Intravenous Doripenem at 500 Milligrams versus Levofloxacin at 250 Milligrams, with an Option To Switch to Oral Therapy, for Treatment of Complicated Lower Urinary Tract Infection and Pyelonephritis

ABSTRACT The prospective, multicenter, double-blind study presented in this report evaluated whether or not intravenous (IV) administration of doripenem, a carbapenem with bactericidal activity against gram-negative and gram-positive uropathogens, is inferior to IV administration of levofloxacin in the treatment of complicated urinary tract infection (cUTI). Patients (n = 753) with complicated lower UTI or pyelonephritis were randomly assigned to receive IV doripenem at 500 mg every 8 h (q8h) or IV levofloxacin at 250 mg q24h. Patients in both treatment arms were eligible to switch to oral levofloxacin after 3 days of IV therapy to complete a 10-day treatment course if they demonstrated significant clinical and microbiological improvements. The microbiological cure rate (primary end point) was determined at the test-of-cure (TOC) visit occurring 5 to 11 days after the last dose of antibiotic. For the microbiologically evaluable patients (n = 545), the microbiological cure rates were 82.1% and 83.4% for doripenem and levofloxacin, respectively (95% confidence interval [CI] for the difference, −8.0 to 5.5%); in the microbiological modified intent-to-treat cohort (n = 648), the cure rates were 79.2% and 78.2%, respectively. Clinical cure rates at the TOC visit were 95.1% in the doripenem arm and 90.2% in the levofloxacin arm (95% CI around the difference in cure rates [doripenem cure rate minus levofloxacin cure rate], 0.2% to 9.6%). Both treatment regimens were generally well tolerated. Doripenem was found not to be inferior to levofloxacin in terms of therapeutics and is now approved for use in the United States and Europe for the treatment of adults with cUTI, including pyelonephritis. As fluoroquinolone resistance increases, doripenem may become a more important option for successful treatment of cUTIs, including treatment of pyelonephritis.

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1367. Clinical Cure in Secondary Efficacy Populations in Patients With Complicated Urinary Tract Infection Treated With ZTI-01 (Fosfomycin for Injection): Findings From the ZEUS Trial

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1198 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S418-S419 ◽

Cited By ~ 1

Author(s):

Keith Kaye ◽

Louis B Rice ◽

Viktor Stus ◽

Olexsiy Sagan ◽

Elena Fedosiuk ◽

...

Keyword(s):

United States ◽

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Clinical Cure ◽

Complicated Urinary Tract Infection ◽

The United States ◽

Research Support ◽

Gram Negative ◽

Cure Rates

Abstract Background ZTI-01 (fosfomycin for injection) is an investigational epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has a broad spectrum of in vitro activity, including multidrug-resistant Gram-negative pathogens, and is being developed for the treatment of patients with complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States. Methods ZEUS was a multicenter, double-blind, Phase 2/3 trial in hospitalized adults with cUTI and AP to evaluate safety and efficacy. Randomized patients received 6 g ZTI-01 q8h or 4.5 g IV piperacillin/tazobactam (PIP-TAZ) q8h for 7 days; patients with baseline bacteremia could receive up to 14 days; study continued to late follow-up (LFU, 26 ± 2 days). Oral step-down therapy was prohibited. ZTI-01 met the primary endpoint of noninferiority to PIP-TAZ. Secondary objectives included comparing clinical cure rates (assessed by investigator) in the modified intent-to-treat (MITT), microbiologic MITT (m-MITT), clinical evaluable (CE), and microbiologic evaluable (ME) populations at test-of-cure (TOC, Day 19 ± 2 days). Results There were 464 patients randomized who received study drug. In all populations, clinical cure rates at TOC were high and similar between treatment groups (>90%) (table). Conclusion These results demonstrate consistent efficacy in multiple secondary efficacy populations for patients with cUTI and AP who were treated with either ZTI-01 or PIP-TAZ. If approved by FDA, ZTI-01 may provide a new IV option with a differentiated MOA for patients in the United States with serious Gram-negative infections. 95% confidence intervals (CIs, two-sided) were computed using a continuity-corrected Zstatistic. Disclosures K. Kaye, Zavante Therapeutics, Inc.: Scientific Advisor, Consulting fee. L. B. Rice, Zavante Therapeutics, Inc.: Scientific Advisor, Consulting fee. V. Stus, Zavante Therapeutics, Inc.: Investigator, Research support. O. Sagan, Zavante Therapeutics, Inc.: Investigator, Research support. E. Fedosiuk, Zavante Therapeutics, Inc.: Investigator, Research support. A. Das, Zavante Therapeutics, Inc.: Consultant, Consulting fee. D. Skarinksy, Zavante Therapeutics, Inc.: Employee and Shareholder, Salary. P. B. Eckburg, Zavante Therapeutics, Inc.: Consultant and Shareholder, Consulting fee. K. Manvelian, Zavante Therapeutics, Inc.: Employee and Shareholder, Salary. E. J. Ellis-Grosse, Zavante Therapeutics, Inc.: Employee and Shareholder, Salary.

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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

Clinical Infectious Diseases ◽

10.1093/cid/ciz181 ◽

2019 ◽

Vol 69 (12) ◽

pp. 2045-2056 ◽

Cited By ~ 30

Author(s):

Keith S Kaye ◽

Louis B Rice ◽

Aaron L Dane ◽

Viktor Stus ◽

Olexiy Sagan ◽

...

Keyword(s):

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Acute Pyelonephritis ◽

Therapeutic Option ◽

Elevated Serum ◽

Complicated Urinary Tract Infection ◽

The United States ◽

Success Rates ◽

Gram Negative

Abstract Background 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. Methods 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. Results 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]: −0.4, 20.8). Clinical cure rates at test of cure (TOC, day 19–21) 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. Conclusions 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. Clinical Trial Registration NCT02753946

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Identification and Pretherapy Susceptibility of Pathogens in Patients with Complicated Urinary Tract Infection or Acute Pyelonephritis Enrolled in a Clinical Study in the United States from November 2004 Through April 2006

Clinical Therapeutics ◽

10.1016/j.clinthera.2007.10.008 ◽

2007 ◽

Vol 29 (10) ◽

pp. 2215-2221 ◽

Cited By ~ 14

Author(s):

Janet Peterson ◽

Simrati Kaul ◽

Mohammed Khashab ◽

Alan Fisher ◽

James B. Kahn

Keyword(s):

United States ◽

Urinary Tract Infection ◽

Urinary Tract ◽

Clinical Study ◽

Tract Infection ◽

Acute Pyelonephritis ◽

Complicated Urinary Tract Infection ◽

The United States

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Safety and tolerability of ertapenem versus ceftriaxone in a double-blind study performed in children with complicated urinary tract infection, community-acquired pneumonia or skin and soft-tissue infection

International Journal of Antimicrobial Agents ◽

10.1016/j.ijantimicag.2008.08.005 ◽

2009 ◽

Vol 33 (2) ◽

pp. 163-167 ◽

Cited By ~ 13

Author(s):

Adriano Arguedas ◽

Jaime Cespedes ◽

Francesc Aseni Botet ◽

Jeffrey Blumer ◽

Ram Yogev ◽

...

Keyword(s):

Urinary Tract Infection ◽

Urinary Tract ◽

Soft Tissue ◽

Tract Infection ◽

Soft Tissue Infection ◽

Complicated Urinary Tract Infection ◽

Community Acquired Pneumonia ◽

Blind Study ◽

Double Blind Study ◽

Double Blind

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Risk factors for hospital readmission following complicated urinary tract infection

Scientific Reports ◽

10.1038/s41598-021-86246-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tanya Babich ◽

Noa Eliakim-Raz ◽

Adi Turjeman ◽

Miquel Pujol ◽

Jordi Carratalà ◽

...

Keyword(s):

Risk Factors ◽

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Medical Condition ◽

Hospital Readmissions ◽

Multivariable Analysis ◽

Significant Risk ◽

Complicated Urinary Tract Infection ◽

Negative Influence

AbstractHospital readmissions following severe infections are a major economic burden on the health care system and have a negative influence on patients' quality of life. Understanding the risk factors for readmission, particularly the extent to which they could be prevented, is of a great importance. In this study we evaluated potentially preventable risk factors for 60-day readmission in patients surviving hospitalization for complicated urinary tract infection (cUTI). This was a multinational, multicentre retrospective cohort study conducted in Europe and the Middle East. Our cohort included survivors of hospitalization due to cUTI during the years 2013–2014. The primary outcome was 60-day readmission following index hospitalization. Patient characteristics that could have influenced readmission: demographics, infection presentation and management, microbiological and clinical data; were collected via computerized medical records from infection onset up to 60 days after hospital discharge. Overall, 742 patients were included. The cohort median age was 68 years (interquartile range, (IQR) 55–80) and 43.3% (321/742) of patients were males. The all-cause 60-day readmission rate was 20.1% (149/742) and more than half were readmitted for infection [57.1%, (80/140)]. Recurrent cUTI was the most frequent cause for readmission [46.4% (65/140)]. Statistically significant risk factors associated with 60-day readmission in multivariable analysis were: older age (odds ratio (OR) 1.02 for an one-year increment, confidence interval (CI) 1.005–1.03), diabetes mellitus (OR 1.63, 95% CI 1.04–2.55), cancer (OR 1.7, 95% CI 1.05–2.77), previous urinary tract infection (UTI) in the last year (OR 1.8, 95% CI: 1.14–2.83), insertion of an indwelling bladder catheter (OR 1.62, 95% CI 1.07–2.45) and insertion of percutaneous nephrostomy (OR 3.68, 95% CI 1.67–8.13). In conclusion, patients surviving hospitalization for cUTI are frequently re-hospitalized, mostly for recurrent urinary infections associated with a medical condition that necessitated urinary interventions. Interventions to avoid re-admissions should target these patients.

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