Daptomycin

Daptomycin is a cyclic lipopeptide with rapid concentration-dependent bactericidal activity against Gram-positive cocci. It is used for MRSA bacteraemia, right-sided endocarditis, complicated skin infection and vancomycin-resistant enterococcal infection. It is inactivated by pulmonary surfactant and is not used for pneumonia.

Classification. Cyclic lipopeptide.

Mechanism. Inserts into the bacterial membrane in a calcium-dependent manner, causes ion leakage and depolarisation, and halts DNA, RNA and protein synthesis.

Spectrum. MRSA, MSSA, coagulase-negative staphylococci, streptococci, Enterococcus faecalis and faecium (including vancomycin-resistant strains). Not active against Gram-negative bacilli.

Pharmacokinetics. IV only. Half-life about 8 hours. Protein binding about 92%. About 78% excreted unchanged in urine. Poor lung penetration; CSF penetration is low but used at high dose in specialist practice.

Dose by actual body weight. No loading dose.

Adults.

• Complicated skin and soft tissue infection: 4 mg/kg IV once daily for 7 to 14 days.
• Staphylococcus aureus bacteraemia and right-sided endocarditis: 6 mg/kg once daily is the labelled dose; 8 to 10 mg/kg is commonly used for bacteraemia, endocarditis, bone and joint infection.
• Duration at least 14 days for uncomplicated bacteraemia, 4 to 6 weeks for endocarditis and 6 weeks or longer for bone infection.
• Vancomycin-resistant Enterococcus faecium infection: 8 to 12 mg/kg once daily, often with a second agent such as ampicillin or fosfomycin, under specialist direction.
• Not for pneumonia.

Children 1 to 17 years.

• Skin infection, once daily: age 12 to 17 years 5 mg/kg; 7 to 11 years 7 mg/kg; 2 to 6 years 9 mg/kg; 1 to under 2 years 10 mg/kg.
• Bacteraemia, once daily: age 12 to 17 years 7 mg/kg; 7 to 11 years 9 mg/kg; 1 to 6 years 12 mg/kg.

Alternatives. Vancomycin, linezolid, teicoplanin, ceftaroline.

Contraindications. Hypersensitivity to daptomycin.

Adverse effects. Nausea, diarrhoea, constipation, headache, injection-site reaction, rash, raised creatine kinase. Serious: myopathy and rhabdomyolysis, eosinophilic pneumonia (cough, fever and hypoxia usually after 2 to 4 weeks), peripheral neuropathy, anaphylaxis, drug rash with eosinophilia, Clostridioides difficile infection, tubulointerstitial nephritis.

Interactions. Statins and fibrates increase myopathy risk (suspend statins where possible); some thromboplastin reagents give falsely prolonged PT and INR, so draw samples before the next dose.

Common prescribing errors. Using it for pneumonia, using 4 mg/kg for bacteraemia, no baseline and weekly creatine kinase, and not adjusting the interval in renal failure.

Special groups.

• Pregnancy and breastfeeding: limited data; use if needed.
• Older adults: adjust by kidney function.
• Kidney impairment: creatinine clearance under 30 mL/min, including haemodialysis and peritoneal dialysis, give the usual dose every 48 hours; give after dialysis on dialysis days.
• Liver impairment: no adjustment.
• Obesity: use actual body weight.

Preparation. Reconstitute each 350 or 500 mg vial with 0.9% sodium chloride only (never glucose); 50 mg/mL. Give by IV injection over 2 minutes or infusion over 30 minutes.

Baseline and monitoring.

• Baseline: creatine kinase, creatinine, weight, medication review (statins), cultures.
• During treatment: creatine kinase weekly (twice weekly if renal impairment, a statin or raised baseline); creatinine weekly; ask about muscle pain and respiratory symptoms.
• Stop if creatine kinase is over 5 times the upper limit of normal with symptoms or over 10 times without symptoms.

Stop rules. Stop for myopathy, eosinophilic pneumonia, severe skin reaction or anaphylaxis.

Referral and escalation. Infectious diseases for bacteraemia, endocarditis, bone infection, vancomycin-resistant enterococci and persistent positive cultures.