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Daptomycin

Daptomycin is a cyclic lipopeptide antibiotic.

Molecular Formula: C72H101N17O26

Uses

Daptomycin is used for the treatment of complicated skin and skin structure infections caused by susceptible gram-positive bacteria. The drug should not be used in the treatment of pneumonia.

Daptomycin

Skin and Skin Structure Infections

Daptomycin is used IV for the treatment of complicated skin and skin structure infections caused by susceptible Staphylococcus aureus (including oxacillin-resistant strains [previously known as methicillin-resistant S. aureus or MRSA]), Streptococcus pyogenes (group A b-hemolytic streptococci), S. agalactiae (group B streptococci), S. dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible strains only).

To reduce the development of drug-resistant bacteria and maintain daptomycin efficacy, the drug should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. Concomitant use of another anti-infective may be indicated if documented or presumptive pathogens also include gram-negative or anaerobic bacteria.

Clinical Experience

In 2 randomized, multicenter, comparative studies in adults with complicated skin and skin structure infections (e.g., wound infection, major abscess, ulcer infection, complicated cellulitis), clinical success rates reported with daptomycin (4 mg/kg IV once every 24 hours) were similar to those reported with vancomycin (1 g IV every 12 hours) or a penicillinase-resistant penicillin (i.e., nafcillin, oxacillin, or cloxacillin [IV preparation no longer commercially available in the US], or flucloxacillin [not commercially available in the US] at a dosage of 4-12 g IV daily). After a minimum of 4 days of IV treatment, patients could be switched to oral anti-infective therapy if clinical improvement was observed; however, most patients (approximately 90%) received IV therapy exclusively.

Clinical success was achieved in 63-80% of patients receiving daptomycin and 61-81% of those receiving comparator agents, based on intent-to-treat analysis. In a subset of patients who were microbiologically evaluable and stratified according to the infecting pathogen, the daptomycin clinical success rate was 73% in those with infections caused by E. faecalis (vancomycin-susceptible strains only), 75% in those with oxacillin-resistant S. aureus, 86% in those with oxacillin-susceptible S. aureus, 85% in those with S. agalactiae, 94% in those with S. pyogenes, and 100% in those with S. dysgalactiae subsp. equisimilis.

Dosage and Administration

Reconstitution and Administration

Daptomycin is administered by IV infusion over 30 minutes. The commercially available daptomycin lyophilized powder for injection must be reconstituted and diluted prior to administration. Vials labeled as containing 250 or 500 mg of daptomycin should be reconstituted with 5 or 10 mL of 0.9% sodium chloride injection, respectively, and then further diluted with 0.9% sodium chloride injection. The final concentration of the diluted solution should not exceed 20 mg/mL. Strict aseptic technique must be observed in preparing daptomycin solutions since the drug contains no preservative. Daptomycin solutions should be inspected visually for particulate matter prior to administration.

Reconstituted daptomycin solution is stable in the vial or IV infusion bag for 12 hours at room temperature or up to 48 hours when refrigerated at 2-8°C; the combined time (vial and infusion bag) at room temperature or under refrigeration should not exceed 12 or 48 hours, respectively. Additives and other drugs should not be added to the daptomycin solution or infused simultaneously through the same IV line. If the same IV line is used for sequential infusion of different drugs, the line should be flushed with a compatible infusion solution (i.e., 0.9% sodium chloride injection, lactated Ringer’s injection) before and after infusion of daptomycin.

Daptomycin is not compatible with dextrose-containing diluents (e.g., 5% dextrose injection).

General Dosage

Skin and Skin Structure Infections

For the treatment of complicated skin and skin structure infections in adults, the usual IV dosage of daptomycin is 4 mg/kg once every 24 hours for 7-14 days. Because the risk of serum creatine kinase (CK, creatine phosphokinase, CPK) elevations may be increased with more frequent dosing, daptomycin doses should not be administered more than once daily.

Special Populations

Because daptomycin is eliminated principally by renal excretion, patients with creatinine clearance less than 30 mL/minute, including those requiring hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), should receive a reduced daptomycin dosage of 4 mg/kg once every 48 hours. In hemodialysis patients, dosing of the drug should be timed so that doses are given on hemodialysis days (following the procedure) whenever possible.

No dosage adjustment is necessary in patients with mild to moderate hepatic impairment; pharmacokinetics of the drug have not been evaluated in patients with severe hepatic impairment. No dosage adjustment is necessary in geriatric patients with normal renal function and no dosage adjustment is recommended based on gender or weight.

Cautions

Contraindications

Known hypersensitivity to daptomycin.

Warnings/Precautions

Warnings

Clostridium difficile-associated Colitis Reported with numerous anti-infectives, including daptomycin; may range in severity from mild to life-threatening. Evaluate and monitor patients who develop diarrhea during therapy.

General Precautions

Superinfection Overgrowth of nonsusceptible organisms may occur. If superinfection occurs, appropriate therapy should be instituted.

Musculoskeletal Effects

Increases in serum creatine kinase (CK, creatine phosphokinase, CPK) were reported in 2.8% of patients receiving daptomycin compared with 1.8% of those receiving comparator agents during clinical trials. Increases in serum CK appear to be more frequent when daptomycin is given more frequently than once daily.

Patients receiving daptomycin should be monitored for the development of muscle pain or weakness, particularly of the distal extremities. Serum CK concentrations should be monitored weekly in patients receiving daptomycin; patients who develop unexplained increases in serum CK during therapy should be monitored more frequently.

Daptomycin should be discontinued in patients with unexplained manifestations suggestive of myopathy in conjunction with increases in CK greater than 1000 U/L (i.e., approximately 5 times the upper limit of normal) or in patients without reported symptoms who have substantial increases in serum CK concentrations (i.e., at least 10 times the upper limit of normal). Temporary discontinuance of drugs associated with rhabdomyolysis (e.g., hydroxymethylglutaryl-CoA [HMG-CoA] reductase inhibitors) should be considered in patients receiving daptomycin.

Nervous System Effects

Decreases in nerve conduction velocity and adverse effects (e.g., paresthesias, Bell’s palsy), possibly suggestive of peripheral or cranial neuropathy, have been reported rarely in patients receiving daptomycin. In phase III clinical studies, 0.7% of patients receiving either daptomycin or a comparator agent experienced paresthesias; however, no patients were diagnosed with new or worsening peripheral neuropathy. Clinicians should be alert to possible manifestations of neuropathy in patients receiving daptomycin.

Specific Populations Pregnancy Category B. Lactation

It is not known whether daptomycin is distributed into milk. Caution is advised if the drug is administered in nursing women.

Pediatric Use

Safety and efficacy not established in children younger than 18 years of age.

Geriatric Use

When the total number of patients studied in phase III clinical trials of daptomycin is considered, 27% were 65 years of age or older, while 12.% were 75 years of age and older. In 2 clinical trials in patients with skin and skin structure infections, lower clinical success rates were observed and treatment-emergent adverse effects were more common in geriatric patients compared with younger adults.

Hepatic Impairment

The pharmacokinetics of daptomycin were not altered in patients with moderate hepatic impairment when compared with healthy individuals without liver disease. Daptomycin has not been studied in patients with severe hepatic impairment.

Renal Impairment

Following the administration of a single dose of daptomycin (4 mg/kg IV), plasma clearance was decreased and area under the concentration-time curve (AUC) was increased with decreasing renal function. Mean AUC values were not substantially different in patients with creatinine clearances of 30-80 mL/minute, but were approximately 2 and 3 times higher in patients with creatinine clearances less than 30 mL/minute and in hemodialysis/CAPD patients, respectively, than in patients with normal renal function. Dosage adjustment is recommended.

Common Adverse Effects

Adverse effects occurring in 2% or more of patients receiving daptomycin in clinical trials include constipation, nausea, injection site reactions, headache, diarrhea, insomnia, rash, vomiting, abnormal liver function test results, CK (CPK) elevations, pruritus, fungal infections, urinary tract infections, hypotension, dizziness, renal failure, anemia, dyspnea, and fever.

Drug Interactions

Drugs Metabolized by Hepatic Microsomal Enzymes

Daptomycin does not inhibit or induce cytochrome P-450 (CYP) isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4; pharmacokinetic interactions with drugs metabolized by these isoenzymes unlikely.

Aztreonam

Maximum serum concentration and AUC of daptomycin or aztreonam were not substantially altered after concurrent use of single doses of daptomycin (6 mg/kg IV) and aztreonam (1 g IV); clinically important pharmacokinetic interaction unlikely. No dosage adjustment is recommended with concurrent use.

HMG-CoA Reductase Inhibitors

Potential pharmacologic interaction (risk of myopathy, manifested as muscle pain or weakness in association with increased serum CK [CPK] concentrations). Although there were no reports of skeletal myopathy when healthy individuals receiving simvastatin were treated concurrently with daptomycin (4 mg/kg once every 24 hours for 14 days), the manufacturer states that experience with concurrent use of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors and daptomycin is limited and temporary discontinuance of the HMG-CoA reductase inhibitor should be considered in patients receiving daptomycin.

Probenecid

Concurrent use of probenecid (500 mg 4 times daily) and a single daptomycin dose (4 mg/kg IV) did not substantially alter the maximum plasma concentration or AUC of daptomycin; clinically important pharmacokinetic interaction unlikely. No dosage adjustment necessary.

Tobramycin Potential pharmacokinetic interaction

Mean maximum plasma concentration and AUC of daptomycin were increased by approximately 13 and 9%, respectively, while mean maximum plasma concentration and AUC of tobramycin were decreased by approximately 11 and 7%, respectively, when daptomycin (2 mg/kg IV) and tobramycin (1 mg/kg IV) were used concurrently; however, these differences were not statistically significant. The extent of the interaction between daptomycin and tobramycin at the recommended daptomycin dosage (4 mg/kg) is not known. Caution is advised when tobramycin is used concurrently with daptomycin.

Warfarin

Concurrent use of daptomycin (6 mg/kg IV once every 24 hours for 5 days) and warfarin (single 25-mg oral dose) did not result in substantial effects on the pharmacokinetics of either drug or substantial alterations of international normalized ratio (INR) values. However, because experience with concurrent use of daptomycin and warfarin is limited, the manufacturer recommends that anticoagulant activity be monitored for the first several days after initiation of daptomycin in patients receiving warfarin therapy.

Description

Daptomycin is a cyclic lipopeptide antibiotic produced by fermentation of Streptomyces roseosporus. The drug differs structurally and pharmacologically from other currently available anti-infective agents. In vitro studies indicate that daptomycin exhibits rapid concentration-dependent bactericidal effects against susceptible gram-positive bacteria. Daptomycin binds to bacterial cell membranes and causes rapid membrane depolarization in susceptible bacteria, which leads to inhibition of protein, DNA, and RNA synthesis and results in cell death. Daptomycin is active against many gram-positive bacteria, but is inactive against gram-negative bacteria.

The drug is active in vitro and in clinical infections against most strains of Staphylococcus aureus (including oxacillin-resistant strains [previously known as methicillin-resistant S. aureus or MRSA]), Streptococcus pyogenes (group A b-hemolytic streptococci), S. agalactiae (group B streptococci), S. dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible strains only).

Daptomycin also has demonstrated in vitro activity against Corynebacterium jeikeium, E. faecalis (vancomycin-resistant strains), E. faecium (including vancomycin-resistant strains), S. epidermidis (including oxacillin-resistant strains), and S. haemolyticus; however, the safety and efficacy of daptomycin in treating clinical infections caused by these bacteria have not been established in adequate and well-controlled studies to date.

No mechanism of resistance or transferable elements that confer resistance to daptomycin have been identified to date. Reduced susceptibility to daptomycin (8- to 32-fold increase in minimum inhibitory concentration [MIC]) has been produced in vitro by serial passage of S. aureus in the presence of increasing concentrations of the drug. In clinical studies to date, resistance to daptomycin has emerged only rarely. In one case, S. aureus resistant to daptomycin was isolated from a patient who received the drug at less than the protocol-specified dosage during the first 5 days of therapy. In the second case, resistant E. faecalis was isolated from a patient with an infected decubitus ulcer. Cross-resistance has not been observed between daptomycin and other anti-infectives to date.

Daptomycin exhibits nearly linear pharmacokinetics at dosages up to 6 mg/kg IV once daily for 7 days. Peak plasma concentrations of the drug generally are attained within 0.5-0. hours and steady-state concentrations are achieved by the third daily dose. Daptomycin has an elimination half-life of about 8 hours following administration of 4 mg/kg IV once daily for 7 days. The drug is approximately 92% bound to plasma proteins, principally albumin.

Daptomycin is eliminated principally by renal excretion, with approximately 78 and 6% of an administered dose recovered in urine and feces, respectively. It is not known if daptomycin is a substrate of the cytochrome P-450 (CYP) isoenzyme system. In vitro studies using human hepatocytes indicate that daptomycin does not inhibit or induce CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.

Advice to Patients

Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed. Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs. Importance of reporting possible manifestations of adverse effects such as diarrhea, muscle pain or weakness, or neuropathy promptly to clinicians. Importance of reporting persistent or worsening symptoms of infection.

Overview

For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the manufacturer’s labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Daptomycin Parenteral For injection, for 250 mg Cubicin®, (preservative-free) IV infusion Cubist 500 mg Cubicin®, (preservative-free) Cubist

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