Piperacillin/Tazobactam Versus Carbapenems in Non-bacteremic UTI Due to -ESBL-producing Enterobacteriaceae

Study Overview
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Brief Summary
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This study evaluates the efficacy in achieving clinical cure in non-bacteremic urinary tract infections (UTI) caused by Escherichia coli or Klebsiella pneumoniae producers of extended-spectrum β-lactamases (ESBL) in adult patients. Half of participants will receive Piperacillin/Tazobactam as treatment, while the other half will receive Carbapenems. The investigators will verify that Piperacillin/Tazobactam is not inferior in achieving clinical cure, and that is not associated with a higher risk of adverse events in the directed treatment of non-bacteremic UTI compared to Carbapenems. The researchers hope to improve the use of antibiotics in the non-bacteremic UTI, reducing the collateral damage related to a deterioration in the prognosis of patients and the generation of resistant germs caused by the use of broad-spectrum antibiotics as carbapenems.

Detailed Description
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Urinary tract infection (UTI) is a common cause of hospitalization worldwide, the prevalence throughout the life of UTI has been reported in about 50,000 cases per 100,000 women and 13,000 per 100,000 men in the United States. Hospitalization for community-acquired UTI is about 33%. Furthermore, the UTI related to bladder catheterization during hospitalization is the most common type of infection acquired, representing 40% of all nosocomial infections. UTI hospitalization is associated with a high cost to the healthcare system. The diagnosis of UTI is based on demonstrating the presence of bacteria urine in patients with suggestive clinical manifestations and verifying the host's inflammatory response to infection. The most common etiological agents include Escherichia coli, Klebsiella spp, and Proteus spp, with different prevalence and antibiotic susceptibility profiles among different populations. Currently the appropriate treatment of UTI is a growing concern in the medical community because Gram-negative, specifically Enterobacteriaceae, bacteria have acquired genes encoding antibiotic resistance mechanisms. The β-lactamase spread spectrum (ESBL) are documented with increasing frequency among microorganisms causing UTI. Current treatment options for ESBL bacteria include nitrofurantoin, fosfomycin, piperacillin-tazobactam, carbapenems, and aminoglycosides. Carbapenems and piperacillin-tazobactam are antibiotics used in medical practice for many years, both therapies are licensed for the treatment of non-bacteremic UTI; however, so far there is not enough evidence to discriminate the best choice for the treatment of non-bacteremic UTI (although carbapenems are considered drugs of choice for infections caused by these microorganisms), but carbapenems use has been associated with an increased risk of collateral damage related to the generation of resistant germs. The investigators will compare between piperacillin/tazobactam and carbapenems the effectiveness in achieving clinical cure for non-bacteremic UTI caused by ESBL microorganisms. Researchers principal hypothesis is that Piperacillin/tazobactam is not inferior to carbapenems in achieving clinical cure in the targeted treatment of UTI caused by non-bacteremic due to E. coli or K. pneumoniae ESBL in adults requiring hospitalization. Researchers will verify too if Piperacillin/Tazobactam is not associated with increased risk of adverse events during the targeted treatment of non-bacteremic ITU caused by E. coli or K. pneumoniae ESBL in adults requiring hospital admission, compared with Carbapenems therapy. To perform the protocol researchers follows the recommendations for the design of trials investigating treatment options for resistant bacteria multidrug (Uncomplicated Urinary Tract Infections: Developing Drugs for Treatment) of the United States Agency for Food and Drug Administration (FDA). Participants will be included in the study with informed consent. The study variables will be obtained by patient interview and review of medical history. Variables will be recorded in a computerized database developed specifically for this study, with exclusive access for the researchers. The estimated project duration is 2 years expected to begin in april of 2019.

Official Title
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Piperacillin/Tazobactam Versus Carbapenems in Non-bacteremic Urinary Tract Infections Due to Extended-spectrum β-lactamase (ESBL)-Producing Escherichia Coli or Klebsiella Pneumoniae - (CAPITIS Study)

Conditions
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Urinary Tract Infections, Enterobacteriaceae Infections, Infection Due to ESBL Bacteria, Carbapenem, Escherichia Coli Infection, Klebsiella Pneumoniae Infection, Clinical Trial, Drug Resistance, Bacterial

Intervention / Treatment
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* Drug: Meropenem
* Drug: Ertapenem 1000 MG
* Drug: Piperacillin, Tazobactam 4-0.5G Solution for Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (≥18 years) with hospital admission for non-bacteremic UTI caused by E. coli or K. pneumoniae ESBL susceptible to piperacillin/tazobactam and carbapenems. Presence of any risk factor associated with UTI due to ESBL germs: older age 64 years, diabetes mellitus, bladder catheter, previous antibiotics in the last 6 months, hospitalization in the last 6 months, urological surgery in the last 30 days, infections recurrent urinary. Diagnosis of UTI confirmed by: 1) fever, 2) urine culture> 100000 CFU with isolation E. coli or K. pneumoniae ESBL susceptible to piperacillin / tazobactam and carbapenems, and 3) lumbar and / or abdominal pain with or without low urinary symptoms (dysuria, tenesmus, urgency), and 4) no other cause that explains the patient's symptoms Signed informed consent. Negative pregnancy test in fertile women. Exclusion Criteria: Non-acceptance of participation in the study. Pregnancy. Hypersensitivity and/or previous intolerance to penicillins, piperacillin/tazobactam or carbapenems. Bacteremia, hematogenous infection or other concomitant infection. Immunosuppression. In case of obstructive uropathy, lack of early surgical resolution. Evidence of acute or chronic prostatitis. Renal abscess Polycystic disease in the kidneys. Palliative care or life expectancy <90 days. Heart failure (NYHA) functional class III or IV. Liver cirrhosis. Renal insufficiency in dialysis treatment. Empirical active treatment against bacteria isolated by urine cultures other than E. coli or K. pneumoniae BLEE. Participation in another clinical trial for infections. Hypersensitivity to amide-type local anesthetics.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Carbapenems group<br>Meropenem (1g intravenously every 8 hours or adjusted to renal function) or Ertapenem (1g intravenously every 24 hours or adjusted to renal function) by 10 days. | Drug: Meropenem<br>* Carbapenems group intervention.<br>Drug: Ertapenem 1000 MG<br>* Carbapenems group intervention.<br>|
| Active Comparator: Piperacillin/tazobactam.<br>Piperacillin / Tazobactam (4.5gr intravenously every 6 hours or adjusted to renal function) by 10 days. | Drug: Piperacillin, Tazobactam 4-0.5G Solution for Injection<br>* Piperacillin/Tazobactam group intervention.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical cure. | Complete resolution of non-bacteremic urinary tract infection signs or symptoms (dysuria, urinary frequency, urinary urgency, suprapubic pain or temperature greater than 38 degrees Celsius) present at trial entry (and no new signs or symptoms) until the duration of investigational antibacterial drug therapy. Investigators will compare the rate of clinical cure between the two treatment lines. | At 5-7 day after the end of treatment (cure test), or for early response after 5 days from the start of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microbiologic cure. | Clinical cure (primary outcome) and demonstration that the bacterial pathogen found at trial entry is reduced to fewer than 100.000 CFU/mL on control urine culture. Investigators will compare the rate of microbiologic cure between the two treatment lines. | At the 5-7 day after the end of treatment (cure test). | 
| Mortality in patient follow-up. | All-cause Mortality Rate in the CAPITIS Study Population (Piperacillin/Tazobactam Versus Carbapenems in Non-bacteremic Urinary Tract Infections Due to Extended-spectrum β-lactamase (ESBL)-Producing Escherichia Coli or Klebsiella Pneumoniae. | Until day 30 after the first day of administration of the study drugs. | 
| Length of hospital stay in patient follow-up. | Time since the assignment of the randomization until the patient leaves the hospital. | Until day 30 after the first day of administration of the study drugs. | 
| Relapse. | Proportion of Subjects in the CAPITIS Study Population with a Relapse (All Indications). Development of non-bacteremic urinary tract infection signs or symptoms (dysuria, urinary frequency, urinary urgency, suprapubic pain or temperature greater than 38 degrees Celsius) in patients with previous clinical and microbiological cure, plus positive urine culture with the same microorganism isolated in initial culture. Investigators will compare the risk of relapse with each regimen. | Daily until day 30 after the first day of administration of the study drugs. | 
| Reinfection. | Proportion of Subjects in the CAPITIS Study Population With a Reinfection (All Indications). Development of non-bacteremic urinary tract infection signs or symptoms (dysuria, urinary frequency, urinary urgency, suprapubic pain or temperature greater than 38 degrees Celsius) in patients with previous clinical and microbiological cure, plus positive urine culture with different strains isolated in initial culture. Investigators will compare the risk of reinfection with each regimen. | Daily until day 30 after the first day of administration of the study drugs. | 
| Resistant clinical isolates in patient follow-up. | Proportion of Subjects in the CAPITIS Study Population With Resistant clinical isolates. Appearance of clinical isolates of Escherichia coli or Klebsiella pneumoniae resistant piperacillin/tazobactam or carbapenems demonstrated in urine cultures will be evaluated. | Daily until day 30 after the first day of administration of the study drugs. | 
| Adverse events in patient follow-up. | Proportion of Subjects in the CAPITIS Study Population With Adverse events (All Indications). Any related adverse event occurring from the signing the informed consent form to end of follow. Investigators have created a data collection notebook, a daily follow-up will be made in the participants and adverse events in patient will be recorded. | Daily until day 30 after the first day of administration of the study drugs. | 
| ICU admission in patient follow-up. | Proportion of Subjects in the CAPITIS Study Population With ICU admission (All Indications). Any admission to intensive care unit occurs from signing the informed consent form to end of patient follow. Investigators have created a data collection notebook, a daily follow-up will be made in the participants and all admission in ICU will be recorded. | Daily until day 30 after the first day of administration of the study drugs. | 
| Clinical or microbiological failure of antibiotic therapy in patient follow-up. | Proportion of Subjects in the CAPITIS Study Population With Clinical or microbiological failure of antibiotic therapy (All Indications). Failure to achieve clinical or microbiologic cure until day 30, or die at any time since signing the informed consent form to end of follow-up. Authors defined the clinical therapeutic failure as the persistence of at least one urinary symptom in the patient at the time of follow-up despite antibiotic therapy. Microbiological failure has been defined as the persistence of bacteria isolation major to 10.000 UFC/ml in second urine culture carried out in the study participant despite antibiotic therapy. Investigators have created a questionnaire which will be checked daily with a urinary symptoms list. All findings will be recorded in a data collection notebook. | Daily until day 30 after the first day of administration of the study drugs. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult, Equivalence Trial, Randomized Controlled Trial, Comparative Study, Anti-Bacterial Agents/therapeutic use*, Meropenem, Ertapenem, Piperacillin, Tazobactam Drug Combination, Escherichia coli Infections/drug therapy, Klebsiella Infections/drug therapy