Daptomycin

J01X - Other antibacterials ATC J01XX09 Small molecule approved 2003 Parenteral Natural product

JFDA label: Xeracine 500 mg

Mechanism of Action

Inhibitor of Cell membrane — Cell membrane inhibitor

Target	Action	Gene / class
Cell membrane efficacy	INHIBITOR

Indications

Approved

S. aureus bacteremia
Skin and skin structure infections, complicated

Off-label

Diabetic foot infections
Endocarditis (due to S. aureus [left-sided] or Enterococcus), treatment (adults)
Endocarditis, treatment (pediatric)
Osteomyelitis and/or septic arthritis due to methicillin-resistant Staphylococcus aureus
Osteomyelitis, native vertebral
Vancomycin-resistant enterococci (VRE) bacteremia

Antimicrobial Spectrum

Expected / intrinsic spectrum (EUCAST breakpoints & labels) — not local resistance. Source: EUCAST v16 · curated · openfda-label.

Bacteria

Organism	Activity	MIC
Coagulase-negative staphylococci	Susceptible	1.0 mg/L
Enterococcus faecalis	Susceptible	4.0 mg/L
Enterococcus faecium	Susceptible	4.0 mg/L
Staphylococcus aureus	Susceptible	1.0 mg/L
Staphylococcus epidermidis	Active	—
Staphylococcus haemolyticus	Active	—
Streptococcus A/B/C/G	Susceptible	12.0 mg/L
Streptococcus agalactiae	Active	—
Streptococcus dysgalactiae	Active	—
Streptococcus pyogenes	Active	—
Staphylococcus aureus	Resistant	1.0 mg/L

Class profile

gramStatus	Gram+
spectrumBreadth	Narrow
atypicalCoverage	No
isBactericidal	1
moaCategory	Cell membrane depolarization (lipopeptide, calcium-dependent)
pdIndex	Concentration-dependent
postAntibioticEffect	Prolonged
mrsaCoverage	1
resistanceMechanisms	Membrane charge alteration (MprF/lysyl-phosphatidylglycerol),Cell wall thickening

Contraindications

Source: Lexicomp

Hypersensitivity to daptomycin or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (6)

Common Chest pain · edema · hypertension · hypotension

Not Known Atrial fibrillation · atrial flutter

Nervous system disorders (5)

Common dizziness · headache · Insomnia

Not Known Hallucination · hypoesthesia (including oral)

Hepatobiliary disorders (4)

Common Abnormal hepatic function tests · increased serum alkaline phosphatase

Not Known Increased serum ALT · increased serum AST

Renal and urinary disorders (4)

Not Known Fungal urinary tract infection · proteinuria · Renal insufficiency · vulvovaginal candidiasis

Blood and lymphatic system disorders (1)

Not Known Lymphadenopathy

Metabolism and nutrition disorders (1)

Not Known Increased serum phosphate

Gastrointestinal disorders (8)

Common abdominal pain · Diarrhea · vomiting

Not Known Decreased appetite · epigastric distress · gingival pain · oral candidiasis · xerostomia

Skin and subcutaneous tissue disorders (3)

Common diaphoresis · Pruritus · skin rash

Musculoskeletal and connective tissue disorders (2)

Common Increased creatine phosphokinase

Not Known Dyskinesia

Eye disorders (1)

Not Known Blurred vision

Ear and labyrinth disorders (1)

Not Known Tinnitus

Infections and infestations (5)

Common bacteremia · Gram-negative organism infection · sepsis

Not Known Candidiasis · fungal septicemia

General disorders and administration site conditions (1)

Common Fever

Respiratory, thoracic and mediastinal disorders (2)

Common dyspnea · Pharyngolaryngeal pain

Dosing

Source: Lexicomp

Diabetic foot infections without osteomyelitis (off-label use): IV: 4 mg/kg once daily (Lipsky 2005) Endocarditis, treatment: IV: S. aureus (right-sided, native valve): Note: Clinical trial demonstrating noninferiority to standard therapy for S. aureus right-sided endocarditis included only patients with native valve infective endocarditis (Fowler 2006) Manufacturer labeling: 6 mg/kg once daily for 2 to 6 weeks Alternate recommendation: 8 to 10 mg/kg once daily (IDSA [Liu 2011]) S. aureus (left-sided, native valve) (off-label use): ≥8 mg/kg once daily for 6 weeks, consultation with infectious disease specialist recommended for dosage selection (AHA [Baddour 2015]) Enterococcus (penicillin-, aminoglycoside-, and vancomycin-resistant) (off-label use): 10 to 12 mg/kg once daily for a minimum of 6 weeks; combination therapy with ampicillin, ceftaroline, or another antibiotic may be considered in patients with persistent bacteremia or strains with relatively high MICs to daptomycin within the susceptible range ( Osteomyelitis due to MRSA (off-label use): IV: 6 mg/kg once daily for a minimum of 8 weeks; some experts combine with rifampin (in patients with concurrent bacteremia, initiate rifampin after clearance of bacteremia) (IDSA [Liu 2011]) Osteomyelitis, native vertebral (off-label use) (IDSA [Berbari 2015]): IV: Staphylococci (oxacillin-susceptible or -resistant): 6 to 8 mg/kg once daily for 6 weeks Enterococcus spp (penicillin-susceptible or -resistant): 6 mg/kg once daily for 6 weeks. Note: In patients with infective endocarditis, the addition of an aminoglycoside for 4 to 6 weeks is recommended Prosthetic joint infection (off-label use): IV: Enterococcus spp (penicillin-susceptible or -resistant) (alternative treatment): 6 mg/kg every 24 hours for 4 to 6 weeks (consider adding an aminoglycoside), followed by an oral antibiotic suppressive regimen if a debridement and retention strategy or 1-stage exchange is chosen (Osmon 2013) Staphylococci (oxacillin-susceptible or -resistant) (alternative treatment): 6 mg/kg every 24 hours for 2 to 6 weeks (used in combination with rifampin if a debridement and retention strategy or 1-stage exchange is chosen), followed by oral antibiotic treatment (and suppressive regimen if a debridement and retention strategy or 1-stage exchange is chosen) (Osmon 2013) S. aureus bacteremia: IV Manufacturer labeling: 6 mg/kg once daily for 2 to 6 weeks Alternate recommendation: 8 to 10 mg/kg once daily for complicated bacteremia (IDSA [Liu 2011]) Septic arthritis due to MRSA (off-label use): IV: 6 mg/kg once daily for 3 to 4 weeks (IDSA [Liu 2011]) Skin and skin structure infections, complicated: IV: 4 mg/kg once daily for 7 to 14 days VRE bacteremia (off-label use): IV: 6 to 8 mg/kg once daily (Casapao 2013; Gallagher 2009); however, based on pharmacokinetic data, higher doses (up to 12 mg/kg once daily) may be appropriate for difficult to treat infections (Benvenuto 2006). Additional trials may be necessary to further de

(For additional information see "Daptomycin: Pediatric drug information") Endocarditis, treatment (off-label use; AHA [Baltimore 2015]): Due to Staphylococcus (MRSA or vancomycin resistant/intolerant): IV: Children Children ≥6 years and Adolescents: 6 mg/kg/dose every 24 hours Skin and skin structure infections, complicated: Children and Adolescents: IV: 1 to 2 to 6 years: 9 mg/kg once daily 7 to 11 years: 7 mg/kg once daily 12 to 17 years: 5 mg/kg once daily ≥18 years: Refer to adult dosing. Duration of therapy: ≤14 days S. aureus bacteremia: Children and Adolescents: IV: 1 to 6 years: 12 mg/kg once daily 7 to 11 years: 9 mg/kg once daily 12 to 17 years: 7 mg/kg once daily ≥18 years: Refer to adult dosing. Duration of therapy: ≤42 days

Refer to adult dosing.

Adults: CrCl ≥30 mL/minute: No dosage adjustment necessary. CrCl Skin and soft tissue infections: 4 mg/kg every 48 hours Staphylococcal bacteremia: 6 mg/kg every 48 hours End-stage renal disease (ESRD) on intermittent hemodialysis (IHD): Note: Hemodialysis: Dialyzable: 15% (removed by 4-hour hemodialysis session); 50% (removed by 4-hour high permeability intermittent hemodialysis session) (Salama 2010). A notable amount of drug may be removed in the last 30 minutes of dialysis; administration after dialysis is completed is preferred (Haselden 2013). Manufacturer's labeling: Dose as in CrCl Alternate dosing: Administer usual recommended dose (ie, 4 or 6 mg/kg) on 48 hour intradialytic days; increase dose by 50% after dialysis on the 72 hour intradialytic day (eg, if the dose is 6 mg/kg for a patient on a Monday, Wednesday, Friday dialysis schedule, administer 6 mg/kg after dialysis on Monday and Wednesday and on Friday administer 9 mg/kg after dialysis) (Haselden 2013, Patel 2011). Peritoneal dialysis (PD): Dose as in CrCl Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment: Continuous veno-venous hemodialysis (CVVHD): 8 mg/kg every 48 hours (Vilay 2010) Note: For other forms of CRRT (eg, CVVH or CVVHDF), dosing as with CrCl max. May consider 4 to 6 mg/kg every 24 hours (or 8 mg/kg every 48 hours) depending on site or severity of infection or if not responding to standard dosing; therapeutic drug monitoring and/or more frequent serum CPK levels may be necessary (Heintz 2009). Slow extended daily dialysis (or extended dialysis): 6 mg/kg every 24 hours (Kielstein 2010); Note: Dialysis should be initiated within 8 hours of administering daptomycin dose to avoid dose accumulation. Children and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary. Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

Eosinophilic pneumonia

Use may result in eosinophilic pneumonia; generally develops 2 to 4 weeks after therapy initiation. Monitor for signs and symptoms of eosinophilic pneumonia, including new onset or worsening fever, dyspnea, difficulty breathing, new infiltrates on chest imaging studies, and/or >25% eosinophils present in bronchoalveolar lavage. Discontinue use immediately with signs/symptoms of eosinophilic pneumonia and initiate appropriate treatment (ie, corticosteroids). May reoccur with re-exposure.

Hypersensitivity

Hypersensitivity reactions and anaphylaxis (including angioedema, and drug rash with eosinophilia and systemic symptoms [DRESS]) have been reported with use; discontinue use immediately with signs/symptoms of hypersensitivity and initiate appropriate treatment.

Myopathy/rhabdomyolysis

May be associated with an increased incidence of myopathy; rhabdomyolysis, with or without acute renal failure, has also been reported. Discontinue in patients with signs and symptoms of myopathy in conjunction with an increase in CPK (>5 times ULN or 1,000 units/L) or in asymptomatic patients with a CPK ≥10 times ULN or >2,000 units/L. Myopathy may occur more frequently at dose and/or frequency in excess of recommended dosages. Consider temporarily interrupting therapy with other agents associated with rhabdomyolysis (eg, HMG-CoA reductase inhibitors) during daptomycin therapy.

Peripheral neuropathy

Symptoms suggestive of peripheral neuropathy have been observed with treatment; monitor for new-onset or worsening neuropathy.

Superinfection

Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment. Disease-related concerns:

Persisting or relapsing S. aureus bacteremia or endocarditis

Repeat blood cultures in patients with persisting or relapsing S. aureus bacteremia/endocarditis or poor clinical response. If culture is positive for S. aureus, perform minimum inhibitory concentration (MIC) susceptibility testing of the isolate and diagnostic evaluation of the patient to rule out sequestered foci of infection. Appropriate surgical intervention (eg, debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of a change in antibacterial therapy may be necessary.

Renal impairment

Use with caution in patients with renal impairment; dosage adjustment required in severe renal impairment (CrCl Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Pediatric

Avoid use in pediatric patients

Pregnancy & Lactation

Pregnancy

Adverse events were not observed in animal reproduction studies. Successful use of daptomycin during the second and third trimesters of pregnancy has been described; however, only limited information is available from case reports.

Lactation

Low concentrations of daptomycin have been detected in breast milk; however, daptomycin is poorly absorbed orally. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. In general, antibiotics that are present in breast milk may cause non-dose-related modification of bowel flora. Monitor infants for GI disturbanc

Monitoring

Efficacy	Culture and susceptibility testing; clinical resolution (temperature, WBC, CRP, procalcitonin)
Toxicity	Renal function (dose adjustment in renal impairment); hepatic function for hepatically cleared agents; signs of C. difficile infection (diarrhoea)
Clinical pearl	Culture results guide de-escalation to narrower-spectrum therapy. Review antibiotic appropriateness at 48–72 h (antimicrobial stewardship).
Counseling	Complete the full course. Report persistent diarrhoea, rash, or lack of improvement after 48–72 h.

Chemistry & Properties

Formula	C72H101N17O26
Molecular weight	1620.69 g/mol
IUPAC name	(3S)-3-[[(2R)-4-amino-2-[[(2S)-2-(decanoylamino)-3-(1H-indol-3-yl)propanoyl]amino]-4-oxobutanoyl]amino]-4-[[(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-nonazacyclohentriacont-30-yl]amino]-4-oxobutanoic acid
CAS	103060-53-3
PubChem CID	21585658
InChIKey	`DOAKLVKFURWEDJ-RWDRXURGSA-N`

SMILES

CCCCCCCCCC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H]1C(=O)NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@@H]([C@H](C)CC(=O)O)C(=O)N[C@@H](CC(=O)c2ccccc2N)C(=O)O[C@@H]1C

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	2.522 h
Volume of distribution	0.219 L/kg
Protein binding	45.7%
BBB penetrant	No

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (12, DDInter)

Interacting drug	Severity	Management
Celecoxib	moderate
Cyclosporine	moderate
Diclofenac	moderate
Ethinylestradiol	moderate
Ibuprofen	moderate
Iobenguane (I-131)	moderate
Mycophenolic acid	moderate
Picosulfuric acid	moderate
Rosuvastatin	moderate
Simvastatin	moderate
Dicoumarol	minor
Warfarin	minor

Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Xeracine	Vial 500 mg	1 vial	MS PHARMA/JORDAN	—