Oritavancin for CIED Infections With MDR Gram-positive Cocci

Официальное название

Oritavancin as a Therapeutic Regimen for Cardiac Implantable Electronic Devices Infections With Multidrug-resistant Gram-positive Cocci

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Administration of a single or repeated dose of a long half-life antibiotic - oritavancin
  Intravenous 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 thera
• Препарат Administration of a repeated dose of a short half-life antibiotic - vancomycin
  Intravenous 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).

Первичные конечные точки

• Co-primary efficacy endpoint - treatment success rate [Срок оценки: 3 months]
• Co-primary safety endpoint - no treatment-related Serious Adverse Events [Срок оценки: 3 months]

Вторичные конечные точки (6)

• Clinical response rate [Срок оценки: 3 months]
• Median time to clinical response [Срок оценки: 3 months]
• Recurrent infection rate [Срок оценки: 3 months]
• Rehospitalization rate due to recurrent infection [Срок оценки: 3 months]
• Proportion of cases in which infection worsened from superficial or local to systemic despite drug therapy [Срок оценки: 3 months]
• Proportion of cases in which alternative "rescue" antibiotic therapy was used due to treatment failure [Срок оценки: 3 months]

Критерии участия

Критерии включения

• 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 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.

Критерии исключения

• 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)
• History of hypersensitivity to vancomycin or another glycopeptide antibiotics (applies to the control group only)
• No possibility of temporarily interrupting/initiating alternative therapy to intravenous infusion of unfractionated heparin
• Pregnancy or breastfeeding
• Lack of informed written consent of the patient to participate in the study

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Польша · 1 центр

• Department of Electrocardiology and Heart Failure, Medical University of Silesia in Katowi — Katowice

Публикации

• Gladysz-Wanha S, Joniec M, Wanha W, Pilat E, Drzewiecka A, Gardas R, Biernat J, Weglarzy A, Golba KS. Transvenous lead extraction safety and efficacy in infected and noninfected patients using mechanical-only tools: Prospective registry from a high-volume center. Heart Rhythm. 2024 Apr;21(4):427-435. doi: 10.1016/j.hrthm.2023.12.015. Epub 2023 Dec 28. PMID 38157921
• Olsen T, Jorgensen OD, Nielsen JC, Thogersen AM, Philbert BT, Johansen JB. Incidence of device-related infection in 97 750 patients: clinical data from the complete Danish device-cohort (1982-2018). Eur Heart J. 2019 Jun 14;40(23):1862-1869. doi: 10.1093/eurheartj/ehz316. PMID 31155647
• Stewart CL, Turner MS, Frens JJ, Snider CB, Smith JR. Real-World Experience with Oritavancin Therapy in Invasive Gram-Positive Infections. Infect Dis Ther. 2017 Jun;6(2):277-289. doi: 10.1007/s40121-017-0156-z. Epub 2017 Apr 6. PMID 28386776
• Morrisette T, Miller MA, Montague BT, Barber GR, McQueen RB, Krsak M. On- and off-label utilization of dalbavancin and oritavancin for Gram-positive infections. J Antimicrob Chemother. 2019 Aug 1;74(8):2405-2416. doi: 10.1093/jac/dkz162. PMID 31322694
• Rubino CM, Bhavnani SM, Moeck G, Bellibas SE, Ambrose PG. Population pharmacokinetic analysis for a single 1,200-milligram dose of oritavancin using data from two pivotal phase 3 clinical trials. Antimicrob Agents Chemother. 2015;59(6):3365-72. doi: 10.1128/AAC.00176-15. Epub 2015 Mar 30. PMID 25824211
• Carvalhaes CG, Sader HS, Streit JM, Castanheira M, Mendes RE. Activity of Oritavancin against Gram-Positive Pathogens Causing Bloodstream Infections in the United States over 10 Years: Focus on Drug-Resistant Enterococcal Subsets (2010-2019). Antimicrob Agents Chemother. 2022 Feb 15;66(2):e0166721. doi: 10.1128/AAC.01667-21. Epub 2021 Nov 22. PMID 34807761
• Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, Pulcini C, Kahlmeter G, Kluytmans J, Carmeli Y, Ouellette M, Outterson K, Patel J, Cavaleri M, Cox EM, Houchens CR, Grayson ML, Hansen P, Singh N, Theuretzbacher U, Magrini N; WHO Pathogens Priority List Working Group. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacter PMID 29276051
• Lupia T, De Benedetto I, Bosio R, Shbaklo N, De Rosa FG, Corcione S. Role of Oritavancin in the Treatment of Infective Endocarditis, Catheter- or Device-Related Infections, Bloodstream Infections, and Bone and Prosthetic Joint Infections in Humans: Narrative Review and Possible Developments. Life (Basel). 2023 Apr 6;13(4):959. doi: 10.3390/life13040959. PMID 37109488

Идентификаторы

NCT: NCT07013552 · KPOD.07.07-IW.07-0004/24

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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