Evaluation of Piperacillin-Tazobactam and Temocillin as Carbapenem Alternatives in ICU Patients with ESBL-Producing Enterobacteriaceae Infections

The primary objective of this study is to demonstrate that in patients hospitalized in the intensive care unit (ICU) with severe infections caused by **extended-spectrum beta-lactamase (ESBL)**-producing Enterobacteriaceae, treatment with a carbapenem-sparing agent, specifically piperacillin/tazobactam or temocillin, is non-inferior to a carbapenem in terms of mortality. This is clinically relevant as it may provide alternative treatment options that could help in reducing the use of carbapenems, thereby potentially mitigating the development of antibiotic resistance.

Secondary objectives include comparing carbapenem-sparing agents (piperacillin/tazobactam or temocillin) to carbapenem in terms of:

• Relapse/recurrence of ESBL infection
• Secondary nosocomial infection
• Antibiotic allergy and adverse events
• Antibiotic consumption
• ICU and hospital length of stay
• Organ failure kinetics

The clinical trial involves **patients hospitalized in the ICU** with severe infections caused by **ESBL-producing Enterobacteriaceae**. The study population includes both male and female participants aged 18 years and older. Participants are selected based on their hospitalization in the ICU and the presence of a severe infection, with or without sepsis or septic shock, as defined by the Sepsis-3 criteria. The pathogen responsible for the infection must be susceptible to meropenem and either piperacillin/tazobactam or temocillin. The trial includes a vulnerable population, and informed consent is required from the patient or a legal representative. The sponsor has not provided information regarding the total number of participants. Participants must be affiliated with social security, excluding AME. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **piperacillin/tazobactam** and **temocillin** as alternatives to **carbapenem** in treating severe infections caused by extended-spectrum beta-lactamase (ESBL)-producing Gram-negative Enterobacteriaceae in patients hospitalized in the intensive care unit (ICU). This study is a randomized, double-blind, controlled trial with an estimated duration from March 2023 to June 2026. The primary objective is to demonstrate non-inferiority in terms of mortality when using carbapenem-sparing agents compared to carbapenem. The trial will include patients aged 18 years and older, who are hospitalized in the ICU with a severe infection caused by ESBL-producing Enterobacteriaceae, and who have provided informed consent.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on the inclusion criteria, such as the presence of a severe infection and susceptibility of the pathogen to the study drugs. Following randomization, participants will receive treatment for a maximum period of 21 days. Follow-up visits will be conducted to assess primary and secondary endpoints, including mortality at 30 days, relapse rates, clinical failure, and adverse events. The end-of-study visit will occur at day 90 post-randomization to evaluate long-term outcomes such as the 90-day mortality rate and rates of secondary infections.

The expected length of participant involvement is approximately 90 days, with conditions for early termination including withdrawal of consent, adverse events, or protocol violations. The study will monitor various secondary endpoints, such as ICU and hospital length of stay, antibiotic-free days, and the rate of faecal colonization with carbapenem-resistant Gram-negative bacilli. The trial aims to provide valuable insights into the potential of carbapenem-sparing agents in managing severe infections in critically ill patients.

The clinical trial involves the administration of **MEROPENEM ARROW**, a pharmaceutical product containing **meropenem anhydrous** as the active substance. This medication is provided in the form of a powder for solution for injection or infusion. The maximum daily dose is 6 grams, with a total maximum dose of 126 grams over a treatment period of up to 21 days. The route of administration is via infusion. The product is manufactured by EUGIA PHARMA (MALTA) LTD and is not a pediatric formulation. Compliance with the dosing schedule is monitored throughout the trial.

Another treatment used in the study is **PIPERACILLINE/TAZOBACTAM PANPHARMA**, which contains the active substances **piperacillin** and **tazobactam**. This medication is also provided as a powder for solution for infusion. The maximum daily dose is 18 grams, with a total maximum dose of 378 grams over a 21-day treatment period. The administration is conducted via infusion, and the product is manufactured by PANPHARMA. This formulation is not intended for pediatric use, and participant adherence to the dosing regimen is closely monitored.

The study also includes the administration of **NEGABAN**, which contains **temocillin sodium** as the active ingredient. This product is available as a powder for solution for injection or infusion. The maximum daily dose is 8 grams, with a total maximum dose of 128 grams over a treatment period of up to 21 days. The route of administration is infusion, and the product is manufactured by EUMEDICA / BELGIUM. It is not a pediatric formulation, and compliance with the dosing schedule is ensured throughout the trial.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the **mortality** rate at 30 days from the date of randomization. Secondary endpoints include the 90-day mortality rate, relapse rates of ESBL infection at day 30, and clinical failure rate at day 30, which encompasses relapse of ESBL infection or death between randomization and day 30. Additional secondary endpoints involve the rate of antibiotic allergy, adverse events, ICU and hospital length of stay, ICU-free and hospital-free days at day 30, and antibiotic-free days at day 30. The kinetics of organ failure will be evaluated from randomization to day 30 post-randomization using the sequential organ failure assessment (SOFA) score and its components. Other secondary endpoints include the rate of fecal colonization with carbapenem-resistant Gram-negative bacilli at the end of treatment, ICU discharge, and day 90, as well as the rate of Clostridium difficile infection and secondary nosocomial infection at day 90. The proportion of patients exceeding the recommended duration of antimicrobial treatment for the index episode and those who change their treatment before the recommended duration without relapse will also be assessed.