Daptomycin

Daptomycin is a novel lipopeptide antibiotic used in the treatment of certain infections caused by Gram-positive organisms. It is a naturally-occurring compound found in the soil saprotroph Streptomyces roseosporus. Its distinct mechanism of action means that it may be useful in treating infections caused by multi-resistant bacteria. It is marketed in the United States under the trade name Cubicin (Cubist Pharmaceuticals).

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History

The compound was originally discovered by researchers at Eli Lilly and Company in the 1980s, who designated the compound LY 146032.

The compound showed promise in Phase I/II clinical trials for the treatment of infections caused by Gram-positive organisms. However, high dose therapy was found to be associated with adverse effects on skeletal muscle, including myalgia and the potential for myositis, and Lilly ceased development. The rights to LY 146032 were subsequently acquired by Cubist Pharmaceuticals in 1997, which subsequently marketed the drug under the trade name CUBICIN following U.S. Food and Drug Administration (FDA) approval in November 2003. CUBICIN is marketed in the EU and several other countries by Novartis following its buying of Chiron Corporation, whom previously held those licences. Outside of the US, CUBICIN is available in Germany and the UK, with further launches expected in 2007.^[2][3]

Pharmacology

Daptomycin has a distinct mechanism of action, disrupting multiple aspects of bacterial cell membrane function. It appears to bind to the membrane and cause rapid depolarisation, resulting in a loss of membrane potential leading to inhibition of protein, DNA and RNA synthesis, which results in bacterial cell death.

The bactericidal activity of daptomycin is concentration-dependent. There is in vitro evidence of synergy with β-lactam antibiotics.

Microbiology

Daptomycin is active against Gram-positive bacteria only. It has proven in vitro activity against enterococci (including glycopeptide-resistant Enterococci (GRE)), staphylococci (including methicillin-resistant Staphylococcus aureus), streptococci and corynebacteria.

Clinical use

Indications

Daptomycin is approved in the United States for skin and skin structure infections caused by Gram-positive infections, Staphylococcus aureus bacteraemia and right-sided S. aureus endocarditis.

Efficacy

Daptomycin has been shown to be not inferior to standard therapies (nafcillin, oxacillin, flucloxacillin or vancomycin) in the treatment of bacteraemia and right-sided endocarditis caused by Staphylococcus aureus.^[4]

In Phase III clinical trials, limited data showed that daptomycin was associated with poor outcomes in patients with left-sided endocarditis. It is inactivated by pulmonary surfactants and is not indicated for the treatment of pneumonia. Daptomycin has not been studied in patients with prosthetic valve endocarditis or meningitis.^[5]

Dosage and presentation

In skin and soft tissue infections, 4 mg/kg daptomycin is given intravenously once daily. For S. aureus bacteraemia or right-sided endocarditis, the approved dose is 6 mg/kg given intravenously once daily.

The dose of daptomycin must be reduced in renal impairment. There is no information available on dosing in people less than 18 years of age.

Daptomycin is supplied as a sterile preservative-free pale yellow to light brown lyophilised 500 mg cake that must be reconstituted with 0.9% saline prior to use.

Adverse effects

Adverse drug reactions associated with daptomycin therapy include:^[6]

• Cardiovascular: hypotension (2.4%), hypertension (1.1%), edema, cardiac failure, supraventricular tachycardia
• Central nervous system: headache (5.4%), insomnia (4.5%), dizziness (2.2%), anxiety, confusion, vertigo, paraesthesia
• Dermatological: rash (4.3%), pruritus (2.8%), eczema
• Endocrine: hypokalaemia, hyperglycemia, hypomagnesemia, increased serum bicarbonate, other electrolyte disturbances
• Gastrointestinal: constipation (6.2%), nausea (5.8%), diarrhea (5.2%), vomiting (3.2%), dyspepsia (0.9%), abdominal pain, decreased appetite, stomatitis, flatulence
• Hematological: anemia (2.1%), leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased international normalised ratio (INR)
• Hepatic: abnormal liver function tests (3%) (including alkaline phosphatase and lactate dehydrogenase), jaundice
• Musculoskeletal: elevated creatine kinase (CK) levels (2.8–10.5%), limb pain (1.5%), arthralgia (0.9%), myalgia, muscle cramps, muscle weakness, osteomyelitis
• Renal: acute renal failure (2.2%)
• Respiratory: dyspnea (2.1%)
• Other: injection site reactions (5.8%), fever (1.9%), hypersensitivity

There are also reports of myopathy and rhabdomyolysis occurring in patients simultaneously taking statins but whether this is due entirely to the statin or whether daptomycin potentiates this effect is unknown. Due to the limited data available, the manufacturer recommends that statins be temporarily discontinued while the patient is receiving daptomycin therapy.

References