What is the treatment for adverse effects of daptomycin (Daptomycin)?

From the Guidelines

Daptomycin-induced eosinophilic pneumonia (AEP) requires immediate discontinuation of daptomycin as the primary treatment. Once daptomycin is stopped, corticosteroid therapy is typically initiated, with prednisone 40-60 mg daily (or equivalent) being the standard approach, as seen in general clinical practice guidelines 1. This steroid regimen is usually continued for 2-4 weeks with a gradual taper based on clinical response. Supportive care including supplemental oxygen should be provided as needed based on the severity of respiratory symptoms. Most patients show significant improvement within 1-2 weeks after daptomycin discontinuation and steroid initiation. Alternative antibiotics should be selected to replace daptomycin for the underlying infection, avoiding lipopeptide antibiotics due to potential cross-reactivity. Rechallenge with daptomycin is contraindicated as recurrence of AEP can be more severe. The mechanism of daptomycin-induced AEP involves an immune-mediated hypersensitivity reaction where daptomycin or its metabolites act as haptens, triggering eosinophil recruitment to the lungs and subsequent inflammation. Early recognition is crucial as the condition can progress to respiratory failure if not promptly addressed.

Some studies suggest that high-dose daptomycin (10 mg/kg/day) may be effective in certain cases, but this is not directly applicable to AEP treatment 1. The use of daptomycin in combination with other agents has been explored, but again, this is more relevant to its use in treating infections rather than AEP specifically 1. The primary concern in managing AEP is the immediate cessation of daptomycin and the initiation of supportive and corticosteroid therapy to mitigate the immune-mediated response and prevent further complications.

Given the potential severity of AEP and the importance of prompt intervention, the approach to treatment should prioritize discontinuation of the offending agent and initiation of supportive care, with a focus on minimizing morbidity, mortality, and impact on quality of life. This approach is consistent with general principles of managing drug-induced hypersensitivity reactions and is supported by the available evidence, although direct studies on AEP are limited 1.

From the FDA Drug Label

The most common adverse reactions that occurred in ≥5% of adult patients with S aureus bacteremia/endocarditis (receiving 6 mg/kg daptomycin for injection) are displayed in Table 7.

Table 7: Incidence of Adverse Reactions that Occurred in ≥5% of Adult Patients in the Daptomycin for Injection Treatment Group and ≥ the Comparator Treatment Group in the S aureus Bacteremia/Endocarditis Trial Adverse Reaction* Adult Patients n (%) Daptomycin for Injection 6 mg/kg (N=120) Comparator† (N=116) Infections and infestations Sepsis NOS 6 (5%) 3 (3%) Bacteremia 6 (5%) 0 (0%) Gastrointestinal disorders Abdominal pain NOS 7 (6%) 4 (3%) General disorders and administration site conditions Chest pain 8 (7%) 7 (6%) Edema NOS 8 (7%) 5 (4%) Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain 10 (8%) 2 (2%) Skin and subcutaneous tissue disorders Pruritus 7 (6%) 6 (5%) Sweating increased 6 (5%) 0 (0%) Psychiatric disorders Insomnia 11 (9%) 8 (7%) Investigations Blood creatine phosphokinase increased 8 (7%) 1 (1%) Vascular disorders Hypertension NOS 7 (6%) 3 (3%)

The treatment of daptomycin adverse events (AEs) includes:

• Monitoring for signs of musculoskeletal toxicity, such as muscle pain or weakness, and elevated creatine phosphokinase (CPK) levels 2
• Managing gastrointestinal disorders, such as abdominal pain and diarrhea
• Addressing skin and subcutaneous tissue disorders, such as pruritus and sweating
• Monitoring for psychiatric disorders, such as insomnia
• Managing vascular disorders, such as hypertension In case of serious adverse events, such as sepsis or bacteremia, discontinuation of daptomycin may be necessary 2.

From the Research

Treatment of Daptomycin-Associated Myopathy

• Daptomycin-associated myopathy has been identified in 2%-14% of patients, and rhabdomyolysis is a known adverse effect 3
• Risk factors for daptomycin-associated myopathy include deep abscess treatment, antihistamine coadministration, and statin coadministration 3
• Obesity and statin coadministration are independent risk factors for rhabdomyolysis 3
• Twice-weekly creatine phosphokinase (CPK) monitoring and consideration of withholding statins are recommended during coadministration of daptomycin and statins 3

Muscle Pain Associated with Daptomycin

• Muscle pain without pronounced CPK elevation can occur in patients receiving daptomycin 4
• Daptomycin can cause significant myopathy with or without pronounced CPK elevation 4
• Clinicians should recognize that significant myopathy with daptomycin can occur without pronounced CPK elevation 4

Factors Affecting CPK Elevation

• Baseline CPK value and concomitant use of hydrophobic statins are independent factors affecting CPK elevation 5
• Concomitant use of hydrophilic statins is not an independent factor affecting CPK elevation 5
• Patients who receive hydrophobic statins and have high baseline CPK values are at high risk for CPK elevation 5

Clinical Pharmacokinetics of Daptomycin

• Daptomycin is not absorbed from the gastrointestinal tract and needs to be administered parenterally 6
• The distribution of daptomycin is limited due to its negative charge at physiological pH and its high binding to plasma proteins 6
• The elimination of daptomycin is mainly renal, with about 50% of the dose excreted unchanged in the urine 6
• Therapeutic drug monitoring of daptomycin may be of interest for certain patients, such as intensive care unit patients, patients with renal or hepatic insufficiency, dialysis patients, obese patients, or children 6

Efficacy and Safety of Standard- and High-Dose Daptomycin

• Standard doses of daptomycin at 4 and 6 mg/kg are used for the treatment of skin and soft tissue infections and bacteraemia, respectively 7
• High doses of daptomycin are recommended for complicated infections by Gram-positive organisms 7
• The incidence of CPK elevation is significantly lower in the standard-dose group than in the high-dose group 7
• Standard-dose daptomycin is associated with significantly lower treatment success than high-dose daptomycin in patients with complicated bacteraemia/infective endocarditis 7