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Generic Name: Daptomycin
Class: Cyclic Lipopeptides
VA Class: AM900
Chemical Name: N - Decanoyl - l - tryptophyl - l - asparaginyl - l - aspartyl - l - threonylglycyl - l - ornithyl - l - aspartyl - d - alanyl - l - aspartylglycyl - d - seryl - threo - 3 - methyl - l - glutamyl - 3 - anthraniloyl - l - alanine ε1-lactone
Molecular Formula: C72H101N17O26
CAS Number: 103060-53-3

Introduction

Antibacterial; cyclic lipopeptide antibiotic.1 3 5

Uses for Cubicin

Skin and Skin Structure Infections

Treatment of complicated skin and skin structure infections caused by susceptible Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA]), Streptococcus pyogenes (group A β-hemolytic streptococci), S. agalactiae (group B streptococci), S. dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible strains only).1

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Concomitant use of another anti-infective may be indicated if documented or presumptive pathogens also include gram-negative or anaerobic bacteria.1

Bacteremia

Treatment of bacteremia (blood stream infection) caused by susceptible S. aureus (including MRSA).1

May be used for treatment of S. aureus bacteremia in patients with right-sided infective endocarditis.1 Efficacy not established in patients with left-sided infective endocarditis caused by S. aureus;1 limited data suggest a poor outcome in such patients despite daptomycin treatment.1

Concomitant use of another anti-infective may be indicated if documented or presumptive pathogens also include gram-negative or anaerobic bacteria.1

Persisting or relapsing S. aureus infection has been reported in some patients.1 (See Persisting or Relapsing Staphylococcus aureus Infection under Cautions.)

Has not been studied in patients with prosthetic valve endocarditis or meningitis.1

Cubicin Dosage and Administration

Administration

IV Infusion

Administer by IV infusion.1

Lyophilized powder for infusion must be reconstituted and diluted prior to administration.1

Vials are for single use only.1

Additives and other drugs should not be added to daptomycin solutions or infused simultaneously through the same IV line.1 If the same IV line is used for sequential infusion of different drugs, the line should be flushed with a compatible infusion solution (see Compatibility under Stability) before and after infusion of daptomycin.1

Do not use in conjunction with ReadyMed elastomeric infusion pumps; stability studies identified an impurity (i.e., 2-mercaptobenzothiazole) leaching from this pump system into the daptomycin solution.1

Reconstitution and Dilution

Reconstitute powder for infusion by adding 10 mL of 0.9% sodium chloride injection to vial containing 500 mg of daptomycin.1

Gently rotate vial to ensure that entire product is wetted.1 Allow vial to remain undisturbed for 10 minutes, then rotate or swirl for a few minutes (as needed) to obtain a completely reconstituted solution.1 To minimize foaming, avoid agitating or vigorously shaking vial during or after reconstitution.1

Reconstituted solution should be further diluted with 0.9% sodium chloride injection1 to a final concentration of ≤20 mg/mL.6

Use strict aseptic technique when preparing daptomycin solutions since the drug contains no preservatives.1

Rate of Administration

IV infusions are given over 30 minutes.1

Dosage

Adults

Skin and Skin Structure Infections
Complicated Infections
IV

4 mg/kg once every 24 hours for 7–14 days.1

Do not administer more frequently than once daily.1 (See Musculoskeletal Effects under Cautions.)

Bacteremia
IV

6 mg/kg once every 24 hours for at least 2–6 weeks.1 Base duration of treatment on clinical diagnosis.1 Limited safety data regarding use beyond 28 days; however, some patients in a clinical study received daptomycin for >6 weeks.1

Do not administer more frequently than once daily.1 (See Musculoskeletal Effects under Cautions.)

Special Populations

Hepatic Impairment

Dosage adjustment not necessary in adults with mild to moderate hepatic impairment;1 pharmacokinetics not evaluated in adults with severe hepatic impairment.1

Renal Impairment

Reduce dosage in adults with Clcr <30 mL/minute and in those undergoing hemodialysis or CAPD.1

For treatment of complicated skin and skin structure infections in adults with Clcr <30 mL/minute, reduce dosage to 4 mg/kg IV once every 48 hours.1

For treatment of bacteremia in adults with Clcr <30 mL/minute, reduce dosage to 6 mg/kg IV once every 48 hours.1

In hemodialysis patients, give dose on hemodialysis days following the procedure, if possible.1

Geriatric Patients

No dosage adjustments except those related to renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Obese Patients

Dosage adjustment not warranted.1

Cautions for Cubicin

Contraindications

  • Known hypersensitivity to daptomycin.1

Warnings/Precautions

Warnings

Eosinophilic Pneumonia

Eosinophilic pneumonia reported in some patients receiving daptomycin.1 7 8 9 10 11 12 Patients generally developed fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates 2–4 weeks after the drug was initiated.1 7 8 9 10 11 12 Improvement or resolution of symptoms generally occurred when daptomycin was discontinued;1 7 8 9 10 11 12 most patient received treatment with systemic corticosteroids.1 7 8 9 10 11 12 Reinitiation of daptomycin has resulted in recurrence of eosinophilic pneumonia.1 7 8 11

FDA determined that there appears to be a temporal association between daptomycin and development of eosinophilic pneumonia.7 To date, there have been 7 probable and 36 possible cases of eosinophilic pneumonia reported in patients receiving daptomycin;7 some were receiving the drug for uses not approved by FDA.7 8 9 Consider that eosinophilic pneumonia can progress to respiratory failure and is potentially fatal if not quickly recognized and appropriately managed.7 8 9 11

Closely monitor for signs and symptoms of eosinophilic pneumonia (e.g., new onset or worsening fever, dyspnea, difficulty breathing, new pulmonary infiltrates).1 7 8 9 10 11 12

Immediately discontinue daptomycin if there are any signs or symptoms of eosinophilic pneumonia.1 7 8 9 10 11 12 Initiate prompt medical evaluation;1 7 8 9 10 11 12 treatment with systemic corticosteroids is recommended.1 8 9 10 11 12

Superinfection/Clostridium difficile-associated Colitis

Possible emergence and overgrowth of nonsusceptible bacteria or fungi.1 Careful observation of the patient is essential.1 Institute appropriate therapy if superinfection occurs.1

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.1 13 14 15 16 C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all anti-infectives, including daptomycin, and may range in severity from mild diarrhea to fatal colitis.1 Hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1

Consider CDAD if diarrhea develops during or after therapy and manage accordingly.1 13 14 15 16 Obtain a careful medical history since CDAD may occur as late as 2 months or longer after anti-infective therapy is discontinued.1

If CDAD is suspected or confirmed, anti-infectives not directed against C. difficile should be discontinued.1 Manage moderate to severe cases with fluid, electrolyte, and protein supplementation, anti-infective therapy active against C. difficile (e.g., oral metronidazole or vancomycin), and surgical evaluation when clinically indicated.1 13 14 15 16

General Precautions

Persisting or Relapsing Staphylococcus aureus Infection

Treatment failure due to persisting or relapsing S. aureus infection has occurred in patients receiving daptomycin;1 fatalities reported.1 S. aureus isolates with reduced susceptibility or resistance to daptomycin have been reported and have emerged during therapy with the drug.1 19 20 21

In a clinical study in patients with bacteremia, 15.8% of daptomycin-treated patients and 9.6% of patients receiving a comparator anti-infective (vancomycin or a penicillinase-resistant penicillin) had persisting or relapsing S. aureus infections;1 some fatalities occurred.1 In vitro studies indicated isolates from some of these patients developed reduced susceptibility to the anti-infective during or following treatment.1 Most patients with persisting or relapsing infections had deep-seated infections and did not receive necessary surgical intervention.1

Perform repeat blood cultures in patients with persisting or relapsing infection or with poor clinical outcomes.1 If cultures are positive for S. aureus, perform in vitro susceptibility testing using standardized MIC procedures.1 Also perform diagnostic evaluation to rule out sequestered foci of infection.1 Surgical intervention (e.g., debridement, removal of prosthetic devices, valve replacement surgery) and/or a change in anti-infective regimen may be required.1

Musculoskeletal Effects

Increases in serum CK concentrations have been reported in patients receiving daptomycin.1 Occurs more frequently if the drug is given more frequently than once daily.1

Monitor for development of muscle pain or weakness, particularly of distal extremities.1 Determine serum CK concentrations weekly during daptomycin treatment;1 more frequent determinations are indicated in those who develop unexplained increases in serum CK concentrations and in those previously or concomitantly treated with an HMG-CoA reductase inhibitor (statin).1 In those with renal impairment, monitor serum CK concentrations and renal function more frequently.1

Discontinue daptomycin in patients with unexplained signs or symptoms of myopathy in conjunction with increases in CK >1000 U/L (i.e., approximately 5 times the ULN) or in patients without reported symptoms who have substantial increases in serum CK concentrations (i.e., >2000 U/L [≥10 times the ULN]).1

Consider temporarily discontinuing drugs associated with rhabdomyolysis (e.g., HMG-CoA reductase inhibitors) during daptomycin treatment.1 (See Specific Drugs under Drug Interactions.)

Nervous System Effects

Decreases in nerve conduction velocity and adverse effects (e.g., paresthesia, Bell’s palsy) possibly suggestive of peripheral or cranial neuropathy reported rarely.1

Be alert to possible manifestations of neuropathy.1

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of daptomycin and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.1

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1

If documented or presumed pathogens include gram-negative or anaerobic bacteria, concomitant use of an anti-infective active against such bacteria may be indicated.1 (See Uses.)

Do not use for treatment of pneumonia.1

Safety and efficacy not studied in patients with prosthetic valve endocarditis or meningitis.1

Specific Populations

Pregnancy

Category B.

Lactation

Not known whether distributed into milk.1 Use with caution.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

In clinical studies, success rates were lower and incidence of treatment-emergent adverse effects were higher in patients ≥65 years of age compared with younger adults.1

Consider age-related decreases in renal function when selecting dosage and adjust dosage if necessary.1 (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

Pharmacokinetics not altered in patients with moderate hepatic impairment (Child-Pugh class B);1 not studied in patients with severe hepatic impairment.1

Renal Impairment

Clearance decreased; AUC and half-life increased in patients with renal impairment.1

Monitor renal function and serum CK concentrations more frequently in patients with renal insufficiency.1

Dosage adjustment necessary in patients with Clcr <30 mL/minute.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Patients treated for complicated skin and skin structure infections: GI effects (constipation, nausea, diarrhea, vomiting), injection site reactions, nervous system effects (headache, insomnia, dizziness), rash, pruritus, abnormal liver function test results, CK elevations, infections (fungal, urinary tract), hypotension, renal failure, anemia, dyspnea, fever.1

Patients treated for bacteremia: GI effects (diarrhea, vomiting, constipation, nausea, dyspepsia, loose stools, abdominal pain), musculoskeletal and connective tissue disorders (pain in extremity, back pain), nervous system effects (headache, dizziness, insomnia, anxiety), respiratory disorders (pharyngolaryngeal pain, pleural effusion), infections (urinary tract, osteomyelitis, sepsis, bacteremia), peripheral edema, pyrexia, chest pain, edema, asthenia, rash, pruritus, erythema, increased sweating, CK elevations, hypertension, hyperkalemia, hypokalemia, anemia, hypotension.1

Interactions for Cubicin

Does not inhibit or induce CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, or 3A4; pharmacokinetic interactions with drugs metabolized by these CYP isoenzymes unlikely.1

Specific Drugs and Laboratory Tests

Drug

Interaction

Comments

Aminoglycosides

Tobramycin: Increased daptomycin plasma concentrations and AUC and decreased tobramycin plasma concentrations and AUC1

In vitro evidence of synergistic antibacterial effects against staphylococci and enterococci1 17 in studies using gentamicin and tobramycin;17 additive or indifferent antibacterial effects also reported, but antagonism did not occur17

Tobramycin: Clinical importance of pharmacokinetic interaction unclear; use concomitantly with caution1

β-Lactam anti-infectives

Aztreonam: Clinically important pharmacokinetic interactions unlikely1 6

In vitro evidence of synergistic antibacterial effects against staphylococci and enterococci1 17 in studies using penicillins (ampicillin, oxacillin, ampicillin and sulbactam, piperacillin and tazobactam, ticarcillin and clavulanate), cephalosporins (cefepime, ceftriaxone), aztreonam, or imipenem;17 additive or indifferent antibacterial effects also reported, but antagonism generally did not occur17

Aztreonam: Dosage adjustment not necessary if used concomitantly1

HMG-CoA reductase inhibitors (statins)

Potential pharmacologic interaction (risk of myopathy manifested as muscle pain or weakness in association with increased serum CK concentrations);1 increased serum CK concentrations reported in some patients previously or concomitantly treated with an HMG-CoA reductase inhibitor1

Simvastatin: No evidence of increased adverse effects when used concomitantly with daptomycin in healthy adults1

Experience with concurrent use is limited; consider temporarily discontinuing HMG-CoA reductase inhibitor during daptomycin treatment1

Probenecid

Clinically important pharmacokinetic interactions unlikely1 6

Dosage adjustment not necessary1

Rifampin

In vitro evidence of synergistic antibacterial effects against staphylococci and enterococci, including some vancomycin-resistant enterococci;1 17 additive or indifferent antibacterial effects also reported, but antagonism did not occur17

Tests, coagulation

Daptomycin causes concentration-dependent false prolongation of PT and elevated INR if certain recombinant thromboplastin reagents are used for these tests1

Interference with PT/INR may be minimized by drawing blood samples for coagulation tests near the time of daptomycin trough plasma concentrations; consider that trough plasma concentrations may still be high enough to interfere with these tests1

If abnormally elevated PT/INR results are reported in a patient receiving daptomycin, repeat coagulation testing using blood specimens drawn just prior to the next daptomycin dose (i.e., at trough concentrations);1 if results remain substantially elevated over what would otherwise be expected, consider alternative methods of measuring PT/INR and evaluate patient for other causes of abnormally elevated PT/INR1

Warfarin

No evidence of pharmacologic or pharmacokinetic interaction1

Experience with concurrent use is limited; closely monitor anticoagulant activity during the first several days if daptomycin is initiated in patients receiving warfarin 1

Cubicin Pharmacokinetics

Absorption

Bioavailability

Generally exhibits linear and time-independent pharmacokinetics at a dosage of 4–12 mg/kg IV once every 24 hours.1

Steady-state trough serum concentrations are achieved by the third daily dose.1

Distribution

Plasma Protein Binding

90–93% bound to plasma proteins, principally albumin.1

Elimination

Metabolism

In vitro studies indicate daptomycin is not metabolized by CYP isoenzymes.1 Inactive metabolites have been detected in urine; site and extent of metabolism have not been identified.1

Elimination Route

Eliminated principally by renal excretion; approximately 78 and 6% of a dose recovered in urine and feces, respectively.1

Half-life

Mean elimination half-life at steady state is 7.7–8.3 hours in adults.1

Special Populations

In geriatric adults ≥75 years of age, clearance is reduced approximately 35% and AUC is increased approximately 58% compared with younger adults (18–30 years of age).1

Pharmacokinetics not altered in adults with moderate hepatic impairment (Child-Pugh class B); pharmacokinetics not studied in adults with severe hepatic impairment.1

Clearance is decreased and AUC and half-life increased in adults with renal impairment compared with adults with normal renal function.1 Mean half-life is 10.75 hours in those with mild renal impairment (Clcr 50–80 mL/minute), 14.7 hours in those with moderate renal impairment (Clcr 30 to <50 mL/minute), or 27.83 hours in those with severe renal impairment (Clcr <30 mL/minute).1

In obese adults, plasma clearance of daptomycin normalized to total body weight is approximately 15% lower in those who are moderately obese and 23% lower in those who are extremely obese compared with nonobese adults.1 This difference is most likely the result of differences in renal clearance of daptomycin.1

Stability

Storage

Parenteral

Powder for Injection

2–8°C.1 Avoid excessive heat.1

Following reconstitution, stable in original vial for up to 12 hours at room temperature or up to 48 hours at 2–8°C.1 After further dilution, stable in infusion bag for 12 hours at room temperature or 48 hours when refrigerated.1 Combined storage time (vial and infusion bag) should be ≤12 hours at room temperature or ≤48 hours when refrigerated.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Not compatible with dextrose-containing solutions.1

Compatible

Ringer’s injection, lactated1

Sodium chloride 0.9%1

Actions and Spectrum

  • Lipopeptide antibiotic.1 3 5

  • Usually bactericidal in action.1 5 19

  • Binds to cell membranes in susceptible bacteria and causes rapid membrane depolarization leading to inhibition of protein, DNA, and RNA synthesis and cell death.1 5

  • Spectrum of activity includes many gram-positive bacteria;1 inactive against gram-negative bacteria.6

  • Gram-positive aerobes: Active in vitro and in clinical infections against Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA]),1 18 19 Streptococcus pyogenes (group A β-hemolytic streptococci),1 S. agalactiae (group B streptococci),1 S. dysgalactiae subsp. equisimilis,1 and Enterococcus faecalis (vancomycin-susceptible strains only).1 Also active in vitro against some strains of Corynebacterium jeikeium,1 E. faecalis (vancomycin-resistant strains),1 E. faecium (including vancomycin-resistant strains),1 S. epidermidis (including oxacillin-resistant strains),1 and S. haemolyticus.1

  • Reduced susceptibility to daptomycin has been produced in vitro by serial passage of S. aureus in the presence of increasing concentrations of the drug.2 In addition, daptomycin-resistant S. aureus strains have emerged in patients treated with the drug.1 20 21 Mechanism of resistance or transferable elements that might confer resistance to daptomycin not identified to date.1 19 21

  • Cross-resistance between daptomycin and other anti-infectives not clearly identified to date.1 2 Although further study is needed, there is some evidence that some strains of MRSA that develop resistance to daptomycin also may develop resistance or reduced susceptibility to vancomycin20 21 and that daptomycin-resistant MRSA may emerge during daptomycin therapy in some patients with prior exposure to vancomycin.20

Advice to Patients

  • Importance of patients immediately informing clinicians if they develop new or worsening fever, cough, shortness of breath, or difficulty breathing.7

  • Importance of contacting a clinician if muscle pain or weakness, particularly of the extremities, occurs.1

  • Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.1 Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1

  • Importance of reporting persistent or worsening symptoms of infection.6

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Daptomycin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

500 mg

Cubicin

Cubist

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions December 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Cubist Pharmaceuticals. Cubicin (daptomycin for injection) prescribing information. Lexington, MA; 2003 Sep.

2. Silverman JA, Oliver N, Andrew T. Resistance studies with daptomycin. Antimicrob Agents Chemother. 2001; 45:1799-1802. [PubMed 11353628]

3. Tally FP, DeBruin MF. Development of daptomycin for gram-positive infections. J Antimicrob Chemother. 2000; 46:523-6. [IDIS 454808] [PubMed 11020247]

4. Wise R, Gee T, Andrews JM et al. Pharmacokinetics and inflammatory fluid penetration of intravenous daptomycin in volunteers. Antimicrob Agents Chemother. 2002; 46:31-3. [IDIS 474163] [PubMed 11751107]

5. Silverman JA, Pelmutter NG, Shaprio HM. Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus. Antimicrob Agents Chemother. 2003; 47:2538-44. [PubMed 12878516]

6. Cubist Pharmaceuticals, Lexington, MA: Personal communication.

7. US Food and Drug Administration. FDA Drug Safety Communication: Eosinophilic pneumonia associated with the use of Cubicin (daptomycin). 2010 Jul 29. From FDA website.

8. Miller BA, Gray A, Leblanc TW et al. Acute eosinophilic pneumonia secondary to daptomycin: a report of three cases. Clin Infect Dis. 2010; 50:e63-8. [PubMed 20420515]

9. Lal Y, Assimacopoulos AP. Two cases of daptomycin-induced eosinophilic pneumonia and chronic pneumonitis. Clin Infect Dis. 2010; 50:737-40. [PubMed 20121418]

10. Shinde A, Seifi A, DelRe S et al. Daptomycin-induced pulmonary infiltrates with eosinophilia. J Infect. 2009; 58:173-4. [PubMed 19046602]

11. Hayes D, Anstead MI, Kuhn RJ. Eosinophilic pneumonia induced by daptomycin. J Infect. 2007; 54:e211-3. [PubMed 17207858]

12. Kakish E, Wiesner AM, Winstead PS et al. Acute respiratory failure due to daptomycin induced eosinophilic pneumonia. Respir Med CME. 2008; 1:235–7.

13. Johnson S, Gerding DN. Clostridium difficile-associated diarrhea. Clin Infect Dis. 1998; 26:1027-36. [IDIS 407733] [PubMed 9597221]

14. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. Am J Gastroenterol. 1997; 92:739-50. [IDIS 386628] [PubMed 9149180]

15. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile-associated disease. Am J Health-Syst Pharm. 1998; 55:1407-11. [IDIS 407213] [PubMed 9659970]

16. Wilcox MH. Treatment of Clostridium difficile infection. J Antimicrob Chemother. 1998; 41(Suppl C):41-6. [IDIS 407246] [PubMed 9630373]

17. Steenbergen JN, Mohr JF, Thorne GM. Effects of daptomycin in combination with other antimicrobial agents: a review of in vitro and animal model studies. J Antimicrob Chemother. 2009; 64:1130-8. [PubMed 19825818]

18. Mendes RE, Moet GJ, Janechek MJ et al. In Vitro activity of telavancin against a contemporary worldwide collection of Staphylococcus aureus isolates. Antimicrob Agents Chemother. 2010; 54:2704-6. [PubMed 20385851]

19. Sader HS, Becker HK, Moet GJ et al. Antimicrobial activity of daptomycin tested against Staphylococcus aureus with vancomycin MIC of 2 microg/mL isolated in the United States and European hospitals (2006-2008). Diagn Microbiol Infect Dis. 2010; 66:329-31. [PubMed 20159377]

20. Hsu LY, Leong M, Balm M et al. Six cases of daptomycin non-susceptible Staphylococcus aureus bacteremia in Singapore. J Med Microbiol. 2010; :. [PubMed 20705729]

21. Lee CH, Wang MC, Huang IW et al. Development of Daptomycin Nonsusceptibility with Heterogeneous Vancomycin-Intermediate Resistance and Oxacillin Susceptibility in Methicillin-Resistant Staphylococcus aureus during High-Dose Daptomycin Treatment. Antimicrob Agents Chemother. 2010; 54:4038-40. [PubMed 20585116]

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