Clinical trial NCT03891433: Piperacillin/Tazobactam Versus Carbapenems in Non-bacteremic UTI Due to -ESBL-producing Enterobacteriaceae
Official title: 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)
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE4
Conditions: Urinary Tract Infections
Enterobacteriaceae Infections
Infection Due to ESBL Bacteria
Carbapenem
Escherichia Coli Infection
Klebsiella Pneumoniae Infection
Clinical Trial
Drug Resistance, Bacterial
Keywords: 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
Lead sponsor: Universidad del Norte
Sponsor class: OTHER
First posted: 2019-03-27
Enrollment: 198
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Clinical cure.
timeFrame: At 5-7 day after the end of treatment (cure test), or for early response after 5 days from the start of treatment.
Secondary outcomes:
measure: Microbiologic cure.
timeFrame: At the 5-7 day after the end of treatment (cure test).
measure: Mortality in patient follow-up.
timeFrame: Until day 30 after the first day of administration of the study drugs.
measure: Length of hospital stay in patient follow-up.
timeFrame: Until day 30 after the first day of administration of the study drugs.
measure: Relapse.
timeFrame: Daily until day 30 after the first day of administration of the study drugs.
measure: Reinfection.
timeFrame: Daily until day 30 after the first day of administration of the study drugs.
measure: Resistant clinical isolates in patient follow-up.
timeFrame: Daily until day 30 after the first day of administration of the study drugs.
measure: Adverse events in patient follow-up.
timeFrame: Daily until day 30 after the first day of administration of the study drugs.
measure: ICU admission in patient follow-up.
timeFrame: Daily until day 30 after the first day of administration of the study drugs.
measure: Clinical or microbiological failure of antibiotic therapy in patient follow-up.
timeFrame: Daily until day 30 after the first day of administration of the study drugs.
Other outcomes:
Locations:
city: Soledad
country: Colombia
facility: Universidad del Norte´s Hospital
state: Atlantico
Study officials:
affiliation: Universidad del Norte´s Hospital-Infectious Diseases.
name: Diego F Viasus Perez, MD. PhD.
role: PRINCIPAL_INVESTIGATOR
affiliation: Universidad del Norte
name: Andres F Estupinan Bohorquez, MD
role: PRINCIPAL_INVESTIGATOR
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citation: Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M, Alenazi TH, Arabi Y, Falcone M, Bassetti M, Righi E, Rogers BA, Kanj S, Bhally H, Iredell J, Mendelson M, Boyles TH, Looke D, Miyakis S, Walls G, Al Khamis M, Zikri A, Crowe A, Ingram P, Daneman N, Griffin P, Athan E, Lorenc P, Baker P, Roberts L, Beatson SA, Peleg AY, Harris-Brown T, Paterson DL; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN). Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial. JAMA. 2018 Sep 11;320(10):984-994. doi: 10.1001/jama.2018.12163.