Piperacillin-tazobactam versus Carbapenem in Ceftriaxone resistant Community-acquired Acute Pyelonephritis: A Non-inferior Open Labelled Randomised Controlled Trial

This will be an open labelled non-inferiority randomised controlled trial to demonstrate the non-inferiority of piperacillin-tazobactam for the treatment of acute pyelonephritis caused by ceftriaxone resistant Enterobacteriaceae. The study will be conducted at AIIMS Jodhpur, department of General Medicine after the duly approval from institutional ethical committee and registration in clinical trial registry-India (CTRI). The PICOT of this will be following:

 Population: All patient with age equal or more than 18 years, diagnosed with acute pyelonephritis (clinico-radiological and microbiological) and urine culture showing isolation of ceftriaxone resistant Enterobacteriaceae.

Intervention: Patient will receive piperacillin-tazobactam 4.5 gm intravenous 6 hourly

Comparison: With Meropenem (Carbapenem)

Outcome: Clinical and microbiological failure

Time: Approximately 2 years since inception of study (Ethical approval and first  recruitment)

The research question will examine the clinical and microbiological efficacy of piperacillin-tazobactam for treating acute pyelonephritis caused by ESBL-producing, ceftriaxone-resistant isolates. The study aims to assess the effectiveness of piperacillin-tazobactam in treating ceftriaxone-resistant (ESBL-producing Enterobacteriaceae) acute pyelonephritis and to compare its efficacy with standard carbapenem therapy. The primary outcome will be a composite measure of clinical failure (persistent fever more than 38 degree celsius and leukocytosis, WBC more than 12,000 from day 3 to 5 post-randomization), microbiological failure (presence of the index organism in urine culture at day 3-5 post-randomization), and microbiological relapse (reappearance of the index microorganism any time from completion of therapy to day 30 post-randomization). Secondary outcomes will include all-cause mortality at 30 days post-randomization in both groups (piperacillin-tazobactam and meropenem), as well as the following additional measures: a) change in initial antibiotic regimen/escalation of antibiotics, b) emergence of resistance to the treatment regimen during therapy or within 30 days post-randomization, c) detection of carbapenemase and ESBL-producing genes in ceftriaxone-resistant isolates, d) length of hospital/ICU stay, e) need for vasopressor support or occurrence of septic shock, and f) distribution and correlation of various ESBL genes with outcomes in patients treated with piperacillin-tazobactam and meropenem.

This study will include all hospitalized adults (aged 18 years or more) diagnosed with acute pyelonephritis, who have an isolated culture of E. coli, Klebsiella, or Proteus species from at least one urine sample, showing resistance to ceftriaxone but susceptibility to both piperacillin-tazobactam and meropenem. Exclusion criteria include patients with septic shock, those receiving end-of-life care, as well as individuals with emphysematous pyelonephritis, renal abscesses, end-stage renal disease, or disseminated infections. The primary objective of this study is to establish that piperacillin-tazobactam is non-inferior to meropenem in the treatment of acute pyelonephritis caused by ceftriaxone-resistant Enterobacteriaceae.