A Phase 3, Multi-Center, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Cefepime/Nacubactam or Aztreonam/Nacubactam Compared to Imipenem/Cilastatin in the Treatment of Complicated Urinary Tract Infections or Acute Uncomplicated Pyelonephritis, in Adults
Phase: PHASE3
Conditions: Complicated Urinary Tract Infection, Acute Pyelonephritis, cUTI, AP
Sponsor: Meiji Seika Pharma Co., Ltd.

 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 3, Multi-Center, Randomized, Double-Blind Study to 
Evaluate the Efficacy and Safety of Cefepime/Nacubactam or 
Aztreonam/Nacubactam Compared to Imipenem/Cilastatin in the 
Treatment of Complicated Urinary Tract Infections or Acute 
Uncomplicated Pyelonephritis, in Adults 
 
Investigational Product: 1 g Nacubactam for injection 
Protocol Number: OP0595-5 
EudraCT Number: 2021-001441-12 
 
Sponsor: 
Meiji Seika Pharma Co., Ltd. 
4-16, Kyobashi 2-chome 
Chuo-ku, Tokyo 104-8002 
Japan 
Telephone: (+81) 3-3273-3745 
Fax: (+81) 3-3273-3795 
 
Original Protocol (Version 1.0): 05 November 2021 
Amendment 1 (Version 2.0): 31 January 2022 
Amendment 2 (Version 3.0): 31 August 2022 
Amendment 3 (Version 4.0): 27 September 2022 
Amendment 4 (Version 5.0): 20 December 2023 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Meiji Seika Pharma Co., Ltd. except to the extent that disclosure would be required 
by law and for the purpose of evaluating and/or conducting a clinical study for Meiji Seika 
Pharma Co., Ltd. You are allowed to disclose the contents of this document only to your 
Institutional Review Board or Independent Ethics Committee and study personnel directly 
involved with conducting this protocol. Persons to whom the information is disclosed must be 
informed that the information is confidential and proprietary to Meiji Seika Pharma Co., Ltd. and 
that it may not be further disclosed to third parties. 

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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Meiji Seika Pharma Co., Ltd. to study personnel under my supervision. I will discuss this 
material with them to ensure they are fully informed about the study product and study procedures. 
I will let them know that this information is confidential and proprietary to Meiji Seika 
Pharma Co., Ltd. and that it may not be further disclosed to third parties. I understand that the 
study may be terminated or enrollment suspended at any time by Meiji Seika Pharma Co., Ltd., 
with or without cause, or by me if it becomes necessary to protect the best interests of the study 
patients. 
I agree to conduct this study in full accordance with the laws and regulations of the country in 
which the study is conducted, Institutional Review Board/Ethic Committee Regulations, 
International Council for Harmonisation Guidelines for Good Clinical Practices, current 
Declaration of Helsinki, and the Regulation (EU) No. 536/2014 or applicable regulatory 
requirements. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Principal Investigator’s Signature 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Principal Investigator’s Printed Name 
 

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SYNOPSIS 
TITLE: A Phase 3, Multi-Center, Randomized, Double-Blind Study to Evaluate the Efficacy and 
Safety of Cefepime/Nacubactam or Aztreonam/Nacubactam Compared to Imipenem/Cilastatin in 
the Treatment of Complicated Urinary Tract Infections or Acute Uncomplicated Pyelonephritis, 
in Adults 
SHORT TITLE: A Phase 3 Study to Evaluate the Efficacy and Safety of Cefepime/Nacubactam 
or Aztreonam/Nacubactam Compared to Imipenem/Cilastatin in the Treatment of Complicated 
Urinary Tract Infections or Acute Uncomplicated Pyelonephritis in Adults 
PROTOCOL NUMBER: OP0595-5 
INVESTIGATIONAL PRODUCT: 1 g Nacubactam for injection 
PHASE: 3 
INDICATION: Complicated urinary tract infection (cUTI) and acute uncomplicated 
pyelonephritis (AP) 
OBJECTIVES: 
The primary objective of this study is to assess the efficacy and safety of cefepime/nacubactam 
and to assess the safety of aztreonam/nacubactam administered by intravenous (IV) infusion 
compared to imipenem/cilastatin in patients with cUTI or AP.  
The secondary objectives of this study are the following: 
• To assess the efficacy of aztreonam/nacubactam administered by IV infusion in patients with 
cUTI or AP;  
• To assess the efficacy of cefepime/nacubactam and aztreonam/nacubactam administered by 
IV infusion in patients with secondary bacteremia due to cUTI or AP; 
• To assess the pharmacokinetics (PK) of cefepime/nacubactam and aztreonam/nacubactam 
administered by IV infusion in patients with cUTI or AP; and 
• To 
assess 
clinical 
and 
microbiological 
response 
of 
cefepime/nacubactam 
and 
aztreonam/nacubactam administered by IV infusion per type of pathogen, type of resistance, 
and antimicrobial susceptibility. 

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POPULATION: 
Inclusion criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Male or female patients ≥ 18 years of age (or age of legal consent, whichever is older) at the 
time of obtaining informed consent and who can be hospitalized throughout the Treatment 
Period; 
2. Weight ≤ 140 kg; 
3. Expectation, in the opinion of the Investigator, that the patient’s cUTI or AP will require 
treatment with at least 5 days of IV antibiotics; 
4. Diagnosis of cUTI or AP as defined in the tables below: 
Note: If a patient meets the criteria for cUTI below and also has flank pain or costo-vertebral 
angle tenderness, the patient will be randomized as cUTI instead of AP. 

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cUTI 
Signs or symptoms evidenced by 
at least 2 of the following 
Pyuria evidenced by 1 of the 
following 
At least 1 of the following 
associated risks 
• 
Chills, rigors, or fever. Fever 
(oral or tympanic temperature 
≥ 38°C 
[≥ 100.4°F] 
or 
rectal/core 
temperature 
≥ 38.3°C [≥ 100.9°F]) must be 
observed and documented by a 
healthcare 
provider 
within 
24 hours of Screening; 
• 
Suprapubic, pelvic, or lower 
abdominal pain; 
• 
Nausea or vomiting within 
24 hours of Screening; 
• 
Dysuria, 
increased 
urinary 
frequency, or urinary urgency; 
or 
• 
Elevated 
WBC 
count 
(> 10,000/mm3) or left shift 
(> 15% immature PMNs). 
• 
Positive leukocyte esterase on 
urinalysis; 
• 
WBC count ≥ 10/mm3 in 
unspun urine; or 
• 
WBC count ≥ 10/hpf in urine 
sediment. 
• 
Implanted 
urinary 
tract 
instrumentation (eg, ureteric 
stents or other urinary tract 
prosthetic material), ongoing 
intermittent 
bladder 
catheterization, or presence of 
an indwelling bladder catheter 
(Note: 
Indwelling 
bladder 
catheters that have been in 
place prior to Screening must 
be removed or replaced prior to 
collection of the Screening 
urine for urinalysis and culture, 
unless removal or replacement 
is 
considered 
unsafe 
or 
contraindicated); 
• 
Current known functional or 
anatomical abnormality of the 
urogenital 
tract, 
including 
anatomic abnormalities of the 
urinary 
tract, 
neurogenic 
bladder, or post-void residual 
urine volume of ≥ 100 mL 
within the past 6 months; 
• 
Partial obstructive uropathy 
(eg, nephrolithiasis, fibrosis, 
urethral 
stricture) 
that 
is 
expected to be medically or 
surgically treated during study 
drug therapy (prior to EOT); 
• 
Urinary retention, including 
urinary retention in men due to 
previously diagnosed BPH; or 
• 
Azotemia, defined as blood 
urea nitrogen > 20 mg/dL 
(> 7.14 mmol/L) (or blood urea 
> 42.8 mg/dL 
[> 7.13 mmol/L]), or serum 
creatinine 
> 1.4 
mg/dL 
(>123.79 
µmol/L), due 
to 
known prior intrinsic renal 
disease. 
BPH = benign prostatic hyperplasia; cUTI = complicated urinary tract infection; EOT = End of Treatment; hpf = high-power 
field; PMN = polymorphonuclear leukocyte; WBC = white blood cell. 

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AP 
Signs or symptoms evidenced by 
at least 2 of the following 
Pyuria evidenced by 1 of the 
following 
At least 1 of the following 
associated risks 
• 
Chills, rigors, or fever. Fever 
(oral or tympanic temperature 
≥ 38°C [≥ 100.4°F] or 
rectal/core temperature 
≥ 38.3°C [≥ 100.9°F]) must be 
observed and documented by a 
healthcare provider within 
24 hours of Screening; 
• 
Flank pain (onset within 7 days 
prior to randomization); 
• 
Costo-vertebral angle 
tenderness on physical 
examination; 
• 
Nausea or vomiting within 
24 hours of Screening; 
• 
Dysuria, increased urinary 
frequency, or urinary urgency; 
or 
• 
Elevated WBC count 
(> 10,000/mm3) or left shift 
(> 15% immature PMNs). 
• 
Positive leukocyte esterase on 
urinalysis; 
• 
WBC count ≥ 10/mm3 in 
unspun urine; or 
• 
WBC count ≥ 10/hpf in urine 
sediment. 
Not applicable. 
AP = acute uncomplicated pyelonephritis; hpf = high-power field; PMN = polymorphonuclear leukocyte; WBC = white blood 
cell. 
5. Patient has a baseline positive urine culture specimen obtained within 48 hours prior to the 
first dose of study drug; 
Note: Patients may be enrolled in this study and start IV study drug therapy before the 
Investigator knows the results of the baseline urine culture, if all other entry criteria are 
fulfilled. If known, the screening/baseline urine culture taken within 48 hours prior to the first 
dose of study drug contains ≥ 105 colony-forming units (CFU)/mL of a Gram-negative 
uropathogen susceptible to meropenem and imipenem, and the culture is not considered 
contaminated. If a patient grows ≥ 3 bacterial organisms ≥ 105 CFU/mL in the urine, the urine 
culture will be considered contaminated. An organism will not be considered a contaminant if 
the organism grows ≥ 105 CFU/mL in a urine culture and also grows in a concurrently obtained 
blood culture. If a patient’s baseline urine culture is negative after randomization, the 
Investigator decides whether the patient should continue to receive the study drug or should 
discontinue the study drug and initiate non-study antibiotics. 
Note: Imipenem and meropenem susceptible pathogen is defined as a Gram-negative pathogen 
by susceptibility data of minimum inhibitory concentration (MIC) less than 2 µg/mL to 
imipenem and meropenem OR imipenem and meropenem disk diffusion (zone diameter 
≥ 22 mm). If MIC or disk diffusion data are not available in the local laboratory or before the 
availability of MIC or disk diffusion results, each site can use other susceptibility testings and 
criteria in the institution as the initial evidence of imipenem and meropenem susceptible 
pathogen for enrollment. In any case, pathogen identification and susceptibility testing 
performed at the central laboratory will be used to determine imipenem and meropenem 
susceptible pathogen in the final study analysis. 

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6. Female patients who are no longer of childbearing potential must meet 1 of the following 
criteria: 
a. Women ≥ 50 years of age who are considered postmenopausal as they have been 
amenorrhoeic for ≥ 12 months; 
b. Women < 50 years of age who are considered postmenopausal as they have been 
amenorrhoeic for ≥ 12 months and if the follicle-stimulating hormone (FSH) level is in the 
postmenopausal range. If the FSH level is not available at the time of randomization, the 
patient must have a negative urine and/or serum pregnancy test and agree to use 
contraception methods until the FSH result is available; or 
c. Documented permanent sterilization, defined as hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy. 
7. Female patients of childbearing potential must have a negative urine and/or serum pregnancy 
test (serum β-human chorionic gonadotropin) at Screening; 
Note: Females of childbearing potential include female patients who have experienced 
menarche (or begin menarche over the course of the study), and who are not postmenopausal 
or permanently sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral 
salpingectomy). 
8. Patients must agree to use contraception methods as defined below:  
a. Female patients of childbearing potential will be included if they are either sexually 
inactive (abstinent) for 90 days prior to the first dose of study drug, or are using one of the 
following highly effective birth control methods (ie, results in < 1% failure rate when used 
consistently and correctly): 
i. Intrauterine device in place for at least 3 months prior to the first dose of study 
drug and throughout the study; 
ii. Surgical sterilization of the partner (provided they are the sole sexual partner), 
defined as vasectomy for 6 months minimum and assessed as surgical success; 
iii. Combined (estrogen or progestogen containing) hormonal contraception 
associated with the inhibition of ovulation (either oral, intravaginal, or 
transdermal); 
iv. Progestogen only hormonal contraception associated with the inhibition of 
ovulation (either oral, injectable, or implantable); 
v. Intrauterine hormone releasing system; or 
vi. Bilateral tubal occlusion. 
Note: Sexual abstinence or use of contraceptive measures must continue throughout the study 
and for 12 weeks after the last dose of study drug. 
Note: Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. In this study, abstinence is only acceptable if in line with the patient’s preferred 
and usual lifestyle. Periodic abstinence (calendar, symptothermal, post-ovulation methods), 

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withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea methods are not 
acceptable methods of contraception. 
b. Male patients with female partners of childbearing potential must use highly effective 
methods of birth control during their participation in the study and for 12 weeks after the 
last dose of study drug. In addition, male patients with female partners of childbearing 
potential must also use a condom during their participation in the study and for 12 weeks 
after the last dose of study drug. 
Note: Highly effective methods of birth control for male patients enrolled in the study include 
the following: surgical sterilization (vasectomy assessed as surgical success) of patient at least 
6 months before Screening or a female partner of childbearing potential (provided they are the 
sole female sexual partner) using highly effective contraception as described in Inclusion 
Criterion #8a). 
9. Female patients must agree to not donate eggs, or retrieve eggs for her own use from the time 
of informed consent until 12 weeks after the last dose, or male patients must agree to not freeze 
or donate sperm starting from the time of informed consent until 12 weeks after the last dose; 
10. Willing to comply with all study activities and procedures, whether in the hospital or after 
discharge, for the duration of the study; and 
11. Able to provide signed, written informed consent prior to any study-related procedures being 
performed. 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Has a known imipenem- and/or meropenem-resistant Gram-negative uropathogen 
(≥ 105 CFU/mL), isolated from study-qualifying urine culture; 
Note: If after randomization the susceptibility testing indicates resistance to imipenem and/or 
meropenem, the patient may remain on the study at the Investigator’s discretion. 
2. Has known or suspected single or concurrent infection with Acinetobacter species or other 
organisms that are not adequately covered by the study drug (eg, concurrent viral, 
mycobacterial, or fungal infection) and needs to be managed with other anti-infectives; 
Note: Patients with qualifying pathogen coinfected (or suspected to be coinfected) with a 
Gram-positive pathogen may be administered narrow spectrum, open-label glycopeptide (eg, 
vancomycin), oxazolidinone (eg, linezolid), or daptomycin concomitantly with the study drug 
at the Investigator’s discretion.  
3. Has only a known Gram-positive primary uropathogen (≥ 105 CFU/mL), isolated from 
study-qualifying urine culture;  

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4. Has a known study-qualifying urine culture with ≥ 3 bacterial organisms ≥ 105 CFU/mL; 
Note: A Gram-negative organism will not be considered a contaminant if the organism grows 
≥ 105 CFU/mL in a urine culture and also grows in a concurrently obtained blood culture.  
5. Has a complete obstruction of any portion of the urinary tract that is not anticipated to be 
medically or surgically relieved during this study therapy and before End of Treatment (EOT); 
6. Has a previous or planned cystectomy or permanent urinary diversion (eg, ileal loop, cutaneous 
ureterostomy); 
7. Has a refractory vesicoureteral reflux (Grade 4 or 5); 
8. Has a suspected or confirmed perinephric or renal corticomedullary abscess or polycystic 
kidney disease; 
9. Has suspected or confirmed prostatitis, orchitis, epididymitis, urethritis, or sexually 
transmitted disease; 
10. Has a non-renal source of infection concurrently that could interfere with the evaluation of 
response to the study drug; 
11. Has any recent history of accidental trauma to the pelvis (in the pelvic cavity) or urinary tract; 
12. Requires bladder irrigation with antibiotics or requires antibiotics to be administered directly 
via urinary catheter; 
13. Has received a potentially effective systemic antibacterial therapy within 48 hours prior to the 
first dose of study drug, with the exception of any of the following: 
a. Receipt of a single dose of a short-acting antibacterial agent (APPENDIX C) (no more 
than 15% of patients will be enrolled with this exception); 
b. Receipt of > 48 hours of prior antibiotic therapy and, in the Investigator’s opinion, failed 
that prior antibiotic therapy (ie, worsening signs and symptoms); or 
c. Documented to have cUTI or AP caused by a pathogen that is not susceptible to the prior 
antibiotic therapy. 
14. Has a history of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious allergic 
reaction to carbapenems, cephems, penicillins, other β-lactam antibiotics, or any β-lactamase 
inhibitors (eg, tazobactam, sulbactam, or clavulanic acid); 
15. Has a history of epilepsy or known seizure disorder (excluding a history of childhood febrile 
seizures); 
16. Is considered unlikely to survive the study period or has a rapidly progressive or terminal 
illness; 
17. Is a female patient who is pregnant or breastfeeding; 
18. Is a female patient who expects to be pregnant or a male patient who expects their partner to 
be pregnant from the time of informed consent until 12 weeks after the last dose;  
19. Has current or anticipated neutropenia (< 500 polymorphonuclear neutrophils/mm3, obtained 
from the local laboratory at Screening); 

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20. Has platelet count < 50,000 per microliter; 
21. Has renal transplantation and received antibacterial drug prophylaxis within 48 hours before 
screening and/or likely to receive antibacterial drug prophylaxis during the study period; 
22. Has participated in other clinical study within 90 days before this clinical study, or plans to 
participate in any other clinical study during the course of the study;  
23. Has an estimated creatinine clearance (CrCl) < 30 mL/min or > 240 mL/min based on the 
Cockcroft-Gault formula or is receiving hemodialysis or peritoneal dialysis; 
24. Has prior exposure to nacubactam alone or in combination with another product; 
25. Has gross hematuria that is not caused by infectious diseases;  
26. Meets Hy’s criteria of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
> 3 × upper limit of normal (ULN) and total bilirubin > 2 × ULN;  
Note: Patients with AST and/or ALT up to 5 × ULN are eligible if these elevations are acute 
and are documented as being directly related to the infectious process being treated.  
27. Has evidence of significant hepatic disease or dysfunction, including known acute viral 
hepatitis or hepatic encephalopathy; 
28. Has manifestations of end-stage liver disease, such as ascites or hepatic encephalopathy; 
29. Has a known history of HIV with either a cluster of differentiation 4 count < 200 cells/mm3 at 
the last measurement or current diagnosis of another acquired immunodeficiency 
syndrome-defining illness; 
30. Has an uncomplicated urinary tract infection (UTI) except AP (acute uncomplicated cystitis 
that does not meet the cUTI disease definition [see Inclusion Criterion #4]); 
31. Has any condition that, in the opinion of the Investigator, would compromise the safety of the 
patient or the quality of the data (eg, due to underlying disease, comorbidity, clinically 
meaningful laboratory abnormality), including a potential concern about a history of a disease 
that may compromise the safety of the patient during the course of the study (eg, history of 
clinically significant QT interval prolongation, clinically important congenital syndromes, 
etc);  
Note: Patients with electrolytes that are above or below the normal value range and deemed 
by the PI to be clinically significant may be excluded.  
32. Is anticipated to begin a new drug that is classified as high risk of prolonging the QT interval 
(listed in APPENDIX D) during the treatment period;  
Note: If patients have been using the drugs listed in APPENDIX D prior to the enrollment and 
need to continue using them and patient meets all entry criteria, the patient can be enrolled and 
continue using them during the study period.  
33. Heart-rate-corrected QT interval by the Fridericia formula (QTcF) > 470 msec at Screening;  
Note: If QTcF exceeds 470 msec, the electrocardiogram (ECG) may be repeated 2 more times 
after rest and the mean of the 3 values will be used to determine the subject’s eligibility. 

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34. Clinically significant bradycardia with a heart rate < 50 bpm;  
Note: Patients with such a low heart may have their heart rate repeated up to 2 additional 
times to determine eligibility.  
35. Diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); and 
Note: A SARS-CoV-2 test (genetic testing will be suggested but other antigen testing is 
allowed) should be conducted at Screening for highly suspected Coronavirus Disease 2019 
(COVID-19) patients at the Investigator’s discretion. Patients who are tested for SARS-CoV-2 
will be started on study drug only after a negative result is confirmed. 
Note: Patients eligible for the study with the exception of meeting COVID-19 criteria will be 
allowed to rescreen more than 2 weeks after testing positive and must have a negative test 
result for eligibility. 
36. Is using or planning to use any of the excluded medications and/or procedures except opioids 
and urinary anesthetics listed in Section 5.6.1 within the time period specified. 
WITHDRAWAL CRITERIA: 
Patients may be discontinued from study drug for any of the following reasons but will still be 
followed for safety assessments approximately 7 to 14 days after Early Termination (ET): 
1. Occurrence of a treatment-emergent adverse event (TEAE) that warrants study drug 
discontinuation in the judgment of the Investigator;  
2. Occurrence of exacerbation of underlying disease that warrants study drug discontinuation in 
the judgment of the Investigator; 
3. Patient ineligibility after the start of the study in the judgment of the Investigator;  
4. Required use of prohibited concomitant medications except urinary anesthetics and opioid 
drugs; 
5. Significant prolongation of the QT/QTc interval (QTcF > 500 msec or increase from baseline 
> 60 msec) as measured by the mean of 3 values after study drug administration; or 
6. Occurrence of an event that warrants discontinuation in the judgment of the Investigator. 
Participation of a patient in this clinical study may be discontinued for any of the following 
reasons: 
1. The patient withdraws consent or requests discontinuation from the study for any reason;  
2. Pregnancy;  
3. Termination of the study by the Sponsor or the regulatory authority; or 
4. The patient is suspected/diagnosed with SARS-CoV-2 infection and warrants discontinuation 
in the judgment of the Investigator.  
5. Insufficient therapeutic effect of the study drug that could lead to clinical worsening, or lack 
of clinical progress in the judgement of investigators; 

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STUDY DESIGN AND DURATION: 
This is a multi-center, randomized, double-blind study to evaluate the efficacy and safety of 
cefepime/nacubactam or aztreonam/nacubactam compared to imipenem/cilastatin for the 
treatment of cUTI or AP, in adults.  
In this study, the efficacy and safety of cefepime/nacubactam is primarily evaluated because 
cefepime has a broader antibacterial spectrum (Gram-positive and Gram-negative bacteria) and 
cefepime/nacubactam is expected to be frequently used for infections caused by Class A and/or D 
carbapenemase-producing Enterobacterales while aztreonam has an indication only for 
Gram-negative bacteria and aztreonam/nacubactam is positioned to be used only for infections 
caused by Class B carbapenemase-producing Enterobacterales in principle. 
Approximately 600 patients will be randomized in a 2:1:1 ratio to receive either 2 g cefepime/1 g 
nacubactam, 2 g aztreonam/1 g nacubactam, or 1 g imipenem/1 g cilastatin.  
Dosage of cefepime, aztreonam, nacubactam, and imipenem/cilastatin according to renal function 
is shown in Table S1.  
Randomization will be stratified by entry diagnosis (cUTI or AP) and by geographic region (Japan, 
China, or Other). At least 30% of patients will have a diagnosis of AP and at least 60% will have 
a diagnosis of cUTI.  
Patients with secondary bacteremia (defined as an organism[s] isolated from a non-contaminated 
blood culture that is the same as the cUTI/AP-qualifying organism[s] isolated from a urine culture 
or genitourinary tissue culture) will be included in the study, but categorized by the primary 
indication and recorded as having secondary bacteremia. 
Study drug will be administered every 8 hours (± 1 hour) via an IV infusion over a period of 
60 minutes (± 15 minutes). All patients will be treated for a minimum of 5 days (ie, 15 IV 
infusions) to 10 days. Duration may continue for up to 14 days in selected situations (eg, baseline 
bacteremia), after discussion with the Medical Monitor. Patients will return for 2 follow-up visits: 
a Test of Cure visit (TOC) (7 [± 2] days after EOT [Day 10 to 23]) and a Follow-Up visit (FUP) 
(14 [±2] days after EOT [Day 17 to 30]). Patients who withdraw from the study early will undergo 
an Early Termination (ET) visit. Study drug administration should be discontinued in patients 
whose baseline urine culture does not meet the requirements for a baseline qualifying pathogen 
and, in the opinion of the Investigator, the patient does not have a UTI and the patient is not 
improving.  
For instances when a patient grows only a Gram-negative organism resistant to imipenem and/or 
meropenem, the patient should discontinue study drug but may remain in the study to complete 
all study assessments. 
Figure S1 presents a schematic of the study design. 

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Figure S1. Study Design  
 
AP = acute uncomplicated pyelonephritis; cUTI = complicated urinary tract infection; EA = Early Assessment; EOT = End of 
Treatment; FUP = Follow-Up visit; TOC = Test of Cure visit. 
Patients with a qualifying Gram-negative uropathogen coinfected (or suspected to be coinfected) 
with a Gram-positive uropathogen detected after randomization may be administered narrow 
spectrum, open-label glycopeptide (eg, vancomycin), oxazolidinone (eg, linezolid), or daptomycin 
concomitantly with the blinded study drug at the Investigator’s discretion. Investigators should 
discuss such cases with the Medical Monitor.  
Patients will be monitored for safety throughout the duration of the study. Safety assessments will 
include vital signs, physical examinations, clinical laboratory assessments, adverse event (AE) 
assessments, and 12-lead ECGs. A urine and/or serum pregnancy test will be performed at 
Screening and FUP/ET for female patients of childbearing potential only and postmenopausal 
women < 50 years of age, if the follicle-stimulating hormone (FSH) level is not available at the 
time of randomization.  
An independent Data Safety Monitoring Board (DSMB) will review accumulated safety data and 
will also review serious AEs on an ongoing basis. The DSMB will make recommendations based 
on the safety data. Further details regarding the data safety monitoring guidelines will be included 
in the DSMB Charter. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Patients will receive either 2 g cefepime/1 g nacubactam, 2 g aztreonam/1 g nacubactam, or 
1 g imipenem/1 g cilastatin every 8 hours (± 1 hour) for at least 5 days and up to 14 days. Study 
drug will be administered via IV infusion over a period of 60 minutes (± 15 minutes). 
If CrCl is ≥ 30 and < 60 mL/min, patients will receive 1 g cefepime/0.5 g nacubactam or 1 g 
aztreonam/0.5 g nacubactam or 0.5 g imipenem/0.5 g cilastatin every 8 hours. If CrCl is ≥ 60 and 
< 90 mL/min, patients will receive 2 g cefepime/1 g nacubactam or 2 g aztreonam/1 g nacubactam 
or 0.75 g imipenem/0.75 g cilastatin every 8 hours. If CrCl is ≥ 90 and ≤ 240 mL/min, patients 
will receive 2 g cefepime/1 g nacubactam or 2 g aztreonam/1 g nacubactam or 1 g imipenem/1 g 
cilastatin every 8 hours. Dosage of nacubactam, cefepime, and aztreonam, and imipenem/cilastatin 
according to renal function are shown in Table S1. 

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Table S1. Study Drug Dosage According to Renal Function 
CrCl (mL/minute) 
Cefepime or 
Aztreonam (g) 
Nacubactam (g) 
Imipenem/Cilastatin 
(g) 
Interval (hour) 
≥ 90 and ≤ 240 
2 
1 
1/1 
8 
≥ 60 and < 90 
2 
1 
0.75/0.75 
8 
≥ 30 and < 60 
1 
0.5 
0.5/0.5 
8 
CrCl = creatinine clearance. 
For patients with moderate renal impairment at baseline whose CrCl drops below 30 mL/min after 
baseline, serum creatinine should be repeated to confirm the initial result and estimate CrCl. 
Patients may need to be discontinued from the study, according to the Investigator’s judgment or 
when the patient’s safety is at risk. 
CrCl will be calculated based on the Cockcroft-Gault formula: 
• Male: Creatinine clearance mL/min = (140 – age) × weight (kg) / (72 × serum creatinine 
[mg/dL]); and 
• Female: Creatinine clearance mL/min = 0.85 × ([140 – age] × weight [kg] / [72 × serum 
creatinine (mg/dL)]). 
EFFICACY ENDPOINTS:  
The primary efficacy endpoint is the proportion of patients who achieve composite clinical and 
microbiological success at TOC in the Microbiological Modified Intent-to-Treat (m-MITT) 
Population. Composite clinical and microbiological success is defined as the composite clinical 
outcome of cure and the microbiological outcome of eradication.  
Secondary efficacy endpoints for cUTI and AP 
The secondary efficacy endpoints for cUTI and AP include the following: 
• The proportion of patients with composite clinical and microbiological success at TOC in the 
Clinically Evaluable (CE) and Microbiologically Evaluable (ME) Populations; 
• The proportion of patients with composite clinical and microbiological success at Early 
Assessment (EA), EOT, and FUP in the m-MITT Population; 
• The proportion of patients with a microbiological outcome of eradication at EA, EOT, TOC, 
and FUP in the m-MITT Population and at TOC in the ME Population; 
• The proportion of patients with a clinical outcome of cure at EA, EOT, TOC, and FUP in the 
m-MITT Population and at TOC in the CE and ME Populations;  
• The proportion of patients with a clinical outcome of cure at EA, EOT, TOC, and FUP in the 
m-MITT Population and at TOC in the CE and ME Populations and microbiological outcome 
of eradication at EA, EOT, TOC, and FUP in the m-MITT Population and at TOC in the ME 
Population per type of pathogen, type of resistance, and antimicrobial susceptibility; and  
• The proportion of patients with composite clinical outcome of recurrence and/or 
microbiological outcome of recurrence at the FUP in the m-MITT, CE, and ME population. 

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Secondary efficacy endpoints for secondary bacteremia 
Patients with cUTI/AP who meet the following conditions will be determined programmatically 
as secondary bacteremia: 
• Isolation of a Gram-negative bacteria from at least 1 blood culture at baseline AND this 
isolated pathogen is also identified from the site of infection; AND 
• At least 1 of the following within 24 hours prior to the first dose of study drug: 
a. Fever (oral or tympanic temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature 
≥ 38.3°C [≥ 100.9°F]) OR hypothermia (rectal/core temperature < 35°C [< 95°F]); 
b. Elevated peripheral white blood cell (WBC) count (> 10,000/mm3); 
c. > 15% immature polymorphonuclear neutrophils (bands) regardless of peripheral WBC 
count; 
d. Leukopenia (WBC < 4,500/mm3); 
e. Tachycardia > 100 bpm; 
f. Tachypnea > 20 breaths/min; 
g. Hypotension, systolic < 90 mmHg; or 
h. C-reactive protein > 20 mg/dL.  
Clinical outcome of cure from secondary bacteremia is defined as complete resolution or 
significant improvement of the baseline signs and symptoms of secondary bacteremia. 
The secondary efficacy endpoints for secondary bacteremia include the following:  
• The proportion of patients with composite clinical and microbiological success of cUTI or AP 
at TOC in the m-MITT, CE, and ME Populations; 
• The proportion of patients with a clinical outcome of cure from cUTI or AP at TOC in the 
m-MITT, CE, and ME Populations;  
• The proportion of patients with a microbiological outcome of eradication from cUTI or AP at 
TOC in the m-MITT and ME Populations; 
• The proportion of patients with a clinical outcome of cure from secondary bacteremia at TOC 
in the m-MITT, CE, and ME Populations; 
• The proportion of patients with a microbiological outcome of eradication from secondary 
bacteremia at TOC in the m-MITT and ME Populations; 
• The proportion of patients in the m-MITT and ME Populations free from the definition of 
secondary bacteremia AND a clinical outcome of cure from cUTI or AP AND a 
microbiological outcome of eradication from cUTI or AP at TOC; and 
• The proportion of patients who are free from secondary bacteremia at TOC in the m-MITT 
and ME Populations. 

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The exploratory efficacy endpoints include the following:  
• Clinical response at EA, EOT, TOC, and FUP, as defined by the following parameters: 
a. Signs and symptoms of cUTI; and 
b. Proportion of patients in cure, improvement, failure, recurrence, or indeterminate 
categories for clinical response. 
• Microbiological response at EA, EOT, TOC, and FUP, as defined by the following parameters: 
a. Bacterial load in CFU/mL for cUTI causative pathogens in urine; and 
b. Proportion of patients in eradication, persistence, recurrence, or indeterminate categories 
for microbiological response. 
CLINICAL OUTCOME: 
cUTI/AP 
Assessment of clinical outcome will be completed at EA, EOT, TOC, FUP, and ET. The 
Investigator will assign a clinical outcome as defined in Table S2. 
Table S2. Clinical Outcome Criteria 
Category 
Criteria 
Cure 
The complete resolution (or return to premorbid state) of the baseline signs and symptoms of cUTI or AP 
that were present at Screening (and no new urinary symptoms or worsening of symptoms consistent with 
the specific baseline condition), such that no further antimicrobial therapy is warranted. Symptom 
resolution does not necessarily include pre-infection baseline symptoms associated with the patient’s 
pre-study condition (eg, anatomic abnormalities that predispose to cUTI, such as symptoms associated with 
the presence of an indwelling urinary catheter). This outcome category can be used at EA, EOT, TOC, 
FUP, and ET. 
Improvement 
Lessening, incomplete resolution, or no worsening of baseline clinical signs and symptoms, but continued 
IV therapy for management is warranted. This outcome category can only be used at EA. 
Failure 
Patients who experience any 1 of the following: 
• 
At EA and EOT, worsening of baseline clinical signs and symptoms or the development of new clinical 
signs and symptoms of infection, sufficient to stop study drug and initiate non-study antimicrobial; 
• 
At TOC and FUP, persistence or incomplete resolution of baseline clinical signs and symptoms of 
infection, requiring additional antibiotic therapy; 
• 
At any visit until TOC, a change in the patient’s baseline Gram-negative antimicrobial therapy to treat 
the baseline infection (other than dose adjustment) after randomization; 
• 
Withdrawal from the study due to an AE or due to lack of clinical improvement; or 
• 
Death of the patient during the study. 
This outcome category can be used at EA, EOT, TOC, FUP, and ET. 
Recurrence 
Baseline signs and symptoms were present at FUP after a response of cure. This outcome category can 
only be used at FUP. 
Indeterminate 
Clinical outcome cannot be determined. This outcome category can be used at EA, EOT, TOC, FUP, and 
ET. 
AE = adverse event; AP = acute uncomplicated pyelonephritis; cUTI = complicated urinary tract infection; EA = Early 
Assessment; EOT = End of Treatment; ET = Early Termination; FUP = Follow-Up visit; IV = intravenous(ly); TOC = Test of 
Cure visit. 

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MICROBIOLOGICAL OUTCOME:  
The criteria for microbiological outcome are defined in Table S3 and Table S4. Microbiological 
outcome will be determined programmatically based on the results from the site of infection.  
Table S3. Microbiological Outcome Criteria for cUTI or AP 
Category 
Criteria 
Eradication 
The baseline qualifying Gram-negative pathogen(s) is reduced to < 103 CFU/mL in urine culture. 
Persistence 
Demonstration that 1 or more of the baseline Gram-negative pathogen(s) remains continuously present in 
urine culture at ≥ 103 CFU/mL. 
Recurrence 
Isolation of the same baseline Gram-negative pathogen(s) ≥ 103 CFU/mL from urine culture after a 
response of eradication. 
Indeterminate 
No urine culture is available, or the culture cannot be interpreted for any reason. 
Microbiological outcome will not be evaluated in the following cases: 
• 
New pathogen infection – the post-baseline organism is different from the baseline Gram-negative organism but is thought 
to be a pathogen based on a number of reasons that will be delineated in the protocol (eg, Gram-negative, obtained in 
multiple cultures); or 
• 
Contaminant – the post-baseline organism is different from the baseline Gram-negative organism but is identified as a 
common skin flora organism and has not been cultured from another site. 
Note: The qualifying pathogen is defined as a single Gram-negative organism at a concentration ≥ 105 CFU/mL in a 
non-contaminated urine culture.  
Note: Presumed eradication is assessed at FUP and categorized as eradication only if the baseline qualifying Gram-negative 
pathogen(s) is eradicated (reduced to < 103 CFU/mL) at TOC, and a urine sample cannot be collected but there is a clinical 
outcome of cure at FUP. Therefore, a urine sample should also be collected at FUP, unless the baseline qualifying 
Gram-negative pathogen(s) is eradicated (reduced to < 103 CFU/mL) at TOC. 
AP = acute uncomplicated pyelonephritis; CFU = colony-forming unit(s); cUTI = complicated urinary tract infection; 
FUP = Follow-Up visit; TOC = Test of Cure visit. 
 
Table S4. Microbiological Outcome Criteria for Secondary Bacteremia 
Category 
Criteria 
Eradication 
The baseline qualifying Gram-negative pathogen(s) is negative in blood culture. Presumed eradication is 
defined as eradication. 
Persistence 
The baseline qualifying Gram-negative pathogen(s) is positive in blood culture.  
Recurrence 
Isolation of the same Gram-negative pathogen(s) from blood culture after a response of eradication. 
Indeterminate 
No blood culture is available or the culture cannot be interpreted for any reason.  
Microbiological outcome will not be evaluated in the following cases: 
• 
New pathogen infection – the post-baseline organism is different from the baseline Gram-negative organism but is thought 
to be a pathogen based on a number of reasons that will be delineated in the protocol (eg, Gram-negative, obtained in 
multiple cultures); or 
• 
Contaminant – the post-baseline organism is different from the baseline Gram-negative organism but is identified as a 
common skin flora organism and has not been cultured from another site.  
Note: Presumed eradication is assessed at TOC when the baseline qualifying Gram-negative pathogen(s) is negative for at least 
48 hours in subsequent blood cultures taken during the treatment period and there is a clinical outcome of cure at TOC. 
TOC = Test of Cure visit.  
COMPOSITE CLINICAL AND MICROBIOLOGICAL SUCCESS 
The algorithm for composite clinical and microbiological success at EA, EOT, TOC, FUP, and 
ET is summarized in Table S5.  

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Table S5. Composite Clinical and Microbiological Success 
Clinical 
Outcome 
Microbiological Outcome 
Eradication 
Persistence 
Recurrence1 
Indeterminate 
Cure 
Success 
Failure 
Failure 
Failure 
Failure2 
Failure 
Failure 
Failure 
Failure  
Indeterminate 
Clinical outcome for the 
last visit before EA, EOT, 
TOC, FUP, or 
ET = failure; 
otherwise = indeterminate 
Failure 
Failure 
Clinical outcome for the 
last visit before EA, EOT, 
TOC, FUP, or 
ET = failure; 
otherwise = indeterminate 
1. 
For an outcome of recurrence, patients must have documented prior eradication at any prior time point. 
2. 
In the assessment of clinical outcome at EA, category of “improvement” is included. In the assessment of clinical outcome 
at FUP, category of “recurrence” is included. 
EA = Early Assessment; EOT = End of Treatment; ET = Early Termination; FUP = Follow-Up visit; TOC = Test of Cure visit. 
PHARMACOKINETIC ASSESSMENTS: 
Blood samples for PK analysis will be collected from all patients. All patients will be assigned to 
either a multiple PK sampling or a sparse PK sampling group at the discretion of the Investigator. 
Infusion start and end times, as well as PK sampling times, will be recorded in the source 
documents. The method of PK sample handling is detailed in the Laboratory Manual provided by 
the Sponsor.  
In the case of multiple sampling, the PK plasma samples will be used to estimate PK parameters 
of nacubactam, cefepime, and aztreonam such as area under the plasma concentration-time curve, 
maximum observed plasma concentration, time to reach maximum observed plasma 
concentration, total drug clearance, terminal elimination half-life, minimum observed plasma 
concentration, and predicted steady-state volume of distribution using a non-compartmental 
model. PK parameters will be summarized using appropriate descriptive statistics. 
Scatter plots of plasma concentrations of nacubactam, cefepime, and aztreonam from multiple 
sampling and sparse sampling will be drawn, respectively. 
PK characterization and evaluation of plasma exposures of nacubactam, cefepime, and aztreonam 
will be performed using plasma concentrations from all patients in the cefepime/nacubactam and 
aztreonam/nacubactam treatment groups by means of population PK (PPK) modeling methods. 
PK/pharmacodynamic (PD) analysis will be performed by analyzing the relationship between 
individual PK/PD parameters and individual clinical/biological efficacy data, and PPK analysis 
and PK/PD analysis will be conducted independently of this protocol and the results of both 
analyses will be reported independently of the Clinical Study Report for this study.  
The PK samples will be collected from all treatment groups to maintain the blind. Only PK 
samples obtained from the cefepime/nacubactam and aztreonam/nacubactam groups will be 
analyzed (using a validated assay) by the bioanalytical laboratory. While the PK analyses will be 
ongoing during the study, the Sponsor and all study personnel will remain blinded to the results 
(see Section 5.3.2). 

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Multiple PK sampling 
In the case the patient is assigned to multiple sampling, samples will be collected on Day 1 after 
the first infusion of the day: 
• At the end of the infusion (± 5 minutes); and 
• At 2, 4, 6, and 8 hours (± 10 minutes) after the start of the study drug infusion. The sample 
will be collected prior to the start of the next infusion.  
Note: At least 4 time points, including 1 hour after the start of the study drug infusion (first infusion 
on that day) on Day 1, are needed. 
If multiple PK sampling cannot be conducted on Day 1, it should be conducted on Day 3 or Day 5 
instead. If sampling occurs on Day 3 or Day 5, samples can be collected after any of the 3 infusions 
on that day. 
Table S6 provides the sampling times for multiple PK assessments. 
Table S6. Sampling Times for Multiple PK Assessments 
Multiple PK Sampling Time (Time Allowance) 
Day 1 
(Post-Randomization)1 
Day 3 
Day 5 
End of infusion (± 5 minutes) 
X 
(X) 
(X) 
2 hours (± 10 minutes) after the start of infusion 
X 
(X) 
(X) 
4 hours (± 10 minutes) after the start of infusion 
X 
(X) 
(X) 
6 hours (± 10 minutes) after the start of infusion 
X 
(X) 
(X) 
8 hours (± 10 minutes) after the start of infusion2 
X 
(X) 
(X) 
(X) denotes samples that are only to be performed on Day 3 or Day 5 if multiple sampling could not be conducted on Day 1. If 
sampling occurs on Day 3 or Day 5, samples can be collected after any of the 3 infusions on that day. 
1. 
The PK sample should be taken after the first infusion of that day. 
2. 
Sample should be collected prior to the start of the next infusion. 
Note: At least 4 time points, including 1 hour after the start of the study drug infusion (first infusion on that day) on Day 1, are 
needed.  
PK = pharmacokinetic(s). 
Sparse PK sampling 
In the case the patient is assigned to sparse sampling, samples will be collected on Day 1, Day 3, 
or Day 5, after any of the 3 infusions on that day: 
• Around the end of the infusion; 
• Around 2 to 4 hours after the start of the study drug infusion; and 
• Around 4 to 8 hours after the start of the study drug infusion. The sample will be collected 
prior to the start of the next infusion. 
Note: At least 2 time points after the start of the study drug infusion (for any of the 3 infusions on 
that day) on Day 1, Day 3, or Day 5 are needed. 
Table S7 provides the sampling times for sparse PK assessments. 
Table S7. Sampling Times for Sparse PK Assessments 
Sparse PK Sampling Time  
Day 1 
(Post-Randomization)1 
Day 31 
Day 51 
Around the end of infusion  
X 
(X) 
(X) 
Around 2 to 4 hours after the start of infusion 
X 
(X) 
(X) 
Around 4 to 8 hours after the start of infusion2 
X 
(X) 
(X) 

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(X) denotes samples that are only to be performed on Day 3 or Day 5 if sparse sampling could not be conducted on Day 1. 
1. 
The PK sample should be taken after any of the 3 infusions of that day. 
2. 
Sample should be collected prior to the start of the next infusion. 
Note: At least 2 time points after the start of the study drug infusion (for any of the 3 infusions on that day) on Day 1, Day 3, 
or Day 5 are needed.  
PK = pharmacokinetic(s). 
 
OTHER ASSESSMENTS: 
The exploratory variables for this study are the minimum inhibitory concentrations (MIC) for 
cefepime/nacubactam, aztreonam/nacubactam, and nacubactam for causative uropathogens.  
Bacterial whole genome sequencing analysis, or other appropriate methods, may be conducted 
from purified cultures of bacterial isolates to explore type of resistance. 
MICROBIOLOGY ASSESSMENTS: 
Urine culture 
Urine samples will be obtained at Screening, prior to the first dose of study drug on Day 1, EA, 
EOT, TOC, FUP (if clinically indicated), and ET.  
Urine samples for microbiological testing will be collected by clean-catch midstream, intermittent 
urethral catheter (straight catheterization using sterile technique), a newly inserted Foley catheter 
(no bag specimens allowed), bladder needle aspiration, suprapubic catheter, nephrostomy tube, or 
ureter aspiration.  
A urine sample taken within 48 hours prior to the first dose of study drug can be used for screening 
and baseline microbiologic assessments if the organism(s) isolated from cultures is available to be 
sent to the central laboratory for analysis. However, all patients who had a urine sample not taken 
by the method specified in the protocol must have a repeat urine sample culture obtained prior to 
the start of study drug administration. This sample should be taken as close to randomization as 
possible (within 2 hours prior to the first dose of study drug, if possible). A repeat urine sample 
must be obtained prior to the start of study drug for any patients enrolled after receiving a single 
dose of a short-acting antibiotic or patients who failed preceding antimicrobial therapy. The 
sample should be collected as close to randomization as possible (within 2 hours prior to the first 
dose of study drug, if possible).  
Up to 2 Gram-negative bacterial isolates per urine culture (at concentrations of  105 CFU/mL of 
urine) will be considered as qualifying pathogens. If a patient grows  3 bacterial organisms 
 105 CFU/mL in the urine, the urine culture will be considered contaminated. An organism will 
not be considered a contaminant if the organism grows 105 CFU/mL in a urine culture and also 
grows in a concurrently obtained blood culture. 
Prior to the first dose of study drug, urine samples submitted for culture must have a 
urinalysis/dipstick and microscopic analysis performed at the local laboratory. Gram staining (or 
other possible testings) should be performed if available.  
At each sampling point, the local laboratory will culture each urine sample for organism 
identification, quantification, and susceptibility testing (only at Screening).  
Imipenem and meropenem susceptible pathogen is defined as a Gram-negative pathogen by 
susceptibility data of minimum inhibitory concentration (MIC) less than 2 µg/mL to imipenem 
and meropenem OR imipenem and meropenem disk diffusion (zone diameter  22 mm). If MIC 

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or disk diffusion data are not available in the local laboratory or before the availability of MIC or 
disk diffusion results, each site can use other susceptibility testings and criteria in the institution 
as the initial evidence of imipenem and meropenem susceptible pathogen for enrollment. In any 
case, pathogen identification and susceptibility testing performed at the central laboratory will be 
used to determine imipenem and meropenem susceptible pathogen in the final study analysis. 
Prior to the first dose of study drug, only organisms at concentrations of ≥ 105 CFU/mL of urine 
and not deemed to be a contaminant as detailed in the Microbiology Laboratory Manual will be 
sent to the central laboratory for confirmation of identification, susceptibility testing, and possible 
molecular testing; if the same organism grows in urine (at concentrations of ≥ 105 CFU/mL) and 
blood, these organisms should be sent to the central laboratory.  
For all post-baseline urine cultures, only organisms at concentrations of ≥ 103 CFU/mL of urine 
and not deemed to be a contaminant as detailed in the Microbiology Laboratory Manual will be 
sent to the central laboratory for confirmation of identification, susceptibility testing, and possible 
molecular testing.  
If a patient’s baseline urine culture is negative at the time a negative culture is confirmed but the 
patient is improving, the Investigator can keep the patient on treatment. If the baseline urine culture 
is negative at the time a negative culture is confirmed and the patient is not improving, study 
treatment will be stopped, and the patient will be followed for safety assessments approximately 
7 to 14 days after ET.  
Qualifying pathogen 
A qualifying pathogen is defined as a single Gram-negative organism at a concentration 
≥ 105 CFU/mL in a non-contaminated urine culture. If a culture grows ≥ 3 bacterial organisms 
≥ 105 CFU/mL in the urine, the urine culture will be considered contaminated. A Gram-negative 
organism will not be considered a contaminant if the organism grows ≥105 CFU/mL in a urine 
culture and also grows in a concurrently obtained blood culture. 
The list of Gram-negative uropathogens that may be considered causative in cUTI or AP is 
included in Table S8. Organisms identified during the study that are not listed in Table S8 as 
uropathogens or as contaminants in the Microbiology Laboratory Manual will be assessed on a 
case-by-case basis. 
Table S8. Potential Uropathogens 
Potential Gram-Negative Uropathogens 
Citrobacter freundii 
Citrobacter koseri 
Enterobacter cloacae 
Escherichia coli 
Klebsiella aerogenes 
Klebsiella oxytoca 
Klebsiella pneumoniae 
Morganella morganii 
Proteus mirabilis 
Proteus vulgaris 
Providencia rettgeri 
Providencia stuartii 
Pseudomonas aeruginosa 
Serratia marcescens 
Blood culture 
Two sets of blood culture samples from 2 separate venipuncture sites will be obtained at Screening 
and prior to the first dose of study drug on Day 1 for baseline blood cultures (duplicate assessments 
do not need to be performed if Screening and Day 1 occur on the same day or within 24 hours). 
The blood culture should be obtained within the allowed Screening Period and within 48 hours 

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prior to the first dose of study drug to align with the requirement to have a urine sample taken 
within 48 hours. 
Each set of blood culture samples will include 1 aerobic and 1 anaerobic bottle (an additional 
aerobic bottle is allowed if anaerobic culture is not standard practice at the site). However, for 
cUTI and AP, a single aerobic blood culture is sufficient if it is not the institution’s standard of 
care to obtain an anerobic culture. If a blood culture is positive at baseline for an organism obtained 
in a concurrently collected urine sample, blood cultures will be collected until the baseline 
qualifying Gram-negative pathogen(s) is negative for at least 48 hours in subsequent blood 
cultures. Additional blood cultures will be collected at the Investigator’s discretion. In that case, 
2 sets of blood culture samples from 2 separate venipuncture sites will be obtained. The frequency 
of repeating those blood cultures should be at the discretion of the Investigator, but there must be 
documentation of a negative blood culture 48 hours after any baseline blood culture or after any 
subsequent blood culture is found to be positive. For patients with fever spikes (oral or tympanic 
temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature ≥ 38.3°C [≥ 100.9°F]) during the study, 
additional blood samples may be obtained at the time of the fever spike. Specimens will be sent 
to the local laboratory for culture identification and susceptibility testing (only at Screening). All 
isolates from blood culture will be sent to the central laboratory for confirmation of identification, 
susceptibility testing, and possible molecular testing as outlined in the Microbiology Laboratory 
Manual. 
SAFETY ASSESSMENTS: 
The safety parameters include the incidence, severity, causality, and seriousness of TEAEs and 
the evaluation of changes from baseline in safety laboratory test results, 12-lead ECGs, vital signs, 
and physical examinations. 
STATISTICAL ANALYSES: 
Intent-to-Treat (ITT) Population: All patients who are randomized. 
Modified Intent-to-Treat (MITT) Population: All patients who meet ITT criteria and receive any 
amount of study drug. 
m-MITT Population: All randomized patients who meet MITT criteria and who have a baseline 
qualifying pathogen that susceptible to imipenem and meropenem (see Section 7.1.3.1 for the 
definition of a qualifying pathogen). The definition of imipenem and meropenem susceptible 
pathogen is described in Inclusion Criterion #5. 
CE Population: All patients who meet the definition for the MITT Population and who meet the 
following important components of the study as specified in the protocol: 
• Receive at least 80% of the intended doses of randomized study drug treatment; 
• Have a clinical assessment at TOC, unless criteria for clinical failure were met at an earlier 
timepoint; 

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• Did not receive concomitant antibacterial treatment with a non-study antibacterial drug to 
which the uropathogen was susceptible between the time of the baseline culture and the TOC 
culture, unless criteria for clinical failure were met; and 
• Do not have any other major protocol violations that would affect assessment of efficacy. 
ME Population: Patients who meet the definition for both the m-MITT and CE Populations. In 
addition, to be included in the ME Population, patients must not have a microbiological outcome 
at TOC of Indeterminate. However, any interpretable positive urine culture obtained from EOT 
through TOC will be carried forward to TOC.  
Safety Population: All patients who receive at least 1 dose of study drug during the study. 
PK Population: All patients in the Safety Population who have at least 1 analyzable PK sample.  
Analysis of Efficacy 
The statistical and analytical plans presented below are an overview of key analysis methods. 
Details of the analysis will be specified in the Statistical Analysis Plan (SAP). 
The primary efficacy endpoint is the proportion of patients who achieve complete composite 
clinical and microbiological success at TOC in the m-MITT Population. The non-inferiority 
hypothesis test is a 1-sided hypothesis test performed at the 2.5% level of significance. This is 
based on the lower limit of the 2-sided 95% confidence intervals (CIs) for the observed difference 
in the proportion of patients with composite clinical and microbiological success 
(cefepime/nacubactam group minus imipenem/cilastatin group) at the TOC. Patients with missing 
data will be included in the denominator for the calculation of success rate. Thus, patients with 
missing data will be considered as failures for the analysis. The primary analysis is based on a CI 
computed using the Miettinen and Nurminen method. If the lower limit of the 2-sided 95% CI for 
the difference between treatment groups at TOC in the m-MITT Population is > -15.0%, the null 
hypotheses will be rejected and non-inferiority will be concluded based on the primary efficacy 
endpoint. 
If non-inferiority is declared for the primary efficacy endpoint, a test for superiority will be 
performed using a hierarchical gatekeeping approach for overall control of the Type 1 error. For 
this analysis, if the lower bound of the 95% CI for the treatment difference in treatment success at 
TOC in the m-MITT Population is > 0.0%, superiority will be declared. 
Furthermore, if non-inferiority of the cefepime/nacubactam group is declared for the primary 
efficacy endpoint, the non-inferiority hypothesis test for the aztreonam/nacubactam group will be 
performed using a hierarchical gatekeeping approach for overall control of the Type 1 error. For 
this analysis, and for the treatment difference (aztreonam/nacubactam group minus 
imipenem/cilastatin group) in treatment success at TOC, the same approach as in the 
cefepime/nacubactam group will be used. 
For the secondary efficacy endpoints, the number and percentage of patients with each response 
will be summarized by treatment group. The 2-sided 95% CI for the difference between treatment 
groups in the proportion of patients with favorable response will be presented using the same 
approach as for the primary analyses. 
Plasma nacubactam, cefepime, and aztreonam concentrations and PK parameters obtained by 
analyzing plasma concentrations of nacubactam, cefepime, and aztreonam from multiple sampling 

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groups using non-compartmental analysis methods will be summarized using the appropriate 
descriptive statistics, which will be fully outlined in the SAP.  
PPK analyses will be performed using nacubactam, cefepime, and aztreonam plasma 
concentrations from all patients in the cefepime/nacubactam and aztreonam/nacubactam treatment 
groups. PK/PD analyses will be performed by analyzing the relationship between individual 
estimated PK/PD parameters and individual efficacy data. The results of both analyses will be 
reported independently of the Clinical Study Report for this study. 
Analysis of Safety 
Safety analyses will be performed on all patients in the Safety Population. Analyses will be based 
on TEAEs, vital signs, clinical laboratory assessments, physical examination findings, and 12-lead 
ECGs. Safety analyses in general will be descriptive and will be presented in tabular format with 
the appropriate summary statistics. 
SAMPLE SIZE DETERMINATION: 
Using a 15% non-inferiority margin, 1-sided alpha of 0.025, 80% power, a composite clinical and 
microbiological success rate of 70% in each treatment group (cefepime/nacubactam, 
imipenem/cilastatin) at TOC, and a 2:1 allocation ratio, a total of 330 patients are required in the 
m-MITT Population. In addition, 110 patients will be required in the m-MITT Population for the 
aztreonam/nacubactam group, the same as the imipenem/cilastatin group, in order to evaluate 
efficacy and safety of the aztreonam/nacubactam group. Assuming 75% of patients will be 
evaluable for the m-MITT Population, a total of approximately 600 patients will be randomized 
using a 2:1:1 allocation ratio (300 patients in the cefepime/nacubactam group, 150 patients in the 
aztreonam/nacubactam group, and 150 patients in the imipenem/cilastatin group). A review of the 
overall percentage of patients in the m-MITT Population will be conducted after approximately 
60% of patients are randomized. Based on this assessment, the sample size may be adjusted to 
ensure the study remains sufficiently powered. 
SITES: Approximately 90 sites in Europe and Asia Pacific 
SPONSOR: 
Meiji Seika Pharma Co., Ltd. 
4-16, Kyobashi 2-chome 
Chuo-ku, Tokyo 104-8002 
Japan 
Telephone: (+81) 3-3273-3745 
Fax: (+81) 3-3273-3795 

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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 26 
List of Tables ................................................................................................................................ 31 
List of Figures ............................................................................................................................... 32 
List of Abbreviations and Definition of Terms............................................................................. 33 
1 Introduction and Background Information ............................................................................. 36 
1.1 
Nacubactam ................................................................................................................... 36 
1.2 
Nonclinical Studies ....................................................................................................... 36 
1.2.1 Microbiology ..................................................................................................... 37 
1.2.2 Toxicology and Safety Pharmacology .............................................................. 39 
1.3 
Clinical Pharmacology Studies ..................................................................................... 39 
1.3.1 Study OP0595-1 (Australia) .............................................................................. 40 
1.3.2 Study OP0595-2 (Japan) ................................................................................... 41 
1.3.3 Study OP0595-3 (Japan) ................................................................................... 41 
1.3.4 Study OP0595-4 (Japan) ................................................................................... 42 
1.3.5 Study NP30052 (United States) ........................................................................ 42 
1.3.6 Study NP39380 (United States) ........................................................................ 43 
1.3.7 Study NP39596 (Latvia, Serbia, Poland, and United States) ............................ 43 
1.3.8 Study NP39750 (United States) ........................................................................ 43 
1.4 
Rationale for Dose Selection ......................................................................................... 44 
1.5 
Risk/Benefit Assessment ............................................................................................... 45 
1.5.1 Risk Assessment ................................................................................................ 45 
1.5.2 Benefit Assessment ........................................................................................... 45 
1.5.3 Overall Risk/Benefit Conclusion ...................................................................... 45 
2 Study Objectives ..................................................................................................................... 46 
2.1 
Primary Objective ......................................................................................................... 46 
2.2 
Secondary Objectives .................................................................................................... 46 
3 Study Description.................................................................................................................... 47 

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3.1 
Summary of Study Design ............................................................................................ 47 
3.2 
Study Indication ............................................................................................................ 48 
4 Selection and Withdrawal of Patients ..................................................................................... 49 
4.1 
Inclusion Criteria ........................................................................................................... 49 
4.2 
Exclusion Criteria .......................................................................................................... 53 
4.3 
Withdrawal Criteria ....................................................................................................... 56 
5 Study Treatments .................................................................................................................... 58 
5.1 
Treatment Groups .......................................................................................................... 58 
5.2 
Rationale for Dosing ..................................................................................................... 58 
5.3 
Randomization and Blinding ......................................................................................... 59 
5.3.1 Randomization .................................................................................................. 59 
5.3.2 Blinding ............................................................................................................. 59 
5.4 
Breaking the Blind ........................................................................................................ 60 
5.5 
Drug Supplies ................................................................................................................ 60 
5.5.1 Formulation and Packaging ............................................................................... 60 
5.5.2 Study Drug Preparation and Dispensing ........................................................... 60 
5.5.3 Study Drug Administration ............................................................................... 60 
5.5.3.1 Dosing in patients with renal insufficiency ........................................ 61 
5.5.4 Treatment Compliance ...................................................................................... 61 
5.5.5 Storage and Accountability ............................................................................... 61 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 62 
5.6.1 Excluded Medications and/or Procedures ......................................................... 62 
5.6.2 Restricted Medications and/or Procedures ........................................................ 63 
5.6.3 Allowed Medications and/or Procedures .......................................................... 63 
5.6.4 Documentation of Prior and Concomitant Medication Use .............................. 63 
6 Study Procedures .................................................................................................................... 65 
6.1 
Informed Consent .......................................................................................................... 65 
6.2 
Screening Period ........................................................................................................... 65 
6.2.1 Day 1 ................................................................................................................. 68 
6.2.1.1 Pre-randomization ............................................................................... 68 
6.3 
Randomization .............................................................................................................. 70 
6.4 
Treatment Period ........................................................................................................... 70 

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6.4.1 Day 1 ................................................................................................................. 70 
6.4.1.1 Post-randomization ............................................................................. 70 
6.4.2 Day 2 ................................................................................................................. 71 
6.4.3 Day 3 ................................................................................................................. 72 
6.4.4 Day 4 (Early Assessment) ................................................................................. 73 
6.4.5 Day 5 to Day 14 ................................................................................................ 75 
6.4.6 End of Treatment ............................................................................................... 76 
6.5 
Follow-Up Period .......................................................................................................... 78 
6.5.1 Test of Cure Visit .............................................................................................. 78 
6.5.2 Follow-Up Visit ................................................................................................. 79 
6.6 
Criteria for Premature Discontinuation of Study Drug or Patient Withdrawal From the 
Study .............................................................................................................................. 80 
6.6.1 Premature Discontinuation of Study Drug Administration ............................... 80 
6.6.2 Withdrawal From the Study .............................................................................. 82 
7 Efficacy Assessments.............................................................................................................. 85 
7.1 
Primary Efficacy Endpoint ............................................................................................ 85 
7.1.1 Assessment of Clinical Signs and Symptoms ................................................... 85 
7.1.1.1 cUTI/AP .............................................................................................. 85 
7.1.2 Clinical Outcome ............................................................................................... 85 
7.1.3 Microbiological Outcome ................................................................................. 86 
7.1.3.1 Microbiology assessments .................................................................. 87 
7.1.4 Composite Clinical and Microbiological Success ............................................. 89 
7.2 
Secondary Efficacy Endpoints ...................................................................................... 90 
7.2.1 Secondary Efficacy Endpoints for cUTI and AP .............................................. 90 
7.2.2 Secondary Efficacy Endpoints for Secondary Bacteremia................................ 90 
7.3 
Exploratory Efficacy Endpoints .................................................................................... 91 
7.4 
Pharmacokinetic Assessments ....................................................................................... 92 
7.4.1 Multiple PK Sampling ....................................................................................... 92 
7.4.2 Sparse PK Sampling .......................................................................................... 93 
7.5 
Other Assessments ........................................................................................................ 94 
8 Safety Assessments ................................................................................................................. 95 
8.1 
Adverse Events .............................................................................................................. 95 
8.1.1 Treatment-Emergent Adverse Events ............................................................... 96 

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8.1.2 Adverse (Drug) Reaction .................................................................................. 96 
8.1.3 Unexpected Adverse Drug Reaction ................................................................. 96 
8.1.4 Assessment of Adverse Events by the Investigator .......................................... 96 
8.2 
Serious Adverse Events ................................................................................................. 98 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 98 
8.4 
Pregnancy Reporting ..................................................................................................... 99 
8.5 
Expedited Reporting ...................................................................................................... 99 
8.6 
Special Situation Reports ............................................................................................ 100 
8.7 
Clinical Laboratory Evaluations .................................................................................. 101 
8.8 
Vital Signs ................................................................................................................... 101 
8.9 
Electrocardiograms ...................................................................................................... 101 
8.10 Physical Examinations ................................................................................................ 102 
9 Statistics ................................................................................................................................ 103 
9.1 
Analysis Populations ................................................................................................... 103 
9.2 
Statistical Methods ...................................................................................................... 103 
9.2.1 Analysis of Efficacy ........................................................................................ 103 
9.2.1.1 Primary efficacy analysis .................................................................. 103 
9.2.1.2 Secondary efficacy analyses ............................................................. 104 
9.2.1.3 Pharmacokinetic analyses ................................................................. 104 
9.2.1.4 Population pharmacokinetic analyses and 
pharmacokinetic/pharmacodynamic analyses ................................... 104 
9.2.2 Analysis of Safety ........................................................................................... 104 
9.2.3 Interim Analysis .............................................................................................. 104 
9.2.4 Data Safety Monitoring Board ........................................................................ 105 
9.2.5 Sample Size Determination ............................................................................. 105 
10 Data Management and Record Keeping ............................................................................... 106 
10.1 Data Management ....................................................................................................... 106 
10.1.1 Data Handling ................................................................................................. 106 
10.1.2 Computer Systems ........................................................................................... 106 
10.1.3 Data Entry ....................................................................................................... 106 
10.1.4 Medical Information Coding ........................................................................... 106 
10.1.5 Data Validation ............................................................................................... 106 
10.2 Record Keeping ........................................................................................................... 106 

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10.3 End of Study ................................................................................................................ 107 
11 Investigator Requirements and Quality Control ................................................................... 108 
11.1 Ethical Conduct of the Study ...................................................................................... 108 
11.2 Institutional Review Board/Independent Ethics Committee ....................................... 108 
11.3 Informed Consent ........................................................................................................ 108 
11.4 Patient Card ................................................................................................................. 109 
11.5 Study Monitoring Requirements ................................................................................. 109 
11.6 Protocol Compliance ................................................................................................... 109 
11.7 Protocol Deviations ..................................................................................................... 110 
11.8 Disclosure of Data ....................................................................................................... 110 
11.9 Data Protection ............................................................................................................ 110 
11.10 Retention of Records ................................................................................................... 111 
11.11 Publication Policy ....................................................................................................... 111 
11.12 Financial Disclosure .................................................................................................... 111 
11.13 Insurance and Indemnity ............................................................................................. 111 
11.14 Legal Aspects .............................................................................................................. 111 
12 Study Administrative Information ........................................................................................ 112 
12.1 Protocol Amendments ................................................................................................. 112 
12.2 Study Results ............................................................................................................... 112 
13 References ............................................................................................................................. 113 
APPENDIX A: SCHEDULE OF PROCEDURES ..................................................................... 114 
APPENDIX B: CLINICAL LABORATORY ASSESSMENTS ............................................... 118 
APPENDIX C: ALLOWED AND DISALLOWED PRIOR ANTIBIOTICS ........................... 120 
APPENDIX D: DRUG LISTS CLASSIFIED AS HIGH RISK OF QT PROLONGATION .... 121 

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LIST OF TABLES 
Table 1. 
Antimicrobial Activity of Cefepime/Nacubactam and Aztreonam/Nacubactam in a 
1:1 Ratio Against 2027 Randomly Selected Enterobacterales and Non-Fermenting 
Species ........................................................................................................................ 38 
Table 2. 
Overview of Clinical Pharmacology Studies .............................................................. 40 
Table 3. 
Study Drug .................................................................................................................. 58 
Table 4. 
Study Drug Dosage According to Renal Function ..................................................... 61 
Table 5. 
Clinical Outcome Criteria ........................................................................................... 86 
Table 6. 
Microbiological Outcome Criteria for cUTI or AP .................................................... 86 
Table 7. 
Microbiological Outcome Criteria for Secondary Bacteremia ................................... 87 
Table 8. 
Potential Uropathogens ............................................................................................... 89 
Table 9. 
Composite Clinical and Microbiological Success ...................................................... 90 
Table 10. Sampling Times for Multiple PK Assessments .......................................................... 93 
Table 11. Sampling Times for Sparse PK Assessments ............................................................. 93 

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LIST OF FIGURES 
Figure 1. Study Design ............................................................................................................... 48 
 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AP 
Acute uncomplicated pyelonephritis 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC0-∞ 
Area under the plasma concentration-time curve from time 0 to 
infinity 
AUC0-8 
Area under the plasma concentration-time curve from time 0 to 
8 hours 
BLI 
β-lactamase inhibitor 
CE 
Clinically Evaluable 
CFR 
Code of Federal Regulations 
CFU 
Colony-forming unit(s) 
CI 
Confidence interval 
Cmax 
Maximum observed plasma concentration  
Cmin 
Minimum observed plasma concentration 
COVID-19 
Coronavirus Disease 2019 
CRA 
Clinical research associate 
CrCl 
Creatinine clearance 
CTA 
Clinical trial authorisation 
cUTI 
Complicated urinary tract infection 
DSMB 
Data Safety Monitoring Board 
EA 
Early Assessment 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EIU 
Exposure In Utero 
ELF 
Epithelial lining fluid 
EOT 
End of Treatment 
ESBL 
Extended-spectrum β-lactamase 
ET 
Early Termination 
EU 
European Union 
FSH 
Follicle-stimulating hormone 
FUP 
Follow-Up visit 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GLP 
Good Laboratory Practice 

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Abbreviation 
Definition 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IV 
Intravenous(ly) 
KPC 
Klebsiella pneumoniae carbapenemase 
LPLO 
Last patient last observation 
MBL 
Metallo-β-lactamase 
ME 
Microbiologically Evaluable 
MIC 
Minimum inhibitory concentration  
MIC50 
Minimum inhibitory concentration required to inhibit growth of 
50% of organisms 
MIC90 
Minimum inhibitory concentration required to inhibit growth of 
90% of organisms 
MITT 
Modified Intent-to-Treat 
m-MITT 
Microbiological Modified Intent-to-Treat 
NIMP 
Non-investigational medicinal product 
OXA 
Oxacillinase 
PBP2 
Penicillin-binding protein 2 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PPK 
Population pharmacokinetics 
PTA 
Probability of target attainment 
QTc 
Heart-rate-corrected QT interval 
QTcF 
Heart-rate-corrected QT interval by the Fridericia formula 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
spp. 
Species 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Terminal elimination half-life 
TEAE 
Treatment-emergent adverse event 
TID 
Three times a day 
TOC 
Test of Cure visit 
ULN 
Upper limit of normal 

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Abbreviation 
Definition 
UTI 
Urinary tract infection 
WBC 
White blood cell 

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1 
 INTRODUCTION AND BACKGROUND INFORMATION  
Urinary tract infections (UTIs) are a major cause of hospital admissions and are associated with 
significant morbidity and mortality, as well as a high economic burden. The majority of UTIs are 
those acquired in the community setting (57.4%), whereas 35.6% are healthcare associated and 
7% are nosocomial. UTIs can be classified according to the anatomic site of infection, such as 
cystitis or pyelonephritis, and are further classified into complicated or uncomplicated, irrespective 
of the site and severity of the infection. Complicated UTIs (cUTIs) occur in subjects with anatomic 
or functional abnormalities of the urinary tract or in those with significant medical or surgical 
comorbidities. The microbiology of cUTI is characterized by greater variety of organisms and an 
increased likelihood of antimicrobial resistance as compared with uncomplicated UTIs. 
The most common causative bacteria in cUTI are Gram-negative bacteria including Escherichia 
coli, Klebsiella species (spp.), Proteus spp., Enterobacter cloacae, Serratia marcescens, and 
Pseudomonas aeruginosa. A variety of therapeutic drugs for bacterial infections are available, but 
β-lactam antibiotics such as penicillins are the most important group among therapeutic drugs in 
terms of efficacy and safety. In particular, carbapenems could be important as they can also be 
indicated for intractable infections, and the emergence of resistant bacteria to them is a very serious 
problem. The mechanisms by which pathogenic bacteria acquire resistance to β-lactam antibiotics 
vary, but the most important and general one is the inactivation (degradation) of the drug by the 
production of β-lactamase. Currently, it is said there are over 2,000 species of β-lactamases, which 
are classified into Class A to D. Extended-spectrum β-lactamase (ESBL) and AmpC enzyme, 
which degrade third-generation cephalosporins of therapeutic importance, and carbapenemase, 
which degrades carbapenems, have also been reported. Carbapenemase can be classified in several 
types, including Class A Klebsiella pneumoniae carbapenemase (KPC) type enzyme, Class D 
oxacillinase (OXA) -48 like enzyme, Class B New Delhi metallo-β-lactamase (MBL) type 
enzyme, imipenemase type enzyme, and Verona integron-encoded MBL type enzyme as 
representative enzymes, and resistant bacteria with different enzymatic types have been isolated 
from region to region. 
1.1 
Nacubactam 
Nacubactam is a novel diazabicyclooctane-type β-lactamase inhibitor (BLI) that was discovered 
by Meiji Seika Pharma Co., Ltd., and is in clinical development in support of the intended 
coadministration with either cefepime or aztreonam. Nacubactam, when paired with β-lactams, 
has been shown to restore or potentiate the efficacy against Ambler Class A, B, C, and D 
β-lactamase-producing Gram-negative bacteria in a nonclinical setting. Nacubactam has been 
shown to have a dual mode of action: (i) as an inhibitor of serine β-lactamases (Classes A and C 
and some Class D), resulting in protection of the partner β-lactam, and (ii) as an inhibitor of 
penicillin-binding protein 2 (PBP2) of Enterobacterales, resulting in antibacterial activity and 
‘enhancing’ the activity of β-lactam agents. When administered in combination with a β-lactam 
(cefepime or aztreonam), nacubactam therefore has the potential to treat infections caused by 
carbapenem-resistant Enterobacterales, including MBL -producing bacteria, which represents an 
area of significant unmet medical need. 
1.2 
Nonclinical Studies 
Please refer to the current Investigator’s Brochure (IB) for detailed information regarding 
nonclinical studies.  

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1.2.1 
Microbiology 
β-lactams (cefepime or aztreonam) in combination with nacubactam showed potent activity 
against Enterobacterales, including β-lactamase-producing isolates. Nacubactam potentiated 
cefepime or aztreonam activity against Pseudomonas aeruginosa with depressed AmpC or 
acquired ESBL, but not against isolates producing MBL. In case of Acinetobacter baumannii, 
nacubactam achieved no significant potentiation of aztreonam or cefepime against OXA or MBL 
positive isolates. In addition, nacubactam did not show the combination effect with cefepime or 
aztreonam against Gram-positive pathogens.  
Antimicrobial activities of β-lactam alone and in combination with nacubactam were investigated 
against 1,722 Enterobacterales, 203 P. aeruginosa, and 102 Acinetobacter spp. (Table 1). These 
randomly selected isolates were collected globally and mainly in 2018 (94.1%). Against all the 
Enterobacterales tested, the minimum inhibitory concentration (MIC) required to inhibit growth 
of 50% of organisms (MIC50) of β-lactam/nacubactam (1:1) was generally similar to that of 
β-lactam alone but the MIC required to inhibit growth of 90% of organisms (MIC90) of the 
combination was greatly improved compared with β-lactam alone against Enterobacterales, 
reflecting the likelihood that many of these organisms produce various β-lactamases. Against the 
non-fermenter bacteria, the β-lactam/nacubactam (1:1) combination lowered the MIC50 and MIC90 
by 2-fold at most, compared with β-lactam alone.  

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Table 1. Antimicrobial Activity of Cefepime/Nacubactam and Aztreonam/Nacubactam in a 1:1 Ratio Against 
2027 Randomly Selected Enterobacterales and Non-Fermenting Species 
Organism 
Number 
of 
Isolates 
MIC (mg/L) 
Cefepime 
Cefepime/Nacubactam1 
Aztreonam 
Aztreonam/Nacubactam1 
Imipenem 
MIC50 
MIC90 
MIC50 
MIC90 
MIC50 
MIC90 
MIC50 
MIC90 
MIC50 
MIC90 
Enterobacterales 
1722 
0.06 
32 
0.06 
0.5 
0.12 
> 32 
0.06 
1 
≤0.12 
1 
Asia-Pacific 
686 
0.06 
16 
0.03 
0.25 
0.06 
32 
0.06 
0.5 
≤0.12 
1 
Europe 
690 
0.06 
> 32 
0.06 
0.5 
0.12 
> 32 
0.06 
1 
≤0.12 
1 
Other regions2 
346 
0.06 
32 
0.06 
0.5 
0.12 
> 32 
0.06 
1 
≤0.12 
1 
Pseudomonas 
aeruginosa 
203 
2 
16 
2 
8 
8 
32 
8 
16 
1 
>8 
Acinetobacter 
spp. 
102 
32 
> 64 
16 
64 
64 
> 64 
32 
> 64 
>8 
>8 
1. 
The combinatorial concentration of nacubactam in combination with β-lactam agent was a fixed ratio of 1:1. 
2. 
North America and Latin America 
MIC = minimum inhibitory concentration; MIC50 = minimum inhibitory concentration required to inhibit growth of 50% of organisms; MIC90 = minimum inhibitory 
concentration required to inhibit growth of 90% of organisms; spp. = species.  

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1.2.2 
Toxicology and Safety Pharmacology 
The pivotal toxicology and safety pharmacology studies intended to support safety claims were 
conducted in accordance with Organisation for Economic Co-operation and Development 
Principles of Good Laboratory Practice (GLP). Additional supportive toxicological studies were 
conducted as scientifically carefully conducted non-GLP studies. 
Rats and cynomolgus monkeys were chosen for nonclinical in vivo safety studies; initial, 
exploratory safety studies were also conducted in dogs. Repeat-dose toxicity studies of up to 
28 days in rats and cynomolgus monkeys have been completed. Nacubactam was well tolerated in 
single-dose and repeat-dose toxicity studies in rats and cynomolgus monkeys. There was no overt 
toxicity up to the maximum feasible doses tested with once daily intravenous (IV) administration 
up to 4 weeks. The no observed-adverse-effect-level was set at the maximum doses tested 
(1,000 mg/kg/day in rats and 500 mg/kg/day in cynomolgus monkeys). Nacubactam was also 
tested in combination with cefepime or aztreonam in 28 day-repeat IV dose combination studies 
in rats. There was no exacerbation of toxicity derived from each test substance or new toxicity 
observed. 
The genotoxicity, reproductive and developmental toxicity (fertility and early embryonic 
development to implantation and embryo-fetal development), antigenicity, and phototoxicity were 
investigated, and none identified findings of concern. 
1.3 
Clinical Pharmacology Studies 
Table 2 provides an overview of completed clinical pharmacology studies.  
 
 

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Table 2. Overview of Clinical Pharmacology Studies 
Study No. 
(Country)  
Objectives 
No. of  
Subjects 
Dose of 
Nacubacta
m 
Concomitan
t Drug 
Administrat
ion  
Population  
OP0595-1 
(Australia) 
Safety, 
tolerability, and 
PK 
40 
0.05, 0.15, 
0.5, 1, and 2 g 
and placebo 
- 
Single dose 
Healthy male 
volunteers  
OP0595-2 
(Japan) 
Safety, 
tolerability, and 
PK 
20 
1 and 2 g and 
placebo 
- 
Single dose 
and repeated 
administration 
Healthy male 
volunteers 
8 
4 g and 
placebo 
- 
Single dose 
OP0595-3 
(Japan) 
Safety, 
tolerability, and 
PK 
8 
2 g  
Cefepime 2 g 
Single dose 
Healthy male 
volunteers 
8 
Aztreonam 
2 g 
8 
Meropenem 
2 g 
8 
Piperacillin 
4 g 
OP0595-4 (Japan) 
Safety, 
tolerability, and 
PK 
8 
2 g and 
placebo 
Cefepime 2 g 
Repeated 
administration 
Healthy male 
volunteers 
8 
Aztreonam 
2 g 
NP30052 (United 
States) 
Safety, 
tolerability, and 
PK 
16 
1 and 2 g and 
placebo 
- 
Repeated 
administration 
Healthy male 
and female 
volunteers 
15 
4 g and 
placebo 
- 
Single dose 
and repeated 
administration 
8 g and 
placebo 
Single dose 
15 
2 g and 
placebo 
Meropenem 
2 g 
Single dose 
and repeated 
administration 
NP39380 (United 
States) 
PK parameters of 
nacubactam in 
patients with renal 
impairment and 
ESRD 
29 
1 g  
- 
Single dose 
Patients with 
renal 
impairment 
NP39596 (Latvia, 
Serbia, Poland, and 
United States) 
PK variability in 
patients with 
cUTI 
20 
2 g  
Meropenem 
2 g 
Repeated 
administration 
Patients with 
a cUTI 
NP39750 (United 
States) 
Characterization 
of intrapulmonary 
penetration 
21 
2 g  
Meropenem 
2 g 
Single dose 
Healthy male 
and female 
volunteers 
cUTI = complicated urinary tract infection; No. = number; PK = pharmacokinetic(s); ESRD = end-stage renal disease. 
1.3.1 
Study OP0595-1 (Australia) 
Following a 30-minute IV infusion, the nacubactam plasma profile peaked at 30 minutes 
post-infusion followed by a decrease in plasma levels. Apparent terminal elimination half-life (t½) 
for nacubactam was 1.8 hours (nacubactam 0.15 g group) to 2.4 hours (nacubactam 2 g group). 
The maximum observed plasma concentration (Cmax) ranged from 2.7 μg/mL (nacubactam 0.05 g 
group) to 112.2 µg/mL (nacubactam 2 g group). Area under the plasma concentration-time curve 
(AUC) from time 0 to infinity (AUC0-∞) ranged from 5.2 μg∙hr/mL (nacubactam 0.05 g group) to 
229.2 µg∙hr/mL (nacubactam 2 g group). Cmax and AUC0-∞ increased dose-dependently. 
Treatment-emergent adverse events (TEAEs) were reported in 30% of subjects (12 of 40 subjects). 
The incidence of TEAEs was 33.3% (2 of 6 subjects) in the nacubactam 0.05, 0.5, and 1 g groups, 

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respectively, 16.7% (1 of 6 subjects) in the nacubactam 0.15 g and 2 g groups, respectively, and 
40.0% (4 of 10 subjects) in the placebo group. All TEAEs recovered on or before Day 14. 
The most frequently reported TEAE was headache. Events considered possibly related to the 
investigational product were headache reported in 3 subjects. All other TEAEs were considered to 
be not related or unlikely related to the investigational product. 
There were no serious adverse events (SAEs) or deaths reported and no subjects were withdrawn 
from the study due to a TEAE. No clinically important abnormal findings or changes were reported 
in vital signs, electrocardiograms (ECGs), physical findings, or laboratory parameters, such as 
blood chemistry and urinalysis, including items affected by renal function such as 
N-acetyl-β-d-glucosaminidase and β2-microglobulin. 
1.3.2 
Study OP0595-2 (Japan) 
The Cmax and AUC0-∞ of plasma nacubactam increased with increasing dosage after single IV 
administration (90-minute IV infusion) of nacubactam 1, 2, or 4 g, and dose proportionality was 
confirmed. The Cmax and AUC0-∞ of plasma nacubactam also increased with increasing dosage 
after multiple IV administrations (over 90-minute IV infusion) of nacubactam 1 or 2 g three times 
a day (TID) for 7 days. The minimum observed plasma concentration (Cmin) values on Day 4 (the 
second day of multiple administrations) and later were almost constant, and values of Cmax and 
AUC0-∞ on Day 9 (the seventh day of multiple administration) were almost the same as those in 
the single administration, and it was considered that nacubactam reached its steady state promptly 
after the start of administration with little accumulation.  
In addition, almost all of nacubactam was excreted in the urine in the unchanged form by 24 hours 
after the single administration of nacubactam (Day 1) and on the seventh day of multiple 
administrations (Day 9), and nacubactam was considered to be a type of drug with renal excretion. 
Regarding the safety of nacubactam after single and multiple administrations, no safety issue was 
reported, as there were no SAEs, and the grade of adverse events (AEs) developed were mild, 
recovered without treatment, or the causal relationship with the investigational drug was judged to 
be not related. 
The effect of nacubactam administration on the QT/QTc interval was investigated, and 
prolongation of the QT/QTc interval associated with the increase in the plasma nacubactam 
concentration was not reported. 
1.3.3 
Study OP0595-3 (Japan) 
When a single dose of nacubactam 2 g with concomitant administration of each concomitant drug 
(cefepime 2 g, aztreonam 2 g, meropenem 2 g, and piperacillin 4 g) was administered IV over a 
period of 60 minutes to Japanese healthy adult males, the plasma concentrations of nacubactam 
were similar to those after administration of nacubactam alone. The urinary excretion rate of 
nacubactam did not change with concomitant drug administration. Based on these findings, it was 
confirmed that administration of nacubactam with concomitant administration of cefepime, 
aztreonam, meropenem, or piperacillin did not affect the pharmacokinetics (PK) of nacubactam. 
When nacubactam was concomitantly administered, plasma concentrations of cefepime, 
aztreonam, meropenem, or piperacillin were similar to those of administration of each concomitant 
drug alone. The urinary excretion rate of each concomitant drug did not change with the 

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administration of nacubactam. Based on these findings, it was confirmed that administration of 
each concomitant drug with concomitant administration of nacubactam did not affect the PK of 
cefepime, aztreonam, meropenem, and piperacillin. 
As a result of investigating the safety of nacubactam and each concomitant drug as single 
administration, and nacubactam with each concomitant drug as combination administration, no 
SAEs or TEAEs leading to discontinuation of the investigational product were reported in any 
treatment conditions. All TEAEs reported were mild in severity, and the subjects recovered 
without treatment. The causality with the investigational product was judged to be not related. 
Based on these findings, the safety and tolerability after administration of nacubactam with 
concomitant administration of cefepime, aztreonam, meropenem, or piperacillin were confirmed. 
1.3.4 
Study OP0595-4 (Japan) 
Multiple IV administration of nacubactam 2 g with cefepime 2 g or aztreonam 2 g TID every 
8 hours for 7 days (60-minute IV infusion) in Japanese healthy adult males was conducted to 
investigate the safety, tolerability, and PK.  
Following multiple IV administration of nacubactam with cefepime TID for 7 days (60-minute IV 
infusion), the geometric mean ratios (Day 7/Day 1) of Cmax, AUC from time 0 to 8 hours (AUC0-8), 
and AUC0-∞ for nacubactam and cefepime were all approximately 1.0 (1.0101 to 1.0956), and the 
changes in exposure of both drugs with multiple concomitant administrations were little. 
Following multiple IV administration of nacubactam with aztreonam TID for 7 days (60-minute 
IV infusion), the geometric mean ratios (Day 7/Day 1) of Cmax, AUC0-8, and AUC0-∞ for 
nacubactam and aztreonam were all approximately 1.0 (0.9102 to 1.0250), and the changes in 
exposure of both drugs with multiple concomitant administration were little. 
Plasma concentrations of nacubactam, cefepime, and aztreonam reached the steady-state up to 
Day 4, and the mean accumulation ratios based on Cmax and AUC0-8 were in the range of 0.9115 to 
1.0985. 
There were no SAEs in this study. There was 1 TEAE (seborrhoeic dermatitis) leading to the 
discontinuation of study in 1 subject in the “nacubactam with cefepime” group of cohort 1. All of 
the 3 TEAEs reported in the “nacubactam with cefepime” group of cohort 1 were mild. One subject 
with transaminases increased was reported as recovering without treatment, and one subject with 
haematuria recovered without treatment. One subject with seborrhoeic dermatitis recovered 
following the treatment provided. For all these TEAEs, the causality with the investigational 
product or concomitant drug was judged to be “not related.” 
1.3.5 
Study NP30052 (United States) 
Safety, tolerability, and PK were assessed following multiple IV administrations of nacubactam in 
non-Japanese healthy adult males and females. 
Tolerability of nacubactam after single IV administration from 1 to 8 g, or after multiple 
administrations from 1 to 4 g TID for 7 days by IV infusions over 1.5 hours or longer per 
administration were similar to placebo and no safety concern of clinical importance was reported. 
Tolerability was confirmed following a concomitant IV administration of nacubactam 2 g and 
meropenem 2 g administered as IV infusion over 1.5 hours via a double lumen catheter TID for 

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7 days. The safety profile of the concomitant IV administration was similar compared with that of 
meropenem alone. 
The PK of nacubactam was linear up to 4 g TID of multiple administrations or 8 g of single 
administration. No clinically important drug-drug interaction between nacubactam and 
meropenem was found. 
1.3.6 
Study NP39380 (United States) 
PK was examined following single IV administration of nacubactam 1 g over 0.5 hours in patients 
with decreased kidney function and with end stage renal failure. 
It was confirmed that renal impairment had a great effect on the PK of nacubactam. A good 
linearity was observed between renal function and clearance of nacubactam or renal clearance. 
Similar relationships were also obtained by multiple methods for measurement and estimation of 
renal function. No clear correlation was obtained between the distribution volume of nacubactam 
and renal function. The total exposure of nacubactam was higher in patients with decreased renal 
function than in subjects with normal renal function. Nacubactam was easily removed by 
hemodialysis, and was removed over 60% on average with 4 hours of hemodialysis. The clearance 
of nacubactam with dialysis was estimated to be approximately 10 L/hr. 
Nacubactam was well tolerated in all subjects receiving a single dose of nacubactam 1 g, and no 
apparent effect on renal impairment was reported for the safety profile. 
1.3.7 
Study NP39596 (Latvia, Serbia, Poland, and United States) 
The PK was examined following multiple IV administrations (the maximum period of 
administration was 14 days) of nacubactam 2 g and meropenem 2 g TID over at least 1.5 hours in 
cUTI patients. 
No apparent changes were observed in apparent total body clearance, renal clearance, or apparent 
volume of distribution at steady state after multiple administration of nacubactam. Accumulation 
of plasma concentrations was limited after multiple TID doses, even in patients with decreased 
renal function. Inter-individual recovery of nacubactam in urine varied largely, but differences in 
plasma PK parameters were not large. 
The PK characteristics of meropenem in cUTI patients were confirmed, and they were consistent 
with the data obtained in other studies. 
The tolerability was confirmed after IV administration of nacubactam 2 g and meropenem 2 g TID 
for up to 14 days. No apparent issue on the safety was reported, and reported events were consistent 
with known safety profiles of meropenem. 
1.3.8 
Study NP39750 (United States) 
Intra-pulmonary transferability was examined following single IV administration of nacubactam 
2 g and meropenem 2 g over 1.5 hours via a double lumen catheter in non-Japanese healthy adult 
males and females. 
The concentration of nacubactam in the epithelial lining fluid (ELF) was about one-third of the 
corresponding plasma concentration at each time point, and the average ratio of the concentration 
in the ELF to the plasma concentration was 39%. 

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Since the ratio of ELF to plasma concentration was almost constant over the observation period 
and the estimated half-lives in ELF and plasma were comparable (1.82 and 1.71 hours, 
respectively), rapid equilibrium between ELF concentration and plasma concentration was 
considered. 
1.4 
Rationale for Dose Selection  
In setting the dose regimen for cefepime/nacubactam or aztreonam/nacubactam, a population PK 
(PPK) model has been developed using PK data from administration of nacubactam to healthy 
volunteers and volunteers with impaired renal function, and published PPK models were used for 
cefepime or aztreonam. The PK/pharmacodynamics (PD) target values for nacubactam in 
combination with cefepime or aztreonam were determined based on mainly in vitro 
one-compartment infection model and those for cefepime and aztreonam were identified from 
published literature. Monte Carlo simulation using the PPK models of the three drugs and MIC 
distributions of cefepime or aztreonam in combination with nacubactam was conducted to evaluate 
probability of target attainment (PTA).  
Dose levels of 2 g cefepime/1 g nacubactam or 2 g aztreonam/1 g nacubactam every 8 hours were 
selected for this study based principally on PTA analyses described above. 
When dose regimens of 2 g cefepime/1 g nacubactam or 2 g aztreonam/1 g nacubactam were 
assumed, maximum MIC at which probability of PK/PD targets exceeding 90% were 8 mg/L 
(European Committee on Antimicrobial Susceptibility Testing breakpoint for cefepime and 
aztreonam resistance) using net bacterial stasis in vitro PK/PD target, 4 mg/L using 1-log10 
colony-forming unit (CFU) reduction from baseline in vitro PK/PD target, and 2 mg/L using 
2-log10 CFU reduction from baseline in vitro PK/PD target, respectively.  
Namely, 2 g cefepime/1 g nacubactam or 2 g aztreonam/1 g nacubactam every 8 hours showed 
greater than 90% PTA at MIC90 value (2 mg/L) against target organisms.  
In addition, 1 g cefepime/1 g nacubactam or 1 g aztreonam/1 g nacubactam every 8 hours was able 
to reduce the bacterial burden and prevent the amplification of resistance sub-populations within 
the hollow fiber infection model using β-lactamase positive Enterobacterales, including 
carbapenemase-producing isolates, over the 10-day period.  
Therefore, 2 g cefepime/1 g nacubactam or 2 g aztreonam/1 g nacubactam every 8 hours were 
assumed to be more effective than 1 g cefepime/1 g nacubactam or 1 g aztreonam/1 g nacubactam 
every 8 hours.  
Furthermore, the cefepime/nacubactam and aztreonam/nacubactam dosing regimens by creatinine 
clearance (CrCl)-based dosing group were determined considering the consistency of Day 1 AUC 
values among simulated patients over the range of CrCl values evaluated relative to those for 
simulated patients with normal renal function after administration of 2 g cefepime/1 g nacubactam 
or 2 g aztreonam/1 g nacubactam every 8 hours.  
In previous clinical pharmacology studies, the safety and tolerability of nacubactam following a 
single IV infusion of nacubactam up to 8 g were confirmed in healthy Caucasian adult male 
subjects, and the safety and tolerability of a single IV infusion of nacubactam up to 4 g were also 
confirmed in healthy Japanese adult male subjects. Studies using a single dose of 2 g of 
nacubactam in combination with 2 g of β-lactams (meropenem, cefepime, or aztreonam) and 
multiple doses of 2 g of nacubactam in combination with 2 g of β-lactams (meropenem, cefepime, 

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or aztreonam) TID for 7 days were conducted and no severe AEs were observed. In addition, 
co-administration of 1 g of nacubactam and 1 g of β-lactams (cefepime or aztreonam) showed 
promising potency against causative pathogens in nonclinical PK/PD studies. And the selected 
dose and dosage regimen also considered to be safe based on the non-clinical studies.  
Overall, based on these results from clinical pharmacology studies (the PK and safety data) and 
non-clinical PK/PD studies, the dose of 2 g cefepime or 2 g aztreonam in combination with 1 g 
nacubactam every 8 hours was chosen for this study.  
1.5 
Risk/Benefit Assessment 
Summaries of findings from both clinical and nonclinical studies conducted with nacubactam can 
be found in the IB. The following sections outline the risk assessment for this protocol. 
1.5.1 
Risk Assessment 
There are no important identified risks associated with the use of nacubactam. 
1.5.2 
Benefit Assessment 
Nacubactam is a novel BLI in development for the treatment of serious Gram-negative bacterial 
infections. It has inhibitory activities encompassing Class A (ESBL and KPC) and Class C (AmpC) 
β-lactamases; it also acts as an antibiotic by inhibiting PBP2 of Enterobacterales and enhancing 
the activity of β-lactam agents, which mainly binds to penicillin-binding protein 3. 
When used with β-lactam antibiotics, nacubactam has been shown to be active against 
carbapenemase-producing Enterobacterales (including KPC and Class B [metallo-] and Class D 
[oxacillinase] carbapenemases) in in vitro and in vivo studies. 
1.5.3 
Overall Risk/Benefit Conclusion 
Nacubactam exhibited good safety and tolerability in repeat-dose nonclinical toxicology studies.  
Overall, no significant safety concerns have been prospectively identified about the use of the 
repeat-dose combination of nacubactam with cefepime or nacubactam with aztreonam in healthy 
volunteers. 
There were no serious adverse reactions or deaths identified in all clinical studies; one SAE of 
moderate musculoskeletal chest pain, considered unrelated to nacubactam and that resulted in 
interruption of study treatment, was reported in Study NP39596. The same patient in 
Study NP39596 later withdrew from study treatment because of diarrhea and nausea. One SAE of 
severe atrial fibrillation associated with hypertension, considered unrelated to nacubactam, was 
reported in Study NP39380. One AE leading to withdrawal from study treatment was mild 
seborrhoeic dermatitis that occurred in Study OP0595-4. No subjects were withdrawn because of 
an AE in any other company-sponsored interventional studies. 
The overall clinical safety profile is favorable to the risk/benefit assessment of nacubactam. 

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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to assess the efficacy and safety of cefepime/nacubactam 
and to assess the safety of aztreonam/nacubactam administered by IV infusion compared to 
imipenem/cilastatin in patients with cUTI or acute uncomplicated pyelonephritis (AP). 
2.2 
Secondary Objectives 
The secondary objectives of this study are the following: 
• To assess the efficacy of aztreonam/nacubactam administered by IV infusion in patients with 
cUTI or AP; 
• To assess the efficacy of cefepime/nacubactam and aztreonam/nacubactam administered by IV 
infusion in patients with secondary bacteremia due to cUTI or AP; 
• To assess the PK of cefepime/nacubactam and aztreonam/nacubactam administered by IV 
infusion in patients with cUTI or AP; and 
• To 
assess 
clinical 
and 
microbiological 
response 
of 
cefepime/nacubactam 
and 
aztreonam/nacubactam administered by IV infusion per type of pathogen, type of resistance, 
and antimicrobial susceptibility. 

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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a multi-center, randomized, double-blind study to evaluate the efficacy and safety of 
cefepime/nacubactam or aztreonam/nacubactam compared to imipenem/cilastatin for the 
treatment of cUTI or AP, in adults.  
In this study, the efficacy and safety of cefepime/nacubactam is primarily evaluated because 
cefepime has a broader antibacterial spectrum (Gram-positive and Gram-negative bacteria) and 
cefepime/nacubactam is expected to be frequently used for infections caused by Class A and/or D 
carbapenemase-producing Enterobacterales while aztreonam has an indication only for 
Gram-negative bacteria and aztreonam/nacubactam is positioned to be used only for infections 
caused by Class B carbapenemase-producing Enterobacterales in principle. 
Approximately 600 patients will be randomized in a 2:1:1 ratio to receive either 2 g cefepime/1 g 
nacubactam, 2 g aztreonam/1 g nacubactam, or 1 g imipenem/1 g cilastatin.  
Dosage of cefepime, aztreonam, nacubactam, and imipenem/cilastatin according to renal function 
is shown in Table 4. 
Randomization will be stratified by entry diagnosis (cUTI or AP) and by geographic region (Japan, 
China, or Other). At least 30% of patients will have a diagnosis of AP and at least 60% will have 
a diagnosis of cUTI.  
Patients with secondary bacteremia (defined as an organism[s] isolated from a non-contaminated 
blood culture that is the same as the cUTI/AP-qualifying organism[s] isolated from a urine culture 
or genitourinary tissue culture) will be included in the study, but categorized by the primary 
indication and recorded as having secondary bacteremia. 
Study drug will be administered every 8 hours (± 1 hour) via an IV infusion over a period of 
60 minutes (± 15 minutes). All patients will be treated for a minimum of 5 days (ie, 15 IV 
infusions) to 10 days. Duration may continue for up to 14 days in selected situations (eg, baseline 
bacteremia), after discussion with the Medical Monitor. Patients will return for 2 follow-up visits: 
a Test of Cure visit (TOC) (7 [± 2] days after End of Treatment (EOT) [Day 10 to 23]) and a 
Follow-Up visit (FUP) (14 [±2] days after EOT [Day 17 to 30]). Patients who withdraw from the 
study early will undergo an Early Termination (ET) visit. Study drug administration should be 
discontinued in patients whose baseline urine culture does not meet the requirements for a baseline 
qualifying pathogen and, in the opinion of the Investigator, the patient does not have a UTI and 
the patient is not improving.  
For instances when a patient grows only a Gram-negative organism resistant to imipenem and/or 
meropenem, the patient should discontinue study drug but may remain in the study to complete all 
study assessments. 
Figure 1 presents a schematic of the study design.  

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Figure 1. Study Design 
 
AP = acute uncomplicated pyelonephritis; cUTI = complicated urinary tract infection; EA = Early Assessment; EOT = End of 
Treatment; FUP = Follow-Up visit; TOC = Test of Cure visit. 
Patients with a qualifying Gram-negative uropathogen coinfected (or suspected to be coinfected) 
with a Gram-positive uropathogen detected after randomization may be administered narrow 
spectrum, open-label glycopeptide (eg, vancomycin), oxazolidinone (eg, linezolid), or daptomycin 
concomitantly with the blinded study drug at the Investigator’s discretion. Investigators should 
discuss such cases with the Medical Monitor.  
Patients will be monitored for safety throughout the duration of the study. Safety assessments will 
include vital signs, physical examinations, clinical laboratory assessments, AE assessments, and 
12-lead ECGs. A urine and/or serum pregnancy test will be performed at Screening and FUP/ET 
for female patients of childbearing potential only and postmenopausal women < 50 years of age, 
if the follicle-stimulating hormone (FSH) level is not available at the time of randomization.  
An independent Data Safety Monitoring Board (DSMB) will review accumulated safety data and 
will also review SAEs on an ongoing basis. The DSMB will make recommendations based on the 
safety data. Further details regarding the data safety monitoring guidelines will be included in the 
DSMB Charter. 
3.2 
Study Indication 
The indication for this study is the treatment of cUTI and AP.  

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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
4.1 
Inclusion Criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Male or female patients ≥ 18 years of age (or age of legal consent, whichever is older) at the 
time of obtaining informed consent and who can be hospitalized throughout the Treatment 
Period; 
2. Weight ≤ 140 kg; 
3. Expectation, in the opinion of the Investigator, that the patient’s cUTI or AP will require 
treatment with at least 5 days of IV antibiotics; 
4. Diagnosis of cUTI or AP as defined in the tables below: 
Note: If a patient meets the criteria for cUTI below and also has flank pain or costo-vertebral 
angle tenderness, the patient will be randomized as cUTI instead of AP. 

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cUTI 
Signs or symptoms evidenced by 
at least 2 of the following 
Pyuria evidenced by 1 of the 
following 
At least 1 of the following 
associated risks 
• 
Chills, rigors, or fever. Fever 
(oral or tympanic temperature 
≥ 38°C 
[≥ 100.4°F] 
or 
rectal/core 
temperature 
≥ 38.3°C [≥ 100.9°F]) must be 
observed and documented by a 
healthcare 
provider 
within 
24 hours of Screening; 
• 
Suprapubic, pelvic, or lower 
abdominal pain; 
• 
Nausea or vomiting within 
24 hours of Screening; 
• 
Dysuria, 
increased 
urinary 
frequency, or urinary urgency; 
or 
• 
Elevated 
WBC 
count 
(> 10,000/mm3) or left shift 
(> 15% immature PMNs).  
• 
Positive leukocyte esterase on 
urinalysis; 
• 
WBC count ≥ 10/mm3 in 
unspun urine; or 
• 
WBC count ≥ 10/hpf in urine 
sediment. 
• 
Implanted 
urinary 
tract 
instrumentation (eg, ureteric 
stents or other urinary tract 
prosthetic material), ongoing 
intermittent 
bladder 
catheterization, or presence of 
an indwelling bladder catheter 
(Note: 
Indwelling 
bladder 
catheters that have been in place 
prior to Screening must be 
removed or replaced prior to 
collection of the Screening 
urine for urinalysis and culture, 
unless removal or replacement 
is 
considered 
unsafe 
or 
contraindicated); 
• 
Current known functional or 
anatomical abnormality of the 
urogenital 
tract, 
including 
anatomic abnormalities of the 
urinary 
tract, 
neurogenic 
bladder, or post-void residual 
urine volume of ≥ 100 mL 
within the past 6 months; 
• 
Partial obstructive uropathy 
(eg, nephrolithiasis, fibrosis, 
urethral 
stricture) 
that 
is 
expected to be medically or 
surgically treated during study 
drug therapy (prior to EOT); 
• 
Urinary retention, including 
urinary retention in men due to 
previously diagnosed BPH; or 
• 
Azotemia, defined as blood 
urea nitrogen > 20 mg/dL 
(> 7.14 mmol/L) (or blood urea 
> 42.8 mg/dL 
[> 7.13 mmol/L]), 
or 
serum 
creatinine 
> 1.4 
mg/dL 
(>123.79 
µmol/L), 
due 
to 
known prior intrinsic renal 
disease. 
BPH = benign prostatic hyperplasia; cUTI = complicated urinary tract infection; EOT = End of Treatment; hpf = high-power 
field; PMN = polymorphonuclear leukocyte; WBC = white blood cell. 
 

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AP 
Signs or symptoms evidenced by 
at least 2 of the following 
Pyuria evidenced by 1 of the 
following 
At least 1 of the following 
associated risks 
• 
Chills, rigors, or fever. Fever 
(oral or tympanic temperature 
≥ 38°C [≥ 100.4°F] or 
rectal/core temperature 
≥ 38.3°C [≥ 100.9°F]) must be 
observed and documented by a 
healthcare provider within 
24 hours of Screening; 
• 
Flank pain (onset within 7 days 
prior to randomization); 
• 
Costo-vertebral angle 
tenderness on physical 
examination; 
• 
Nausea or vomiting within 
24 hours of Screening; 
• 
Dysuria, increased urinary 
frequency, or urinary urgency; 
or 
• 
Elevated WBC count 
(> 10,000/mm3) or left shift 
(> 15% immature PMNs). 
• 
Positive leukocyte esterase on 
urinalysis; 
• 
WBC count ≥ 10/mm3 in 
unspun urine; or 
• 
WBC count ≥ 10/hpf in urine 
sediment. 
Not applicable. 
AP = acute uncomplicated pyelonephritis; hpf = high-power field; PMN = polymorphonuclear leukocyte; WBC = white blood 
cell. 
5. Patient has a baseline positive urine culture specimen obtained within 48 hours prior to the first 
dose of study drug; 
Note: Patients may be enrolled in this study and start IV study drug therapy before the 
Investigator knows the results of the baseline urine culture, if all other entry criteria are 
fulfilled. If known, the screening/baseline urine culture taken within 48 hours prior to the first 
dose of study drug contains ≥ 105 CFU/mL of a Gram-negative uropathogen susceptible to 
meropenem and imipenem, and the culture is not considered contaminated. If a patient grows 
≥ 3 bacterial organisms ≥ 105 CFU/mL in the urine, the urine culture will be considered 
contaminated. An organism will not be considered a contaminant if the organism grows 
≥ 105 CFU/mL in a urine culture and also grows in a concurrently obtained blood culture. If a 
patient’s baseline urine culture is negative after randomization, the Investigator decides 
whether the patient should continue to receive the study drug or should discontinue the study 
drug and initiate non-study antibiotics. 
Note: Imipenem and meropenem susceptible pathogen is defined as a Gram-negative pathogen 
by susceptibility data of minimum inhibitory concentration (MIC) less than 2 µg/mL to 
imipenem and meropenem OR imipenem and meropenem disk diffusion (zone diameter 
≥ 22 mm). If MIC or disk diffusion data are not available in the local laboratory or before the 
availability of MIC or disk diffusion results, each site can use other susceptibility testings and 
criteria in the institution as the initial evidence of imipenem and meropenem susceptible 
pathogen for enrollment. In any case, pathogen identification and susceptibility testing 
performed at the central laboratory will be used to determine imipenem and meropenem 
susceptible pathogen in the final study analysis. 

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6. Female patients who are no longer of childbearing potential must meet 1 of the following 
criteria: 
a. Women ≥ 50 years of age who are considered postmenopausal as they have been 
amenorrhoeic for ≥ 12 months; 
b. Women < 50 years of age who are considered postmenopausal as they have been 
amenorrhoeic for ≥ 12 months and if the FSH level is in the postmenopausal range. If the 
FSH level is not available at the time of randomization, the patient must have a negative 
urine and/or serum pregnancy test and agree to use contraception methods until the FSH 
result is available; or 
c. Documented permanent sterilization, defined as hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy. 
7. Female patients of childbearing potential must have a negative urine and/or serum pregnancy 
test (serum β-human chorionic gonadotropin) at Screening; 
Note: Females of childbearing potential include female patients who have experienced 
menarche (or begin menarche over the course of the study), and who are not postmenopausal 
or permanently sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral 
salpingectomy). 
8. Patients must agree to use contraception methods as defined below:  
a. Female patients of childbearing potential will be included if they are either sexually 
inactive (abstinent) for 90 days prior to the first dose of study drug, or are using one of the 
following highly effective birth control methods (ie, results in < 1% failure rate when used 
consistently and correctly): 
i. Intrauterine device in place for at least 3 months prior to the first dose of study 
drug and throughout the study; 
ii. Surgical sterilization of the partner (provided they are the sole sexual partner), 
defined as vasectomy for 6 months minimum and assessed as surgical success; 
iii. Combined (estrogen or progestogen containing) hormonal contraception 
associated with the inhibition of ovulation (either oral, intravaginal, or 
transdermal); 
iv. Progestogen only hormonal contraception associated with the inhibition of 
ovulation (either oral, injectable, or implantable); 
v. Intrauterine hormone releasing system; or 
vi. Bilateral tubal occlusion. 
Note: Sexual abstinence or use of contraceptive measures must continue throughout the study 
and for 12 weeks after the last dose of study drug. 
Note: Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. In this study, abstinence is only acceptable if in line with the patient’s preferred 
and usual lifestyle. Periodic abstinence (calendar, symptothermal, post-ovulation methods), 

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withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea methods are not 
acceptable methods of contraception. 
b. Male patients with female partners of childbearing potential must use highly effective 
methods of birth control during their participation in the study and for 12 weeks after the 
last dose of study drug. In addition, male patients with female partners of childbearing 
potential must also use a condom during their participation in the study and for 12 weeks 
after the last dose of study drug. 
Note: Highly effective methods of birth control for male patients enrolled in the study include 
the following: surgical sterilization (vasectomy assessed as surgical success) of patient at least 
6 months before Screening or a female partner of childbearing potential (provided they are the 
sole female sexual partner) using highly effective contraception as described in Inclusion 
Criterion #8a). 
9. Female patients must agree to not donate eggs, or retrieve eggs for her own use from the time 
of informed consent until 12 weeks after the last dose, or male patients must agree to not freeze 
or donate sperm starting from the time of informed consent until 12 weeks after the last dose; 
10. Willing to comply with all study activities and procedures, whether in the hospital or after 
discharge, for the duration of the study; and 
11. Able to provide signed, written informed consent prior to any study-related procedures being 
performed. 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Has a known imipenem- and/or meropenem-resistant Gram-negative uropathogen 
(≥ 105 CFU/mL), isolated from study-qualifying urine culture; 
Note: If after randomization the susceptibility testing indicates resistance to imipenem and/or 
meropenem, the patient may remain on the study at the Investigator’s discretion. 
2. Has known or suspected single or concurrent infection with Acinetobacter spp. or other 
organisms that are not adequately covered by the study drug (eg, concurrent viral, 
mycobacterial, or fungal infection) and needs to be managed with other anti-infectives; 
Note: Patients with qualifying pathogen coinfected (or suspected to be coinfected) with a 
Gram-positive pathogen may be administered narrow spectrum, open-label glycopeptide (eg, 
vancomycin), oxazolidinone (eg, linezolid), or daptomycin concomitantly with the study drug 
at the Investigator’s discretion.  
3. Has only a known Gram-positive primary uropathogen (≥ 105 CFU/mL), isolated from 
study-qualifying urine culture;  
4. Has a known study-qualifying urine culture with ≥ 3 bacterial organisms ≥ 105 CFU/mL; 
Note: A Gram-negative organism will not be considered a contaminant if the organism grows 
≥ 105 CFU/mL in a urine culture and also grows in a concurrently obtained blood culture. 
5. Has a complete obstruction of any portion of the urinary tract that is not anticipated to be 
medically or surgically relieved during this study therapy and before EOT; 

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6. Has a previous or planned cystectomy or permanent urinary diversion (eg, ileal loop, cutaneous 
ureterostomy); 
7. Has a refractory vesicoureteral reflux (Grade 4 or 5); 
8. Has a suspected or confirmed perinephric or renal corticomedullary abscess or polycystic 
kidney disease; 
9. Has suspected or confirmed prostatitis, orchitis, epididymitis, urethritis, or sexually transmitted 
disease; 
10. Has a non-renal source of infection concurrently that could interfere with the evaluation of 
response to the study drug; 
11. Has any recent history of accidental trauma to the pelvis (in the pelvic cavity) or urinary tract; 
12. Requires bladder irrigation with antibiotics or requires antibiotics to be administered directly 
via urinary catheter; 
13. Has received a potentially effective systemic antibacterial therapy within 48 hours prior to the 
first dose of study drug, with the exception of any of the following: 
a. Receipt of a single dose of a short-acting antibacterial agent (APPENDIX C) (no more than 
15% of patients will be enrolled with this exception); 
b. Receipt of > 48 hours of prior antibiotic therapy and, in the Investigator’s opinion, failed 
that prior antibiotic therapy (ie, worsening signs and symptoms); or 
c. Documented to have cUTI or AP caused by a pathogen that is not susceptible to the prior 
antibiotic therapy. 
14. Has a history of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious allergic 
reaction to carbapenems, cephems, penicillins, other β-lactam antibiotics, or any BLIs 
(eg, tazobactam, sulbactam, or clavulanic acid); 
15. Has a history of epilepsy or known seizure disorder (excluding a history of childhood febrile 
seizures); 
16. Is considered unlikely to survive the study period or has a rapidly progressive or terminal 
illness; 
17. Is a female patient who is pregnant or breastfeeding; 
18. Is a female patient who expects to be pregnant or a male patient who expects their partner to 
be pregnant from the time of informed consent until 12 weeks after the last dose;  
19. Has current or anticipated neutropenia (< 500 polymorphonuclear neutrophils/mm3, obtained 
from the local laboratory at Screening); 
20. Has platelet count < 50,000 per microliter; 
21. Has renal transplantation and received antibacterial drug prophylaxis within 48 hours before 
screening and/or likely to receive antibacterial drug prophylaxis during the study period; 
22. Has participated in other clinical study within 90 days before this clinical study, or plans to 
participate in any other clinical study during the course of the study;  

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23. Has an estimated CrCl < 30 mL/min or > 240 mL/min based on the Cockcroft-Gault formula 
or is receiving hemodialysis or peritoneal dialysis; 
24. Has prior exposure to nacubactam alone or in combination with another product; 
25. Has gross hematuria that is not caused by infectious diseases; 
26. Meets Hy’s criteria of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
> 3 × upper limit of normal (ULN) and total bilirubin > 2 × ULN;  
Note: Patients with AST and/or ALT up to 5 × ULN are eligible if these elevations are acute 
and are documented as being directly related to the infectious process being treated.  
27. Has evidence of significant hepatic disease or dysfunction, including known acute viral 
hepatitis or hepatic encephalopathy; 
28. Has manifestations of end-stage liver disease, such as ascites or hepatic encephalopathy; 
29. Has a known history of HIV with either a cluster of differentiation 4 count < 200 cells/mm3 at 
the last measurement or current diagnosis of another acquired immunodeficiency 
syndrome-defining illness; 
30. Has an uncomplicated UTI except AP (acute uncomplicated cystitis that does not meet the 
cUTI disease definition [see Inclusion Criterion #4]); 
31. Has any condition that, in the opinion of the Investigator, would compromise the safety of the 
patient or the quality of the data (eg, due to underlying disease, comorbidity, clinically 
meaningful laboratory abnormality), including a potential concern about a history of a disease 
that may compromise the safety of the patient during the course of the study (eg, history of 
clinically significant QT interval prolongation, clinically important congenital syndromes, 
etc); 
Note: Patients with electrolytes that are above or below the normal value range and deemed by 
the PI to be clinically significant may be excluded.  
32. Is anticipated to begin a new drug that is classified as high risk of prolonging the QT interval 
(listed in APPENDIX D) during the treatment period; 
Note: If patients have been using the drugs listed in APPENDIX D prior to the enrollment and 
need to continue using them and patient meets all entry criteria, the patient can be enrolled and 
continue using them during the study period.  
33. Heart-rate-corrected QT interval by the Fridericia formula (QTcF) > 470 msec at Screening;  
Note: If QTcF exceeds 470 msec, the ECG may be repeated 2 more times after rest and the 
mean of the 3 values will be used to determine the subject’s eligibility. 
34. Clinically significant bradycardia with a heart rate <50 bpm;  
Note: Patients with such a low heart may have their heart rate repeated up to 2 additional 
times to determine eligibility. 
35. Diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); and 
Note: A SARS-CoV-2 test (genetic testing will be suggested but other antigen testing is 
allowed) should be conducted at Screening for highly suspected Coronavirus Disease 2019 

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(COVID-19) patients at the Investigator’s discretion. Patients who are tested for SARS-CoV-2 
will be started on study drug only after a negative result is confirmed. 
Note: Patients eligible for the study with the exception of meeting COVID-19 criteria will be 
allowed to rescreen more than 2 weeks after testing positive and must have a negative test 
result for eligibility.  
36. Is using or planning to use any of the excluded medications and/or procedures except opioids 
and urinary anesthetics listed in Section 5.6.1 within the time period specified. 
4.3 
Withdrawal Criteria 
Patients may be discontinued from study drug for any of the following reasons but will still be 
followed for safety assessments approximately 7 to 14 days after Early Termination (ET): 
1. Occurrence of a TEAE that warrants study drug discontinuation in the judgment of the 
Investigator;  
2. Occurrence of exacerbation of underlying disease that warrants study drug discontinuation in 
the judgment of the Investigator; 
3. Patient ineligibility after the start of the study in the judgment of the Investigator; 
4. Required use of prohibited concomitant medications except urinary anesthetics and opioid 
drugs; 
5. Significant prolongation of the QT/QTc interval (QTcF > 500 msec or increase from baseline 
> 60 msec) as measured by the mean of 3 values after study drug administration; or 
6. Occurrence of an event that warrants discontinuation in the judgment of the Investigator. 
Participation of a patient in this clinical study may be discontinued for any of the following 
reasons: 
1. The patient withdraws consent or requests discontinuation from the study for any reason;  
2. Pregnancy;  
3. Termination of the study by the Sponsor or the regulatory authority; or 
4. The patient is suspected/diagnosed with SARS-CoV-2 infection and warrants discontinuation 
in the judgment of the Investigator. 
5. Insufficient therapeutic effect of the study drug that could lead to clinical worsening, or lack 
of clinical progress in the judgement of investigators; 
If a patient withdraws prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete the full panel of assessments scheduled for the 
ET visit. The reason for patient withdrawal must be documented in the electronic case report form 
(eCRF).  
Patients who discontinue from study drug and complete the ET visit but are not discontinued from 
the study should continue to complete all safety assessments approximately 7 to 14 days after ET. 
AE assessment must be performed, but other assessments should be performed at the discretion of 
the Investigator, if clinically indicated. 

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In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records. 
Withdrawn patients will not be replaced.  

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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Approximately 600 patients who have a diagnosis of cUTI or AP will be randomized in a 
2:1:1 ratio to 1 of the following 3 treatment groups:  
• 2 g cefepime/1 g nacubactam every 8 hours for at least 5 days and up to 14 days via IV infusion 
over a period of 60 minutes;  
• 2 g aztreonam/1 g nacubactam every 8 hours for at least 5 days and up to 14 days via IV 
infusion over a period of 60 minutes; or 
• 1 g imipenem/1 g cilastatin every 8 hours for at least 5 days and up to 14 days via IV infusion 
over a period of 60 minutes.  
A summary of study drug information is provided in Table 3.  
Table 3. Study Drug 
Study Drug 
Name 
Cefepime 
Aztreonam 
Nacubactam 
Imipenem/Cilastatin 
Dose/dosing 
schedule1 
2 g/every 8 hours for at least 5 days 
and up to 14 days over a period of 
60 minutes 
1 g/every 8 hours for at least 5 days and up to 14 days over a 
period of 60 minutes 
Route of 
administration 
IV 
Dose stopping 
criteria 
If the discontinuation criteria are met. 
Treatment Period 
5 to 14 days 
Follow-up Periods 
14 (± 2) days after EOT 
Commercially or 
locally supplied 
Centrally 
Centrally2 
Centrally 
Centrally 
1. 
Dosage of cefepime, aztreonam, nacubactam, and imipenem/cilastatin according to renal function are shown in Table 4. 
2. 
Aztreonam in China will be distributed by Fobeni.  
EOT = End of Treatment; IV = intravenous. 
Dosage of cefepime, aztreonam, nacubactam, and imipenem/cilastatin according to renal function 
is shown in Table 4.  
5.2 
Rationale for Dosing 
Dose levels of 2 g cefepime/1 g nacubactam or 2 g aztreonam/1 g nacubactam every 8 hours were 
selected for this study based principally on percent probabilities of PK/PD target attainment using 
PPK models for cefepime, aztreonam, and nacubactam, nonclinical PK/PD targets for efficacy, in 
vitro surveillance data, and Monte Carlo simulation. 
In previous clinical pharmacology studies, the safety and tolerability of nacubactam following a 
single IV infusion of nacubactam up to 8 g were confirmed in healthy Caucasian adult male 
subjects, and the safety and tolerability of a single IV infusion of nacubactam up to 4 g were also 
confirmed in healthy Japanese adult male subjects. Studies using a single dose of 2 g of 
nacubactam in combination with 2 g of β-lactams (meropenem, cefepime, or aztreonam) and 
multiple doses of 2 g of nacubactam in combination with 2 g of β-lactams (meropenem, cefepime, 
or aztreonam) TID for 7 days were conducted and no severe AEs were observed. In addition, 
co-administration of 1 g of nacubactam and 1 g of β-lactams (cefepime or aztreonam) showed 

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promising potency against causative pathogens in nonclinical PK/PD studies. And the selected 
dose and dosage regimen also considered to be safe based on the non-clinical studies. 
Given these results, the proposed dose regimen for this study (2 g of cefepime/1 g of nacubactam 
or 2 g aztreonam/1 g nacubactam, every 8 hours) was deemed to be safe and potent against 
pathogens from target indications (cUTI/AP) (see Section 1.4). 
Dose adjustments will be made for patients with renal insufficiency (see Section 5.5.3.1). 
5.3 
Randomization and Blinding 
5.3.1 
Randomization 
Patients will be randomized to receive either cefepime/nacubactam, aztreonam/nacubactam, or 
imipenem/cilastatin through a centralized Interactive Response Technology (IRT). The patient will 
be randomized after the inclusion and exclusion criteria are verified. A manual will be provided 
that describes the IRT and includes complete user instructions. 
To ensure balance among treatment arms, the randomization will be stratified by type of infection 
(AP or cUTI) and geographic region (Japan, China, or Other). 
Enrollment of patients who have received a single dose of a short-acting oral or IV antibacterial 
agent for cUTI within 48 hours prior to the first dose of study drug will be limited to 15% of 
patients. 
In order to enroll at least 30% of patients with a diagnosis of AP, enrollment for cUTI should be 
no more than 70% but at least 60% of all randomized patients.  
After fulfillment of all study entry criteria, patients will be assigned a treatment assignment number 
via the IRT. In a randomization notification addressed only to the unblinded pharmacist (or 
appropriately qualified unblinded designee) at the study site, the treatment assignment number and 
corresponding treatment assignment will be specified. Patients will be randomized in a 2:1:1 ratio. 
A blinded randomization notification will be sent to the appropriate blinded site personnel. 
5.3.2 
Blinding 
The Investigator, site personnel, Sponsor, and the Sponsor's designees involved in blinded 
monitoring, data management, or other aspects of the study will be blinded to treatment 
assignment. The site pharmacist or qualified designee who will prepare the IV infusion solution 
will be unblinded so that he/she may obtain the assigned drug and prepare the IV dosing solutions. 
The drug supply itself will not be blinded. The infusion bag containing the reconstituted study drug 
will be identified with the patient’s identification number, but will not identify the specific drug 
product. An amber IV bag cover will be placed over the infusion bag for every patient to aid in 
maintaining the blind. Refer to the Pharmacy Manual for further instruction on maintaining the 
blind during the study. The vendor who will conduct PK measurement will be also unblinded. For 
the details of blinding, a separate document will be prepared and followed.  
There will be a limited unblinded team at the Sponsor and Contract Research Organization (CRO) 
to support the study pharmacists/designees who will have access to treatment assignment 
information. The unblinded Sponsor and CRO team will not be involved in review of the clinical 
database or decisions regarding patient care. 

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5.4 
Breaking the Blind 
Unblinding by request of an Investigator should occur only in the event of an emergency or AE 
for which it is necessary to know the study treatment to determine an appropriate course of therapy 
for the patient. If the Investigator must identify the treatment assignment of an individual patient, 
the Investigator or qualified designee should request the study drug information from the IRT. The 
documentation received from the IRT indicating the code break must be retained with the patient’s 
source documents in a secure manner so as not to unblind the treatment assignment to other site or 
Sponsor personnel. The Investigator is also advised not to reveal the study treatment assignment 
to other site or Sponsor personnel. 
Prior to unblinding, and if the situation allows, the Investigator should try to contact the site 
monitor or the Medical Monitor in order to get additional information about the study drug. If this 
is impractical, the Investigator must notify the site monitor or the Medical Monitor as soon as 
possible, without revealing the treatment assignment of the unblinded patient. The Investigator 
must document the patient identification and the date and time for breaking the blind and must 
clearly explain the reasons for breaking the code. 
For patients who are unblinded and withdrawn from the study, ET procedures should be 
completed.  
5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
Nacubactam is a white crystalline powder that is freely soluble in water and aqueous 0.9% sodium 
chloride solution. It is insoluble in ethanol and diethyl ether. Nacubactam is not hygroscopic.  
Each vial of nacubactam contains 1 g of nacubactam anhydride (sterile crystalline powder).  
Study drugs will be labeled according to the requirements of local law and legislation, as well as 
current Good Manufacturing Practices and Good Clinical Practice (GCP) guidelines.  
5.5.2 
Study Drug Preparation and Dispensing 
An unblinded pharmacist (or qualified designee) will prepare the study drug according to the 
requirements outlined in the Pharmacy Manual. The IV bags will be labeled with the date and time 
of study drug preparation and patient identification number using the study supplied labels and 
will be transferred to the blinded study staff for administration to the patient. Reconstituted study 
drug should be administered according to the requirements outlined in the Pharmacy Manual.  
5.5.3 
Study Drug Administration 
Study drug will be administered every 8 hours (± 1 hour) via an IV infusion over a period of 
60 minutes (± 15 minutes). The administration of nacubactam requires the use of an in-line filter, 
according to the details outlined in the Pharmacy Manual. All patients will be treated for a 
minimum of 5 days (ie, 15 IV infusions) to 10 days. Duration may continue for up to 14 days in 
selected situations (eg, baseline bacteremia), after discussion with the Medical Monitor. The time 
at which each infusion is started and stopped must be collected and recorded in the eCRF. Instances 
where the dose is interrupted by more than 10 minutes should be noted in the source documents. 
Infusions that fall outside of every 8-hour dosing (± 1 hour) will be captured as protocol deviations.  

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5.5.3.1 
Dosing in patients with renal insufficiency 
If CrCl is ≥ 30 and < 60 mL/min, patients will receive 1 g cefepime/0.5 g nacubactam or 1 g 
aztreonam/0.5 g nacubactam or 0.5 g imipenem/0.5 g cilastatin every 8 hours. If CrCl is ≥ 60 and 
< 90 mL/min, patients will receive 2 g cefepime/1 g nacubactam or 2 g aztreonam/1 g nacubactam 
or 0.75 g imipenem/0.75 g cilastatin every 8 hours. If CrCl is ≥ 90 and ≤ 240 mL/min, patients will 
receive 2 g cefepime/1 g nacubactam or 2 g aztreonam/1 g nacubactam or 1 g imipenem/1 g 
cilastatin every 8 hours. Dosage of nacubactam, cefepime, and aztreonam, and imipenem/cilastatin 
according to renal function are shown in Table 4.  
Table 4. Study Drug Dosage According to Renal Function 
CrCl (mL/min) 
Cefepime or 
Aztreonam (g) 
Nacubactam (g) 
Imipenem/Cilastatin 
(g) 
Interval (hour) 
≥ 90 and ≤ 240 
2 
1 
1/1 
8 
≥ 60 and < 90 
2 
1 
0.75/0.75 
8 
≥ 30 and < 60 
1 
0.5 
0.5/0.5 
8 
CrCl = creatinine clearance. 
For patients with moderate renal impairment at baseline whose CrCl drops below 30 mL/min after 
baseline, serum creatinine should be repeated to confirm the initial result and estimate CrCl. 
Patients may need to be discontinued from the study, according to the Investigator’s judgment or 
when the patient’s safety is at risk. 
CrCl will be calculated based on the Cockcroft-Gault formula: 
• Male: Creatinine clearance mL/min = (140 – age) × weight (kg) / (72 × serum creatinine 
[mg/dL]); and 
• Female: Creatinine clearance mL/min = 0.85 × ([140 – age] × weight [kg] / [72 × serum 
creatinine (mg/dL)]). 
5.5.4 
Treatment Compliance 
The infusion date, start and stop times, and volume of study drug administered IV will be recorded 
in the source documents and eCRF. Treatment compliance will be calculated based on the number 
of doses received and expected as detailed in the Statistical Analysis Plan (SAP).  
5.5.5 
Storage and Accountability 
The unblinded pharmacists or designated unblinded personnel will ensure that all study drugs are 
stored in a locked secured area (with access limited to appropriate study personnel) under 
recommended storage conditions and in accordance with the protocol. Study drug, nacubactam 
(1 g/vial, 14 vials/box), should be stored at 2 to 8°C. Concomitant drug, cefepime and aztreonam, 
and comparator, imipenem/cilastatin, should be stored according to the Pharmacy Manual. 
Further instructions for returning and/or destroying study drugs will be provided in the Pharmacy 
Manual.  

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5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
Treatment with any of the following concomitant medications or procedures is prohibited from 
randomization to EOT: 
• Valproic acid; 
Rationale: It may affect patient safety. 
• Divalproex sodium; 
Rationale: It may affect patient safety. 
• Probenecid; and 
Rationale: It may affect patient safety. 
• Drugs listed in APPENDIX D, but if patients have used the drugs listed in APPENDIX D prior 
to the enrollment and need to continue using them and all entry criteria have been fulfilled, the 
patient can be enrolled and continue using them during the study period. These drugs should 
be kept at a stable dose during the study period, to the extent possible. Should dosing need to 
be adjusted during the study period (ie, for the treatment of an AE or for the worsening of the 
underlying condition), these drugs should be used with caution.  
Rationale: It may affect patient safety. 
Treatment with any of the following concomitant medications or procedures is prohibited from 
time of obtaining informed consent to FUP: 
• Receipt of antibacterial drugs for surgical prophylaxis and subsequent development of cUTI 
or AP;  
Rationale: It may affect the efficacy assessments. 
• Receipt of antimicrobial prophylaxis for recurrent cUTI and subsequent presentation of signs 
and symptoms consistent with an active new cUTI or AP; 
Rationale: It may affect the efficacy assessments. 
• Immunosuppressive therapy such as cancer chemotherapy or medication for rejection of 
transplantation; 
Rationale: It may affect the efficacy assessments. 
• Bladder irrigation with antibiotics or antibiotics administered directly via urinary catheter; 
Rationale: It may affect the efficacy assessments. 
• Urinary tract surgery within 7 days prior to randomization or has urinary tract surgery planned 
during the study period (except surgery required for relieving an obstruction or placing urinary 
tract instrumentation); 
Rationale: It may affect the efficacy assessments. 

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• Non-study antibacterial drug therapy that would potentially affect the outcome of the 
evaluation of cUTI/AP, including but not limited to, antibacterials with potential activity 
against uropathogens, antibacterial drug prophylaxis, and antibacterial bladder irrigation (see 
Section 5.6.3); 
Rationale: It may affect the efficacy assessments. 
• Urinary anesthetics (eg, phenazopyridine hydrochloride), as these agents will interfere with 
clinical assessments; and 
Rationale: It may not affect the efficacy assessments directly, but it may affect some clinical 
symptoms because it is commonly used. 
• Opioid drugs. 
Rationale: It may not affect the efficacy assessments directly, but it may affect some clinical 
symptoms because it is commonly used. 
5.6.2 
Restricted Medications and/or Procedures 
Treatment with any of the following concomitant medications is restricted: 
• Drugs with antipyretic and analgesic effects (eg, non-steroidal anti-inflammatory drugs and 
acetaminophen): 
a. For on demand use, patients should refrain from using the drugs the day of and before 
clinical assessment of the Early Assessment (EA)/EOT/TOC/FUP to the extent possible; 
and 
b. For long-term use, the drugs should be used during the clinical study period (from obtaining 
informed consent to FUP) at a fixed dosage before the onset of symptoms of the primary 
disease to extent possible. 
Rationale: It may not affect the efficacy assessments directly, but it may affect some clinical 
symptoms because it is commonly used. 
• See APPENDIX C for a list of allowed and disallowed prior antibiotics.  
Rationale: It may affect the efficacy assessments. 
5.6.3 
Allowed Medications and/or Procedures 
Patients with a qualifying Gram-negative uropathogen coinfected (or suspected to be coinfected) 
with a Gram-positive uropathogen detected after randomization may be administered narrow 
spectrum, open-label glycopeptide (eg, vancomycin), oxazolidinone (eg, linezolid), or daptomycin 
concomitantly with the blinded study drug at the Investigator’s discretion. Investigators should 
discuss such cases with the Medical Monitor. 
5.6.4 
Documentation of Prior and Concomitant Medication Use 
Reasonable efforts will be made to determine all relevant treatment (concomitant medications, 
including all prescription/non-prescription medications, herbal medications, vitamin supplements, 
supportive therapies, and concomitant non-pharmacologic treatments) received by the patient 
within 14 days before administration of study drug and during the study, which will be recorded 

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in the eCRF. The medication name, route of administration, dose, frequency, indication, and 
duration of the treatment/procedure (start and stop dates) will be recorded. Concomitant treatments 
(non-pharmacologic treatments) include any surgical or diagnostic procedures. 

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6 
STUDY PROCEDURES 
Study procedures will follow the Schedule of Procedures (APPENDIX A).  
6.1 
Informed Consent 
Signed informed consent must be obtained before any study-related procedures are performed. See 
Section 11.3 for details on informed consent.  
6.2 
Screening Period 
Urine culture, blood culture, blood sampling and urine sampling for clinical laboratory 
assessments, body temperature, and 12-lead ECG collected as part of standard of care may be used 
as Screening data prior to informed consent. 
The following procedures will be performed at Screening on Day -1 to Day 1 (in the event that 
Screening and Day 1 occur on the same day or within 24 hours, duplicate assessments do not need 
to be performed; however, laboratory assessment samples for Day 1 chemistry, lipid, hematology, 
coagulation, and urinalysis need to be sent to the central laboratory in addition to local laboratory. 
Moreover, in case Screening culture is used as a baseline culture, it needs to be sent to the central 
laboratory in addition to local laboratory):  
• Obtain signed informed consent; 
• Record demographic information (age, sex, race, and ethnicity);  
• Record medical/surgical history; 
• Record prior medications; 
• Review inclusion/exclusion criteria;  
• Perform urine and/or serum pregnancy test at the local laboratory for female patients of 
childbearing potential only and postmenopausal women < 50 years of age who have been 
amenorrhoeic for ≥ 12 months, if the FSH level is not available at the time of randomization;  
• Perform FSH test for female patients < 50 years of age who are considered postmenopausal as 
they have been amenorrhoeic for ≥ 12 months; 
• Perform SARS-CoV-2 test (if clinically indicated); 
Note: A SARS-CoV-2 test (genetic testing will be suggested but other antigen testing is 
allowed) should be conducted at Screening for highly suspected COVID-19 patients at the 
Investigator’s discretion. Patients who are tested for SARS-CoV-2 will be started on study 
drug only after a negative result is confirmed. 
Note: Patients eligible for the study with the exception of meeting COVID-19 criteria will be 
allowed to rescreen more than 2 weeks after testing positive and must have a negative test 
result for eligibility. 
• Assess clinical signs and symptoms; 
Note: When possible, the same study personnel should complete the assessments at the same 
time each day. Maximum daily body temperature (defined as the maximum temperature 
reported on a single calendar day) will be recorded. Body temperature may be taken per the 

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site’s preferred method (oral, tympanic, or rectal/core) and will be recorded in the appropriate 
eCRF. The same method of measuring the patient’s body temperature should be used 
throughout the study. Body temperature recorded within 24 hours prior to the time of obtaining 
consent may be used. However, the temperature may be used only if it was measured by oral, 
tympanic, or rectal/core temperature, as specified in the protocol, and was observed and 
recorded by the site staff. The following signs and symptoms will be assigned a classification 
of absent, mild, moderate, or severe: chills, rigors, urinary frequency, urinary urgency, dysuria, 
nausea, vomiting, lower abdominal pain, suprapubic pain, pelvic pain, flank pain, and 
costo-vertebral angle tenderness.  
• Collect urine sample for urine culture; 
Note: Urine samples will be collected by clean-catch midstream, intermittent urethral catheter 
(straight catheterization using sterile technique), a newly inserted Foley catheter (no bag 
specimens allowed), bladder needle aspiration, suprapubic catheter, nephrostomy tube, or 
ureter aspiration. The local laboratory will culture each urine sample for organism 
identification, quantification, and susceptibility testing (only at Screening). Prior to the first 
dose of study drug, urine samples submitted for culture must have a urinalysis/dipstick and 
microscopic analysis performed at the local laboratory. Gram staining (or other possible 
testings) should be performed if available. Prior to the first dose of study drug, only organisms 
at concentrations of ≥ 105 CFU/mL of urine and not deemed to be a contaminant as detailed in 
the Microbiology Laboratory Manual will be sent to the central laboratory for confirmation of 
identification, susceptibility testing, and possible molecular testing; unless the same organism 
grows in urine (at concentrations of ≥ 105 CFU/mL) and blood, these organisms should be sent 
to the central laboratory. 
A urine sample taken within 48 hours prior to the first dose of study drug, to support diagnosis 
or to treat a medical condition, can be used for screening and baseline microbiologic 
assessments if the organism(s) isolated from cultures is available to be sent to the central 
laboratory for analysis. However, all patients who had a urine sample not taken by the method 
specified in the protocol must have a repeat urine sample culture obtained prior to the start of 
study drug administration. This sample should be taken as close to randomization as possible 
(within 2 hours prior to the first dose of study drug, if possible). A repeat urine sample must 
be obtained prior to the start of study drug for any patients enrolled after receiving a single 
dose of a short-acting antibiotic or patients who failed preceding antimicrobial therapy. 
• Collect blood sample for blood culture; 
Note: Two sets of blood culture samples from 2 separate venipuncture sites will be obtained at 
Screening and prior to the first dose of study drug on Day 1 for baseline blood cultures 
(duplicate assessments do not need to be performed if Screening and Day 1 occur on the same 
day or within 24 hours). The blood culture should be obtained within the allowed Screening 
Period and within 48 hours prior to the first dose of study drug to align with the requirement 
to have a urine sample taken within 48 hours. Each set of blood culture samples will include 
1 aerobic and 1 anaerobic bottle (an additional aerobic bottle is allowed if anaerobic culture is 
not standard practice at the site). However, for cUTI and AP, a single aerobic blood culture is 
sufficient if it is not the institution’s standard of care to obtain an anerobic culture. Specimens 
will be sent to the local laboratory for culture identification and susceptibility testing (only at 
Screening). All isolates from blood culture will be sent to the central laboratory for 

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confirmation of identification, susceptibility testing, and possible molecular testing as outlined 
in the Microbiology Laboratory Manual. 
• Collect samples for clinical laboratory assessments as follows: 
a. White blood cell (WBC) with differential; 
b. Urinalysis (leukocyte esterase; microscopy will be performed only as needed, based on 
positive dipstick test results); 
c. Blood urea nitrogen or blood urea (if azotemia is suspected); 
d. Serum pregnancy (if female patient of childbearing potential); 
e. FSH (for female patients < 50 years of age who are considered postmenopausal as they 
have been amenorrhoeic for ≥ 12 months); 
f. Platelet count; 
g. Serum creatinine; 
h. AST/ALT; 
i. Total bilirubin; 
j. Electrolytes (sodium, chloride, potassium, magnesium, calcium, bicarbonate [for 
bicarbonate, if applicable, at the local laboratory]); and 
k. COVID-19 test (if highly suspected). 
Note: Clinical laboratory assessments for these analytes will be performed by the local 
laboratory.  
Note: It is permitted that these laboratory samples are obtained up to 24 hours prior to the 
Screening Period to determine eligibility, as long as the patient’s clinical status has not changed 
significantly. 
• Perform complete physical examination, including source documentation of skin, head and 
neck, heart, lung, abdomen, extremities, back/flank/costo-vertebral angle tenderness, 
neuromuscular assessments, height, and weight; 
• Record vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature); 
Note: Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, and 
body temperature. Vital signs should be collected at the same times as assessments of signs 
and symptoms Patients should be resting in a semi-recumbent position for at least 5 minutes 
prior to and during measurement of vital signs. Body temperature may be taken per the site’s 
preferred method (oral, tympanic, or rectal/core) and will be recorded in the appropriate eCRF. 
The same method of measuring the patient’s body temperature should be used throughout the 
study. Body temperature recorded within 24 hours prior to the time of obtaining consent may 
be used. However, the temperature may be used only if it was measured by oral, tympanic, or 
rectal/core temperature, as specified in the protocol, and was observed and recorded by the site 
staff. 

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• Perform 12-lead ECG; and 
Note: If QTcF exceeds 470 msec, the ECG may be repeated 2 more times after rest and the 
mean of the 3 values will be used to determine the subject’s eligibility. 
Note: 12-lead ECG recorded within 24 hours prior to the time of obtaining consent may be 
used. 
• Assess AEs. 
Note: AEs will be assessed after signed informed consent is obtained. Any medical condition 
already present at Screening should be recorded as medical history and not be reported as an 
AE unless the medical condition or signs or symptoms present at baseline changes in severity, 
frequency, or seriousness at any time during the study. In this case, it should be reported as an 
AE.  
6.2.1 
Day 1 
6.2.1.1 
Pre-randomization 
The following procedures will be performed on Day 1 prior to randomization (in the event that 
Screening and Day 1 occur on the same day or within 24 hours, duplicate assessments do not need 
to be performed; however, laboratory assessment samples for Day 1 chemistry, lipid, hematology, 
coagulation, and urinalysis need to be sent to the central laboratory in addition to local laboratory. 
Moreover, in case screening culture is used as a baseline culture, it needs to be sent to the central 
laboratory in addition to local laboratory): 
• Record concomitant medications (if clinically indicated); 
• Review inclusion/exclusion criteria (if clinically indicated); 
• Assess clinical signs and symptoms (if clinically indicated); 
Note: When possible, the same study personnel should complete the assessments at the same 
time each day. Maximum daily body temperature (defined as the maximum temperature 
reported on a single calendar day) will be recorded. Body temperature may be taken per the 
site’s preferred method (oral, tympanic, or rectal/core) and will be recorded in the appropriate 
eCRF. The same method of measuring the patient’s body temperature should be used 
throughout the study. The following signs and symptoms will be assigned a classification of 
absent, mild, moderate, or severe: chills, rigors, urinary frequency, urinary urgency, dysuria, 
nausea, vomiting, lower abdominal pain, suprapubic pain, pelvic pain, flank pain, and 
costo-vertebral angle tenderness. 
• Collect urine sample for urine culture within 2 hours prior to the first dose of study drug (if 
clinically indicated); 
Note: Urine samples will be collected by clean-catch midstream, intermittent urethral catheter 
(straight catheterization using sterile technique), a newly inserted Foley catheter (no bag 
specimens allowed), bladder needle aspiration, suprapubic catheter, nephrostomy tube, or 
ureter aspiration. The local laboratory will culture each urine sample for organism 
identification, quantification, and susceptibility testing (only at Screening). Prior to the first 
dose of study drug, urine samples submitted for culture must have a urinalysis/dipstick and 
microscopic analysis performed at the local laboratory. Gram staining (or other possible 

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testings) should be performed if available. Prior to the first dose of study drug, only organisms 
at concentrations of ≥ 105 CFU/mL of urine and not deemed to be a contaminant as detailed in 
the Microbiology Laboratory Manual will be sent to the central laboratory for confirmation of 
identification, susceptibility testing, and possible molecular testing; unless the same organism 
grows in urine (at concentrations of ≥ 105 CFU/mL) and blood, these organisms should be sent 
to the central laboratory. 
A urine sample taken within 48 hours prior to the first dose of study drug, to support diagnosis 
or to treat a medical condition, can be used for screening and baseline microbiologic 
assessments if the organism(s) isolated from cultures is available to be sent to the central 
laboratory for analysis. However, all patients who had a urine sample not taken by the method 
specified in the protocol must have a repeat urine sample culture obtained prior to the start of 
study drug administration. A repeat urine sample must be obtained prior to the start of study 
drug for any patients enrolled after receiving a single dose of a short-acting antibiotic or 
patients who failed preceding antimicrobial therapy. 
• Collect blood sample for blood culture (if clinically indicated); 
Note: Two sets of blood culture samples from 2 separate venipuncture sites will be obtained at 
Screening and prior to the first dose of study drug on Day 1 for baseline blood cultures 
(duplicate assessments do not need to be performed if Screening and Day 1 occur on the same 
day or within 24 hours). The blood culture should be obtained within the allowed Screening 
Period and within 48 hours prior to the first dose of study drug to align with the requirement 
to have a urine sample taken within 48 hours. Each set of blood culture samples will include 
1 aerobic and 1 anaerobic bottle (an additional aerobic bottle is allowed if anaerobic culture is 
not standard practice at the site). However, for cUTI and AP, a single aerobic blood culture is 
sufficient if it is not the institution’s standard of care to obtain an anerobic culture. Specimens 
will be sent to the local laboratory for culture identification and susceptibility testing (only at 
Screening). All isolates from blood culture will be sent to the central laboratory for 
confirmation of identification, susceptibility testing, and possible molecular testing as outlined 
in the Microbiology Laboratory Manual. 
• Collect samples for clinical laboratory assessments (chemistry, lipid, hematology, coagulation, 
and urinalysis) (if clinically indicated);  
Note: Clinical laboratory assessments for chemistry, lipid, hematology, coagulation, and 
urinalysis will be performed by the central laboratory. In principle, serum creatinine (see 
Section 5.5.3.1) will be performed daily at local laboratory. 
• Perform a limited, symptom-directed physical examination (if clinically indicated); 

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• Record vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) (if clinically indicated); and 
Note: Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, and 
body temperature. Vital signs should be collected at the same times as assessments of signs 
and symptoms Patients should be resting in a semi-recumbent position for at least 5 minutes 
prior to and during measurement of vital signs. Body temperature may be taken per the site’s 
preferred method (oral, tympanic, or rectal/core) and will be recorded in the appropriate eCRF. 
The same method of measuring the patient’s body temperature should be used throughout the 
study. 
• Assess AEs (if clinically indicated). 
6.3 
Randomization 
Patients will be randomized on Day 1, after pre-randomization procedures are performed, in a 
2:1:1 ratio to receive either 2 g cefepime/1 g nacubactam, 2 g aztreonam/1 g nacubactam, or 
1 g imipenem/1 g cilastatin. Dosage of cefepime, aztreonam, nacubactam, and imipenem/cilastatin 
according to renal function is shown in Table 4. Randomization will be stratified by type of 
infection (AP or cUTI) and by geographic region (Japan, China, or Other). 
6.4 
Treatment Period 
6.4.1 
Day 1 
6.4.1.1 
Post-randomization 
The following procedures will be performed on Day 1 after randomization: 
• Collect blood sample for blood culture (if clinically indicated); 
Note: If a blood culture is positive at baseline for an organism obtained in a concurrently 
collected urine sample, blood cultures will be collected until the baseline qualifying 
Gram-negative pathogen(s) is negative for at least 48 hours in subsequent blood cultures. 
Additional blood cultures will be collected at the Investigator’s discretion. In that case, 2 sets 
of blood culture samples from 2 separate venipuncture sites will be obtained. The frequency 
of repeating those blood cultures should be at the discretion of the Investigator, but there must 
be documentation of a negative blood culture 48 hours after any baseline blood culture or after 
any subsequent blood culture is found to be positive. For patients with fever spikes (oral or 
tympanic temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature ≥ 38.3°C [≥ 100.9°F]) 
during the study, additional blood samples may be obtained at the time of the fever spike. 
Specimens will be sent to the local laboratory for culture identification and susceptibility 
testing (only at Screening). All isolates from blood culture will be sent to the central laboratory 
for confirmation of identification, susceptibility testing, and possible molecular testing as 
outlined in the Microbiology Laboratory Manual. 
• Administer study drug; 
• Collect blood samples for PK analysis; 
Note: In the case the patient is assigned to multiple sampling, samples will be collected on 
Day 1 after the first infusion of the day: at the end of the infusion (± 5 minutes) and at 2, 4, 6, 

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and 8 hours (± 10 minutes) after the start of the study drug infusion. The sample will be 
collected prior to the start of the next infusion (Note: At least 4 time points, including 1 hour 
after the start of the study drug infusion (first infusion on that day) on Day 1, are needed.). If 
multiple PK sampling cannot be conducted on Day 1, it should be conducted on Day 3 or Day 5 
instead. If sampling occurs on Day 3 or Day 5, samples can be collected after any of the 
3 infusions on that day. In the case the patient is assigned to sparse sampling, samples will be 
collected on Day 1, Day 3, or Day 5, after any of the 3 infusions on that day: around the end 
of the infusion, around 2 to 4 hours after the start of the study drug infusion, and around 4 to 
8 hours after the start of the study drug infusion. The sample will be collected prior to the start 
of the next infusion (Note: At least 2 time points after the start of the study drug infusion (for 
any of the 3 infusions on that day) on Day 1, Day 3, or Day 5 are needed.). Infusion start and 
end times, as well as PK sampling times, will be recorded in the source documents. The method 
of PK sample handling is detailed in the Laboratory Manual provided by the Sponsor. 
• Perform 12-lead ECG (immediately after completion of the first administration of study drug); 
and 
• Assess AEs. 
6.4.2 
Day 2 
The following procedures will be performed on Day 2: 
• Record concomitant medications;  
• Assess clinical signs and symptoms; 
Note: When possible, the same study personnel should complete the assessments at the same 
time each day. Maximum daily body temperature (defined as the maximum temperature 
reported on a single calendar day) will be recorded. Body temperature may be taken per the 
site’s preferred method (oral, tympanic, or rectal/core) and will be recorded in the appropriate 
eCRF. The same method of measuring the patient’s body temperature should be used 
throughout the study. The following signs and symptoms will be assigned a classification of 
absent, mild, moderate, or severe: chills, rigors, urinary frequency, urinary urgency, dysuria, 
nausea, vomiting, lower abdominal pain, suprapubic pain, pelvic pain, flank pain, and 
costo-vertebral angle tenderness. 
• Collect blood sample for blood culture (if clinically indicated); 
Note: If a blood culture is positive at baseline for an organism obtained in a concurrently 
collected urine sample, blood cultures will be collected until the baseline qualifying 
Gram-negative pathogen(s) is negative for at least 48 hours in subsequent blood cultures. 
Additional blood cultures will be collected at the Investigator’s discretion. In that case, 2 sets 
of blood culture samples from 2 separate venipuncture sites will be obtained. The frequency 
of repeating those blood cultures should be at the discretion of the Investigator, but there must 
be documentation of a negative blood culture 48 hours after any baseline blood culture or after 
any subsequent blood culture is found to be positive. For patients with fever spikes (oral or 
tympanic temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature ≥ 38.3°C [≥ 100.9°F]) 
during the study, additional blood samples may be obtained at the time of the fever spike. 
Specimens will be sent to the local laboratory for culture and identification. All isolates from 
blood culture will be sent to the central laboratory for confirmation of identification, 

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susceptibility testing, and possible molecular testing as outlined in the Microbiology 
Laboratory Manual. 
• Collect samples for clinical laboratory assessments (chemistry, lipid, hematology, coagulation, 
and urinalysis) (if clinically indicated);  
Note: Clinical laboratory assessments for chemistry, lipid, hematology, coagulation, and 
urinalysis will be performed by the central laboratory. While the patient is receiving study 
drug, additional clinical laboratory assessments may be performed by the central laboratory at 
the Investigator’s discretion. In principle, serum creatinine (see Section 5.5.3.1) will be 
performed daily at the local laboratory.  
• Perform a limited, symptom-directed physical examination (if clinically indicated); 
• Record vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature); 
• Assess AEs; and  
• Administer study drug.  
6.4.3 
Day 3 
The following procedures will be performed on Day 3: 
• Record concomitant medications;  
• Assess clinical signs and symptoms; 
Note: When possible, the same study personnel should complete the assessments at the same 
time each day. Maximum daily body temperature (defined as the maximum temperature 
reported on a single calendar day) will be recorded. Body temperature may be taken per the 
site’s preferred method (oral, tympanic, or rectal/core) and will be recorded in the appropriate 
eCRF. The same method of measuring the patient’s body temperature should be used 
throughout the study. The following signs and symptoms will be assigned a classification of 
absent, mild, moderate, or severe: chills, rigors, urinary frequency, urinary urgency, dysuria, 
nausea, vomiting, lower abdominal pain, suprapubic pain, pelvic pain, flank pain, and 
costo-vertebral angle tenderness. 
• Collect blood samples for PK analysis (if necessary); 
Note: In the case the patient is assigned to multiple sampling, samples will be collected on 
Day 1 after the first infusion of the day: at the end of the infusion (± 5 minutes) and at 2, 4, 6, 
and 8 hours (± 10 minutes) after the start of the study drug infusion. The sample will be 
collected prior to the start of the next infusion (Note: At least 4 time points, including 1 hour 
after the start of the study drug infusion (first infusion on that day) on Day 1, are needed.). If 
multiple PK sampling cannot be conducted on Day 1, it should be conducted on Day 3 or Day 5 
instead. If sampling occurs on Day 3 or Day 5, samples can be collected after any of the 
3 infusions on that day. In the case the patient is assigned to sparse sampling, samples will be 
collected on Day 1, Day 3, or Day 5, after any of the 3 infusions on that day: around the end 
of the infusion, around 2 to 4 hours after the start of the study drug infusion, and around 4 to 
8 hours after the start of the study drug infusion. The sample will be collected prior to the start 
of the next infusion (Note: At least 2 time points after the start of the study drug infusion (for 

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any of the 3 infusions on that day) on Day 1, Day 3, or Day 5 are needed.). Infusion start and 
end times, as well as PK sampling times, will be recorded in the source documents. The method 
of PK sample handling is detailed in the Laboratory Manual provided by the Sponsor. 
• Collect blood sample for blood culture (if clinically indicted); 
Note: If a blood culture is positive at baseline for an organism obtained in a concurrently 
collected urine sample, blood cultures will be collected until the baseline qualifying 
Gram-negative pathogen(s) is negative for at least 48 hours in subsequent blood cultures. 
Additional blood cultures will be collected at the Investigator’s discretion. In that case, 2 sets 
of blood culture samples from 2 separate venipuncture sites will be obtained. The frequency 
of repeating those blood cultures should be at the discretion of the Investigator, but there must 
be documentation of a negative blood culture 48 hours after any baseline blood culture or after 
any subsequent blood culture is found to be positive. For patients with fever spikes (oral or 
tympanic temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature ≥ 38.3°C [≥ 100.9°F]) 
during the study, additional blood samples may be obtained at the time of the fever spike. 
Specimens will be sent to the local laboratory for culture and identification. All isolates from 
blood culture will be sent to the central laboratory for confirmation of identification, 
susceptibility testing, and possible molecular testing as outlined in the Microbiology 
Laboratory Manual. 
• Collect samples for clinical laboratory assessments (chemistry, lipid, hematology, coagulation, 
and urinalysis) (if clinically indicted);  
Note: Clinical laboratory assessments for chemistry, lipid, hematology, coagulation, and 
urinalysis will be performed by the central laboratory. While the patient is receiving study 
drug, additional clinical laboratory assessments may be performed by the central laboratory at 
the Investigator’s discretion. In principle, serum creatinine (see Section 5.5.3.1) will be 
performed daily at the local laboratory.  
• Perform a limited, symptom-directed physical examination (if clinically indicated); 
• Record vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature); 
• Assess AEs; and  
• Administer study drug. 
6.4.4 
Day 4 (Early Assessment)  
The following procedures will be performed on Day 4 (± 1 day) at the EA visit: 
• Record concomitant medications;  
Note: If the EA visit is conducted on Day 3 or Day 5 (within the allowed window), this 
assessment should still be conducted on Day 4 as part of the standard safety assessments. 
• Assess clinical signs and symptoms; 
Note: When possible, the same study personnel should complete the assessments at the same 
time each day. Maximum daily temperature (defined as the maximum temperature reported on 
a single calendar day) will be recorded. Body temperature may be taken per the site’s preferred 

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method (oral, tympanic, or rectal/core) and will be recorded in the appropriate eCRF. The same 
method of measuring the patient’s body temperature should be used throughout the study. The 
following signs and symptoms will be assigned a classification of absent, mild, moderate, or 
severe: chills, rigors, urinary frequency, urinary urgency, dysuria, nausea, vomiting, lower 
abdominal pain, suprapubic pain, pelvic pain, flank pain, and costo-vertebral angle tenderness. 
Note: If the EA visit is conducted on Day 3 or Day 5 (within the allowed window), this 
assessment should still be conducted on Day 4 as part of the standard safety assessments. 
• Assess clinical outcome; 
• Collect urine sample for urine culture; 
Note: Urine samples will be collected by clean-catch midstream, intermittent urethral catheter 
(straight catheterization using sterile technique), a newly inserted Foley catheter (no bag 
specimens allowed), bladder needle aspiration, suprapubic catheter, nephrostomy tube, or 
ureter aspiration. The local laboratory will culture each urine sample for organism 
identification and quantification. Only organisms at concentrations of ≥ 103 CFU/mL of urine 
and not deemed to be a contaminant as detailed in the Microbiology Laboratory Manual will 
be sent to the central laboratory for confirmation of identification, susceptibility testing, and 
possible molecular testing. 
• Collect blood sample for blood culture (if clinically indicted); 
Note: If a blood culture is positive at baseline for an organism obtained in a concurrently 
collected urine sample, blood cultures will be collected until the baseline qualifying 
Gram-negative pathogen(s) is negative for at least 48 hours in subsequent blood cultures. 
Additional blood cultures will be collected at the Investigator’s discretion. In that case, 2 sets 
of blood culture samples from 2 separate venipuncture sites will be obtained. The frequency 
of repeating those blood cultures should be at the discretion of the Investigator, but there must 
be documentation of a negative blood culture 48 hours after any baseline blood culture or after 
any subsequent blood culture is found to be positive. For patients with fever spikes (oral or 
tympanic temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature ≥ 38.3°C [≥ 100.9°F]) 
during the study, additional blood samples may be obtained at the time of the fever spike. 
Specimens will be sent to the local laboratory for culture and identification. All isolates from 
blood culture will be sent to the central laboratory for confirmation of identification, 
susceptibility testing, and possible molecular testing as outlined in the Microbiology 
Laboratory Manual. 
Note: If the EA visit is conducted on Day 3 or Day 5 (within the allowed window), this 
assessment should still be conducted on Day 4 as part of the standard safety assessments. 
• Collect samples for clinical laboratory assessments (chemistry, lipid, hematology, coagulation, 
and urinalysis);  
Note: Clinical laboratory assessments for chemistry, lipid, hematology, coagulation, and 
urinalysis will be performed by the central laboratory. In principle, serum creatinine (see 
Section 5.5.3.1) will be performed daily at the local laboratory.  
Note: If the EA visit is conducted on Day 3 or Day 5 (within the allowed window), this 
assessment should still be conducted on Day 4 as part of the standard safety assessments. 

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• Perform a limited, symptom-directed physical examination (if clinically indicated); 
Note: If the EA visit is conducted on Day 3 or Day 5 (within the allowed window), this 
assessment should still be conducted on Day 4 as part of the standard safety assessments. 
• Record vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature); 
Note: If the EA visit is conducted on Day 3 or Day 5 (within the allowed window), this 
assessment should still be conducted on Day 4 as part of the standard safety assessments. 
• Perform 12-lead ECG (immediately after completion of the administration of study drug); 
• Assess AEs; and  
Note: If the EA visit is conducted on Day 3 or Day 5 (within the allowed window), this 
assessment should still be conducted on Day 4 as part of the standard safety assessments. 
• Administer study drug. 
6.4.5 
Day 5 to Day 14  
All patients will be treated for a minimum of 5 days (ie, 15 IV infusions) to 10 days. Duration may 
continue for up to 14 days in selected situations (eg, baseline bacteremia), after discussion with 
the Medical Monitor. 
EOT may occur anytime from Day 5 to Day 14. Treatment may continue for up to 14 days for 
patients with a positive blood culture at baseline at the discretion of the Investigator. EOT 
assessments are to be conducted on the day of, or within 24 hours following, the day of the last 
dose of study drug. 
The following procedures will be performed from Day 5 to Day 14: 
• Record concomitant medications;  
• Assess clinical signs and symptoms; 
Note: When possible, the same study personnel should complete the assessments at the same 
time each day. Maximum daily body temperature (defined as the maximum temperature 
reported on a single calendar day) will be recorded. Body temperature may be taken per the 
site’s preferred method (oral, tympanic, or rectal/core) and will be recorded in the appropriate 
eCRF. The same method of measuring the patient’s body temperature should be used 
throughout the study. The following signs and symptoms will be assigned a classification of 
absent, mild, moderate, or severe: chills, rigors, urinary frequency, urinary urgency, dysuria, 
nausea, vomiting, lower abdominal pain, suprapubic pain, pelvic pain, flank pain, and 
costo-vertebral angle tenderness. 
• Collect blood samples for PK analysis (on Day 5 only) (if necessary); 
Note: In the case the patient is assigned to multiple sampling, samples will be collected on 
Day 1 after the first infusion of the day: at the end of the infusion (± 5 minutes) and at 2, 4, 6, 
and 8 hours (± 10 minutes) after the start of the study drug infusion. The sample will be 
collected prior to the start of the next infusion (Note: At least 4 time points, including 1 hour 
after the start of the study drug infusion (first infusion on that day) on Day 1, are needed.). If 
multiple PK sampling cannot be conducted on Day 1, it should be conducted on Day 3 or Day 5 

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instead. If sampling occurs on Day 3 or Day 5, samples can be collected after any of the 
3 infusions on that day. In the case the patient is assigned to sparse sampling, samples will be 
collected on Day 1, Day 3, or Day 5, after any of the 3 infusions on that day: around the end 
of the infusion, around 2 to 4 hours after the start of the study drug infusion, and around 4 to 
8 hours after the start of the study drug infusion. The sample will be collected prior to the start 
of the next infusion (Note: At least 2 time points after the start of the study drug infusion (for 
any of the 3 infusions on that day) on Day 1, Day 3, or Day 5 are needed.). Infusion start and 
end times, as well as PK sampling times, will be recorded in the source documents. The method 
of PK sample handling is detailed in the Laboratory Manual provided by the Sponsor. 
• Collect blood sample for blood culture (if clinically indicated); 
Note: If a blood culture is positive at baseline for an organism obtained in a concurrently 
collected urine sample, blood cultures will be collected until the baseline qualifying 
Gram-negative pathogen(s) is negative for at least 48 hours in subsequent blood cultures. 
Additional blood cultures will be collected at the Investigator’s discretion. In that case, 2 sets 
of blood culture samples from 2 separate venipuncture sites will be obtained. The frequency 
of repeating those blood cultures should be at the discretion of the Investigator, but there must 
be documentation of a negative blood culture 48 hours after any baseline blood culture or after 
any subsequent blood culture is found to be positive. For patients with fever spikes (oral or 
tympanic temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature ≥ 38.3°C [≥ 100.9°F]) 
during the study, additional blood samples may be obtained at the time of the fever spike. 
Specimens will be sent to the local laboratory for culture and identification. All isolates from 
blood culture will be sent to the central laboratory for confirmation of identification, 
susceptibility testing, and possible molecular testing as outlined in the Microbiology 
Laboratory Manual. 
• Collect samples for clinical laboratory assessments (chemistry, lipid, hematology, coagulation, 
and urinalysis) (if clinically indicated);  
Note: Clinical laboratory assessments for chemistry, lipid, hematology, coagulation, and 
urinalysis will be performed by the central laboratory. While the patient is receiving study 
drug, additional clinical laboratory assessments may be performed by the central laboratory at 
the Investigator’s discretion. In principle, serum creatinine (see Section 5.5.3.1) will be 
performed daily at the local laboratory.  
• Perform a limited, symptom-directed physical examination (if clinically indicated); 
• Record vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature); 
• Assess AEs; and  
• Administer study drug. 
6.4.6 
End of Treatment 
EOT may occur anytime from Day 5 to Day 14. Treatment may continue for up to 14 days for 
patients with a positive blood culture at baseline at the discretion of the Investigator. EOT 
assessments are to be conducted on the day of, or within 24 hours following, the day of the last 
dose of study drug. 

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The following procedures will be performed at EOT: 
• Record concomitant medications;  
• Assess clinical signs and symptoms; 
Note: When possible, the same study personnel should complete the assessments at the same 
time each day. Maximum daily body temperature (defined as the maximum temperature 
reported on a single calendar day) will be recorded. Body temperature may be taken per the 
site’s preferred method (oral, tympanic, or rectal/core) and will be recorded in the appropriate 
eCRF. The same method of measuring the patient’s body temperature should be used 
throughout the study. The following signs and symptoms will be assigned a classification of 
absent, mild, moderate, or severe: chills, rigors, urinary frequency, urinary urgency, dysuria, 
nausea, vomiting, lower abdominal pain, suprapubic pain, pelvic pain, flank pain, and 
costo-vertebral angle tenderness. 
• Assess clinical outcome; 
• Collect urine sample for urine culture; 
Note: Urine samples will be collected by clean-catch midstream, intermittent urethral catheter 
(straight catheterization using sterile technique), a newly inserted Foley catheter (no bag 
specimens allowed), bladder needle aspiration, suprapubic catheter, nephrostomy tube, or 
ureter aspiration. The local laboratory will culture each urine sample for organism 
identification and quantification. Only organisms at concentrations of ≥ 103 CFU/mL of urine 
and not deemed to be a contaminant as detailed in the Microbiology Laboratory Manual will 
be sent to the central laboratory for confirmation of identification, susceptibility testing, and 
possible molecular testing. 
• Collect blood sample for blood culture (if clinically indicated); 
Note: If a blood culture is positive at baseline for an organism obtained in a concurrently 
collected urine sample, blood cultures will be collected until the baseline qualifying 
Gram-negative pathogen(s) is negative for at least 48 hours in subsequent blood cultures. 
Additional blood cultures will be collected at the Investigator’s discretion. In that case, 2 sets 
of blood culture samples from 2 separate venipuncture sites will be obtained. The frequency 
of repeating those blood cultures should be at the discretion of the Investigator, but there must 
be documentation of a negative blood culture 48 hours after any baseline blood culture or after 
any subsequent blood culture is found to be positive. For patients with fever spikes (oral or 
tympanic temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature ≥ 38.3°C [≥ 100.9°F]) 
during the study, additional blood samples may be obtained at the time of the fever spike. 
Specimens will be sent to the local laboratory for culture and identification. All isolates from 
blood culture will be sent to the central laboratory for confirmation of identification, 
susceptibility testing, and possible molecular testing as outlined in the Microbiology 
Laboratory Manual.  
• Collect samples for clinical laboratory assessments (chemistry, lipid, hematology, coagulation, 
and urinalysis);  
Note: Clinical laboratory assessments for chemistry, lipid, hematology, coagulation, and 
urinalysis will be performed by the central laboratory.  

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• Perform a limited, symptom-directed physical examination (if clinically indicated); 
• Record vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature); and 
• Assess AEs. 
6.5 
Follow-Up Period 
Following the Treatment Period, patients will return for 2 follow-up visits: the TOC (7 [± 2] days 
after EOT [Day 10 to 23]) and the FUP (14 [±2] days after EOT [Day 17 to 30]).  
6.5.1 
Test of Cure Visit 
The TOC will occur 7 [± 2] days after EOT [Day 10 to 23]. The following procedures will be 
performed at TOC: 
• Record concomitant medications;  
• Assess clinical signs and symptoms; 
Note: When possible, the same study personnel should complete the assessments at the same 
time each day. Maximum daily body temperature (defined as the maximum temperature 
reported on a single calendar day) will be recorded. Body temperature may be taken per the 
site’s preferred method (oral, tympanic, or rectal/core) and will be recorded in the appropriate 
eCRF. The same method of measuring the patient’s body temperature should be used 
throughout the study. The following signs and symptoms will be assigned a classification of 
absent, mild, moderate, or severe: chills, rigors, urinary frequency, urinary urgency, dysuria, 
nausea, vomiting, lower abdominal pain, suprapubic pain, pelvic pain, flank pain, and 
costo-vertebral angle tenderness. 
• Assess clinical outcome; 
• Collect urine sample for urine culture; 
Note: Urine samples will be collected by clean-catch midstream, intermittent urethral catheter 
(straight catheterization using sterile technique), a newly inserted Foley catheter (no bag 
specimens allowed), bladder needle aspiration, suprapubic catheter, nephrostomy tube, or 
ureter aspiration. The local laboratory will culture each urine sample for organism 
identification and quantification. Only organisms at concentrations of ≥ 103 CFU/mL of urine 
and not deemed to be a contaminant as detailed in the Microbiology Laboratory Manual will 
be sent to the central laboratory for confirmation of identification, susceptibility testing, and 
possible molecular testing. 
• Collect blood sample for blood culture (if clinically indicated); 
Note: If a blood culture is positive at baseline for an organism obtained in a concurrently 
collected urine sample, blood cultures will be collected until the baseline qualifying 
Gram-negative pathogen(s) is negative for at least 48 hours in subsequent blood cultures. 
Additional blood cultures will be collected at the Investigator’s discretion. In that case, 2 sets 
of blood culture samples from 2 separate venipuncture sites will be obtained. The frequency 
of repeating those blood cultures should be at the discretion of the Investigator, but there must 
be documentation of a negative blood culture 48 hours after any baseline blood culture or after 

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any subsequent blood culture is found to be positive. For patients with fever spikes (oral or 
tympanic temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature ≥ 38.3°C [≥ 100.9°F]) 
during the study, additional blood samples may be obtained at the time of the fever spike. 
Specimens will be sent to the local laboratory for culture and identification. All isolates from 
blood culture will be sent to the central laboratory for confirmation of identification, 
susceptibility testing, and possible molecular testing as outlined in the Microbiology 
Laboratory Manual. 
• Collect samples for clinical laboratory assessments (chemistry, lipid, hematology, coagulation, 
and urinalysis);  
Note: Clinical laboratory assessments for chemistry, lipid, hematology, coagulation, and 
urinalysis will be performed by the central laboratory.  
• Perform a limited, symptom-directed physical examination (if clinically indicated); 
• Record vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature); and 
• Assess AEs. 
6.5.2 
Follow-Up Visit  
The FUP will occur 14 [±2] days after EOT [Day 17 to 30] and should be performed as an in-person 
visit. The following procedures will be performed at the FUP: 
• Record concomitant medications;  
• Perform urine and/or serum pregnancy test at the local laboratory for female patients of 
childbearing potential only and postmenopausal women < 50 years of age who have been 
amenorrhoeic for ≥ 12 months, if the FSH level is not available at the time of randomization;  
• Assess clinical signs and symptoms; 
Note: When possible, the same study personnel should complete the assessments at the same 
time each day. Maximum daily temperature (defined as the maximum temperature reported on 
a single calendar day) will be recorded. Body temperature may be taken per the site’s preferred 
method (oral, tympanic, or rectal/core) and will be recorded in the appropriate eCRF. The same 
method of measuring the patient’s body temperature should be used throughout the study. The 
following signs and symptoms will be assigned a classification of absent, mild, moderate, or 
severe: chills, rigors, urinary frequency, urinary urgency, dysuria, nausea, vomiting, lower 
abdominal pain, suprapubic pain, pelvic pain, flank pain, and costo-vertebral angle tenderness. 
• Assess clinical outcome; 
• Collect urine sample for urine culture; 
Note: Presumed eradication is assessed at FUP and categorized as eradication only if the 
baseline qualifying Gram-negative pathogen(s) is eradicated (reduced to < 103 CFU/mL) at 
TOC, and a urine sample cannot be collected but there is a clinical outcome of cure at FUP. 
Therefore, a urine sample should also be collected at FUP, unless the baseline qualifying 
Gram-negative pathogen(s) is eradicated (reduced to < 103 CFU/mL) at TOC. 

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Note: Urine samples will be collected by clean-catch midstream, intermittent urethral catheter 
(straight catheterization using sterile technique), a newly inserted Foley catheter (no bag 
specimens allowed), bladder needle aspiration, suprapubic catheter, nephrostomy tube, or 
ureter aspiration. The local laboratory will culture each urine sample for organism 
identification and quantification. Only organisms at concentrations of ≥ 103 CFU/mL of urine 
and not deemed to be a contaminant as detailed in the Microbiology Laboratory Manual will 
be sent to the central laboratory for confirmation of identification, susceptibility testing, and 
possible molecular testing. 
• Collect samples for clinical laboratory assessments (chemistry, lipid, hematology, coagulation, 
and urinalysis);  
Note: Clinical laboratory assessments for chemistry, lipid, hematology, coagulation, and 
urinalysis will be performed by the central laboratory.  
• Perform a limited, symptom-directed physical examination (if clinically indicated); 
• Record vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature); and 
• Assess AEs. 
6.6 
Criteria for Premature Discontinuation of Study Drug or Patient Withdrawal 
From the Study 
Patients should be encouraged to complete all study assessments. However, patients may 
discontinue study drug or withdraw consent to participate in this study at any time. 
6.6.1 
Premature Discontinuation of Study Drug Administration 
Premature discontinuation of study drug administration is defined as the discontinuation of study 
drug before the anticipated full course of study drug required for effective treatment of a patient’s 
infection. The minimum duration of study drug therapy is 5 days. Patients may be discontinued 
from study drug for any of the following reasons but will still be followed for safety assessments 
approximately 7 to 14 days after ET: 
1. Occurrence of a TEAE that warrants study drug discontinuation in the judgment of the 
Investigator;  
2. Occurrence of exacerbation of underlying disease that warrants study drug discontinuation in 
the judgment of the Investigator; 
3. Patient ineligibility after the start of the study in the judgment of the Investigator; 
4. Required use of prohibited concomitant medications except urinary anesthetics and opioid 
drugs; 
5. Significant prolongation of the QT/QTc interval (QTcF > 500 msec or increase from baseline 
> 60 msec) as measured by the mean of 3 values after study drug administration; or 
6. Occurrence of an event that warrants discontinuation in the judgment of the Investigator. 
For patients who are withdrawn from the study drug prior to completion, the assessments and 
procedures listed below will be performed at ET. Patients who complete the ET visit but are not 

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discontinued from the study should continue to complete safety assessments approximately 7 to 
14 days after ET. 
The following assessments and procedures will be performed at the ET visit: 
• Record concomitant medications;  
• Perform urine and/or serum pregnancy test at the local laboratory for female patients of 
childbearing potential only and postmenopausal women < 50 years of age who have been 
amenorrhoeic for ≥ 12 months, if the FSH level is not available at the time of randomization;  
• Assess clinical signs and symptoms; 
Note: When possible, the same study personnel should complete the assessments at the same 
time each day. Maximum daily temperature (defined as the maximum temperature reported on 
a single calendar day) will be recorded. Body temperature may be taken per the site’s preferred 
method (oral, tympanic, or rectal/core) and will be recorded in the appropriate eCRF. The same 
method of measuring the patient’s body temperature should be used throughout the study. The 
following signs and symptoms will be assigned a classification of absent, mild, moderate, or 
severe: chills, rigors, urinary frequency, urinary urgency, dysuria, nausea, vomiting, lower 
abdominal pain, suprapubic pain, pelvic pain, flank pain, and costo-vertebral angle tenderness. 
• Assess clinical outcome; 
• Collect urine sample for urine culture;  
Note: Urine samples will be collected by clean-catch midstream, intermittent urethral catheter 
(straight catheterization using sterile technique), a newly inserted Foley catheter (no bag 
specimens allowed), bladder needle aspiration, suprapubic catheter, nephrostomy tube, or 
ureter aspiration. The local laboratory will culture each urine sample for organism 
identification and quantification. Only organisms at concentrations of ≥ 103 CFU/mL of urine 
and not deemed to be a contaminant as detailed in the Microbiology Laboratory Manual will 
be sent to the central laboratory for confirmation of identification, susceptibility testing, and 
possible molecular testing. 
• Collect blood sample for blood culture (if clinically indicated); 
Note: If a blood culture is positive at baseline for an organism obtained in a concurrently 
collected urine sample, blood cultures will be collected until the baseline qualifying 
Gram-negative pathogen(s) is negative for at least 48 hours in subsequent blood cultures. 
Additional blood cultures will be collected at the Investigator’s discretion. In that case, 2 sets 
of blood culture samples from 2 separate venipuncture sites will be obtained. The frequency 
of repeating those blood cultures should be at the discretion of the Investigator, but there must 
be documentation of a negative blood culture 48 hours after any baseline blood culture or after 
any subsequent blood culture is found to be positive. For patients with fever spikes (oral or 
tympanic temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature ≥ 38.3°C [≥ 100.9°F]) 
during the study, additional blood samples may be obtained at the time of the fever spike. 
Specimens will be sent to the local laboratory for culture and identification. All isolates from 
blood culture will be sent to the central laboratory for confirmation of identification, 
susceptibility testing, and possible molecular testing as outlined in the Microbiology 
Laboratory Manual. 

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• Collect samples for clinical laboratory assessments (chemistry, lipid, hematology, coagulation, 
and urinalysis);  
Note: Clinical laboratory assessments for chemistry, lipid, hematology, coagulation, and 
urinalysis will be performed by the central laboratory. 
• Perform a limited, symptom-directed physical examination (if clinically indicated); 
• Record vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature);  
• Perform 12-lead ECG (if clinically indicated); and 
• Assess AEs. 
Patients who complete the ET visit but are not discontinued from the study should continue to 
complete all safety assessments approximately 7 to 14 days after ET. 
Note: AE assessment must be performed, but other assessments should be performed at the 
discretion of the Investigator, if clinically indicated.  
The following safety assessments and procedures will be performed at the Safety Assessment Visit 
approximately 7 to 14 days after ET: 
• Assess AEs; 
• Collect samples for clinical laboratory assessments (chemistry, lipid, hematology, coagulation, 
and urinalysis) (if clinically indicated); 
Note: Clinical laboratory assessments for chemistry, lipid, hematology, coagulation, and 
urinalysis will be performed by the central laboratory. 
• Perform a limited, symptom-directed physical examination (if clinically indicated); 
• Record vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) (if clinically indicated); and 
• Perform 12-lead ECG (if clinically indicated). 
6.6.2 
Withdrawal From the Study 
Participation of a patient in this clinical study may be discontinued for any of the following 
reasons: 
1. The patient withdraws consent or requests discontinuation from the study for any reason;  
2. Pregnancy;  
3. Termination of the study by the Sponsor or the regulatory authority; or 
4. The patient is suspected/diagnosed with SARS-CoV-2 infection and warrants discontinuation 
in the judgment of the Investigator. 
5. Insufficient therapeutic effect of the study drug that could lead to clinical worsening, or lack 
of clinical progress in the judgement of investigators; 

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For patients who are withdrawn from the study, the following assessments and procedures will be 
encouraged to be performed at ET: 
• Record concomitant medications;  
• Perform urine and/or serum pregnancy test at the local laboratory for female patients of 
childbearing potential only and postmenopausal women < 50 years of age who have been 
amenorrhoeic for ≥ 12 months, if the FSH level is not available at the time of randomization;  
• Assess clinical signs and symptoms; 
Note: When possible, the same study personnel should complete the assessments at the same 
time each day. Maximum daily temperature (defined as the maximum temperature reported on 
a single calendar day) will be recorded. Body temperature may be taken per the site’s preferred 
method (oral, tympanic, or rectal/core) and will be recorded in the appropriate eCRF. The same 
method of measuring the patient’s body temperature should be used throughout the study. The 
following signs and symptoms will be assigned a classification of absent, mild, moderate, or 
severe: chills, rigors, urinary frequency, urinary urgency, dysuria, nausea, vomiting, lower 
abdominal pain, suprapubic pain, pelvic pain, flank pain, and costo-vertebral angle tenderness. 
• Assess clinical outcome; 
• Collect urine sample for urine culture;  
Note: Urine samples will be collected by clean-catch midstream, intermittent urethral catheter 
(straight catheterization using sterile technique), a newly inserted Foley catheter (no bag 
specimens allowed), bladder needle aspiration, suprapubic catheter, nephrostomy tube, or 
ureter aspiration. The local laboratory will culture each urine sample for organism 
identification and quantification. Only organisms at concentrations of ≥ 103 CFU/mL of urine 
and not deemed to be a contaminant as detailed in the Microbiology Laboratory Manual will 
be sent to the central laboratory for confirmation of identification, susceptibility testing, and 
possible molecular testing. 
• Collect blood sample for blood culture (if clinically indicated); 
Note: If a blood culture is positive at baseline for an organism obtained in a concurrently 
collected urine sample, blood cultures will be collected until the baseline qualifying 
Gram-negative pathogen(s) is negative for at least 48 hours in subsequent blood cultures. 
Additional blood cultures will be collected at the Investigator’s discretion. In that case, 2 sets 
of blood culture samples from 2 separate venipuncture sites will be obtained. The frequency 
of repeating those blood cultures should be at the discretion of the Investigator, but there must 
be documentation of a negative blood culture 48 hours after any baseline blood culture or after 
any subsequent blood culture is found to be positive. For patients with fever spikes (oral or 
tympanic temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature ≥ 38.3°C [≥ 100.9°F]) 
during the study, additional blood samples may be obtained at the time of the fever spike. 
Specimens will be sent to the local laboratory for culture and identification. All isolates from 
blood culture will be sent to the central laboratory for confirmation of identification, 
susceptibility testing, and possible molecular testing as outlined in the Microbiology 
Laboratory Manual. 

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• Collect samples for clinical laboratory assessments (chemistry, lipid, hematology, coagulation, 
and urinalysis);  
Note: Clinical laboratory assessments for chemistry, lipid, hematology, coagulation, and 
urinalysis will be performed by the central laboratory. 
• Perform a limited, symptom-directed physical examination (if clinically indicated); 
• Record vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature);  
• Perform 12-lead ECG (if clinically indicated); and 
• Assess AEs. 

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7 
EFFICACY ASSESSMENTS 
7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients who achieve composite clinical and 
microbiological success at TOC in the Microbiological Modified Intent-to-Treat (m-MITT) 
Population. Composite clinical and microbiological success is defined as the composite clinical 
outcome of cure and the microbiological outcome of eradication.  
7.1.1 
Assessment of Clinical Signs and Symptoms 
Clinical signs and symptoms will be assessed as indicated in APPENDIX A. When possible, the 
same study personnel should complete the assessments at the same time each day. Maximum daily 
body temperature (defined as the maximum temperature reported on a single calendar day) will be 
recorded. Body temperature may be taken per the site’s preferred method (oral, tympanic, or 
rectal/core) and will be recorded in the appropriate eCRF. The same method of measuring the 
patient’s body temperature should be used throughout the study.  
7.1.1.1 
cUTI/AP 
The following signs and symptoms of cUTI/AP will be assessed:  
• Chills, rigors, or fever;  
• Dysuria, increased urinary frequency, or urinary urgency; 
• Nausea; 
• Vomiting; 
• Positive leukocyte esterase;  
• Suprapubic, pelvic, or lower abdominal pain; 
• Elevated WBC count; 
• Flank pain; and 
• Costo-vertebral angle tenderness. 
7.1.2 
Clinical Outcome 
Assessment of clinical outcome will be completed at EA, EOT, TOC, FUP, and ET. The 
Investigator will assign a clinical outcome as defined in Table 5. 

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Table 5. Clinical Outcome Criteria  
Category 
Criteria 
Cure 
The complete resolution (or return to premorbid state) of the baseline signs and symptoms of cUTI or AP 
that were present at Screening (and no new urinary symptoms or worsening of symptoms consistent with 
the specific baseline condition), such that no further antimicrobial therapy is warranted. Symptom 
resolution does not necessarily include pre-infection baseline symptoms associated with the patient’s 
pre-study condition (eg, anatomic abnormalities that predispose to cUTI, such as symptoms associated with 
the presence of an indwelling urinary catheter). This outcome category can be used at EA, EOT, TOC, 
FUP, and ET. 
Improvement 
Lessening, incomplete resolution, or no worsening of baseline clinical signs and symptoms, but continued 
IV therapy for management is warranted. This outcome category can only be used at EA. 
Failure 
Patients who experience any 1 of the following: 
• 
At EA and EOT, worsening of baseline clinical signs and symptoms or the development of new clinical 
signs and symptoms of infection, sufficient to stop study drug and initiate non-study antimicrobial; 
• 
At TOC and FUP, persistence or incomplete resolution of baseline clinical signs and symptoms of 
infection, requiring additional antibiotic therapy; 
• 
At any visit until TOC, a change in the patient’s baseline Gram-negative antimicrobial therapy to treat 
the baseline infection (other than dose adjustment) after randomization; 
• 
Withdrawal from the study due to an AE or due to lack of clinical improvement; or 
• 
Death of the patient during the study. 
This outcome category can be used at EA, EOT, TOC, FUP, and ET. 
Recurrence 
Baseline signs and symptoms were present at FUP after a response of cure. This outcome category can 
only be used at FUP. 
Indeterminate 
Clinical outcome cannot be determined. This outcome category can be used at EA, EOT, TOC, FUP, and 
ET. 
AE = adverse event; AP = acute uncomplicated pyelonephritis; cUTI = complicated urinary tract infection; EA = Early 
Assessment; EOT = End of Treatment; ET = Early Termination; FUP = Follow-Up visit; IV = intravenous(ly); TOC = Test of 
Cure visit. 
7.1.3 
Microbiological Outcome 
The criteria for microbiological outcome are defined in Table 6 and Table 7. Microbiological 
outcome will be determined programmatically based on the results from the site of infection.  
Table 6. Microbiological Outcome Criteria for cUTI or AP 
Category 
Criteria 
Eradication 
The baseline qualifying Gram-negative pathogen(s) is reduced to < 103 CFU/mL in urine culture. 
Persistence 
Demonstration that 1 or more of the baseline Gram-negative pathogen(s) remains continuously present 
in urine culture at ≥ 103 CFU/mL. 
Recurrence 
Isolation of the same baseline Gram-negative pathogen(s) ≥ 103 CFU/mL from urine culture after a 
response of eradication. 
Indeterminate 
No urine culture is available, or the culture cannot be interpreted for any reason. 
Microbiological outcome will not be evaluated in the following cases: 
• 
New pathogen infection – the post-baseline organism is different from the baseline Gram-negative organism but is thought 
to be a pathogen based on a number of reasons that will be delineated in the protocol (eg, Gram-negative, obtained in 
multiple cultures); or 
• 
Contaminant – the post-baseline organism is different from the baseline Gram-negative organism but is identified as a 
common skin flora organism and has not been cultured from another site. 
Note: The qualifying pathogen is defined as a single Gram-negative organism at a concentration ≥ 105 CFU/mL in a 
non-contaminated urine culture. 
Note: Presumed eradication is assessed at FUP and categorized as eradication only if the baseline qualifying Gram-negative 
pathogen(s) is eradicated (reduced to < 103 CFU/mL) at TOC, and a urine sample cannot be collected but there is a clinical 
outcome of cure at FUP. Therefore, a urine sample should also be collected at FUP, unless the baseline qualifying Gram-negative 
pathogen(s) is eradicated (reduced to < 103 CFU/mL) at TOC. 
AP = acute uncomplicated pyelonephritis; CFU = colony-forming unit(s); cUTI = complicated urinary tract infection; 
FUP = Follow-Up visit; TOC = Test of Cure visit. 

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Table 7. Microbiological Outcome Criteria for Secondary Bacteremia 
Category 
Criteria 
Eradication 
The baseline qualifying Gram-negative pathogen(s) is negative in blood culture. Presumed eradication is 
defined as eradication. 
Persistence 
The baseline qualifying Gram-negative pathogen(s) is positive in blood culture.  
Recurrence 
Isolation of the same Gram-negative pathogen(s) from blood culture after a response of eradication. 
Indeterminate 
No blood culture is available or the culture cannot be interpreted for any reason.  
Microbiological outcome will not be evaluated in the following cases: 
• 
New pathogen infection – the post-baseline organism is different from the baseline Gram-negative organism but is thought 
to be a pathogen based on a number of reasons that will be delineated in the protocol (eg, Gram-negative, obtained in 
multiple cultures); or 
• 
Contaminant – the post-baseline organism is different from the baseline Gram-negative organism but is identified as a 
common skin flora organism and has not been cultured from another site. 
Note: Presumed eradication is assessed at TOC when the baseline qualifying Gram-negative pathogen(s) is negative for at least 
48 hours in subsequent blood cultures taken during the treatment period and there is a clinical outcome of cure at TOC. 
TOC = Test of Cure visit.  
7.1.3.1 
Microbiology assessments 
Urine culture 
Urine samples will be obtained at Screening, prior to the first dose of study drug on Day 1, EA, 
EOT, TOC, FUP (if clinically indicated), and ET.  
Urine samples for microbiological testing will be collected by clean-catch midstream, intermittent 
urethral catheter (straight catheterization using sterile technique), a newly inserted Foley catheter 
(no bag specimens allowed), bladder needle aspiration, suprapubic catheter, nephrostomy tube, or 
ureter aspiration.  
A urine sample taken within 48 hours prior to the first dose of study drug can be used for screening 
and baseline microbiologic assessments if the organism(s) isolated from cultures is available to be 
sent to the central laboratory for analysis. However, all patients who had a urine sample not taken 
by the method specified in the protocol must have a repeat urine sample culture obtained prior to 
the start of study drug administration. This sample should be taken as close to randomization as 
possible (within 2 hours prior to the first dose of study drug, if possible). A repeat urine sample 
must be obtained prior to the start of study drug for any patients enrolled after receiving a single 
dose of a short-acting antibiotic or patients who failed preceding antimicrobial therapy. The sample 
should be collected as close to randomization as possible (within 2 hours prior to the first dose of 
study drug, if possible).  
Up to 2 Gram-negative bacterial isolates per urine culture (at concentrations of ≥ 105 CFU/mL of 
urine) will be considered as qualifying pathogens. If a patient grows ≥ 3 bacterial organisms 
≥ 105 CFU/mL in the urine, the urine culture will be considered contaminated. An organism will 
not be considered a contaminant if the organism grows ≥ 105 CFU/mL in a urine culture and also 
grows in a concurrently obtained blood culture. 
Prior to the first dose of study drug, urine samples submitted for culture must have a 
urinalysis/dipstick and microscopic analysis performed at the local laboratory. Gram staining (or 
other possible testings) should be performed if available.  
At each sampling point, the local laboratory will culture each urine sample for organism 
identification, quantification, and susceptibility testing (only at Screening).  

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Imipenem and meropenem susceptible pathogen is defined as a Gram-negative pathogen by 
susceptibility data of minimum inhibitory concentration (MIC) less than 2 µg/mL to imipenem 
and meropenem OR imipenem and meropenem disk diffusion (zone diameter ≥ 22 mm). If MIC 
or disk diffusion data are not available in the local laboratory or before the availability of MIC or 
disk diffusion results, each site can use other susceptibility testings and criteria in the institution 
as the initial evidence of imipenem and meropenem susceptible pathogen for enrollment. In any 
case, pathogen identification and susceptibility testing performed at the central laboratory will be 
used to determine imipenem and meropenem susceptible pathogen in the final study analysis. 
Prior to the first dose of study drug, only organisms at concentrations of ≥ 105 CFU/mL of urine 
and not deemed to be a contaminant as detailed in the Microbiology Laboratory Manual will be 
sent to the central laboratory for confirmation of identification, susceptibility testing, and possible 
molecular testing; if the same organism grows in urine (at concentrations of ≥ 105 CFU/mL) and 
blood, these organisms should be sent to the central laboratory.  
For all post-baseline urine cultures, only organisms at concentrations of ≥ 103 CFU/mL of urine 
and not deemed to be a contaminant as detailed in the Microbiology Laboratory Manual will be 
sent to the central laboratory for confirmation of identification, susceptibility testing, and possible 
molecular testing.  
If a patient’s baseline urine culture is negative at the time a negative culture is confirmed but the 
patient is improving, the Investigator can keep the patient on treatment. If the baseline urine culture 
is negative at the time a negative culture is confirmed and the patient is not improving, study 
treatment will be stopped, and the patient will be followed for safety assessments approximately 
7 to 14 days after ET.  
Qualifying pathogen 
A qualifying pathogen is defined as a single Gram-negative organism at a concentration 
≥ 105 CFU/mL in a non-contaminated urine culture. If a culture grows ≥ 3 bacterial organisms 
≥ 105 CFU/mL in the urine, the urine culture will be considered contaminated. A Gram-negative 
organism will not be considered a contaminant if the organism grows ≥ 105 CFU/mL in a urine 
culture and also grows in a concurrently obtained blood culture. 
The list of Gram-negative uropathogens that may be considered causative in cUTI or AP is 
included in Table 8. Organisms identified during the study that are not listed in Table 8 as 
uropathogens or as contaminants in the Microbiology Laboratory Manual will be assessed on a 
case-by-case basis. 

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Table 8. Potential Uropathogens 
Potential Gram-Negative Uropathogens 
Citrobacter freundii 
Citrobacter koseri 
Enterobacter cloacae 
Escherichia coli 
Klebsiella aerogenes 
Klebsiella oxytoca 
Klebsiella pneumoniae 
Morganella morganii 
Proteus mirabilis 
Proteus vulgaris 
Providencia rettgeri 
Providencia stuartii 
Pseudomonas aeruginosa 
Serratia marcescens 
Blood culture 
Two sets of blood culture samples from 2 separate venipuncture sites will be obtained at Screening 
and prior to the first dose of study drug on Day 1 for baseline blood cultures (duplicate assessments 
do not need to be performed if Screening and Day 1 occur on the same day or within 24 hours). 
The blood culture should be obtained within the allowed Screening Period and within 48 hours 
prior to the first dose of study drug to align with the requirement to have a urine sample taken 
within 48 hours. 
Each set of blood culture samples will include 1 aerobic and 1 anaerobic bottle (an additional 
aerobic bottle is allowed if anaerobic culture is not standard practice at the site). However, for 
cUTI and AP, a single aerobic blood culture is sufficient if it is not the institution’s standard of 
care to obtain an anerobic culture. If a blood culture is positive at baseline for an organism obtained 
in a concurrently collected urine sample, blood cultures will be collected until the baseline 
qualifying Gram-negative pathogen(s) is negative for at least 48 hours in subsequent blood 
cultures. Additional blood cultures will be collected at the Investigator’s discretion. In that case, 
2 sets of blood culture samples from 2 separate venipuncture sites will be obtained. The frequency 
of repeating those blood cultures should be at the discretion of the Investigator, but there must be 
documentation of a negative blood culture 48 hours after any baseline blood culture or after any 
subsequent blood culture is found to be positive. For patients with fever spikes (oral or tympanic 
temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature ≥ 38.3°C [≥ 100.9°F]) during the study, 
additional blood samples may be obtained at the time of the fever spike. Specimens will be sent to 
the local laboratory for culture identification and susceptibility testing (only at Screening). All 
isolates from blood culture will be sent to the central laboratory for confirmation of identification, 
susceptibility testing, and possible molecular testing as outlined in the Microbiology Laboratory 
Manual. 
7.1.4 
Composite Clinical and Microbiological Success 
The algorithm for composite clinical and microbiological success at EA, EOT, TOC, FUP, and ET 
is summarized in Table 9. 

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Table 9. Composite Clinical and Microbiological Success  
Clinical Outcome 
Microbiological Outcome 
Eradication 
Persistence 
Recurrence1 
Indeterminate 
Cure 
Success 
Failure 
Failure 
Failure 
Failure2 
Failure 
Failure 
Failure 
Failure 
Indeterminate 
Clinical outcome for the 
last visit before EA, EOT, 
TOC, FUP, or 
ET = failure; 
otherwise = indeterminate 
Failure 
Failure 
Clinical outcome for the 
last visit before EA, EOT, 
TOC, FUP, or 
ET = failure; 
otherwise = indeterminate 
1. 
For an outcome of recurrence, patients must have documented prior eradication at any prior time point. 
2. 
In the assessment of clinical outcome at EA, category of “improvement” is included. In the assessment of clinical outcome 
at FUP, category of “recurrence” is included. 
EA = Early Assessment; EOT = End of Treatment; ET = Early Termination; FUP = Follow-Up visit; TOC = Test of Cure visit. 
7.2 
Secondary Efficacy Endpoints 
The clinical outcome criteria (Table 5), microbiological outcome criteria (Table 6), and composite 
clinical and microbiological success (Table 9) also apply to the secondary efficacy assessments.  
7.2.1 
Secondary Efficacy Endpoints for cUTI and AP 
The secondary efficacy endpoints for cUTI and AP include the following: 
• The proportion of patients with composite clinical and microbiological success at TOC in the 
Clinically Evaluable (CE) and Microbiologically Evaluable (ME) Populations;  
• The proportion of patients with composite clinical and microbiological success at EA, EOT, 
and FUP in the m-MITT Population; 
• The proportion of patients with a microbiological outcome of eradication at EA, EOT, TOC, 
and FUP in the m-MITT Population and at TOC in the ME Population; 
• The proportion of patients with a clinical outcome of cure at EA, EOT, TOC, and FUP in the 
m-MITT Population and at TOC in the CE and ME Populations;  
• The proportion of patients with a clinical outcome of cure at EA, EOT, TOC, and FUP in the 
m-MITT Population and at TOC in the CE and ME Populations and microbiological outcome 
of eradication at EA, EOT, TOC, and FUP in the m-MITT Population and at TOC in the ME 
Population per type of pathogen, type of resistance, and antimicrobial susceptibility; and 
• The proportion of patients with composite clinical outcome of recurrence and/or 
microbiological outcome of recurrence at the FUP in the m-MITT, CE, and ME population. 
7.2.2 
Secondary Efficacy Endpoints for Secondary Bacteremia 
Patients with cUTI/AP who meet the following conditions will be determined programmatically 
as secondary bacteremia: 
• Isolation of a Gram-negative bacteria from at least 1 blood culture at baseline AND this 
isolated pathogen is also identified from the site of infection; AND 

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• At least 1 of the following within 24 hours prior to the first dose of study drug: 
a. Fever (oral or tympanic temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature 
≥ 38.3°C [≥ 100.9°F]) OR hypothermia (rectal/core temperature < 35°C [< 95°F]); 
b. Elevated peripheral WBC count (> 10,000/mm3); 
c. > 15% immature polymorphonuclear neutrophils (bands) regardless of peripheral WBC 
count; 
d. Leukopenia (WBC < 4,500/mm3); 
e. Tachycardia > 100 bpm; 
f. Tachypnea > 20 breaths/min; 
g. Hypotension, systolic < 90 mmHg; or 
h. C-reactive protein > 20 mg/dL. 
Clinical outcome of cure from secondary bacteremia is defined as complete resolution or 
significant improvement of the baseline signs and symptoms of secondary bacteremia. 
The secondary efficacy endpoints for secondary bacteremia include the following:  
• The proportion of patients with composite clinical and microbiological success of cUTI or AP 
at TOC in the m-MITT, CE, and ME Populations; 
• The proportion of patients with a clinical outcome of cure from cUTI or AP at TOC in the 
m-MITT, CE, and ME Populations;  
• The proportion of patients with a microbiological outcome of eradication from cUTI or AP at 
TOC in the m-MITT and ME Populations; 
• The proportion of patients with a clinical outcome of cure from secondary bacteremia at TOC 
in the m-MITT, CE, and ME Populations; 
• The proportion of patients with a microbiological outcome of eradication from secondary 
bacteremia at TOC in the m-MITT and ME Populations; 
• The proportion of patients in the m-MITT and ME Populations free from the definition of 
secondary bacteremia AND a clinical outcome of cure from cUTI or AP AND a 
microbiological outcome of eradication from cUTI or AP at TOC; and 
• The proportion of patients who are free from secondary bacteremia at TOC in the m-MITT and 
ME Populations. 
7.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints include the following:  
• Clinical response at EA, EOT, TOC, and FUP, as defined by the following parameters: 
a. Signs and symptoms of cUTI; and 
b. Proportion of patients in cure, improvement, failure, recurrence, or indeterminate 
categories for clinical response. 

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• Microbiological response at EA, EOT, TOC, and FUP, as defined by the following parameters: 
a. Bacterial load in CFU/mL for cUTI causative pathogens in urine; and 
b. Proportion of patients in eradication, persistence, recurrence, or indeterminate categories 
for microbiological response. 
7.4 
Pharmacokinetic Assessments 
Blood samples for PK analysis will be collected from all patients. All patients will be assigned to 
either a multiple PK sampling or a sparse PK sampling group at the discretion of the Investigator.  
Infusion start and end times, as well as PK sampling times, will be recorded in the source 
documents. The method of PK sample handling is detailed in the Laboratory Manual provided by 
the Sponsor.  
In the case of multiple sampling, the PK plasma samples will be used to estimate PK parameters 
of nacubactam, cefepime, and aztreonam such as AUC, Cmax, time to reach maximum observed 
plasma concentration, total drug clearance, t½, Cmin, and predicted steady-state volume of 
distribution using a non-compartmental model. PK parameters will be summarized using 
appropriate descriptive statistics.  
Scatter plots of plasma concentrations of nacubactam, cefepime, and aztreonam from multiple 
sampling and sparse sampling will be drawn, respectively. 
PK characterization and evaluation of plasma exposures of nacubactam, cefepime, and aztreonam 
will be performed using plasma concentrations from all patients in the cefepime/nacubactam and 
aztreonam/nacubactam treatment groups by means of PPK modeling methods. PK/PD analysis 
will be performed by analyzing the relationship between individual PK/PD parameters and 
individual clinical/biological efficacy data, and PPK analysis and PK/PD analysis will be 
conducted independently of this protocol and the results of both analyses will be reported 
independently of the Clinical Study Report for this study.  
The PK samples will be collected from all treatment groups to maintain the blind. Only PK samples 
obtained from the cefepime/nacubactam and aztreonam/nacubactam groups will be analyzed 
(using a validated assay) by the bioanalytical laboratory. While the PK analyses will be ongoing 
during the study, the Sponsor and all study personnel will remain blinded to the results (see 
Section 5.3.2). 
7.4.1 
Multiple PK Sampling 
In the case the patient is assigned to multiple sampling, samples will be collected on Day 1 after 
the first infusion of the day: 
• At the end of the infusion (± 5 minutes); and 
• At 2, 4, 6, and 8 hours (± 10 minutes) after the start of the study drug infusion. The sample will 
be collected prior to the start of the next infusion.  
Note: At least 4 time points, including 1 hour after the start of the study drug infusion (first infusion 
on that day) on Day 1, are needed. 

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If multiple PK sampling cannot be conducted on Day 1, it should be conducted on Day 3 or Day 5 
instead. If sampling occurs on Day 3 or Day 5, samples can be collected after any of the 3 infusions 
on that day. 
Table 10 provides the sampling times for multiple PK assessments. 
Table 10. Sampling Times for Multiple PK Assessments 
Multiple PK Sampling Time (Time Allowance) 
Day 1 
(Post-Randomization)1 
Day 3 
Day 5 
End of infusion (± 5 minutes) 
X 
(X) 
(X) 
2 hours (± 10 minutes) after the start of infusion 
X 
(X) 
(X) 
4 hours (± 10 minutes) after the start of infusion 
X 
(X) 
(X) 
6 hours (± 10 minutes) after the start of infusion 
X 
(X) 
(X) 
8 hours (± 10 minutes) after the start of infusion 
X 
(X) 
(X) 
(X) denotes samples that are only to be performed on Day 3 or Day 5 if multiple sampling could not be conducted on Day 1. If 
sampling occurs on Day 3 or Day 5, samples can be collected after any of the 3 infusions on that day. 
1. 
The PK sample should be taken after the first infusion of that day. 
2. 
Sample should be collected prior to the start of the next infusion. 
Note: At least 4 time points, including 1 hour after the start of the study drug infusion (first infusion on that day) on Day 1, are 
needed.  
PK = pharmacokinetic(s). 
7.4.2 
Sparse PK Sampling 
In the case the patient is assigned to sparse sampling, samples will be collected on Day 1, Day 3, 
or Day 5, after any of the 3 infusions on that day: 
• Around the end of the infusion; 
• Around 2 to 4 hours after the start of the study drug infusion; and 
• Around 4 to 8 hours after the start of the study drug infusion. The sample will be collected 
prior to the start of the next infusion. 
Note: At least 2 time points after the start of the study drug infusion (for any of the 3 infusions on 
that day) on Day 1, Day 3, or Day 5 are needed. 
Table 11 provides the sampling times for sparse PK assessments. 
Table 11. Sampling Times for Sparse PK Assessments 
Sparse PK Sampling Time  
Day 1 
(Post-Randomization)1 
Day 31 
Day 51 
Around the end of infusion  
X 
(X) 
(X) 
Around 2 to 4 hours after the start of infusion 
X 
(X) 
(X) 
Around 4 to 8 hours after the start of infusion2 
X 
(X) 
(X) 
(X) denotes samples that are only to be performed on Day 3 or Day 5 if sparse sampling could not be conducted on Day 1. 
1. 
The PK sample should be taken after any of the 3 infusions of that day. 
2. 
Sample should be collected prior to the start of the next infusion. 
Note: At least 2 time points after the start of the study drug infusion (for any of the 3 infusions on that day) on Day 1, Day 3, or 
Day 5 are needed.  
PK = pharmacokinetic(s). 

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7.5 
Other Assessments 
The exploratory variables for this study are the minimum inhibitory concentrations for 
cefepime/nacubactam, aztreonam/nacubactam, and nacubactam for causative uropathogens.  
Bacterial whole genome sequencing analysis, or other appropriate methods, may be conducted 
from purified cultures of bacterial isolates to explore type of resistance. 

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8 
SAFETY ASSESSMENTS 
The safety parameters include the incidence, severity, causality, and seriousness of TEAEs and the 
evaluation of changes from baseline in safety laboratory test results, 12-lead ECGs, vital signs, 
and physical examinations. 
8.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and/or unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not related to the investigational medicinal product. 
All AEs, including observed or volunteered problems, complaints, or symptoms, are to be recorded 
on the appropriate eCRF. All AEs will be followed until resolution, stabilization, the event is 
otherwise explained by the Investigator, or the patient is lost to follow-up.  
AEs, which include clinical laboratory test variables, will be monitored and documented from the 
time of informed consent until the study participation is complete. Patients should be instructed to 
report any AE that they experience to the Investigator, whether or not they think the event is due 
to study treatment. Beginning with the signing of informed consent, Investigators should make an 
assessment for AEs at each visit and record the event on the appropriate eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE on the eCRF. Additionally, 
the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, 
or transfusion) should be recorded as an AE, not the procedure itself.  
Any medical condition already present at Screening should be recorded as medical history and not 
be reported as an AE unless the medical condition or signs or symptoms present at baseline changes 
in severity, frequency, or seriousness at any time during the study. In this case, it should be reported 
as an AE. 
Clinically significant abnormal laboratory or other examination (eg, 12-lead ECG) findings that 
are detected during the study or are present at Screening and significantly worsen during the study 
should be reported as AEs, as described below. The Investigator will exercise his or her medical 
and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. Clinically significant abnormal laboratory values occurring 
during the clinical study will be followed until repeat tests return to normal, stabilize, or are no 
longer clinically significant. Abnormal test results that are determined to be an error should not be 
reported as an AE. Laboratory abnormalities or other abnormal clinical findings (eg, 12-lead ECG 
abnormalities) should be reported as an AE if any of the following are applicable: 
• If an intervention is required as a result of the abnormality; 
• If action taken with the study drug is required as a result of the abnormality; or 
• Based on the clinical judgment of the Investigator. 

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8.1.1 
Treatment-Emergent Adverse Events 
A TEAE is defined as a new event that occurs during or after the first dose of study treatment or 
any event present at baseline that worsens in either intensity or frequency after the first dose of 
study treatment.  
8.1.2 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an AE is at least a reasonable possibility, ie, the 
relationship cannot be ruled out. 
8.1.3 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For nacubactam, the reference 
safety information is included in the IB currently in force. The reference safety information will 
be reviewed yearly, and the periodicity of the review will be harmonized with the reporting period 
of the Development Safety Update Report. 
8.1.4 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each AE as mild, moderate, or severe, and 
will also categorize each AE as to its potential relationship to study drug using the categories of 
yes or no. 
Assessment of severity 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
Note: Regardless of severity, some events may also meet seriousness criteria (see Section 8.2).  
Causality assessment 
The relationship of an AE to the administration of the study drug is to be assessed according to the 
following definitions: 
No (not related, unlikely to be related) – The time course between the administration of study drug 
and the occurrence or worsening of the AE rules out a causal relationship and another cause 
(concomitant drugs, therapies, complications, etc) is suspected. 
Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE is consistent with a causal relationship and 
no other cause (concomitant drugs, therapies, complications, etc) can be identified. 
The criteria of the relationship is defined as below: 
Not Related: There is no association between the study drug and the reported event. 
Unlikely to be Related: The temporal sequence of the event with study drug administration makes 
a causal relationship improbable and/or other factors also provide plausible explanations. 

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Possibly Related: Treatment with the study drug caused or contributed to the AE. That is, the event 
follows a reasonable temporal sequence from the time of study drug administration, and/or, follows 
a known response pattern to the study drug, but could have been produced by other factors. 
Probably Related: A reasonable temporal sequence of the event with study drug administration 
exists and, based upon the known pharmacological action of the drug, known or previously 
reported adverse reactions to the drug or class of drugs, or judgment based on the Investigator’s 
clinical experience, the association of the event with study drug administration seems likely. 
Definitely Related: a definite causal relationship exists between the drug administration and the 
AE, and other conditions (eg, concurrent illness, progression/expression of disease state, or 
concurrent medication reaction) do not appear to explain the event. The definition implies a 
reasonable possibility of a causal relationship between the event and the study drug. This means 
that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
• The temporal sequence from study drug administration- 
The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases- 
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the patient may have. 
• Concomitant drug- 
The other drugs the patient is taking or the treatment the patient receives should be examined 
to determine whether any of them might be recognized to cause the event in question. 
• Known response pattern for this class of study drug- 
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
• Exposure to physical and/or mental stresses- 
The exposure to stress might induce adverse changes in the recipient and provide a logical and 
better explanation for the event. 
• The pharmacology and PK of the study drug- 
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drug should be considered. 
Action taken with study drug 
• Drug Withdrawn; 
• Dose Interrupted; 
• Dose Reduced; 
• Dose Increased; 
• Dose Not Changed; 

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• Not Applicable; or 
• Unknown. 
8.2 
Serious Adverse Events 
An AE or adverse reaction is considered serious if, in the view of either the Investigator or Sponsor, 
it results in any of the following outcomes: 
• Death; 
• A life-threatening AE; 
Note: An AE or adverse reaction is considered “life-threatening” if, in view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death. It does 
not include an event that, had it occurred in a more severe form, might have caused death. 
• Requires hospitalization or prolongation of existing hospitalizations; 
Note: Any hospital admission with at least one overnight stay will be considered an inpatient 
hospitalization. An emergency room or urgent care visit without hospital admission will not 
be recorded as an SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent, or elective treatment of a pre-existing condition 
that did not worsen from Baseline. However, unexpected complications and/or prolongation 
of hospitalization that occur during elective surgery should be recorded as AEs and assessed 
for seriousness. Admission to the hospital for social or situational reasons (ie, no place to stay, 
live too far away to come for hospital visits, respite care) will not be considered inpatient 
hospitalizations.  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• A congenital anomaly/birth defect; or 
• An important medical event. 
Note: Important medical events that do not meet any of the above criteria may be considered 
an SAE when, based upon appropriate medical judgment, they may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalizations, or the development of drug dependency. 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial reports 
All SAEs occurring from the time of informed consent until 30 days following the last 
administration of study drug must be reported to Medpace Clinical Safety within 24 hours of the 
knowledge of the occurrence. After the 30-day reporting window, any SAE that the Investigator 
considers related to study drug must be reported to Medpace Clinical Safety or the 
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To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically by the EDC system and will retrieve the form. If the event meets serious criteria and 
it is not possible to access the EDC system, send an email to Medpace Safety at 
medpace-safetynotification@medpace.com or call the Medpace SAE reporting line (phone 
number listed in Section 8.6), and fax/email the completed paper SAE form to Medpace (contact 
information listed in Section 8.6) within 24 hours of awareness. When the EDC system becomes 
available, the SAE information must be entered within 24 hours of the system becoming available. 
Follow-up reports 
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or email. If 
it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs.  
8.4 
Pregnancy Reporting 
If a patient becomes pregnant during the study or within the safety follow up period defined in the 
protocol, the Investigator is to stop dosing with study drug(s) immediately and the patient should 
be withdrawn from the study. Procedures at ET should be implemented at that time.  
A pregnancy is not considered to be an AE or SAE; however, it must be reported to Medpace 
Clinical Safety within 24 hours of knowledge of the event. Medpace Clinical Safety will then 
provide the Investigator/site the Exposure In Utero (EIU) form for completion. The 
Investigator/site must complete the EIU form and fax/email it back to Medpace Clinical Safety.  
If the female partner of a male patient becomes pregnant while the patient is receiving study drug 
or within the safety follow up period defined in the protocol, the Investigator should notify 
Medpace Clinical Safety as described above.  
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. Once 
the outcome of the pregnancy is known, the EIU form should be completed and faxed/emailed to 
Medpace Clinical Safety. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (ie, postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
8.5 
Expedited Reporting 
The Sponsor/designee will report all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSARs) that are fatal or life-threatening as soon as possible to the applicable 
competent authorities in all the Member States concerned, and to the Central Ethics Committee, 
and in any case no later than 7 days after knowledge by the Sponsor/designee of such a case. 
Relevant follow-up information will subsequently be communicated within an additional 8 days.  

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All other SUSARs will be reported to the applicable competent authorities concerned, and to the 
Central Ethics Committee concerned as soon as possible but within a maximum of 15 days of first 
knowledge by the Sponsor/designee.  
The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in country-specific legislation.  
The Sponsor/designee will also inform all Investigators as required per local regulation. 
The requirements above refer to the requirements relating to investigational medicinal product. 
Expedited reporting of SUSARs related to comparators is also required in line with the 
requirements above. Expedited reporting of SUSARs related to non-investigational medicinal 
products (NIMPs) (and any other NIMPs) is not required. Listings of the cases related to NIMPs 
will be included in the Development Safety Update Report. 
8.6 
Special Situation Reports 
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints. 
• Overdose: Refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the protocol. Clinical judgment should always be applied. In 
cases of a discrepancy in the drug accountability, overdose will be established only when it is 
clear that the patient has taken additional dose(s) or the Investigator has reason to suspect that 
the patient has taken additional dose(s).  
• Misuse: Refers to situations where the medicinal product is intentionally and inappropriately 
used in a way that is not in accordance with the protocol instructions or local prescribing 
information and may be accompanied by harmful physical and/or psychological effects.  
• Abuse: Is defined as persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
• Medication error: Is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product by a healthcare professional, patient, or consumer, respectively. The 
administration or consumption of the unassigned treatment and administration of an expired 
product are always reportable as medication errors, cases of patients missing doses of 
investigational product are not considered reportable as medication error. 
• Product complaint: Is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution. A special situations form 
will only be completed if a complaint is associated with an adverse drug reaction.  
All special situation events as described above must be reported on the Special Situations Report 
form and faxed/emailed to Medpace Clinical Safety (contact information listed below) within 
24 hours of knowledge of the event. All AEs associated with these Special Situation reports should 
be reported as AEs or SAEs as well as recorded on the AE eCRF and/or the SAE report form. 
Details of the symptoms and signs, clinical management, and outcome should be provided, when 
available. 

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Safety Contact Information: Medpace Clinical Safety 
Medpace SAE reporting line – United States: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-570-5196 
Email: medpace-safetynotification@medpace.com 
 
Medpace SAE reporting line – Europe: 
Telephone: +49 89 89 55 718 44 
Fax: +49 89 89 55 718 104 
Email: medpace-safetynotification@medpace.com 
8.7 
Clinical Laboratory Evaluations 
Samples for clinical laboratory assessments (chemistry, lipid, hematology, coagulation, and 
urinalysis) will be obtained as indicated in APPENDIX A.  
A urine and/or serum pregnancy test will be performed as indicated in APPENDIX A for female 
patients of childbearing potential only and postmenopausal women, if the FSH level is not 
available at the time of randomization. An FSH test will be performed as indicated in 
APPENDIX A for female patients < 50 years of age who are considered postmenopausal as they 
have been amenorrhoeic for ≥ 12 months. If the FSH level is not available at the time of 
randomization, the patient must have a negative pregnancy test and agree to use contraception 
methods until the FSH result is available. 
See APPENDIX B for a list of central clinical laboratory assessments.  
8.8 
Vital Signs 
Vital signs will be measured as indicated in APPENDIX A. Vital signs include systolic and 
diastolic blood pressure, heart rate, respiratory rate, and body temperature.  
Body temperature may be taken per the sites’ preferred method (oral, tympanic, or rectal/core) and 
will be recorded in the appropriate eCRF. The same method of measuring the patient’s body 
temperature should be used throughout the study. At Screening, body temperature recorded within 
24 hours prior to the time of obtaining consent may be used. However, the temperature may be 
used only if it was measured by oral, tympanic, or rectal/core temperature, as specified in the 
protocol, and was observed and recorded by the site staff. Vital signs should be collected at the 
same time as assessments of signs and symptoms.  
Patients should be resting in a semi-recumbent position for at least 5 minutes prior to and during 
measurement of vital signs.  
8.9 
Electrocardiograms 
12-lead ECGs will be performed as indicated in APPENDIX A.  
At Screening, a 12-lead ECG recorded within 24 hours prior to the time of obtaining consent may 
be used. 

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8.10 
Physical Examinations 
A complete physical examination will be performed as indicated in APPENDIX A and must 
include source documentation of skin, head and neck, heart, lung, abdomen, extremities, 
back/flank/costo-vertebral angle tenderness, and neuromuscular assessments. Height and weight 
will be measured as indicated in APPENDIX A. A limited, symptom-directed physical 
examination will occur as indicated in APPENDIX A if clinically indicated. 

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9 
STATISTICS 
9.1 
Analysis Populations 
Intent-to-Treat (ITT) Population: All patients who are randomized. 
Modified Intent-to-Treat (MITT) Population: All patients who meet ITT criteria and receive any 
amount of study drug. 
m-MITT Population: All randomized patients who meet MITT criteria and who have a baseline 
qualifying pathogen that susceptible to imipenem and meropenem (see Section 7.1.3.1 for the 
definition of a qualifying pathogen). The definition of imipenem and meropenem susceptible 
pathogen is described in Section 4.1 (Inclusion Criterion #5). 
CE Population: All patients who meet the definition for the MITT Population and who meet the 
following important components of the study as specified in the protocol: 
• Receive at least 80% of the intended doses of randomized study drug treatment; 
• Have a clinical assessment at TOC, unless criteria for clinical failure were met at an earlier 
timepoint; 
• Did not receive concomitant antibacterial treatment with a non-study antibacterial drug to 
which the uropathogen was susceptible between the time of the baseline culture and the TOC 
culture, unless criteria for clinical failure were met; and 
• Do not have any other major protocol violations that would affect assessment of efficacy. 
ME Population: Patients who meet the definition for both the m-MITT and CE Populations. In 
addition, to be included in the ME Population, patients must not have a microbiological outcome 
at TOC of Indeterminate. However, any interpretable positive urine culture obtained from EOT 
through TOC will be carried forward to TOC.  
Safety Population: All patients who receive at least 1 dose of study drug during the study. 
PK Population: All patients in the Safety Population who have at least 1 analyzable PK sample.  
9.2 
Statistical Methods 
9.2.1 
Analysis of Efficacy 
The statistical and analytical plans presented below are an overview of key analysis methods. 
Details of the analysis will be specified in the SAP.  
9.2.1.1 
Primary efficacy analysis 
The primary efficacy endpoint is the proportion of patients who achieve complete composite 
clinical and microbiological success at TOC in the m-MITT Population. The non-inferiority 
hypothesis test is a 1-sided hypothesis test performed at the 2.5% level of significance. This is 
based on the lower limit of the 2-sided 95% confidence intervals (CIs) for the observed difference 
in the proportion of patients with composite clinical and microbiological success 
(cefepime/nacubactam group minus imipenem/cilastatin group) at the TOC. Patients with missing 
data will be included in the denominator for the calculation of success rate. Thus, patients with 
missing data will be considered as failures for the analysis. The primary analysis is based on a CI 

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computed using the Miettinen and Nurminen method. If the lower limit of the 2-sided 95% CI for 
the difference between treatment groups at TOC in the m-MITT Population is > -15.0%, the null 
hypotheses will be rejected and non-inferiority will be concluded based on the primary efficacy 
endpoint. 
If non-inferiority is declared for the primary efficacy endpoint, a test for superiority will be 
performed using a hierarchical gatekeeping approach for overall control of the Type 1 error. For 
this analysis, if the lower bound of the 95% CI for the treatment difference in treatment success at 
TOC in the m-MITT Population is > 0.0%, superiority will be declared. 
Furthermore, if non-inferiority of the cefepime/nacubactam group is declared for the primary 
efficacy endpoint, the non-inferiority hypothesis test for the aztreonam/nacubactam group will be 
performed using a hierarchical gatekeeping approach for overall control of the Type 1 error. For 
this analysis, and for the treatment difference (aztreonam/nacubactam group minus 
imipenem/cilastatin group) in treatment success at TOC, the same approach as in the 
cefepime/nacubactam group will be used.  
9.2.1.2 
Secondary efficacy analyses 
For the secondary efficacy endpoints, the number and percentage of patients with each response 
will be summarized by treatment group. The 2-sided 95% CI for the difference between treatment 
groups in the proportion of patients with favorable response will be presented using the same 
approach as for the primary analyses. 
9.2.1.3 
Pharmacokinetic analyses 
Plasma nacubactam, cefepime, and aztreonam concentrations and PK parameters obtained by 
analyzing plasma concentrations of nacubactam, cefepime, and aztreonam from multiple sampling 
groups using non-compartmental analysis methods will be summarized using the appropriate 
descriptive statistics, which will be fully outlined in the SAP. 
9.2.1.4 
Population pharmacokinetic analyses and pharmacokinetic/pharmacodynamic 
analyses 
PPK analyses will be performed using nacubactam, cefepime, and aztreonam plasma 
concentrations from all patients in the cefepime/nacubactam and aztreonam/nacubactam treatment 
groups. PK/PD analyses will be performed by analyzing the relationship between individual 
estimated PK/PD parameters and individual efficacy data. The results of both analyses will be 
reported independently of the Clinical Study Report for this study. 
9.2.2 
Analysis of Safety 
Safety analyses will be performed on all patients in the Safety Population. Analyses will be based 
on TEAEs, vital signs, clinical laboratory assessments, physical examination findings, and 12-lead 
ECGs. Safety analyses in general will be descriptive and will be presented in tabular format with 
the appropriate summary statistics. 
9.2.3 
Interim Analysis 
No interim analysis is planned for the study. 

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9.2.4 
Data Safety Monitoring Board 
An independent DSMB will review accumulated safety data and will also review SAEs on an 
ongoing basis. The DSMB will make recommendations based on the safety data. Further details 
regarding the data safety monitoring guidelines will be included in the DSMB Charter. 
9.2.5 
Sample Size Determination 
Using a 15% non-inferiority margin, 1-sided alpha of 0.025, 80% power, a composite clinical and 
microbiological success rate of 70% in each treatment group (cefepime/nacubactam, 
imipenem/cilastatin) at TOC, and a 2:1 allocation ratio, a total of 330 patients are required in the 
m-MITT Population. In addition, 110 patients will be required in the m-MITT Population for the 
aztreonam/nacubactam group, the same as the imipenem/cilastatin group, in order to evaluate 
efficacy and safety of the aztreonam/nacubactam group. Assuming 75% of patients will be 
evaluable for the m-MITT Population, a total of approximately 600 patients will be randomized 
using a 2:1:1 allocation ratio (300 patients in the cefepime/nacubactam group, 150 patients in the 
aztreonam/nacubactam group, and 150 patients in the imipenem/cilastatin group). A review of the 
overall percentage of patients in the m-MITT Population will be conducted after approximately 
60% of patients are randomized. Based on this assessment, the sample size may be adjusted to 
ensure the study remains sufficiently powered. 

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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the clinical research associate (CRA) 
during monitoring visits. The CRAs will verify data recorded in the EDC system with source 
documents. All corrections or changes made to any study data must be appropriately tracked in an 
audit trail in the EDC system. An eCRF will be considered complete when all missing, incorrect, 
and/or inconsistent data has been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure username and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Medical Dictionary for Regulatory Activities (latest) for medical history and AEs; and 
• World Health Organization Drug Dictionary for prior and concomitant medications. 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
10.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  

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10.3 
End of Study 
The end of the study is defined as the date when the last patient last observation (LPLO) occurs. 
LPLO is expected to occur at the FUP of the last patient in the study.  

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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
GCP is an international ethical and scientific quality standard for designing, conducting, recording, 
and reporting studies that involve human patients. Compliance with this standard provides public 
assurance that the rights, safety, and wellbeing of study patients are protected, consistent with the 
principles that have their origin in the Declaration of Helsinki, and that the clinical study data are 
credible. 
11.2 
Institutional Review Board/Independent Ethics Committee 
The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will review all 
appropriate study documentation in order to safeguard the rights, safety, and wellbeing of patients. 
The study will only be conducted at sites where IRB/IEC approval has been obtained. The protocol, 
IB, informed consent form (ICF), advertisements (if applicable), written information given to the 
patients, safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the Investigator. 
Federal regulations and International Council for Harmonisation (ICH) Guidelines require that 
approval be obtained from an IRB/IEC prior to participation of patients in research studies. Prior 
to study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to a patient or 
patient’s legal guardian must be approved by the IRB/IEC. 
No drug will be released to the site for dosing until clinical trial authorisation (CTA) execution has 
been confirmed by the Sponsor. 
It is the responsibility of the Sponsor or their designee to obtain the approval of the responsible 
ethics committees according to the national regulations.  
The study will only start in the respective sites once the respective committee’s written approval 
has been given. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB/IEC prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements.  
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and should document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the ICF must be maintained by the Investigator and is subject to inspection by a 
representative of the Sponsor, their representatives, auditors, the IRB/IEC, and/or regulatory 
agencies. A copy of the signed ICF will be given to the patient. The method of obtaining and 
documenting informed consent will comply with ICH GCP and all applicable regulatory 
requirement(s). 

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11.4 
Patient Card 
The patient will receive a patient card to be carried at all times from discharge to the FUP. The 
patient card will state that the patient is participating in a clinical research study, type of treatment, 
number of treatment packs received, and contact details in case of an SAE. 
11.5 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, ICH GCP, Directive 2001/20/EC, applicable regulatory requirements, and the 
Declaration of Helsinki, and that valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. Before 
the enrollment of any patient in this study, the Sponsor or their designee will review with the 
Investigator and site personnel the following documents: protocol, IB, eCRFs and procedures for 
their completion, informed consent process, and the procedure for reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data are 
entered by the site, the CRA will review the data for safety information, completeness, accuracy, 
and logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her study staff will be expected to cooperate with the 
monitor and provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
11.6 
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol. Modifications to the 
protocol should not be made without the agreement of both the Investigator and Sponsor. Changes 
to the protocol will require written IRB/IEC approval/favorable opinion, when applicable, prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
participants. The IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited 
review, and approval/favorable opinion for minor change(s) in ongoing studies that have the 
approval/favorable opinion of the IRB/IEC. The Sponsor will submit all protocol modifications to 
the regulatory authority(ies) in accordance with the governing regulations. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
participants, the Investigator will contact the Sponsor, if circumstances permit, to discuss the 
planned course of action. Any departures from the protocol must be documented in the source 
documentation and must be reported to the IRB/IEC as required by applicable local requirements. 

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11.7 
Protocol Deviations 
According to ICH E3, a protocol deviation is any change, divergence, or departure from the study 
design or procedures defined in the protocol. Major protocol deviations are a subset of protocol 
deviations that may significantly impact the completeness, accuracy, and/or reliability of the study 
data or that may significantly affect a participant's rights, safety, or well-being. A major deviation 
is an accidental or unintentional change to, or non-compliance with the protocol approved 
procedures without prior Sponsor and IRB approval. Major deviations include entering the study 
without satisfying entry criteria, developing withdrawal criteria without being withdrawn, 
receiving the wrong or incorrect dose, receiving excluded concomitant treatment. Minor protocol 
deviations are those which do not affect the scientific soundness of the protocol or the rights, safety 
or welfare of the participant. Minor deviations may include timing of tests and procedures, the 
order of testing, procedural changes, etc.  
Deviations from clinical protocol requirements will be reviewed and evaluated on an ongoing basis 
and, as necessary, appropriate corrective actions put into place. 
11.8 
Disclosure of Data 
Data generated by this study must be available for inspection by the Sponsor or their designee, 
applicable foreign health authorities, and the IRB/IEC as appropriate. Patients or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
11.9 
Data Protection 
The conduct of this study and the processing of any personal data collected from each patient (or 
from a patient’s healthcare professional or other relevant third-party sources) by the Sponsor or its 
designee, the site, or the Investigator for use in the study will fully adhere to the requirements set 
out in applicable data protection and medical privacy laws or regulations, including, without 
limitation, the General Data Protection Regulation (GDPR) European Union (EU) 2016/679 and 
EU Directive 95/46/EEC. The Sponsor or its designee shall ensure that, at all times, it has an 
appropriate legal basis for processing personal data under applicable data protection laws. 
Site-based organizational and technical arrangements to avoid unauthorized access vary by site 
but all include access-controlled/access-limited document control and technical solutions, 
including passwords and security control measures to protect study-specific data, both in paper 
and electronic format. 
The Investigators shall provide coded data to the Sponsor or its designee, which do not reveal the 
patient’s name, full date of birth, or any other information that can identify the patient. All personal 
information shall be replaced with a Subject Identification Code before any information leaves the 
investigative sites.  
The Investigator shall report any data breaches that occur to the Sponsor or its designee, without 
undue delay. The Sponsor has implemented a Business Practice to address data breaches that 
complies with the requirements of applicable laws and regulations, including the GDPR. The data 
breach procedures in the Business Practice provide specific responses to actual or potential threats 
and involve investigation, containment, and mitigation. If applicable, the authorities and the data 

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patients shall be notified of a data breach within the required timeframes of the applicable laws 
and regulations, including those of the GDPR. 
11.10 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.  
11.11 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 
11.12 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 
11.13 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out patient liability 
insurance for all patients who have given their consent to the clinical study. This cover is designed 
for the event that a fatality, physical injury, or damage to health occurs during the clinical study’s 
execution. Insurance cover will be maintained in accordance with the laws and regulation of the 
applicable countries. 
11.14 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a CTA. 
The study will commence (ie, initiation of study centers) when the CTA and favorable Ethics 
opinion have been received.  

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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB/IEC and, where appropriate, regulatory authority, unless immediate implementation of the 
change is necessary for patient safety. In this case, the situation must be documented and reported 
to the regulatory authority and/or the IRB/IEC, as appropriate (per country regulations). 
12.2 
Study Results 
A summary of the results of the study will be available within 1 year of the completion of the 
study, unless a deferral is granted. 

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13 
REFERENCES 
OP0595 Investigator’s Brochure, Edition 6, 14 January 2022. 

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APPENDIX A: SCHEDULE OF PROCEDURES 
Day (± Visit Window) 
Screening Period 
Treatment Period 
Follow-Up Period 
ET 
TOC 
FUP 
Screening 
1a 
2 
3 
4 (EA)  
(± 1 day) 
5  
to  
14b 
EOTb 
7 [± 2] 
days 
after 
EOT 
[Day 10 
to 23] 
14 [±2] 
days 
after 
EOT 
[Day 17 
to 30]c 
Unschy 
 
-1 to 1a 
Pre-
Randomization 
Post-
Randomization 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xa 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medicationse 
X 
Xa 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationf 
X 
Xa,f 
 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Vital signsg 
X 
Xa 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGh 
X 
 
X 
 
 
X 
 
 
 
 
X 
Pregnancy test 
Xi 
 
 
 
 
 
 
 
 
Xi 
Xi 
FSH 
Xj 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 test 
Xk 
 
 
 
 
 
 
 
 
 
 
Clinical signs and 
symptomsl  
X 
Xa 
 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of clinical 
outcome 
 
 
 
 
 
X 
 
X 
X 
X 
X 
PK blood samplingm 
 
 
Xn 
 
Xn 
 
Xn 
 
 
 
 
Urine cultureo 
X 
Xa,p 
 
 
 
X 
 
X 
X 
Xq 
X 
Blood culturer  
X 
Xa 
Xs 
Xs 
Xs 
Xs 
Xs 
Xs 
Xs 
 
Xs 
Clinical laboratory 
assessmentst 
X 
Xa 
 
Xu 
Xu 
X 
Xu 
X 
X 
X 
X 
Randomizationv 
 
X 
 
 
 
 
 
 
 
 
 
Study drug administrationw 
 
 
X 
X 
X 
X 
X 
 
 
 
 
AEsx 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a. 
All procedures will be performed at Screening on Day -1 to Day 1. Urine culture, blood culture, blood sampling and urine sampling for clinical laboratory assessments, body 
temperature, and 12-lead ECG collected as part of standard of care may be used as Screening data prior to informed consent. In the event that Screening and Day 1 occur on the 
same day or within 24 hours, duplicate assessments do not need to be performed; however, laboratory assessment samples for Day 1 chemistry, lipid, hematology, coagulation, 
and urinalysis need to be sent to the central laboratory. Moreover, in case screening culture is used as a baseline culture, it needs to be sent to the central laboratory in addition 
to local laboratory. 

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b. 
EOT may occur anytime from Day 5 to Day 14. Treatment may continue for up to 14 days for patients with a positive blood culture at baseline at the discretion of the Investigator. 
EOT assessments are to be conducted on the day of, or within 24 hours following, the day of the last dose of study drug. 
c. 
The FUP should be performed as an in-person visit.  
d. 
Signed informed consent must be obtained before any study-related procedures are performed. 
e. 
Reasonable efforts will be made to determine all relevant treatment (concomitant medications, including all prescription/non-prescription medications, herbal medications, 
vitamin supplements, supportive therapies, and concomitant non-pharmacologic treatments) received by the patient within 14 days before administration of study drug and 
during the study, which will be recorded in the eCRF. The medication name, route of administration, dose, frequency, indication, and duration of the treatment/procedure (start 
and stop dates) will be recorded. Concomitant treatments (non-pharmacologic treatments) include any surgical or diagnostic procedures. If the EA visit is conducted on Day 3 
or Day 5 (within the allowed window), this assessment should still be conducted on Day 4 as part of the standard safety assessments. 
f. 
A complete physical examination will be performed at Screening and must include source documentation of skin, head and neck, heart, lung, abdomen, extremities, 
back/flank/costo-vertebral angle tenderness, and neuromuscular assessments. Height and weight will be measured at Screening only. A limited, symptom-directed physical 
examination will occur at subsequent visits if clinically indicated. If the EA visit is conducted on Day 3 or Day 5 (within the allowed window), this assessment should still be 
conducted on Day 4 as part of the standard safety assessments. 
g. 
Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature. Vital signs should be collected at the same times as assessments of 
signs and symptoms. Patients should be resting in a semi-recumbent position for at least 5 minutes prior to and during measurement of vital signs. If the EA visit is conducted 
on Day 3 or Day 5 (within the allowed window), this assessment should still be conducted on Day 4 as part of the standard safety assessments. 
h. 
12-lead ECG at Post-Randomization on Day 1 should be done immediately after completion of the first administration of study drug. 
i. 
For female patients of childbearing potential only and postmenopausal women < 50 years of age who have been amenorrhoeic for ≥ 12 months, if the FSH level is not available 
at the time of randomization, a urine and/or serum pregnancy test (serum β-human chorionic gonadotropin) will be performed within 1 day prior to study entry at the local 
laboratory at Screening and at FUP/ET. 
j. 
For female patients < 50 years of age who are considered postmenopausal as they have been amenorrhoeic for ≥ 12 months. If the FSH level is not available at the time of 
randomization, the patient must have a negative pregnancy test and agree to use contraception methods until the FSH result is available. 
k. 
A SARS-CoV-2 test (genetic testing will be suggested but other antigen testing is allowed) should be conducted at Screening for highly suspected COVID-19 patients at the 
Investigator’s discretion. Patients who are tested for SARS-CoV-2 will be started on study drug only after a negative result is confirmed. Patients eligible for the study with the 
exception of meeting COVID-19 criteria will be allowed to rescreen more than 2 weeks after testing positive and must have a negative test result for eligibility. 
l. 
When possible, the same study personnel should complete the assessments at the same time each day. Maximum daily body temperature (defined as the maximum temperature 
reported on a single calendar day) will be recorded. Body temperature may be taken per the site’s preferred method (oral, tympanic, or rectal/core) and will be recorded in the 
appropriate eCRF. The same method of measuring the patient’s body temperature should be used throughout the study. Body temperature recorded within 24 hours prior to the 
time of obtaining consent may be used. However, the temperature may be used only if it was measured by oral, tympanic, or rectal/core temperature, as specified in the protocol, 
and was observed and recorded by the site staff. If the EA visit is conducted on Day 3 or Day 5 (within the allowed window), this assessment should still be conducted on Day 4 
as part of the standard safety assessments. 
m. Blood samples for PK analysis will be collected from all patients. All patients will be assigned to either a multiple PK sampling or a sparse PK sampling group at the discretion 
of the Investigator. In the case the patient is assigned to multiple sampling, samples will be collected on Day 1 after the first infusion of the day: at the end of the infusion 
(± 5 minutes) and at 2, 4, 6, and 8 hours (± 10 minutes) after the start of the study drug infusion. The sample will be collected prior to the start of the next infusion. Note: At 
least 4 time points, including 1 hour after the start of the study drug infusion (first infusion on that day) on Day 1 are needed. If multiple PK sampling cannot be conducted on 
Day 1, it should be conducted on Day 3 or Day 5 instead. If sampling occurs on Day 3 or Day 5, samples can be collected after any of the 3 infusions on that day. In the case 
the patient is assigned to sparse sampling, samples will be collected on Day 1, Day 3, or Day 5, after any of the 3 infusions on that day: around the end of the infusion, around 
2 to 4 hours after the start of the study drug infusion, and around 4 to 8 hours after the start of the study drug infusion. The sample will be collected prior to the start of the next 
infusion. Note: At least 2 time points after the start of the study drug infusion (for any of the 3 infusions on that day) on Day 1, Day 3, or Day 5 are needed. Infusion start and 
end times, as well as PK sampling times, will be recorded in the source documents. The method of PK sample handling is detailed in the Laboratory Manual provided by the 
Sponsor.  
n. 
To be performed on Day 3 or Day 5 only if multiple and/or sparse sampling could not be conducted on Day 1.  
o. 
Urine samples will be collected by clean-catch midstream, intermittent urethral catheter (straight catheterization using sterile technique), a newly inserted Foley catheter (no 
bag specimens allowed), bladder needle aspiration, suprapubic catheter, nephrostomy tube, or ureter aspiration. The local laboratory will culture each urine sample for organism 
identification, quantification, and susceptibility testing (only at Screening). Prior to the first dose of study drug, urine samples submitted for culture must have a 

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urinalysis/dipstick and microscopic analysis performed at the local laboratory. Gram staining (or other possible testings) should be performed if available. Prior to the first dose 
of study drug, only organisms at concentrations of ≥ 105 CFU/mL of urine and not deemed to be a contaminant as detailed in the Microbiology Laboratory Manual will be sent 
to the central laboratory for confirmation of identification, susceptibility testing, and possible molecular testing; unless the same organism grows in urine and blood, in which 
case these organisms should be sent to the central laboratory regardless of CFU/mL. For all post-baseline urine cultures, only organisms at concentrations of ≥ 103 CFU/mL of 
urine and not deemed to be a contaminant as detailed in the Microbiology Laboratory Manual will be sent to the central laboratory for confirmation of identification, susceptibility 
testing, and possible molecular testing. 
p. 
A urine sample taken within 48 hours prior to the first dose of study drug, to support diagnosis or to treat a medical condition, can be used for screening and baseline microbiologic 
assessments if the organism(s) isolated from cultures is available to be sent to the central laboratory for analysis. However, all patients who had a urine sample not taken by the 
method specified in the protocol must have a repeat urine sample culture obtained prior to the start of study drug administration. This sample should be taken as close to 
randomization as possible (within 2 hours prior to the first dose of study drug, if possible). A repeat urine sample must be obtained prior to the start of study drug for any patients 
enrolled after receiving a single dose of a short-acting antibiotic or patients who failed preceding antimicrobial therapy. The sample should be collected as close to randomization 
as possible (within 2 hours prior to the first dose of study drug, if possible). 
q. 
Presumed eradication is assessed at FUP and categorized as eradication only if the baseline qualifying Gram-negative pathogen(s) is eradicated (reduced to < 103 CFU/mL) at 
TOC, and a urine sample cannot be collected but there is a clinical outcome of cure at FUP. Therefore, a urine sample should also be collected at FUP, unless the baseline 
qualifying Gram-negative pathogen(s) is eradicated (reduced to < 103 CFU/mL) at TOC. 
r. 
Two sets of blood culture samples from 2 separate venipuncture sites will be obtained at Screening and prior to the first dose of study drug on Day 1 for baseline blood cultures 
(duplicate assessments do not need to be performed if Screening and Day 1 occur on the same day or within 24 hours). The blood culture should be obtained within the allowed 
Screening Period and within 48 hours prior to the first dose of study drug to align with the requirement to have a urine sample taken within 48 hours. Each set of blood culture 
samples will include 1 aerobic and 1 anaerobic bottle (an additional aerobic bottle is allowed if anaerobic culture is not standard practice at the site). However, for cUTI and 
AP, a single aerobic blood culture is sufficient if it is not the institution’s standard of care to obtain an anerobic culture. Specimens will be sent to the local laboratory for culture 
identification and susceptibility testing. All isolates from blood culture will be sent to the central laboratory for confirmation of identification, susceptibility testing, and possible 
molecular testing as outlined in the Microbiology Laboratory Manual. If the EA visit is conducted on Day 3 or Day 5 (within the allowed window), this assessment should still 
be conducted on Day 4 as part of the standard safety assessments. 
s. 
If a blood culture is positive at baseline for an organism obtained in a concurrently collected urine sample, blood cultures will be collected until the baseline qualifying 
Gram-negative pathogen(s) is negative for at least 48 hours in subsequent blood cultures. Additional blood cultures will be collected at the Investigator’s discretion. In that case, 
2 sets of blood culture samples from 2 separate venipuncture sites will be obtained. The frequency of repeating those blood cultures should be at the discretion of the Investigator, 
but there must be documentation of a negative blood culture 48 hours after any baseline blood culture or after any subsequent blood culture is found to be positive. For patients 
with fever spikes (oral or tympanic temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature ≥ 38.3°C [≥ 100.9°F]) during the study, additional blood samples may be obtained 
at the time of the fever spike. Specimens will be sent to the local laboratory for culture identification and susceptibility testing (only at Screening). All isolates from blood 
culture will be sent to the central laboratory for confirmation of identification, susceptibility testing, and possible molecular testing as outlined in the Microbiology Laboratory 
Manual. 
t. 
Includes chemistry, lipid, hematology, coagulation, and urinalysis. Clinical laboratory assessments for chemistry, hematology, and urinalysis will be performed at the local 
laboratory at Screening and by the central laboratory at baseline and EA, EOT, TOC, FUP, and ET. It is permitted that these labs are obtained up to 24 hours prior to the 
Screening Period to determine eligibility, as long as the patient’s clinical status has not changed significantly. In principle, serum creatinine will be performed daily at the local 
laboratory. See APPENDIX B for a list of clinical laboratory assessments. If the EA visit is conducted on Day 3 or Day 5 (within the allowed window), this assessment should 
still be conducted on Day 4 as part of the standard safety assessments. 
u. 
While the patient is receiving study drug, additional clinical laboratory assessments may be performed by the central laboratory at the Investigator’s discretion.  
v. 
Patients will be randomized on Day 1, after pre-randomization procedures are performed, in a 2:1:1 ratio to receive either 2 g cefepime/1 g nacubactam, 2 g aztreonam/1 g 
nacubactam, or 1 g imipenem/1 g cilastatin. Dosage of cefepime, aztreonam, nacubactam, and imipenem/cilastatin according to renal function is shown in Table 4. 
Randomization will be stratified by entry diagnosis (cUTI or AP) and by geographic region (Japan, China, or Other). 
w. Study drug will be administered every 8 hours (± 1 hour) via an IV infusion over a period of 60 minutes (± 15 minutes). The administration of nacubactam requires the use of 
an in-line filter, according to the details outlined in the Pharmacy Manual. All patients will be treated for a minimum of 5 days (ie, 15 IV infusions) to 10 days. Duration may 
continue for up to 14 days in selected situations (eg, baseline bacteremia), after discussion with the Medical Monitor. 
x. 
AEs will be assessed after signed informed consent is obtained. Any medical condition already present at Screening should be recorded as medical history and not be reported 
as an AE unless the medical condition or signs or symptoms present at baseline changes in severity, frequency, or seriousness at any time during the study. In this case, it should 

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be reported as an AE. If the EA visit is conducted on Day 3 or Day 5 (within the allowed window), this assessment should still be conducted on Day 4 as part of the standard 
safety assessments. 
y. 
Patients who discontinue from study drug and complete the ET visit but are not discontinued from the study should continue to complete all safety assessments approximately 
7 to 14 days after ET. AE assessment must be performed, but other assessments should be performed at the discretion of the Investigator, if clinically indicated (see Sections 6.6, 
6.6.1, and 6.6.2). 
AE = adverse event; AP = acute uncomplicated pyelonephritis; CFU = colony-forming unit(s); COVID-19 = Coronavirus Disease 2019; cUTI = complicated urinary tract infection; 
EA = Early Assessment; ECG = electrocardiogram; eCRF = electronic case report form; EOT = End of Treatment; ET = Early Termination; FSH = follicle-stimulating hormone; 
FUP = Follow-Up visit; IV = intravenous(ly); PK = pharmacokinetic(s); SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TOC = Test of Cure visit; 
Unsch = unscheduled. 
 

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APPENDIX B: CLINICAL LABORATORY ASSESSMENTS 
Clinical laboratory assessments for chemistry, hematology, urinalysis, pregnancy (if applicable), 
follicle-stimulating hormone (if applicable), and Coronavirus Disease 2019 (COVID-19) (if 
applicable) will be performed by the local laboratory at Screening to determine patient eligibility. 
Sites can assess at least some of the laboratory tests listed in Section 6.2 at Screening. Those 
assessments and additional assessments listed below will be performed by the central laboratory 
at baseline and post-baseline to monitor patient safety. During the study period, additional clinical 
laboratory assessments may be performed locally at the Investigator’s discretion, as needed, for 
management of the patient.  
Standard Safety Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate (if applicable at the local 
laboratory) 
Blood urea/blood urea nitrogen 
Calcium 
Chloride 
C-reactive protein 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate 
γ-glutamyl transferase 
Glucose 
Inorganic phosphorus 
Lactate dehydrogenase 
Lipase 
Potassium 
Sodium 
Magnesium 
Total bilirubin 
Total protein 
Uric acid 
 
Lipid Panel 
High-density lipoprotein cholesterol 
Low-density lipoprotein cholesterol 
Total cholesterol 
Triglycerides 
 
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count and differential [1] 
 
1. 
Manual microscopic review will be performed only if white blood cell count and/or differential values are out of reference 
range. 
 
Coagulation 
International normalized ratio  
Partial thromboplastin time  
Prothrombin time 
 
 

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Urinalysis 
Appearance (color, clarity) 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy [1] 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
1. 
Microscopy will be performed only as needed based on positive dipstick test results. 
 
Pregnancy Test 
Serum β-human chorionic gonadotropin or urine pregnancy test [1] 
1. 
Pregnancy test will be performed at the local laboratory for female patients of childbearing potential only and in 
postmenopausal women < 50 years of age who have been amenorrhoeic for ≥ 12 months, if follicle-stimulating hormone 
levels are not available at the time of randomization.  
 
Endocrinology 
Follicle-stimulating hormone [1] 
1. 
Follicle-stimulating hormone in women < 50 years of age who are considered postmenopausal as they have been 
amenorrhoeic for ≥ 12 months.  
 
Serology 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1] 
1. 
A SARS-CoV-2 test (genetic testing will be suggested but other antigen testing is allowed) should be conducted at 
Screening for highly suspected COVID-19 patients at the Investigator’s discretion. Patients who are tested for 
SARS-CoV-2 will be started on study drug only after a negative result is confirmed. Patients eligible for the study 
with the exception of meeting COVID-19 criteria will be allowed to rescreen more than 2 weeks after testing positive 
and must have a negative test result for eligibility. 
 

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APPENDIX C: ALLOWED AND DISALLOWED PRIOR ANTIBIOTICS 
Allowed Antibiotics (1 dose within 48 hours prior to the first dose 
of study drug [1]) 
Disallowed Antibiotics 
Penicillins 
Amoxicillin 
Nafcillin 
Benzathine/Penicillin-G Procaine 
Amoxicillin-clavulanate 
Oxacillin 
Amoxicillin-sulbactam 
Penicillin-G or -V 
Ampicillin 
Piperacillin 
Ampicillin-sulbactam 
Piperacillin-tazobactam 
Dicloxacillin 
Ticarcillin-clavulanate 
Cephalosporins 
Cefaclor 
Ceftolozane-tazobactam 
Cefixime (400 mg) 
Cefadroxil 
Cefpodoxime 
Ceftriaxone 
Cefazolin 
Cefprozil 
Cefdinir 
Ceftaroline 
Cefepime 
Loracarbef 
Cefixime (200 mg) 
Ceftibuten 
Cefditoren 
Cefuroxime 
Cefotaxime 
Cephalexin 
Cefoperazone (with or without 
sulbactam 
Ceftazidime (with or without 
avibactam 
Cefmetazole 
 
Carbapenems 
Doripenem 
Meropenem 
Ertapenem 
Imipenem 
Meropenem-vaborbactam 
Glycopeptides 
Telavancin 
Vancomycin 
Dalbavancin 
Oritavancin 
Fluoroquinolones 
Ciprofloxacin 
Ofloxacin 
Levofloxacin 
Prulifloxacin 
Norfloxacin 
Pefloxacin 
Moxifloxacin 
Tosufloxacin 
 
Macrolides 
Clarithromycin 
Erythromycin 
Azithromycin 
Clarithromycin XL 
Tetracyclines 
Doxycycline (100 mg) 
Minocycline 
Doxycycline 
(200 mg) 
Tigecycline 
Minocycline extended release 
Oxazolidinones 
Linezolid 
Tedizolid 
Miscellaneous 
Clindamycin 
Nitrofurantoin 
Fosfomycin (intravenous and oral) 
Metronidazole 
Nalidixic acid 
Plazomicin 
Pipemidic acid 
Amikacin 
Trimethoprim-sulfamethoxazole/ Co-
trimoxazole 
Gentamicin 
1. 
Prior (within 48 hours prior to the first dose of study drug) administration of potentially effective systemic antibacterial 
therapy is an Exclusion Criterion; however, patients may be eligible for the study despite prior antimicrobial therapy if 
they received a single dose of a single short-acting systemic antibiotic within 48 hours prior to the first dose of study drug. 
For the purposes of this protocol, short-acting is defined as having a dosage frequency of more than once a day. If a patient 
received a prior short-acting systemic antibiotic that is not listed here, the Investigator must contact the Medical Monitor 
to ensure patient eligibility. 
 

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APPENDIX D: DRUG LISTS CLASSIFIED AS HIGH RISK OF QT 
PROLONGATION 
Generic Name 
Drug Class 
Aclarubicin  
Anti-cancer 
Amiodarone 
Antiarrhythmic 
Anagrelide 
Phosphodiesterase 3 inhibitor 
Arsenic trioxide 
Anti-cancer 
Astemizole  
Antihistamine 
Azithromycin 
Antibiotic 
Bepridil 
Antianginal 
Cesium Chloride 
toxin 
Chloroquine 
Antimalarial 
Chlorpromazine 
Antipsychotic / Antiemetic 
Chlorprothixene  
Antipsychotic 
Cilostazol 
Phosphodiesterase 3 inhibitor 
Ciprofloxacin 
Antibiotic 
Cisapride  
GI stimulant 
Citalopram 
Antidepressant, SSRI 
Clarithromycin 
Antibiotic 
Cocaine 
Local anesthetic 
Disopyramide 
Antiarrhythmic 
Dofetilide 
Antiarrhythmic 
Domperidone  
Antiemetic 
Donepezil 
Cholinesterase inhibitor 
Dronedarone 
Antiarrhythmic 
Droperidol 
Antipsychotic / Antiemetic 
Erythromycin 
Antibiotic 
Escitalopram 
Antidepressant, SSRI 
Flecainide 
Antiarrhythmic 
Fluconazole 
Antifungal 
Gatifloxacin  
Antibiotic 
Grepafloxacin  
Antibiotic 
Halofantrine  
Antimalarial 
Haloperidol 
Antipsychotic 
Hydroquinidine (Dihydroquinidine)  
Antiarrhythmic 
Hydroxychloroquine 
Antimalarial, Anti-inflammatory 
Ibogaine  
Psychedelic 
Ibutilide 
Antiarrhythmic 
Levofloxacin 
Antibiotic 
Levomepromazine (Methotrimeprazine)  
Antipsychotic 
Levomethadyl acetate  
Opioid agonist 
Levosulpiride  
Antipsychotic 
Meglumine antimoniate  
Antiparasitic 
Mesoridazine  
Antipsychotic 
Methadone 
Opioid agonist 
Moxifloxacin 
Antibiotic 
Nifekalant  
Antiarrhythmic 
Ondansetron 
Antiemetic 
Oxaliplatin 
Anti-cancer 
Papaverine hydrochloride (Intra-coronary) 
Vasodilator, Coronary 
Pentamidine 
Antifungal 

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Generic Name 
Drug Class 
Pimozide 
Antipsychotic 
Probucol  
Antilipemic 
Procainamide 
Antiarrhythmic 
Propofol 
Anesthetic, general 
Quinidine 
Antiarrhythmic 
Roxithromycin  
Antibiotic 
Sertindole  
Antipsychotic, atypical 
Sevoflurane 
Anesthetic, general 
Sotalol 
Antiarrhythmic 
Sparfloxacin  
Antibiotic 
Sulpiride  
Antipsychotic, atypical 
Sultopride  
Antipsychotic, atypical 
Terfenadine  
Antihistamine 
Terlipressin  
Vasoconstrictor 
Terodiline  
Muscle relaxant 
Thioridazine 
Antipsychotic 
Vandetanib 
Anti-cancer