Daptomycin (Cubicin) disrupts the cell membrane of Gram-positive bacteria.

Daptomycin Uses:

• Complicated skin and skin structure infections:

  • Treatment of complicated skin and skin structure infections caused by:
    • Staphylococcus aureus (methicillin-sensitive and resistant species),
    • Streptococcus pyogenes,
    • Streptococcus agalactiae,
    • Streptococcus dysgalactiae subspecies equisimilis, and
    • Enterococcus faecalis (vancomycin sensitive species only) in adult and pediatric patients( 1-17 years old).

• Staphylococcus Aureus bacteremia:

  • Treatment of methicillin-sensitive and methicillin-resistant staphylococcus aureus bacteremia in adults (involving right-sided infective endocarditis).
  • Treatment of staphylococcus aureus bacteremia in pediatric patients (1-17 years)

Limitations of use: Cannot be used for treating pneumonia.

• Off Label Use of Daptomycin in Adults:

  • CSF shunt infection
  • Diabetic foot infections
  • Treatment of Left-sided endocarditis (caused by Staphylococcus aureus /Enterococcus)
  • Treatment of Bacterial meningitis
  • Septic arthritis or osteomyelitis due to MRSA (methicillin-resistant staphylococcus aureus
  • Native vertebral osteomyelitis
  •  Staphylococci (oxacillin-susceptible /resistant) or Enterococcus (penicillin-susceptible /resistant) causing prosthetic joint infection
  • Bacteremia secondary to vancomycin-resistant enterococci (VRE)

Daptomycin dose in Adults

Daptomycin dose in the treatment of Cerebrospinal fluid shunt infection:

• Pathogen-specific therapy (for instance, staphylococci including MRSA, C. acnes, and resistant enterococci):

  • 6 mg/kg once daily intravenous or 6 to 10 mg/kg intravenous once a day in combination with rifampicin.

• Intraventricular (preservative-free preparation in addition to intravenous dose):

  • 2 to 5 mg single dose/day.
  • Case reports have used varying dosages:
    • 10 mg once daily for 2 days, followed by 10 mg every 48 hours, 5 to 10 mg every 72 hours, or 5 mg once a day for 3 days, followed by 5 mg every 72 hours.

To ensure adequate distribution of the drug in cerebrospinal fluid, the drain should be clamped for thirty minutes to 1 hour while administering an intraventricular dose.

Note:

For patients who cannot tolerate parenteral therapy after the removal of CSF shunt (or when CSF shunt cannot be removed), intraventricular therapy is indicated.

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Daptomycin dose in the treatment of Diabetic foot infections without osteomyelitis (off-label):

• 4 mg/kg intravenous dose once every 24 hours.

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Daptomycin Dose in the treatment of endocarditis:

• Right-sided native valve Staphylococcus aureus:

  • Manufacturer labeling:

    • 6 mg/kg once a day for 2 to 6 weeks

  • Alternate dosage:

    • 8 to 10 mg/kg every 24 hours

• Left-sided native valve Staphylococcus aureus:

  • 8 mg/kg or more once a day for 6 weeks, the dose should be prescribed by an infectious disease specialist.

• Endocarditis caused by Enterococcus (resistant to penicillins,  aminoglycoside, and vancomycin):

  • 10 to 12 mg/kg once a day for a minimum of 6 weeks.
  • Patients with persistent bacteremia should be switched to combination therapy with other antibiotics such as ampicillin, ceftaroline or strains with relatively high MICs to daptomycin within the susceptible range (<4 mcg/mL).

Daptomycin alternative dosage treatment of healthcare-associated Bacterial Meningitis:

• Pathogen-specific therapy (eg, staphylococci including MRSA):

  • 6 to 10 mg/kg intravenous once daily.

Daptomycin Dose in the Treatment of Osteomyelitis caused by  MRSA:

• 6 mg/kg intravenous once a day for a minimum of 8 weeks.
• Add on therapy with rifampin (in patients with bacteremia, initiate rifampin after clearance of bacteremia) can be considered.

Daptomycin for the treatment of native vertebral  Osteomyelitis:

• Staphylococci (oxacillin sensitive or resistant):

  • 6 to 8 mg/kg intravenous once daily for 6 weeks

• Enterococcus spp (penicillin-sensitive/ resistant):

  • 6 mg/kg once intravenous daily for 6 weeks.
  • Note: add on therapy with an aminoglycoside ( for 4 to 6 weeks ) is recommended in patients with infective endocarditis

Daptomycin dose in the treatment of prosthetic joint infection:

• Enterococcus spp (penicillin-sensitive/resistant)

  • 6 mg/kg intravenous every 24 hours for 4 to 6 weeks.
  • In case of debridement and retention strategy or stage I exchange, the addition of an aminoglycoside followed by the suppressive oral antibiotic is advised.

• Staphylococci (oxacillin-susceptible or -resistant):

  • 6 mg/kg intravenous every 24 hours for 2 to 6 weeks.
  • It should be used in combination with rifampin if a debridement and retention strategy or 1-stage exchange is chosen, followed by oral antibiotic treatment (and suppressive regimen if a debridement and retention strategy or 1-stage exchange is chosen)

Daptomycin Dose in the treatment of staphylococcus aureus bacteremia:

• Manufacturer labeling:

  • 6 mg/kg intravenous once daily for 2 to 6 weeks

• Alternate dosage:

  • 8 to 10 mg/kg intravenous once daily for complicated bacteremia.

Daptomycin Dose in the treatment of Septic arthritis caused by Methicillin-Resistant Staphylococcus Aureus:

• 6 mg/kg intravenous once daily for 3 to 4 weeks.

Daptomycin Dose in the treatment of complicated skin and skin structure infections:

• 4 mg/kg intravenous once a day for 7 to 14 days

Daptomycin Dose in the Treatment of Vancomycin-resistant enterococci (VRE) bacteremia:

• 6 to 8 mg/kg intravenous once daily.
• daptomycin doses ≥9 mg/kg and ≥10 mg/kg every 24 hours have been associated with decreased mortality, in addition to increased benefit from combination therapy with a beta-lactam.
• The maximum dose has not been determined.
• The use of doses as high as 15 mg/kg has been reported.
• Higher doses should be used with caution as they can lead to various adverse effects.

Daptomycin dose in Childrens

Note:

• Daptomycin is not routinely used as first-line therapy in paedriatic patients.
• The manufacturer recommends avoiding use in patients <12 months due to musculoskeletal, neuromuscular, and nervous system adverse effects observed in neonatal canine models.

Daptomycin General dosing for severe infections caused by susceptible organisms:

• Young infants (less than 2 months of age):

  • 6 mg/kg/dose intravenous every 12 hours.

• Infants:

  • The reported dosing range is 8 to 10 mg/kg/dose intravenous every 24 hours.

• Children 1 to 5 years:

  • 10 mg/kg/ intravenous once a day.

• Children 6 years to 11 years:

  • 7 mg/kg/dose intravenous once daily.

• Children ≥12 years and Adolescents:

  • 4 to 6 mg/kg intravenous dose once daily.

Daptomycin Dose for the treatment of Bacteremia caused by Staphylococcus aureus:

Note: For the treatment of Methicillin-Resistant Staphylococcal Aureus, guideline dosing is not reflective of the inverse relationship between age and mg/kg dose.

• Children and Adolescents:

  • The treatment duration variable based on clinical response in the trials was up to 42 days.

• Children ≤ 6 years:

  • 12 mg/kg/ intravenous dose every 24 hours

• Children: 7 to 11 years:

  • 9 mg/kg intravenous dose every 24 hours

• Children ≥ 12 years and Adolescents < 17 years:

  • 7 mg/kg intravenous dose every 24 hours

• Adolescents ≥ 18 years:

  • 6 mg/kg intravenous dose every 24 hours

Daptomycin dose in the treatment of endocarditis caused by Staphylococcus (MRSA or vancomycin-resistant):

• Children <6 years:

  • 10 mg/kg intravenous dose every 24 hours

• Children ≥6 years and Adolescents:

  • 6 mg/kg intravenous dose every 24 hours

Daptomycin dose in the treatment of Osteomyelitis or septic arthritis caused by MRSA infection: 

• Children and Adolescents:

  • 6 to 10 mg/kg intravenous dose once daily

Daptomycin Dose in complicated Skin and skin structure infections caused by susceptible Staphylococcus aureus:

Note: For treatment of MRSA, guideline dosing is not reflective of the inverse relationship between age and mg/kg dose.

• Children and Adolescents:

  • Treatment duration: Up to 14 days

• Children: 1 to <2 years:

  • 10 mg/kg intravenous dose every 24 hours

• Children: 2 to 6 years:

  • 9 mg/kg intravenous dose every 24 hours

• Children: 7 to 11 years:

  • 7 mg/kg intravenous dose every 24 hours

• Children and Adolescents:

  • 12 to 17 years: 5 mg/kg intravenous dose every 24 hours

• Adolescents ≥18 years:

  • 4 mg/kg intravenous dose every 24 hours

Pregnancy Risk Factor: C

• Negative effects in animal reproduction have not been shown.
• There is limited information available about the success of daptomycin use in the second and third trimesters.

Daptomycin use during breastfeeding:

• Although daptomycin is found in breast milk in a lower quantity, oral absorption is quite poor.
• According to the manufacturer's instructions, the decision about whether to continue breastfeeding or not during therapy will depend on the risks to infant exposure and the benefits to the mother.
• Breast milk can cause non-dose-related changes in the bowel flora.
• Monitor infants for Gastrointestinal disorders.

Daptomycin (Cubicin) dose in renal disease:

• Creatinine Clearance ≥30 mL/minute:

  • No dosage adjustment required

• Creatinine Clearance <30 mL/minute:

  • Skin and soft tissue infections:

    • 4 mg/kg every 48 hours

  • Staphylococcal bacteremia:

    • 6 mg/kg every 48 hours

• End-stage renal disease (ESRD) on intermittent hemodialysis (IHD):

  • Note:

    • It is 15% Dialyzable via hemodialysis, 50% is removed by 4-hour high permeability intermittent hemodialysis session.
    • A notable amount of drug may be removed in the last 30 minutes of dialysis.
    • Administration after dialysis is completed is preferred.

  • Dose as per Manufacturer's labeling:

    • Dose as in Creatinine Clearance <30 mL/minute (administer after hemodialysis on dialysis days).

  • Alternate dosing:

    • Administer the usual recommended dose (4 or 6 mg/kg) on 48 hour intradialytic days.
    • Increase the dose by 50% after dialysis on the 72-hour intradialytic day (eg, if the dose is 6 mg/kg for a patient on a Monday, Wednesday, Friday dialysis schedule, administer 6 mg/kg after dialysis on Monday and Wednesday and on Friday administer 9 mg/kg after dialysis).

  • Peritoneal dialysis (PD):

    • Dose as in Creatinine Clearance <30 mL/minute

• Continuous renal replacement therapy (CRRT):

  • Drug clearance is affected by the method of renal replacement, filter type, and flow rate.
  • Appropriate dosing requires adequate monitoring of pharmacologic response, early adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate).
  • The following are general recommendations only (based on dialysate flow/ ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment.

    • Continuous venovenous hemodialysis (CVVHD):

    • 8 mg/kg every 48 hours
• Note:
  • Dosage such as  4 to 6 mg/kg every 24 hours (or 8 mg/kg every 48 hours) depending on the response and the site or severity of the infection.
  • Therapeutic drug monitoring and/or more frequent serum CPK levels may be necessary.

    • Slow extended daily dialysis (or extended dialysis):

      • 6 mg/kg every 24 hours
    • Note:
      • Dialysis should be started within 8 hours of administering daptomycin dose to prevent toxicity.

Daptomycin (Cubicin) dose in liver disease:

• Mild to moderate impairment (Child-Pugh class A or B):

  • No dosage adjustment necessary.

• Severe impairment (Child-Pugh class C):

  • There are no dosage adjustments provided in the manufacturer's labeling (it has not been studied).

Side Effects of Daptomycin (Common):

• Cardiovascular:

  • Chest Pain
  • Edema
  • Hypertension
  • Hypotension

• Central Nervous System:

  • Insomnia
  • Headache
  • Dizziness

• Dermatologic:

  • Pruritus
  • Diaphoresis
  • Skin Rash

• Gastrointestinal:

  • Diarrhea
  • Abdominal Pain
  • Vomiting

• Genitourinary:

  • Urinary Tract Infection

• Hepatic:

  • Abnormal liver Function Tests
  • Increased Serum Alkaline Phosphatase

• Infection:

  • Gram-Negative Organism Infection
  • Bacteremia
  • Sepsis

• Neuromuscular & Skeletal:

  • Increased Creatine Phosphokinase

• Respiratory:

  • Pharyngolaryngeal Pain
  • Dyspnea

• Miscellaneous:

  • Fever

Uncommon Side effects of daptomycin (Cubicin):

• Cardiovascular:

  • Atrial Fibrillation
  • Atrial Flutter

• Central Nervous System:

  • Hallucination
  • Hypoesthesia (Including Oral)

• Endocrine & Metabolic:

  • Increased Serum Phosphate

• Gastrointestinal:

  • Decreased Appetite
  • Epigastric Distress
  • Gingival Pain
  • Oral Candidiasis
  • Xerostomia

• Genitourinary:

  • Fungal Urinary Tract Infection
  • Proteinuria
  • Vulvovaginal Candidiasis

• Hematologic & Oncologic:

  • lymph node enlargement

• Hepatic:

  • Increased Serum ALT
  • Increased Serum AST

• Infection:

  • Candidiasis
  • Fungal Septicemia

• Neuromuscular & Skeletal:

  • Dyskinesia

• Ophthalmic:

  • Blurred Vision

• Otic:

  • ringing sensation in ears

• Renal:

  • Renal Insufficiency

Contraindication of Daptomycin (Cubicin):

• Allergy to any component of the formulation or daptomycin

Warnings and precautions

• Eosinophilic pneumonia:

  • Eosinophilic pneumonia can be caused by daptomycin; it usually develops between 2 and 4 weeks after treatment initiation.
  • You should be aware of signs and symptoms such as fever, shortness, chest pain, worsening, or new onset, or worsening, of eosinophilic pneumonia.
  • If you notice signs or symptoms of eosinophilic pneumonia, stop using the medication immediately and seek appropriate treatment (e.g. corticosteroids).
  • Re-exposure may cause recurrences.

• Hypersensitivity

  • It can cause hypersensitivity reactions and anaphylaxis, including angioedema and drug rash with Eosinophilia or systemic symptoms [DRESS]). In this instance, it should be immediately removed and the appropriate treatment should begin.

• Myopathy/ rhabdomyolysis:

  • Daptomycin can be associated with myopathy and rhabdomyolysis with or without acute kidney failure.
  • Myopathy, an increase in CPK (>5x upper normal limit or 1000 units/L), or in patients who are symptomatic and have a CPK >=10x upper normal limit or >2,000 unit/L should prompt the drug to be discontinued.
  • Myopathy can be caused by higher doses.
  • You might consider temporarily suspending therapy while you are receiving daptomycin therapy.

• Peripheral neuropathy:

  • When daptomycin is administered, symptoms of peripheral neuropathy are often reported.

• Superinfection

  • Clostridium difficile-associated diarrhea (Clostridium difficile-associated diarrhea) can develop after long-term therapy.

• Endocarditis or Staphylococcus Aureus bacteremia persistant and/or relapsing:

  • Repeat blood cultures in patients with persisting or relapsing staphylococcus aureus bacteremia/endocarditis or poor clinical response.
  • To rule out sequestered foci, perform minimum inhibitory dose (MIC) susceptibility testing on the culture if it is positive.
  • It may be necessary to perform appropriate surgical intervention, such as removal of prosthetic devices or valve replacement surgery, and/or consider changing antibacterial therapy.

• Renal impairment

  • In severe renal impairment (Creatinine Clearance 30mL/minute), dosage adjustment is necessary.
  • Limited data (eg subgroup analysis) from cSSSI trials and endocarditis trials suggests possible decreased clinical efficacy (relatively to comparators).

Daptomycin: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor D (Consider therapy modifications)
HMG-CoA Reductase Inhibitors (Statins)	DAPTOmycin may have an adverse/toxic effect. Particularly, there may be an increase in the risk of skeletal muscles toxicity. Treatment: Before you start daptomycin, consider temporarily stopping HMGCoA reductase inhibitor treatment. Regular (i.e. at least weekly) monitoring is recommended for CPK concentrations if used in combination.

 

Monitor:

• Monitor signs and symptoms of infection.
• Creatinine Phosphokinase should be monitored once a week during therapy.
• If the patient is on concurrent statin therapy, monitoring should be more frequent.
• Check for early red flags such as unexplained CPK increase, renal impairment, myopathy, especially in distal extremities.
• Peripheral neuropathy should also be taken into account.
• The monitoring of signs/symptoms of eosinophilic pneumonia should be done regularly.

How to administer Daptomycin (Cubicin)?

• Administer as an intravenous infusion over half an hour.
• Can be given as Intravenous push in two minutes.
• ReadyMED elastomeric infusion pumps (Cardinal Health, Inc) should not be used in combination due to an impurity (2-mercaptobenzothiazole) leaking from the pump system into the daptomycin solution.

Intraventricular (off-label route):

• Only preservative-free preparation is recommended.
• In order to have a proper distribution of the drug in a Cerebrospinal fluid solution, the drain should be clamped for a half-hour to 60 minutes after administration.

Mechanism of action of Daptomycin (Cubicin):

• After binding to cells membrane components, Daptomycin causes rapid depolarization and inhibits intracellular synthesis. 
• Daptomycin is bactericidal in a concentration-dependent manner.

Protein binding is

• 90% to 93% It is 84%-88% for patients who have a Creatinine Clearance less than 30ml/minute

Metabolism:

• We have detected very small amounts of oxidative metabolisms

Half-life elimination:

• Neonates and Infants less than 3 months: Median: 6.2 hours (range: 3.7 to 9 hours)
• Children 2 to 6 years: Mean range: 5.3 to 5.7 hours
• Children 7 to 11 years: 5.6 ± 2.2 hours
• Children 12 to 17 years: 6.7 ± 2.2 hours
• Adults: 8 to 9 hours (up to 28 hours in renal impairment)

Excretion:

• Urine (78%; primarily as unchanged drug), feces (5.7%)

Clearance:

• Neonates and Infants less than 3 months of age: Median: 21 mL/hour/kg (range: 16 to 34 mL/hour/kg)
• Children 2 to 6 years: 19 to 20 mL/hour/kg
• Children 7 to 11 years: 17 mL/hour/kg (Abdel-Rahman 2008)
• Children: 12 to 17 years: 11 mL/hour/kg (Abdel-Rahman 2008)
• Adults: 8.3 to 9 mL/hour/kg

Daptomycin Brand Names (International):

• Cubicin
• Cubicin RF

Daptomycin Brand Names in Pakistan:

No Brands Available in Pakistan.