Daptomycin

Drug information
    Introduction
    Antimicrobial activity
    Dose/Routes of administration
    Therapeutic Drug Monitoring (checking levels)
    Pharmacokinetics
    Allergy advice
    Key interactions (include BNF black dot)
    Side effects and monitoring required
Drug indications
    Prophylaxis indications in LTHT
    Treatment indications in LTHT
    Prescribing restriction: FULLY RESTRICTED
    Microbiology Laboratory Testing Issues

This document provides guidelines for Microbiologists [including trainees] regarding the situations in which it would be appropriate to consider the use of Daptomycin . This document is supplementary to, and should be used in conjunction with, the summary of product characteristics.

The use of Daptomycin can be considered within its currently approved LTHT Drugs and Therapeutics Group [DTG] application; other indications will require chairman’s action.

Daptomycin is a cyclic lipopeptide antibiotic with potent bactericidal activity against most Gram positive organisms, including multiple antibiotic-resistant strains.  The mechanism of action has been described as being novel and it involves the insertion into and disruption of the functional integrity of the Gram positive plasma membrane. This results in rapid loss of membrane potential, cessation of macromolecular synthesis and cell death.

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Daptomycin is active against a range of aerobic and anaerobic Gram positive bacteria but has no significant anti Gram negative activity.

Daptomycin should be co-administered with appropriate antibacterial agents or other agents should be considered in cases of mixed infections where Gram negative and/or certain types of anaerobic bacteria are suspected.

Daptomycin has in vitro activity against:
Staphylococcus aureus [meticillin resistant and meticillin susceptible strains]
Coagulase negative staphylococci
Streptococci [including β-haemolytic streptococci and Streptococcus pneumoniae]
Enterococci

Daptomycin does not have in vitro activity against:
Gram negative bacteria

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Daily dose varies between 4 mg/kg and 6mg/kg administered over 30 minutes once every 24 hours   
Depending on the clinical indication, as below.

Dose adjustment in renal impairment/failure
Dosage adjustments are required in patients with a creatinine clearance of <30ml/min, including those receiving haemodialysis or CAPD. The recommended dosing interval for patients with a creatinine clearance of <30ml/min is every 48 hours. Haemodialysis patients should receive their dose after the dialysis session. The mg/kg dosing regimen should reflect the clinical indication e.g. 6mg/kg 48 hourly for endocarditis

Dosage adjustments based on age are not recommended for elderly patients with normal renal function.

Dose in obesity
No dosage adjustment is recommended for obese patients.

Dose in liver failure
It is unlikely that dosage adjustments would be necessary since there is no in vitro evidence of liver metabolism.

Paediatric doses
Daptomycin is not listed in the BNFc.
The pharmacokinetics of Daptomycin after a single 4 mg/kg dose of Cubicin were evaluated in three groups of paediatric patients with proven or suspected Gram-positive infection (2-6 years, 7-11 years and 12-17 years). The pharmacokinetics of Daptomycin following a single 4 mg/kg dose in adolescents aged 12-17 years are generally similar to those of healthy adult subjects with normal renal function however efficacy was not assessed in this study.

There is no specific dosing guideline because the number of paediatric patients treated with Daptomycin is currently too small. Based on published papers to date, 4–6 mg/kg once daily may be an appropriate initial dose for children 7–17 years of age, with a dose of 6–10 mg/kg once daily for children 2–6 years of age and 6 mg/kg twice daily for infants to account for the more rapid clearance observed in this age group.

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Not required.
Check creatinine phosphokinase at baseline and weekly intervals during therapy.

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Absorption: Daptomycin must be given by intravenous infusion; there is no oral preparation available.

Distribution: The distribution of Daptomycin is limited to plasma and interstitial fluid and is highly bound to plasma proteins. Blood brain barrier penetration – Animal model work suggests that daptomycin does cross the blood CSF barrier (Cottagnoud et al., 2004) but there is no clinical evidence to support use of Daptomycin for central nervous system infections.

Excretion/metabolism: It is not known whether Daptomycin is a substrate of the cytochrome P-450 system. It is primarily excreted by the kidneys. Renal elimination does not appear to be dose dependent.

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Anaphylaxis/hypersensitivity reactions have been reported with Daptomycin . If an allergic reaction to daptomycin occurs, discontinue use and institute appropriate therapy.

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Increased risk of myopathy when Daptomycin is given with the following:

• ciclosporin (preferably avoid concomitant use)
• fibrates (preferably avoid concomitant use)
• statins (preferably avoid concomitant use)

[THIS LIST IS NOT EXHAUSTIVE]

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Creatinine phosphokinase should be measured at baseline and weekly intervals during therapy.
Muscle aches, myalgia and myopathy are recognised side effects.
Constipation [6.2%], nausea [5.8%], injection site reaction [5.8%], headache [5.4%], diarrhoea [5.2%], insomnia [4.5%], rash [4.3%] and vomiting [3.2%].
Liver function abnormalities [3.0%], elevated creatinine phosphokinase [2.8%], pruritus [2.8%], arthralgia [0.9%] (Schriever et al., 2005).

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Daptomycin is not recommended for this purpose.

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There are concerns about resistance developing on treatment. In some complex situations, Daptomycin may be combined with other agents like rifampicin.

1. Skin and soft tissue infections in adults caused by Gram positive organisms when beta-lactams, glycopepetide, clindamycin or oral linezolid therapy cannot be used because of

• intolerance,
• contraindications,
• failure of therapy, or
• antimicrobial resistance.

The recommended dose is 4 mg/kg administered once every 24 hours for 7-14 days.  If infection has not resolved in this period clinical review is recommended.

2. Right-sided infective endocarditis [RIE] due to Staphylococcus aureus when beta-lactams or glycopepetide therapy cannot be used because of:

• intolerance,
• contraindications,
• failure of therapy, or
• antimicrobial resistance

The recommended dose is 6 mg/kg administered once every 24 hours [see dose adjustments for patients with renal insufficiency]. The duration of therapy should be in accordance with available official recommendations. See LTHT guidelines for PVE, NVE.

3. Staphylococcus aureus bloodstream infection when associated with cSSTI when beta-lactams, glycopepetides, clindamycin or oral linezolid therapy cannot be used because of:

• intolerance,
• contraindications,
• failure of therapy, or
• antimicrobial resistance

The recommended dose is 6 mg/kg administered once every 24 hours [see above for dose adjustments in patients with renal insufficiency]. The duration of therapy may need to be longer than 14 days in accordance with the perceived risk of complications in the individual patient.

Unlicensed indication:

4. Infective endocarditis caused by susceptible Gram positive organisms [including left sided Staphylococcus aureus endocarditis] when beta-lactam or glycopepetide therapy cannot be used because of:

• intolerance,
• contraindications,
• failure of therapy, or
• antimicrobial resistance.

The recommended dose is 6 mg/kg administered once every 24 hours [see above for dose adjustments in patients with renal insufficiency].

5. Bloodstream infection caused by susceptible Gram positive organisms (except where the primary infection is pulmonary) when beta-lactams, glycopepetides, clindamycin or oral linezolid therapy cannot be used because of:

• intolerance,
• contraindications,
• failure of therapy, or
• antimicrobial resistance.

The recommended dose is 6 mg/kg administered once every 24 hours [see above for dose adjustments in patients with renal insufficiency]. The duration of therapy may need to be longer than 14 days in accordance with the perceived risk or presence of complications in the individual patient.

Daptomycin can facilitate OPAT.

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Daptomycin can only be prescribed with approval from a consultant medical microbiologist/Infectious disease physician.  The prescribing clinician will be required to complete a generic restricted antimicrobial request form which will be used to audit use.

Microbiology trainees can recommend dapomycin in categories 1-3 but should discuss the recommendation with the on-call Consultant at the earliest opportunity.

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Microbiology determination required on known pathogen.

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