Daptomycin (Cubicin) is the first antibiotic in a class known as lipopeptides and has a unique mechanism of action. 5. Experience with the coadministration of HMG-CoA reductase inhibitors and daptomycin for injection in patients is limited; therefore, consideration should be given to suspending use of HMG-CoA reductase inhibitors temporarily in patients receiving daptomycin for injection. Animal Data Administer daptomycin for injection intravenously in 0.9% sodium chloride injection once every 24 hours for up to 14 days. Do not leave it in the car or on a window sill. The rates of the most common adverse reactions, organized by body system, observed in adult patients with cSSSI (receiving 4 mg/kg daptomycin for injection) are displayed in Table 6. If TIN is suspected, discontinue daptomycin for injection promptly and institute appropriate treatment. Daptomycin does not seem to be effective for infections caused by enterococci, including Enterococcus faecalis and E. faecium. Daptomycin binds to bacterial cell membranes and causes a rapid depolarization of membrane potential. Musculoskeletal and Connective Tissue Disorders: myalgia In general, body weight-normalized total body clearance in pediatric patients was higher than in adults and increased with a decrease of age, whereas elimination half-life tends to decrease with a decrease of age. These effects were found to be reversible within 28 days after treatment had stopped. S. aureus was isolated from a patient in a compassionate-use trial and from 7 patients in the S. aureus bacteremia/endocarditis trial [see Clinical Studies (14.2)]. Maternal body weight gain and food consumption were decreased at 75 mg/kg/day. No adverse effects were observed in the dogs that received daptomycin at 10 mg/kg/day, the NOAEL, with associated Cmax and AUCinf values of 62 mcg/mL and 247 mcg•h/mL, respectively (or 0.6 and 0.4-fold the adult human Cmax and AUC, respectively at the 6 mg/kg dose). It is a naturally occurring compound found in the soil saprotroph Streptomyces roseosporus. Administer daptomycin for injection intravenously in 0.9% sodium chloride injection once every 24 hours for up to 42 days. In the S. aureus bacteremia/endocarditis trial involving adult patients, daptomycin for injection was discontinued in 20/120 (16.7%) patients due to an adverse reaction, while comparator was discontinued in 21/116 (18.1%) patients. • Pediatric Patients 7 to 17 years of Age: Administer daptomycin for injeciton intravenously by infusion over a 30-minute period [see Dosage and Administration (2.3, 2.5, 2.7)]. Avoid use of daptomycin for injection in pediatric patients younger than one year of age due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs [see Warnings and Precautions (5.7) and Nonclinical Toxicology (13.2)]. Daptomycin for Injection Administered over a 2-Minute Period in Adults Daptomycin is an injectable antibiotic with activity versus a variety of Gram positive bacteria. Daptomycin for injection is supplied in single-dose vials, each containing 500 mg daptomycin as a sterile, lyophilized cake or powder. It is unlikely that daptomycin will inhibit or induce the metabolism of … If confronted with an abnormally high PT/INR result in a patient being treated with daptomycin for injection, it is recommended that clinicians: No patients 1 to <2 years of age were enrolled. No embryo/fetal effects were noted at the highest dose of 75 mg/kg/day, a dose approximately 4-fold higher than in humans at the maximum recommended dose of 6mg/kg (based on body surface area). Following administration of daptomycin for injection 4 mg/kg q24h by IV infusion over a 30-minute period, the mean CLT was 9%, 22%, and 46% lower among subjects and patients with mild (CLCR 50 to 80 mL/min), moderate (CLCR 30 to <50 mL/min), and severe (CLCR <30 mL/min) renal impairment, respectively, than in those with normal renal function (CLCR >80 mL/min). Administer the appropriate volume of the reconstituted daptomycin for injection (concentration of 50 mg/mL) to adult patients intravenously either by injection over a two (2) minute period or by intravenous infusion over a thirty (30) minute period [see Dosage and Administration (2.2, 2.4, 2.7)]. Avoid use of daptomycin for injection in pediatric patients younger than 12 months due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs with intravenous daptomycin [see Nonclinical Toxicology (13.2)]. The infusion rate should be maintained at 1.67 mL/minute over the 30-minute period. Patients who develop these signs and symptoms while receiving daptomycin for injection should undergo prompt medical evaluation, and daptomycin for injection should be discontinued immediately. Currently, there are no known transferable elements that confer resistance to daptomycin. See full prescribing information for CUBICIN. Streptococcus pyogenes. A total of 246 patients ≥18 years of age (124 daptomycin for injection, 122 comparator) with S. aureus bacteremia were randomized from 48 centers in the US and Europe. Biological E. Limited, India. The mechanism of resistance is unknown. Daptomycin is a cyclic lipopeptide antibiotic that has a unique mechanism of action. Adults with S.aureus Bacteremia/Endocarditis The success rates in the PP population were 54.4% (43/79) in patients treated with daptomycin for injection and 53.3% (32/60) in patients treated with comparator (difference = 1.1% [95% CI −15.6, 17.8]). It has proven in vitro activity against enterococci (including glycopeptide-resistant enterococci (GRE)), staphylococci (including methicillin-resistant Staphylococcus aureus), streptococci,[19] corynebacteria and stationary-phase Borrelia burgdorferi persisters. Psychiatric Disorders: hallucination NOS Light Protection Tests. This loss of membrane potential causes inhibition of DNA, RNA, and protein synthesis, which results in bacterial cell death. ‡AUC0-24 , area under the concentration-time curve from 0 to 24 hours; t1/2 , elimination half-life; Vss , volume of distribution at steady-state; CLT , total plasma clearance; Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Daptomycin (lipopeptide): typically used for VRE and MRSA, but has had poor efficacy in clinical trials for CAP. Complicated Skin and Skin Structure Infection Trials in Adults The recommended dosage regimens based on age for pediatric patients with cSSSI are shown in Table 1. The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with daptomycin for injection. In healthy adult subjects, concomitant administration of daptomycin for injection and simvastatin had no effect on plasma trough concentrations of simvastatin, and there were no reports of skeletal myopathy [see Clinical Pharmacology (12.3)]. Minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. Final diagnoses and outcome assessments at Test of Cure (6 weeks after the last treatment dose) were made by a treatment-blinded Adjudication Committee, using protocol-specified clinical definitions and a composite primary efficacy endpoint (clinical and microbiological success) at the Test of Cure visit. The mean and standard deviation (SD) pharmacokinetic parameters of daptomycin at steady-state following intravenous (IV) administration of daptomycin for injection over a 30-minute period at 4 to 12 mg/kg q24h to healthy young adults are summarized in Table 11. The recommended dosage regimens based on age for pediatric patients with S. aureus bloodstream infections (bacteremia) are shown in Table 2. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only).Pediatric … The clinical success rates determined at 7 to 14 days after last dose of therapy (IV and oral) (TOC visit) were 88% (45/51) for daptomycin for injection and 77% (17/22) for comparator. Package of 1 (NDC 31722-102-10). Most patients who failed due to persisting or relapsing S. aureus infection had deep-seated infection and did not receive necessary surgical intervention [see Warnings and Precautions (5.9)]. In patients who receive daptomycin for injection, CPK levels should be monitored weekly, and more frequently in patients who received recent prior or concomitant therapy with an HMG-CoA reductase inhibitor or in whom elevations in CPK occur during treatment with daptomycin for injection. This has been demonstrated both by time-kill curves and by MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. Daptomycin, sold under the brand name Cubicin among others, is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms. In addition, treatment-emergent adverse events were more common in patients ≥65 years of age than in patients <65 years of age. Severity was dose-dependent. Intravenous Infusion over a period of 30 or 60 minutes [20] Daptomycin resistance emerged in five of the six cases while they were treated. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. The following in vitro data are available, but their clinical significance is unknown. CUBICIN ® (daptomycin for injection) Dosing Adult patients. Metabolic/Nutritional System: hypomagnesemia, increased serum bicarbonate, electrolyte disturbance [29] Within each module are catalytic domains that carry out the elongation of the growing peptidyl chain. The chemical formula is C72H101N17026 and MW is 1620.27. 2. The efficacy of daptomycin for injection in the treatment of adult patients with S. aureus bacteremia was demonstrated in a randomized, controlled, multinational, multicenter, open-label trial. There are limited safety data for the use of daptomycin for injection for more than 28 days of therapy. Warfarin Limited published data report that daptomycin is present in human milk at infant doses of 0.1% of maternal dose; there is no information on effects of daptomycin on breastfed infant or effects of daptomycin on milk production; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on … If an allergic reaction to daptomycin for injection occurs, discontinue the drug and institute appropriate therapy [see Adverse Reactions (6.2)]. Biosynthesis is initiated by the coupling of decanoic acid to the N-terminal tryptophan, followed by the coupling of the remaining amino acids by nonribosomal peptide synthetase (NRPS) mechanisms. Musculoskeletal System: myalgia, muscle cramps, muscle weakness, arthralgia *CLCR, creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; CAPD, continuous ambulatory peritoneal dialysis; AUC0-∞, area under the concentration-time curve extrapolated to infinity; AUCss, area under the concentration-time curve calculated over the 24-hour dosing interval at steady-state; Cmin,ss, trough concentration at steady-state; NA, not applicable. Table 16: Clinical Success Rates by Infecting Pathogen in the cSSSI Trials in Adult Patients (Population: Microbiologically Evaluable). Long-term carcinogenicity studies in animals have not been conducted to evaluate the carcinogenic potential of daptomycin for injection. aureus. Patients were enrolled into 4 age groups [see Clinical Studies (14.1)], and intravenous daptomycin for injection doses of 5 to 10 mg/kg once daily were administered. The following reactions, not included above, were reported as possibly or probably drug-related in the daptomycin for injection-treated group: Its distinct mechanism of action makes it useful in treating infections caused by multiple drug-resistant bacteria. Simvastatin CDAD must be considered in all patients who present with diarrhea following antibacterial use. It inserts into the cell membrane in a phosphatidylglycerol-dependent fashion, where it then aggregates. Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Patients could switch to oral therapy after clinical improvement was demonstrated (no minimum IV dosing was required). • Eosinophilic pneumonia [see Warnings and Precautions (5.3)] To reduce the development of drug-resistant bacteria and maintain the effectiveness of daptomycin for injection and other antibacterial drugs, daptomycin for injection should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. †Doses of daptomycin for injection in excess of 6 mg/kg have not been approved. No nerve effects were noted in juvenile dogs following 14 days of dosing at doses up to 75 mg/kg/day. Daptomycin is a cyclic lipopeptide antibiotic produced by Streptomyces roseosporus. The dosage regimen for daptomycin for injection in pediatric patients with renal impairment has not been established. Its distinct mechanism of action makes it useful in treating infections caused by multiple drug-resistant bacteria. In animals, daptomycin administration has been associated with effects on skeletal muscle. In juvenile dogs, nerve effects were noted at lower daptomycin blood concentrations than in adult dogs following 28 days of dosing. • Myopathy and rhabdomyolysis [see Warnings and Precautions (5.2)] Pediatric Patients (1 to 17 Years of Age) Daptomycin is a cyclic lipopeptide antibiotic that has a unique mechanism of action. Modules 6-11, which catalyze the condensation of L-ornithine, L-aspartate, D-alanine, L-aspartate, glycine, and D-serine are encoded for the dptBC gene (Figure 5). They do not treat viral infections (e.g., the common cold). The median age among the 235 patients in the ITT population was 53 years (range: 21 to 91 years); 30/120 (25%) in the daptomycin for injection group and 37/115 (32%) in the comparator group were ≥65 years of age. [medical citation needed], Daptomycin resistance is still uncommon,[when?] At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for daptomycin against isolates of genus or organism group. [23], In Phase III clinical trials, limited data showed daptomycin to be associated with poor outcomes in patients with left-sided endocarditis. Complicated Skin and Skin Structure Infection Trials in Adults Patients treated with daptomycin for injection were (51%) male, (49%) female and (46 %) Caucasian and (32 %) Asian. No evidence of adverse developmental outcomes was observed. Table 4: Clinical Success Rates by Renal Function and Treatment Group in Phase 3 cSSSI Trials in Adult Patients (Population: ITT), In a subgroup analysis of the ITT population in the Phase 3 S. aureus bacteremia/endocarditis trial, clinical success rates, as determined by a treatment-blinded Adjudication Committee [see Clinical Studies (14.2)], in the daptomycin for injection-treated adult patients were lower in patients with baseline CLCR<50 mL/min (see Table 5). Thirty-five patients treated with an anti-staphylococcal semi-synthetic penicillin received vancomycin initially for 1 to 3 days, pending final susceptibility results for the S. aureus isolates. Of the 37 patients with an entry diagnosis of Definite Endocarditis, all (100%) had a final diagnosis of infective endocarditis, and of the 144 patients with an entry diagnosis of Possible Endocarditis, 15 (10%) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee. Patients were randomized 2:1 to receive daptomycin for injection or a standard of care (SOC) comparator, which included intravenous therapy with either vancomycin, clindamycin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin, or cloxacillin). Daptomycin is a cyclic lipopeptide compound with 13 amino acids and which comprises of a core with hydrophilic properties and also a tail which has high lipophilicity. Gastrointestinal Disorders: dry mouth, epigastric discomfort, gingival pain, hypoesthesia oral Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, since these infections can be refractory to antimicrobial therapy and may require colectomy. Blood/Lymphatic System: leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased International Normalized Ratio (INR) Cardiac Disorders: atrial fibrillation, atrial flutter, cardiac arrest There were no differences in Cmax[see Use in Specific Populations (8.5)]. 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