Comparative Efficacy of Temocillin Sodium Versus Meropenem and Ertapenem Sodium in Treating Enterobacteriaceae Bacteremia Resistant to Third-Generation Cephalosporins

The primary objective of this study is to demonstrate the **non-inferiority** of temocillin compared to carbapenems in terms of efficacy and safety for the targeted treatment of **bacteraemia** due to Enterobacterales resistant to third-generation cephalosporins. This is clinically relevant as it aims to provide evidence supporting the use of temocillin as an alternative treatment option for these infections, potentially reducing reliance on carbapenems and addressing antibiotic resistance concerns.

Secondary objectives include:

• Providing specific information about the efficacy and safety of temocillin and carbapenems in subgroups of patients typically excluded from randomized trials, such as severely ill patients, the elderly, immunocompromised individuals, and patients with renal insufficiency.
• Gathering further information on the pharmacokinetics and pharmacodynamics of temocillin.
• Assessing the minimum inhibitory concentration (MIC) of temocillin for Enterobacterales resistant to third-generation cephalosporins, based on their mechanisms of resistance.

The clinical trial involves a study population comprising **hospitalized adult patients** aged 18 years or older, presenting with bacteremia due to **Enterobacterales**. Both male and female participants are included, and the trial considers a vulnerable population. The total number of participants is not provided by the sponsor. Participants were selected based on the presence of monomicrobial isolation of Enterobacterales in blood culture, with the microorganism being resistant to third-generation cephalosporins and sensitive to temocillin and meropenem. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Key inclusion criteria include the requirement for intravenous treatment for a minimum of four days post-randomization, or three days if prior empirical treatment was appropriate, and the necessity for informed consent. Additionally, potentially fertile patients must have a negative pregnancy test. The study aims to evaluate the non-inferiority of temocillin compared to carbapenems in treating infections caused by Enterobacterales resistant to third-generation cephalosporins.

The clinical trial is designed to evaluate the **non-inferiority** of temocillin compared to carbapenems, specifically in the treatment of **bacteraemia** caused by Enterobacterales resistant to third-generation cephalosporins. This is a randomized, pragmatic trial with a double-blind, controlled design. The trial is expected to run from December 15, 2020, to December 31, 2025. Participants will be involved for a maximum of 14 days, which is the duration of the treatment period. The trial includes several key phases, starting with an inclusion (screening) visit to assess eligibility based on specific criteria, such as the presence of monomicrobial Enterobacterales in blood culture and resistance to third-generation cephalosporins.

Following the screening, eligible participants will be randomized to receive either temocillin or a comparator antibiotic, administered intravenously. The primary endpoint is a composite measure of success, including clinical success at the test of cure, survival at day 28, and absence of adverse events leading to treatment modification. Secondary endpoints include 28-day mortality, length of hospital stay, and the development of resistance or superimposed infections. Study visits will occur at baseline, during treatment, and at the end-of-study visit, which will assess the primary and secondary endpoints.

Participants may be withdrawn from the study if they experience significant adverse events, require a change in therapy due to perceived treatment failure, or if they do not adhere to the study protocol. The trial aims to provide evidence supporting the use of temocillin in treating infections due to resistant Enterobacterales, potentially influencing future treatment guidelines. The study is not categorized as low intervention and is classified as a Phase III clinical trial.

The clinical trial involves the administration of three **antibiotics**: **Meropenem**, **Temocillin**, and **Ertapenem Sodium**. **Meropenem** is utilized as a comparator treatment in this study. It is administered in the form of a pharmaceutical formulation identified as PHF00230MIG. The maximum daily dose of **Meropenem** is 3 grams, with a total maximum dose of 3 grams over a treatment period of up to 14 days. The route of administration is **intravenous use**, ensuring direct delivery into the bloodstream for optimal efficacy. Participant compliance with the dosing schedule is monitored throughout the trial.

**Temocillin Sodium** serves as the test treatment in this trial. It is provided in a pharmaceutical form designated as PHF00231MIG. The maximum daily dose for **Temocillin Sodium** is 6 grams, with a total maximum dose of 6 grams over a treatment period of up to 14 days. Similar to **Meropenem**, **Temocillin Sodium** is administered via **intravenous use**. The trial aims to demonstrate the non-inferiority of **Temocillin** compared to carbapenems, such as **Meropenem**, in treating bacteraemia due to Enterobacterales resistant to third-generation cephalosporins.

**Ertapenem Sodium** is another comparator treatment used in the study. It is administered in the same pharmaceutical form as **Meropenem**, PHF00230MIG. The maximum daily dose for **Ertapenem Sodium** is 1 gram, with a total maximum dose of 1 gram over a treatment period of up to 14 days. The administration route is **intravenous use**, consistent with the other treatments in the trial. The study protocol includes monitoring participant compliance with the dosing regimen to ensure accurate assessment of the treatment's efficacy and safety.

Efficacy in this clinical trial will be assessed using a composite primary endpoint termed "success." This endpoint includes several parameters: clinical success at the test of cure (TOC), survival at day 28, no requirement to discontinue or alter the assigned drug due to adverse events, perceived treatment failure, or the emergence of a superimposed infection, no necessity to extend therapy beyond 14 days, and the absence of recurrence up to day 28. Secondary endpoints will further evaluate efficacy through measures such as 28-day mortality, length of hospital stay and therapy (both intravenous and total), frequency and severity of adverse events, resistance development during therapy, and the rate of recurrence, including reinfections, until day 28.

Additional secondary endpoints include changes in the Sequential Organ Failure Assessment (SOFA) score and, for patients over 70 years of age, changes in the Barthel scales. Exploratory variables will be assessed at the coordinating center, including serum temocillin levels and temocillin minimum inhibitory concentration (MIC) in **Enterobacterales** according to resistance mechanisms to third-generation cephalosporins. Exposure variables such as age, sex, underlying chronic conditions, and other clinical factors will also be considered. The trial aims to demonstrate the non-inferiority of temocillin compared to carbapenems in treating bacteraemia due to **Enterobacterales** resistant to third-generation cephalosporins.