54: Daptomycin use in adult critical care patients

In this episode I’ll discuss the use of daptomycin in the context of adult critically ill patients.
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Mechanism of action

Daptomycin demonstrates concentration-dependent bactericidal activity against essentially all gram positive organisms.  It has a unique mechanism of action.  Daptomycin binds to bacterial cell membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of DNA, RNA, and protein synthesis, which results in bacterial cell death.

Indications

Due to daptomycin’s high cost (~$1/mg) and the principle of reserving certain antibiotics for resistant or serious infections, daptomycin is frequently restricted and used second line unless allergies, resistance, or contraindications to other agents exist.

FDA approved

Daptomycin is approved for use in complicated skin and skin structure infections and in staphylococcal bacteremia including right sided endocarditis.

Off label

Daptomycin is also used for osteomyelitis, septic arthritis, hepatic or splenic abscess, and severe infections caused by methicillin resistant staphylococcus aureus or vancomycin resistant enterococci.

Pregnancy category

Daptomycin is pregnancy category B.

Dosing

In general, the more severe the infection the higher the dose of daptomycin that should be used.

Skin infection

For skin infection use daptomycin 4mg/kg IV q24 hrs.

All other infections

For all other infections use daptomycin 6 mg/kg IV q24 hrs.

Many references as well as the ID Society of America MRSA Guidelines say “some experts recommend higher doses of 8-10mg/kg”.  This appears to be due to the idea that higher doses are safe and might prevent the development of on-treatment resistance.  A manufacturer sponsored study examining this concept was recently terminated due to lack of enrollment.  A recent article proposed using higher doses of daptomycin to prevent the development of resistance.  Keep an eye out for changes in dose recommendations for daptomycin!

Update: Evidence for higher doses has gotten stronger – see episode 153 and episode 254.

Renal dose adjustment

Daptomycin is primarily excreted in the urine and needs to be adjusted for renal impairment.  Because daptomycin exhibits concentration-dependent killing (similar to aminoglycosides) the frequency – not the dose – is reduced.

Creatinine clearance less than 30 mL/min or hemodialysis

Reduce the frequency of daptomycin to q48 hrs in the setting of creatinine clearance less than 30 mL/min or hemodialysis.

Continuous renal replacement therapy

Most references state to reduce the frequency of daptomycin to q48 hrs in the setting of continuous renal replacement therapy.  However, for severe infections at least one author recommends using daptomycin every 24 hours if the patient is on continuous venovenous hemodiafiltration.  Go to episode 13 for more on the dosing of antibiotics in the setting of continuous renal replacement therapy.

Hepatic adjustment

No dose adjustment is indicated in mild to moderate hepatic impairment.  Daptomycin has not been well studied in patients with severe hepatic impairment.

Noteable adverse effects

Myopathy with or without creatine phosphokinase (CPK) elevation occurs in a dose dependent manner with daptomycin use.  This is reversible with cessation of daptomycin therapy.

Rarely, daptomycin has been associated with eosinophilic pneumonia.  This has generally occurred with use for longer than 2 weeks.

Resistance

On-treatment resistance of daptomycin is known to occur.  If a patient receiving daptomycin has persistent bacteremia, this may signal the development of resistance.

Monitoring

I check creatinine phosphokinase levels weekly in patients on daptomycin, and I’ll increase this to several times per week if the patient is on continuous renal replacement therapy or if a dose > 6mg/kg is being used.

Drug interactions

There is a widely considered interaction between statins and daptomycin, and it is recommended to withhold the statin while giving daptomycin.  This interaction does not appear to be clinically meaningful, as CPK elevations and myopathy that occur when using daptomycin and statins resolve quickly.  Think twice about withholding a statin during daptomycin therapy, especially if the patient has a compelling need for the statin such as a recent myocardial infarction.  Instead, increase your frequency of monitoring CPK to several times per week.

Clinical pearls

1. Daptomycin is inactivated by lung surfactant and cannot be used for pneumonia.  It is OK however to use daptomycin in the setting of infective endocarditis with septic pulmonary embolii.

2. There is no such thing as a STAT daptomycin dose.  The powder takes a long time (at least 15 minutes) to dissolve.

3. Daptomycin has no anticoagulant effect but it may falsely prolong the INR.  If this occurs, draw the INR 24 hours after the daptomycin dose to minimize the effect.

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If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.

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