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

NCT ID: NCT05565222

Last Updated: 2023-04-18

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 600 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-03-11
• Study Completion Date: 2026-06-30

Brief 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.

Conditions

Sepsis; Septic Shock

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Piperacillin/tazobactam or temocillin

Piperacillin/tazobactam, 4.5 g by intravenous route every 6 hours (adjusted in case of renal failure). Piperacillin/tazobactam will be infused over 4 hours. Duration of treatment will be adjusted according to the site of infection Temocillin, 6g/24 hours infused continuously by intravenous route after 2 g loading dose (adjusted in case of renal failure). Temocillin will be infused continuously. Duration of treatment will be adjusted according to the site of infection

Group Type: EXPERIMENTAL

Piperacillin/tazobactam or temocillin

Intervention Type: DRUG

Piperacillin/tazobactam : 4.5 g by intravenous route every 6 hours (adjusted in case of renal failure).

Temocillin : 6g/24 hours infused continuously by intravenous route after 2 g loading dose (adjusted in case of renal failure)

Meropenem

2 g every 8 hours by intravenous route (adjusted in case of renal failure). Meropenem will be infused over 2 hours. Duration of treatment will be adjusted according to the site of infection

Group Type: ACTIVE_COMPARATOR

Meropenem

Intervention Type: DRUG

2 g every 8 hours by intravenous route (adjusted in case of renal failure)

Interventions

Piperacillin/tazobactam or temocillin

Piperacillin/tazobactam : 4.5 g by intravenous route every 6 hours (adjusted in case of renal failure).

Temocillin : 6g/24 hours infused continuously by intravenous route after 2 g loading dose (adjusted in case of renal failure)

Intervention Type: DRUG

Meropenem

2 g every 8 hours by intravenous route (adjusted in case of renal failure)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Patients ≥ 18-year-old
• Hospitalized in the ICU
• Severe infection, eg sepsis or septic shock (according to the Sepsis-3 definition) Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, characterized by an increase of Sequential Organ Failure Assessment (SOFA) score of 2 points or more. This increase in 2 points will be calculated the day infection is diagnosed (day of positive culture serving as reference for the infection) as compared to the day before infection onset.

Septic shock is defined as sepsis and persisting hypotension requiring vasopressors to maintain mean arterial pressure ≥65 mmHg and having a serum lactate level >2 mmol/l despite adequate volume resuscitation.

This criterion (sepsis or septic shock) has to be fulfilled within a time frame of +/- 24 hours from the day of infection diagnosis (i.e. the day of positive bacteriological sample).

• Pathogen responsible for infection is an ESBL-producing Enterobacteriaceae susceptible to meropenem and either to piperacillin/tazobactam (minimum inhibitory concentration <8 mg/L) or to temocillin (minimum inhibitory concentration ≤8 mg/L)

Exclusion Criteria

• Affiliation to social security (AME excluded)

• Pregnancy or breastfeeding
• Known allergy to beta-lactam
• Patient with severe neutropenia, as defined by absolute neutrophil count <0.5x109/L
• Infection requiring prolonged antimicrobial treatment (endocarditis; mediastinitis; osteomyelitis/septic arthritis; undrainable/undrained abscess; unremovable/unremoved prosthetic-associated infection)
• Moribund, defined by a SAPS II score at inclusion >75
• Decision of withholding/withdrawing care
• Patient with concomitant infection requiring antibiotics with activity against Gram-negative bacilli, including patient with polymicrobial infection with pathogen resistant to study drugs
• Participation in another interventional study evaluating drugs or being in the exclusion period at the end of a previous study evaluating drugs .
• Hypersensitivity to any components of the formulations

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

LUYT Charles -Edouard

Paris, , France

Site Status: RECRUITING

MAYAUX Julien

Paris, , France

Site Status: RECRUITING

Countries

France

Facility Contacts

LUYT Charles -Edouard, MD

Role: primary

charles-edouard.luyt@aphp.fr

0142163824

MAYAUX Julien, MD

Role: primary

julien.mayaux@aphp.fr

0142167756

Other Identifiers

APHP211034

Identifier Type: -

Identifier Source: org_study_id