{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T22:31:32Z","timestamp":1792276292224,"version":"4.4.0"},"reference-count":17,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2019,3,12]],"date-time":"2019-03-12T00:00:00Z","timestamp":1552348800000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Zavante Therapeutics, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,11,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Hospitalized adults with suspected or microbiologically confirmed cUTI\/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g intravenous (IV) piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic modified intent-to-treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119\/184 patients) vs 54.5% (97\/178 patients), respectively; treatment difference was 10.2% (95% confidence interval [CI]: \u22120.4, 20.8). Clinical cure rates at test of cure (TOC, day 19\u201321) were high and similar between treatments (90.8% [167\/184] vs 91.6% [163\/178], respectively). In post hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in m-MITT were 69.0% (127\/184) for ZTI-01 versus 57.3% (102\/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mild and transient.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ZTI-01 was effective for treatment of cUTI including AP and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gram-negative infections.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>NCT02753946<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cid\/ciz181","type":"journal-article","created":{"date-parts":[[2019,2,28]],"date-time":"2019-02-28T23:15:19Z","timestamp":1551395719000},"page":"2045-2056","source":"Crossref","is-referenced-by-count":147,"title":["Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2\/3 Randomized Trial"],"prefix":"10.1093","volume":"69","author":[{"given":"Keith S","family":"Kaye","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis B","family":"Rice","sequence":"additional","affiliation":[{"name":"Department of Medicine, Warren Alpert Medical School of Brown University and Rhode Island Hospital and The Miriam Hospital, Providence"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron L","family":"Dane","sequence":"additional","affiliation":[{"name":"DaneStat Consulting, Alderly Edge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor","family":"Stus","sequence":"additional","affiliation":[{"name":"Municipal Institution Dnipropetrovsk Medical Academy of Ministry of Health of Ukraine, Dnipro"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olexiy","family":"Sagan","sequence":"additional","affiliation":[{"name":"Municipal Institution Zaporizhzhia Regional Clinical Hospital of Zaporizhzhia, Regional Council Department of Urology, State Institution Zaporizhzhia Medical Academy of Postgraduate Education under the Ministry of Health of Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Fedosiuk","sequence":"additional","affiliation":[{"name":"Brest Regional Hospital, Belarus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita F","family":"Das","sequence":"additional","affiliation":[{"name":"Das Statistical Consulting, Guerneville"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Skarinsky","sequence":"additional","affiliation":[{"name":"Zavante Therapeutics, Inc., San Diego, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul B","family":"Eckburg","sequence":"additional","affiliation":[{"name":"Zavante Therapeutics, Inc., San Diego, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn J","family":"Ellis-Grosse","sequence":"additional","affiliation":[{"name":"Zavante Therapeutics, Inc., San Diego, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,3,6]]},"reference":[{"key":"2019112706205562100_CIT0001","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1093\/cid\/cis503","article-title":"A paradigm shift in drug development for treatment of rare multidrug-resistant gram-negative pathogens","volume":"55","author":"Alemayehu","year":"2012","journal-title":"Clin Infect Dis"},{"key":"2019112706205562100_CIT0002","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1093\/cid\/ciw636","article-title":"Clinical outcomes, drug toxicity, and emergence of ceftazidime-avibactam resistance among patients treated for carbapenem-resistant Enterobacteriaceae infections","volume":"63","author":"Shields","year":"2016","journal-title":"Clin Infect Dis"},{"key":"2019112706205562100_CIT0003","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1128\/CMR.00068-15","article-title":"Fosfomycin","volume":"29","author":"Falagas","year":"2016","journal-title":"Clin Microbiol Rev"},{"key":"2019112706205562100_CIT0004","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.ijantimicag.2009.10.019","article-title":"Antimicrobial susceptibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to fosfomycin","volume":"35","author":"Falagas","year":"2010","journal-title":"Int J Antimicrob Agents"},{"key":"2019112706205562100_CIT0005","volume-title":"Monurol (fosfomycin tromethamine) sachet prescribing information, 2011 February"},{"key":"2019112706205562100_CIT0006","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.cmi.2016.12.005","article-title":"Intravenous fosfomycin-back to the future: systematic review and meta-analysis of the clinical literature","volume":"23","author":"Grabein","year":"2017","journal-title":"Clin Microbiol Infect"},{"key":"2019112706205562100_CIT0007","volume-title":"World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects","author":"World Medical Association","year":"2008"},{"key":"2019112706205562100_CIT0008","volume-title":"Piperacillin\/Tazobactam 4g\/0.5g powder for solution for infusion"},{"key":"2019112706205562100_CIT0009","volume-title":"Phenotypic antibiotic resistance in ZEUS: multi-center, randomized, double-blind phase 2\/3 study of ZTI-01 versus piperacillin-tazobactam (P-T) in the treatment of patients with complicated urinary tract infections (cUTI) including acute pyelonephritis (AP)","author":"Eckburg"},{"key":"2019112706205562100_CIT0010","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1093\/cid\/ciw378","article-title":"Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program","volume":"63","author":"Wagenlehner","year":"2016","journal-title":"Clin Infect Dis"},{"key":"2019112706205562100_CIT0011","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1001\/jama.2018.0438","article-title":"Effect of meropenem-vaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection: the TANGO I randomized clinical trial","volume":"319","author":"Kaye","year":"2018","journal-title":"JAMA"},{"key":"2019112706205562100_CIT0012","doi-asserted-by":"crossref","first-page":"S305","DOI":"10.1093\/ofid\/ofu052.749","article-title":"1041Economic burden associated with key Gram-negative pathogens among patients with complicated urinary tract infections across US hospitals","volume":"1","author":"Mocarski","year":"2014","journal-title":"Open Forum Infect Dis"},{"key":"2019112706205562100_CIT0013","doi-asserted-by":"crossref","first-page":"217","DOI":"10.3390\/antibiotics2020217","article-title":"Molecular mechanisms and clinical impact of acquired and intrinsic fosfomycin resistance","volume":"2","author":"Casta\u00f1eda-Garc\u00eda","year":"2013","journal-title":"Antibiotics (Basel)"},{"key":"2019112706205562100_CIT0014","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/jac\/dkr466","article-title":"Fosfomycin: evaluation of the published evidence on the emergence of antimicrobial resistance in Gram-negative pathogens","volume":"67","author":"Karageorgopoulos","year":"2012","journal-title":"J Antimicrob Chemother"},{"key":"2019112706205562100_CIT0015","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.ijmm.2017.09.019","article-title":"Biological cost of fosfomycin resistance in Escherichia coli in a murine model of urinary tract infection","volume":"307","author":"Pourbaix","year":"2017","journal-title":"Int J Med Microbiol"},{"key":"2019112706205562100_CIT0016","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s40121-015-0092-8","article-title":"Adverse events associated with fosfomycin use: review of the literature and analyses of the FDA adverse event reporting system database","volume":"4","author":"Iarikov","year":"2015","journal-title":"Infect Dis Ther"},{"key":"2019112706205562100_CIT0017","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.ijantimicag.2010.09.002","article-title":"Adverse events associated with intravenous fosfomycin","volume":"37","author":"Florent","year":"2011","journal-title":"Int J Antimicrob Agents"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciz181\/28563656\/ciz181.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cid\/article-pdf\/69\/12\/2045\/31143610\/ciz181.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cid\/article-pdf\/69\/12\/2045\/31143610\/ciz181.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,11,27]],"date-time":"2019-11-27T06:21:24Z","timestamp":1574835684000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/69\/12\/2045\/5370034"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,6]]},"references-count":17,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,3,6]]},"published-print":{"date-parts":[[2019,11,27]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciz181","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,12,15]]},"published":{"date-parts":[[2019,3,6]]}}}