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

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Daptomycin (DB00080)

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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

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Associated Conditions

• Complicated Skin and Skin Structure Infection
• Staphylococcus Aureus Bloodstream Infections (BSI; Bacteremia)

Contraindications & Blackbox Warnings

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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

Target	Actions	Organism
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 C_max between 57.8 ± 3.0 and 183.7 ± 25.0 μg/mL and an AUC_0-24 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 C_max 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 C_max 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 C_max 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 AUC_0-∞ 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 C_max. The AUC_0-∞ is also increased in obese patients by approximately 30%. No significant differences in body weight- and age-adjusted C_max 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

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abacavir	Daptomycin may decrease the excretion rate of Abacavir which could result in a higher serum level.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Daptomycin.
Aceclofenac	Aceclofenac may decrease the excretion rate of Daptomycin which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Daptomycin which could result in a higher serum level.
Acenocoumarol	The risk or severity of bleeding can be increased when Daptomycin is combined with Acenocoumarol.
Acetaminophen	Daptomycin may decrease the excretion rate of Acetaminophen which could result in a higher serum level.
Acetazolamide	Acetazolamide may increase the excretion rate of Daptomycin which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acid	Acetylsalicylic acid may decrease the excretion rate of Daptomycin which could result in a higher serum level.
Acipimox	The risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Daptomycin is combined with Acipimox.
Aclidinium	Daptomycin may decrease the excretion rate of Aclidinium which could result in a higher serum level.

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Food Interactions

No interactions found.

Products

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International/Other Brands

Cidecin / Cubicin

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Cubicin		350 mg	Intravenous	Merck Sharp & Dohme B.V.	2021-03-17	Not applicable
Cubicin	Powder, for solution	500 mg / vial	Intravenous	Cubist Pharmaceuticals, Inc.	2007-12-03	Not applicable
Cubicin	Solution	500 mg	Intravenous	Merck Sharp & Dohme B.V.	2021-03-17	Not applicable
Cubicin	Injection, powder, lyophilized, for solution	500 mg/10mL	Intravenous	Merck Sharp & Dohme Corp.	2003-09-12	Not applicable
Cubicin	Injection	350 mg/350mg	Intravenous	OSO BioPharmaceuticals Manufacturing, LLC	2003-09-12	Not applicable
Cubicin	Solution	500 mg	Intravenous	Merck Sharp & Dohme B.V.	2021-03-17	Not applicable
Cubicin		350 mg	Intravenous	Merck Sharp & Dohme B.V.	2021-03-17	Not applicable
Cubicin RF	Injection, powder, lyophilized, for solution	500 mg/10mL	Intravenous	Merck Sharp & Dohme Corp.	2016-09-13	Not applicable
Cubicin RF	Powder, for solution	500 mg / vial	Intravenous	Cubist Pharmaceuticals, Inc.	2018-01-17	Not applicable
Daptomycin	Injection, powder, lyophilized, for solution	350 mg/7mL	Intravenous	Xellia Pharmaceuticals USA, LLC	2018-07-19	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Daptomycin	Injection, powder, lyophilized, for solution	350 mg/7mL	Intravenous	BE Pharmaceuticals Inc.	2020-08-20	Not applicable
Daptomycin	Injection, powder, lyophilized, for solution	500 mg/10mL	Intravenous	Mylan Institutional LLC	2018-09-04	Not applicable
Daptomycin	Injection, powder, lyophilized, for solution	500 mg/10mL	Intravenous	Civica, Inc.	2019-08-20	Not applicable
Daptomycin	Injection, powder, lyophilized, for solution	500 mg/10mL	Intravenous	Cipla USA Inc.	2019-09-23	Not applicable
Daptomycin	Injection, powder, lyophilized, for solution	500 mg/10mL	Intravenous	Fresenius Kabi USA, LLC	2016-06-28	Not applicable
Daptomycin	Injection, powder, lyophilized, for solution	500 mg/10mL	Intravenous	Meitheal Pharmaceuticals Inc.	2019-06-26	Not applicable
Daptomycin	Injection, powder, lyophilized, for solution	500 mg/10mL	Intravenous	Camber Pharmaceuticals Inc.	2021-01-04	Not applicable
Daptomycin	Injection, powder, lyophilized, for solution	500 mg/10mL	Intravenous	Xellia Pharmaceuticals USA LLC	2018-10-01	Not applicable
Daptomycin	Injection, powder, for solution	500 mg/10mL	Intravenous	Hospira Inc.	2020-10-05	Not applicable
Daptomycin	Injection, powder, lyophilized, for solution	500 mg/10mL	Intravenous	Dr.Reddy's Laboratories Inc.,	2019-05-01	Not applicable

Categories

ATC Codes

J01XX09 — Daptomycin

• J01XX — Other antibacterials
• J01X — OTHER ANTIBACTERIALS
• J01 — ANTIBACTERIALS FOR SYSTEMIC USE
• J — ANTIINFECTIVES FOR SYSTEMIC USE

Drug Categories

• Agents Causing Muscle Toxicity
• Amino Acids, Peptides, and Proteins
• Anti-Bacterial Agents
• Anti-Infective Agents
• Antibacterials for Systemic Use
• Antiinfectives for Systemic Use
• Cyclic Lipopeptides
• Drugs that are Mainly Renally Excreted
• Lipids
• Lipopeptide Antibacterial
• Lipopeptides
• P-glycoprotein substrates
• Peptides
• Peptides, Cyclic

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]

External Links

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

AHFS Codes

• 08:12.28.12 — Cyclic Lipopeptides

FDA label

Download (560 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Not Available	Critically-ill Patients / Hemodialysis Treatment	1
4	Completed	Basic Science	Cellulitis	1
4	Completed	Treatment	Bacteremia	2
4	Completed	Treatment	Bacteremia / Methicillin Susceptible Staphylococcus Aureus Septicemia	1
4	Completed	Treatment	Cellulitis	1
4	Completed	Treatment	Cellulitis / Skin Infections	1
4	Completed	Treatment	Skin Diseases, Infectious	1
4	Completed	Treatment	Staphylococcal Skin Infections	1
4	Completed	Treatment	Wound Infections	1
4	Recruiting	Treatment	Abscesses / CNS Infection / Coagulase Negative Staphylococcal Infection / Diabetic Foot Infection / Infection caused by staphylococci / Osteomyelitis / Septic Arthritis / Vertebral Osteomyelitis	1

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

Form	Route	Strength
Injection	Intravenous	350 mg/350mg
Injection, powder, for solution	Intravenous; Parenteral
Powder, for solution	Intravenous	500 mg / vial
Solution	Intravenous	500 mg
Injection, powder, lyophilized, for solution	Intravenous
Injection, solution	Intravenous	350 mg
Injection, solution	Intravenous	500 mg
Injection, powder, lyophilized, for solution	Intravenous	500 mg/10mL
Injection, solution	Intravenous
Injection, powder, for solution	Intravenous
Injection, powder, lyophilized, for solution	Intravenous	350 mg
Injection, powder, lyophilized, for solution	Intravenous	500 mg
Injection, powder, for solution	Intravenous	500 mg/10mL
Injection, powder, lyophilized, for solution	Intravenous	350 mg/10mL
Injection, powder, lyophilized, for solution	Intravenous	350 mg/7mL
Injection, powder, lyophilized, for solution	Intravenous	50 mg/1mL
Injection, powder, for solution	Parenteral
Powder, for solution	Intravenous	350 mg / vial
Injection	Intravenous	500 mg

Prices

Unit description	Cost	Unit
Cubicin 500 mg vial	272.7USD	vial

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
CA2344318	No	2006-07-04	2019-09-24
US6468967	No	2002-10-22	2019-09-24
US6852689	No	2005-02-08	2019-09-24
US8003673	No	2011-08-23	2028-09-04
USRE39071	No	2006-04-18	2016-06-15
US8058238	No	2011-11-15	2020-11-28
US8129342	No	2012-03-06	2020-11-28
US9138456	No	2015-09-22	2030-11-23

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0173 mg/mL	ALOGPS
logP	-0.47	ALOGPS
logP	-9.4	ChemAxon
logS	-5	ALOGPS
pKa (Strongest Acidic)	2.98	ChemAxon
pKa (Strongest Basic)	9.59	ChemAxon
Physiological Charge	-3	ChemAxon
Hydrogen Acceptor Count	27	ChemAxon
Hydrogen Donor Count	22	ChemAxon
Polar Surface Area	702.02 Å2	ChemAxon
Rotatable Bond Count	35	ChemAxon
Refractivity	393.57 m3·mol-1	ChemAxon
Polarizability	158.96 Å3	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Targets

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with our fully connected ADMET & drug target dataset.

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Accelerate your drug discovery research with our ADMET & drug target dataset

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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]

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Drug created on June 13, 2005 13:24 / Updated on June 12, 2021 01:52