Oritavancin for CIED Infections With MDR Gram-positive Cocci

Overview

The study aimed to conduct a randomized, non-inferiority controlled trial to compare the short- and medium-term efficacy and safety of two antibiotic dosage regimens in cardiac implantable electronic devices (CIED) infections with multidrug-resistant Gram-positive cocci: 1) single-dose therapy with a long-half-life antibiotic (oritavancin) vs. standard 7-14 days of therapy with a short-half-life antibiotic (vancomycin) for CIED surgical incision site or pocket infection; and 2) fractionated therapy with a long-half-life antibiotic (oritavancin) at seven-day intervals compared to standard therapy with a short-half-life antibiotic (vancomycin) fractionated in 2-3 daily doses in cases of lead-related infectious endocarditis.

Study Objectives: This study's purpose is to evaluate the safety and efficacy of two antibiotic dosage regimens in a pilot study of cardiac implantable electronic devices (CIED) infections with multidrug-resistant (MDR) Gram-positive cocci. Study Design: This study is a single-center randomized, non-inferiority, control trial comparing the efficacy and safety of two antibiotic dosage regimens with a long-half-life antibiotic (oritavancin, experimental group) vs. standard therapy with a short-half-life antibiotic (vancomycin, control group). Study Assumptions: The investigators assumed that the efficacy of oritavancin therapy administered as a single intravenous infusion (for surgical incision site infection or pocket infection) or in fractionated doses administered at seven-day intervals (for lead-related infectious endocarditis) would be non-inferior to the efficacy of standard vancomycin therapy administered daily at 8-12 hour intervals and that there would be no difference in the safety profile between the two therapies. Patient Population: Patients aged ≥18 with CIED surgical incision site infection (i.e., superficial acute bacterial skin and skin structure infections, ABSSSI) or deep infections of the generator pocket (PI) complicated or not with lead-related infectious endocarditis (LRIE) (optional) with multidrug-resistant (MDR) Gram-positive cocci. The planned size of the group in the pilot study is 50-100. The planned recruitment period is 15 months, and the observation period is 3 months. Once all inclusion criteria and none of the exclusion criteria are met, patients who have given written informed consent to participate in the study will be randomly assigned to the experimental group and the control group to achieve a 1:1 group size ratio. Intervention: The diagnostic and surgical approach and the duration of antibiotic treatment will be determined depending on the etiological factor and clinical indications by the consensus of European Heart Rhythm Association and Heart Rhythm Society experts on cardiovascular implantable electronic device lead management and extraction and the European Society of Cardiology guidelines for the treatment of infective endocarditis. The intervention under investigation (experimental) will be administering a single or repeated dose of oritavancin. The standard intervention will be administering of repeated doses of vancomycin. Experimental group - Oritavancin dosage: 1. in superficial ABSSSI: Single dose of 1,200 mg (3 vials) administered as a 3-hour intravenous infusion in 5% glucose solution (infusion volume: 1,000 ml); 2. in isolated PI: Single dose of 1,200 mg (3 vials) administered as a 3-hour intravenous infusion in 5% glucose solution (infusion volume: 1,000 ml); 3. in LRIE: First dose of 1,200 mg (3 vials) administered as a 3-hour intravenous infusion in 5% glucose solution (infusion volume: 1,000 ml), subsequent doses of 800 mg (2 vials) administered as a 2-3 hour intravenous infusion at 7-day intervals, to achieve the required duration of drug therapy of 2-6 weeks (counted from the day of TLE). Control group - Vancomycin dosage: 1. in superficial ABSSSI: Repeated doses of 15-20 mg/kg body weight every 8-12 hours (maximum 3,000 mg/day for patients with normal renal function) administered as an hourly intravenous infusion in 0.9% sodium chloride solution (infusion volume: 500-1,000 ml), under monitoring the drug concentration in serum, for 7-10 days (calculated from the beginning of antibiotic therapy, not less than seven days from surgical tissue debridement, if required); 2. in isolated PI: Repeated doses of 15-20 mg/kg body weight every 8-12 hours (maximum 3,000 mg/day for patients with normal renal function) administered as an hourly intravenous infusion in 0.9% sodium chloride solution (infusion volume: 500-1,000 ml), under monitoring the drug concentration in serum, for 10-14 days (counted from the day of surgical debridement of the generator pocket and TLE, if possible); 3. in LRIE: Repeated doses of 15-20 mg/kg body weight every 8-12 hours (maximum 3,000 mg/day for patients with normal renal function) administered as an hourly intravenous infusion in 0.9% sodium chloride solution (infusion volume: 500-1,000 ml), under monitoring the drug concentration in serum, to achieve the required pharmacotherapy time of 2-6 weeks (counted from the day of surgical debridement of the incision site and TLE). Observation: Observation will include 1. Physical examination with the assessment of the CIED implantation site; 2. Routine laboratory tests, including blood count, C-reactive protein (mg/l), procalcitonin (ng/ml), plasma creatinine (mg/dl); 3. Transthoracic echocardiogram with the assessment of bacterial vegetations; 4. Transesophageal echocardiogram with the assessment of bacterial vegetations, with particular emphasis on the tricuspid valve and CIED leads; 5. PET/CT examination with 18F-FDG or SPECT/CT using radioisotope-labeled leukocytes (depending on clinical indications). Evaluation will be performed at 72-120 hours of therapy, after 5-7 and 14 days of therapy, and after 1 and 3 months of therapy, with endpoints assessed at 3 months. Primary endpoints will include a complete cure rate and serious treatment-related adverse events at 3 months of follow-up. Secondary endpoints will include clinical response rates, worsening or recurrence of infection despite drug therapy (including those resulting in rehospitalization and requiring alternative antibiotic therapy), and time to clinical response.