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.
Completed 18 years of age
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
Probable/ definite diagnosis of right-sided LRIE according to modified Dukes criteria (optional criterion)
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
Suspected/confirmed infection with Gram-positive or Gram-negative bacilli or anaerobic bacteria
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)
Confirmed resistance of Gram-positive cocci, which are the etiological factor of the infection, to vancomycin and oritavancin.
History of hypersensitivity to oritavancin or another lipoglycopeptide antibiotic (applies to the experimental group only)
Parallel
Administration of a single or repeated dose of a long half-life antibiotic - oritavancin
DrugIntravenous administration of a single or repeated dose of lipoglycopeptide antibiotic - oritavancin. In superficial ABSSSI or PI: Single dose of 1,200 mg (3 vials) administered as a 3-hour intravenous infusion in 5% glucose solution. In LRIE: First dose of 1,200 mg (3 vials) administered as a 3-hour intravenous infusion in 5% glucose solution, 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 transvenous lead extraction).
Administration of a repeated dose of a short half-life antibiotic - vancomycin
DrugIntravenous administration of repeated doses of glycopeptide antibiotic - vancomycin. Repeated doses of 15-20 mg/kg body weight every 8-12 hours administered as an hourly intravenous infusion in 0.9% sodium chloride solution, under monitoring the drug concentration in serum, for 7-10 days in ABSSSI, for 10-14 days in PI, and for 2-6 weeks in LRIE (counted from the day of transvenous lead extraction).
Co-primary efficacy endpoint - treatment success rate
Treatment success will be defined as obtaining a clinical response and no recurrence of infection at the same site or the site of CIED reimplantation within three months of F/U.
Co-primary safety endpoint - no treatment-related Serious Adverse Events
Any adverse event classified as grade 3-5 according Health Technology Assessment report developed by the Agency for Health Technology Assessment and Tariff System (Poland) and related to using the investigational product (scores of 3-5) will be counted as a safety endpoint.
Clinical response rate
Clinical response will be defined as follows: 1. In the case of ABSSSI: a reduction in the size of the inflammatory lesion by at least 20% compared to the baseline after 48-72 hours of antibiotic therapy (in the case of conservative treatment) or the resolution of ABSSSI/complete healing of the surgical wound assessed after 7-10 days. 2. In the case of isolated PI: a resolution of fever and reduction of inflammatory parameters by ≥50% after 72-120 hours of antibiotic therapy and complete healing of the surgical wound assessed after 10-14 days. 3. In the case of PI complicated by LRIE: a reduction of inflammatory parameters by ≥50% after 72-120 hours of antibiotic therapy, negative control blood cultures after 72 hours, and resolution of fever by the 7th day, complete healing of the surgical wound after 10-14 days and resolution and absence of new echocardiographic signs of infection after the end of antibiotic therapy.
Median time to clinical response
Median time to clinical response defined as above and given in hours or days (as required).
Recurrent infection rate
Recurrence of infection will be defined as CIED infection occurring within three months of the completion of previous treatment, caused by the persistence of bacteria with the same phenotype in the skin and subcutaneous tissue, the device pocket, intracardiac leads, the right-sided endocardium or tricuspid valve.
Rehospitalization rate due to recurrent infection
Hospitalization due to recurrent infection will be defined as a hospital stay resulting from the need for repeated antibiotic administration or repeated surgical intervention related to recurrent infection in the form of ABSSSI, PI, or LRIE (as outlined in point 5).
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Medical University of Silesia
Lead sponsor
Medical Research Agency, Poland
Collaborator
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