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Special Alerts
Eosinophilic Pneumonia Associated with Daptomycin Use
July 2010
The U.S. Food and Drug Administration (FDA) has issued safety information regarding the risk of developing eosinophilic pneumonia during treatment with daptomycin (Cubicin®). Eosinophilic pneumonia is a rare condition due to eosinophils accumulating in the lungs which results in typical pneumonia symptoms (eg, fever, cough, shortness of breath, difficulty breathing), and may lead to progressive respiratory failure if not recognized and managed appropriately. The FDA has reviewed published case reports of daptomycin-associated eosinophilic pneumonia and has also conducted a review of postmarketing adverse events reported between 2004 and 2010 from the FDA's Adverse Event Reporting System (AERS). During the review, 7 cases of eosinophilic pneumonia believed to be likely due to daptomycin use were identified, in addition to another 36 possible cases. Of note, all patients involved in the 7 cases developed eosinophilic pneumonia 2-4 weeks after initiating therapy and all 7 of these patients reported either improvement or resolution of symptoms following discontinuation of daptomycin therapy. As a result, the FDA has requested that Cubist, the manufacturer of Cubicin®, revise the product labeling to further inform prescribers of this association. Immediate discontinuation of daptomycin is recommended if there is clinical suspicion for eosinophilic pneumonia.
Further information may be found at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm220499.htm
Pronunciation
(DAP toe mye sin)
Generic Available (U.S.)
No
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of complicated skin and skin structure infections caused by susceptible aerobic gram-positive organisms; Staphylococcus aureus bacteremia, including right-sided native valve infective endocarditis caused by MSSA or MRSA
Use: Unlabeled
Treatment of severe infections caused by MRSA or VRE
Pregnancy Risk Factor
B
Pregnancy Considerations
Because adverse events were not observed in animal reproduction studies, daptomycin is classified as pregnancy category B. 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
Excreted in breast milk/use caution
Breast-Feeding Considerations
Low concentrations of daptomycin have been detected in breast milk. The manufacturer recommends caution if daptomycin is used during breast-feeding. Per the Canadian product labeling, daptomycin should be discontinued while breast-feeding. The high molecular weight of daptomycin may limit the transfer to the maternal milk. Nondose-related effects could include modification of bowel flora.
Contraindications
Hypersensitivity to daptomycin or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• Eosinophilic pneumonia: Use may result in eosinophilic pneumonia; generally develops 2-4 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 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 1000 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. Use caution in patients receiving other drugs associated with myopathy (eg, HMG-CoA reductase inhibitors).
• 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 and pseudomembranous colitis.
Disease-related concerns:
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required in severe renal impairment (Clcr <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).
Other warnings/precautions:
• Pneumonia use: Not indicated for the treatment of pneumonia due to inactivation by pulmonary surfactant
Adverse Reactions
>10%:
Gastrointestinal: Diarrhea (5% to 12%), vomiting (3% to 12%), constipation (6% to 11%)
Hematologic: Anemia (2% to 13%)
1% to 10%:
Cardiovascular: Peripheral edema (7%), chest pain (7%), hypertension (1% to 6%), hypotension (2% to 5%)
Central nervous system: Insomnia (5% to 9%), headache (5% to7%), fever (2% to 7%), dizziness (2% to 6%), anxiety (5%)
Dermatologic: Rash (4% to 7%), pruritus (3% to 6%), erythema (5%)
Endocrine & metabolic: Hypokalemia (9%), hyperkalemia (5%), hyperphosphatemia (3%)
Gastrointestinal: Nausea (6% to 10%), abdominal pain (6%), dyspepsia (1% to 4%), loose stool (4%), GI hemorrhage (2%)
Genitourinary: Urinary tract infection (2% to 7%)
Hematologic: INR increased (2%), eosinophilia (2%)
Hepatic: Transaminases increased (2% to 3%), alkaline phosphatase increased (2%)
Local: Injection site reaction (3% to 6%)
Neuromuscular & skeletal: CPK increased (3% to 9%), limb pain (2% to 9%), back pain (7%), 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: Osteomyelitis (6%), bacteremia (5%), diaphoresis (5%), sepsis (5%), infection (fungal, 2% to 3%)
<1%, postmarketing, and/or case reports: Anaphylaxis, appetite decreased, arthralgia, atrial fibrillation, atrial flutter, cardiac arrest, coma (post anaesthesia/surgery), dyskinesia, dysphagia, eczema, electrolyte disturbance, eosinophilia, eosinophilic pneumonia, erythema (truncal), eye irritation, fatigue, flatulence, flushing, GI discomfort, gingival pain, hallucination, hives, hypomagnesemia, hypersensitivity, hypoesthesia, jaundice, jitteriness, LDH increased, leukocytosis, lymphadenopathy, mental status change, muscle cramps, muscle weakness, myalgia, myoglobin increased, osteomyelitis, paresthesia, peripheral neuropathy, proteinuria, prothrombin time prolonged, pulmonary eosinophilia, rhabdomyolysis, rigors, serum bicarbonate increased, shortness of breath, stomatitis, supraventricular arrhythmia, taste disturbance, thrombocytopenia, thrombocythemia, tinnitus, vertigo, vesiculobullous rash, vision blurred, xerostomia
Metabolism/Transport Effects
None known.
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. Risk D: Consider therapy modification
Storage
Store under refrigeration at 2°C to 8°C (36°F to 46°F). Intact vials may be stored at room temperature for up to 12 months (data on file [Cubist Pharmaceuticals, 2011]). However, the manufacturer recommends storage under refrigeration. Room temperature stability information should only be utilized in situations where the drug has been inadvertently exposed to prolonged room temperature.
Reconstituted solution (either in vial or in infusion bag) is stable for a cumulative time of 12 hours at room temperature and 48 hours if refrigerated (2°C to 8°C).
Reconstitution
Reconstitute vial with 10 mL NS. 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 following reconstitution in an appropriate volume of NS. Incompatible 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.
Y-site administration: Compatible: Aztreonam, caspofungin, ceftazidime, ceftriaxone, dopamine, doripenem, ertapenem, fluconazole, gentamicin, heparin, levofloxacin, lidocaine.
Compatibility in syringe: Incompatible: Ceftriaxone.
Mechanism of Action
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.
Pharmacodynamics/Kinetics
Distribution: Vss: 0.1 L/kg; Critically-ill patients: Vss: 0.23 ± 0.14 L/kg (Vilay, 2010)
Protein binding: 90% to 93%; 84% to 88% in patients with Clcr<30 mL/minute
Half-life elimination: 8-9 hours (up to 28 hours in renal impairment)
Excretion: Urine (78%; primarily as unchanged drug); feces (6%)
Dosage
I.V.: Adults:
Skin and soft tissue: 4 mg/kg once daily for 7-14 days
Bacteremia, right-sided native valve endocarditis caused by MSSA or MRSA: 6 mg/kg once daily for 2-6 weeks (some experts recommend 8-10 mg/kg once daily for complicated bacteremia or infective endocarditis [Liu, 2011])
Osteomyelitis (unlabeled use): 6 mg/kg once daily for a minimum of 8 weeks (some experts combine with rifampin) (Liu, 2011)
Septic arthritis (unlabeled use): 6 mg/kg once daily for 3-4 weeks (Liu, 2011)
Dosage adjustment in renal impairment: Clcr <30 mL/minute:
Skin and soft tissue infections: 4 mg/kg every 48 hours
Staphylococcal bacteremia: 6 mg/kg every 48 hours
Intermittent hemodialysis or peritoneal dialysis (PD): Dose as in Clcr <30 mL/minute (administer after hemodialysis on dialysis days) or (unlabeled dosing) may administer 6 mg/kg after hemodialysis 3 times weekly (Salama, 2010)
Note: High permeability intermittent hemodialysis removes ~50% during a 4-hour session (Salama, 2010).
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 1-2 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 Clcr<30 mL/minute may result in low Cmax. May consider 4-6 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.
Dosage adjustment in hepatic impairment: No adjustment required for mild-to-moderate impairment (Child-Pugh class A or B); not evaluated in severe hepatic impairment (Child-Pugh class C)
Administration: I.V.
May administer I.V. 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.
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. Canadian labeling recommends CPK monitoring every 48 hours with unexplained muscle pain, tenderness, weakness or cramps. Monitor for signs/symptoms of eosinophilic pneumonia.
Reference Range
Trough concentrations at steady-state:
4 mg/kg once daily: 5.9 ± 1.6 mcg/mL
6 mg/kg once daily: 6.7 ± 1.6 mcg/mL
Note: Trough concentrations are not predictive of efficacy/toxicity. Drug exhibits concentration-dependent bactericidal activity, so Cmax:MIC ratios may be a more useful parameter.
Test Interactions
Daptomycin may cause false prolongation of the PT and increase of INR with certain reagents. This appears to be a dose-dependent phenomenon. Therefore, it is recommended to obtain blood samples immediately prior to next daptomycin dose (eg, trough). If PT/INR elevated, clinicians should repeat PT/INR and evaluate for other causes of hypocoagulation.
Patient Education
This medication is only administered via intravenous infusion. You will be monitored during and after each infusion. Report immediately any burning, pain, or redness at infusion site or any throat tightness, respiratory difficulty, or chest tightness. Report chest pain; unusual headache, insomnia, dizziness, or anxiety; persistent gastrointestinal upset; skin rash; alteration in urination pattern; itching or pain on urination; new onset or worsening fever; difficulty breathing, unusual cough or throat pain; new or unusual muscle or joint pain; or numbness or tingling of extremities.
Geriatric Considerations
The manufacturer reports that in studies of complicated skin and skin structure infections, elderly patients had a lower clinical success rate and a higher incidence of adverse effects (no quantitative data provided in product labeling). Adjust dose in renal impairment.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: Daptomycin should not be used for the treatment of pneumonia, due to the low volume of distribution and inactivation of the drug by surfactant.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause insomnia or dizziness
Mental Health: Effects on Psychiatric Treatment
May cause nausea, vomiting, and diarrhea; concurrent use with SSRIs may produce additive effects
Nursing: Physical Assessment/Monitoring
Use caution in presence of renal impairment; dose adjustment may be necessary. Assess potential for interactions with drugs associated with myopathy, such as HMG-CoA reductase inhibitors. Assess CPK on a regular basis during therapy. Monitor for myopathy, peripheral neuropathy, superinfection, eosinophilic pneumonia [rare], gastrointestinal upset, edema, and hypertension. Teach patient about necessary follow-up care.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution:
Cubicin®: 500 mg
References
Cha R, Grucz RG Jr, and Rybak MJ, “Daptomycin Dose-Effect Relationship Against Resistant Gram-Positive Organisms,” Antimicrob Agents Chemother, 2003, 47(5):1598-603.
Chakraborty A, Roy S, Loeffler J, et al, “Comparison of the Pharmacokinetics, Safety and Tolerability of Daptomycin in Healthy Adult Volunteers Following Intravenous Administration by 30 Min Infusion or 2 Min Injection,” J Antimicrob Chemother, 2009, 64(1):151-8.
Gould FK, Denning DW, Elliott TS, et al, “Guidelines for the Diagnosis and Antibiotic Treatment of Endocarditis in Adults: A Report of the Working Party of the British Society for Antimicrobial Chemotherapy,” J Antimicrob Chemother, 2012, 67(2):269-89.
Heintz BH, Matzke GR, Dager WE, “Antimicrobial Dosing Concepts and Recommendations for Critically Ill Adult Patients Receiving Continuous Renal Replacement Therapy or Intermittent Hemodialysis,” Pharmacotherapy, 2009, 29(5):562-77.
Kielstein JT, Eugbers C, Bode-Boeger SM, et al, “Dosing of Daptomycin in Intensive Care Unit Patients With Acute Kidney Injury Undergoing Extended Dialysis – A Pharmacokinetic Study,” Nephrol Dial Transplant, 2010, 25(5):1537-41.
Liu C, Bayer A, Cosgrove SE, et al, “Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children: Executive Summary,” Clin Infect Dis, 2011, 52(3):285-92.
Miller BA, Gray A, Leblanc TW, et al, “Acute Eosinophilic Pneumonia Secondary to Daptomycin: A Report of Three Cases,” Clin Infect Dis, 2010, 50(11):e63-8.
Richter SS, Kealey DE, Murray CT, et al, “The in vitro Activity of Daptomycin Against Staphylococcus aureus and Enterococcus Species,” J Antimicrob Chemother, 2003, 52(1):123-7.
Salama NN, Segal JH, Churchwell MD, et al, “Single-Dose Daptomycin Pharmacokinetics in Chronic Haemodialysis Patients,” Nephrol Dial Transplant, 2010, 25(4):1279-84.
Silverman JA, Mortin LI, Vanpraagh AD, et al, "Inhibition of Daptomycin by Pulmonary Surfactant: In Vitro Modeling and Clinical Impact," J Infect Dis, 2005, 191(12):2149-52.
Silverman JA, Perlmutter NG, and Shapiro HM, “Correlation of Daptomycin Bactericidal Activity and Membrane Depolarization in Staphylococcus aureus,” Antimicrob Agents Chemother, 2003, 47(8):2538-44.
Tedesco KL and Rybak MJ, “Daptomycin,” Pharmacotherapy, 2004, 24(1):41-57.
Trotman RL, Williamson JC, Shoemaker DM, et al, "Antibiotic Dosing in Critically Ill Adult Patients Receiving Continuous Renal Replacement Therapy," Clin Infect Dis, 2005, 41(8):1159-66.
Vilay MA, Grio M, DePestel DD, et al, “Daptomycin Pharmacokinetics in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis,” Crit Care Med, 2011, 39(1):19-25.
International Brand Names
Lexi-Comp.com
Last full review/revision January 2012
Content last modified January 2012
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