Dalbavancin two dose regimen for the treatment of prosthetic joint infections: new possible options for difficult to treat infectious diseases

Design

Observational, retrospective, case-control pilot study

N= 67

Objective

To evaluate the efficacy and tolerability of dalbavancin two-dose regimen compared to the standard of care for the management of severe orthopedic infections

Study Groups

Dalbavancin (n= 21)

Standard of care (n= 46)

Inclusion Criteria

Patients with severe orthopedic infections

Exclusion Criteria

Incomplete patient chart

Methods

Retrospective chart review captured pertinent patient data, including demographics, laboratory findings, computed tomography (CT) scans, and microbiological data in patients with severe orthopedic infections. Patients were then divided based upon treatment with dalvavancin (1500 mg twice with a 3-week interval) or drug combinations considered standard of care. Patients from both groups were matched based on age, gender, infection site, and microbiological isolate.

Duration

Intervention: 3 weeks with dalbavancin

Follow-up: 3 months

Outcome Measures

Treatment efficacy on clinical cure or infection stabilization, hospital length of stay (LOS), surgical intervention (prosthetic replacement or debridement), and toxicity

Baseline Characteristics

Dalbavancin (n= 21)

Standard of care (n= 46)

Age, years

Male

Infection site

Hip prosthesis

Femoral osteosynthesis

Stabilizzazione vertebrale

Shoulder prosthesis

13 (61.9%)

3 (14.3%)

3 (14.3%)

2 (9.5%)

29 (63%)

6 (13.1%)

5 (10.8%)

6 (13.1%)

Identified microbiological strains

MSSA

MRSA

Staphylococcus hominis

10 (47.6%)

8 (38.1%)

3 (14.3%)

24 (52.1%)

16 (34.8%)

6 (13.1%)

Treatment

Trimethoprim/sulfamethoxazole

Ciprofloxacin + rifampin

Daptomycin

Doxycycline

Linezolid

Linezolid + rifampin

-

-

-

-

-

-

-

10 (21.7%)

9 (19.5%)

10 (21.7%)

3 (6.5%)

4 (8.7%)

6 (13%)

MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus

Results

Endpoint

Dalbavancin (n= 21)

Standard of care (n= 46)

p-value

Clinical infection outcomes

Cure

Stabilization

Treatment failure

17 (81%)

3 (14.3%)

1 (4.7%)

38 (82.6%)

7 (15.2%)

1 (2.2%)

0.87

0.92

0.56

Hospital LOS, days

Surgical intervention

Toxicity

Adverse Events

Serious Adverse Events: All serious adverse events occurred in the standard of care group, with 8 patients experiencing the following: anemia (1/8), intense photophobia (1/8), seizures (1/8), rhabdomyolysis (2/8), and severe thrombocytopenia (3/8).

Percentage that Discontinued due to Adverse Events: Patients in the standard of care group with treatment-emergent adverse events were switched to linezolid (3/8), daptomycin (2/8), and dalbavancin (3/8). 

Study Author Conclusions

Although outcome results were similar compared to other antibiotics administered, dalbavancin was useful in both reducing hospital stay and in terms of toxicity, proving to be one of the best therapeutic options against hard-to-treat due to Gram-positive bacteria.

InpharmD Researcher Critique

Study limitations include a small sample size and retrospective nature. Dalbavancin use was shown to be as efficacious as standard treatment regimens, with no adverse effects reported. Due to some patients having prostheses, these results indicate dalbavancin may be an appropriate option in the setting of prosthetic joint infections.

Dalbavancin for treating prosthetic joint infections caused by Gram-positive bacteria: A proposal for a low dose strategy. A retrospective cohort study

Design

Retrospective cohort study

N=16

Objective

To assess the clinical efficacy and tolerability of dalbavancin (DAL) when utilized to treat prosthetic joint infection (PJI)

Study Groups

All patients (N= 16)

Inclusion Criteria

Adults diagnosed with PJI and treated with DAL 

Exclusion Criteria

Not explicitly stated

Methods

All patients diagnosed with PJI and treated with DAL alone or in combination with other drugs were retrospectively evaluated. Dalbavancin susceptibility of every isolate was studied following Clinical and Laboratory Standards Institute (CLSI) criteria. Patients were appropriately informed about using DAL as an off-label medication for PJI, its potential toxicity and the reasons for choosing DAL in each particular case. Informed consent was obtained from all patients included. A cost-analysis was performed following the DALBUSE study methodology. One year of follow-up without clinical relapse was required after DAL was withdrawn to consider PJI to be cured.

Duration

June 1st 2016 to May 1st 2018

Outcome Measures

Baseline Characteristics

All patients (N= 16)

Age, years (IQR)

Male

Underlying diseases

Diabetes mellitus

Cardiovascular disease

Respiratory tract disease

Neurological disorder

Immunosuppressive therapy

Solid organ transplantation

Hematological malignancy

Chronic renal failure

Psiquiatric disorders

Oral anticoagulation

2 (12.5%)

4 (25%)

1 (6.2%)

4 (25%)

2 (12.5%)

1 (6.2%)

1 (6.2%)

3 (18.7%)

2 (12.5%)

4 (25%)

Age-adjusted Charlson Comorbidity Index, (IQR)

Surgical approach

No surgery

DAIR

One stage

Two stage

Girdlestone

2 (12.5%)

2 (13.3%)

0 (0%)

8 (53.3%)

2 (13.3%) 

Isolated microorganisms

Coagulase-negative staphylococci

MRSA

E. faecium

E. faecalis

7 (43.7%)

4 (25%)

4 (25%)

1 (6.25%)

DAL utilized as Monotherapy 

11 (68.7%)

Received Low Dose Bi-weekly Dalbavancin (LDBD)*

9 (56%)

DAIR= Debridement, Antibiotics, and Implant Retention; IQR= interquartile range; HIV= human immunodeficiency virus; MRSA= methicillin-resistant Staphylococcus aureus

*LDBD Regimen: 1.5 g of DAL as a loading dose, 0.5 g at day seven, then 0.5 g every two weeks for two months in total hip arthroplasty infection and three months in total knee arthroplasty infection 

Results

After concluding dalbavancin (DAL) therapy, excluding patients who died or experienced clinical failure, the remaining patients were followed for a median of 503 days (interquartile range: 434.5 to 567 days).

Excluding one patient who died of an unrelated cause at three months of follow-up, 12 patients (80%) showed no clinical, pathological, biochemical, microbiological, and/or gammagraphic signs of infection.

Two different strains of previously identified microorganisms were found in different tissue samples from two patients at the time of revision surgery, neither of whom presented with clinical symptoms suggestive of persistent infection or polymorphonuclear infiltration in the pathological examination.

None of the identified strains showed non-susceptibility to DAL according to the CLSI criteria.

A total of 571 days of hospitalization were avoided by using DAL as an alternative to daptomycin, which requires prolonged. hospitalization for daily intravenous administration.

Cost analysis estimated a total cost reduction of US$ 264,769. 

Adverse Events

Side effects attributable to medication included one case of mild skin macular rash and one case of mild transient leukopenia.

Study Author Conclusions

To our knowledge, this is the largest single center report on the use of DAL for PJI. Currently, no standard recommendation regarding dosage and duration of treatment exists. Our experience shows that DAL administration for treating Gram-positive PJI allows earlier discharge, reducing hospital stay, and seems to be safe, effective and cost saving. Besides, our study suggests that DAL administration every two weeks (the LDBD regimen) seems to be an effective dosing scheme. Our preliminary results and the true role of DAL in the treatment of PJI should ideally be confirmed by future studies.

InpharmD Researcher Critique

Despite findings suggesting DAL may potentially be an effective treatment in PJI management, the small sample size and single-center retrospective design of the study limit the generalizability of the results. Additionally, varying presentations of patients along with some receiving combo therapy may potentially introduce confounding factors that may have affected the observed outcomes. 

Dalbavancin treatment for prosthetic joint infections in real-life: a national cohort study and literature review

Design

Retrospective cohort study

N= 17

Objective

To evaluate the clinical efficacy of dalbavancin for prosthetic joint infection (PJI) treatment 

Study Groups

All patients (N= 17)

Inclusion Criteria

≥18 years old with PJI treated with at least one dose of dalbavancin

Exclusion Criteria

Not disclosed

Methods

Data was retrospectively collected from physicians via questionnaire regarding the clinical and microbiological characteristics of PIJ, type of PIJ, reason for dalbavancin use, dose and duration of dalbavancin treatment, adverse reactions, and outcome at last visit for each patient. Clinical cure of PIJ was defined as an absence of clinical signs of infection at last visit; clinical failure was defined as persistence or reappearance of infection, switch to suppressive antibiotic treatment, and/or death from infection.

Duration

June 1, 2017 to January 1, 2019

Outcome Measures

Baseline Characteristics

All patients (N= 17)

Age, years (IQR)

Male/Female Ratio

Length of hospitalization, days (IQR)

Comorbidities

Heart failure

Chronic renal failure

Liver failure

Neurological disease

Immunosuppression

Cancer chemotherapy

Immunosuppressive treatment

Diabetes mellitus

5 (29.4%)

4 (23.5%)

2 (11.8%)

2 (11.8%)

6 (35.3%)

1 (5.9%)

1 (5.9%)

4 (23.5%) 

Renal clearance, mL/min (IQR)

87.5 (56.9-104.4)

Site of prosthesis

Hip

Knee

Shoulder

Ankle

Elbow

8 (47.1%)

6 (35.3%)

1 (5.9%)

1 (5.9%)

1 (5.9%)

Positive blood cultures

Previous antibiotic treatments

Duration, days (IQR)

16 (94.1%)

34.5 (31.3-46.8)

Documented infections

Polymicrobial

16 (94.1%)

5 (31.3%)

Microbiology analysis

Staphylococcus spp.

Staphylococcus aureus

Methicillin-resistant S. aureus

Coagulase-negative staphylococci

Staphylococcus epidermidis

Methicillin-resistant S. epidermidis

Enterococcus faecalis

16 (100%)

10 (62.5%)

1 (6.3%)

10 (62.5%)

7 (43.8%)

4 (25%)

1 (6.3%)

Clinical failure of previous antibiotic treatment

1 (5.9%)

Adverse event of previous antibiotic treatment

8 (47.1%)

Bacteria resistant to previous antibiotic treatment

2 (11.8%)

Dalbavancin dosing regimen

1 dose, 1.5 g

2 doses, 7-day interval, 1.5 g × 2

2 doses, 14-day interval, 1.5 g, 1 g

3 doses, 7-day interval, 1.5 g × 3

7 doses, 7-day interval, 1 g × 1, 0.5 g × 6

10 doses, 14-day interval, 1 g × 1, 0.5 g × N

Suppressive, 21-day interval

1.5 g × 1, 0.5 g × N

1.5 g × 3, 0.5 g × N

3 (17.6%)

8 (47.1%)

1 (5.9%) 

1 (5.9%)

1 (5.9%)

1 (5.9%)

2 (11.8%)

1 (5.9%)

1 (5.9%)

IQR, interquartile range; N, number of subsequent doses

Results

Following dalbavancin treatment, the median duration of follow-up was 299 days (IQR 97-476 days). Among the 17 patients treated for PJI with dalbavancin, 8 patients achieved clinical cure, of which 6 were treated with dalbavancin monotherapy. 

Clinical failure was seen in 9 patients, 2 of which died due to PJI infection, 4 patients experienced infection recurrence, and 3 patients received antibiotic suppressive treatment. 

Adverse Events

See Results

Study Author Conclusions

Our study and literature data suggest that use of dalbavancin in PJI could be considered, even as salvage therapy. Dalbavancin appears to be a safe and easy treatment for patients with staphylococcal PJIs.

InpharmD Researcher Critique

Study limitations include small sample size, retrospective physician questionnaire data collection, and high variability in dalbavancin administration regimens and patient dosages making it difficult to compare outcomes. Patients received dalbavancin commonly as a refractory treatment following initial antibiotic treatment, and several patients had polymicrobial infections, potentially confounding clinical outcomes. Overall, study results show the potential use of dalbavancin in PJI treatment but further analysis of treatment efficacy with a standardized dosing regimen is needed. 

Ototoxicity associated with extended dalbavancin treatment for a shoulder prosthetic joint infection

Design

Case presentation

A 55-year-old white man, a former smoker with a history of hypertension (on enalapril 10 mg), pituitary adenoma, and tinnitus (without hearing loss), presented a complex case of prosthetic joint infection (PJI) following a total left shoulder arthroplasty in October 2019 for osteoarthritis. His postoperative course involved multiple surgeries due to complications. Initially, a subscapular tendon rupture required a reoperation 2 months post-surgery, where Cutibacterium acnes was identified and treated with a 3-month course of oral amoxicillin.

Due to persistent shoulder pain, a two-stage revision surgery was performed 7 months later, during which C. acnes was again cultured, and clindamycin was prescribed. Following a 4-week antibiotic-free interval, a reverse total shoulder prosthesis was implanted, but cultures once again grew C. acnes, leading to another course of amoxicillin. A subsequent Debridement, Antibiotics, and Implant Retention (DAIR) procedure was done in September 2021, which cultured C. acnes and two strains of Staphylococcus epidermidis, resistant to ciprofloxacin and clindamycin, but all susceptible to vancomycin. The patient was treated with intravenous dalbavancin (cumulative dose of 2500 mg over four weeks).

During follow-up, the patient reported a gradual decrease in hearing, with audiometry revealing moderate bilateral sensorineural hearing loss. Dalbavancin was discontinued, and no other ototoxic drugs were identified. Despite this, hearing loss persisted, and hearing aids were prescribed. Two months after discontinuation of antibiotics, the patient’s shoulder pain had improved.

Study Author Conclusions

This case report highlights the importance of exercising caution when administering dalbavancin beyond approved dosing guidelines and emphasizes the need for vigilance regarding the potential for ototoxicity.