Daptomycin

Identification

Summary

Daptomycin is a cyclic lipopeptide antibiotic used to treat complicated skin and skin structure infections by susceptible Gram-positive bacteria and bacteremia due to Staphylococcus aureus.

Brand Names
Cubicin
Generic Name
Daptomycin
DrugBank Accession Number
DB00080
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).7,8,21 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.6,21 Daptomycin was first discovered in the early 1980s by researchers at Eli Lilly in soil samples from Mount Ararat in Turkey.8 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.7

Daptomycin was approved by the FDA on September 12, 2003, and is marketed under the name CUBICIN® by Cubist Pharmaceuticals LLC (Merck & Co.).21

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 1620.693
Monoisotopic: 1619.71036644
Chemical Formula
C72H101N17O26
Synonyms
  • Daptomicina
  • Daptomycin
  • Daptomycine
  • Daptomycinum
External IDs
  • LY 146032
  • LY-146032
  • LY-164032

Pharmacology

Indication

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.21

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).21

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.21

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

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.6,21 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.7,8,21 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.7,9,21 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.21

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.21

Mechanism of action

The mechanism of action of daptomycin remains poorly understood. Studies have suggested a direct inhibition of cell membrane/cell wall constituent biosynthesis, including peptidoglycan, uridine diphosphate-N-acid, acetyl-L-alanine, and lipoteichoic acid (LTA). However, no convincing evidence has been presented for any of these models, and an effect on LTA biosynthesis has been ruled out by other studies in S. aureus and E. faecalis.8,10,11

It is well understood that free daptomycin (apo-daptomycin) is a trianion at physiological pH, which binds Ca2+ in a 1:1 stoichiometric ratio to become a monoanion, which is thought to rely primarily on the Asp(7), Asp(9), and L-3MeGlu12 residues that form a DXDG motif.6,7,8 Calcium-binding facilitates daptomycin's insertion into bacterial membranes preferentially due to their high content of the acidic phospholipids phosphatidylglycerol (PG) and cardiolipin (CL), wherein it is proposed that daptomycin can bind two calcium equivalents and form oligomers.7 PG is recognized as the main membrane requirement for daptomycin activity; daptomycin preferentially localizes in PG-rich membrane domains, and mutations affecting PG prevalence are linked to daptomycin resistance.7 Calcium-dependent membrane binding is the generally accepted mechanism of action for daptomycin, but the precise downstream effects are unclear, and numerous models have been proposed.

One mechanism proposes that the daptomycin membrane binding alters membrane fluidity, causing dissociation of cell wall biosynthetic enzymes such as the lipid II synthase MurG and the phospholipid synthase PlsX.8 This is consistent with the observed effects of daptomycin on cell shape in various bacteria at concentrations at or above the minimum inhibitory concentration (MIC).11 Aberrant cell morphology is also consistent with the observed localization of daptomycin at the division septa and a hypothesized role in inhibiting cell division.7 A recent study suggested the formation of tripartite complexes containing calcium-bound daptomycin, PG, and various undecaprenyl-coupled cell envelope precursors, which subsequently include lipid II. This complex is proposed to inhibit cell division, lead to the dispersion of cell wall biosynthetic machinery, and eventually cause lysis of the membrane bilayer at the septum causing cell death.8,12

Another popular model is based on early observations that daptomycin, in a calcium-dependent manner, caused potassium ion leakage and loss of membrane potential in treated bacterial cells.10,13,14 Although this lead some to suggest that daptomycin could bind PG to form oligomeric pores in the bacterial membrane,8 no cell lysis was observed in S. aureus or E. faecalis,7 and the daptomycin-induced ion conduction is inconsistent with pore formation.15 Rather, it has been proposed that daptomycin forms calcium-dependent dimeric complexes in fixed ratios of Dap2Ca3PG2, which can act as transient ionophores.15 The observed loss of membrane potential is suggested to result in a non-specific loss of gradient-dependent nutrient transport, ATP production, and biosynthesis, leading to cell death.7,14

Notably, these models are not strictly mutually exclusive and are supported to varying extents by observed resistance mutations. The strict requirement for PG for daptomycin bactericidal action is supported by mutations in mprF, cls2, pgsA, and the dlt operon in S. aureus, cls in various enterococci, and pgsA, PG synthase, and the dlt operon in E. faecium, all of which alter the bacterial membrane composition and specifically the PG content of bacterial membranes. Other noted mutations in various regulatory systems that control membrane homeostasis also support the cell membrane as the site of daptomycin action. Curiously, in E. faecalis, the most commonly observed form of daptomycin resistance is characterized by abnormal division septa, which supports the cell division-based mechanism of daptomycin action.7,8

TargetActionsOrganism
ACytoplasmic membrane
incorporation into and destabilization
Bacteria
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.16,21 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.16 Steady-state trough concentrations between 5.9 ± 1.6 and 13.7 ± 5.2 μg/mL are reached following the third once-daily dose.21

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.21

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.21

Volume of distribution

Daptomycin has a very small volume of distribution, averaging ~0.1 L/kg in healthy adult subjects independent of dose.16,21 The volume of distribution tends to increase with decreasing renal function, being estimated at ~0.2 L/kg in patients with severe renal impairment.21

Protein binding

Daptomycin reversibly binds plasma proteins between 90-94% and independently of concentration.16,21,18,19 Although daptomycin is mainly bound to serum albumin (HSA; 85-96%), it also binds appreciably to α-1-acid-glycoprotein (AGP; 25-51%).18,19,20 Surface plasmon resonance (SPR) experiments revealed that daptomycin also binds a number of other plasma proteins including α-1-antitrypsin, low-density lipoprotein (LDL), hemoglobin, sex hormone-binding globulin (SHBG), hemopexin, fibrinogen, α2-macroglobulin, β2-microglobulin, high-density lipoprotein (HDL), fibronectin, haptoglobulin, transferrin, and IgG.19 Of these, it was determined that the main determinants of plasma binding were HSA, AGP, α-1-antitrypsin, LDL, SHBG, and hemopexin.19

Consistent with observations regarding calculated distribution volumes, daptomycin protein binding tends to decrease with decreasing renal function, being approximately 88% in patients with creatinine clearance <30 mL/min, approximately 86% in those on hemodialysis, and approximately 84% in those on continuous ambulatory peritoneal dialysis (CAPD).21

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.21 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.17,21

Route of elimination

Daptomycin is excreted primarily by the kidneys, approximately 78% of an administered dose recovered in urine and only 5.7% recovered in feces.16,21 Approximately 52% of the dose, recovered in urine, retains microbiological activity.21

Half-life

Daptomycin has a relatively long half-life, with ranges of 7.5-9 hours depending on dosing schemes and dose strength.16,21 The half-life lengthens in patients with increasing renal impairment, being 27.83 ± 14.85 hours in patients with creatinine clearance <30 mL/min, 30.51 ± 6.51 hours in hemodialysis patients, and 27.56 ± 4.53 hours in continuous ambulatory peritoneal dialysis (CAPD) patients. Daptomycin half-life also tends to decrease with decreasing age.21

Clearance

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 total plasma clearance values between 7.2 ± 1.1 and 9.6 ± 1.3 mL/h/kg, with no clear dose association.16,21 As daptomycin is primarily renally excreted, patients with mild, moderate, and severe renal impairment had reduced total plasma clearance 9, 22, and 46 percent lower than healthy controls, respectively. Daptomycin clearance was also lower in obese (15-23%) and geriatric (aged 75 and older, by 35%) patients, whereas it tended to be higher in pediatric patients, even when normalized for body weight.21

Adverse Effects
Adverseeffects
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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.21

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirDaptomycin may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Daptomycin.
AceclofenacAceclofenac may decrease the excretion rate of Daptomycin which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Daptomycin which could result in a higher serum level.
AcenocoumarolThe risk or severity of bleeding can be increased when Daptomycin is combined with Acenocoumarol.
AcetaminophenDaptomycin may decrease the excretion rate of Acetaminophen which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Daptomycin which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Daptomycin which could result in a higher serum level.
AcipimoxThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Daptomycin is combined with Acipimox.
AclidiniumDaptomycin may decrease the excretion rate of Aclidinium which could result in a higher serum level.
Interactions
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Food Interactions
No interactions found.

Products

Products2
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International/Other Brands
Cidecin / Cubicin
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Cubicin350 mgIntravenousMerck Sharp & Dohme B.V.2021-03-17Not applicableEU flag
CubicinSolution500 mgIntravenousMerck Sharp & Dohme B.V.2021-03-17Not applicableEU flag
CubicinSolution500 mgIntravenousMerck Sharp & Dohme B.V.2021-03-17Not applicableEU flag
CubicinPowder, for solution500 mg / vialIntravenousCubist Pharmaceuticals, Inc.2007-12-03Not applicableCanada flag
CubicinInjection, powder, lyophilized, for solution500 mg/10mLIntravenousMerck Sharp & Dohme Corp.2003-09-12Not applicableUS flag
CubicinInjection350 mg/350mgIntravenousOSO BioPharmaceuticals Manufacturing, LLC2003-09-12Not applicableUS flag
Cubicin350 mgIntravenousMerck Sharp & Dohme B.V.2021-03-17Not applicableEU flag
Cubicin RFPowder, for solution500 mg / vialIntravenousCubist Pharmaceuticals, Inc.2018-01-17Not applicableCanada flag
Cubicin RFInjection, powder, lyophilized, for solution500 mg/10mLIntravenousMerck Sharp & Dohme Corp.2016-09-13Not applicableUS flag
DaptomycinInjection, powder, lyophilized, for solution350 mg/7mLIntravenousXellia Pharmaceuticals USA LLC2019-03-15Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DaptomycinInjection, powder, lyophilized, for solution500 mg/10mLIntravenousMylan Institutional LLC2018-09-04Not applicableUS flag
DaptomycinInjection, powder, lyophilized, for solution500 mg/10mLIntravenousFresenius Kabi USA, LLC2018-04-11Not applicableUS flag
DaptomycinInjection, powder, lyophilized, for solution350 mg/7mLIntravenousBE Pharmaceuticals Inc.2020-08-20Not applicableUS flag
DaptomycinInjection, powder, lyophilized, for solution500 mg/10mLIntravenousAccord Healthcare Inc.2019-06-24Not applicableUS flag
DaptomycinInjection, powder, lyophilized, for solution500 mg/10mLIntravenousMeitheal Pharmaceuticals Inc.2021-06-29Not applicableUS flag
DaptomycinInjection, powder, lyophilized, for solution500 mg/10mLIntravenousCivica, Inc.2019-08-20Not applicableUS flag
DaptomycinInjection, powder, lyophilized, for solution500 mg/10mLIntravenousFresenius Kabi USA, LLC2016-06-28Not applicableUS flag
DaptomycinInjection, powder, lyophilized, for solution50 mg/1mLIntravenousSagent Pharmaceuticals2019-11-15Not applicableUS flag
DaptomycinInjection, powder, lyophilized, for solution500 mg/10mLIntravenousCipla USA Inc.2019-09-23Not applicableUS flag
DaptomycinInjection, powder, lyophilized, for solution500 mg/10mLIntravenousCamber Pharmaceuticals Inc.2021-01-04Not applicableUS flag

Categories

ATC Codes
J01XX09 — Daptomycin
Drug Categories
Classification
Not classified
Affected organisms
  • Gram-positive Bacteria

Chemical Identifiers

UNII
NWQ5N31VKK
CAS number
103060-53-3
InChI Key
DOAKLVKFURWEDJ-QCMAZARJSA-N
InChI
InChI=1S/C72H101N17O26/c1-5-6-7-8-9-10-11-22-53(93)81-44(25-38-31-76-42-20-15-13-17-39(38)42)66(108)84-45(27-52(75)92)67(109)86-48(30-59(102)103)68(110)89-61-37(4)115-72(114)49(26-51(91)40-18-12-14-19-41(40)74)87-71(113)60(35(2)24-56(96)97)88-69(111)50(34-90)82-55(95)32-77-63(105)46(28-57(98)99)83-62(104)36(3)79-65(107)47(29-58(100)101)85-64(106)43(21-16-23-73)80-54(94)33-78-70(61)112/h12-15,17-20,31,35-37,43-50,60-61,76,90H,5-11,16,21-30,32-34,73-74H2,1-4H3,(H2,75,92)(H,77,105)(H,78,112)(H,79,107)(H,80,94)(H,81,93)(H,82,95)(H,83,104)(H,84,108)(H,85,106)(H,86,109)(H,87,113)(H,88,111)(H,89,110)(H,96,97)(H,98,99)(H,100,101)(H,102,103)/t35-,36-,37-,43+,44+,45-,46+,47+,48+,49+,50-,60+,61+/m1/s1
IUPAC Name
(3S)-3-{[(3S,6S,9R,15S,18R,21S,24S,30S,31R)-3-[2-(2-aminophenyl)-2-oxoethyl]-24-(3-aminopropyl)-15,21-bis(carboxymethyl)-6-[(2R)-1-carboxypropan-2-yl]-9-(hydroxymethyl)-18,31-dimethyl-2,5,8,11,14,17,20,23,26,29-decaoxo-1-oxa-4,7,10,13,16,19,22,25,28-nonaazacyclohentriacontan-30-yl]carbamoyl}-3-[(2R)-3-carbamoyl-2-[(2S)-2-decanamido-3-(1H-indol-3-yl)propanamido]propanamido]propanoic acid
SMILES
CCCCCCCCCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H]1[C@@H](C)OC(=O)[C@H](CC(=O)C2=CC=CC=C2N)NC(=O)[C@@H](NC(=O)[C@@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCN)NC(=O)CNC1=O)[C@H](C)CC(O)=O

References

Synthesis Reference

Dennis Keith, "Methods for preparing purified daptomycin." U.S. Patent US20030045484, issued March 06, 2003.

US20030045484
General References
  1. Woodworth JR, Nyhart EH Jr, Brier GL, Wolny JD, Black HR: Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers. Antimicrob Agents Chemother. 1992 Feb;36(2):318-25. [Article]
  2. Tally FP, DeBruin MF: Development of daptomycin for gram-positive infections. J Antimicrob Chemother. 2000 Oct;46(4):523-6. [Article]
  3. Charles PG, Grayson ML: The dearth of new antibiotic development: why we should be worried and what we can do about it. Med J Aust. 2004 Nov 15;181(10):549-53. [Article]
  4. Fowler VG Jr, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, Levine DP, Chambers HF, Tally FP, Vigliani GA, Cabell CH, Link AS, DeMeyer I, Filler SG, Zervos M, Cook P, Parsonnet J, Bernstein JM, Price CS, Forrest GN, Fatkenheuer G, Gareca M, Rehm SJ, Brodt HR, Tice A, Cosgrove SE: Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006 Aug 17;355(7):653-65. [Article]
  5. Lee SY, Fan HW, Kuti JL, Nicolau DP: Update on daptomycin: the first approved lipopeptide antibiotic. Expert Opin Pharmacother. 2006 Jul;7(10):1381-97. [Article]
  6. Heidary M, Khosravi AD, Khoshnood S, Nasiri MJ, Soleimani S, Goudarzi M: Daptomycin. J Antimicrob Chemother. 2018 Jan 1;73(1):1-11. doi: 10.1093/jac/dkx349. [Article]
  7. Taylor SD, Palmer M: The action mechanism of daptomycin. Bioorg Med Chem. 2016 Dec 15;24(24):6253-6268. doi: 10.1016/j.bmc.2016.05.052. Epub 2016 May 28. [Article]
  8. Karas JA, Carter GP, Howden BP, Turner AM, Paulin OKA, Swarbrick JD, Baker MA, Li J, Velkov T: Structure-Activity Relationships of Daptomycin Lipopeptides. J Med Chem. 2020 Nov 25;63(22):13266-13290. doi: 10.1021/acs.jmedchem.0c00780. Epub 2020 Aug 6. [Article]
  9. Silverman JA, Mortin LI, Vanpraagh AD, Li T, Alder J: Inhibition of daptomycin by pulmonary surfactant: in vitro modeling and clinical impact. J Infect Dis. 2005 Jun 15;191(12):2149-52. doi: 10.1086/430352. Epub 2005 May 5. [Article]
  10. Allen NE, Hobbs JN, Alborn WE Jr: Inhibition of peptidoglycan biosynthesis in gram-positive bacteria by LY146032. Antimicrob Agents Chemother. 1987 Jul;31(7):1093-9. doi: 10.1128/aac.31.7.1093. [Article]
  11. Canepari P, Boaretti M, Lleo MM, Satta G: Lipoteichoic acid as a new target for activity of antibiotics: mode of action of daptomycin (LY146032). Antimicrob Agents Chemother. 1990 Jun;34(6):1220-6. [Article]
  12. Grein F, Muller A, Scherer KM, Liu X, Ludwig KC, Klockner A, Strach M, Sahl HG, Kubitscheck U, Schneider T: Ca(2+)-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids. Nat Commun. 2020 Mar 19;11(1):1455. doi: 10.1038/s41467-020-15257-1. [Article]
  13. Alborn WE Jr, Allen NE, Preston DA: Daptomycin disrupts membrane potential in growing Staphylococcus aureus. Antimicrob Agents Chemother. 1991 Nov;35(11):2282-7. doi: 10.1128/aac.35.11.2282. [Article]
  14. Allen NE, Alborn WE Jr, Hobbs JN Jr: Inhibition of membrane potential-dependent amino acid transport by daptomycin. Antimicrob Agents Chemother. 1991 Dec;35(12):2639-42. doi: 10.1128/aac.35.12.2639. [Article]
  15. Huang HW: DAPTOMYCIN, its membrane-active mechanism vs. that of other antimicrobial peptides. Biochim Biophys Acta Biomembr. 2020 Oct 1;1862(10):183395. doi: 10.1016/j.bbamem.2020.183395. Epub 2020 Jun 9. [Article]
  16. Dvorchik BH, Brazier D, DeBruin MF, Arbeit RD: Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects. Antimicrob Agents Chemother. 2003 Apr;47(4):1318-23. doi: 10.1128/aac.47.4.1318-1323.2003. [Article]
  17. Oleson FB, Berman CL, Li AP: An evaluation of the P450 inhibition and induction potential of daptomycin in primary human hepatocytes. Chem Biol Interact. 2004 Nov 20;150(2):137-47. doi: 10.1016/j.cbi.2004.08.004. [Article]
  18. Lee BL, Sachdeva M, Chambers HF: Effect of protein binding of daptomycin on MIC and antibacterial activity. Antimicrob Agents Chemother. 1991 Dec;35(12):2505-8. doi: 10.1128/aac.35.12.2505. [Article]
  19. Schneider EK, Huang JX, Carbone V, Han M, Zhu Y, Nang S, Khoo KK, Mak J, Cooper MA, Li J, Velkov T: Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin. ACS Infect Dis. 2017 Mar 10;3(3):249-258. doi: 10.1021/acsinfecdis.7b00015. Epub 2017 Feb 10. [Article]
  20. Yamasaki K, Sakurama K, Nishi K, Watanabe H, Maruyama T, Seo H, Otagiri M, Taguchi K: Characterization of the Interaction of Daptomycin With Site II on Human Serum Albumin. J Pharm Sci. 2020 Sep;109(9):2919-2924. doi: 10.1016/j.xphs.2020.06.011. Epub 2020 Jun 18. [Article]
  21. FDA Approved Drug Products: CUBICIN (daptomycin) injection [Link]
KEGG Drug
D01080
KEGG Compound
C12013
PubChem Compound
16134395
PubChem Substance
46504551
ChemSpider
10200644
RxNav
22299
ChEBI
600103
ChEMBL
CHEMBL387675
Therapeutic Targets Database
DAP001328
PharmGKB
PA164768820
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Daptomycin
FDA label
Download (560 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedNot AvailableCritically Ill Patients / Hemodialysis Treatment1
4CompletedBasic ScienceCellulitis1
4CompletedTreatmentBacteremia2
4CompletedTreatmentBacteremia / Methicillin Susceptible Staphylococcus Aureus Septicemia1
4CompletedTreatmentCellulitis1
4CompletedTreatmentCellulitis / Skin Infections1
4CompletedTreatmentSkin Diseases, Infectious1
4CompletedTreatmentStaphylococcal Skin Infections1
4CompletedTreatmentWound Infections1
4RecruitingTreatmentAbscesses / CNS Infection / Coagulase Negative Staphylococcal Infection / Infection caused by staphylococci / Infection; Diabetic Foot / Osteomyelitis / Septic Arthritis / Vertebral Osteomyelitis1

Pharmacoeconomics

Manufacturers
  • Cubist pharmaceuticals inc
Packagers
  • Cardinal Health
  • Catalent Pharma Solutions
  • Cubist Pharmaceuticals Inc.
  • Hospira Inc.
  • Oso Biopharmaceuticals Manufacturing LLC
  • Sepracor Pharmaceuticals Inc.
Dosage Forms
FormRouteStrength
InjectionIntravenous350 mg/350mg
Injection, powder, for solutionIntravenous; Parenteral500 MG
Powder, for solutionIntravenous500 mg / vial
SolutionIntravenous500 mg
Injection, powder, lyophilized, for solutionIntravenous
Injection, solutionIntravenous350 mg
Injection, solutionIntravenous500 mg
Injection, powder, lyophilized, for solutionIntravenous500 mg/10mL
Injection, powder, lyophilized, for solutionIntravenous350 mg
Injection, powder, lyophilized, for solutionIntravenous500 mg
Injection, solutionIntravenous
Injection, powder, for solutionParenteral350 MG
Injection, powder, for solutionParenteral500 MG
Injection, powder, for solutionIntravenous350 MG
Injection, powder, for solutionIntravenous500 MG
Injection, powder, for solution350 MG
Injection, powder, for solution500 MG
Injection, powder, for solutionIntravenous500 mg/10mL
Injection, powder, lyophilized, for solutionIntravenous350 mg/7mL
Injection, powder, lyophilized, for solutionIntravenous350 mg/10mL
Injection, powder, lyophilized, for solutionIntravenous50 mg/1mL
Injection, powder, lyophilized, for solutionIntravenous500 mg/10mg
Injection, powder, for solutionParenteral
Powder, for solutionIntravenous350 mg / vial
InjectionIntravenous500 mg
Prices
Unit descriptionCostUnit
Cubicin 500 mg vial272.7USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2344318No2006-07-042019-09-24Canada flag
US6468967No2002-10-222019-09-24US flag
US6852689No2005-02-082019-09-24US flag
US8003673No2011-08-232028-09-04US flag
USRE39071No2006-04-182016-06-15US flag
US8058238No2011-11-152020-11-28US flag
US8129342No2012-03-062020-11-28US flag
US9138456No2015-09-222030-11-23US flag
US10357535No2013-09-112033-09-11US flag
US9655946No2013-09-112033-09-11US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0173 mg/mLALOGPS
logP-0.47ALOGPS
logP-9.4ChemAxon
logS-5ALOGPS
pKa (Strongest Acidic)2.98ChemAxon
pKa (Strongest Basic)9.59ChemAxon
Physiological Charge-3ChemAxon
Hydrogen Acceptor Count27ChemAxon
Hydrogen Donor Count22ChemAxon
Polar Surface Area702.02 Å2ChemAxon
Rotatable Bond Count35ChemAxon
Refractivity393.57 m3·mol-1ChemAxon
Polarizability158.96 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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1. Cytoplasmic membrane
Kind
Group
Organism
Bacteria
Pharmacological action
Yes
Actions
Incorporation into and destabilization
Curator comments
Daptomycin binds bacterial cell membranes and, through various possible mechanisms, causes cell death.
References
  1. Heidary M, Khosravi AD, Khoshnood S, Nasiri MJ, Soleimani S, Goudarzi M: Daptomycin. J Antimicrob Chemother. 2018 Jan 1;73(1):1-11. doi: 10.1093/jac/dkx349. [Article]
  2. Taylor SD, Palmer M: The action mechanism of daptomycin. Bioorg Med Chem. 2016 Dec 15;24(24):6253-6268. doi: 10.1016/j.bmc.2016.05.052. Epub 2016 May 28. [Article]
  3. Karas JA, Carter GP, Howden BP, Turner AM, Paulin OKA, Swarbrick JD, Baker MA, Li J, Velkov T: Structure-Activity Relationships of Daptomycin Lipopeptides. J Med Chem. 2020 Nov 25;63(22):13266-13290. doi: 10.1021/acs.jmedchem.0c00780. Epub 2020 Aug 6. [Article]
  4. Allen NE, Hobbs JN, Alborn WE Jr: Inhibition of peptidoglycan biosynthesis in gram-positive bacteria by LY146032. Antimicrob Agents Chemother. 1987 Jul;31(7):1093-9. doi: 10.1128/aac.31.7.1093. [Article]
  5. Canepari P, Boaretti M, Lleo MM, Satta G: Lipoteichoic acid as a new target for activity of antibiotics: mode of action of daptomycin (LY146032). Antimicrob Agents Chemother. 1990 Jun;34(6):1220-6. [Article]
  6. Grein F, Muller A, Scherer KM, Liu X, Ludwig KC, Klockner A, Strach M, Sahl HG, Kubitscheck U, Schneider T: Ca(2+)-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids. Nat Commun. 2020 Mar 19;11(1):1455. doi: 10.1038/s41467-020-15257-1. [Article]
  7. Alborn WE Jr, Allen NE, Preston DA: Daptomycin disrupts membrane potential in growing Staphylococcus aureus. Antimicrob Agents Chemother. 1991 Nov;35(11):2282-7. doi: 10.1128/aac.35.11.2282. [Article]
  8. Allen NE, Alborn WE Jr, Hobbs JN Jr: Inhibition of membrane potential-dependent amino acid transport by daptomycin. Antimicrob Agents Chemother. 1991 Dec;35(12):2639-42. doi: 10.1128/aac.35.12.2639. [Article]
  9. Huang HW: DAPTOMYCIN, its membrane-active mechanism vs. that of other antimicrobial peptides. Biochim Biophys Acta Biomembr. 2020 Oct 1;1862(10):183395. doi: 10.1016/j.bbamem.2020.183395. Epub 2020 Jun 9. [Article]
  10. FDA Approved Drug Products: CUBICIN (daptomycin) injection [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
Curator comments
Daptomycin is primarily bound to serum albumin in human plasma.
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Lee BL, Sachdeva M, Chambers HF: Effect of protein binding of daptomycin on MIC and antibacterial activity. Antimicrob Agents Chemother. 1991 Dec;35(12):2505-8. doi: 10.1128/aac.35.12.2505. [Article]
  2. Schneider EK, Huang JX, Carbone V, Han M, Zhu Y, Nang S, Khoo KK, Mak J, Cooper MA, Li J, Velkov T: Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin. ACS Infect Dis. 2017 Mar 10;3(3):249-258. doi: 10.1021/acsinfecdis.7b00015. Epub 2017 Feb 10. [Article]
  3. Yamasaki K, Sakurama K, Nishi K, Watanabe H, Maruyama T, Seo H, Otagiri M, Taguchi K: Characterization of the Interaction of Daptomycin With Site II on Human Serum Albumin. J Pharm Sci. 2020 Sep;109(9):2919-2924. doi: 10.1016/j.xphs.2020.06.011. Epub 2020 Jun 18. [Article]
  4. FDA Approved Drug Products: CUBICIN (daptomycin) injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Lee BL, Sachdeva M, Chambers HF: Effect of protein binding of daptomycin on MIC and antibacterial activity. Antimicrob Agents Chemother. 1991 Dec;35(12):2505-8. doi: 10.1128/aac.35.12.2505. [Article]
  2. Schneider EK, Huang JX, Carbone V, Han M, Zhu Y, Nang S, Khoo KK, Mak J, Cooper MA, Li J, Velkov T: Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin. ACS Infect Dis. 2017 Mar 10;3(3):249-258. doi: 10.1021/acsinfecdis.7b00015. Epub 2017 Feb 10. [Article]
  3. Yamasaki K, Sakurama K, Nishi K, Watanabe H, Maruyama T, Seo H, Otagiri M, Taguchi K: Characterization of the Interaction of Daptomycin With Site II on Human Serum Albumin. J Pharm Sci. 2020 Sep;109(9):2919-2924. doi: 10.1016/j.xphs.2020.06.011. Epub 2020 Jun 18. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Inhibitor of serine proteases. Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin. Irreversibly inhibits trypsin, chymotrypsin and plasminogen activator. T...
Gene Name
SERPINA1
Uniprot ID
P01009
Uniprot Name
Alpha-1-antitrypsin
Molecular Weight
46736.195 Da
References
  1. Schneider EK, Huang JX, Carbone V, Han M, Zhu Y, Nang S, Khoo KK, Mak J, Cooper MA, Li J, Velkov T: Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin. ACS Infect Dis. 2017 Mar 10;3(3):249-258. doi: 10.1021/acsinfecdis.7b00015. Epub 2017 Feb 10. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Virus receptor activity
Specific Function
Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clat...
Gene Name
LDLR
Uniprot ID
P01130
Uniprot Name
Low-density lipoprotein receptor
Molecular Weight
95375.105 Da
References
  1. Schneider EK, Huang JX, Carbone V, Han M, Zhu Y, Nang S, Khoo KK, Mak J, Cooper MA, Li J, Velkov T: Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin. ACS Infect Dis. 2017 Mar 10;3(3):249-258. doi: 10.1021/acsinfecdis.7b00015. Epub 2017 Feb 10. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Androgen binding
Specific Function
Functions as an androgen transport protein, but may also be involved in receptor mediated processes. Each dimer binds one molecule of steroid. Specific for 5-alpha-dihydrotestosterone, testosterone...
Gene Name
SHBG
Uniprot ID
P04278
Uniprot Name
Sex hormone-binding globulin
Molecular Weight
43778.755 Da
References
  1. Schneider EK, Huang JX, Carbone V, Han M, Zhu Y, Nang S, Khoo KK, Mak J, Cooper MA, Li J, Velkov T: Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin. ACS Infect Dis. 2017 Mar 10;3(3):249-258. doi: 10.1021/acsinfecdis.7b00015. Epub 2017 Feb 10. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Binds heme and transports it to the liver for breakdown and iron recovery, after which the free hemopexin returns to the circulation.
Specific Function
Heme transporter activity
Gene Name
HPX
Uniprot ID
P02790
Uniprot Name
Hemopexin
Molecular Weight
51676.015 Da
References
  1. Schneider EK, Huang JX, Carbone V, Han M, Zhu Y, Nang S, Khoo KK, Mak J, Cooper MA, Li J, Velkov T: Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin. ACS Infect Dis. 2017 Mar 10;3(3):249-258. doi: 10.1021/acsinfecdis.7b00015. Epub 2017 Feb 10. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Lemaire S, Van Bambeke F, Mingeot-Leclercq MP, Tulkens PM: Modulation of the cellular accumulation and intracellular activity of daptomycin towards phagocytized Staphylococcus aureus by the P-glycoprotein (MDR1) efflux transporter in human THP-1 macrophages and madin-darby canine kidney cells. Antimicrob Agents Chemother. 2007 Aug;51(8):2748-57. doi: 10.1128/AAC.00090-07. Epub 2007 Jun 4. [Article]
  2. Baietto L, D'Avolio A, Cusato J, Pace S, Calcagno A, Motta I, Corcione S, Di Perri G, De Rosa FG: Effect of SNPs in human ABCB1 on daptomycin pharmacokinetics in Caucasian patients. J Antimicrob Chemother. 2015 Jan;70(1):307-8. doi: 10.1093/jac/dku368. Epub 2014 Sep 18. [Article]

Drug created on June 13, 2005 13:24 / Updated on October 22, 2021 23:18