"How it works" series: Daptomycin

Daptomycin (Cubicin) is the first antibiotic in a class known as lipopeptides and has a unique mechanism of action.  Daptomycin is a large molecule with a high molecular weight and has two distinct sections.  One section is a 10 member amino acid ring (illustrated as the big red circle) and the other is the attached lipophilic tail (illustrated as the curvy red line).  The lipophilic tail is capable of direct insertion through the
bacterial cell membrane and no receptor or protein is required to attach to the membrane (this precludes common resistance mechanisms).  By crossing the bacterial cell membrane, a channel is formed which allows for intracellular substances, such as potassium, to be lost from the cell.  This disruption of the cell membrane potential leads to cell death.

This mechanism gives daptomycin a concentration-dependent bactericidal activity against aerobic and anaerobic gram-positive bacteria including staphylococci (including MRSA), E. faecalis, and E. faecium (including some VRE).  The bactericidal nature of daptomycin is one of its notable features because it is bactericidal even when S. aureus is in the stationary phase of growth - likely due to the mechanism of action affecting cell wall permeability rather than DNA replication or wall synthesis like many other antibiotics.  MRSA with a high MIC to vancomycin do unfortunately have a positive association with a high MIC to daptomycin.  Read more about interpreting MICs here.

Other notable features

• Once daily intravenous administration (except q48hr if ClCr <30 mL/min - use actual body weight for this calculation)

• Weight-based dose is usually 4-6 mg/kg for many infections but 10 mg/kg or higher have been studied for some infections

• Clinical trials used total body weight to determine dose (not adjusted or ideal)

• Risk of skeletal muscle toxicity (doesn't affect cardiac muscle)

• It is reasonable and recommended to check CPK weekly

• Not metabolized through liver enzymes so no interactions (just be cautious if other drugs cause muscle toxicity)

• Can cause false elevations in PT/INR

• Depends on thromboplastin reagent used so varies by lab

• If problematic, draw lab prior to administration

• Do not use for pneumonia 

• Penetration to the lung is adequate but it is inactivated by pulmonary surfactant 
• Pulmonary surfactant is composed of phosphatidylglycerol which is also a component of bacterial cell membranes

• So daptomycin inserts itself into pure surfactant vesicles in the lung and has no reversal process - meaning it becomes sequestered there and useless

Reference:
Murray BE, Nannini, EC.  Chapter 31: Glycopeptides (Vancomycin and Teicoplanin), Streptogramins, (Quinupristin-Dalfopristin), and Lipopeptides (Daptomycin).  In: Mandell GL, Bennett JE, Dolin R, eds.  Principles and practice of infectious diseases. 7th ed. Philadelphia, PA: Elsevier; 2010:449-67.

photo by drakosam