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  • CLASSES

    Lipopeptide Antibiotics

    DEA CLASS

    Rx

    DESCRIPTION

    Intravenous, cyclic lipopeptide antibiotic
    Used for susceptible gram-positive infections, including MRSA, complicated skin and skin structure infections, and bacteremia, including patients with right-sided infective endocarditis
    Inactivated by pulmonary surfactant, therefore ineffective for pneumonia

    COMMON BRAND NAMES

    Cubicin, Cubicin RF

    HOW SUPPLIED

    Cubicin/Cubicin RF/Daptomycin Intravenous Inj Pwd F/Sol: 350mg, 500mg

    DOSAGE & INDICATIONS

    For the treatment of Staphylococcus aureus bacteremia.
    Intravenous dosage
    Adults

    6 mg/kg/dose IV every 24 hours for 2 to 6 weeks is the FDA-approved dosage. Doses of 8 to 10 mg/kg/dose IV every 24 hours may be warranted for MRSA. In patients with persistent MRSA bacteremia and vancomycin treatment failures, the clinical practice guidelines recommend 10 mg/kg/dose IV every 24 hours in combination with another agent (gentamicin, rifampin, linezolid, sulfamethoxazole/trimethoprim, or a beta-lactam). Treat for at least 2 weeks for uncomplicated bacteremia and 4 to 6 weeks for complicated bacteremia. Studies have demonstrated the safety of doses of at least 8 mg/kg/dose IV every 24 hours. Limited safety data are available for use beyond 28 days.

    Children and Adolescents 12 to 17 years

    7 mg/kg/dose IV every 24 hours for up to 6 weeks.

    Children 7 to 11 years

    9 mg/kg/dose IV every 24 hours for up to 6 weeks.

    Children 1 to 6 years

    12 mg/kg/dose IV every 24 hours for up to 6 weeks.

    Infants†

    Safety and efficacy have not been established; limited data are available. Based on pharmacokinetic data, doses of 8 to 10 mg/kg/dose IV every 24 hours have been recommended in this age group. 6 to 10 mg/kg/dose IV every 24 hours is suggested by the Infectious Diseases Society of America (IDSA) for bacteremia. 8 mg/kg/dose IV every 24 hours was successfully used in a small study of 12 pediatric patients (n = 9 with bacteremia; age range 14 days to 7 years); microbiologic eradication was achieved in all patients and no drug-related adverse reactions occurred. Treat for 2 to 6 weeks for bacteremia. FDA-approved labeling warns against use; animal data suggests there may be an increased risk for muscular, neuromuscular, and/or nervous system (both peripheral and central) adverse reactions in pediatric patients younger than 12 months of age. Monitoring of daptomycin serum concentrations and creatine phosphokinase (CPK) concentrations is recommended in order to ensure safe and effective therapy.

    Neonates†

    Safety and efficacy have not been established; very limited data are available. Doses of 6 to 15 mg/kg/dose IV every 12 to 24 hours have been successfully used in case reports of neonates and premature neonates (n = 7) with MRSA and vancomycin-resistant enterococcal bacteremia. 6 mg/kg/dose IV every 12 hours is the most commonly reported dose; however, differences in peak concentrations have been observed with this dose between various studies. Doses higher than 6 mg/kg/dose may be necessary in neonates to achieve adequate drug exposure. 8 mg/kg/dose IV every 24 hours was successfully used in a small study of 12 pediatric patients (n = 9 with bacteremia; age range 14 days to 7 years); microbiologic eradication was achieved in all patients and no drug-related adverse reactions occurred. Treat 2 to 6 weeks for bacteremia. FDA-approved labeling warns against use; animal data suggests there may be an increased risk for muscular, neuromuscular, and/or nervous system (both peripheral and central) adverse reactions in pediatric patients younger than 12 months of age. Monitoring of daptomycin serum concentrations and creatine phosphokinase (CPK) concentrations is recommended in order to ensure safe and effective therapy.

    For the treatment of complicated skin and skin structure infections, including infections caused by methicillin-resistant Staphylococcus aureus (MRSA).
    Intravenous dosage
    Adults

    4 mg/kg/dose IV every 24 hours for 7 to 14 days.

    Children and Adolescents 12 to 17 years

    5 mg/kg/dose IV every 24 hours for up to 14 days. Daptomycin was shown to be efficacious, safe, and generally well tolerated compared with the standard of care (SOC; vancomycin, clindamycin) in pediatric patients with complicated skin and skin structure infections caused by gram-positive pathogens in a multicenter, randomized, clinical study (n = 396). Although the study was not powered to confirm noninferiority, clinical success rates in the intent-to-treat population were similar between the 2 groups (91% and 87% for the daptomycin and SOC groups, respectively).

    Children 7 to 11 years

    7 mg/kg/dose IV every 24 hours for up to 14 days. Daptomycin was shown to be efficacious, safe, and generally well tolerated compared with the standard of care (SOC; vancomycin, clindamycin) in pediatric patients with complicated skin and skin structure infections caused by gram-positive pathogens in a multicenter, randomized, clinical study (n = 396). Although the study was not powered to confirm noninferiority, clinical success rates in the intent-to-treat population were similar between the 2 groups (91% and 87% for the daptomycin and SOC groups, respectively).

    Children 2 to 6 years

    9 mg/kg/dose IV every 24 hours for up to 14 days. Daptomycin was shown to be efficacious, safe, and generally well tolerated compared with the standard of care (SOC; vancomycin, clindamycin) in pediatric patients with complicated skin and skin structure infections caused by gram-positive pathogens in a multicenter, randomized, clinical study (n = 396). Although the study was not powered to confirm noninferiority, clinical success rates in the intent-to-treat population were similar between the 2 groups (91% and 87% for the daptomycin and SOC groups, respectively).

    Children younger than 2 years

    10 mg/kg/dose IV every 24 hours for up to 14 days. Daptomycin was shown to be efficacious, safe, and generally well tolerated compared with the standard of care (SOC; vancomycin, clindamycin) in pediatric patients with complicated skin and skin structure infections caused by gram-positive pathogens in a multicenter, randomized, clinical study (n = 396). Although the study was not powered to confirm noninferiority, clinical success rates in the intent-to-treat population were similar between the 2 groups (91% and 87% for the daptomycin and SOC groups, respectively).

    Infants†

    Safety and efficacy have not been established; limited data are available describing the use of daptomycin in pediatric patients. Based on pharmacokinetic data, doses of 8 to 10 mg/kg/dose IV every 24 hours have been recommended in this age group. 8 mg/kg/dose IV every 24 hours was successfully used in a small study of 12 pediatric patients (n = 3 with complicated skin and soft tissue infections; age range 14 days to 7 years); microbiologic eradication was achieved in all patients and no drug-related adverse reactions occurred. FDA-approved labeling warns against use; animal data suggests there may be an increased risk for muscular, neuromuscular, and/or nervous system (both peripheral and central) adverse reactions in pediatric patients younger than 12 months of age. Monitoring of daptomycin serum concentrations and creatine phosphokinase (CPK) concentrations is recommended in order to ensure safe and effective therapy.

    Neonates†

    Safety and efficacy have not been established; very limited data are available. Doses of 6 to 15 mg/kg/dose IV every 12 to 24 hours have been successfully used in case reports of neonates and premature neonates (n = 7) with methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcal bacteremia. 6 mg/kg/dose IV every 12 hours is the most commonly reported dose; however, differences in peak concentrations have been observed with this dose between various studies. Doses higher than 6 mg/kg/dose may be necessary in neonates to achieve adequate drug exposure. 8 mg/kg/dose IV every 24 hours was successfully used in a small study of 12 pediatric patients (n = 3 with complicated skin and soft tissue infections; age range 14 days to 7 years); microbiologic eradication was achieved in all patients and no drug-related adverse reactions occurred. FDA-approved labeling warns against use; animal data suggests there may be an increased risk for muscular, neuromuscular, and/or nervous system (both peripheral and central) adverse reactions in pediatric patients younger than 12 months of age. Monitoring of daptomycin serum concentrations and creatine phosphokinase (CPK) concentrations is recommended in order to ensure safe and effective therapy.

    For the treatment of endocarditis.
    Intravenous dosage
    Adults

    6 mg/kg/dose IV every 24 hours for 2 to 6 weeks is the FDA-approved dosage for right-sided S. aureus endocarditis. Guidelines suggest doses of 8 to 10 mg/kg/dose IV every 24 hours for MRSA endocarditis and 10 to 12 mg/kg/dose IV every 24 hours for multi-drug resistant enterococcal endocarditis as part of combination therapy. Daptomycin is also an alternative option in patients with MSSA left-sided endocarditis. Treat native-valve S. aureus endocarditis for 6 weeks and multi-drug resistant enterococcal endocarditis for more than 6 weeks. Studies have demonstrated the safety of doses of at least 8 mg/kg/dose IV every 24 hours. Limited safety data are available for use beyond 28 days.

    Children and Adolescents 7 to 17 years†

    6 mg/kg/dose IV every 24 hours for 6 weeks is recommended by guidelines.

    Children 1 to 6 years†

    10 mg/kg/dose IV every 24 hours for 6 weeks is recommended by guidelines.

    Infants†

    Safety and efficacy have not been established; limited data are available. Based on pharmacokinetic data, doses of 8 to 10 mg/kg/dose IV every 24 hours have been recommended in this age group. 6 to 10 mg/kg/dose IV every 24 hours is suggested by the Infectious Diseases Society of America (IDSA) for infective endocarditis. 8 mg/kg/dose IV every 24 hours was successfully used in a small study of 12 pediatric patients (n = 9 with bacteremia; age range 14 days to 7 years); microbiologic eradication was achieved in all patients and no drug-related adverse reactions occurred. Guidelines recommend treatment for 6 weeks for endocarditis. FDA-approved labeling warns against use; animal data suggests there may be an increased risk for muscular, neuromuscular, and/or nervous system (both peripheral and central) adverse reactions in pediatric patients younger than 12 months of age. Monitoring of daptomycin serum concentrations and creatine phosphokinase (CPK) concentrations is recommended in order to ensure safe and effective therapy.

    Neonates†

    Safety and efficacy have not been established; very limited data are available. Doses of 6 to 15 mg/kg/dose IV every 12 to 24 hours have been successfully used in case reports of neonates and premature neonates (n = 7) with MRSA and vancomycin-resistant enterococcal bacteremia. 6 mg/kg/dose IV every 12 hours is the most commonly reported dose; however, differences in peak concentrations have been observed with this dose between various studies. Doses higher than 6 mg/kg/dose may be necessary in neonates to achieve adequate drug exposure. 8 mg/kg/dose IV every 24 hours was successfully used in a small study of 12 pediatric patients (n = 9 with bacteremia; age range 14 days to 7 years); microbiologic eradication was achieved in all patients and no drug-related adverse reactions occurred. Guidelines recommend treatment for 6 weeks for endocarditis. FDA-approved labeling warns against use; animal data suggests there may be an increased risk for muscular, neuromuscular, and/or nervous system (both peripheral and central) adverse reactions in pediatric patients younger than 12 months of age. Monitoring of daptomycin serum concentrations and creatine phosphokinase (CPK) concentrations is recommended in order to ensure safe and effective therapy.

    For the treatment of infections due to vancomycin-resistant enterococci (VRE)†.
    Intravenous dosage
    Adults

    Doses of 8 to 12 mg/kg/dose IV every 24 hours have been used safely and effectively in patients with vancomycin-resistant enterococci (VRE) infections, including bloodstream infections. 10 to 12 mg/kg/dose IV every 24 hours is recommended by guidelines for multi-drug resistant enterococcal endocarditis as part of combination therapy.

    Children and Adolescents 7 to 17 years

    Safety and efficacy have not been established; limited data are available describing the use of daptomycin in pediatric patients. 8 to 10 mg/kg/dose IV every 24 hours has been recommended for VRE bacteremia. 8 mg/kg/dose IV every 24 hours was successfully used in a case report of a 10-year old girl with severe sepsis due to vancomycin- and linezolid-resistant Enterococcus faecium (VAN-B VRE).

    Children 1 to 6 years

    Safety and efficacy have not been established; limited data are available describing the use of daptomycin in pediatric patients. Based on pharmacokinetic data, doses of 8 to 10 mg/kg/dose IV every 24 hours have been recommended in this age group. One case report describes the use of daptomycin 4 mg/kg/dose IV every 12 hours in combination with linezolid in a 21-month-old child with vancomycin-resistant enterococcal bacteremia; blood cultures were sterilized 14 days after daptomycin initiation.

    Infants

    Safety and efficacy have not been established; limited data are available describing the use of daptomycin in pediatric patients. Based on pharmacokinetic data, doses of 8 to 10 mg/kg/dose IV every 24 hours have been recommended in this age group. FDA-approved labeling warns against use; animal data suggests there may be an increased risk for muscular, neuromuscular, and/or nervous system (both peripheral and central) adverse reactions in pediatric patients younger than 12 months of age. Monitoring of daptomycin serum concentrations and creatine phosphokinase (CPK) concentrations is recommended in order to ensure safe and effective therapy.

    Neonates

    Safety and efficacy have not been established; very limited data are available. Doses of 6 to 15 mg/kg/dose IV every 12 to 24 hours have been successfully used in case reports of neonates and premature neonates (n = 7) with methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcal bacteremia. 6 mg/kg/dose IV every 12 hours is the most commonly reported dose; however, differences in peak concentrations have been observed with this dose between various studies. Doses higher than 6 mg/kg/dose may be necessary in neonates to achieve adequate drug exposure. FDA-approved labeling warns against use; animal data suggests there may be an increased risk for muscular, neuromuscular, and/or nervous system (both peripheral and central) adverse reactions in pediatric patients younger than 12 months of age. Monitoring of daptomycin serum concentrations and creatine phosphokinase (CPK) concentrations is recommended in neonates in order to ensure safe and effective therapy.

    For the treatment of MRSA-associated bone and joint infections†, including osteomyelitis† and septic/infectious arthritis†, or an orthopedic device-related infection†.
    For the treatment of MRSA-associated osteomyelitis†.
    Intravenous dosage
    Adults

    The Infectious Diseases Society of America (IDSA) recommends 6 mg/kg/dose IV every 24 hours. Rifampin 600 mg PO once daily or 300 to 450 mg PO twice daily may be added; however, in patients with concurrent bacteremia, rifampin should be added after the clearance of the bacteremia. A minimum duration of 8 weeks is recommended; however, an additional 1 to 3 months (or longer for chronic infection or if no debridement performed) of oral rifampin plus either sulfamethoxazole/trimethoprim, doxycycline, minocycline, clindamycin, or a fluoroquinolone may be necessary.

    Children and Adolescents 7 to 17 years

    Safety and efficacy have not been established; limited data are available describing the use of daptomycin in pediatric patients. 6 to 10 mg/kg/dose IV every 24 hours is suggested by the Infectious Diseases Society of America (IDSA) as an alternative to vancomycin for MRSA infections. Treat for 4 to 6 weeks for osteomyelitis. Doses of 7, 9, or 12 mg/kg/dose IV every 24 hours are being investigated in pediatric patients 1 to 17 years with acute hematogenous osteomyelitis; however, this study is ongoing and results are unavailable (clinicaltrials.gov; NCT01922011).

    Children 1 to 6 years

    Safety and efficacy have not been established; limited data are available describing the use of daptomycin in pediatric patients. Based on pharmacokinetic data, doses of 8 to 10 mg/kg/dose IV every 24 hours have been recommended in this age group. 6 to 10 mg/kg/dose IV every 24 hours is suggested by the Infectious Diseases Society of America (IDSA) as an alternative to vancomycin for MRSA infections. Treat for 4 to 6 weeks for osteomyelitis. Doses of 7, 9, or 12 mg/kg/dose IV every 24 hours are being investigated in pediatric patients 1 to 17 years with acute hematogenous osteomyelitis; however, this study is ongoing and results are unavailable (clinicaltrials.gov; NCT01922011).

    Infants

    Safety and efficacy have not been established; limited data are available describing the use of daptomycin in pediatric patients. Based on pharmacokinetic data, doses of 8 to 10 mg/kg/dose IV every 24 hours have been recommended in this age group. 6 to 10 mg/kg/dose IV every 24 hours is suggested by the Infectious Diseases Society of America (IDSA) as an alternative to vancomycin for MRSA infections. Treat for 4 to 6 weeks for osteomyelitis. FDA-approved labeling warns against use; animal data suggests there may be an increased risk for muscular, neuromuscular, and/or nervous system (both peripheral and central) adverse reactions in pediatric patients younger than 12 months of age. Monitoring of daptomycin serum concentrations and creatine phosphokinase (CPK) concentrations is recommended in order to ensure safe and effective therapy.

    Neonates

    Safety and efficacy have not been established; very limited data are available. Doses of 6 to 15 mg/kg/dose IV every 12 to 24 hours have been successfully used in case reports of neonates and premature neonates (n = 7) with methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcal bacteremia. 6 mg/kg/dose IV every 12 hours is the most commonly reported dose; however, differences in peak concentrations have been observed with this dose between various studies. Doses higher than 6 mg/kg/dose may be necessary in neonates to achieve adequate drug exposure. Treat for 4 to 6 weeks for osteomyelitis. FDA-approved labeling warns against use; animal data suggests there may be an increased risk for muscular, neuromuscular, and/or nervous system (both peripheral and central) adverse reactions in pediatric patients younger than 12 months of age. Monitoring of daptomycin serum concentrations and creatine phosphokinase (CPK) concentrations is recommended in order to ensure safe and effective therapy.

    For the treatment of MRSA-associated septic arthritis†.
    Intravenous dosage
    Adults

    The IDSA recommends 6 mg/kg/dose IV every 24 hours for 3 to 4 weeks.

    Children and Adolescents 7 to 17 years

    Safety and efficacy have not been established; limited data are available describing the use of daptomycin in pediatric patients. 6 to 10 mg/kg/dose IV every 24 hours is suggested by the Infectious Diseases Society of America (IDSA) as an alternative to vancomycin for MRSA infections. Treat for at least 3 to 4 weeks for septic/infectious arthritis.

    Children 1 to 6 years

    Safety and efficacy have not been established; limited data are available describing the use of daptomycin in pediatric patients. Based on pharmacokinetic data, doses of 8 to 10 mg/kg/dose IV every 24 hours have been recommended in this age group. 6 to 10 mg/kg/dose IV every 24 hours is suggested by the Infectious Diseases Society of America (IDSA) as an alternative to vancomycin for MRSA infections. Treat for at least 3 to 4 weeks for septic/infectious arthritis.

    Infants

    Safety and efficacy have not been established; limited data are available describing the use of daptomycin in pediatric patients. Based on pharmacokinetic data, doses of 8 to 10 mg/kg/dose IV every 24 hours have been recommended in this age group. 6 to 10 mg/kg/dose IV every 24 hours is suggested by the Infectious Diseases Society of America (IDSA) as an alternative to vancomycin for MRSA infections. Treat for at least 3 to 4 weeks for septic/infectious arthritis. FDA-approved labeling warns against use; animal data suggests there may be an increased risk for muscular, neuromuscular, and/or nervous system (both peripheral and central) adverse reactions in pediatric patients younger than 12 months of age. Monitoring of daptomycin serum concentrations and creatine phosphokinase (CPK) concentrations is recommended in order to ensure safe and effective therapy.

    Neonates

    Safety and efficacy have not been established; very limited data are available. Doses of 6 to 15 mg/kg/dose IV every 12 to 24 hours have been successfully used in case reports of neonates and premature neonates (n = 7) with methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcal bacteremia. 6 mg/kg/dose IV every 12 hours is the most commonly reported dose; however, differences in peak concentrations have been observed with this dose between various studies. Doses higher than 6 mg/kg/dose may be necessary in neonates to achieve adequate drug exposure. Treat for at least 3 to 4 weeks for septic/infectious arthritis. FDA-approved labeling warns against use; animal data suggests there may be an increased risk for muscular, neuromuscular, and/or nervous system (both peripheral and central) adverse reactions in pediatric patients younger than 12 months of age. Monitoring of daptomycin serum concentrations and creatine phosphokinase (CPK) concentrations is recommended in order to ensure safe and effective therapy.

    For the treatment of MRSA-associated prosthetic device infections†.
    Intravenous dosage
    Adults

    The IDSA recommends 6 mg/kg/dose IV every 24 hours plus rifampin 600 mg PO once daily or 300 to 450 mg PO every 12 hours for 2 weeks in patients with early-onset (less than 2 months after surgery) or acute hematogenous prosthetic joint infections involving a stable implant with short duration (3 weeks or less) of symptoms and debridement (but device retention). Additional oral therapy (rifampin plus a fluoroquinolone, sulfamethoxazole; trimethoprim, a tetracycline, or clindamycin) should start after the completion of IV therapy and continue for 3 months for hip infections or for 6 months for knee infections.

    For the treatment of MRSA-associated spinal implant infections†.
    Intravenous dosage
    Adults

    The IDSA recommends 6 mg/kg/dose IV every 24 hours plus rifampin 600 mg PO once daily or 300 to 450 mg PO every 12 hours in patients with early-onset spinal implant infections (30 days or less after surgery) or implants in an actively infected site. Prolonged oral therapy (sulfamethoxazole; trimethoprim, a tetracycline, or clindamycin +/- rifampin, or a fluoroquinolone plus rifampin), should follow parenteral therapy; however, the optimal duration of parenteral and/or oral therapy is unclear. Oral therapy should be continued until spine fusion has occurred. Long term oral suppressive therapy may be considered in select cases, especially if device removal is not possible.

    For the empiric treatment of febrile neutropenia†.
    Intravenous dosage
    Adults

    6 mg/kg/dose IV every 24 hours is recommended by clinical practice guidelines for patients with suspected MRSA, vancomycin-resistant pathogens (VRE), or when vancomycin is not an option. Daptomycin as part of combination therapy with an antibiotic that has gram negative coverage has been successfully used in patients with febrile neutropenia in small studies.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    6 mg/kg/dose IV every 24 hours is FDA-approved maximum dosage; however, doses up to 12 mg/kg/dose IV every 24 hours have been used off-label.

    Geriatric

    6 mg/kg/dose IV every 24 hours is FDA-approved maximum dosage; however, doses up to 12 mg/kg/dose IV every 24 hours have been used off-label.

    Adolescents

    7 mg/kg/dose IV every 24 hours is FDA-approved maximum dosage; however, doses up to 10 mg/kg/dose IV every 24 hours have been used off-label.

    Children

    12 years: 7 mg/kg/dose IV every 24 hours is FDA-approved maximum dosage; however, doses up to 10 mg/kg/dose IV every 24 hours have been used off-label.
    7 to 11 years: 9 mg/kg/dose IV every 24 hours is FDA-approved maximum dosage; however, doses up to 10 mg/kg/dose IV every 24 hours have been used off-label.
    1 to 6 years: 12 mg/kg/dose IV every 24 hours.

    Infants

    Safety and efficacy have not been established; doses up to 10 mg/kg/dose IV every 24 hours have been used off-label.

    Neonates

    Safety and efficacy have not been established; doses up to 15 mg/kg/dose IV every 12 hours have been used off-label.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment required.

    Renal Impairment

    Adults
    CrCl 30 mL/minute or more: No dosage adjustment required.
    CrCl less than 30 mL/minute: 4 mg/kg/dose IV every 48 hours for complicated skin and skin structure infections or 6 mg/kg/dose IV every 48 hours for S. aureus bacteremia.
     
    Pediatric patients
    Dosage adjustments for pediatric patients with renal impairment have not been established; however, the following dose adjustments, based on a dose of 6 mg/kg/dose IV every 24 hours, have been recommended.
    CrCl 30 mL/minute/1.73 m2 or more: No dosage adjustment required.
    CrCl 10 to 29 mL/minute/1.73 m2: 4 mg/kg/dose (67% of a full dose) IV every 24 hours.
    CrCl less than 10 mL/minute/1.73 m2: 4 mg/kg/dose (67% of a full dose) IV every 48 hours.
     
    Neonates
    A dose of 6 mg/kg/dose IV every 24 hours was successfully used in a full-term neonate with renal impairment (serum creatinine 0.6 mg/dL) and vancomycin-resistant enterococcal bacteremia. The patient received an 8-week course of daptomycin, including 6 weeks after last positive blood culture.
     
    Intermittent hemodialysis
    Adults
    4 mg/kg/dose IV every 48 hours for complicated skin and skin structure infections or 6 mg/kg/dose IV every 48 hours for S. aureus bacteremia. When possible, the daptomycin dose should be given after hemodialysis on hemodialysis days.
    Pediatric patients
    4 mg/kg/dose (67% of a full dose) IV every 48 hours after dialysis.
     
    Peritoneal dialysis
    Adults
    4 mg/kg/dose IV every 48 hours for complicated skin and skin structure infections or 6 mg/kg/dose IV every 48 hours for S. aureus bacteremia.
    Pediatric patients
    4 mg/kg/dose (67% of a full dose) IV every 48 hours.
     
    Continuous renal replacement therapy (CRRT)
    Adults
    4 to 6 mg/kg/dose IV every 48 hours.
    Pediatric patients
    8 mg/kg/dose IV every 48 hours.

    ADMINISTRATION

    Injectable Administration

    NOTE: The two distinct formulations of daptomycin, Cubicin RF and Cubicin, have different reconstitution and storage methods.
    For intravenous (IV) administration only.
    Use a 21 gauge or smaller needle for all transfers.
    Because only limited data are available regarding compatibility with other IV substances, additives or other medications should not be added to daptomycin vials or infusion bags.
    The Cubicin RF formulation of daptomycin is compatible with 0.9% Sodium Chloride Injection, Sterile Water for Injection, and Bacteriostatic Water for Injection. The Cubicin formulation of daptomycin is compatible with 0.9% Sodium Chloride Injection and Lactated Ringer's Injection.
    Daptomycin should not be used in conjunction with ReadyMED elastomeric infusion pumps. Stability studies of daptomycin solutions stored in ReadyMED elastomeric infusion pumps identified an impurity, 2-mercaptobenzothiazole (MBT), leaching from this pump system into the daptomycin solution. MBT is used to manufacture rubber and has been reported to leach from rubber stoppers and syringe components into medicinal products. Cutaneous exposure to MBT has been associated with dermal sensitization, and chronic administration of MBT to laboratory rodents has been associated with an increased risk of certain tumors.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Cubicin RF Preparation
    Reconstitution
    Reconstitute a 500 mg vial with 10 mL of Sterile Water for Injection or Bacteriostatic Water for Injection. The vial solution concentration will be 50 mg/mL.
    Do NOT reconstitute with saline products as this will result in a hyperosmotic solution that may result in infusion site reactions if the reconstituted product is administered by IV injection over 2 minutes.
    Transfer the 10 mL of Sterile Water for Injection or Bacteriostatic Water for Injection through the center of the rubber stopper. Point the transfer needle against the inside wall of the vial.
    Prior to use, rotate or swirl the vial for a few minutes to obtain complete reconstitution.
    Vials are not preserved and are for single-use only.
    Storage (Vials): Vials reconstituted with Sterile Water for Injection are stable for 1 day at room temperature, and vials reconstituted with Bacteriostatic Water for Injection are stable for 2 days at room temperature. Vials reconstituted with either solution are stable for 3 days under refrigeration at 2 to 8 degrees C (36 to 46 degrees F).
    Storage (Syringes): Solutions reconstituted with Sterile Water for Injection are stable in polypropylene syringes with an elastomeric plunger stopper for 1 day at room temperature, and solutions reconstituted with Bacteriostatic Water for Injection are stable in this type of syringe for 2 days at room temperature. Solutions reconstituted with Sterile Water for Injection and Bacteriostatic Water for Injection are stable in this syringe for 3 days and 5 days, respectively, under refrigeration at 2 to 8 degrees C (36 to 46 degrees F).
     
    Dilution
    Adults and Pediatric patients 7 to 17 years: Further dilute in 50 mL of 0.9% Sodium Chloride Injection.
    Pediatric patients 1 to 6 years: Further dilute in 25 mL of 0.9% Sodium Chloride Injection.
    Storage: Solutions reconstituted with Sterile Water for Injection or Bacteriostatic Water for Injection that are immediately diluted with 0.9% Sodium Chloride Injection are stable for 19 hours and 2 days, respectively, at room temperature. Solutions reconstituted with Sterile Water for Injection or Bacteriostatic Water for Injection that are immediately diluted with 0.9% Sodium Chloride Injection are stable for 3 days and 5 days, respectively, under refrigeration at 2 to 8 degrees C (36 to 46 degrees F).
     
    Cubicin Preparation (including generics)
    Reconstitution
    To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.
    Reconstitute the daptomycin vial with 0.9% Sodium Chloride for Injection according to the manufacturer’s instructions to a final concentration of 50 mg/mL.
    Transfer the appropriate volume of 0.9% Sodium Chloride for Injection through the center of the rubber stopper. Point the transfer needle against the inside wall of the vial.
    Ensure that all the powder is wetted by gently rotating the vial. Allow the wetted product to stand undisturbed for 10 minutes. Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely reconstituted solution.
    Vials are not preserved and are for single-use only.
    Storage: The reconstituted solution is stable in the vial for 12 hours at room temperature and up to 48 hours if stored under refrigeration at 2 to 8 degrees C (36 to 46 degrees F).
     
    Dilution
    Adults and Pediatric patients 7 to 17 years: Further dilute in 50 mL of 0.9% Sodium Chloride Injection.
    Pediatric patients 1 to 6 years: Further dilute in 25 mL of 0.9% Sodium Chloride Injection.
    Storage: Diluted solutions are stable for 12 hours at room temperature or 48 hours under refrigeration at 2 to 8 degrees C (36 to 46 degrees F). The combined storage time (reconstituted solution in the vial and the diluted solution in the infusion bag) should not exceed 12 hours at room temperature or 48 hours under refrigeration.
     
    Cubicin RF and Cubicin Administration
    NOTE: Daptomycin should NOT be administered as an IV push in pediatric patients.
    IV Push
    Slowly remove the reconstituted 50 mg/mL solution from the vial.
    Administer via slow IV push over 2 minutes.
     
    Intermittent IV Infusion
    Adults and Pediatric patients 7 to 17 years: Infuse over 30 minutes.
    Pediatric patients 1 to 6 years: Infuse over 60 minutes.
    Additives or other medications should not be added to daptomycin or infused simultaneously through the same IV line. If the same IV line is used for sequential infusion of different drugs, flush the line with a compatible IV solution before and after daptomycin administration.

    STORAGE

    Cubicin:
    - Avoid excessive heat (above 104 degrees F)
    - Discard unused portion. Do not store for later use.
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use
    Cubicin RF :
    - Avoid excessive heat (above 104 degrees F)
    - Discard unused portion. Do not store for later use.
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: Do not use daptomycin with ReadyMED elastomeric infusion pumps due to an impurity, 2-mercaptobenzothiazole (MBT), leaching from the system into the daptomycin solution.
     
    Daptomycin is contraindicated in patients with a history of daptomycin hypersensitivity.
     
    Daptomycin is inactivated by pulmonary surfactant and should not be used in treating infections of the lung (e.g., pneumonia). Phase 3 clinical trials of daptomycin in community-acquired pneumonia showed reduced efficacy of daptomycin.

    Colitis, diarrhea, GI disease, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis

    Almost all antibacterial agents have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following daptomycin administration. Daptomycin should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    Myopathy, rhabdomyolysis

    Use daptomycin cautiously in patients with a history of myopathy (e.g., rhabdomyolysis). Daptomycin was associated with increases in serum creatine phosphokinase (CPK) during clinical trials. Rhabdomyolysis, with or without acute renal failure, has also been reported. Monitor patients for muscle pain or weakness, particularly of the distal extremities. Weekly monitoring of CPK concentrations is recommended. More frequent monitoring is recommended in patients who develop unexplained elevations in CPK while receiving daptomycin, those with renal insufficiency (adult patients), and those who received recent prior or concomitant HMG-CoA reductase inhibitor therapy. Discontinue daptomycin in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevation more than 1,000 units/L (approximately 5 times ULN). Consider temporary discontinuation of agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, in patients who are receiving daptomycin.

    Peripheral neuropathy

    Use daptomycin cautiously in patients with a history of peripheral neuropathy. Paresthesias have been reported in clinical studies with daptomycin. Cases of peripheral neuropathy have also been reported in postmarketing surveillance. Monitor patients for signs and symptoms of neuropathy while receiving daptomycin and consider discontinuation if neuropathy occurs.

    Pregnancy

    Data on the use of daptomycin in human pregnancy are insufficient to inform a drug-associated risk. Daptomycin was not teratogenic in rats and rabbits at exposures significantly higher (75 mg/kg/day) than the expected human exposure; maternal toxicity, including decreased body weight gain and food consumption, was observed at the highest dose. Due to a high molecular weight, placental crossing of daptomycin is expected to be limited. However, vancomycin, which is similar in molecular weight to daptomycin, crosses the placenta in the second trimester resulting in detectable concentrations in amniotic fluid and cord blood.

    Breast-feeding

    Daptomycin is excreted in human milk. There are no data on the effects of daptomycin on the breast-fed infant or on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for daptomycin and any potential adverse effects on the breast-fed infant from daptomycin or the underlying maternal condition. In 1 patient treated for a pelvic infection with daptomycin (6.7 mg/kg IV) and ertapenem for 28 days, daptomycin breast-milk concentrations were obtained on day 27 of therapy. Concentrations were highest at 8 hours after the dose with a concentration of 44.7 mcg/L. Twenty hours after the dose, a concentration of 29.2 mcg/L was obtained, and the final sample had no detectable drug (< 25 mcg/L). Estimated milk:plasma ratio was 0.0012. Vancomycin, clindamycin, and sulfamethoxazole; trimethoprim may be potential alternatives to consider during breast-feeding. However, site of infection, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Vancomycin is excreted in breast milk; however, absorption from the GI tract of any ingested vancomycin would be minimal. Alternative antimicrobials that previous American Academy of Pediatrics recommendations considered as usually compatible with breast-feeding include clindamycin and sulfamethoxazole; trimethoprim.

    Infants, neonates

    Safe and effective use of daptomycin have not been established in neonates and infants. Although daptomycin is used off-label in these patients, the FDA-approved product labeling recommends to avoid use in neonates and infants due to the potential for muscular, neuromuscular, and/or nervous system (both peripheral and central) adverse reactions. Animal toxicity studies have found neonatal dogs to have a higher susceptibility for daptomycin-related adverse nervous system and/or muscular reactions compared with either juvenile or adult dogs.

    Geriatric

    During clinical studies of daptomycin for various complicated or serious infections, lower clinical success rates were observed in geriatric patients compared to those younger than 65 years of age. Treatment-emergent adverse reactions were also more common in elderly patients. Daptomycin exposure was higher in healthy elderly patients than in younger adults; however, no dosage adjustment is necessary in geriatric patients with a CrCl 30 mL/minute or more. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.

    Eosinophilic pneumonia

    During postmarketing surveillance, cases of possible daptomycin-associated eosinophilic pneumonia have been reported. In general, the condition has developed after 2 to 4 weeks of daptomycin therapy and improved after stopping the drug and starting steroid therapy. Further, the condition has recurred upon rechallenge. Instruct patients to immediately contact a health care professional if they develop new or worsening fever or respiratory symptoms while receiving daptomycin; prompt evaluation, daptomycin discontinuation, and systemic steroid therapy are recommended.

    Renal failure, renal impairment

    There are limited data to determine clinical efficacy of daptomycin in patients with renal impairment or renal failure. In skin and skin structure infection trials, only 6% of patients had a CrCl < 50 mL/minute in the intent-to-treat (ITT) population. Patients with a CrCl of 30 to 50 mL/minute had a clinical success rate of 47% (n = 15 patients) with daptomycin versus 57% (n = 35 patients) with the comparator. In a subgroup analysis of the ITT population in the S. aureus bacteremia trial, patients with a CrCl of 30 to 50 mL/minute had a lower clinical success rate versus the comparator (14%, n = 14 vs. 41%, n = 17). The manufacturer recommends monitoring renal function and creatine phosphokinase (CPK) more frequently than once weekly in patients with renal impairment. Daptomycin is not recommended in pediatric patients with renal impairment because dosage adjustments have not been established in these patients.

    ADVERSE REACTIONS

    Severe

    eczema vaccinatum / Delayed / 0-1.0
    rhabdomyolysis / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    atrial flutter / Early / Incidence not known
    atrial fibrillation / Early / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    eosinophilic pneumonia / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known

    Moderate

    chest pain (unspecified) / Early / 7.0-7.0
    edema / Delayed / 7.0-7.0
    hypertension / Early / 6.0-6.0
    elevated hepatic enzymes / Delayed / 3.0-3.0
    hypotension / Rapid / 2.4-2.4
    dyspnea / Early / 2.1-2.1
    stomatitis / Delayed / 0-1.0
    jaundice / Delayed / 0-1.0
    myopathy / Delayed / 0-1.0
    eosinophilia / Delayed / 0-1.0
    thrombocytosis / Delayed / 0-1.0
    hypoprothrombinemia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    hypomagnesemia / Delayed / 0-1.0
    peripheral neuropathy / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    dyskinesia / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    bullous rash / Early / Incidence not known
    erythema / Early / Incidence not known
    dysphagia / Delayed / Incidence not known
    candidiasis / Delayed / Incidence not known
    vaginitis / Delayed / Incidence not known
    pseudomembranous colitis / Delayed / Incidence not known
    superinfection / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    prolonged bleeding time / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    hyperphosphatemia / Delayed / Incidence not known

    Mild

    vomiting / Early / 2.7-11.0
    insomnia / Early / 9.0-9.0
    diarrhea / Early / 5.2-7.0
    abdominal pain / Early / 2.0-6.0
    pruritus / Rapid / 3.1-6.0
    headache / Early / 2.7-5.4
    hyperhidrosis / Delayed / 5.0-5.0
    infection / Delayed / 2.4-5.0
    rash / Early / 4.3-4.3
    fever / Early / 3.9-3.9
    dizziness / Early / 2.2-2.2
    weakness / Early / 0-1.0
    flushing / Rapid / 0-1.0
    fatigue / Early / 0-1.0
    dysgeusia / Early / 0-1.0
    muscle cramps / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    myalgia / Early / 0-1.0
    vertigo / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    ocular irritation / Rapid / 0-1.0
    leukocytosis / Delayed / 0-1.0
    hypoesthesia / Delayed / Incidence not known
    anorexia / Delayed / Incidence not known
    nausea / Early / Incidence not known
    xerostomia / Early / Incidence not known
    cough / Delayed / Incidence not known
    vesicular rash / Delayed / Incidence not known
    tinnitus / Delayed / Incidence not known

    DRUG INTERACTIONS

    HMG-CoA reductase inhibitors: (Moderate) Daptomycin has been associated with elevated CPK in clinical trials. HMG-CoA reductase inhibitors are known to cause myopathy. Since data regarding co-administration of daptomycin with HMG-CoA reductase inhibitors are limited, temporary suspension of HMG-CoA reductase inhibitor therapy should be considered in patients receiving daptomycin.
    Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Red Yeast Rice: (Moderate) Certain red yeast rice products (i.e., pre-2005 Cholestin formulations) contain lovastatin. HMG-CoA reductase inhibitors such as lovastatin are known to cause myopathy. Elevated CPK has been reported in clinical trials of daptomycin, a lipopeptide antibiotic. In a placebo-controlled phase I trial of daptomycin that included 10 healthy subjects stabilized on simvastatin therapy, there was no increase in the incidence of adverse reactions nor was myopathy reported. However, data regarding coadministration of daptomycin with HMG-CoA reductase inhibitors are limited; temporary suspension of HMG-CoA reductase inhibitor therapy should be considered in patients receiving daptomycin.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
    Tobramycin: (Moderate) The pharmacokinetics of daptomycin and tobramycin may be altered when the two antibiotics are coadministered. The serum concentration of daptomycin may be increased and the serum concentration of tobramycin may be decreased. The manufacturer recommends caution when daptomycin is coadministered with tobramycin.
    Warfarin: (Moderate) Monitor patients for signs and symptoms of bleeding during coadministration. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. The concomitant use of warfarin with antibiotics may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. In 16 healthy adults, a 5-day daptomycin course coadministered with a single oral dose of warfarin (25 mg) on the fifth day had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR; however, there are no data describing concurrent use beyond a single warfarin dose.

    PREGNANCY AND LACTATION

    Pregnancy

    Data on the use of daptomycin in human pregnancy are insufficient to inform a drug-associated risk. Daptomycin was not teratogenic in rats and rabbits at exposures significantly higher (75 mg/kg/day) than the expected human exposure; maternal toxicity, including decreased body weight gain and food consumption, was observed at the highest dose. Due to a high molecular weight, placental crossing of daptomycin is expected to be limited. However, vancomycin, which is similar in molecular weight to daptomycin, crosses the placenta in the second trimester resulting in detectable concentrations in amniotic fluid and cord blood.

    Daptomycin is excreted in human milk. There are no data on the effects of daptomycin on the breast-fed infant or on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for daptomycin and any potential adverse effects on the breast-fed infant from daptomycin or the underlying maternal condition. In 1 patient treated for a pelvic infection with daptomycin (6.7 mg/kg IV) and ertapenem for 28 days, daptomycin breast-milk concentrations were obtained on day 27 of therapy. Concentrations were highest at 8 hours after the dose with a concentration of 44.7 mcg/L. Twenty hours after the dose, a concentration of 29.2 mcg/L was obtained, and the final sample had no detectable drug (< 25 mcg/L). Estimated milk:plasma ratio was 0.0012. Vancomycin, clindamycin, and sulfamethoxazole; trimethoprim may be potential alternatives to consider during breast-feeding. However, site of infection, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Vancomycin is excreted in breast milk; however, absorption from the GI tract of any ingested vancomycin would be minimal. Alternative antimicrobials that previous American Academy of Pediatrics recommendations considered as usually compatible with breast-feeding include clindamycin and sulfamethoxazole; trimethoprim.

    MECHANISM OF ACTION

    Lipopeptide antibiotics like daptomycin interfere with the integrity of cell wall structure in gram-positive bacteria via a unique mechanism of action. Specifically, lipopeptides bind to bacterial membranes and cause a rapid depolarization of membrane potential; they do not penetrate the bacterial cytoplasm. This loss of membrane potential leads to inhibition of protein, DNA, and RNA synthesis and, eventually, bacterial cell death. Lipopeptides appear to be bactericidal against gram-positive bacteria.[29273]
     
    Ironically, the unique mechanism causes it to be inactivated by pulmonary surfactant. Pulmonary surfactant is primarily dipalmitoylphosphatidylcholine with significant amounts of phosphatidylglycerol which is also a prominent component of gram-positive bacterial membranes. These phospholipids interact with daptomycin and sequester the antibiotic, thereby preventing it from exerting its antibacterial effects.[32686] Phase 3 clinical trials in community-acquired pneumonia showed reduced efficacy of daptomycin.[29273]
     
    Daptomycin displays rapid, concentration-dependent bactericidal activity against Gram-positive bacteria and a 'post-antibiotic effect' (PAE). 'Concentration-dependent killing' describes the principle that bactericidal effects increase as the concentration increases. PAE is where suppression of bacterial growth continues after the antibiotic concentration falls below the bacterial MIC. Based on animal models, the pharmacokinetic/pharmacodynamic (PK/PD) activity of daptomycin appears to correlate best with the area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio for certain pathogens, including S. aureus. The principal PK/PD parameter associated with clinical success has not been determined by trials.[29273] [55016]
     
    The susceptibility interpretive criteria for daptomycin are delineated by pathogen. The MICs are defined for beta-hemolytic streptococci, Streptococcus sp. viridans group, and Staphylococcus sp. as susceptible at 1 mcg/mL or less. The MICs are defined for Enterococcus sp. as susceptible at 4 mcg/mL or less. MICs are not intended to be used for respiratory isolates.[63320] [63321]
     
    Nonsusceptible isolates have emerged during daptomycin therapy. Mechanisms of resistance are not clearly defined; however, single-point mutations in mprF, the lysylphosphatidyglycerol synthetase gene, have been present in resistant strains. Additionally, prior exposure to vancomycin and elevated vancomycin MICs have been associated with increases in daptomycin MICs, which may suggest possible cross-resistance.[46693]

    PHARMACOKINETICS

    Daptomycin is administered intravenously. Protein binding is approximately 90% to 93%, primarily to albumin, and is reversible; it is not altered by daptomycin concentration, dose, or number of doses received. In patients with significant renal impairment, protein binding is decreased. Daptomycin is distributed into lung tissue; however, it is inhibited by pulmonary surfactant. The steady-state volume of distribution in healthy adults is approximately 0.1 L/kg. The metabolism of daptomycin has not been determined; however, inactive metabolites have been identified in the urine. Daptomycin is primarily (78%) excreted by the kidneys; 5.7% of a dose is excreted in the feces. The clearance and elimination half-life of daptomycin in adults is approximately 7 to 9 mL/hour/kg and 8 to 9 hours, respectively.
     
    Affected cytochrome P450 isoenzymes: none
    In vitro studies have shown that daptomycin is not metabolized by human liver microsomes. In vitro studies have also shown that daptomycin does not induce or inhibit the following CYP450 enzymes: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, or 3A4.

    Intravenous Route

    After a 30 minute intravenous infusion of daptomycin, the maximum serum concentrations (Cmax) occur in about 30 to 60 minutes (Tmax). The Cmax is approximately 57.8 mcg/mL for a dose of 4 mg/kg, 93.9 mcg/mL for a dose of 6 mg/kg, 123.3 mcg/mL for a dose of 8 mg/kg, 141.1 mcg/mL for a dose of 10 mg/kg, and 183.7 mcg/mL for a dose of 12 mg/kg. The AUC is 494 mcg x hour/mL for a dose of 4 mg/kg, 632 mcg x hour/mL for a dose of 6 mg/kg, 858 mcg x hour/mL for a dose of 8 mg/kg, 1,039 mcg x hour/mL for a dose of 10 mg/kg, and 1,277 mcg x hour/mL for a dose of 12 mg/kg. The Cmax in inflammatory fluid has a Tmax of about 4 hours. Steady state serum concentrations are obtained in about 3 days. After administration of daptomycin over a 2 minute period, the steady-state AUC value is approximately 475 mcg x hour/mL for a 4 mg/kg dose and 701 mcg x hour/mL for a 6 mg/kg dose. The Cmax for these doses was simulated to be 77.7 mcg/mL for the 4 mg/kg dose and 116.6 mcg/mL for the 6 mg/kg dose.