Pharmacological action -. Bactericidal, antibacterial
Daptomycin is a cyclic lipopeptide natural origin, active only against Gram-positive bacteria.
Daptomycin in the presence of calcium ions binds to the cell membrane (as in the growth phase of the bacterial cell and at rest), it causes the depolarization, resulting in a rapid inhibition of protein synthesis, DNA, RNA and cell death with negligible lysis.
In vitro daptomycin exhibits rapid bactericidal activity (dependent on concentration) against susceptible gram-positive microorganisms. In vivo after a single application (at a dose equivalent to 4 and 6 mg / kg 1 time a day in human) ratio AUC / MIC (area under the curve “concentration-time” / minimal inhibitory concentration) and Cmax / MIC (maximum concentration in blood / Minimal inhibitory concentration) correlated with the efficiency and predictable bactericidal action.
In a group of highly sensitive microorganisms, for which the MIC (according to the European Committee for determining sensitivity to antibiotics – EUCAST) daptomycin is ≤1 mg / L include: Staphylococcus aureus *, Staphylococcus haemolyticus, coagulase negative Staphylococcus, Streptococcus agalactiae *, Streptococcus dysgalactiae subsp equisimilis * , Streptococcus pyogenes *, Streptococcus group G, Clostridium perfringens, Peptostreptococcus spp (* marked types, activity of the drug in respect of which demonstrated in clinical trials, considered as satisfactory).
The group of resistant organisms, for which the MIC (according EUCAST) daptomycin is > 1 mg / L are naturally resistant Gram negative microorganisms
Daptomycin is effective in patients with complicated skin and soft tissue infections (wound infections, subcutaneous abscesses), bacteremia caused by Staphylococcus aureus, including methicillin-resistant strains (infectious endocarditis, including early postoperative endocarditis).
In applying the drug in doses of 4-12 mg / kg 1 time a day for 14 days pharmacokinetics daptomycin basically has a linear character; the equilibrium concentration is reached after 3 days.
In experimental studies, daptomycin is practically not absorbed into the bloodstream when taken orally.
In healthy volunteers the volume of distribution at steady state of daptomycin was approximately 0.1 l / kg, which corresponds to the distribution of the drug in the first place in the extracellular space. In experimental studies, in single or repeated application of daptomycin advantageously distributed in a well-vascularized tissues and to a lesser extent penetrate the BBB and placental barrier.
Daptomycin is reversibly bound to human plasma proteins, regardless of concentration. In healthy volunteers, protein binding is approximately 90%, including with impaired renal function.
In in vitro studies of daptomycin not metabolized or only slightly metabolized by microsomal oxidation systems involving cytochrome P450 enzymes (CYP450).
When administering the drug to people at a dose of 6 mg / kg (based on plasma analysis), and also when using radiolabeled daptomycin, formation of its metabolites have been identified, suggesting lack of systemic metabolism. 4 inactive metabolites found in the urine, the oxidizing product 2 phase I metabolism were present in low concentrations.
The drug is excreted mainly by excretion through the kidneys. Simultaneous treatment with probenecid does not affect the pharmacokinetics of daptomycin, which implies the absence of active tubular secretion of daptomycin in the kidney.
After the on / in the plasma Cl daptomycin was about 7-9 mL / h / kg. Kidney Cl – 4-7 ml / h / kg
When a single application daptomycin 78% excreted in the urine and 5% – faeces. About 50% of the dose of the drug is excreted unchanged in the urine.
Pharmacokinetics in special clinical situations
Patients older than 65 years. Correction dose in patients over 65 years is not required.
Children and adolescents (under 18 years). The pharmacokinetics of daptomycin in children and adolescents (under 18 years) has not been studied.
Patients who are overweight (obese). In patients with moderate (body mass index (BMI) of 25-40 kg / m2 and a pronounced (BMI > 40kg / m2) obesity marked increase AUC by 28 and 42%, respectively, compared with patients with normal body weight But. correction of the dose in patients with overweight is not required.
Floor. Gender patients has no effect on the pharmacokinetics of daptomycin.
Patients with impaired renal function. In the application of daptomycin at a dose of 4 or 6 mg / kg in patients with various degrees of renal impairment (creatinine score Cl) Cl marked decrease and increase AUC daptomycin.
In patients with severe renal impairment (Cl creatinine < 30 ml / min) and renal insufficiency, AUC and T1 / 2 daptomycin increased approximately 2-3-fold compared with healthy volunteers
Patients with impaired liver function. Since in patients with mild to moderate hepatic impairment (< 8 on a scale Child-Pough) pharmacokinetics of daptomycin compared to healthy volunteers is not changed, the correction of the dose in these patients is not required
In patients with severely impaired liver function (> 9 on a scale Child-Pough) pharmacokinetics daptomycin not studied.
Novartis Pharma Stein AG, Switzerland
Lyophilizate for preparation of infusion solution
component of the formulation without the number of
excipients: sodium hydroxide solution ZN
- Complicated skin and soft tissue infections in adults;
- bacteremia caused by Staphylococcus aureus, including or suspected infective endocarditis in adults.
Hypersensitivity to daptomycin or excipients.
- renal dysfunction (Cl creatinine < 80 ml / min);
- severe liver function (> 9 points on a scale Child-Pough);
- Patients older than 65 years.
- severe renal impairment (Cl creatinine < 30 ml / min) – a drug should be administered only in those cases when the expected benefit from the treatment exceeds the potential risk
In clinical studies, treatment with Kubitsin (for 7-14 days), received more than 1,500 people.
The most common adverse reactions were headache, nausea, vomiting, diarrhea, fungal infections, rash, injection site reactions, increased creatine kinase activity and liver enzymes – ALT, ACT and AP
In clinical studies, the following adverse events were observed, the following organs and systems indicating the frequency of occurrence: often (≥1 / 100, < 1/10); sometimes (≥1 / 1000, < 1/100); rarely (≥1 / 10000, < 1/1000), very rare (≤1 / 10000), including: individual messages. In each group, undesirable effects are presented in order of decreasing seriousness.
Infectious diseases: often – a fungal infection; sometimes – urinary tract infection
From the hematopoietic system: sometimes – thrombocythemia, anemia, eosinophilia
Metabolic disorders and nutrition: sometimes – anorexia, hyperglycemia
Psychiatric disorders: uncommon – anxiety, insomnia
From the nervous system and sensory organs: often – headache; sometimes – dizziness, paresthesia, taste disturbances
With the cardiovascular system: sometimes – supraventricular tachycardia, arrythmia, flushing, increased or decreased blood pressure
From the digestive system: often – nausea, vomiting, diarrhea; sometimes – constipation, abdominal pain, dyspepsia, glossitis
Of the liver and biliary tract: sometimes – jaundice
Skin and subcutaneous tissue: often – rash; sometimes – itching, hives
On the part of the musculoskeletal system: sometimes – myositis, muscular weakness, myalgia, arthralgia
From the urinary system: rarely – renal dysfunction
Reproductive and endocrine system: sometimes – vaginitis
On the part of the body in general and local reactions: often – reactions at the site of administration; sometimes – fever, weakness, fatigue, pain
Change the results of laboratory tests: often – a violation of the laboratory indicators of liver function (increased activity of ACT, ALT and alkaline phosphatase), increased CPK activity; sometimes – electrolyte imbalance in plasma creatinine levels, myoglobin, LDH increase
In applying the drug Kubitsin following adverse events were observed in clinical practice:
Immune system: very rarely – hypersensitivity (some spontaneous reports), including pulmonary eosinophilia, vesicular-bullous eruption involving the mucous membranes and the feeling of swelling of the oropharynx, anaphylaxis, postinfuzionnye reactions, including tachycardia, wheezing, fever, chills, systemic flushing, dizziness, syncope, a metallic taste in the mouth.
On the part of the musculoskeletal system: very rarely – rhabdomyolysis. Approximately 50% of cases of rhabdomyolysis observed in patients with pre-existing renal insufficiency or while applying Kubitsin formulation with drugs that cause rhabdomyolysis.
Changing laboratory results: in some cases of myopathy, which is manifested by muscle symptoms and an increase in CPK activity was accompanied by an increase in transaminase levels. Increased activity of transaminases was probably due to the influence of the drug in the skeletal muscles. In most cases, there was an increase of transaminases 1-3 degrees, disappear after cessation of therapy with Kubitsin.
How to accept, acceptance rate and dosage
B / in the form of infusion for at least 30 min.
Complicated skin and soft tissue infections
The recommended adult dose – 4 mg / kg 1 time a day for 7-14 days or until the disappearance of the infection. In developing bacteremia caused by Staphylococcus aureus, administered 6 mg / kg of the drug 1 time per day.
Bacteremia caused by Staphylococcus aureus, including or suspected infective endocarditis
The recommended dose for adults – 6 mg / kg 1 time a knock during 2-6 weeks at the discretion of the attending physician
Patients with impaired renal function. Patients with creatinine Cl ≥30 mL / minute doses of the drug are not required correction.
Patients with Cl creatinine < 30 ml / min or patients receiving hemodialysis or continuous ambulatory peritoneal dialysis, the interval between administrations Kubitsin drug should be increased to 48 hours (this correction dosing interval has not been studied in clinical trials, and based on the data pharmacokinetic modeling ).
Patients with end-stage renal disease Kubitsin drug to be administered on the same day after hemodialysis.
Patients with impaired liver function. Patients with mild to moderate hepatic impairment (< 8 on a scale Child-Pough) drug dose correction is not required
As in patients with severely impaired hepatic function (> 9 points on a scale Child-Pough) the application of the efficacy and safety of daptomycin has not been studied, caution should be exercised in the appointment Kubitsin drug in this category of patients
Patients older than 65 years. Patients aged 65 years with severe lack of renal function preparation administered with caution at 4 or 6 mg / kg 1 time a day.
As experience with the drug Kubitsin in patients older than 65 years is limited, caution should be exercised when using the drug in these patients.
Children and adolescents (under 18 years). As the efficacy and safety Kubitsin in children and adolescents has not been established, the drug is not recommended in these patients.
Rules of preparation and administration of the drug solution Kubitsin
1. To obtain the solution for the on / in the daptomycin at a concentration of 50 mg / ml:
– 350 mg of the lyophilisate can be dissolved in 7.0 ml of 0.9% sodium chloride solution or sterile water for injection;
– 500 mg of lyophilisate to be dissolved in 10.0 ml of 0.9% sodium chloride solution or sterile water for injection
Preparation of the solution preparaat Kubitsin carried out under aseptic conditions. You must delete polypropylene «flip off» cap to detect the central portion of the rubber stopper. 7 or 10 ml 0.9% sodium chloride solution or sterile water for injection sodium injected into the vial through the center of the rubber plug guiding the needle to the wall of the vial. The bottle must be carefully rotated to ensure complete dissolution of the drug, followed by leaving it for 10 minutes. Then, the vial should be shaken gently for 5 minutes to obtain the required reconstituted solution clear. To avoid foaming bottle of the drug can not be shaken vigorously. Complete dissolution of the freeze-dried product usually occurs within 15 minutes.
Prior to the introduction Kubitsin drug should visually check the quality of the dissolution of the drug and the color of the solution. Kubitsin solution preparation should be from pale yellow to light brown. When you change the color or appearance of visible insoluble particulate drug can not be used.
The chemical and physical stability of the dissolved drug in the vial is maintained for 4 hours at 30 ° C; 12 hours at temperatures up to 25 ° C; to 48 hours at 2-8 ° C.
2. The resultant drug solution Kubitsin dilute 50 ml of 0.9% sodium chloride solution and enter / drip for 30 min.
The chemical and physical stability of the diluted solution in infusion bags is stored for 12 hours at a temperature of 25 ° C or 24 hours at 2-8 ° C. From the microbiological point of view of the drug solution diluted to / v administration should be used immediately after preparation. If the prepared infusion solution should not be used immediately, the storage time does not exceed 24 hours at 2-8 ° C.
Summary term storage of daptomycin solution in vial and diluted solution of the drug in the infusion bag should not exceed 12 hours at a temperature of 25 ° C or 24 hours at 2-8 ° C.
3. After a single injection Kubitsin remaining in vial intact drug solution can not be used again.
4. After using the drug properly dispose of all materials should be a way.
You can not mix the drug Kubitsin with glucose-containing solutions.
At a temperature of 2-8 ° C.
Keep out of the reach of children.
Daptomycin is not metabolized or only slightly metabolized involving cytochrome P450 isoenzymes (CYP450) system.
Because in vitro studies, the drug has no clinically significant inducing or inhibitory effect on CYP450 isozymes system (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4), development SUR450-dependent interactions in humans is unlikely.
Experience with simultaneous application of daptomycin drugs whose use may be accompanied myopathy limited. However, several cases of increasing activity of CK and rhabdomyolysis in patients taking the drug Kubitsin together with drugs that cause myopathy. Kubitsin prescribed the drug, along with medicines that cause myopathy should be only in cases where the benefits of therapy outweighs the potential risk.
When applying preaparata Kubitsin with drugs that can cause myopathy, CPK is necessary to control the activity of more than 1 time per week and ensure monitoring of patients for timely detection of any symptoms suggestive of myopathy.
Because daptomycin excretion occurs mainly through renal filtration, its plasma concentration may increase while the use of drugs that reduce renal filtration (including NSAIDs, including selective COX-2 inhibitors). Furthermore, when used with the indicated preparations of daptomycin may develop pharmacodynamic interaction due to the additive effect on renal function.
Should be used with caution preparation Kubitsin with potentially nephrotoxic drugs, providing additional regular monitoring of renal function in all patients (regardless of the initial state of renal function).
In clinical practice, there have been cases of daptomycin interaction with a particular reagent used in the determination of PT / INR. This interaction leads to a pronounced prolongation of PT and increase MHO. In identifying deviations MF / INR in patients receiving treatment with Kubitsin should take into account the possibility of interaction with daptomycin in vitro laboratory reagent. The probability of error in the determination of PV or MHO can be reduced a minimum, if you make a blood sample at the lowest possible concentration of daptomycin in the blood plasma.
If necessary, the drug can be applied (administered w / w) simultaneously with aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.
Incompatibility. Must not be confused with glucose-Kubitsin drug solutions, as well as other drugs, except for the above.
For suspected development mixed infections (including gram-negative and / or anaerobic microorganisms) Kubitsin drug to be combined with appropriate antibiotics. Limited experience with daptomycin for complicated infections of the skin and soft tissue caused by Enterococcus faecalis and Enterococcus faecium, does not allow to draw conclusions about the clinical efficacy of the drug Kubitsin. Experience with the drug in patients after prosthetic valve no. According to clinical studies Kubitsin drug is ineffective in patients with pneumonia, with bacteremia in patients with severe endocarditis caused by Staphylococcus aureus.
Treatment failure due to persistence or recurrence of an infection caused by Staphylococcus aureus, was observed in 19/120 (15.8%) patients receiving the drug Kubitsin, 9/53 (16.7%) – vancomycin and 2/62 (3.2%) – semisynthetic penicillins. In these patients, including 6 people receiving the drug Kubitsin, and 1 patient from the group of vancomycin MIC was an increase during or after therapy. Most patients with persistence or recurrence of infection had deep localized infection and did not receive surgical treatment.
When deep localized infections in order to achieve a clinical effect should promptly conduct appropriate surgery (including wound brushing, removal of prosthetic valve replacement).
Since the use of nearly all antibacterial agents noted the development of antibiotic-associated colitis and pseudomembranous colitis, moderate to severe (life-threatening), should consider the possibility of these adverse events and the application of Kubitsin drug and monitor the status of patients with diarrhea during treatment or shortly after his end.
The mechanism of development of resistance. The mechanism of resistance to daptomycin is not installed.
Reduced sensitivity to daptomycin, as well as to other antibiotics was observed when used in patients with heavy, difficult to treat infections and / or for a long period of time. In a clinical study in the application preparation Kubitsin 6 patients with bacteremia and endocarditis was observed to decrease the sensitivity of daptomycin may cause inefficiency is antibiotic therapy. In clinical practice, also noted some cases of reduced susceptibility to daptomycin. Since the data on the structure of antibiotic resistance differ according to geographical area and change over time, it is recommended to take into account local information on resistance, particularly when treating severe infections. In case of doubt the effectiveness of the drug, at least in respect of certain types of pathogens (subject to local antibiotic resistance), it is recommended to consult with a skilled technician. With the development of antibiotic resistance to daptomycin (superinfection), you must take appropriate measures.
CPK and myopathy. Since in clinical studies of patients receiving drug Kubitsin, increasing activity of CK (≥5 times the upper limit of normal – ≥5 × ULN) without the development of muscular symptoms was more than with the reference drug (1.9 and 0.5%
: respectively), the following guidelines must be observed
– plasma creatine kinase activity of blood determined prior to initiation of therapy and during treatment with Kubitsin regular intervals ≥1 times a week or more) in all patients;
– as in the application of the drug in patients with high levels of CPK (≥5 × ULN) optionally further increasing enzyme activity in these patients must provide control CPK more than 1 time per week;
– determination of CPK more than 1 time per week should be performed in patients with an increased risk of myopathy: severe renal failure (Cl creatinine < 30 ml / min), the simultaneous application of the drug Kubitsin with drugs that cause myopathy (incl ., statins, fibrates and ciclosporin);
– prescribe a drug Kubitsin with drugs causing myopathy should be only in cases where the benefits of therapy outweighs the potential risk;
– when using the drug Kubitsin necessary to ensure monitoring of patients for early detection of symptoms indicating the possible development of myopathy;
– the development of muscle pain, tenderness on pressure, muscle weakness or cramps during therapy with the drug Kubitsin determination of CK activity is carried out every 2 days. In patients with muscle symptoms of unknown etiology and increased CPK ≥5 × ULN, treatment with the drug should be discontinued.
Peripheral neuropathy. In the case of symptoms of peripheral neuropathy, patients should be evaluated and consider discontinuing treatment with Kubitsin.
Renal insufficiency. With the introduction of the drug Kubitsin observed isolated cases of renal failure, but the relationship of the adverse event to the drug has not been established.
In patients with severe renal insufficiency may increase in daptomycin concentration in blood plasma, which leads to an increased risk of myopathy. In clinical studies of renal impairment have been observed more frequently in patients treated with the reference drug than drug Kubitsin.
Effects on ability to drive vehicles and / or operate machinery. Effect on ability to drive vehicles and operate machinery has not been studied. However, considering the safety profile of the drug Kubitsin, the negative impact of the drug on the ability to perform potentially hazardous activities that require high concentration and psychomotor speed reactions, it is unlikely.
Pregnancy and lactation
Use of the drug Kubitsin in pregnant women has not been studied. In experimental studies, daptomycin has no adverse effect on pregnancy, embryonic / fetal development, parturition and postnatal development. Prescribed the drug during pregnancy should only be in cases where the expected benefit to the mother outweighs the potential risk to the fetus.
It is not known whether daptomycin is excreted in breast milk in humans. If necessary, use during lactation breastfeeding baby you want to stop.
Treatment: symptomatic treatment and medical monitoring. Daptomycin is slowly excreted by hemodialysis (about 15% of the dose appears after 4 hours) or by peritoneal dialysis (about 11% of the administered dose is removed after 48 hours).