The Gram-positive bacteria's cell membrane is damaged by daptomycin (Cubicin).

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:

  • Adults with bacteremia caused by methicillin-sensitive and methicillin-resistant Staphylococcus aureus should get treatment (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 intravenously given once day, or 6 to 10 mg/kg intravenously given once daily when combined with rifampicin.

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

  • 2 to 5 mg single dose/day.
  • Case reports have used varying dosages:
    • 5 to 10 mg every 72 hours, 10 mg once daily for two days, then 10 mg every 48 hours, or 5 mg once daily for three days, then 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):

• Intravenous dose of 4 mg/kg given 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 given once day for two to six weeks.

  • Alternate dosage:

    • Every 24 hours, 8 to 10 mg/kg

• 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 given once daily for at least 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):

  • 6–10 mg/kg intravenously administered once day.

Daptomycin Dose in the Treatment of Osteomyelitis caused by  MRSA:

• For at least eight weeks, administer 6 mg/kg intravenously once each day.
• 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):

  • Six weeks of intravenous administration of 6 to 8 mg/kg

• Enterococcus spp (penicillin-sensitive/ resistant):

  • 6 mg/kg once intravenous daily for 6 weeks.
  • Note: Patients with infective endocarditis are advised to get further treatment with an aminoglycoside for four to six weeks.

Daptomycin dose in the treatment of prosthetic joint infection:

• Enterococcus spp (penicillin-sensitive/resistant)

  • 6 mg/kg intravenously given every day for four to six 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 intravenously given every day for two to six 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 intravenously given once per day for 2 to 6 weeks

• Alternate dosage:

  • For complex bacteremia, administer 8–10 mg/kg intravenously once daily.

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

• For 3 to 4 weeks, provide 6 mg/kg intravenously once day.

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

• Thrice daily for seven to fourteen days, 4 mg/kg intravenous

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

• 6 to 8 mg/kg intravenous once daily.
• Daptomycin doses of 9 mg/kg and 10 mg/kg every 24 hours have been linked to a lower mortality rate as well as an improved outcome with beta-lactam combination therapy.
• The maximum dose has not been determined.
• There have been reports of using doses as high as 15 mg/kg.
• Higher doses should be used with caution as they can lead to various adverse effects.

Daptomycin dose in Children

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):

  • Every 12 hours, an intravenous dose of 6 mg/kg.

• Infants:

  • The recommended intravenous dosage range is 8 to 10 mg/kg/dose per 24 hours.

• Children 1 to 5 years:

  • One intravenous dose of 10 mg/kg every day.

• Children 6 years to 11 years:

  • One intravenous dose of 7 mg/kg every day.

• Children ≥12 years and Adolescents:

  • Intravenous dose of 4 to 6 mg/kg given once day.

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:

  • Every day, an intravenous dose of 7 mg/kg

• Adolescents ≥ 18 years:

  • 24 hour intravenous dosage of 6 mg/kg

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

• Children <6 years:

  • Intravenous dosage of 10 mg/kg every 24 hours

• Children ≥6 years and Adolescents:

  • 24 hour intravenous dosage of 6 mg/kg

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

• Children and Adolescents:

  • Once daily intravenous dosage of 6 to 10 mg/kg

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:

  • Intravenous dosage of 10 mg/kg every 24 hours

• Children: 2 to 6 years:

  • 24 hour intravenous dosage of 9 mg/kg

• Children: 7 to 11 years:

  • Every day, an intravenous dose of 7 mg/kg

• Children and Adolescents:

  • 5 mg/kg IV dose every 24 hours for children aged 12 to 17.

• Adolescents ≥18 years:

  • Every 24 hours, an intravenous dose of 4 mg/kg.

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:

  • Dosage adjustment not required

• Creatinine Clearance <30 mL/minute:

  • Skin and soft tissue infections:

    • Every 48 hours, 4 mg/kg

  • Staphylococcal bacteremia:

    • Every 48 hours, 6 mg/kg

• 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):

  • The technique of renal replacement, the type of filter, and the flow rate all have an impact on drug clearance.
  • Adequate monitoring of the pharmacologic response, early adverse events brought on by drug buildup, and drug concentrations in respect to the target trough are all necessary for proper dosing (if appropriate).
  • Based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function, the following general suggestions should not replace clinical judgement.

    • Continuous venovenous hemodialysis (CVVHD):

    • Every 48 hours, 8 mg/kg
• Note:
  • Depending on the response and the site or severity of the illness, the dosage may range from 4 to 6 mg/kg every 24 hours (or 8 mg/kg every 48 hours).
  • 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):

  • No dosage adjustments on manufacturer's labeling 

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.