daptomycin

daptomycin
IUPAC name	N-Decanoyl-L-tryptophyl-L-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-three-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine ε1-lactone
Width	200
Tradename	Cubicin, others
Drugs.com	Monograph
MedlinePlus	a604008
Pregnancy AU	B3
Routes of administration	Intravenous
CAS number	103060-53-3
ATC prefix	J01
ATC suffix	XX09
PubChem	16129629
DrugBank	DB00080
ChemSpiderID	10482159
UNII	NWQ5N31VKK
ChEBI	50845
ChEMBL	744
Chemical formula	C72H101N17O26
Molecular weight	1620.67 g·mol−1
Bioavailability	N/A
Protein bound	90–93%
Metabolism	Not extensively metabolized
Elimination half-life	8–9 hours
Excretion	Kidney (78%)

daptomycin is a cyclic lipopeptide antibiotic derived from the fermentation of Streptomyces roseosporus. It is a bactericidal agent with a unique mechanism of action, primarily used to treat serious Gram-positive bacterial infections. Developed by Cubist Pharmaceuticals, it is a critical therapeutic option for infections caused by resistant pathogens like methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci.

History and development

The discovery of daptomycin originated from research at the Eli Lilly and Company laboratories, where it was isolated from the soil bacterium Streptomyces roseosporus. Initial clinical development was halted in the late 1990s due to concerns over musculoskeletal toxicity observed in trials for community-acquired pneumonia. The compound was subsequently licensed to Cubist Pharmaceuticals, which conducted pivotal trials demonstrating its safety and efficacy for skin and skin structure infections and Staphylococcus aureus bacteremia. The U.S. Food and Drug Administration approved it in 2003, marking a significant advancement in the antibiotic arsenal against resistant Gram-positive organisms.

Mechanism of action

Daptomycin exerts its bactericidal effect through a calcium-dependent binding to the bacterial cell membrane. It inserts into the cytoplasmic membrane, causing rapid depolarization of the membrane potential. This depolarization halts critical intracellular processes such as DNA, RNA, and protein synthesis, leading to bacterial cell death without causing lysis. This unique mechanism distinguishes it from other classes of antibiotics like beta-lactams or glycopeptides, which target cell wall synthesis.

Spectrum of activity

Daptomycin displays potent in vitro activity against a broad range of Gram-positive bacteria. Its spectrum includes Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus and strains with reduced vancomycin susceptibility), Streptococcus pyogenes, Streptococcus agalactiae, and Enterococcus species (including vancomycin-resistant enterococci). It is not active against Gram-negative bacteria due to the inability to penetrate their outer membrane. The Clinical and Laboratory Standards Institute provides specific breakpoint (microbiology) guidelines for interpreting susceptibility testing.

Clinical use

Daptomycin is indicated for the treatment of complicated skin and skin structure infections caused by susceptible Gram-positive organisms. It is also approved for Staphylococcus aureus bacteremia, including those with right-sided infective endocarditis. Administration is exclusively via intravenous infusion, typically once daily. Its use is often reserved for infections where first-line agents like vancomycin have failed or are not tolerated, or in the context of documented resistance, as guided by institutions like the Infectious Diseases Society of America.

Adverse effects and resistance

The most notable adverse effect is myopathy, manifesting as muscle pain or weakness, with associated elevations in creatine phosphokinase. Regular monitoring of creatine phosphokinase levels is recommended. Other potential effects include peripheral neuropathy, eosinophilic pneumonia, and gastrointestinal disturbances. While resistance remains uncommon, emergence has been reported, often associated with mutations in genes like mprF and yycG, which alter cell membrane charge and thickness. Surveillance programs like the SENTRY Antimicrobial Surveillance Program track resistance patterns.

Pharmacokinetics and pharmacodynamics

Daptomycin exhibits linear pharmacokinetics with a volume of distribution approximating total body water. It is highly protein-bound, primarily to human serum albumin, and is not metabolized by the cytochrome P450 system. The primary pharmacodynamic index correlating with efficacy is the ratio of the area under the curve to the minimum inhibitory concentration. Elimination is predominantly renal, requiring dosage adjustment in patients with impaired renal function as defined by the Cockcroft-Gault equation. The prolonged post-antibiotic effect contributes to its once-daily dosing regimen.

Category:Antibiotics Category:Lipopeptide antibiotics