Daptomycin

Mechanism of Action

Daptomycin is a cyclic lipopeptide antibiotic that exerts its bactericidal effect by disrupting multiple aspects of bacterial cell membrane function. Daptomycin binds to the cell membrane of susceptible organisms and causes a rapid depolarization of membrane potential. The loss of membrane potential leads to the intracellular inhibition of DNA, RNA, and protein synthesis. This inhibition ultimately results in bacterial cell death. Daptomycin is only active against gram-positive bacteria.[6][7]

Administration

Daptomycin is FDA-approved for administration by the intravenous route. It is available as 350 mg sterile, preservative-free, pale yellow to light brown lyophilized powder for injection, reconstituted as 50 mg per ml in a single-dose vial. It is administered every 24 hours in patients with a creatinine clearance greater than 30 mL/min. The frequency of administration in patients with renal impairment (CrCl less than 30 mL/min) is every 48 hours. The dose of daptomycin required is indication-specific. The desired dose should be administered over 30 minutes in adults and children over 7. Daptomycin should be infused over 60 minutes in children 1 to 6. Daptomycin administration can also be an intravenous push over 2 minutes in adult patients only.[8][9][10]

Pharmacodynamics/Pharmacokinetics

Route of Administration: Intravenous

Inhibition of bacterial growth: Bactericidal

PK/PD parameter:  Area under the concentration-time curve to minimum inhibitory concentration ratio (correlates well with its antimicrobial activity)

Absorption: Not applicable

The onset of action: Daptomycin has a rapid onset of action

Distribution: Large volume of distribution at steady-state (approximately 1.0 L/kg) in healthy adult patients. The volume of distribution at steady-state in pediatric and critically ill patients is significantly lower.

Protein Binding: 90% to 93%; 84% to 88% in patients with a creatine clearance of less than 30 mL/min.

Metabolism: Research ash detected minimal amounts of oxidative metabolites. In vitro studies suggest human liver microsomes do not metabolize daptomycin.

Clearance: 8.3 to 9 mL/min/kg in adults with normal renal function. Pediatric patients have demonstrated increased clearance.

Half-life: 8 to 9 hours in healthy adults with normal renal function. The elimination half-life can be significantly prolonged in patients with renal impairment (up to 28 hours). Pediatric patients show a shorter elimination half-life.

Excretion: Daptomycin is primarily eliminated as an unchanged drug in the urine (78%), with a lesser amount eliminated in feces (5.7%).

Table 1. Recommended Dose of Daptomycin

Adverse Effects

Adverse effects of daptomycin therapy include myopathy/rhabdomyolysis, eosinophilic pneumonia, and anaphylactic hypersensitivity reactions. Patients may also experience less severe adverse effects such as constipation, headache, insomnia, and skin rash.[11] Daptomycin is associated with an increased incidence of myopathy and rhabdomyolysis. There have been cases reported in patients with and without acute renal failure. Therefore, weekly monitoring of creatine phosphokinase (CPK) levels is recommended for patients receiving daptomycin therapy. More frequent monitoring is recommended in patients with renal impairment or those receiving concomitant HMG CoA reductase inhibitors (statins). The clinicians should discontinue treatment in patients with signs and symptoms of myopathy in conjunction with an elevated CPK (greater than 5 times ULN or greater than 1000 units/L) and asymptomatic patients with a CPK elevation greater than 10 times ULN (greater than 2000 units/L). The incidence of myopathy has been shown to increase with the administration of greater than the recommended dosage. Additionally, providers should consider temporarily discontinuing other agents associated with rhabdomyolysis (eg, HMG-CoA reductase inhibitors) during daptomycin therapy.[12][13]

Daptomycin therapy is also associated with the development of eosinophilic pneumonia, which generally occurs 2 to 4 weeks after initiating therapy. Patients require monitoring for signs and symptoms of eosinophilic pneumonia, including new-onset or worsening fever and new infiltrate on chest imaging. Daptomycin therapy should immediately stop for patients who experience signs and symptoms of eosinophilic pneumonia, and they should receive appropriate treatment. It is important to note that the incidence of eosinophilic pneumonia may reoccur with re-exposure to daptomycin.[14]Rare cases of peripheral neuropathy have been observed in patients receiving daptomycin. Therefore, monitoring for new-onset or worsening neuropathy is recommended. It is important to note that prolonged use of daptomycin can develop a superinfection such as Clostridium difficile-associated diarrhea (CDAD) and pseudomembranous colitis. The incidence of CDAD has been observed to be greater than 2 months after treatment with daptomycin.

Contraindications

Clinical Consideration

Daptomycin is contraindicated in patients with a known hypersensitivity reaction to the drug or any component within the formulation. Although daptomycin does not have other contraindications to its use, there are significant clinical considerations to remember when caring for patients.

Geriatric Patients

Elderly patients are at an increased risk of daptomycin toxicity due to age-related changes in renal function or factors that may enhance the exposure to the medication. However, no dosage adjustments are recommended for patients with a creatinine clearance greater than 30 mL/min.

Pregnancy

Daptomycin is in pregnancy category B; however, there is still limited information available on its use during pregnancy. Case reports describe the successful use of daptomycin during the second and third trimesters of pregnancy. Additionally, animal reproductive studies have not yet determined any evidence of fetal harm from maternal use of daptomycin. Nevertheless, a risk-benefit analysis should be conducted before initiating daptomycin in pregnant patients.

Breastfeeding

Low concentrations of daptomycin have been detected in breast milk (0.1% of the maternal dose). Currently, no information is available on daptomycin's effects on breastfed infants or milk production. Like other antibiotics, maternal use of daptomycin may cause a non-dose-related change in bowel flora. Therefore, breastfed infants should be monitored for gastrointestinal disturbances. Breastfeeding mothers receiving treatment with daptomycin should be advised to consult with their provider and conduct a risk-benefit analysis before breastfeeding.[15]

Renal Impairment

Reduced renal function can lead to the accumulation of daptomycin, thereby increasing the risk of adverse effects. Dose adjustments are necessary for patients with a creatinine clearance of less than 30 mL/min, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). It is recommended that renal function and creatinine phosphokinase (CPK) levels be monitored weekly in patients with renal impairment.[16]

Bacterial Resistance

Like other antibiotics, prolonged or inappropriate treatment with daptomycin can lead to bacterial resistance. Therefore, providers must know about increased antibiotic resistance patterns and practice appropriate antimicrobial stewardship. In addition, patients should be counseled on the importance of medication adherence to prevent developing multidrug-resistant infections.

Drug Interactions

Other medications taken along with daptomycin may increase the risk of adverse effects and drug toxicity. Therefore, dosing adjustments, additional monitoring, and alternative treatment should be considered when combining daptomycin with certain medications. Caution is advised when administering daptomycin with HMG-CoA reductase inhibitors (statins), as this can potentially increase the risk of skeletal muscle toxicity. It is recommended that the administration of HMG-CoA reductase inhibitors be temporarily discontinued while patients receive treatment with daptomycin. If the concomitant administration is unavoidable, close monitoring of CPK should be instated at least once weekly.[13]

Monitoring

Patients receiving daptomycin therapy should be monitored to ensure the safe administration of the medication. Baseline renal function tests are recommended to assess renal impairment and the necessity of dosage adjustments. Additionally, clinicians are recommended to obtain baseline CPK levels in patients requiring treatment for more than 1 week. After that, the CPK requires monitoring at least once weekly. More frequent monitoring of CPK is necessary for patients with current or prior statin therapy, an unexplained elevation in CPK, or renal impairment.[13][17] Patients should also receive monitoring for muscle pain or weakness, new-onset or worsening peripheral neuropathy, and signs or symptoms of eosinophilic pneumonia.[14][18] Furthermore, patients who develop diarrhea should be tested for C. difficile infection.

Toxicity

Supportive care is recommended with the maintenance of glomerular filtration in case of overdose suspected or confirmed with daptomycin.

• Approximately 15% of daptomycin is cleared slowly from the body by hemodialysis (low-flux membrane) over 4 hours. High-flux dialysis membrane hemodialysis may increase the percentage of dose removal.[19]
• Approximately 11% of daptomycin is cleared by peritoneal dialysis over 48 hours.

Enhancing Healthcare Team Outcomes

Healthcare workers, including intensivists, infectious disease specialists, internists, and nurse practitioners who prescribe daptomycin, should monitor the patient to ensure safe medication administration. Baseline renal function tests are recommended to assess renal impairment and the necessity of dosage adjustments. Additionally, clinicians are recommended to obtain baseline CPK levels in patients requiring treatment for more than 1 week. After that, the CPK should be monitored at least once weekly. More frequent monitoring of CPK is necessary for patients with current or prior statin therapy, an unexplained elevation in CPK, or renal impairment. A board-certified infectious disease pharmacist can provide antibiogram data, verify dosing, and work with the nursing staff regarding administration. Nurses can also monitor for adverse events and administer the drug, alerting the attending promptly regarding any concerns. Patients should also be monitored by nursing staff and clinicians for muscle pain or weakness, new-onset or worsening peripheral neuropathy, and signs or symptoms of eosinophilic pneumonia. Furthermore, prescribers should order testing for C. difficile infection when patients develop diarrhea. An interprofessional team of specialty-trained nurses, pharmacists, and clinicians monitoring treatment provides the best patient outcomes.