scholarly journals Heterogeneity of Recent Phase 3 Complicated Urinary Tract Infection Clinical Trials

2021 ◽  
Vol 8 (3) ◽  
Author(s):  
Simon Portsmouth ◽  
Almasa Bass ◽  
Roger Echols ◽  
Glenn Tillotson
Keyword(s):  
Clinical Trials ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Study Design ◽  
Patient Population ◽  
Complicated Urinary Tract Infection ◽  
Gram Negative ◽  
Regulatory Guidelines ◽  
New Antibiotics

Abstract Background For new antibiotics developed to treat antibiotic-resistant Gram-negative infections, the US Food and Drug Administration (FDA) regulatory pathway includes complicated urinary tract infection (cUTI) clinical trials in which the clinical isolates are susceptible to the active control. This allows for inferential testing in a noninferiority study design. Although complying with regulatory guidelines, individual clinical trials may differ substantially in design and patient population. To determine variables that impacted patient selection and outcome parameters, 6 recent cUTI trials that were pivotal to an new drug application (NDA) submission were reviewed. Methods This selective descriptive analysis utilized cUTI trial data, obtained from publicly disclosed information including FDA documents and peer-reviewed publications, from 6 new antibiotics developed to treat multidrug-resistant Gram-negative infections: ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol, plazomicin, and fosfomycin. Eravacycline was not approved for cUTI and is not included. Results Microbiologic modified intent-to-treat sample size, age, proportions of female patients, acute pyelonephritis (AP), Escherichia coli and other pathogens at baseline, protocol-specified switch to oral antibiotic, and the noninferiority margin were compared. Outcome data included clinical response, microbiologic eradication, and composite outcomes, including a subset of patients with AP. Conclusions A study design can follow regulatory guidelines but still have variable populations. The proportion of AP within a study varied greatly and influenced population demographics (age, gender) and baseline microbiology. A smaller proportion of AP resulted in an older patient population, fewer females, less E coli, and lower proportions of patients achieving success. Fluoroquinolones and piperacillin/tazobactam should be reconsidered as active comparators given the high rates of resistance to these antibiotics.

scholarly journals 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

2019 ◽  
Vol 69 (12) ◽  
pp. 2045-2056 ◽  
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

scholarly journals 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

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S418-S419 ◽  
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.

scholarly journals Population Pharmacokinetic Analysis of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Healthy Subjects, Subjects with Various Degrees of Renal Function, and Patients with Complicated Urinary Tract Infection or Acute Uncomplicated Pyelonephritis

2018 ◽  
Vol 62 (2) ◽  
Author(s):  
Nao Kawaguchi ◽  
Takayuki Katsube ◽  
Roger Echols ◽  
Toshihiro Wajima
Keyword(s):  
Urinary Tract Infection ◽  
Renal Function ◽  
Urinary Tract ◽  
Tract Infection ◽  
Healthy Subjects ◽  
Complicated Urinary Tract Infection ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Gram Negative ◽  
Population Pk

ABSTRACT Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens and to calculate the fraction of the time during the dosing interval where the free drug concentration in plasma exceeds the MIC (fT MIC). Population PK models were developed with three renal function markers, body surface area-adjusted estimated glomerular filtration rate (eGFR), absolute eGFR, and creatinine clearance, on the basis of 2,571 plasma concentrations from 91 subjects without infection and 238 patients with infection. The population PK models with each renal function marker adequately described the plasma cefiderocol concentrations. Clear relationships of total clearance (CL) to all renal function markers were observed. Body weight and disease status (with or without infection) were also significant covariates. The CL in patients with infection was 26% higher than that in subjects without infection. The fT MIC values were more than 75% in all patients (and were 100% in most patients), suggesting that a sufficient exposure to cefiderocol was provided by the tested dose regimens (2 g every 8 h as the standard dose regimen) for the treatment of cUTI or AUP caused by Gram-negative pathogens.

Cefiderocol- A New Antimicrobial for Complicated Urinary Tract Infection (CUTI) Caused by Carbapenem Resistant Enterobacteriaceae (CRE)

2021 ◽  
Vol 13 ◽  
Author(s):  
Suparna Chatterjee ◽  
Dwaipayan Sarathi Chakraborty ◽  
Shouvik Choudhury ◽  
Sandeep Lahiry
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Bacterial Infections ◽  
Rapid Development ◽  
Complicated Urinary Tract Infection ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Tract Infections ◽  
Carbapenem Resistant Enterobacteriaceae

: The incidence of Carbapenem resistant gram negative (CRGNB) bacterial infections has increased globally. The wide diversity of strains, multiplicity of infections and rapid development and spread of resistance are a matter of great concern both in community and hospital settings. Cefiderocol is a novel injectable siderophore containing cephalosporin with potent microbicidal activity against most Carbapenem Resistant Enterobacteriaceae (CRE). It has recently been approved by USFDA for the treatment of complicated urinary tract infections (cUTI) caused by susceptible gram-negative microorganisms. This review focuses on the salientpharmacological profile of the drug and the clinical studies that were undertaken.

scholarly journals Risk factors for hospital readmission following complicated urinary tract infection

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.

scholarly journals Cranberry Extract for Symptoms of Acute, Uncomplicated Urinary Tract Infection: A Systematic Review

Antibiotics ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 12
Author(s):  
Oghenekome A. Gbinigie ◽  
Elizabeth A. Spencer ◽  
Carl J. Heneghan ◽  
Joseph J. Lee ◽  
Christopher C. Butler
Keyword(s):  
Clinical Trials ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Antibiotic Use ◽  
Risk Of Bias ◽  
Current Evidence ◽  
Cochrane Library ◽  
Uncomplicated Urinary Tract Infection ◽  
Cranberry Juice

Background: Effective alternatives to antibiotics for alleviating symptoms of acute infections may be appealing to patients and enhance antimicrobial stewardship. Cranberry-based products are already in wide use for symptoms of acute urinary tract infection (UTI). The aim of this review was to identify and critically appraise the supporting evidence. Methods: The protocol was registered on PROSPERO. Searches were conducted of Medline, Embase, Amed, Cinahl, The Cochrane library, Clinicaltrials.gov and WHO International Clinical Trials Registry Platform. We included randomised clinical trials (RCTs) and non-randomised studies evaluating the effect of cranberry extract in the management of acute, uncomplicated UTI on symptoms, antibiotic use, microbiological assessment, biochemical assessment and adverse events. Study risk of bias assessments were made using Cochrane criteria. Results: We included three RCTs (n = 688) judged to be at moderate risk of bias. One RCT (n = 309) found that advice to consume cranberry juice had no statistically significant effect on UTI frequency symptoms (mean difference (MD) −0.01 (95% CI: −0.37 to 0.34), p = 0.94)), on UTI symptoms of feeling unwell (MD 0.02 (95% CI: −0.36 to 0.39), p = 0.93)) or on antibiotic use (odds ratio 1.27 (95% CI: 0.47 to 3.43), p = 0.64), when compared with promoting drinking water. One RCT (n = 319) found no symptomatic benefit from combining cranberry juice with immediate antibiotics for an acute UTI, compared with placebo juice combined with immediate antibiotics. In one RCT (n = 60), consumption of cranberry extract capsules was associated with a within-group improvement in urinary symptoms and Escherichia coli load at day 10 compared with baseline (p < 0.01), which was not found in untreated controls (p = 0.72). Two RCTs were under-powered to detect differences between groups for outcomes of interest. There were no serious adverse effects associated with cranberry consumption. Conclusion: The current evidence base for or against the use of cranberry extract in the management of acute, uncomplicated UTIs is inadequate; rigorous trials are needed.

Sign in / Sign up

Export Citation Format

Share Document