Dalbavancin is a novel antimicrobial against Gram-positive pathogens: clinical experience beyond labelled indications

Abstract

Very limited labelled indications have been approved for the newer antimicrobials. Data on the clinical uses, efficacy and safety of dalbavancin are scarce, thus here we sought to describe our clinical experience. 16-month observational prospective study was performed. 19 (86%) were used under off-label indications. 10 (46%) for osteoarticular infections, 5 (23%) bloodstream infections and 3 (14%) endocarditis. To highlight, one patient received dalbavancin as long-term suppressive therapy. Most frequent use reasons were promptly hospital discharge, 11 (65%), and the presence of resistant organisms involving limited treatment options, 5 (23%). Successful outcome was observed in >95% of the patients and only 1 (4.5%) adverse event was reported. Further evidence beyond labelled indications is urgently needed. Despite the limitations, dalbavancin appears to be a safe and efficient option for adult patients who have tried and/or failed other therapies due to multidrug-resistant Gram-positive organisms.

Introduction

Novel antimicrobials are welcome with excitement and hope as wider and wider the gap between the frequency of multidrug-resistant bacterial infections and the development of available drugs¹ in a moment where the emergence and spread of antimicrobial resistance is considered a global public health threat.²

To ensure microbiological coverage is urgently needed especially for Gram-positive pathogens as they are the second leading cause of healthcare-associated infections.³

Dalbavancin (DAL) is a novel lipoglycopeptide recently approved for acute bacterial skin and skin structure infections (ABSSSI) by Food and Drug Administration and European Medicines Agency, thanks to its unique pharmacokinetics/pharmacodynamics profile. DAL presents an excellent skin and other peripheral compartment penetration achieving good DAL levels above the minimal inhibitory concentration (MICs)  for the Gram-positive pathogens involved. Its prolonged half-life (^8.5 days) allowed even weekly administration offering a more convenient dosing schedule especially for settings where outpatient parenteral antimicrobial therapy (OPAT) is not available like ours.⁴

Unfortunately, the new antibiotics have been approved for very limited indications. Off-label indications⁵ are being widely use in daily practice for these drugs, guided in the best scenarios by antibiotic stewardship experts.

Data on the clinical uses, efficacy and safety of these new antimicrobial agents against Gram-positive microorganisms in real life are scarce, thus here we sought to describe our clinical experience.

Methods

Design settings, targeted antimicrobials and participants

An observational prospective study in a tertiary university hospital in south Spain was conducted. All patients receiving at least one dose of DAL from June 2016 to September 2017 were included regardless age or admission ward.

The Strengthening the Reporting of Observational Studies in Epidemiology guideline was followed (https://www.strobe-statement.org).

Variables, data collection and management

Patient demographics, prescribing department, infection type, pathogen(s) and susceptibility, antimicrobial treatment including: drug, dose, route of administration, length of use, reason for switching to the targeted antimicrobial, adverse events (AE) and clinical outcome were collected by a hospital pharmacist trained in infectious diseases. All patient data were anonymised prior to analysis and entered into a secure electronic case report form.

Once the follow-up period expired, 3 months after the targeted antimicrobial was introduced, clinical outcome was assessed considering it successful when patients completed treatment course without change or addition of antibiotic therapy, and with no additional antibiotics commenced within 48 hours of discontinuation of the targeted antimicrobial therapy.

Standardised definitions for AEs, known as the Common Terminology Criteria for Adverse Events (CTCAE), were applied.

Statistical analysis

Discrete variables were expressed as counts (percentage) and continuous variables as medians and IQRs using the statistical software package SPSS (V.18.0, IBM).

Ethics

Informed consent was waived by the institutional research ethics board due to the merely descriptive nature of the study where data generated for the analysis are not linked to individuals.

Results

Twenty-two consecutive adult patients treated with DAL were included. Demographics, microbiology, therapy characteristics, AEs and clinical outcomes are described in table 1.

Table 1.

Demographics, microbiology, therapy characteristics, adverse events and clinical outcomes

	Dalbavancin n=22
Age, median (IQR)	70 (46–85)
Male	13 (59)
Department
ICU	0
Medical	15 (68)
Surgical	7 (32)
Infection type
Osteoarticular infections	10 (46)
Implanted prosthetic device infection	4/10 (40)
Osteomyelitis	6/10 (60)
Acute bacterial skin and skin structure infections	3 (14)
Endocarditis	3 (14)
Bloodstream infections	5 (23)
Prosthetic graft infection	1 (5)
Microbiology (one patient can hold more than one)
Microbiology samples available	20 (91)
Staphylococcus aureus	12 (55)
Methicillin-resistant Staphylococcus aureus (MRSA)	7/12 (58)
Coagulase-negative staphylococci (CNS)	6 (27)
Methicillin-resistant CNS	4/6 (67)
Enterococcus faecalis	1 (5)
Enterococcus faecium	1 (5)
Reason for use (one patient can hold more than one)
Discharge from hospital	11/17* (65)
Resistant pathogens involved	5 (23)
Difficult vascular access/poor oral adherence	2 (9)
Previous drug-induced toxicity	3 (14)
Previous drug-drug interactions	1 (5)
Off-label use	19 (86)
Treatment
DAL administered following hospitalisation	17 (77.3)
Previous antimicrobials for actual episode	22 (100)
DAL initial—weekly doses
1000 mg–500 mg	14 (63.3)
750 mg–350 mg (renal dose adjustment)	1 (4.5)
1500 mg–1500 mg	1 (4.5)
1500 mg—single dose	6 (27.3)
DAL number of doses†
2 doses	8 (36.4)
Single dose	7 (31.8)
≥5 doses	6 (27.3)
Adverse events
Infusion site reaction	1 (4.5)
Others	0
Outcome
Success treatment	20/21 (95)‡

Except where otherwise specified, data represent numbers (%) of patients.

*Seventeen of 22 patients were hospitalised when dalbavancin was indicated.

† Patient who received 62 doses was excluded 

‡Twenty-one patients have completed treatment.

DAL, dalbavancin; ICU, intensive care unit.

Thirteen (59%) patients were male with a median age of 70 years (IQR: 46–85) mostly from medical departments (68%). Only 3 (14%) patients received DAL for ABSSSI, labelled indication. Principal indications were 10 (46%) cases of osteoarticular infections, mainly osteomyelitis 6/10 (60%), followed by bloodstream infections in 5 (23%) patients and 3 (14%) endocarditis.

In one patient, DAL was administered on a weekly haemodialysis regimen as long-term antibiotic suppressive therapy due to a prosthetic graft Enterococcus faecium infection after abdominal aortic aneurysm. This patient who failed multiple previous antimicrobial regimens and also presented poor vascular access at the end of study period had received >62 doses of DAL.

In 91% of the patients, DAL was used as targeted therapy. The most common isolated pathogens were Staphylococcus aureus (55%) and coagulase-negative staphylococci (27%). In both cases, methicillin-resistant microorganisms were predominant: 58% methicillin-resistant S. aureus and 67% methicillin-resistant coagulase-negative staphylococci.

In all cases, DAL was used in adult patients who have tried and/or failed prior antibiotic therapy, and the most frequent reasons for the indication of this new drug were the promptly hospital discharge in 65% of the cases (17 out of 22 were hospitalised when DAL was indicated), treatment of infections with resistant organisms involving limited treatment options, 23%, and previous drug-induced toxicity in 14%.

Doses regimen varied according to indication and described in table 1. No AEs were observed except in one patient where an infusion site reaction occurred. This AE, despite it was considered as a CTCAE grade 1–2, discontinuation of DAL was decided. The patient on suppressive therapy presented good tolerance to DAL and no AE was reported.

Discussion

In the last years a significant number of promising novel antimicrobial drugs have been licensed, mostly against methicillin-resistant Staphylococcus aureus (MRSA) and other antibiotic-resistant Gram-positive pathogens.

DAL presents clear advantages due to its microbiological activity together with its pharmacokinetics/pharmacodynamics profile allowing unique dosing regimens although results of their pivotal studies may not be sufficient for clinical decisions in real life^{6 7} as they are not consistent with clinical management.

Limited label indications and higher cost make selecting the optimal drug, dose, duration and route of administration even more challenging the practice of stewardship for prescribers.

In our clinical practice, the majority of these drugs (20/23: 87%) were used under off-label indications in patients who had tried and/or failed other therapies all of which prescribed under the umbrella of the antimicrobial stewardship team.

This study was conducted in a university hospital with an intense orthopaedics activity with no outpatient parenteral antibiotic therapy programme available. This may explain the wide use of DAL where 46% was administered for the treatment of osteoarticular infections and in 65% its administration was justified for an earlier hospital discharge.

On the other hand, rising rates of multidrug-resistant organisms are a real challenge to treat for clinicians. In our cohort, a rate of 58% and 67% of MRSA and methicillin-resistant coagulase negative staphylococci was observed.

The reduction in length of hospital stay presents obvious benefits in settings where OPAT programmes are not available. In terms of cost, Bouza et al ⁸ estimated a potential saving of €3064 per Spanish patient by prescribing DAL. Moreover, they concluded that this result is probably underestimated due to some not included direct and indirect costs. This cost analysis was based on a 14-day antibiotic course.

For osteoarticular infections and even more if long-term suppressive therapy is considered, patients have to receive prolonged targeted therapy. As reported, we currently have a patient on DAL for over 60 weeks who presented microbiological failure and AEs to multiple previous intravenous and oral previous antimicrobials.

In terms of safety, in addition to the avoidance of prolonged central line catheters, reference standard therapy for these types of infections includes vancomycin, teicoplanin, daptomycin, linezolid and fluoroquinolones which also have limitations due to toxicity, drug-drug interactions profile and compliance.^9–11 In our cohort, DAL was chosen to avoid those scenarios in 4/22 (18%) of the cases.

Total AE rate was lower than described in literature, where surprisingly, despite the prolonged exposure to it in some of our patients, incidence was 4.5%, and it was due to a self-limiting infusion site reaction. This incidence observed is far inferior to the 32.8% and 20.1% reported by Boucher et al ¹² and Dunne et al,¹³ respectively.

Successful outcome was observed in mostly all patients (20/22: 95%). However, we should consider these data with caution due to the important limitations of this study such as the number of patients included. In addition, illness severity and underlying diseases were not taken into account for the analyses.

Conclusion

The majority of DAL prescriptions were used under off-label indications. Thus, further evidence beyond labelled indications is urgently needed. Despite the limitations, in our clinical practice, the use of these new antimicrobials under the multidisciplinary antimicrobial stewardship team supervision appears to be a promising, safe and effective option for adult patients who have tried and/or failed other therapies due to multidrug-resistant Gram-positive organisms and/or may offer added safety and potential cost reductions due to avoidance of central line catheters and earlier hospital discharge.