Clindamycin as an alternative to vancomycin in patients undergoing aortic cardiac surgery with extracorporeal circulation (ECC): a prospective single-center pharmacokinetic study _ CLINDAPASS

The primary objective is to demonstrate the feasibility of using clindamycin in patients undergoing extracorporeal circulation surgery by verifying that plasma clindamycin concentrations remain above the minimum inhibition concentration of the main bacteria involved in mediastinitis throughout the surgical procedure. This objective addresses the clinical need for effective antibiotic prophylaxis alternatives in cardiac surgery, where maintaining adequate drug concentrations is critical for preventing post-operative infectious complications.

The secondary objectives include:

• To determine the pharmacokinetic parameters of clindamycin under extracorporeal circulation

• To determine the factors of variability in clindamycin pharmacokinetics for patients undergoing bypass surgery

• To determine the diffusion of clindamycin in pericardial fatty tissue

• Description of adverse events according to NCI CTCAE V5 criteria

• Adherence to clindamycin injection protocol according to good clinical practice

• Rate of post-operative mediastinitis up to 3 months post-operatively

• Post-operative morbidity and mortality up to 3 months post-operatively

• To determine the pharmacokinetic parameters of cefazolin under extracorporeal circulation

• To determine the diffusion of cefazolin in pericardial fatty tissue

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consisted of **adult patients** aged 18 years and older undergoing **cardiac surgery** with **extracorporeal circulation (ECC)**. Both **male** and **female** subjects were eligible for participation. Participants were required to be scheduled for morning surgical procedures, with operations added to the schedule at least 24 hours in advance and commencing at 8 a.m. to facilitate blood sample processing during standard working hours. Women of childbearing potential were required to have a negative **pregnancy test** and maintain effective **contraception** throughout the treatment period, as were men of childbearing age. Additional selection criteria included French language comprehension for both oral and written communication, affiliation with social security, and the cognitive ability to understand the study objectives and comply with protocol requirements. The trial enrolled patients capable of providing written informed consent prior to protocol initiation.

This study is a prospective, single-center, **phase 4** pharmacokinetic trial evaluating **clindamycin** as an alternative to vancomycin in patients undergoing **cardiac surgery** with **extracorporeal circulation**. The primary objective is to demonstrate the feasibility of using clindamycin in this surgical setting by verifying that plasma clindamycin concentrations remain above the **minimum inhibition concentration** of the main bacteria involved in **mediastinitis** throughout the surgical procedure. The trial employs an off-label use of clindamycin for **cardiothoracic surgery**, with the medication administered via **intravenous use** at a maximum daily dose of 1500 mg. The study is designed to assess pharmacokinetic parameters including **volume of distribution**, **clearance**, and **elimination half-life**, as well as tissue determination of clindamycin in pericardial fat and correlation with plasma levels.

The estimated recruitment period is planned to commence in November 2025, with the trial expected to conclude in April 2026, resulting in an overall trial duration of approximately 5 months. Participant involvement extends from the screening visit through a 3-month postoperative follow-up period. The study will enroll adult patients aged 18 years or older who are scheduled for cardiac surgery under extracorporeal circulation, with procedures scheduled in the morning to facilitate blood sample processing during working hours. Eligible participants must provide written informed consent, demonstrate comprehension of the study objectives in French, maintain social security affiliation, and comply with protocol requirements. Women of childbearing age must present a negative pregnancy test and utilize effective contraception according to established guidelines during treatment, and men of childbearing age must also employ effective contraception during the treatment period.

The study visit sequence begins with a screening and inclusion visit where eligibility criteria are verified and informed consent is obtained. During the surgical procedure, blood samples are collected to measure clindamycin concentrations at specific time points: at incision, hourly intervals throughout surgery, and at the conclusion of the procedure. If surgery extends beyond 4 hours and clindamycin reinjection is required, additional samples are collected just before reinjection, at the end of reinjection, then hourly and at surgery completion. Postoperative biological data are collected at 6 hours and 24 hours post-surgery, including **creatinine** with calculation of **glomerular filtration rate**, **hepatic enzymes**, **bilirubin** levels, **protidemia** with addition of **α-1 acid glycoprotein**, and documentation of concomitant medications affecting **CYP3A4/5** activity. A 3-month follow-up assessment is conducted via telephone to evaluate mortality and the occurrence of postoperative mediastinitis, defined as a postoperative nosocomial cardiac surgery infection at the surgical site requiring repeat surgery and prolonged antibiotic therapy.

The primary endpoint consists of estimating free plasma clindamycin concentration throughout surgery, calculated from total plasma concentration measurements based on a protein-bound fraction of 80 to 94 percent. The epidemiological threshold minimum inhibition concentration for **Staphylococcus aureus** (0.25 mg/L for clindamycin) serves as the comparison reference, given this bacterium's predominant role in mediastinitis. Secondary endpoints encompass pharmacokinetic parameters, intraoperative vascular filling volumes including blood transfusions, tissue clindamycin concentrations in pericardial fat, recording of **adverse events** and **serious adverse events** from first injection to hospital discharge, documentation of injection timing and duration, postoperative mediastinitis rates with bacterial ecology collection, and 3-month mortality. Additional secondary objectives include comparative pharmacokinetic analysis of **cefazolin** and tissue determination in pericardial fat with correlation to plasma levels of both antibiotics.

Conditions that may lead to early termination from the study include withdrawal of consent, development of serious adverse events requiring discontinuation, protocol violations, investigator decision based on safety concerns, or loss to follow-up. The maximum treatment period is limited to 1 day, reflecting the single perioperative administration strategy. Safety monitoring includes systematic assessment for clinical signs indicative of **anaphylaxis** on medical examination and comprehensive recording of all adverse events throughout the hospitalization period and follow-up phase.

The experimental medication under investigation is **clindamycin**, administered as an **injection** for **intravenous use**. Clindamycin is a chemical **active substance** being evaluated in this study for **off-label use** in cardiothoracic surgery. The **maximum daily dose** is 1500 mg, with a **maximum total dose** of 1500 mg administered over the course of treatment. The **treatment period** is limited to 1 day. The primary objective is to demonstrate the feasibility of using clindamycin in patients undergoing **extracorporeal circulation** surgery by maintaining **plasma concentrations** above the **minimum inhibition concentration** of the main bacteria involved in **mediastinitis** throughout the surgical procedure. Clindamycin serves as the test product in this **prospective single-center pharmacokinetic study**, representing an alternative **prophylactic** approach in aortic cardiac surgery.

Efficacy will be assessed through the evaluation of **clindamycin** plasma concentrations during the surgical procedure. The primary endpoint consists of the estimated free plasma clindamycin concentration measured at specific timepoints throughout surgery, including at incision, hourly intervals, and at the end of surgery. In cases where surgery extends beyond four hours and clindamycin is re-injected, additional measurements will be taken immediately before re-injection, at the end of re-injection, then hourly, and at the end of surgery. The free plasma concentration of clindamycin will be estimated by measuring the total plasma concentration, based on a bound fraction of 80 to 94 percent. These concentrations will be compared to the epidemiological threshold minimum inhibition concentration for Staphylococcus aureus (ECOFF equal to 0.25 mg/L for clindamycin), given that this bacterium is the main pathogen implicated in **mediastinitis**.

Secondary efficacy parameters include pharmacokinetic measurements such as volume of distribution, clearance, and elimination half-life of clindamycin. Tissue determination of clindamycin in pericardial fat and its correlation with plasma levels will be performed. Clinical outcomes will be assessed through the rate of postoperative mediastinitis from Day 0 to three months postoperative, defined as a postoperative nosocomial cardiac surgery infection at the surgical site requiring repeat surgery and prolonged antibiotic therapy. Mortality at three months will be recorded via telephone follow-up. Additional data collection includes patient weight, height, body mass index, post-extracorporeal circulation biological data at six and twenty-four hours (including creatinine with glomerular filtration rate calculation, liver function tests, and alpha-1 acid glycoprotein at induction), documentation of CYP3A4/5 inducer/inhibitor drugs, extracorporeal circulation modalities, blood transfusion volumes, and adverse events from first injection to hospital discharge.