Experience of Real-Life Use of Dalbavancin as an Off-Label Treatment of Complicated Infectious Diseases in a Tertiary Care Hospital Experience ^†

Abstract

Dalbavancin is a lipoglycopeptide indicated for the treatment of acute bacterial skin and skin structure infections. The aim of this study is to describe the cases in which dalbavancin has been used as an off-label treatment for infections by Gram-positive microorganisms. Methods: we carried out a case report series study of all patients treated with dalbavancin as an off-label treatment from January 2017 to March 2022. Results: Dalbavancin was administered to seventeen patients. The most frequent diagnosis was osteoarticular infection in 52.94% of patients. The principal isolated microorganism was Staphylococcus epidermidis (47.00%). The posology of dalbavancin was highly variable and the median number of days of treatment was 14 (1–56). At 3 months of treatment, only two patients died for other reasons and no patient experienced reinfection. Conclusion: dalbavancin is an antibiotic with a novel dosage in infectious diseases by Gram-positive microorganisms that has proven to be highly effective, since there have been no manifested symptoms of reinfection in patients.

1. Introduction

Dalbavancin is a lipoglycopeptide antibiotic whose mechanism of action involves the disruption of cell wall synthesis by binding to the D-alanyl-D-alanine end of the peptidoglycan structure in the forming cell wall, preventing cross-linking (transpeptidation and transglycosylation) of disaccharide subunits, resulting in bacterial cell death. It is active against Gram-positive microorganisms, including different species of multiresistant microorganisms such as methicillin-resistant Staphylococcus aureus (MRSA). It is indicated for the treatment of acute bacterial infections of the skin and soft tissues in adults [1,2].

The most relevant pharmacokinetic feature is its prolonged action (half-life of 14.40 days), which allows for the administration of a single dose of 1500 mg or the administration of two doses of 1000 mg and 500 mg separated by 1 week, according to the data sheet [3,4].

Dalbavancin is usually used off-label, as it has a powerful activity against Gram-positive pathogens that cause bone and joint infections (osteomyelitis), bacteraemias and endocarditis, among others, which are infections that require long-term antibiotic therapy and long periods of hospitalization. Its prolonged action allows for the early discharge of hospitalized patients who require prolonged intravenous antibiotic therapy. This avoids prolonged hospitalization and the risk of acquiring healthcare-associated infections, favors home treatment and, at the same time, ensures adherence to treatment [4,5,6].

The objective of this study is to describe the cases in which dalbavancin has been used as an off-label treatment for infections by Gram-positive microorganisms in a tertiary hospital.

2. Methods

Herein, the case of a series study of all patients treated with dalbavancin as off-label use from January 2017 to March 2022 is reported.

The following demographic, clinical, and pharmacotherapeutic variables were considered: age, sex, justification for the request as off-label, diagnosis, microorganism, location of the infection, previous antibiotic treatment, dalbavancin dosing, duration of treatment, concomitant antibiotic treatment, and follow-up of the patients at 3 months.

Data were collected from the electronic medical record and the electronic prescribing program.

3. Results and Discussion

The study included a total of nineteen patients for whom off-label dalbavancin was requested from the pharmacy service. Two patients were excluded: one of whom died before administration of dalbavancin, and another who was proposed to discontinue the drug that interacted with another effective antibiotic during treatment.

Dalbavancin was administered to seventeen patients (

Table 1. Results of diagnosis, isolated microorganism, location, and posology of our patients. MRSA: methicillin-resistant Staphylococcus aureus; MSSA: methicillin-sensitive Staphylococcus aureus.

	Diagnostic	Microorganism	Location	Dalbavancin Dosage
1	Bacteraemia	Staphylococcus epidermidis	Joint fluid	2 doses of 1500 mg biweekly
2	Osteoarticular infection	MRSA	Joint fluid	1 dose of 1500 mg + 1000 mg biweekly
3	Osteoarticular infection	Staphylococcus epidermidis	Abscess	1 dose of 1500 mg + 1000 mg biweekly
4	Bacteraemia	Staphylococcus epidermidis	Blood culture	1 dose of 1500 mg + 1000 mg biweekly
5	Bacteraemia	MRSA	Blood culture	1 dose of 1500 mg + 1000 mg biweekly
6	Osteoarticular infection	Staphylococcus epidermidis	Osteosynthesis	2 doses of 1500 mg biweekly
7	Bacteraemia	Staphylococcus warneri	Blood culture	Single dose of 1500 mg
8	Endocarditis	MSSA	Ulcer	1 dose of 750 mg + 375 mg weekly
9	Osteoarticular infection	MRSA	Abscess	1 dose of 750 mg + 375 mg weekly
10	Osteoarticular infection	MSSA	Osteosynthesis	1 dose of 1500 mg + 500 mg weekly
11	Bacteraemia	MSSA	Blood culture	Single dose of 1500 mg
12	Osteoarticular infection	Staphylococcus epidermidis	Joint fluid	2 doses of 1500 mg biweekly
13	Endocarditis	Staphylococus haemolyticus	Blood culture	1 dose of 1000 mg + 500 mg at two weeks
14	Osteoarticular infection	MSSA	Blood culture	1 dose of 1000 mg + 500 mg at two weeks
15	Endocarditis	Staphylococcus epidermidis	Blood culture	1 dose of 1000 mg + 500 mg at two weeks
16	Osteoarticular infection	Staphylococcus epidermidis	Osteosynthesis	1 dose of 1000 mg + 500 mg at two weeks
17	Osteoarticular infection	Staphylococcus epidermidis	Osteosynthesis	1 dose of 1000 mg + 500 mg at two weeks

) with a median age of 76 (33–99) years, 64.70% of whom were men. The justification for off-label use in all patients was the early discharge and the impossibility of treatment with other oral antibiotics due to interactions, microbial resistance, adverse effects, and/or severity. All patients were tested for the sensitivity of dalbavancin.

The most frequent diagnosis was osteoarticular infection in 52.94% of patients, followed by bacteremia in 29.40%, and endocarditis in 11.76%. The isolated microorganism was Staphylococcus epidermidis (47.00%), methicillin-resistant Staphylococcus aureus (17.65%), methicillin-sensitive Staphylococcus aureus (23.53%), Staphylococcus haemolyticus (5.89%) and Staphylococcus warneri (5.89%). The microorganisms´ isolation consisted of 33% blood culture, 25% joint fluid, 16.67% abscess, 16.67% osteosynthesis, and 8.33% ulcer.

All patients were treated with other antibiotics before starting dalbavancin. Previous antibiotic treatments were daptomycin in 13 patients (76.47%) (9 of them also received other antibiotics before), linezolid in 3 patients (17.65%) (2 of them also received other antibiotics before), and others in 2 patients (11.76%).

Dalbavancin dosing was highly variable: two doses of 1500 mg biweekly (17.65%; n = 3), one dose of 1000 mg + 500 mg at two weeks (29.41%; n = 5), one dose of 1500 mg + 1000 mg biweekly (23.53%; n = 4), a single dose of 1500 mg (11.76%; n = 2), one dose of 750 mg + 375 mg weekly (11.76%; n = 2), and one dose of 1500 mg + 500 mg weekly (5.89%; n = 1).

The median number of days of treatment was 14 (1–56). Concomitant oral antibiotics were used in 29.41% of cases: rifampicin (n = 5) and levofloxacin (n = 2). After 3 months of treatment, only two patients died for others reasons and no patient experienced reinfection.

Our hospital’s use of dalbavancin is largely similar to other hospitals in real-life situations.

A recently published systematic review (2020), which included 38 studies (18 randomized controlled trials/case series and 20 case reports) on the use of dalbavancin and oritavancin in indications other than acute bacterial skin and soft tissue infections, showed a success rate of 73% for osteoarticular infection (the most common indication), 68% for endocarditis and cardiac device-related infections, and 75% for catheter-related infections [2].

In a multicenter retrospective study including 101 patients receiving dalbavancin from September 2016 to March 2018, the infections treated were prosthetic joint infection (31%), osteomyelitis (29%), endocarditis (25%), and acute bacterial skin and soft tissue infections (12%). Sixty-three per cent of patients received other antibiotics concomitantly. The total cumulative mean dose of dalbavancin was 3,357 mg (±2283 mg). Outcomes and tolerability were measured at 90 days, with a clinical success rate of 89%. Side effects occurred in 3/101 patients [6].

Furthermore, in a retrospective observational study conducted in a hospital in our setting, which included 102 patients treated with dalbavancin (69.6% off label) from October 2016 to August 2019, 89 patients (93.7%) had a clinical and microbiological resolution of infection at the end of the study. The most frequent indications were catheter-related bacteraemia (15.7%) and endocarditis (13.6%). The main reason for switching to dalbavancin was early patient discharge (79.4%, n = 81). The median reduction in length of hospital stay was 14 days per patient, with an estimated saving of about EUR 4550 per patient. In addition, a trend towards a significant improvement in quality-of-life outcomes with dalbavancin has been observed. Outpatients reported significantly higher comfort and satisfaction [1].

4. Conclusions

Dalbavancin is an antibiotic with a novel dosing in Gram-positive infectious diseases such as endocarditis and osteomyelitis that require long periods of treatment, due to its pharmacokinetic characteristics. Its main contribution in our setting has been to allow earlier hospital discharge in patients who did not have oral alternatives and the only reason for hospitalization was the need for intravenous antibiotic treatment.

In this study, we observed several cases of off-label dalbavancin use in a tertiary hospital. Most of our patients achieved clinical success, with resolution of the infection and no relapses occurring in the 3-month follow-up period after finishing treatment. The two patients who died in our study died from other reasons than the cause that motivated the prescription of dalbavancin.

Our results show that the potential use of dalbavancin extends beyond the authorized indication in clinical practice; it has been shown to be highly effective as no patient manifested symptoms of reinfection.

For these reasons, we have developed a protocol in our hospital for the use of dalbavancin as an off-label treatment in severe Gram-positive infections. Its use is restricted to patients who meet all of the following criteria:

• Severe and/or complex infections caused by Gram-positive microorganisms sensitive to dalbavancin (treatment directed by microbiology results);
• Patients requiring prolonged antibiotic treatment (≥2 weeks);
• Linezolid being contraindicated due to the risk of developing serotonin syndrome when prescribed antidepressants (serotonin reuptake inhibitors, tricyclic antidepressants) or due to this drug’s high risk of toxicity due to renal failure (creatinine clearance (CrCl) < 30 mL/min) and/or alteration of the previous hemogram.