Pharmacological properties of the drug Teicoplanin
Glycopeptide antibiotic with bactericidal action. Forms a complex with acyl-D-alanyl-D-alanine of the bacterial membrane mucopeptide, blocks its formation, suppresses the formation of spheroplasts. It is well absorbed after intramuscular administration, bioavailability is about 90%, and in the blood it is 90–95% bound to plasma proteins. Penetrates very slowly into tissues and organs. The half-life is 150 hours. It is excreted mainly by the kidneys (up to 80%). Active against aureus and coagulase-negative staphylococci (including those resistant to methicillin and other β-lactam antibiotics), streptococci, enterococci (including Enterococcus faecium ), Listeria monocytogenes , micrococci, corynebacteria of the JK , gram-positive anaerobic bacteria, including Clostridium difficile , and peptococci. Antibiotic resistance develops slowly, and there is no cross-resistance with antibiotics from other groups.
The problems of modern antibacterial therapy explain the increased interest in glycopeptide antibiotics active against the most resistant gram-positive cocci: methicillin-resistant staphylococci, penicillin-resistant pneumococci and enterococci.
The purpose of this study was to analyze the clinical, microbiological efficacy and tolerability of the drug teicoplanin. We observed 42 patients who were prescribed antibiotics in empirical and targeted therapy regimens or for the purpose of antibiotic prophylaxis. All patients received teicoplanin intravenously.
The duration of therapy ranged from 7 to 28 days, antibiotic prophylaxis - 24 or 48 hours. All patients who were prescribed an antibiotic for therapeutic purposes had signs of an infectious process: body temperature above 37.5°C for 2 days or more, inflammatory changes in hemogram and documented foci of infection.
In the empirical antibacterial therapy regimen, teicoplanin was prescribed for infections resistant to methicillin-resistant staphylococci, penicillin-resistant pneumococci, enterococci: nosocomial pneumonia, abdominal abscesses, infected bedsores, postoperative wounds, vascular infections, infected arteriovenous fistula thrombosis. After the isolation of strains of microorganisms sensitive to teicoplanin from the blood, 9 people received it in a regimen of targeted etiotropic therapy. Three patients were prescribed teicoplanin for the purpose of antibiotic prophylaxis of wound infections during surgical interventions, including cardiac surgery. To monitor adverse and undesirable reactions after taking teicoplanin, laboratory monitoring was carried out. Laboratory parameters were examined in patients before antibiotics were prescribed, 72 hours after the first dose, and upon completion of the course of antibiotic therapy.
Advances in modern medicine in the fields of surgery, cardiology, transplantology, oncology, and resuscitation have led to aggressive antibiotic therapy and an increase in the number of patients at high risk of developing severe, including nosocomial infections, which has led to an increase in the incidence of infections caused by gram-positive microorganisms [I]. Infections can manifest themselves in a wide variety of ways, affecting the skin, soft tissues, upper and lower respiratory, urinary tract, bone and connective tissue. Infections caused by gram-positive microorganisms are increasingly being recorded, which are associated with the implantation of prostheses, catheterization of great vessels, leading to sepsis and endocarditis. Strains of Staphylococcus aureus (MRSA) and coagulase-negative methicillin-resistant staphylococci (MRSE), characterized by resistance to all β-lactam antibiotics and, as a rule, aminoglycosides, fluoroquinolones, and rifampicin, appeared and spread. In this situation, glycopeptides are the drugs of choice that retain activity against methicillin-resistant strains of staphylococci [2].
Another problem of modern antibacterial therapy is the increasing resistance of Streptococcus pneumoniae to penicillin, cephalosporins, macrolides, and cotrimoxazole. Glycopeptide antibiotics are the drugs of choice for the treatment of infections caused by multi-resistant pneumococcal strains [3].
Increasingly, difficulties arise in the treatment of enterococcal urinary tract infections, wound sepsis, endocarditis, the frequency of which in intensive care units has increased significantly in recent years. Vancomycin has until now been considered as the drug of choice for severe enterococcal infections, but its widespread use in clinical practice has caused the exchange of genetic elements between strains of enterococci and the development of resistance of microorganisms to it. Since 1987, there has been a clear trend towards an increase in the frequency of isolation of vancomycin-resistant enterococci (VRE).
For example, in US hospitals from 1989 to 1993 it increased from 0.3 to 7.9%, and in intensive care units - to 13.6% [4, 5].
Thus, these problems of antibacterial therapy are the reason for interest in glycopeptide antibiotics active against methicillin-resistant staphylococci, penicillin-resistant pneumococci and enterococci [6].
There are 2 representatives of the class of glycopeptides on the pharmaceutical market of the Republic of Belarus: vancomycin and teicoplanin. The natural antibiotic vancomycin is well known to doctors, since it has been used to treat infections since 1958. However, the toxicity (nephrotoxicity and ototoxicity, transient neutropenia, allergic reactions, phlebitis) and tolerability problems (redness of the upper shoulder girdle with intravenous administration) of vancomycin limit and complicate its use in severe cases. patients [7]. Another drug with certain advantages over vancomycin is teicoplanin, an antibiotic synthesized and first used in clinical practice in Italy in 1988.
Antimicrobial activity of teicoplanin. Teicoplanin has activity against gram-positive aerobic and anaerobic bacteria (Staphylococcus spp., including methicillin-resistant strains, Streptococcus spp., Enterococcus spp., Listeria monocytogenes, Peptostreptococcus spp., Corynebacterium jeikeium, Propionibacterium acnes, Clostridium spp., including C. difficile). The mechanism of action of teicoplanin is associated with inhibition of the 2nd stage of peptidoglycan formation and suppression of bacterial cell wall synthesis [8].
Teicoplanin is similar in many characteristics to vancomycin, but in vitro it is 2-4 times more active against methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus, enterococci, and streptococci (Table 1) [9]. The antibiotic is capable of suppressing strains of Enterococcus faecalis that are resistant to vancomycin, the relevance of which is constantly increasing [9].
Pharmacokinetics of teicoplanin. The bioavailability of teicoplanin when administered intramuscularly is about 90%. The greatest differences in the pharmacokinetics of these two antibiotics are in the degree of binding to plasma proteins and the rate of elimination. Teicoplanin is almost completely (95%) bound to plasma proteins, while for vancomycin this figure is about 55%. Teicoplanin, due to its greater lipophilicity, penetrates better into tissues and phagocytic cells. The half-life of teicoplanin is 40-120 hours, which allows it to be used once a day (Table 2) [10-12].
Tolerability of teicoplanin. In terms of tolerability, teicoplanin has a number of advantages over vancomycin: the frequency of side effects does not exceed 10%, for vancomycin - 20-40% and depends on the degree of purity of the drug (chromatographically purified is better tolerated) and the severity of the patient's condition. Teicoplanin does not cause the development of “red man” syndrome - skin hyperemia and pain when the drug is administered intravenously faster than 1 g per 1 hour of infusion. The incidence of nephrotoxic effects in controlled studies at a dose of 6 mg/kg was no more than 0.6%. Ototoxic effects were observed only when combined with aminoglycosides. Teicoplanin can be administered either intravenously or intramuscularly. When administered intramuscularly, it does not cause pain or the development of necrosis in the injection area [10, II].
In world health practice, there is extensive experience in the use of teicoplanin for the treatment of infections of the skin and soft tissues, bones and joints, and pseudomembranous colitis (Clostridium difficile) [13]. Studies conducted in different European countries on the treatment of infective endocarditis with teicoplanin showed its high effectiveness [14-16]. However, today the antibiotic remains “new” for practicing doctors in the republic.
The positive properties of teicoplanin served as the basis for its inclusion in the formulary list of the Republican Scientific and Practical Center "Cardiology" in 2011, the 4th city clinical hospital named after. N. E. Savchenko - in 2012
The purpose of this study is to analyze the clinical, microbiological effectiveness, as well as tolerability of teicoplanin in regimens of empirical and targeted antibiotic therapy and antibiotic prophylaxis of infectious complications during surgical interventions.
Material and methods
Under supervision at the 4th City Clinical Hospital named after. N. E. Savchenko Minsk and in the Republican Scientific and Practical Center “Cardiology” there were 42 patients who were prescribed teicoplanin in the regimens of empirical and targeted antibacterial therapy or for the purpose of antibiotic prophylaxis of infectious complications during surgical interventions (Table 3). Among the examined patients, there were 23 (54.8%) men and 19 (45.2%) women, average age 61 [59–71] years.
The adequacy of the initial treatment regimen was assessed after 72 hours, and the effectiveness - after the end of the course of treatment (after 7-28 days, depending on the nosological form). Therapy was considered effective in the following cases: 72 hours after the first administration of the antibiotic, the patient’s general health improved, signs of intoxication decreased, body temperature decreased, and inflammatory changes decreased; at the end of the course of treatment, patients showed persistent positive clinical and laboratory dynamics of the disease, and the fact of sanitization of the source of infection was stated; There were no infectious complications in the postoperative period.
All patients received Teicoplanin-tf (TriplePharm JLLC, Republic of Belarus) intravenously. The duration of the course of therapy ranged from 7 to 28 days, antibiotic prophylaxis - 24 or 48 hours (for cardiac surgery patients) after the end of the operation.
Statistical processing of the results was carried out using EXCEL 2007, STAT1ISTICA 6.1 programs (StatSoft, USA). Compliance of the distribution of features with the law of normal distribution was established using the Shapiro-Wilk test. If the data were normally distributed, the data were compared using the Student's t test; otherwise, using the Mann–Whitney test. Quantitative indicators, depending on the type of distribution, were presented as the mean value (M) and standard deviation (s) or as the median (Me) and interquartile range [LQ-UQ].
To compare quantitative data depending on the type of their distribution, parametric and nonparametric statistical methods were used. Differences were considered statistically significant at P <0.05 [17, 18].
Thus, at the present stage of development of domestic healthcare, when there is an increase in the number of patients with a high risk of infection with gram-positive microorganisms, it is necessary to pay attention to the increasing role of multidrug-resistant problematic pathogens (staphylococci and enterococci) of infectious complications and sepsis. In this situation, teicoplanin can be used as an antibacterial drug.
REFERENCES 1.Vincent JL, Bihari DJ, Suter PM, et al. // JAMA.- 1995.- Vol. 274.— P. 639—644. 2.Duckworth GL // Br. Med. J.—1993.—Vol. 307.— P. 1049—1052. 3.Klugman KP // Eur. J. Clin. Microb. Inf. Dis.— 1994.— Vol. 13.— P. 1—2. 4.National Nosocomial Infections Surveillance System participating hospitals. CDC. Nosocomial enterococci resistant to vancomycin.—United States, 1989—1993. 5. Zeckel ML // J. Chemother. - 1997. - Vol. 9.— P. 311—335. 6. Felmingham D. // Antibiotics and Chemotherapy / Ed. p. O. Grady, HP Lambert, RG Finch, D. Greenwood. - New York, 1997. - P. 363-368. 7. Kozlov S. N., Strachunsky L. S. Modern antimicrobial chemotherapy: A guide for doctors. - M., 2009. 8. Yakovlev S. V. // Antibiotics and chemotherapy. - 1999. No. 2. - P. 3 -8. 9. Spencer RC, Goering R. // Int. J. Antimicrob. Agents.—1995.Vol.5.—P. 169–177. 10. Rational antimicrobial pharmacotherapy: Hand. for medical practitioners / Ed. ed. V. P. Yakovleva, S. V. Yakovleva. - M., 2003. (Rational pharmacotherapy: A series of guidelines for practicing physicians. T. 2). 11.Parenti F., Schito G.C., Couvalin P. // J. Chemother-.- 2000.Vol. 12 (Suppl. S).—P. S—14. 12.Harding I., Sorgel F. // Ibid.— P. 15-20. 13.Naber CK, Erbel R, Baddour LM, Horstkotte D. // Int. J. Agents.—2007.—Vol. 29.— P. 262—265. 14. Wilson AP, Gaya H. // J. Antimicrob. Chemother.— 1996.Vol. 38.— P. S07—S21. 15.Murdoch DR, Corey GR, Hoen B., et al. //Arch. Int. Med.—2009.—Vol. 169.— P. 463—473. 16.Brogden RN, Peters DH // Drugs. - 1994. - Vol. 47.— P. 823—854. 17. Mamaev A. N. Fundamentals of medical statistics. - M., 2011. 18. Rebrova O. Yu. Statistical analysis of medical data. Using the STAT15TICA application package.—M, 2002.
Received 04/04/14.
Address for correspondence: Samson Alla Alekseevna.
4th City Clinical Hospital named after N. E. Savchenko. 220036, Minsk, st. R. Luxembourg, 110; sl. tel. (8-017) 208-95-74. Key words:
glycopeptides, gram-positive microorganisms, staphylococcal infection, teicoplanin, enterococcal infection
Author(s):
Samson A. A., Bulgak A. G., Toropilov D. M., Yanushko V. Ya.
Medical institution: 4th city clinical hospital named after N. E. Savchenko, Republican Scientific and Practical Center “Cardiology” of the Ministry of Health of the Republic of Belarus
Use of the drug Teicoplanin
IM, IV (bolus or drip). Initial dose for adults: 400 mg IV 1-2 times a day for the first 1-3 days, then 200-400 mg per day IV or IM. For burns and endocarditis, the maintenance dose is up to 12 mg/kg per day. For pseudomembranous colitis - 200 mg 2 times a day. To prevent infectious complications during orthopedic or maxillofacial operations during anesthesia, a single dose of 400 mg is administered intravenously. The initial dose for children aged 2 months to 16 years is 10 mg/kg IV every 12 hours 3 times, then 6–10 mg/kg 1 time per day IV or IM; at the age of up to 2 months - 16 mg/kg (in the form of a 30-minute IV infusion) on the first day, maintenance dose - 8 mg/kg 1 time per day IV. In patients with impaired renal function, dose adjustment begins on the 4th day to maintain serum concentrations at 10 mg/l. When creatinine clearance is 40–60 ml/min, the maintenance dose is either reduced by half or administered once every 2 days. For patients with creatinine clearance less than 40 ml/min or on hemodialysis, 1/3 of the dose is administered daily or once every 3 days.
TEICOPLANIN (Teicoplanin)
The drug TEICOPLANIN is administered parenterally (intravenously or intramuscularly). Intravenous (IV) administration can be done by either IV injection over 3-5 minutes, or IV infusion over 30 minutes. In newborns, the drug should be administered only as an intravenous infusion.
Dosage regimen for adults and adolescents 16-18 years of age with normal renal function
Treatment of infections caused by drug-sensitive gram-positive bacteria (endocarditis; septicemia; bone and joint infections; lower respiratory tract infections; skin and soft tissue infections; urinary tract infections)
For moderate to severe infections of the skin and soft tissues, urinary tract, and lower respiratory tract infections, the initial dose of teicoplanin is 400 mg once daily IV on the first day, followed by a maintenance dose of 200 mg once daily IV or intramuscularly (IM).
For the treatment of severe bone and joint infections, septicemia, endocarditis, the initial dose is 400 mg IV every 12 hours for the first three doses, followed by a maintenance dose of 400 mg IV or IM once daily. For severe infections, the minimum serum concentration should not be lower than 10 mg/l.
Maximum concentrations determined 1 hour after intravenous administration of 400 mg are usually in the range from 20 to 50 mg/l.
In some cases (in burn patients or in patients with endocarditis), the maintenance dose can be up to 12 mg/kg body weight per day. Standard doses of 200 mg and 400 mg correspond to doses of 3 mg/kg and 6 mg/kg body weight. In patients weighing more than 85 kg, it is recommended to adjust the dose of the drug based on body weight, adhering to the same therapeutic regimen: moderate-to-severe infections 3 mg/kg, severe infections 6 mg/kg.
Patients with peritonitis that developed as a complication of continuous ambulatory peritoneal dialysis
After a single loading dose of 400 mg intravenously, in the first week, 20 mg/L is injected into each reservoir with a peritoneal dialysis solution, in the second week, 20 mg/L is injected into every second reservoir with a peritoneal dialysis solution, in the third week, 20 mg/L into the peritoneal dialysis solution reservoir for overnight dialysis.
Antimicrobial prophylaxis during orthopedic surgery,
for
dental operations (for example, prevention of endocarditis in patients with artificial heart valves):
400 mg of teicoplanin (or 6 mg/kg for a patient weighing more than 85 kg) as a single intravenous injection during induction of anesthesia.
Pseudomembranous colitis caused by C. difficile :
200 mg teicoplanin orally twice daily.
Dosage regimen in children
Children over 2 months up to 16 years:
For most Gram-positive infections, the recommended initial dose is 10 mg/kg body weight IV at 12-hour intervals for the first three doses, followed by a maintenance dose of 6 mg/kg body weight administered IM or IV once daily.
For severe infections and neutropenia, the recommended initial dose is 10 mg/kg body weight IV at 12-hour intervals for the first three doses, followed by a maintenance dose of 10 mg/kg body weight administered IV once daily.
Children under 2 months, including newborns:
The recommended initial dose is 16 mg/kg body weight IV on the first day, followed by a maintenance dose of 8 mg/kg body weight IV once daily. IV administration should be carried out by IV infusion over 30 minutes.
Dosage regimen in elderly patients
With normal renal function, no dosage adjustment is required.
Dosage regimen in adults with renal failure
Until the 4th day of treatment with teicoplanin, no dosage adjustment is required. From the fourth day onwards, the administered dose should maintain the serum teicoplanin concentration at 10 mg/l.
For moderate renal failure (creatinine clearance 40-60 ml/min): the maintenance dose should be halved, either by administering the previous dose once every two days, or by administering half the dose once a day.
In severe renal failure (creatinine clearance less than 40 ml/min) and in patients on hemodialysis: the maintenance dose should be reduced by three times, either by administering the previous dose every third day, or by administering 1/3 of the previous dose once a day . Teicoplanin is not excreted during hemodialysis.
Duration of treatment
The therapeutic response in most patients with infections caused by pathogens sensitive to the antibiotic is observed within 48-72 hours after the start of drug administration. The total duration of treatment is determined individually and depends on the type and severity of the infection and the clinical response of the individual patient. For endocarditis and osteomyelitis, treatment for 3 weeks or more is recommended; in this case, the drug TEICOPLANIN should not be administered for more than 4 months.
Preparation of the solution
3.2 sterile water should be slowly introduced into the Teicoplanin vial, gently shaking the vial until the powder is completely dissolved, while avoiding the formation of foam. It is very important that the entire drug is dissolved, even the part that is located near the stopper.
When shaking the solution, foam forms, which makes it difficult to extract the required volume of solution. However, if teicoplanin is completely dissolved, the foam does not change the concentration of the remaining solution of 200 mg in 3.2 ml in a vial of TEICOPLANIN 200 mg and 400 mg in 3.2 ml in a vial of TEICOPLANIN 400 mg. If the solution turns out to be foamy, then you should leave it to stand for about 15 minutes to reduce the amount of foam.
You should slowly remove the teicoplanin solution from the bottle, trying to remove it completely by piercing the middle of the rubber stopper with a needle. The reproduced solution will contain 200 mg of teicoplanin in 3.2 ml in a vial of TEICOPLANIN 200 mg and 400 mg in 3.2 ml in a vial of TEICOPLANIN 400 mg.
It is important that the solution is prepared correctly and that the solution is carefully removed from the bottle; Improper preparation of the solution may lead to the administration of a smaller dose than required.
The prepared solution is isotonic and has a pH of 6.5-7.5.
The prepared solution can be administered directly by injection or further diluted with 0.9% sodium chloride solution, Ringer's solution, Hartmann's solution, 5% dextrose solution, peritoneal dialysis solution containing 1.36 % or 3.86% dextrose.
Side effects of the drug Teicoplanin
Nausea, vomiting, diarrhea, increased activity of liver transaminases and alkaline phosphatase, renal failure, increased serum creatinine levels, facial flushing, flushing, dizziness, headache, hearing loss, tinnitus, vestibular disorders, exfoliative dermatitis, toxic skin necrosis, syndrome Stevens-Johnson, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, eosinophilia, allergic reactions (rash, itching, urticaria, fever, angioedema, bronchospasm, anaphylactic shock); local manifestations: pain at the injection site, erythema, thrombophlebitis (with intravenous administration), abscess at the site of intramuscular injection.
