Lavoro svolto da Irene Moro e Claudia Vaccheris.
Description
Daptomycin, the first in a class of agents known as lipopeptides, is a cyclic antibiotic produced by the soil saprotroph Streptomyces roseosporus. It is marketed under the name “Cubicin”, and it's used in the treatment of certain infections caused by Gram-positive organisms. Its distinct mechanism of action means that it may be useful in treating infections caused by multi-resistant bacteria.
The efficacy and safety of Daptomycin: first in a new class of antibiotics for Gram-positive bacteria. 2006
Indications
Daptomycin has been shown to be effective in skin and soft tissue infections caused by Gram-positive organisms, as well as in Staphylococcus aureus bacteraemia and right-sided S. aureus endocarditis. It binds avidly to pulmonary surfactant, and therefore it is not indicated for treatment of pneumonia. Its role in the treatment of bone and joint infections is not well-defined.
Daptomycin in the treatment of skin, soft-tissue and invasive infections due to Gram-positive bacteria. 2006
Daptomycin in the treatment of patients with infective endocarditis: experience from a registry. 2007
Daptomycin is active against Gram-positive bacteria only, including a wide variety of multidrug-resistant nosocomial pathogens: Enterococci (including glycopeptide-resistant Enterococci GRE), Staphylococci (including vancomycin-intermediate and methicillin-resistant S. Aureus), Streptococci (including those causing soft tissue and parenchimal abscesses, S.anginosus, S.constellatus, S.intermedius) and Corynebacteria.
Daptomycin against multiple drug-resistant staphylococcus and enterococcus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations. 2003
Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathogens. 2004
Daptomycin tested against 915 bloodstream isolates of viridans group streptococci (eight species) and streptococcus Bovis. 2005
Antimicrobial activity and spectrum of Daptomycin: results from the surveillance program in Australia and New Zeland (2008). 2010
Daptomycin has been shown to be not inferior to standard therapies (nafcillin, oxacillin, flucloxacillin or vancomycin) in the treatment of bacteraemia and right-sided endocarditis caused by Staphylococcus aureus.
Daptomycin compared to standard therapy for the treatment of native valve endocarditis. 2010
Pharmacokinetics
Daptomycin is administered intravenously or by injection. It has a high protein binding (up to 90-95%), and a half-life of 7-11 hours (up to 28 hours in renal impairment).
Elimination is mainly renal (78%; primarily as unchanged drug); a small amount is eliminated by faeces (5.7%)
An evaluation of the P450 inhibition and induction potencial of daptomycin in primary human hepatocytes. 2004
Moderate liver impairment has no influence on daptomycin pharmacokinetics. 2004
Molecular mechanism
Daptomycin consists of thirteen amino acids, ten of which are arranged in a cyclic fashion, and three that adorn an exocyclic tail.
It presents a particular mechanism of action, disrupting multiple aspects of bacterial cell membrane function. It appears to bind to the membrane and cause rapid depolarization due to potassium efflux; the resulting loss of membrane potential leads to inhibition of protein, DNA and RNA synthesis, and then to bacterial cell death.
Dosage and presentation
In skin and soft tissue infections, 4 mg/kg daptomycin is given intravenously once daily. For S. aureus bacteraemia or right-sided endocarditis, the approved dose is 6 mg/kg given intravenously once daily.
Daptomycin is given all 48 hours in patients with renal impairment, clearance < 30 ml/min. Daptomycin is applicable as 30-min-infusion or 2-min-injection.
Side effects and toxicity
Adverse drug reactions associated with daptomycin therapy include local injection site reactions, rash, pruritus, headache, gastrointestinal reactions (constipation, diarrhea, nausea, vomiting), haematological effects (anemia, eosinophilia, raised INR).
Less frequent, but important, are adverse effects on skeletal muscle which may appear as increases in CPK, myalgia, muscle cramps, muscle weakness or myositis during therapy, up to rhabdomyolisis.
Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis. 2010
Muscle pain associated with daptomycin. 2004
Rhabdomyolysis during therapy with daptomycin. 2006
The overall incidence of severe myopathy might seem acceptable, for instance in comparison with that of HMG-CoA reductase inhibitors, where its frequency is estimated to be 0.1%. Nevertheless, before start and during daptomycin therapy weekly monitoring of CPK levels is recommended.
According to the manufacturer daptomycin should be discontinued in patients with unexplained signs of myopathy in conjunction with CPK elevation, or in patients without marked symptoms who have marked elevations in CPK. Concomitant therapy with drugs that also may cause myopathy, rhabdomyolysis or CPK elevation should be avoided, and the manufacturer recommends that statins be temporarily discontinued while the patient is receiving daptomycin therapy.
Rhabdomyolysis and acute renal failure associated with the co-administration of daptomycin and an HMG-CoA reductase inhibitor. 2009
Possible hepatotoxicity with abnormal liver function tests, ending after discontinuation of daptomycin, was observed in some cases.
Some cases of acute renal failure during daptomycin therapy were also reported.
Severe myopathy and possible hepatotoxicity related to daptomycin. 2005
Daptomycin-induced acute renal and hepatic toxicity without rhabdomyolysis. 2008
Therefore, although daptomycin-induced liver or renal injury appear to be uncommon, clinicians should consider periodic monitoring of liver function and renal function tests to identify potential adverse effects.
Although daptomycin may not cause significantly higher rates of pulmonary adverse effects when compared with vancomycin or penicillinase-resistant penicillins, there have been a few case reports of pulmonary complications ( eosinophilic pneumonia, even life-threatening, and organizing pneumonia) associated with daptomycin administration.
Organizing pneumonia and pulmonary eosinophilic infiltration associated with daptomycin. 2007
FDA classifies daptomycin as pregnancy category B.
Resistance
Daptomycin resistance is uncommon, but some cases have been described during therapy of infections caused by S.Aureus.
The microbiological definition of resistance to daptomycin has not been established for S. aureus; organisms with a daptomycin MIC of 1 mg/mL are considered susceptible, and those with a daptomycin MIC of 11 mg/mL are considered nonsusceptible.
Wild-type S. aureus with daptomycin MICs greater than the susceptible range are rare but have been recovered from patients who received vancomycin, patients who never received daptomycin, and patients who were antibiotic naive [44, 45]. Although spontaneous resistance is uncommon, it can be induced by serial passage in increasing concentrations of daptomycin [46].
No definitive resistance mechanism has been identified, although genetic mutations have been described.
Findings of in vitro studies suggest a correlation between the minimum inhibitory concentrations of daptomycin and vancomycin.
Although clinical practitioners must monitor for daptomycin resistance, the available data support the use of daptomycin in the treatment of methicillin-resistant S. aureus bacteremia and endocarditis.
Perspectives on Daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. 2007
Development of Daptomycin resistance in vivo in methicillin-resistant Staphylococcus aureus. 2005
Susceptibility relationship between vancomycin and daptomycin in Staphylococcus aureus: facts and assumptions. 2009
