Amendment no.1: Piperacillin/tazobactam was selected to be used as a comparator in this complicated urinary tract infection (cUTI) trial due to its antibacterial spectrum, its pharmacokinetic properties and due to the fact that it is a beta-lactam/beta-lactamase inhibitor combination very similar to the cefepime/AAI101 combination. Inclusion Criterion 3 was revised to define permanent sterilization for women who are no longer of childbearing potential. A new Exclusion Criterion 1 was added to exclude patients who have qualifying Gram-positive primary pathogen at >=10^5 colony-forming units (CFU)/mL. Exclusion Criterion 2 was revised to reflect piperacillin/tazobactam as the comparator drug. Exclusion Criterion 7 was revised to define the exceptions to the receipt of potentially effective systemic antibacterial therapy for continuous duration of >24 hours during the previous 72 hours before study-qualifying baseline urine is collected. Exclusion Criterion 10 was adjusted to match the extended duration of treatment. Exclusion Criterion 15 was revised to note glomerular filtration rate rather than creatinine clearance. Exclusion Criterion 25 was revised to further define the time prior to Screening regarding the administration of experimental medication. Piperacillin/tazobactam will be administered over a period of 2 hours once every 8 hours (q8h) for 7 days. Possible treatment duration was extended from 7 to 10 days to 7 to 14 days in patients with a positive blood culture at baseline. The criteria for microbiological outcome were revised. Prothrombin and partial thromboplastin time were added to clinical laboratory assessments. The number of sites was reduced from 120 to 115. The schedule of procedures and clinical laboratory analytes was updated to reflect the changes specified herein, where applicable. Other minor edits were made throughout the document to improve clarity, consistency, and to correct grammatical errors.

Amendment no.2: This amendment was developed in response to Food and Drug Administration (FDA) feedback during the end of Phase 2 meeting and a review of the amended protocol. Other minor edits were made throughout the document to correct grammatical errors and inconsistencies. The study population was updated to specify that at least 50% of patients will have complicated urinary tract infection (cUTI) and at least 30% will have acute pyelonephritis (AP). Exclusion Criterion 15 was revised to specify that patients with impairment of renal function with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 are excluded from the study. In Exclusion Criterion 22, it was specified that patients with current clinically significant liver disease, including any form of known liver cirrhosis are also excluded from the study. Dosing in patients with renal insufficiency was updated to be consistent with Exclusion Criterion 15. It was specified that a triplicate 12-lead electrocardiogram (ECG) will be performed at Screening and Day 4. It was clarified that up to 2 Gram-negative bacterial isolates per urine culture (at concentrations of >=10^5 CFU/mL of urine) will be considered as qualifying pathogens. The overall response to a clinical outcome of Cure and microbiological outcome of Indeterminate was updated to Indeterminate. Secondary efficacy parameters were updated to include additional subsets of patients. Protocol Section was added to clarify adverse events of special interest. Sample size determination was revised. Direct bilirubin and C-reactive protein were added to the clinical laboratory analysis. The relevant protocol tables and schedule of procedures were updated to reflect the changes specified herein, where applicable.

Amendment no.3: This amendment was developed in response to Food and Drug Administration feedback during the end of Phase 2 meeting and a review of the amended protocol. Other minor edits were made throughout the document to correct grammatical errors and inconsistencies. Inclusion Criterion 7 was updated to clarify that if the patient has met the criteria for complicated urinary tract infection (cUTI) and acute pyelonephritis (AP), the infection type would be considered cUTI for randomization and analysis purposes. Collection of blood samples for PK analysis was clarified for Day 7 and the Early Termination visit. A Study Scheme figure was added. Dosing in patients with renal insufficiency was updated to clarify confirmation for patients with normal renal function or mild or moderate renal impairment at baseline. Collection of laboratory assessments was updated to clarify collections on Day 7; Days 8, 9, 11, 12, or 13; and Day 10. Adverse events of special interest were updated for the new laboratory assessment collected on Day 10. Criteria for study drug discontinuation were updated. Expedited reporting was clarified. The relevant protocol tables and schedule of procedures were updated to reflect the changes specified herein, where applicable.

Amendment no.4: This amendment was developed in response to Food and Drug Administration feedback during the End of Phase 2 meeting and a review of the amended protocol. Other minor edits were made throughout the document to correct grammatical errors and inconsistencies. Study design was updated to include that the Test of Cure (TOC) visit will occur 7 days after End of Treatment (EOT) (EOT + 7 days [±2 days]) for patients receiving 7 days of treatment and 19 days after randomization (randomization + 19 days [±2 days]) for patients receiving more than 7 days of treatment. The Late Follow-up (LFU) visit was also updated to clarify that the LFU visit should not take place earlier than 3 days after the TOC visit. It was specified that for patients without bacteremia, treatment cannot be prolonged for more than 7 days. The blood samples collection time for laboratory assessments on Day 1 was clarified. It was clarified that in patients with moderate renal impairment, dose adjustment is applicable from Day 1 of dosing. Direct bilirubin was removed from the screening laboratory assessments for eligibility. The relevant protocol tables and schedule of procedures were updated to reflect the changes specified herein, where applicable.