Daptomycin

Absorption

Daptomycin administered as a 30 minute IV infusion to healthy volunteers in doses of 4, 6, 8, 10, and 12 mg/kg once daily resulted in a Cmax between 57.8 ± 3.0 and 183.7 ± 25.0 μg/mL and an AUC0-24 of between 494 ± 75 and 1277 ± 253 μg*h/mL. Daptomycin pharmacokinetics are generally linear, with some variation observed above 6 mg/kg, and the Cmax and AUC values are approximately 20% higher at steady-state, suggesting some accumulation. Steady-state trough concentrations between 5.9 ± 1.6 and 13.7 ± 5.2 μg/mL are reached following the third once-daily dose.
The data for a single daptomycin dose of 6 mg/kg administered IV over 30 minutes was used to estimate steady-state Cmax values for both 4 and 6 mg/kg doses administered over two minutes, which were estimated at 77.7 ± 8.1 and 116.6 ± 12.2 μg/mL, respectively. Administration of IV daptomycin (4 or 6 mg/kg) over two minutes did not allow for measurement of the Cmax but resulted in steady-state AUC values of 475 ± 71 and 701 ± 82 μg*h/mL.
Patients with severe renal impairment and those on dialysis had mean steady-state AUC values approximately 2-3 times higher than those with normal renal function. No clinically significant differences in daptomycin pharmacokinetics were observed in patients with mild to moderate hepatic impairment. The mean AUC0-∞ obtained in healthy elderly individuals (75 years of age and older) was approximately 58% higher than in healthy young adult controls, with no difference in Cmax. The AUC0-∞ is also increased in obese patients by approximately 30%. No significant differences in body weight- and age-adjusted Cmax or AUC was observed in pediatric patients.

Toxicity

Toxicity information regarding daptomycin is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as myopathy, rhabdomyolysis, muscular/neurological system symptoms, eosinophilic pneumonia, tubulointerstitial nephritis, vomiting/diarrhea, abdominal pain, headache, dizziness, pyrexia, sweating, and pruritus. Symptomatic and supportive measures are recommended, including maintenance of glomerular filtration. Due to its high serum protein binding, daptomycin is not easily removed by hemodialysis (~15% of a dose over four hours) or peritoneal dialysis (~11% of a dose over 48 hours). High-flux membranes in hemodialysis may improve the quantity of daptomycin removed using this approach.

Description

Daptomycin is the first entry of a new class of cyclic lipopeptide antibiotics that disrupts multiple aspects of bacterial membrane function including disruption of membrane potential and amino acid transport, inhibition of lipoteichoic acid synthesis and inhibition of peptidoglycan synthesis. It is indicated for the treatment of complicated skin and skinstructure infections (cSSSI) caused by a range of Gram-positive bacteria. This is distinct from previous classes of antibiotics that inhibit bacterial cell wall biosynthesis, bacterial DNA replication, and folate coenzyme biosynthesis. Due to this unique mechanism, cross-resistance has not been noted with any other class of antibiotics. It is produced by the fermentation of Streptomyces roseporus. The fatty acid side chain is a key determinant of acute toxicity, with the ten-carbon chain least acutely toxic to mice. Daptomycin has shown efficacy in a variety of animal models versus several Grampositive infectious agents including methicillin-susceptible S aureus, vancomycinresistant E faecalis, spyogenes and S pneumoniae. It retains in vitro activity against methicillin, vancomycin and linezolid-resistant strains including Staphylococcus aureus (MRSA and VRSA), which is the leading cause of hospital-acquired infections (nosocomial infections (Nis)). The MIC values against Gram-positive pathogens are relatively low, ranging from 0.06 to 2.0 mg/mL. In two clinical studies treating patients (ca. 1090 for both arms of both studies) with complicated skin and soft tissue infections (cSSTIs) in which gram-positive pathogens were suspected and parenteral antibiotics were required, daptomycin provided similar clinical success rates as compared to standard therapy with vancomycin or semisynthetic penicillins such as cloxacillin, oxacillin, or flucloxacillin. The daptomycin treated group showed more rapid improvement as noted by scoring on day three or four and also had a shorter duration of treatment versus the standard therapy group (7 vs 8 days). It is dosed once daily (4 mg/kg/day) by intravenous infusion and has a half-life of 8.1 h. It is primarily cleared renally and thus requires dosing adjustments for those with severe renal insufficiency (CLCR ,30 mL/min). Clinical safety of daptomycin is similar to other antibiotics.

Chemical properties

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Originator

Lilly (US)

The Uses of Daptomycin

Daptomycin is a member of the A 21978 complex of high molecular weight cyclic lipopeptides with potent antibiotic activity, notably against MRSA, VISA and VRSA bacterial strains. Originally isolated from Streptomyces roseosprous by Eli Lily in the 1980s, daptomycin was selected and developed by Cubist Pharmaceticals for human use. Daptomycin exhibits Ca-dependent depolarisation of the bacterial membrane resulting in loss of membrane potential leading to inhibition of DNA, RNA and protein synthesis which results in cell death.

The Uses of Daptomycin

Cyclic lipopeptide antibiotic derived from a fermentation product of Streptomyces roseosporus; disrupts plasma membrane function in gram-positive bacteria. Antibacterial.

The Uses of Daptomycin

antiviral, RT inhibitor

The Uses of Daptomycin

immunosuppressant

Indications

Daptomycin is indicated for the treatment of complicated skin and skin structure infections (cSSSI) in patients one year of age and older. It is also indicated for the treatment of Staphylococcus aureus bloodstream infections (bacteremia) in patients one year of age and older, including in adult patients with right-sided infective endocarditis.
Daptomycin is not indicated for the treatment of pneumonia or left-sided infective endocarditis due to S. aureus. Use is not recommended in pediatric patients younger than one year of age due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central).
As with all antibacterial drugs, it is strongly suggested to perform sufficient testing before treatment initiation in order to confirm an infection caused by susceptible bacteria. Failure to do so may result in suboptimal treatment, treatment failure, and the development of drug-resistant bacteria.

Background

Daptomycin is a cyclic lipopeptide antibacterial agent with a broad spectrum of activity against Gram-positive bacteria, including methicillin-susceptible and -resistant Staphylococcus aureus (MSSA/MRSA) and vancomycin-resistant Enterococci (VRE). Chemically, daptomycin comprises 13 amino acids, including several non-standard and D-amino acids, with the C-terminal 10 amino acids forming an ester-linked ring and the N-terminal tryptophan covalently bonded to decanoic acid. Daptomycin was first discovered in the early 1980s by researchers at Eli Lilly in soil samples from Mount Ararat in Turkey. Early work on developing daptomycin was abandoned due to observed myopathy but was resumed in 1997 when Cubist Pharmaceuticals Inc. licensed daptomycin; it was found that a once-daily dosing scheme reduced side effects while retaining efficacy.
Daptomycin was approved by the FDA on September 12, 2003, and is marketed under the name CUBICIN? by Cubist Pharmaceuticals LLC (Merck & Co.).

What are the applications of Application

Daptomycin is calcium-dependent lipopeptide antibiotic

Definition

ChEBI: A polypeptide comprising N-decanoyltryptophan, asparagine, aspartic acid, threonine, glycine, ornithine, aspartic acid, D-alanine, aspartic acid, glycine, D-serine, threo-3-methylglutamic ac d and 3-anthraniloylalanine (also known as kynurinine) coupled in sequence and lactonised by condensation of the carboxylic acid group of the 3-anthraniloylalanine with the alcohol group of the threonine residue.

brand name

Cubicin (Cubist).

Pharmaceutical Applications

A semisynthetic lipopeptide derived from a fermentation product of Streptomyces roseosporus.
Daptomycin is a cyclic peptide with a lipophilic tail and thus resembles the polymyxins structurally. Its useful activity is restricted to Gram-positive cocci, notably Staph. aureus and its chief attraction is that it retains activity against multiresistant strains. Its activity in vitro is greatly potentiated by the presence of calcium (but not magnesium) ions and in these conditions it is more potently bactericidal than the glycopeptides.

Pharmacokinetics

Daptomycin is a cyclic lipopeptide antibacterial agent produced as a fermentation product by the soil microbe Streptomyces roseosporus. The daptomycin core consists of 13 amino acids, including three D-amino acids, ornithine, 3-methyl-glutamic acid, and kynurenine, with the C-terminal 10 amino acids forming an ester-linked ring and the N-terminal tryptophan covalently bonded to decanoic acid. Daptomycin is active against aerobic Gram-positive bacteria, including clinically relevant strains such as methicillin-susceptible and -resistant Staphylococcus aureus (MSSA/MRSA), vancomycin-resistant S. aureus, vancomycin-resistant Enterococci (VRE), Staphylococcus spp., Streptococcus spp., Clostridiodes difficile, Clostridium perfringens, Finegoldia magna, and Propionibacterium acnes, among others. Although daptomycin is active against Streptococcus pneumoniae in vitro, it is inhibited by lung surfactant, and hence is not effective for the treatment of pneumonia or other similar lung infections. Daptomycin exhibits rapid concentration-dependent bactericidal activity in vitro, which correlates best with the ratio of the area under the concentration-time curve to the minimum inhibitory concentration (AUC/MIC) in animal models of infection.
Like other antibacterial agents, daptomycin carries a risk of severe hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). There have been reports of myopathy, rhabdomyolysis, and increased creatine phosphokinase (CPK) levels in patients taking daptomycin, which increased when daptomycin was given more than once per day. Patients should be monitored for CPK levels and, in those with renal impairment, renal function, at least once per week and should consider temporarily suspending the use of HMG-CoA reductase inhibitors. Daptomycin should not be administered more than once per day. Severe adverse reactions such as tubulointerstitial nephritis and peripheral neuropathy have been reported, which may require treatment discontinuation. Based on animal studies, patients less than one year of age may experience serious muscular, neuromuscular, and nervous system effects; daptomycin is not recommended for use in patients under one year of age. Patients undergoing daptomycin treatment may experience eosinophilic pneumonia and Clostridioides difficile-associated diarrhea, both of which may require the cessation of antibacterial treatment and initiation of symptomatic/supportive measures. Persisting or relapsing S. aureus bacteremia and endocarditis should be investigated for sequestered foci of infection and the possibility of daptomycin resistance; the dose or treatment regimen may require adjusting. Patients with moderate to severe renal impairment (creatine clearance < 50 mL/min) experienced reduced clinical benefit from daptomycin treatment based on limited data. Clinically relevant daptomycin plasma concentrations have significantly affected prothrombin time and International Normalized Ratio (INR) measurements. As with all antibiotics, daptomycin use may promote the overgrowth of non-susceptible organisms and the development of resistant organisms; daptomycin use should be limited to cases where it is proven or strongly suspected that an infection is caused by susceptible bacteria.

Pharmacokinetics

Oral absorption: Poor
C_max 4 mg/kg intravenous infusion :55 mg/L end infusion
Plasma half-life: 8–9 h
Volume of distribution:c.0.1 L/kg
Plasma protein binding: 92–95%
Oral absorption is poor and it is administered intravenously. It is eliminated predominantly by the kidneys, about half the dose being excreted unchanged within 24 h. The plasma halflife increases in patients with impaired renal function so that the dosage interval should be extended. Around 10% of an administered dose is removed by peritoneal and hemodialysis.

Clinical Use

Daptomycin is a fermentation product having a cyclic lipopeptide structure. It is primarily active against Gram-positive infections, especially those involved in skin/skin structure infections. It is given IV but must be administered over a period of 30 minutes or more. It binds to cell membranes and causes depolarization, which interrupts protein, DNA, and RNA synthesis. Daptomycin is bactericidal. Although resistance can be achieved in vitro, resistance has been slow to emerge in the clinic. Patients should be monitored for muscle pain or weakness, because some incidence of elevated serum creatinine phosphokinase is associated with its use. A small number of clinical trial patients also developed conditions related to decreases in nerve conduction (e.g., paresthesias and Bell's palsy). Daptomycin is eliminated primarily by the kidney, so dose adjustment may be necessary in cases of renal insufficiency.

Side Effects

It is generally well-tolerated, but gastrointestinal side effects, headache and various other adverse reactions occur with varying frequency. Less commonly, but more seriously, myalgia, muscle weakness and myositis may occur requiring regular monitoring of creatine kinase during treatment. Rhabdomyolysis has been reported, but is very rare.

Drug interactions

In vitro experiments using human hepatocytes demonstrated that daptomycin has no effects on hepatic CYP450-mediated drug metabolism and, therefore, suggest that daptomycin is unlikely to show potential for pharmacokinetic interactions with concomitantly administered drugs that are metabolized by CYP450 isoforms. Drug interaction single- and multiple-dose studies were performed in healthy subjects. No clinically relevant interactions were found when daptomycin 2–6 mg/kg was administered with aztreonam, tobramycin, warfarin, simvastatin, and probenecid. Although no specific drug interactions have been detected when daptomycin is co-administered with HMG-CoA reductase inhibitors (e.g. simvastatin), a number of patients who developed creatine phosphokinase (CPK) increases in a study of daptomycin efficacy in S. aureus bacteremia/endocarditis were receiving concomitant HMGCoA reductase inhibitors. Thus, monitoring of CPK levels is probably warranted in patients with risk factors and timely cessation of potential agents if myopathy is noted.

Metabolism

Radiolabeled daptomycin administered to five healthy adults revealed the presence of inactive metabolites in the urine. A separate study using 6 mg/kg daptomycin in healthy adults revealed small amounts of three oxidative and one unidentified metabolite(s) in urine but not in plasma. The site of metabolism is unclear, as studies using human hepatocytes suggest that daptomycin effectively does not interact at all with the various CYP450 enzymes present in the liver.

Metabolism

In-vitro studies indicate that daptomycin is not metabolised by, and does not affect, the cytochrome P450 isoenzyme system. Little or no metabolism is thought to take place although 4 minor metabolites have been detected in the urine
Daptomycin is excreted mainly via renal filtration with about 78% and 6% of a dose recovered in the urine and faeces, respectively

storage

-20°C

References

1) Jung?et al. (2004),?Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin; Chem. Biol.,?11?949 2) Steenbergen?et al. (2005),?Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections; J. Antimicrob. Chemother.,?55?283