Dalbavancin versus standard combination therapy for Gram‑positive infective endocarditis: a randomized controlled trial assessing 90‑day treatment success

The primary objective is to assess whether dalbavancin administered to patients with infective endocarditis caused by Gram‑positive cocci increases treatment success at day 90 compared with recommended standard antibiotic regimens, addressing a critical need for more effective therapy. Secondary objectives include:

• Evaluation of the intervention’s impact on health‑economic parameters, neurological outcome, the gut microbiome and resistance development, and quality of life and mental health.
• Assessment of safety outcomes associated with the study drug.
• Characterisation of pharmacokinetic and pharmacodynamic profiles.

The trial enrolled adult patients (≥ 18 years) of both sexes with confirmed infective left-sided endocarditis involving native or prosthetic mitral or aortic valves caused by Gram‑positive cocci susceptible to dalbavancin. Participants were required to provide written informed consent and to have left‑sided valve infection meeting the specified microbiological criteria. Both female and male patients were eligible, and the study population comprised individuals with a diagnosis of endocarditis; no additional lifestyle restrictions (e.g., diet, physical activity) were stipulated. The sponsor did not provide information on the total number of participants enrolled.

The study is a multicenter, randomized, double-blind, controlled Phase III trial evaluating the efficacy and safety of dalbavancin versus a regimen of standard intravenous‑oral antibiotics in adults with left‑sided infective endocarditis caused by gram‑positive cocci. Participants are allocated 1:1 to receive either a single 1500 mg intravenous dose of dalbavancin or the investigator‑selected standard therapy, with matching placebos used to maintain blinding. Recruitment is planned from October 2026 to December 2029, and each enrolled subject is followed for up to 12 months after the first dose. The visit schedule includes a screening visit to verify inclusion criteria and obtain consent, a baseline visit (Day 0) for randomization and administration of study medication, and follow‑up assessments at Day 7, Day 30, Day 90 (the primary endpoint assessing the Desirability of Outcome Ranking), Day 180, and Day 365 (end‑of‑study visit). Safety evaluations continue until 14 days after the last dose. Participants remain in the trial for the full 12‑month period unless early termination criteria are met, which include a drug‑related serious adverse event, withdrawal of informed consent, need for rescue antimicrobial therapy, protocol non‑compliance, loss to follow‑up, or death.

The investigational product is dalbavancin, supplied as an intravenous solution at a dose of 1500 mg administered as a single infusion over 30 minutes; repeat dosing may be employed per protocol‑specified schedule.

Levofloxacin for intravenous use is provided at 1 g per dose, administered once daily by infusion.

Levofloxacin for oral use is supplied at 1 g per dose, taken once daily as a tablet.

Benzylpenicillin potassium for intravenous use is supplied at 60 000 000 IU per dose, administered every 4 hours.

Doxycycline for oral use is supplied at 0.3 g per dose, taken twice daily.

Doxycycline for intravenous use is supplied at 0.3 g per dose, administered once daily.

Daptomycin for intravenous use is supplied at 6 mg/kg per dose, given once daily.

Ciprofloxacin for intravenous use is supplied at 1.2 g per dose, administered once daily.

Ciprofloxacin for oral use is supplied at 1.5 g per dose, taken twice daily.

Cefotaxime for intravenous use is supplied at 12 g per dose, administered every 8 hours.

Amoxicillin for oral use is supplied at 6 g per dose, taken three times daily.

Amoxicillin for oral use (alternative regimen) is supplied at 2.5 g per dose, taken three times daily.

Ceftriaxone for intravenous use is supplied at 4 g per dose, administered once daily.

Moxifloxacin for oral use is supplied at 0.4 g per dose, taken once daily.

Moxifloxacin for intravenous use is supplied at 0.4 g per dose, administered once daily.

Cefalexin for oral use is supplied at 4 g per dose, taken twice daily.

Fosfomycin for intravenous use is supplied at 24 g per dose, administered once daily.

Ampicillin for intravenous use is supplied at 15 g per dose, administered every 6 hours.

Ampicillin for intravenous use (alternative regimen) is supplied at 8 g per dose, administered every 6 hours.

Rifampicin for oral use is supplied at 1.2 g per dose, taken once daily.

Rifampicin for intravenous use is supplied at 1.2 g per dose, administered once daily.

Flucloxacillin for intravenous use is supplied at 12 g per dose, administered every 6 hours.

Cefaclor for oral use is supplied at 4 g per dose, taken twice daily.

Sulfamethoxazole for oral use is supplied at 8 g per dose, taken twice daily.

Sulfamethoxazole for intravenous use is supplied at 2 g per dose, administered once daily.

Trimethoprim for oral use is supplied at 1.6 g per dose, taken twice daily.

Trimethoprim for intravenous use is supplied at 0.4 g per dose, administered once daily.

Imipenem for intravenous use is supplied at 4 g per dose, administered every 8 hours.

Cilastatin for intravenous use is supplied at 4 g per dose, co‑administered with imipenem.

Sulbactam for intravenous use is supplied at 4 g per dose, administered every 8 hours.

Linezolid for oral use is supplied at 1.2 g per dose, taken twice daily.

Linezolid for intravenous use is supplied at 1.2 g per dose, administered once daily.

Vancomycin for intravenous use is supplied at 60 mg/kg per dose, administered every 12 hours.

Phenoxymethylpenicillin for oral use is supplied at 6 000 000 IU per dose, taken three times daily.

Gentamicin sulfate for intravenous use is supplied at 6 mg/kg per dose, administered every 8 hours.

Cilastatin (as part of the imipenem‑cilastatin combination) is administered intravenously at 4 g per dose.

Teicoplanin for intravenous use is supplied at 24 mg/kg per dose, administered once daily after loading.

Meropenem for intravenous use is supplied at 6 g per dose, administered every 8 hours.

Clavulanic acid for oral use is supplied at 375 mg per dose, combined with amoxicillin.

Ceftaroline fosamil for intravenous use is supplied at 1.8 g per dose, administered every 12 hours.

Cefazolin for intravenous use is supplied at 12 g per dose, administered every 8 hours.

Benzylpencillin potassium for intravenous use is supplied at 60 000 000 IU per dose, administered every 4 hours.

Ceftriaxone (alternative regimen) for intravenous use is supplied at 4 g per dose, administered once daily.

Efficacy will be evaluated primarily by comparing the Desirability of Outcome Ranking (DOOR) on Day 90 between the dalbavancin group and the standard‑therapy group. Five mutually exclusive DOOR categories will be assigned: alive with no events, alive with one event, alive with two events, alive with three events, and death within 90 days. Events considered for the ranking are cardiac surgery, infectious complications, and embolic events.

Secondary efficacy assessments include health‑economic parameters (hospital length of stay, antibiotic therapy costs, days of work disability) recorded at Day 90. Neurological status will be measured using the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) at Day 90 and at 1 year. Health‑related quality of life will be captured with the PROMIS‑29 domain‑specific T‑scores and pain intensity, the EQ‑5D‑5L index and visual analogue scale, and the RNLI total score, also at Day 90 and 1 year. Overall mortality, occurrence of cardiac surgery, infectious complications, embolic events, and the Clinical Frailty Scale will be documented at both Day 90 and 1 year. Treatment‑related adverse events will be collected from baseline (T0) through end of treatment plus 14 days. In the dalbavancin arm, drug‑level concentrations will be measured for pharmacokinetic analysis at T1, T2, T14, and, when applicable, at T21/28/35. Microbiome composition and resistance development will be evaluated from nasopharyngeal and rectal swabs or stool samples at baseline, Day 90, and 1 year.