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DAPTOmycin

Pronunciation

Pronunciation

(DAP toe mye sin)

Index Terms

  • Cidecin
  • Dapcin
  • LY146032

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Cubicin: 500 mg (1 ea)

Brand Names: U.S.

  • Cubicin

Pharmacologic Category

  • Antibiotic, Cyclic Lipopeptide

Pharmacology

Daptomycin binds to components of the cell membrane of susceptible organisms and causes rapid depolarization, inhibiting intracellular synthesis of DNA, RNA, and protein. Daptomycin is bactericidal in a concentration-dependent manner.

Distribution

Vss:

Neonates and Infants <3 months: Median: 0.21 L/kg (range: 0.11 to 0.34 L/kg) (Cohen-Wolkowiez 2012)

Children 2 to 6 years: 0.14 L/kg (Abdel-Rahman 2008; Abdel-Rahman 2011)

Children 7 to 17 years: 0.11 ± 0.02 L/kg (Abdel-Rahman 2008)

Adults: 0.1 L/kg; Critically-ill patients: Vss: 0.23 ± 0.14 L/kg (Vilay 2010)

Metabolism

Minor amounts of oxidative metabolites have been detected; does not induce or inhibit cytochrome P450 enzymes

Excretion

Urine (78%; primarily as unchanged drug); feces (6%)

Clearance:

Neonates and Infants <3 months: Median: 21 mL/hour/kg (range: 16 to 34 mL/hour/kg) (Cohen-Wolkowiez 2012)

Children 2 to 6 years: 19 to 20 mL/hour/kg (Abdel-Rahman 2008; Abdel-Rahman 2011)

Children 7 to 11 years: 17 mL/hour/kg (Abdel-Rahman 2008)

Children: 12 to 17 years: 11 mL/hour/kg (Abdel-Rahman 2008)

Adults: 8.3 to 9 mL/hour/kg

Half-Life Elimination

Neonates and Infants <3 months: Median: 6.2 hours (range: 3.7 to 9 hours) (Cohen-Wolkowiez 2012)

Children 2 to 6 years: Mean range: 5.3 to 5.7 hours (Abdel-Rahman 2008; Abdel-Rahman 2011)

Children 7 to 11 years: 5.6 ± 2.2 hours (Abdel-Rahman 2008)

Children 12 to 17 years: 6.7 ± 2.2 hours (Abdel-Rahman 2008)

Adults: 8 to 9 hours (up to 28 hours in renal impairment)

Protein Binding

90% to 93%; 84% to 88% in patients with CrCl <30 mL/minute

Special Populations: Renal Function Impairment

Mean total plasma clearance was 9%, 22%, and 46% lower in patients with mild (CrCl 50 to 80 mL/minute), moderate (CrCl 30 to <50 mL/minute), and severe (CrCl <30 mL/minute) renal impairment, respectively, compared with those with healthy renal function. Mean AUC, half-life, and Vd at steady state increased with decreasing renal function.

Special Populations: Elderly

Mean total clearance is reduced approximately 35% and AUC is increased approximately 58% in elderly patients compared with younger healthy subjects.

Special Populations Note

Obesity: Plasma clearance was 15% and 23% lower and AUC increased by 30% and 31% in moderately obese patients and extremely obese patients, respectively, compared with nonobese controls.

Use: Labeled Indications

Skin and skin structure infections, complicated: For the treatment of complicated skin and skin structure infections caused by susceptible isolates of the following gram-positive bacteria: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subspecies equisimilis, and Enterococcus faecalis (vancomycin-susceptible strains only).

S. aureus bloodstream infections:

For the treatment of S. aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates.

Patients with persisting or relapsing S. aureus infection or poor clinical response should have repeat blood cultures. If a culture is positive for S. aureus, perform minimum inhibitory concentration (MIC) susceptibility testing of the isolate using a standardized procedure and diagnostic evaluation to rule out sequestered foci of infection.

General information: Daptomycin is not indicated for the treatment of pneumonia.

Use: Unlabeled

Treatment of severe infections caused by MRSA or VRE; treatment of prosthetic joint infection caused by staphylococci (oxacillin-susceptible or -resistant) or Enterococcus (penicillin-susceptible or -resistant)

Contraindications

Hypersensitivity to daptomycin

Dosing: Adult

Infective endocarditis, treatment:

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:

US labeling: 6 mg/kg once daily for 2 to 6 weeks

Canadian labeling: 6 mg/kg once daily for 10 days to 6 weeks; may consider an additional 2 weeks of therapy

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 or ceftaroline may be considered in patients with persistent bacteremia or strains with high MICs (3 mcg/mL) (AHA [Baddour 2015])

Osteomyelitis (off-label use): IV: 6 mg/kg once daily for a minimum of 8 weeks (some experts combine with rifampin) (Liu 2011)

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 (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 followed by oral antibiotic treatment and suppressive regimens (Osmon 2013)

S. aureus bloodstream infections:

Manufacturer labeling:

US labeling: 6 mg/kg once daily for 2 to 6 weeks

Canadian labeling: 6 mg/kg once daily for 10 days to 6 weeks; may consider an additional 2 weeks of therapy

Alternate recommendation: 8 to 10 mg/kg once daily for complicated bacteremia (IDSA [Liu 2011])

Septic arthritis (off-label use): IV: 6 mg/kg once daily for 3 to 4 weeks (Liu 2011)

Skin and skin structure infections, complicated: 4 mg/kg once daily for 7 to 14 days

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute:

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 <30 mL/minute (administer after hemodialysis on dialysis days).

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 <30 mL/minute

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 <30 mL/minute may result in low Cmax. 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.

Dosing: Hepatic Impairment

No dosage adjustment necessary for mild-to-moderate impairment (Child-Pugh class A or B). Not evaluated in severe hepatic impairment (Child-Pugh class C).

Reconstitution

Reconstitute vial with 10 mL NS to a concentration of 50 mg/mL. Add NS to vial and rotate gently to wet powder. Allow to stand for 10 minutes, then gently swirl to obtain completely reconstituted solution. Do not shake or agitate vial vigorously. If administering via IVPB, further dilute in 50 mL NS prior to administration.

Administration

May administer IV push over 2 minutes or infuse IVPB over 30 minutes. Do not use in conjunction with ReadyMED® elastomeric infusion pumps (Cardinal Health, Inc) due to an impurity (2-mercaptobenzothiazole) leaching from the pump system into the daptomycin solution.

Compatibility

Stable in NS or LR; incompatible with dextrose-containing solutions.

Storage

Store original packages at 2°C to 8°C (36°F to 46°F); avoid excessive heat. Daptomycin vials are for single use only.

US labeling: Reconstituted solution is stable in the vial for 12 hours at room temperature or up to 48 hours if refrigerated at 2°C to 8°C (36°F to 46°F). The diluted solution is stable in the infusion bag for 12 hours at room temperature or 48 hours if refrigerated. The combined time (reconstituted solution in vial and diluted solution in infusion bag) should not exceed 12 hours at room temperature or 48 hours refrigerated. Extended storage information for reconstituted vial and diluted solution may be available; contact product manufacturer to obtain current recommendations.

Canadian labeling: Reconstituted solution is stable in the vial or infusion solution for 12 hours at 25°C (77°F) or up to 10 days if refrigerated at 2°C to 8°C (36°F to 46°F) under normal lighting. The manufacturer recommends using reconstituted solution within 72 hours if stored under refrigeration. The combined time (reconstituted solution in vial and diluted solution in infusion bag) should not exceed 12 hours at up to 25°C (77°F) or 10 days at 2°C to 8°C (36°F to 46°F).

Drug Interactions

HMG-CoA Reductase Inhibitors: May enhance the adverse/toxic effect of DAPTOmycin. Specifically, the risk of skeletal muscle toxicity may be increased. Management: Consider temporarily stopping HMG-CoA reductase inhibitor therapy prior to daptomycin. If used together, regular (i.e., at least weekly) monitoring of CPK concentrations is recommended. Consider therapy modification

Test Interactions

Daptomycin may cause false prolongation of the PT and increase of INR with certain recombinant thromboplastin reagents. This appears to be a dose-dependent phenomenon. If PT/INR is elevated, repeat PT/INR immediately prior to next daptomycin dose (eg, trough). If PT/INR remains elevated, repeat PT/INR using alternate reagents (if available) and evaluate for other causes of elevated PT/INR.

Adverse Reactions

>10%:

Gastrointestinal: Diarrhea (5% to 12%), vomiting (3% to 12%), constipation (6% to 11%)

Hematologic & oncologic: Anemia (2% to 13%)

1% to 10%:

Cardiovascular: Chest pain (7%), peripheral edema (7%), hypertension (1% to 6%), hypotension (2% to 5%)

Central nervous system: Insomnia (5% to 9%), headache (5% to7%), dizziness (2% to 6%), anxiety (5%)

Dermatologic: Skin rash (4% to 7%), pruritus (3% to 6%), diaphoresis (5%), erythema (5%)

Endocrine & metabolic: Hypokalemia (9%), hyperkalemia (5%), hyperphosphatemia (3%)

Gastrointestinal: Nausea (6% to 10%), abdominal pain (6%), dyspepsia (1% to 4%), loose stools (4%), gastrointestinal hemorrhage (2%)

Genitourinary: Urinary tract infection (2% to 7%)

Hematologic & oncologic: Eosinophilia (2%), increased INR (2%)

Hepatic: Increased serum transaminases (2% to 3%), increased serum alkaline phosphatase (2%)

Infection: Gram-negative organism infection (8%), bacteremia (5%), sepsis (5%), fungal infection (2% to 3%)

Local: Injection site reaction (3% to 6%)

Neuromuscular & skeletal: Increased creatine phosphokinase (3% to 9%), limb pain (2% to 9%), back pain (7%), osteomyelitis (6%), weakness (5%), arthralgia (1% to 3%)

Renal: Renal failure (2% to 3%)

Respiratory: Pharyngolaryngeal pain (8%), pleural effusion (6%), cough (3%), pneumonia (3%), dyspnea (2% to 3%)

Miscellaneous: Fever (2% to 7%)

<1% (Limited to important or life-threatening): Atrial fibrillation, atrial flutter, candidiasis, cardiac arrest, Clostridium difficile associated diarrhea, coma (post anaesthesia/surgery), eczema, eosinophilic pneumonitis, hallucination, hypomagnesemia, hypersensitivity, jaundice, increased lactate dehydrogenase, lymphadenopathy, mental status changes, neutropenia (Knoll 2013), oral candidiasis, peripheral neuropathy, proteinuria, prolonged prothrombin time, renal insufficiency, rhabdomyolysis, increased serum bicarbonate, Stevens-Johnson syndrome, stomatitis, supraventricular cardiac arrhythmia, thrombocytopenia, thrombocythemia

Warnings/Precautions

Concerns related to adverse effects:

• 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: May be associated with an increased incidence of myopathy; 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. Myopathy may occur more frequently at dose and/or frequency in excess of recommended dosages. Consider temporarily interrupting therapy with other agents associated with an increased risk of myopathy (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 <30 mL/minute). Limited data (eg, subgroup analysis) from cSSSI and endocarditis trials suggest possibly reduced clinical efficacy (relative to comparators) in patients with baseline moderate renal impairment (<50 mL/minute).

Special populations:

• Pediatric: Although not approved for use in children, the manufacturer recommends to avoid use in pediatric patients <12 months due to risk of potential muscular, neuromuscular, and/or nervous systems effects observed in neonatal canines.

Monitoring Parameters

Monitor signs and symptoms of infection. CPK should be monitored at least weekly during therapy; more frequent monitoring if current or prior statin therapy, unexplained CPK increases, and/or renal impairment. Monitor for muscle pain or weakness, especially if noted in distal extremities. Monitor for new onset or worsening peripheral neuropathy. Canadian labeling recommends CPK monitoring every 48 hours with unexplained muscle pain, tenderness, weakness or cramps. Monitor for signs/symptoms of eosinophilic pneumonia.

Pregnancy Risk Factor

B

Pregnancy Considerations

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.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, headache, injection site irritation, insomnia, sweating a lot, or pharyngitis. Have patient report immediately to prescriber severe loss of strength and energy, burning or numbness feeling, muscle pain, muscle weakness, dark urine, jaundice, urinary retention, change in amount of urine passed, cough, shortness of breath, angina, edema, or signs of Clostridium difficile (C. diff)-associated diarrhea (stomach pain or cramps, very loose or watery stools, or bloody stools) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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