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Daptomycin - the first representative of a new class of antibiotics

Over the past three decades, the number of nosocomial infections caused by Staphylococcus aureus and antimicrobial resistant enterococci has increased dramatically. In addition, methicillin-resistant S.aureus (MRSA), as well as nosocomial infections, are increasingly causing community-acquired infections. The antibiotic glycopeptide vancomycin has remained the drug of choice for the treatment of MRSA infections for many years, however, excessive use of vancomycin has led to the recent emergence of the first cases of resistance. Other drugs currently used to treat infections caused by MRSA include teicoplanin glycopeptide, a combination of chinupristine / dalphopristin streptogramins, and linezolid oxazolidinone. However, the clinical value of each of these drugs is limited by one or more factors, including the spectrum of antibacterial activity, the complexity of the route of administration, side effects, and the increased prevalence of resistant strains. It is therefore not surprising that the search for new antibacterial drugs active against Gram (+) infections remains a priority area in the field of drug development. Today, several drugs are under development, including ceftobiprol, dalbavancin, daptomycin, oritavancin, telavancin and tigecycline. However, many of these antibiotics belong to existing classes of drugs, and therefore rapid formation of resistance due to cross-resistance with existing drugs is possible.

Daptomycin (daptomycin) is the first drug in a new group of antibiotics classified as cyclic lipopeptides.

Daptomycin was originally obtained from Streptomyces roseosporus as part of a screening program for soil microorganisms. The drug has been developed at Eli Lilly since 1985. The initial development program was interrupted after volunteers detected cases of myopathy in the first phase of clinical trials, probably caused by the use of daptomycin. After some time, with the accumulation of data on the frequency, consequences and treatment of drug-induced myopathy, as well as the need to develop new drugs, especially those active against MRSA, the potential clinical value daptomycin has been revised. In 1997, Cubist Pharmaceuticals Inc. purchased a patent for daptomycin in Lilly and restarted clinical trials using a new dosing regimen - once daily - to preserve the antimicrobial effect and reduce potential toxicity. Chiron BioPharmaceuticals, licensed by Cubist, is testing the drug in Europe and in some other regions except the United States. Daptomycin has been approved in the United States since 2003 for use in complicated skin and soft tissue infections caused by gram (+) pathogens; in early 2006, it is expected to obtain authorization to use daptomycin for complicated gram (+) skin and soft tissue infections in Europe.

The mechanism of action of daptomycin is different from that of all currently known antibiotics. The molecule is a cyclic lipopeptide composed of 13 amino acid residues, having a hydrophilic nucleus and a hydrophobic tail. The hydrophobic tail, by a calcium-dependent mechanism, binds irreversibly to the cell membrane of gram (+) bacteria. A channel forms, leading to rapid depolarization of the cell membrane due to the release of potassium and possibly other ions from the cytoplasm. As a result of a gross violation of the synthesis of macromolecules, the death of bacterial cells occurs. Unlike beta-lactam antibiotics, the bactericidal action of daptomycin is not associated with cell destruction.

Daptomycin has a relatively long half-life of 8 to 9 hours, allowing it to be administered once a day. The pharmacokinetics of the drug at doses of 4, 6 and 8 mg / kg per day is stable and predictable (the maximum concentration (Cmax) is 58, 99 and 133 mg / l, the 24-hour zone under the pharmacokinetic curve ( PFC) is 494, 747 and 1130 mg / h per liter, respectively). A small volume of distribution (0.1 l / kg) indicates that the drug remains mainly in the plasma and intercellular fluid. Daptomycin is mainly excreted in the urine (78%), while approximately 50% of the active substance is excreted unchanged in the urine within 24 hours. A small part of the drug (6%) is excreted in the feces.

The binding of daptomycin to plasma proteins, mainly albumin, is approximately 92%. However, its connection with plasma proteins is weaker than the irreversible connection with the bacterial membrane, and therefore the bioavailability of daptomycin is much higher than one would expect, judging by the level of binding to proteins.

Since daptomycin does not inhibit or induce cytochrome P450 enzymes, and there is currently no known drug interaction with other drugs, daptomycin can be used in combination with a variety of other drugs.

Daptomycin has been shown to be very active against gram (+) pathogens, including susceptible and multidrug-resistant staphylococci and enterococci. In Vitro with intermediate sensitivity to vancomycin. In general, daptomycin was more active against all of the microorganisms tested, except Enterococcus faecium, for which it showed the same activity as chinupristine / dalphopristine. It should be noted that daptomycin is also active in vitro against recently isolated strains of S.aureus resistant to vancomycin in Michigan and Pennsylvania (Hershey) (IPC 1.0 and 0.5 mg / l, respectively).

Daptomycin rapidly exhibits bactericidal activity in vitro. At a concentration 4 times higher than the MPC, daptomycin caused the death of 99.9% of the MRSA in 8 hours, that is to say that the bactericidal effect developed more quickly than linezolid and quinupristine / dalphopristine (p less than 0.05).

On the pharmacodynamic model of endocardial vegetation, the activity of daptomycin, nafcillin, linezolid and vancomycin, separately and in combination with gentamicin, was compared for high concentrations (9.5 log10 CFU / g ) and moderate (5.5 log10 CFU / g) of concentrations sensitive to methicillin S. aureus (MSSA) and MRSA for 72 hours The dosage schedules used in humans have been modeled for each drug. A comparable bactericidal effect (death of 99.9% of bacteria) was observed in nafcillin (only for MSSA), vancomycin and daptomycin compared to moderate concentrations, with a faster manifestation of bactericidal effect in daptomycin and nafcillin compared to vancomycin (4 vs 32 h, respectively)) At a high concentration of microorganisms, daptomycin showed a bactericidal effect against MSSA and MRSA after 24 hours, while vancomycin, linezolid and nafcillin failed to show bactericidal action during the entire 72 hour study period. The addition of gentamicin accelerated the bactericidal effect of daptomycin up to 8 hours, of nafcillin up to 48 hours, but had no effect on the activity of vancomycin and linezolid. In addition, the bactericidal activity of daptomycin also persisted in the stationary phase, which is an important fact in the treatment of deep infections.

The bactericidal activity of daptomycin was also evaluated by the ratio of the minimum bactericidal concentration (MBC) to the MIC. The bactericidal activity of daptomycin against S.aureus and S.epidermidis (MBC in both dilutions of MIC) was higher than that of vancomycin, linezolid and chinupristine / dalfopristine.

A study was also carried out on the activity of combinations of daptomycin with other antibiotics, most often in relation to Enterococcus spp. Synergism was observed for vancomycin-resistant enterococci strains using a combination of daptomycin and rifampicin. An additive or synergistic effect was also manifested in the combination of daptomycin with ampicillin in relation to E.faecalis and E.faecium, and in the combination daptomycin with gentamicin in relation to ampicillin-resistant E.faecium. The antagonism between daptomycin and other antibiotics has not been identified.

Daptomycin is characterized by a prolonged post-antibiotic effect, which depends on the concentration and lasts up to 6 hours compared to S.aureus and E.faecalis in the presence of free calcium at physiological concentrations.

History has shown that whenever a new antibiotic becomes available for widespread use, clinically significant resistance to it builds up over time. So far, studies on in vitro have shown that it is difficult to obtain strains resistant to daptomycin. The unique mechanism of action of daptomycin is directed to the bacterial cell wall, and generally the spread of resistance between bacteria is relatively slow, compared, for example, to resistance associated with changes in rRNA. More than 20 passages are required in the presence of daptomycin to produce a small number of strains with reduced sensitivity. In the clinical use of the drug, resistance formation also occurs slowly and to date, only three cases E.faecium with MPC greater than 32 mg / l, one E.faecalis with MPC have been described as 16 mg / l and five S. aureus with an MIC of 2-8 mg / l.

None of the daptomycin-resistant mutants obtained in vitro had resistance to vancomycin or ampicillin, due to the difference in the mechanisms of action of these three drugs. The development of cross-resistance between daptomycin, glycopeptides and beta-lactams is unlikely due to the unique mechanism of action of daptomycin.

The US Food and Drug Administration has approved the use of daptomycin in the treatment of complicated Gram (+) infections of the skin and soft tissue based on two clinical trials. A total of 1,092 patients aged 18 to 85 with abscesses, wound infections and infected diabetic foot ulcers participated. Daptomycin at a dose of 4 mg / kg, administered intravenously once daily for 30 minutes, was compared to vancomycin at a dose of 1 g, administered intravenously twice daily for 60 minutes, or antistaphylococcal penicillin (cloxacillin, fluxloxacillin, oxacillin or nafcillin) administered intravenously at a dose of 4 to 12 g once a day for 7 to 14 days. Both studies have shown that daptomycin is not less effective than comparison antibiotics. An analysis consistent with the intention to apply the treatment showed that the clinical efficacy rate was 71.5% and 71.1% respectively for daptomycin and the comparison drugs (95% confidence interval of - 5.8 to 5.0). Among patients undergoing full treatment, the indicator was 83.4% and 84.2%, respectively.

Daptomycin is currently approved in the United States for the treatment of complicated skin and soft tissue infections caused by S.aureus (including MRSA), Streptococcus pyogenes , Streptococcus agalactiae, Streptococcus dysgalactiae equisimilis and E.faecalis (only strains sensitive to vancomycin). The European Medicines Agency is currently considering the use of daptomycin for the treatment of complicated gram (+) infections of the skin and soft tissues. Studies on the efficacy of daptomycin in other infections are also underway. A recent international, multicenter, prospective, randomized, controlled, open-label third phase study evaluated the efficacy of daptomycin in patients with endocarditis and bacteremia caused by S.aureus. Patients with bacteremia (MSSA or MRSA) were randomly assigned to one of the treatment groups. For 2 to 6 weeks, daptomycin was administered at a dose of 6 mg / kg per day, semi-synthetic penicillin at a dose of 2 g 6 times a day or vancomycin at standard doses 2 times a day. MRSA was isolated from 37% and 38% of patients in the daptomycin group and the control group, respectively. Patients in the comparison group received the first 4 days of intravenous gentamicin therapy. The study found that the efficacy of daptomycin was not less than that of the comparator drugs.

The efficacy of daptomycin in the treatment of community-acquired pneumonia was evaluated in two international clinical trials of the third phase, which included nearly 1,000 patients. The clinical efficacy of daptomycin was lower than that of ceftriaxone, which may be explained by a significant decrease in the activity of daptomycin in the presence of surfactant. In this regard, daptomycin is not used to treat pneumonia.

In two studies on the efficacy of daptomycin in complicated skin and soft tissue infections, the drug was characterized by good tolerance. The frequency and distribution of adverse events during treatment with daptomycin (n = 534) and the comparison drugs (n = 558) were comparable. Most of the adverse events were considered to be unrelated to treatment and were of mild or moderate severity. One or more side effects were seen in 18% of patients treated with daptomycin and in 21% of patients in the comparison group. The most common adverse events were gastrointestinal dysfunction, injection site reactions and headache, and the frequency was comparable to or less than that of the control group. The total number of patients who discontinued treatment in each group was 2.8%.

Due to the possibility of damage to muscle tissue when using daptomycin, which was reported at the start of the study, when the drug was administered several times a day, the level of creatine phosphokinase (CPK) was carefully monitored throughout the studies. CPK levels were comparable in patients of all groups before, during and after the end of treatment. In a study of the efficacy of daptomycin in complicated skin and soft tissue infections, an increase in CPK levels was noted in 9.3% of patients in the daptomycin group and 8.9% of patients in the group for comparison. Only in two (0.2%) patients treated with daptomycin, the increase in CPK was accompanied by myalgia and / or muscle weakness. In both cases, the clinical signs and laboratory abnormalities disappeared completely after stopping treatment with daptomycin.

Daptomycin is the first representative of a new class of antibiotics, cyclic lipopeptides. The drug is characterized by a bactericidal effect manifesting itself quickly against a wide range of gram (+) pathogens, including MRSA, S.aureus with intermediate sensitivity to vancomycin, vancomycin resistant to S.aureus and to enterococci resistant to vancomycin. It has a strong activity against bacteria both in the growth phase and in the stationary phase. In clinical trials, daptomycin has shown a good safety and efficacy profile comparable to a standard treatment for complicated infections of the skin and soft tissues. The likelihood of resistance formation among bacteria is low due to the unique mechanism of action of the drug.

Daptomycin has been used in clinical practice in the United States since 2003 and is currently approved for the treatment of complicated skin and soft tissue infections; the drug is expected to be available in Europe in early 2006. The results of recent and ongoing clinical trials will help establish the range of clinical use of daptomycin as a possible alternative to currently available drugs, in particular glycopeptides, in the treatment of other Gram (+) infections.