Daptomycin - Drug Monograph

Introduction

Daptomycin is a cyclic lipopeptide antibiotic with potent bactericidal activity against Gram-positive organisms. First approved by the FDA in 2003, it represents an important therapeutic option for treating serious infections caused by resistant Gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).

Mechanism of Action

Daptomycin exerts its bactericidal effect through a unique calcium-dependent mechanism. The drug inserts its lipid tail into the bacterial cell membrane, causing rapid depolarization of the membrane potential. This disruption of the electrical gradient across the membrane leads to inhibition of protein, DNA, and RNA synthesis, ultimately causing bacterial cell death without lysis. The calcium requirement is essential for daptomycin's activity, as it facilitates the conformational change needed for membrane insertion.

Indications

FDA-approved indications include:

• Complicated skin and skin structure infections (cSSSI)
• Staphylococcus aureus bloodstream infections (bacteremia)
• Right-sided infective endocarditis caused by S. aureus

Off-label uses (supported by clinical evidence):

• Vancomycin-resistant enterococcal infections
• Osteomyelitis
• Prosthetic joint infections
• Persistent MRSA bacteremia

Dosage and Administration

• cSSSI: 4 mg/kg IV once daily
• Bacteremia/Endocarditis: 6 mg/kg IV once daily

• Administer by IV infusion over 30 minutes
• Dosage adjustment required for renal impairment:

- CrCl <30 mL/min: 6 mg/kg every 48 hours - Hemodialysis: Administer after dialysis session

• Hepatic impairment: No dosage adjustment required
• Elderly: Adjust based on renal function
• Pediatrics: Safety and efficacy not established under 18 years

Pharmacokinetics

Contraindications

• Hypersensitivity to daptomycin or any component of the formulation
• Concomitant use with HMG-CoA reductase inhibitors (statins) due to increased risk of myopathy

Warnings and Precautions

• Myopathy and rhabdomyolysis reported
• CPK levels should be monitored weekly; more frequently in patients with renal impairment

• Eosinophilic pneumonia reported (fever, dyspnea, diffuse pulmonary infiltrates)
• Clostridium difficile-associated diarrhea
• Development of drug-resistant bacteria
• Peripheral neuropathy reported

Drug Interactions

• HMG-CoA reductase inhibitors: Increased risk of myopathy/rhabdomyolysis (contraindicated)
• Tobramycin: Minor increase in daptomycin AUC
• Warfarin: Possible potentiation of anticoagulant effect (monitor INR)

Adverse Effects

• Constipation
• Nausea
• Headache
• Insomnia
• Injection site reactions
• Elevated CPK

• Rhabdomyolysis (<1%)
• Eosinophilic pneumonia (<0.5%)
• Peripheral neuropathy
• Clostridium difficile-associated diarrhea
• Hypersensitivity reactions

Monitoring Parameters

• CPK levels
• Renal function (BUN, creatinine)
• Signs/symptoms of infection
• Culture and sensitivity results

• CPK weekly (more frequently if elevated or renal impairment)
• Renal function regularly
• Signs of myopathy (muscle pain, weakness, dark urine)
• Respiratory status (for eosinophilic pneumonia)
• Clinical response to therapy

• Resolution of infection
• Adverse event resolution

Patient Education

• Report any muscle pain, tenderness, weakness, or dark urine immediately
• Complete full course of therapy unless directed otherwise
• Inform all healthcare providers about daptomycin use
• Notify physician if diarrhea develops during or after treatment
• Understand that regular blood tests are necessary to monitor for side effects
• Do not use statin medications while receiving daptomycin
• Report any new respiratory symptoms (shortness of breath, cough, fever)

References

1. FDA Prescribing Information: Cubicin (daptomycin) [2023] 2. Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathogens. Clin Infect Dis. 2004;38(7):994-1000. 3. Arbeit RD, Maki D, Tally FP, et al. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis. 2004;38(12):1673-1681. 4. Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355(7):653-665. 5. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52(3):e18-e55. 6. Cubicin® [package insert]. Lexington, MA: Cubist Pharmaceuticals; 2023. 7. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing. CLSI supplement M100. 33rd ed. Wayne, PA: CLSI; 2023.