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.

Inclusion Criteria:

1. Completed 18 years of age
2. Presence of signs and symptoms of superficial ABSSSI or PI in the form of a) redness/warmth/swelling/pain or b) separation of the edges of the surgical incision with signs of inflammation or the need for repeated surgical debridement of the wound or c) the presence of decubitus of the skin and subcutaneous tissue in area of the generator or skin abscess/erosion of the device pocket, with purulent discharge from the wound or discharge giving a positive microbial culture
3. Probable/ definite diagnosis of right-sided LRIE according to modified Dukes criteria (optional criterion)
4. Suspected/confirmed infection with drug-resistant Gram-positive cocci, i.e., Staphylococcus spp. (Stahphylococcus aureus or coagulase-negative staphylococci), Streptococcus spp. or Enterococcus spp. sensitive to oritavancin
5. Suspected/confirmed infection with Gram-positive cocci, i.e., Staphylococcus spp., Streptococcus spp., Enterococcus spp., sensitive to vancomycin or oritavancin and beta-lactam antibiotics in patients with a history of type I anaphylaxis to penicillin.

Exclusion Criteria:

1. Suspected/confirmed infection with Gram-positive or Gram-negative bacilli or anaerobic bacteria
2. Suspected/confirmed community-acquired infection or infection with Gram-positive cocci sensitive to betalactam antibiotics, including penicillin, ampicillin, or methicillin, based on empirical data or cultures (does not apply to patients with a history of type I anaphylaxis to penicillin)
3. Confirmed resistance of Gram-positive cocci, which are the etiological factor of the infection, to vancomycin and oritavancin.
4. History of hypersensitivity to oritavancin or another lipoglycopeptide antibiotic (applies to the experimental group only)
5. History of hypersensitivity to vancomycin or another glycopeptide antibiotics (applies to the control group only)
6. No possibility of temporarily interrupting/initiating alternative therapy to intravenous infusion of unfractionated heparin
7. Pregnancy or breastfeeding
8. Lack of informed written consent of the patient to participate in the study

The raw IPD data that underlie results in a publications will be openly available.

A link to the IPD data that underlie results in a publication will be available immediately after the manuscript is accepted and published.

The raw IPD data and supporting Information will be openly available in the Polish Platform of Medical Research (https://ppm.edu.pl/search/researchdata?ps=20\&t=simple\&showRel=false\&lang=pl\&qp=\&cid=1577414) under the CC BY license.

The study will be blinded only at the randomization stage. A different time model for antibiotic dosing does not allow for blinding of the Care Provider and allows the Participant to easily identify the type of antibiotic administered based on the information obtained in the consent form for the study.