis set)

Secondary: Per-patient microbiological response at EOT (IV) (ME at EOT (IV) analysis set)

Secondary: Per-patient microbiological response at EOT (IV) (ME at EOT (IV) analysis set)

Secondary: Per-patient microbiological response at TOC (ME at TOC analysis set)

Secondary: Per-patient microbiological response at TOC (ME at TOC analysis set)

Secondary: Per-patient microbiological response at LFU (ME at LFU analysis set)

Secondary: Per-patient microbiological response at LFU (ME at LFU analysis set)

Secondary: Per-patient microbiological response at EOT (IV) (Extended ME at EOT (IV) analysis set)

Secondary: Per-patient microbiological response at EOT (IV) (Extended ME at EOT (IV) analysis set)

Secondary: Per-patient microbiological response at TOC (Extended ME at TOC analysis set)

Secondary: Per-patient microbiological response at TOC (Extended ME at TOC analysis set)

Secondary: Per-patient microbiological response at LFU (Extended ME at LFU analysis set)

Secondary: Per-patient microbiological response at LFU (Extended ME at LFU analysis set)

Secondary: Investigator determined clinical response at EOT (IV) (mMITT analysis set)

Secondary: Investigator determined clinical response at EOT (IV) (mMITT analysis set)

Secondary: Investigator determined clinical response at TOC (mMITT analysis set)

Secondary: Investigator determined clinical response at TOC (mMITT analysis set)

Secondary: Investigator determined clinical response at LFU (mMITT analysis set)

Secondary: Investigator determined clinical response at LFU (mMITT analysis set)

Secondary: Investigator determined clinical response at EOT (IV) (ME at EOT (IV) analysis set)

Secondary: Investigator determined clinical response at EOT (IV) (ME at EOT (IV) analysis set)

Secondary: Investigator determined clinical response at TOC (ME at TOC analysis set)

Secondary: Investigator determined clinical response at TOC (ME at TOC analysis set)

Secondary: Investigator determined clinical response at LFU (ME at LFU analysis set)

Secondary: Investigator determined clinical response at LFU (ME at LFU analysis set)

Secondary: Investigator determined clinical response at EOT (IV) (Extended ME at EOT (IV) analysis set)

Secondary: Investigator determined clinical response at EOT (IV) (Extended ME at EOT (IV) analysis set)

Secondary: Investigator determined clinical response at TOC (Extended ME at TOC analysis set)

Secondary: Investigator determined clinical response at TOC (Extended ME at TOC analysis set)

Secondary: Investigator determined clinical response at LFU (Extended ME at LFU analysis set)

Secondary: Investigator determined clinical response at LFU (Extended ME at LFU analysis set)

Secondary: Investigator determined clinical response at EOT (IV) (CE at EOT (IV) analysis set)

Secondary: Investigator determined clinical response at EOT (IV) (CE at EOT (IV) analysis set)

Secondary: Investigator determined clinical response at TOC (CE at TOC analysis set)

Secondary: Investigator determined clinical response at TOC (CE at TOC analysis set)

Secondary: Investigator determined clinical response at LFU (CE at LFU analysis set)

Secondary: Investigator determined clinical response at LFU (CE at LFU analysis set)

Secondary: Investigator determined clinical response at TOC for patients infected by ceftazidime-resistant Gram-negative pathogen (mMITT analysis set)

Secondary: Investigator determined clinical response at TOC for patients infected by ceftazidime-resistant Gram-negative pathogen (mMITT analysis set)

Secondary: Investigator determined clinical response at TOC for patients infected by ceftazidime-resistant Gram-negative pathogen (ME at TOC analysis set)

Secondary: Investigator determined clinical response at TOC for patients infected by ceftazidime-resistant Gram-negative pathogen (ME at TOC analysis set)

Secondary: Investigator determined clinical response at TOC for patients infected by ceftazidime-resistant Gram-negative pathogen (Extended ME at TOC analysis set)

Secondary: Investigator determined clinical response at TOC for patients infected by ceftazidime-resistant Gram-negative pathogen (Extended ME at TOC analysis set)

Secondary: Per-patient microbiological response at TOC in patients infected by ceftazidime-resistant Gram-negative pathogen (mMITT analysis set)

Secondary: Per-patient microbiological response at TOC in patients infected by ceftazidime-resistant Gram-negative pathogen (mMITT analysis set)

Secondary: Per-patient microbiological response at TOC in patients infected by ceftazidime-resistant Gram-negative pathogen (ME at TOC analysis set)

Secondary: Per-patient microbiological response at TOC in patients infected by ceftazidime-resistant Gram-negative pathogen (ME at TOC analysis set)

Secondary: Per-patient microbiological response at TOC in patients infected by ceftazidime-resistant Gram-negative pathogen (Extended ME at TOC analysis set)

Secondary: Per-patient microbiological response at TOC in patients infected by ceftazidime-resistant Gram-negative pathogen (Extended ME at TOC analysis set)

Secondary: Time to first defervescence while on IV study therapy (mMITT analysis set)

Secondary: Time to first defervescence while on IV study therapy (mMITT analysis set)

Secondary: Time to first defervescence while on IV study therapy (ME at TOC analysis set)

Secondary: Time to first defervescence while on IV study therapy (ME at TOC analysis set)

Secondary: Time to first defervescence while on IV study therapy (Extended ME at TOC analysis set)

Secondary: Time to first defervescence while on IV study therapy (Extended ME at TOC analysis set)

Secondary: Time to first defervescence while on IV study therapy (CE at TOC analysis set)

Secondary: Time to first defervescence while on IV study therapy (CE at TOC analysis set)

Secondary: Per-pathogen microbiological response at EOT (IV) for baseline pathogen (mMITT analysis set)

Secondary: Per-pathogen microbiological response at EOT (IV) for baseline pathogen (mMITT analysis set)

Secondary: Per-pathogen microbiological response at TOC for baseline pathogen (mMITT analysis set)

Secondary: Per-pathogen microbiological response at TOC for baseline pathogen (mMITT analysis set)

Secondary: Per-pathogen microbiological response at LFU for baseline pathogen (mMITT analysis set)