Lipopeptides

The lipopeptide class has one systemic member, daptomycin, a cyclic lipopeptide with rapid concentration-dependent bactericidal activity against Gram-positive bacteria including MRSA, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. It is a principal agent for MRSA bacteraemia, right-sided endocarditis and bone and device-related infection.

Mechanism. In the presence of calcium, daptomycin inserts into the cytoplasmic membrane of Gram-positive cells, forms oligomers, depolarises the membrane and halts DNA, RNA and protein synthesis. It is inactivated by pulmonary surfactant, so it is ineffective in pneumonia.

Pharmacokinetics. Not absorbed orally. Highly protein-bound (about 92 percent), half-life about 8 hours, eliminated mainly by the kidney. Poor penetration into lung and CSF (although higher doses are used in CNS infection), good penetration into skin, bone (variable) and vegetations.

Spectrum. MRSA, MSSA, streptococci, enterococci (including E. faecium and VRE with higher doses), Corynebacterium. No activity against Gram-negatives.

Resistance. Mutations in membrane genes (mprF, yycG, dltABCD) cause non-susceptibility, often arising on treatment with low doses and cross-resistance with vancomycin-intermediate strains.

Daptomycin is the single systemic agent. Compared with vancomycin it has more rapid killing, no level monitoring, and no nephrotoxicity, but needs creatine kinase monitoring and cannot be used for pneumonia. Compared with linezolid it is bactericidal and parenteral only.

Adult regimens (normal renal function; dose by actual body weight, once daily).

• Skin and soft tissue infection: 4 mg/kg IV every 24 hours for 7 to 14 days.
• S. aureus bacteraemia and right-sided endocarditis: 6 mg/kg every 24 hours; many specialists use 8 to 10 mg/kg for bacteraemia, osteomyelitis and prosthetic infection.
• Vancomycin-resistant enterococcal infection: 10 to 12 mg/kg every 24 hours, often combined with a beta-lactam (ampicillin, ceftaroline) in bacteraemia or endocarditis.
• Persistent MRSA bacteraemia: daptomycin 8 to 10 mg/kg with ceftaroline or fosfomycin, under specialist advice.
• Administration: infuse over 30 minutes, or give as a 2-minute IV push.
• Children: weight-based and age-dependent doses (higher in younger children); specialist advice.

Selection. Alternative to vancomycin where vancomycin fails, MIC is 1.5 mg/L or more, renal risk is high, or the patient has VRE. Not for pneumonia (including septic pulmonary emboli with consolidation) or meningitis as sole therapy. Cover Gram-negatives and anaerobes separately where relevant.

Contraindications. Hypersensitivity. Not used for pneumonia.

Serious effects.

• Myopathy and rhabdomyolysis: stop if creatine kinase exceeds 5 times the upper limit with symptoms, or 10 times without symptoms.
• Eosinophilic pneumonia (fever, dyspnoea, infiltrates after 2 to 4 weeks; treated by stopping).
• Peripheral neuropathy; raised transaminases; C. difficile infection; DRESS; tubulointerstitial nephritis (rare).

Interactions. HMG-CoA reductase inhibitors (statins) increase the risk of myopathy and are held during therapy; interference with some prothrombin time assays. No CYP metabolism.

Monitoring. Creatine kinase at baseline and weekly (twice weekly in renal impairment or statin co-treatment); renal function; weekly check of symptoms of myalgia and cough; echocardiography and repeat cultures in bacteraemia.

Special groups.

• Renal impairment: creatinine clearance under 30 mL/min or dialysis, the same dose every 48 hours; haemodialysis patients receive it after dialysis.
• Obesity: dose by actual body weight, with caution at higher exposure.
• Hepatic impairment: no adjustment in mild to moderate disease.
• Pregnancy and breastfeeding: limited data; used when no alternative exists.
• Older adults: monitor for myopathy and renal function.