Daptomycin

Identification

Name
Daptomycin
Accession Number
DB00080  (BTD00111, BIOD00111)
Type
Small Molecule
Groups
Approved, Investigational
Description

Daptomycin is a lipopeptide antibiotic that kills susceptible gram positive bacteria by disrupting their membrane potential. It is a naturally-occurring compound found in the soil bacterium Streptomyces roseosporus. Antibiotics are used in the treatment of infections caused by bacteria. They work by killing bacteria or preventing their growth. Daptomycin will not work for colds, flu, or other virus infections. It was approved in September 2003 for the treatment of complicated skin and soft tissue infections. It has a safety profile similar to other agents commonly administered to treat gram-positive infections.

Structure
Thumb
Synonyms
Not Available
External IDs
LY 146032
Product Ingredients
Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CubicinPowder, for solution500 mgIntravenousCubist Pharmaceuticals, Inc.2007-12-03Not applicableCanada
CubicinInjection, powder, lyophilized, for solution500 mg/10mLIntravenousMerck Sharp & Dohme Limited2003-09-12Not applicableUs
Cubicin RFPowder, for solution500 mgIntravenousCubist Pharmaceuticals, Inc.Not applicableNot applicableCanada
Cubicin RFInjection, powder, lyophilized, for solution500 mg/10mLIntravenousMerck Sharp & Dohme Limited2016-07-06Not applicableUs
DaptomycinInjection, powder, lyophilized, for solution500 mg/10mLIntravenousTeva Parenteral Medicines, Inc.2016-06-15Not applicableUs
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DaptomycinInjection, powder, lyophilized, for solution500 mg/10mLIntravenousFresenius Kabi2016-06-28Not applicableUs
DaptomycinInjection, powder, lyophilized, for solution500 mg/10mLIntravenousHospira, Inc.2014-09-12Not applicableUs
Approved Over the Counter Products
Not Available
Unapproved/Other Products
Not Available
International/Other Brands
Not Available
Brand mixtures
Not Available
Categories
UNII
NWQ5N31VKK
CAS number
103060-53-3
Weight
Average: 1620.693
Monoisotopic: 1619.71036644
Chemical Formula
C72H101N17O26
InChI Key
DOAKLVKFURWEDJ-RWDRXURGSA-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
SMILES
CCCCCCCCCC(=O)N[[email protected]@H](CC1=CNC2=C1C=CC=C2)C(=O)N[[email protected]@H](CC(N)=O)C(=O)N[[email protected]@H](CC(O)=O)C(=O)N[[email protected]]1[[email protected]@H](C)OC(=O)[[email protected]](CC(=O)C2=C(N)C=CC=C2)NC(=O)[[email protected]@H](NC(=O)[[email protected]@H](CO)NC(=O)CNC(=O)[[email protected]](CC(O)=O)NC(=O)[[email protected]@H](C)NC(=O)[[email protected]](CC(O)=O)NC(=O)[[email protected]](CCCN)NC(=O)CNC1=O)[[email protected]](C)CC(O)=O

Pharmacology

Indication

For the treatment of complicated skin and skin structure infections caused by susceptible strains of Gram-positive microorganisms.

Structured Indications
Pharmacodynamics

Daptomycin is a 13 member amino acid cyclic lipopeptide antibiotic active against Gram-positive bacteria only. It has proven in vitro activity against enterococci (including glycopeptide-resistant Enterococci (GRE)), staphylococci (including methicillin-resistant Staphylococcus aureus), streptococci and corynebacteria. Daptomycin is derived from the fermentation product of Streptomyces roseosporus.

Mechanism of action

Daptomycin appears to bind or insert into the outer membrane of gram positive bacteria. The binding and integration of daptomycin into the cell membrane is calcium dependent. Calcium ions cause a conformational change in daptomycin, augmenting its amphipathicity (hydrophilic head group and hydrophobic tail group), leading to incorporation into the cell membrane. This binding causes rapid depolarisation, resulting in a loss of membrane potential leading to inhibition of protein, DNA and RNA synthesis, which results in bacterial cell death. The bactericidal activity of daptomycin is concentration-dependent. There is in vitro evidence of synergy with β-lactam antibiotics.

TargetActionsOrganism
ABacterial outer membrane
incorporation into and destabilization
ULipoteichoic acid synthesis
inhibitor
Gram positive bacteria
Absorption

Generally exhibits linear and time-independent pharmacokinetics at a dosage of 4–12 mg/kg IV once every 24 hours. Steady-state trough serum concentrations are achieved by the third daily dose.

Volume of distribution
  • 0.1 L/Kg [healthy adult subjects]
Protein binding

Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The overall mean binding ranged from 90 to 93%.

Metabolism

Minor amounts of three oxidative metabolites and one unidentified compound have been detected in urine. The site of metabolism has not been identified.

Route of elimination

Daptomycin is excreted primarily by the kidney. In a mass balance study of 5 healthy subjects using radiolabeled daptomycin, approximately 78% of the administered dose was recovered from urine based on total radioactivity (approximately 52% of the dose based on microbiologically active concentrations) and 5.7% of the dose was recovered from feces (collected for up to 9 days) based on total radioactivity. Because renal excretion is the primary route of elimination, dosage adjustment is necessary in patients with severe renal insufficiency (CLCR <30 mL/min)

Half life

Half-life elimination: 8-9 hours (up to 28 hours in renal impairment)

Clearance

Excreted primarily in the urine as unchanged drug (78%) and in the feces (6%)

Toxicity
Not Available
Affected organisms
  • Enteric bacteria and other eubacteria
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AtorvastatinThe risk or severity of adverse effects can be increased when Atorvastatin is combined with Daptomycin.Approved
BCG vaccineThe therapeutic efficacy of Bcg can be decreased when used in combination with Daptomycin.Investigational
CerivastatinThe risk or severity of adverse effects can be increased when Cerivastatin is combined with Daptomycin.Withdrawn
FluvastatinThe risk or severity of adverse effects can be increased when Fluvastatin is combined with Daptomycin.Approved
LovastatinThe risk or severity of adverse effects can be increased when Lovastatin is combined with Daptomycin.Approved, Investigational
MevastatinThe risk or severity of adverse effects can be increased when Mevastatin is combined with Daptomycin.Experimental
Picosulfuric acidThe therapeutic efficacy of Picosulfuric acid can be decreased when used in combination with Daptomycin.Approved
PitavastatinThe risk or severity of adverse effects can be increased when Pitavastatin is combined with Daptomycin.Approved
PravastatinThe risk or severity of adverse effects can be increased when Pravastatin is combined with Daptomycin.Approved
RosuvastatinThe risk or severity of adverse effects can be increased when Rosuvastatin is combined with Daptomycin.Approved
SimvastatinThe risk or severity of adverse effects can be increased when Simvastatin is combined with Daptomycin.Approved
UbidecarenoneThe risk or severity of adverse effects can be increased when Coenzyme Q10 is combined with Daptomycin.Experimental
Food Interactions
Not Available

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. [PubMed:1318678 ]
  2. Tally FP, DeBruin MF: Development of daptomycin for gram-positive infections. J Antimicrob Chemother. 2000 Oct;46(4):523-6. [PubMed:11020247 ]
  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. [PubMed:15540967 ]
  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. [PubMed:16914701 ]
  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. [PubMed:16805723 ]
  6. Link [Link]
External Links
KEGG Drug
D01080
KEGG Compound
C12013
ChemSpider
10482098
ChEBI
600103
ChEMBL
CHEMBL387675
Therapeutic Targets Database
DAP001328
PharmGKB
PA164768820
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Daptomycin
ATC Codes
J01XX09 — Daptomycin
AHFS Codes
Not Available
PDB Entries
Not Available
FDA label
Download (560 KB)
MSDS
Not Available

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedTreatmentDrug Interactions / Pharmacokinetics1
1CompletedNot AvailableInfections, Gram-Positive Bacterial1
1CompletedBasic ScienceConcurrent Antibiotic Treatment / Gram Positive Infection1
1CompletedBasic ScienceEnd-Stage Renal Disease (ESRD)1
1CompletedBasic ScienceGram Positive Bacterial Infections1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentSepsis1
1RecruitingTreatmentMeningitis1
1, 2CompletedTreatmentEnd-Stage Renal Disease (ESRD) / Renal Failure Chronic Requiring Hemodialysis1
2CompletedSupportive CareFevers / Infection NOS / Menopausal Hot Flushes / Neutropenias / Sweating / Unspecified Adult Solid Tumor, Protocol Specific1
2CompletedTreatment(Susceptible or Methicillin Resistant) / Acute Bacterial Skin and Skin-structure Infection(ABSSSI) Due to Staphylococcus Aureus (MSSA)1
2CompletedTreatmentBloodstream Infections1
2CompletedTreatmentInfections, Bacterial / Skin-structure infections1
2CompletedTreatmentOsteomyelitis1
2CompletedTreatmentSoft Tissues Infections1
2CompletedTreatmentStaphylococcus Aureus1
2RecruitingTreatmentBacteremia1
2RecruitingTreatmentOsteomyelitis1
2TerminatedTreatmentBacteremia Due to Staphylococcus Aureus1
2TerminatedTreatmentEndocarditis, Bacterial / Infective Endocarditis1
2TerminatedTreatmentInfected Spacers / Prosthetic Joint Infections of Hip / Prosthetic Joint Infections of Knee1
2Unknown StatusTreatmentBacteremia1
2Unknown StatusTreatmentInfection caused by staphylococci1
2Unknown StatusTreatmentInfections, Gram-Positive Bacterial1
2, 3TerminatedTreatmentAscites / Liver Cirrhosis / Nosocomial Spontaneous Bacterial Peritonitis1
3CompletedNot AvailableCritical Care / Gram Positive Bacteria / Renal Failure1
3CompletedNot AvailablePneumonia, Bacterial2
3CompletedPreventionInfection, Postoperative Wound / Late Effects of Surgery / Pharmacokinetics / Staphylococcus Aureus / Surgical Site Infections1
3CompletedTreatmentAcute Hematogenous Osteomyelitis1
3CompletedTreatmentBacteremia / Endocarditis, Bacterial1
3CompletedTreatmentInfection NOS1
3CompletedTreatmentInfection caused by staphylococci1
3CompletedTreatmentInfectious / Skin Diseases1
3Not Yet RecruitingTreatmentStaphylococcus Aureus Bacteraemia1
3RecruitingTreatmentBacteremia1
3RecruitingTreatmentStaphylococcus Aureus Infections1
3TerminatedTreatmentDiabetic Foot1
3TerminatedTreatmentInfections, Gram-Positive Bacterial1
3TerminatedTreatmentNeutropenia, Febrile1
3TerminatedTreatmentSkin Diseases, Infectious / Soft Tissues Infections1
4CompletedNot AvailableCritically Ill / Hemodialysis-dependent patients1
4CompletedBasic ScienceCellulitis1
4CompletedPreventionMRSA Infections1
4CompletedTreatmentBacteremia1
4CompletedTreatmentCellulitis1
4CompletedTreatmentCellulitis / Skin-structure infections1
4CompletedTreatmentSkin Diseases, Infectious1
4CompletedTreatmentStaphylococcal Skin Infections1
4CompletedTreatmentWound Infections1
4RecruitingTreatmentBacteremia1
4RecruitingTreatmentBacteremia / Methicillin Susceptible Staphylococcus Aureus Septicemia1
4TerminatedNot AvailableAntimicrobial Prophylaxis1
4TerminatedHealth Services ResearchComplicated Skin or Skin Structure Infection1
4TerminatedPreventionAcute Bacterial Skin and Skin Structure Infections / Bacteremia / Endocarditis / Health Care Associated Pneumonia / Osteomyelitis/Septic Arthritis1
4TerminatedPreventionInfection caused by staphylococci / Methicillin-Resistant Staphylococcus Aureus (MRSA)1
4TerminatedTreatmentBacteremia1
4TerminatedTreatmentDiabetic Foot1
4TerminatedTreatmentEndocarditis, Bacterial1
4TerminatedTreatmentImpaired Renal Function / S. Aureus Bacteremia / Skin and Subcutaneous Tissue Bacterial Infections1
4TerminatedTreatmentInfective Endocarditis1
4TerminatedTreatmentSoft Tissues Infections1
4TerminatedTreatmentStaphylococcal Skin Infections1
4TerminatedTreatmentWound Infections1
4WithdrawnDiagnosticBurn Injuries1
Not AvailableCompletedNot AvailableChronic Kidney Disease (CKD) / Infections, Bacterial1
Not AvailableRecruitingNot AvailableHeart Assist Device1
Not AvailableRecruitingNot AvailableShock, Septic1
Not AvailableTerminatedDiagnosticMeningitis1
Not AvailableUnknown StatusTreatmentAcute Renal Failure (ARF) / Postoperative / Sepsis1
Not AvailableWithdrawnSupportive CareInfection NOS / Neutropenias / Unspecified Adult Solid Tumor, Protocol Specific / Unspecified Childhood Solid Tumor, Protocol Specific1

Pharmacoeconomics

Manufacturers
  • Cubist pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous500 mg
Injection, powder, lyophilized, for solutionIntravenous500 mg/10mL
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)
CA2344318 No2006-07-042019-09-24Canada
US6468967 No1999-09-242019-09-24Us
US6852689 No1999-09-242019-09-24Us
US8003673 No2008-09-042028-09-04Us
USRE39071 No1996-06-152016-06-15Us
US8058238 No2000-11-282020-11-28Us
US8129342 No2000-11-282020-11-28Us
US9138456 No2010-11-232030-11-23Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0173 mg/mLALOGPS
logP-0.47ALOGPS
logS-5ALOGPS
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as cyclic depsipeptides. These are natural or synthetic compounds having sequences of amino and hydroxy carboxylic acid residues (usually α-amino and α-hydroxy acids) connected in a ring. The residues are commonly but not necessarily regularly alternating.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Peptidomimetics
Sub Class
Depsipeptides
Direct Parent
Cyclic depsipeptides
Alternative Parents
Pentacarboxylic acids and derivatives / Alkyl-phenylketones / Alpha amino acid esters / Macrolides and analogues / Macrolactams / 3-alkylindoles / Aniline and substituted anilines / Aryl alkyl ketones / Benzoyl derivatives / Substituted pyrroles
show 16 more
Substituents
Cyclic depsipeptide / Pentacarboxylic acid or derivatives / Alpha-amino acid ester / Alkyl-phenylketone / Macrolide / Macrolactam / Alpha-amino acid or derivatives / 3-alkylindole / Phenylketone / Indole
show 41 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
lipopeptide, heterodetic cyclic peptide, macrolide, macrocycle, lipopeptide antibiotic (CHEBI:600103 )

Targets

1. Bacterial outer membrane
Kind
Group
Organism
Pharmacological action
Yes
Actions
Incorporation into and destabilization
References
  1. Jerala R: Synthetic lipopeptides: a novel class of anti-infectives. Expert Opin Investig Drugs. 2007 Aug;16(8):1159-69. [PubMed:17685866 ]
  2. 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. [PubMed:16805723 ]
  3. Guay DR: Daptomycin: the first approved lipopeptide antimicrobial. Consult Pharm. 2004 Jul;19(7):614-28. [PubMed:16553491 ]
  4. Jung D, Rozek A, Okon M, Hancock RE: Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin. Chem Biol. 2004 Jul;11(7):949-57. [PubMed:15271353 ]
2. Lipoteichoic acid synthesis
Kind
Action
Organism
Gram positive bacteria
Pharmacological action
Unknown
Actions
Inhibitor
References
  1. Canepari P, Boaretti M: Lipoteichoic acid as a target for antimicrobial action. Microb Drug Resist. 1996 Spring;2(1):85-9. [PubMed:9158727 ]
  2. 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. [PubMed:2168145 ]
Drug created on June 13, 2005 07:24 / Updated on September 01, 2017 10:23