Piperacillin-tazobactam and Temocillin as Carbapenem-alternatives for the Treatment of Severe Infections Due to Extended-spectrum Beta-lactamase-Producing Gram-negative Enterobacteriaceae in the Intensive Care Unit - Trial NCT05565222

Timeline & Enrollment

Primary Outcome

Mortality

Summary

Infections due to extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are a
 major public health concern, in particular in the intensive care unit (ICU), due to the
 increase in their incidence. Carbapenems are the treatment of choice of these infections, but
 their increased use may select for carbapenem resistance in Gram-negative bacilli, which
 currently represents the greatest threat in terms of antibiotic resistance. Several
 retrospective studies have shown that the use of non-carbapenem antibiotics (mainly the
 association of piperacillin/tazobactam, but also cefepime and temocillin) may be safe
 alternatives to carbapenems to treat these pathogens when the strain is susceptible to the
 corresponding antibiotic. However, one recent randomized controlled study, the Merino trial,
 failed to demonstrate the non-inferiority of piperacillin/tazobactam, as compared to
 meropenem, in patients with Gram-negative bacilli bacteremia resistant to third generation
 cephalosporins (mainly ESBL producers). However, the patients included in that study were not
 ICU patients, dosing and modalities of piperacillin/tazobactam administration were not
 optimal (30-min infusion whereas 4-hours infusion may be associated with better outcome), and
 cause of death of patients in the piperacillin/tazobactam arm were not due to antimicrobial
 treatment failure (mostly death due to care withdrawal in cancer patients). Recently, a
 retrospective bicenter study performed in ICU patients showed that outcome of patients with
 severe infection (i.e. sepsis and septic shock according to the Sepsis-3 definition) due to
 ESBL-producing Enterobacteriaceae susceptible to non-carbapenem agents treated with a
 non-carbapenem agent was similar to that of patients treated with carbapenems.
 
 Given the scarcity of data in ICU patients, the disputable results of the Merino trial, we
 will therefore conduct a multicenter, randomized, open-label trial of non-carbapenem
 beta-lactam (piperacillin/tazobactam or temocillin) treatment vs. meropenem treatment for
 ESBL-producing Enterobaceriaceae severe infection in ICU patients. Our hypothesis is that a
 non-carbapenem beta-lactam treatment is non-inferior to carbapenem treatment in patients with
 ESBL-producing Enterobacteriaceae severe infection in the ICU.

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