Daptomycin (daptomycin)

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Daptomycin is administered by IV injection (adults only) or IV infusion (adults and pediatric patients 1-17 years of age).

Daptomycin is commercially available for IV use as 2 different formulations: a lyophilized powder for solution that does not contain sucrose and a lyophilized powder for solution that contains 713 mg of sucrose per vial. Instructions for storage, reconstitution, and dilution differ for the 2 daptomycin formulations and recommendations for the specific formulation used should be followed.

Additives and other drugs should not be added to daptomycin solutions or infused simultaneously through the same IV line. If the same IV line is used for sequential infusion of different drugs, the line should be flushed with a compatible infusion solution before and after infusion of daptomycin. Daptomycin is not compatible with dextrose-containing diluents (e.g., 5% dextrose injection).

Daptomycin should not be used in conjunction with ReadyMed(R) elastomeric infusion pumps since stability studies identified an impurity (i.e., 2-mercaptobenzothiazole) leaching from this pump system into the daptomycin solution.

Strict aseptic technique must be observed in preparing daptomycin solutions since the drug contains no preservative. Daptomycin solutions should be inspected visually for particulate matter prior to administration.

Daptomycin for injection (formulation not containing sucrose): The lyophilized powder should be stored at 2-8degreesC. The reconstituted daptomycin solution (in the original vial) and reconstituted and further diluted solutions (in an IV infusion bag) are stable for 12 hours at room temperature or up to 48 hours when refrigerated at 2-8degreesC; the combined storage time (reconstituted vial and diluted infusion bag) at room temperature or under refrigeration should not exceed 12 or 48 hours, respectively.

Daptomycin for injection (formulation containing sucrose): The lyophilized powder should be stored at 20-25degreesC, but may be exposed to 15-30degreesC. The stability of reconstituted daptomycin solution and reconstituted and further diluted solutions varies based on the specific diluent and container used. (See Table 1.)

Table 1: Stability of Daptomycin (formulation containing sucrose) After Reconstitution

Container Diluent Stability at Stability at 20-25degreesC 2-8degreesC Vial Sterile water for 1 day 3 days injection Bacteriostatic 2 days 3 days water for injection Syringe Sterile water for 1 day 3 days injection Bacteriostatic 2 days 5 days water for injection Infusion bag Reconstituted 19 hours 3 days with sterile water for injection and immediate dilution in 0.9% sodium chloride injection Reconstituted 2 days 5 days with bacteriostatic water for injection and immediate dilution in 0.9% sodium chloride injection

Polypropylene syringe with elastomeric plunger stopper.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antibiotics/Fecal Microbiota

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Antimicrobials/Live Typhoid Vaccine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Daptomycin/Hmg-Coa Reductase Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown but may involve additive or synergistic effects on skeletal muscle.

CLINICAL EFFECTS: Concurrent use of HMG-CoA reductase inhibitors and daptomycin can result in elevated creatinine phosphokinase (CPK) levels and skeletal muscle effects.(1)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: The manufacturer of daptomycin recommends considering suspending HMG-CoA reductase inhibitor therapy in patients receiving daptomycin. CPK levels should be monitored more frequently than the weekly standard frequency in patients who have recently received HMG-CoA reductase therapy or in whom concurrent therapy is warranted. Closely monitor patients for the development of muscle pain and/or weakness.(1)

DISCUSSION: In the Phase 3 Staphylococcus aureus bacteremia/endocarditis trial, 5 of 22 patients who received prior or concurrent HMG Co-A reductase inhibitor therapy developed CPK elevations greater than 500 U/L. At a dose of 6 mg/kg of daptomycin, a total of 11 patients developed CPK elevations greater than 500 U/L. Of these, 4 had prior or concurrent HMG Co-A reductase therapy. Rhabdomyolysis in patients treated concurrently with HMG Co-A reductase inhibitors has been reported in post-marketing experience.(1) In 20 healthy subjects, concurrent simvastatin (40 mg daily) and daptomycin (4 mg/kg daily) was not associated with a higher incidence of adverse effects when compared to 10 subjects receiving placebo.(1)

There are no moderate interactions for this drug.

*Known hypersensitivity to daptomycin.

There are no contraindication contraindications for this drug.

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Clostridioides difficile infection
• Eosinophilic pneumonia
• Myopathy with CK elevation

• Peripheral neuropathy

Adverse effects occurring in >=2% of adult patients receiving daptomycin for the treatment of complicated skin and skin structure infections in clinical trials include diarrhea, nervous system effects (headache, dizziness), rash, abnormal liver function test results, elevated serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations, urinary tract infections, hypotension, and dyspnea.

Adverse effects occurring in >=2% of pediatric patients receiving daptomycin for the treatment of complicated skin and skin structure infections in a clinical trial include diarrhea, vomiting, abdominal pain, pruritus, pyrexia, elevated CK concentrations, and headache.

Adverse effects occurring in >=5% of adult patients receiving daptomycin for the treatment of bacteremia/endocarditis in a clinical trial include abdominal pain, insomnia, pharyngolaryngeal pain, infections (sepsis, bacteremia), chest pain, edema, pruritus, increased sweating, elevated CK concentrations, and hypertension.

Adverse effects occurring in >=5% of pediatric patients receiving daptomycin for the treatment of bacteremia in a clinical trial include vomiting and elevated CK concentrations.

More Frequent

• Abnormal hepatic function tests
• Dyspnea

Less Frequent

• Acute cognitive impairment
• Anemia
• Candidiasis
• Chest pain
• Edema
• Fungal infection
• Hypertension
• Hypotension
• Increased creatine kinase level
• Renal failure
• Skin rash
• Urinary tract infection

Rare or Very Rare

• Acute generalized exanthematous pustulosis
• Altered mental status
• Anaphylaxis
• Angioedema
• Atrial fibrillation
• Atrial flutter
• Bacterial sepsis
• Blistering skin
• Bullous dermatitis
• Clostridioides difficile infection
• DRESS syndrome
• Dyskinesia
• Dysphagia
• Eosinophilia
• Eosinophilic pneumonia
• Erythema
• Fever
• Hallucinations
• Hyperkalemia
• Hypersensitivity drug reaction
• Hypomagnesemia
• Interstitial nephritis
• Jaundice
• Leukocytosis
• Lymphadenopathy
• Metabolic alkalosis
• Muscle weakness
• Myopathy
• Rhabdomyolysis
• Stevens-johnson syndrome
• Supraventricular arrhythmias
• Thrombocytopenic disorder
• Thrombocytosis
• Toxic epidermal necrolysis
• Vesicular rash

More Frequent

• Diarrhea
• Headache disorder

Less Frequent

• Anorexia
• Dizziness
• Hyperhidrosis
• Insomnia
• Pruritus of skin

Rare or Very Rare

• Abdominal distension
• Acute abdominal pain
• Blurred vision
• Chills
• Cough
• Cramps
• Dysgeusia
• Eczema
• Fatigue
• Flushing
• General weakness
• Gingival pain
• Myalgia
• Nausea
• Ocular irritation
• Paresthesia
• Peripheral neuropathy
• Proteinuria
• Stomatitis
• Tinnitus
• Urticaria
• Vertigo
• Visual changes
• Vomiting
• Vulvovaginal candidiasis
• Xerostomia

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Safety and efficacy of daptomycin have not been established in pediatric patients <1 year of age.

Use of daptomycin should be avoided in children younger than 12 months of age because of the potential risk of adverse muscular, neuromuscular, peripheral nervous system, and CNS effects; such adverse effects have been observed in neonatal dogs receiving IV daptomycin.

The safety and efficacy of daptomycin for the treatment of complicated skin and skin structure infections and S. aureus bacteremia have been established in the pediatric patients 1-17 years of age. Use of daptomycin for injection in these age groups is supported by evidence from adequate and well-controlled studies in adults, with additional data from pharmacokinetic studies in pediatric patients, and from safety, efficacy, and pharmacokinetic studies in pediatric patients with complicated skin and skin structure infections and S. aureus bacteremia.

Daptomycin has not been studied in pediatric patients with other bacterial infections. Daptomycin is not indicated in pediatric patients with renal impairment because dosage of the drug has not been established in these patients.

Data on the use of daptomycin in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. No evidence of adverse developmental outcomes was observed in animal reproduction studies performed in rats and rabbits administered IV daptomycin during organogenesis at doses 2 and 4 times, respectively, the recommended 6-mg/kg human dose (on a body surface area basis).

According to limited published data, daptomycin is distributed into human milk at infant doses of 0.1% of the maternal dose. The effects of daptomycin on the breast-fed infant or on milk production are unknown. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for daptomycin and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.

Dosage adjustments based solely on age are not necessary when daptomycin is used in geriatric patients, but dosage adjustments are indicated in those with renal impairment.

Among the total number of adult patients studied in phase 3 clinical trials of daptomycin for the treatment of complicated skin and skin structure infections, 27% were >=65 years of age and 12% were >=75 years of age. In a phase 3 clinical trial of daptomycin for the treatment of bacteremia and endocarditis in adults, 25% of patients were >=65 years of age and 16% were >=75 years of age. There was some evidence from these studies that clinical success rates were lower and treatment-emergent adverse effects were more common in geriatric patients >=65 years of age compared with younger adults.

Although daptomycin exposures are higher in healthy geriatric adults than in healthy young adults, adjustment of daptomycin dosage is not necessary in geriatric patients based solely on age. However, age-related decreases in renal function should be considered when selecting dosage in geriatric patients.