Daptomycin

Pronunciation: (DAP-toe-MYE-sin)
Class: Lipopeptide

Trade Names

Cubicin
- Injection, lyophilized powder for solution 500 mg

Pharmacology

Binds to bacterial membranes and causes a rapid depolarization of membrane potential, which inhibits protein, DNA, and RNA synthesis, resulting in bacterial cell death.

Pharmacokinetics

Absorption

Steady-state concentrations are achieved by the third daily dose. C _max ranges from 57.8 to 183.7 mcg/mL over a dose range of 4 to 12 mg/kg.

Distribution

Vd at steady state is approximately 0.1 L/kg. The mean serum protein binding is approximately 90% to 93%.

Metabolism

Site of metabolism has not been identified.

Elimination

Primarily excreted by the kidney (78%) and feces (5.7%). Half-life ranges from 7.7 to 8.3 over a dose range of 4 to 12 mg/kg.

Special Populations

Renal Function Impairment

Mean total plasma Cl was 9%, 22%, and 46% lower in patients with mild (CrCl 50 to 80 mL/min), moderate (CrCl 30 to less than 50 mL/min), and severe (CrCl less than 30 mL/min) renal impairment, respectively, compared with those with healthy renal function. Mean AUC, half-life, and Vd at steady state increased with decreasing renal function. Dosage adjustment is required in patients with severe renal impairment.

Hepatic Function Impairment

Pharmacokinetics were not altered in patients with moderate hepatic impairment and have not been evaluated in patients with severe hepatic impairment.

Elderly

Mean total Cl is reduced approximately 35% and AUC is increased approximately 58% in elderly patients compared with younger healthy subjects. No dosage adjustment is required in elderly patients with healthy renal function.

Children

Pharmacokinetics have not been established.

Gender

No clinically significant gender-related differences in pharmacokinetics have been observed. No dosage adjustment is needed based on gender.

Obesity

Plasma Cl was 15% and 23% lower and AUC increased by 30% and 31% in moderately obese patients and extremely obese patients, respectively, compared with nonobese controls. No dosage adjustment is needed.

Indications and Usage

Treatment of complicated skin and skin structure infections caused by susceptible strains of gram-positive microorganisms; treatment of Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis caused by methicillin-susceptible and methicillin-resistant isolates.

Unlabeled Uses

Treatment of vancomycin-resistant Enterococcus faecium .

Contraindications

Hypersensitivity to daptomycin.

Dosage and Administration

Complicated skin and skin structure infections
Adults

IV 4 mg/kg once every 24 h for 7 to 14 days.

S. aureus bloodstream infection
Adults

IV 6 mg/kg once every 24 h for a minimum of 2 to 6 weeks.

Renal function impairment
Adults

IV For patients with CrCl less than 30 mL/min, including those on hemodialysis or continuous ambulatory peritoneal dialysis, administer 4 mg/kg for complicated skin and skin structure infections or 6 mg/kg for S. aureus bloodstream infections once every 48 h.

General Advice

For IV infusion only.
Reconstitute powder using 10 mL of sodium chloride 0.9% injection.
Reconstituted solution should be further diluted in sodium chloride 0.9% injection and infused over 30 min.
If other drugs are being administered through the same IV line, flush IV line before and after infusion of daptomycin with sodium chloride 0.9% injection or Ringer's lactate injection.
Do not mix with dextrose-containing diluents. Do not use in conjunction with ReadyMED elastomeric infusion pumps.

Storage/Stability

Store vials in refrigerator (36° to 46°F). Reconstituted solution is stable (in the vial or infusion bag) for 12 h at room temperature (68° to 77°F) or up to 48 h if stored under refrigeration. The combined storage time (reconstituted solution in vial and diluted solution in infusion bag) should not exceed 12 h at room temperature or 48 h under refrigeration.

Drug Interactions

HMG-CoA reductase inhibitors (eg, simvastatin)

If possible, consider temporarily discontinuing HMG-CoA reductase inhibitors, which have been known to cause rhabdomyolysis, until daptomycin therapy has been completed.

Tobramycin

C _max and AUC of daptomycin increased 12.7% and 8.7%, respectively, while C _max and AUC of tobramycin decreased 10.7% and 6.6%, respectively, when daptomycin and tobramycin were coadministered. Use with caution.

Laboratory Test Interactions

Daptomycin may cause a concentration-dependent false prolongation of PT and elevation of INR when certain recombinant thromboplastin reagents are utilized for assay. The possibility of an erroneous PT/INR result may be minimized by drawing specimens for PT or INR testing near the time of daptomycin trough plasma concentrations. However, sufficient daptomycin concentrations may be present at trough to cause a laboratory test interaction.

Adverse Reactions

Cardiovascular

Hypertension (6%); hypotension (5%); cardiac failure (1% to 2%).

CNS

Insomnia (9%); headache (7%); dizziness (6%); anxiety, asthenia (5%); confusion (1% to 2%).

Dermatologic

Rash (7%); pruritus (6%); erythema, sweating increased (5%); cellulitis (1% to 2%).

EENT

Pharyngolaryngeal pain (8%); sore throat (1% to 2%).

GI

Diarrhea, vomiting (12%); constipation (11%); nausea (10%); abdominal pain (6%); dyspepsia, loose stool (4%); GI hemorrhage (2%).

Genitourinary

UTI (7%); acute renal failure, renal failure (3%); vaginal candidiasis (2%).

Hepatic

Abnormal LFTs (3%).

Hematologic-Lymphatic

Anemia (13%); eosinophilia (2%).

Hypersensitivity

Anaphylaxis, hypersensitivity reactions, including difficulty swallowing, hives, pruritus, pulmonary eosinophilia, shortness of breath, and truncal erythema (postmarketing).

Lab Tests

Elevated CPK (7%); increased blood phosphorus (3%); increased blood alkaline phosphatase, increased INR (2%).

Local

Injection-site reactions (6%); injection-site erythema (3%).

Metabolic-Nutritional

Hypokalemia (9%); edema, peripheral edema (7%); hyperkalemia (5%); decreased appetite, hyperglycemia, hypoglycemia (1% to 2%).

Musculoskeletal

Pain in extremity (9%); back pain (7%); arthralgia (3%); limb pain (2%); rhabdomyolysis (postmarketing).

Respiratory

Pleural effusion (6%); cough, dyspnea, pneumonia (3%); eosinophilic pneumonia (postmarketing).

Miscellaneous

Gram-negative infections (8%); chest pain, pyrexia (7%); osteomyelitis (6%); bacteremia, sepsis (5%); fungal infection (3%); candidal infection, fever (2%).

Precautions

Monitor

Monitor patient for GI, CNS, musculoskeletal, and general body adverse reactions. Note any signs or symptoms of myopathy or neuropathy. In patients receiving warfarin, monitor anticoagulant activity for the first several days after initiating daptomycin therapy. Monitor CPK levels weekly. Monitor CPK more frequently if patient is also on an HMG-CoA reductase inhibitor or if unexplained elevations in CPK occur. In patients with renal impairment, monitor renal function and CPK more frequently.

Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Lower clinical success rates and increased adverse reactions have been observed in patients 65 y and older.

Renal Function

Dosage adjustment is needed in patients with severe renal impairment (CrCl less than 30 mL/min), including patients receiving hemodialysis or chronic ambulatory peritoneal dialysis.

Superinfection

May result in bacterial or fungal overgrowth of nonsusceptible microorganisms.

Clostridium difficile –associated diarrhea

Must be considered a possibility in patients with diarrhea.

Eosinophilic pneumonia

Has been reported with symptoms including fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates. Generally developed within 2 to 4 wk of starting therapy and improved upon discontinuation of daptomycin and initiation of treatment with steroids.

Myopathy/CPK elevation

Discontinue daptomycin in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevation of more than 1,000 units/L (approximately 5 × ULN), or in patients without reported symptoms who have marked elevations in CPK of more than 2,000 units/L (at least 10 × ULN).

Peripheral neuropathy

Has been reported; be alert to signs and symptoms.

Persisting or relapsing S. aureus infection

Perform repeat blood cultures. If culture is positive for S. aureus , perform minimum inhibitory concentration susceptibility testing of the isolate, as well as diagnostic evaluation. Consider appropriate surgical intervention and changes in the antibiotic regimen.

Overdosage

Symptoms

No data available.

Patient Information

Advise patient, family, or caregiver that medication will be prepared and administered by a health care provider in a health care setting.
Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment.
Advise patient to report injection-site pain or redness; muscle weakness, pain, or tenderness; abnormal sensations in the legs or arms (eg, pain, numbness); cough; breathlessness; or fever to health care provider.
Advise patient to report the following signs of superinfection to health care provider: black, furry tongue; foul-smelling stools; vaginal itching or discharge; white patches in the mouth.
Warn patient that diarrhea containing blood or pus may be a sign of a serious disorder. Advise patients to seek medical care if noted and not to treat at home.