The purpose of the study is to demonstrate the safety and efficacy of ZTI-01 (IV fosfomycin) as non-inferior to piperacillin/tazobactam in overall success (clinical cure and microbiologic eradication) for the treatment of hospitalized patients with complicated urinary tract infections (cUTI) or acute pyelonephritis (AP).

This is a multi-center, randomized, double-blind, parallel-group study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of ZTI-01 (IV fosfomycin) compared to piperacillin/tazobactam in the treatment of hospitalized adults with cUTI or AP. Diagnosed and prescreened hospitalized patients will be randomized 1:1 to receive one of two intravenous treatments: 6 g ZTI-01 three times daily (18g total daily dose) or 4.5 g piperacillin/tazobactam three times daily (13.5g total daily dose) for 7 calendar days, with option to extend treatment up to 14 days in patients with positive blood culture at pretreatment. Patients will participate in the study for approximately 26 days. Urine cultures will be obtained and organisms quantified for qualified patients at baseline, during treatment, at end of treatment (EOT), at test of cure (TOC) and late follow up visits (LFU). Blood cultures will be obtained at baseline and repeated if positive throughout the study. Safety and efficacy evaluations will include vital signs, labs, physical exams, ECG and overall response as evaluated by the Investigator. Pharmacokinetic samples will be obtained (sparse sampling) for all patients.

Inclusion Criteria:

1. A signed informed consent form (ICF);
2. Male or female, at least 18 years of age;
3. Diagnosis requires hospitalization and treatment with intravenous (IV) antibiotics;
4. Documented or suspected cUTI or AP including at least 2 protocol defined signs and symptoms and a urine specimen with evidence of pyuria plus at least one protocol defined associated risk
5. Pretreatment baseline urine culture specimen
6. Expectation that any implanted urinary instrumentation will be removed or replaced not longer than 24 hours, after randomization;
7. Expectation that patient will survive anticipated duration of the study;
8. Patient requires initial hospitalization to manage the cUTI or AP;
9. Women of childbearing potential have had a negative pregnancy test before randomization and be willing to consistently use a highly effective method of contraception
10. Male study participants will be required to use condoms with a spermicide throughout study

Exclusion Criteria:

1. Presence of any of the following conditions: perinephric abscess, renal corticomedullary abscess, uncomplicated urinary tract infection, recent history of trauma to the pelvis or urinary tract, polycystic kidney disease, chronic vesicoureteral reflux, previous or planned renal transplantation; patients receiving dialysis/hemodialysis/CVVH, previous or planned cystectomy or ileal loop surgery; known or suspected infection; caused by pathogen resistant to study treatment antibiotics
2. Presence of suspected or confirmed acute bacterial prostatitis, orchitis, epididymitis, or chronic bacterial prostatitis as determined by history and/or physical examination;
3. Gross hematuria requiring intervention;
4. Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period;
5. Creatinine clearance <20 mL/min using the Cockcroft-Gault formula;
6. Non-renal source of infection such as endocarditis, osteomyelitis, abscess, meningitis, or pneumonia diagnosed within 7 days prior to randomization;
7. Signs of severe sepsis as defined per protocol;
8. Pregnant or breastfeeding women;
9. Known seizure disorder requiring current treatment with anti-seizure medication which would prohibit the patient from complying with the protocol;
10. Cancer chemotherapy, immunosuppressive medications for transplantation, or medications for rejection of transplantation with 30 days of randomization;
11. Significant hepatic disease or dysfunction, including known acute viral hepatitis or hepatic encephalopathy;
12. ALT/AST >5 × ULN or total bilirubin >3 × ULN at Screening;
13. Receipt of any potentially-effective systemic antibiotic with activity against Gram-negative uropathogens for more than 24 hours within the 72-hour window prior to randomization (exceptions defined in protocol);
14. Requirement for additional systemic antibiotic therapy (other than study drug) or antifungal therapy for vaginal candidiasis;
15. Likely to require the use of an antibiotic for cUTI or AP prophylaxis during the study;
16. Known history of HIV virus infection and known recent CD4 count <200/mm3;
17. Presence of significant immunodeficiency or an immunocompromised condition and long-term use of systemic corticosteroids;
18. Presence of neutropenia;
19. Presence of thrombocytopenia;
20. A QT interval corrected using Fridericia's formula >480 msec;
21. History of significant hypersensitivity or allergic reaction to fosfomycin, any contraindication to the use of piperacillin/tazobactam;
22. Participation in a clinical study involving investigational medication or investigational device within the last 30 days prior to randomization;
23. Inability, in the judgment of the Investigator, to tolerate the salt load required for study drug administration;
24. Unable or unwilling, in the judgment of the Investigator, to comply with the protocol;
25. Any patients previously randomized in this study.

Individual IPD data will be shared in listings with FDA, IRB/ECs, Data Monitoring Committee

ongoing submissions to IND

IND/NDA submission, CTA submissions