Clinical trial NCT07013552: Oritavancin for CIED Infections With MDR Gram-positive Cocci
Official title: Oritavancin as a Therapeutic Regimen for Cardiac Implantable Electronic Devices Infections With Multidrug-resistant Gram-positive Cocci
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Cardiac Implantable Electronic Device Infections
Infective Endocarditis
Multidrug-resistant Bacteria Screening
Gram Positive Bacterial Infection
Antibiotic Resistant Strain
Antibiotic Therapy
Healthcare Associated Infections
Keywords: Cardiac implantable electronic device
Gram-positive cocci
Health-care associated infections
Lead-related infective endocarditis
Multidrug-resistant bacteria
Pocket infection
Lead sponsor: Medical University of Silesia
Sponsor class: OTHER
Collaborators: name: Medical Research Agency, Poland
First posted: 2025-06-10
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized 1:1 to the intervention and control groups.

Experimental group:

Oritavancin dosage in superficial ABSSSI or PI: Single dose of 1,200 mg (3 vials) administered as a 3-hour intravenous infusion.

Oritavancin dosage in LRIE: First dose of 1,200 mg (3 vials) administered as a 3-hour intravenous infusion, 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).

Control group:

Vancomycin dosage: Repeated doses of 15-20 mg/kg body weight every 8-12 hours administered as an hourly intravenous infusion for 7-10 days in ABSSSI, for 10-14 days in PI, and for 2-6 weeks in LRIE.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Co-primary efficacy endpoint - treatment success rate
timeFrame: 3 months
measure: Co-primary safety endpoint - no treatment-related Serious Adverse Events
timeFrame: 3 months
Secondary outcomes:
measure: Clinical response rate
timeFrame: 3 months
measure: Median time to clinical response
timeFrame: 3 months
measure: Recurrent infection rate
timeFrame: 3 months
measure: Rehospitalization rate due to recurrent infection
timeFrame: 3 months
measure: Proportion of cases in which infection worsened from superficial or local to systemic despite drug therapy
timeFrame: 3 months
measure: Proportion of cases in which alternative "rescue" antibiotic therapy was used due to treatment failure
timeFrame: 3 months
Other outcomes:
Locations:
city: Katowice
country: Poland
facility: Department of Electrocardiology and Heart Failure, Medical University of Silesia in Katowice
state: Silesian Voivodeship
Study officials:
affiliation: Department of Basic Biomedical Science, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Poland
name: Beata Sarecka-Hujar, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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 bacteria and tuberculosis. Lancet Infect Dis. 2018 Mar;18(3):318-327. doi: 10.1016/S1473-3099(17)30753-3. Epub 2017 Dec 21.
citation: 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.
citation: Thomas G, Henao-Martinez AF, Franco-Paredes C, Chastain DB. Treatment of osteoarticular, cardiovascular, intravascular-catheter-related and other complicated infections with dalbavancin and oritavancin: A systematic review. Int J Antimicrob Agents. 2020 Sep;56(3):106069. doi: 10.1016/j.ijantimicag.2020.106069. Epub 2020 Jun 27.
citation: Esposito S, Blasi F, Curtis N, Kaplan S, Lazzarotto T, Meschiari M, Mussini C, Peghin M, Rodrigo C, Vena A, Principi N, Bassetti M. New Antibiotics for Staphylococcus aureus Infection: An Update from the World Association of Infectious Diseases and Immunological Disorders (WAidid) and the Italian Society of Anti-Infective Therapy (SITA). Antibiotics (Basel). 2023 Apr 12;12(4):742. doi: 10.3390/antibiotics12040742.
citation: Corey GR, Arhin FF, Wikler MA, Sahm DF, Kreiswirth BN, Mediavilla JR, Good S, Fiset C, Jiang H, Moeck G, Kabler H, Green S, O'Riordan W; SOLO I, SOLO II Investigators. Pooled analysis of single-dose oritavancin in the treatment of acute bacterial skin and skin-structure infections caused by Gram-positive pathogens, including a large patient subset with methicillin-resistant Staphylococcus aureus. Int J Antimicrob Agents. 2016 Nov;48(5):528-534. doi: 10.1016/j.ijantimicag.2016.07.019. Epub 2016 Sep 13.
citation: Giske CG, Turnidge J, Canton R, Kahlmeter G; EUCAST Steering Committee. Update from the European Committee on Antimicrobial Susceptibility Testing (EUCAST). J Clin Microbiol. 2022 Mar 16;60(3):e0027621. doi: 10.1128/JCM.00276-21. Epub 2021 Aug 4.
citation: Delgado V, Ajmone Marsan N, de Waha S, Bonaros N, Brida M, Burri H, Caselli S, Doenst T, Ederhy S, Erba PA, Foldager D, Fosbol EL, Kovac J, Mestres CA, Miller OI, Miro JM, Pazdernik M, Pizzi MN, Quintana E, Rasmussen TB, Ristic AD, Rodes-Cabau J, Sionis A, Zuhlke LJ, Borger MA; ESC Scientific Document Group. 2023 ESC Guidelines for the management of endocarditis. Eur Heart J. 2023 Oct 14;44(39):3948-4042. doi: 10.1093/eurheartj/ehad193. No abstract available.
citation: Milman A, Wieder-Finesod A, Zahavi G, Meitus A, Kariv S, Shafir Y, Beinart R, Rahav G, Nof E. Complicated Pocket Infection in Patients Undergoing Lead Extraction: Characteristics and Outcomes. J Clin Med. 2023 Jun 29;12(13):4397. doi: 10.3390/jcm12134397.
citation: Kusumoto FM, Schoenfeld MH, Wilkoff BL, Berul CI, Birgersdotter-Green UM, Carrillo R, Cha YM, Clancy J, Deharo JC, Ellenbogen KA, Exner D, Hussein AA, Kennergren C, Krahn A, Lee R, Love CJ, Madden RA, Mazzetti HA, Moore JC, Parsonnet J, Patton KK, Rozner MA, Selzman KA, Shoda M, Srivathsan K, Strathmore NF, Swerdlow CD, Tompkins C, Wazni O. 2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction. Heart Rhythm. 2017 Dec;14(12):e503-e551. doi: 10.1016/j.hrthm.2017.09.001. Epub 2017 Sep 15. No abstract available.
citation: Blomstrom-Lundqvist C, Traykov V, Erba PA, Burri H, Nielsen JC, Bongiorni MG, Poole J, Boriani G, Costa R, Deharo JC, Epstein LM, Saghy L, Snygg-Martin U, Starck C, Tascini C, Strathmore N; ESC Scientific Document Group. European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Europace. 2020 Apr 1;22(4):515-549. doi: 10.1093/europace/euz246.
citation: Polewczyk A, Jachec W, Polewczyk M, Nowosielecka D, Brzozowski W, Kutarski A. Outcomes in patients with definite and possible infective endocarditis related to a cardiac implantable electronic device. Pol Arch Intern Med. 2024 Aug 8;134(7-8):16775. doi: 10.20452/pamw.16775. Epub 2024 Jun 17.
citation: Bongiorni MG, Kennergren C, Butter C, Deharo JC, Kutarski A, Rinaldi CA, Romano SL, Maggioni AP, Andarala M, Auricchio A, Kuck KH, Blomstrom-Lundqvist C; ELECTRa Investigators. The European Lead Extraction ConTRolled (ELECTRa) study: a European Heart Rhythm Association (EHRA) Registry of Transvenous Lead Extraction Outcomes. Eur Heart J. 2017 Oct 21;38(40):2995-3005. doi: 10.1093/eurheartj/ehx080.
citation: Chmielarczyk A, Pomorska-Wesolowska M, Romaniszyn D, Wojkowska-Mach J. Healthcare-Associated Laboratory-Confirmed Bloodstream Infections-Species Diversity and Resistance Mechanisms, a Four-Year Retrospective Laboratory-Based Study in the South of Poland. Int J Environ Res Public Health. 2021 Mar 9;18(5):2785. doi: 10.3390/ijerph18052785.
citation: Joshi S, Shallal A, Zervos M. Vancomycin-Resistant Enterococci: Epidemiology, Infection Prevention, and Control. Infect Dis Clin North Am. 2021 Dec;35(4):953-968. doi: 10.1016/j.idc.2021.07.002.
citation: Cerini P, Meduri FR, Tomassetti F, Polidori I, Brugneti M, Nicolai E, Bernardini S, Pieri M, Broccolo F. Trends in Antibiotic Resistance of Nosocomial and Community-Acquired Infections in Italy. Antibiotics (Basel). 2023 Mar 24;12(4):651. doi: 10.3390/antibiotics12040651.