Imipenem+Cilastatin, 1 piece, 500 mg+500 mg, powder for solution for infusion

Pharmacological properties of the drug Tienam

Tienam is indicated for the treatment of mixed infections caused by strains of aerobic and anaerobic microorganisms sensitive to it. Most pathogens of mixed infections are representatives of fecal microflora, microflora of the vagina, skin or oral cavity. Bacteroides fragilis is an anaerobic pathogen, most often isolated from patients with mixed infections and, as a rule, resistant to aminoglycosides, cephalosporins and penicillins, but sensitive to Thienam. Tienam is effective in the treatment of many infections caused by aerobic and anaerobic gram-positive and gram-negative microorganisms resistant to cephalosporins, including cefazolin, cefoperazone, cephalothin, cefoxitin, cefotaxime, moxalactam, cefamandole, ceftazidime and ceftriaxone. Most infections caused by pathogens resistant to aminoglycosides (gentamicin, amikacin, tobramycin) and/or penicillins (ampicillin, carbenicillin, penicillin-G, ticarcillin, piperacillin, azlocillin, mezlocillin) are sensitive to treatment with the drug. Tienam is not indicated for the treatment of meningitis. Thienam is a broad-spectrum β-lactam antibiotic, consisting of two components: imipenem, the first representative of a new class of β-lactam antibiotics, the thienamycins, and cilastatin sodium, a specific enzyme inhibitor that blocks the metabolism of imipenem in the kidneys and significantly increases the concentration of unchanged imipenem in the urinary tract. . The weight ratio of imipenem and cilastatin sodium in Tienam is 1:1. The class of thienamycin antibiotics, to which imipenem belongs, is characterized by a wider spectrum of bactericidal action compared to any of the antibiotics already studied. Thienam is a powerful inhibitor of bacterial cell wall synthesis and has a bactericidal effect against a wide range of gram-positive and gram-negative pathogenic aerobic and anaerobic microorganisms. Like modern cephalosporin and penicillin drugs, Thienam has a broad spectrum of action against gram-negative microorganisms, but unlike others, it is the only drug that has a pronounced effect against gram-positive microorganisms, previously sensitive only to the action of earlier narrow-spectrum β-lactam antibiotics. Thienam's spectrum of action includes Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis and Bacteroides fragilis , a diverse group of problematic pathogens usually resistant to other antibiotics. Tienam is resistant to bacterial β-lactamase, which makes it effective against many microorganisms such as Pseudomonas aeruginosa Serratia spp., and Enterobacter ., which are naturally resistant to most β-lactam antibiotics. The antibacterial spectrum of action of Tienam is wider than any other antibiotic already studied, and includes almost all clinically significant pathogenic microorganisms. Microorganisms for which Tienam is usually effective in vitro include: - Gram-negative aerobic bacteria: Achromobacter ., Acinetobacter (formerly Mima-Herellea ), Aeromonas hydrophila , Alcaligenes spp., Bordetella bronchicanis, Bordetella bronchiseptica, Bordetella pertussis, Brucella melitensis , Campylobacter , Capnocytophaga spp ., Citrobacter , Citrobacter diversus, Citrobacter freundii, Eikenella corrodens . , Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (including β-lactamase producing strains), Haemophilus parainfluenzae, Hafnia alvei , Klebsiella spp. (Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella pneumoniae) , Moraxella spp., Morganella morganii (formerly Proteus morganii ), Neisseria gonorrhoeae (including penicillinase-producing strains), Neisseria meningitidis , Pasteurella spp., Pasteurella multocida, Plesiomonas shigelloide s , Proteus spp. ( Proteus mirabilis, Proteus vulgaris ), Providencia spp . ( Proteus alcalifaciens, Providencia rettgeri (formerly Proteus rettgeri ), Providencia stuartii ), Pseudomonas spp., including Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas pseudomallei, Pseudomonas putida, P seudomonas stutzeri, Xanthomonas maltophili a (formerly Pseudomonas maltophilia ) and some strains of Pseudomonas cepacia (generally insensitive to Tienam), Salmonella spp., Salmonella typhi, Serratia spp., Serratia proteamaculans (formerly Serratia liquefaciens ), Serratia marcescens , Shigella spp., Yersinia spp . (formerly Pasteurella ) , Yersinia enterocolitica, Yersinia pseudotuberculosis ; - gram-positive aerobic bacteria: Bacillus species, Enterococcus faecalis, Erysipelothrix rhusiopathiae, Listeria monocytogenes , Nocardia , Pediococcus species, Staphylococcus aureus (including penicillinase-forming strains), Staphylococcus epidermidis (including penicillinase-forming strains), Staphylococcus saprophyticus, Streptococcus agalact iae, Streptococcus group C, Streptococcus group G, Streptococcus pneumoniae, Streptococcus pyogenes, Viridans group streptococci (including α- and γ-hemolytic strains); Enterococcus faecium and some methicillin-resistant staphylococci are insensitive to Tienam; - gram-negative anaerobic bacteria: Bacteroides ( Bacteroides distasonis (formerly Bacteroides asaccharolyticus ), Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus ), Biophilia wadsworthia , Fusobacterium ( Fusobacterium necrophorum, Fusobacterium n ucleatum ), Porphyromonas asaccharolytica (formerly Bacteroides asacchrolyticus ), Prevotella bivia (formerly Bacteroides bivius ), Prevotella disiens (formerly Bacteroides disiens ), Prevotella intermedia (formerly Bacteroides vulgatus intermedius ), Prevotella melaninogenica (formerly Bacteroides melaninogenicus ), Veillonella spp .; - gram-positive anaerobic bacteria: Actinomyces , Bifidobacterium , Clostridium , Clostridium perfringens , Eubacterium Lactobacillus species, Mobiluncus species , Microaerophilic streptococcus , Peptococcus species , Peptostreptococcus , Propionibacterium (including P. acnes ); - others: Mycobacterium fortuitum, Mycobacterium smegmatis. in vitro studies indicate that imipenem has a synergistic effect with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa . In healthy volunteers, intravenous infusion of Thienam at a dose of 500 mg over 20 minutes was accompanied by peak plasma levels of imipenem ranging from 21 to 58 mcg/ml. The half-life of imipenem in blood plasma was 1 hour. About 70% of the administered antibiotic was detected unchanged in the urine within 10 hours; further excretion of the drug in the urine was not observed. When using the drug Tienam according to the schedule every 6 hours, no accumulation of imipenem in the blood plasma or urine was detected in patients with normal renal function. Co-administration of Tienam and probenecid resulted in minimal increases in plasma levels and half-life of imipenem. When used alone, imipenem is metabolized in the kidneys by dihydropeptidase-1. Individual urinary recovery ranges from 5–40%, with an average of 15–20% in several studies. The binding of imipenem to human serum proteins is about 20%. Cilastatin, a specific inhibitor of the enzyme dehydropeptidase-1, effectively inhibits the metabolism of imipenem, so the simultaneous use of imipenem and cilastatin allows one to achieve therapeutic antibacterial levels of imipenem in urine and blood plasma. Peak cilastatin levels following a 20-minute IV infusion of Tienam 500 mg ranged from 21 to 55 mcg/mL. The half-life of cilastatin from the blood plasma is about 1 hour. About 70–80% of the dose of cilastatin is excreted unchanged in the urine within 10 hours after administration of the drug Tienam. After this, cilastatin is not detected in the urine. About 10% was determined as a metabolite of N-acetyl, which has an inhibitory effect on dehydropeptidase, which is comparable to that of the parent drug cilastatin. The combined use of Tienam and probenecid led to a 2-fold increase in plasma levels and an increase in the half-life of cilastatin, but did not affect the recovery of cilastatin in the urine. The binding of cilastatin to human serum proteins is about 40%.

The place of carbapenems in the treatment of NP

Taking into account the timing of the development of NP, early NP is distinguished, occurring within the first five days from the moment of hospitalization, which is characterized by pathogens that are sensitive to traditionally used antibacterial drugs; late NP, developing no earlier than the fifth day of hospitalization, which is characterized by a high risk of the presence of multidrug-resistant bacteria and a less favorable prognosis [1]. To select initial antibiotic therapy, the presence of risk factors for multidrug-resistant pathogens is important: high levels of local resistance of pathogens (in a given health care facility or department), the development of NP after 5 days or more from the start of hospitalization, taking immunosuppressants and/or the presence of an immunosuppressive state in the patient, taking antibiotics for the last 90 days, inpatient treatment for more than 2 days in the last 90 days, being in a nursing home, infusion therapy at home, chronic dialysis in the last 30 days, having a family member with diseases caused by multidrug-resistant pathogens [2, 12]. ABT NP includes early and adequate empirical therapy in adequate doses of optimal duration and de-escalation based on culture results and response to therapy (4D rule: drug, dose, duration, de-escalation) [1, 2, 7, 10]. When choosing empirical broad-spectrum antibiotic therapy, it is necessary to take into account the patient’s risk factors for the presence of multidrug-resistant microflora and local data on resistance [8].

The etiological structure of early NP with or without risk factors for multidrug-resistant microflora is close to that in community-acquired pneumonia, therefore it is recommended to prescribe antipseudomonas without antipseudomonas and anti-MRSA activity: third generation antistreptococcal cephalosporins (cefotaxime, ceftriaxone), or fluoroquinolones (ofloxacin, moxifloxacin, levofloxacin ), or piperacillin/tazobactam, or a carbapenem without antipseudomonal activity - ertapenem.

The most common pathogens of late NP are Pseudomonas aeruginosa, Enterobacteriaceae (producing extended spectrum β-lactamases - ESBL+), Acinetobacter spp., mecitillin-resistant Staphylococcus aureus (MRSA). Proposed ABT regimens should have antipseudomonas and antistaphylococcal activity, and also act on strains of enterobacteria that produce ESBL+: cephalosporins with antipseudomonas activity (ceftazidime or cefepime), antipseudomonas carbapenems (meropenem, imipenem, doripenem) or antipseudomonal β-lactam + β-lactamase inhibitor (piperacillin/tazobactam). Pending culture results, a fluoroquinolone (ciprofloxacin or levofloxacin) or aminoglycoside may be added to therapy for additional activity against resistant gram-negative bacteria. If the presence of ESBL+ or AmpC-β-lactamase-producing drugs (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter spp. or Enterobacter spp.) is suspected, carbapenems should be the drugs of choice. If there is a risk of MRSA, vancomycin or linezolid should be added [1, 2, 5, 6, 7, 12]. The use of antipseudomonas carbapenems (meropenem, doripenem or imipenem) as initial therapy in combination with drugs active against MRSA (linezolid, vancomycin) is justified in severe cases of NP-IVL, in patients who are critically ill as a result of the development of multiple organ failure or septic shock.

Indications for use of the drug Tienam

Polymicrobial and mixed aerobic-anaerobic infections, primary therapy even before identifying the causative microorganism. Infections caused by microorganisms sensitive to the drug: – intra-abdominal infections; – lower respiratory tract infections; – gynecological infections; - urinary tract infections; – infections of bones and joints; – infections of the skin and soft tissues. Prophylaxis To prevent the occurrence of certain postoperative infections in patients undergoing surgery with or at risk of infection, or if these infections lead to particularly severe consequences.

Use of the drug Tienam

The total daily dose and method of administration of the drug Tienam are determined in terms of imipenem, taking into account the type and severity of the infection; the dose is distributed over several equal administrations, taking into account the degree of sensitivity of the pathogen(s), kidney function and body weight. Treatment: dosage regimen for adult patients with normal renal function Doses given in table. 1, is prescribed to patients with normal renal function (creatinine clearance 70 ml/min/1.73 m2) and a body weight of at least 70 kg. The dose should be reduced in patients with creatinine clearance ≤70 ml/min/1.73 m2 (Table 2) and/or with body weight ≤70 kg. In patients with significantly reduced body weight and/or moderate/severe renal impairment, dose reduction is particularly important. Most infections can be treated with a daily dose of 1–2 g (imipenem), divided into 3–4 doses. When treating moderate infections, you can also use a daily dose schedule of 1 g (imipenem) 2 times a day. In the case of infections caused by less sensitive organisms, the daily dose of Thienam can be increased to a maximum of 4 g (imipenem) per day or 50 mg/kg per day, whichever dose is lower. Each dose not exceeding 500 mg of Thienam (imipenem) for intravenous use should be administered over 20–30 minutes. Each dose above 500 mg (imipenem) should be administered over at least 40–60 minutes. If the patient experiences nausea during the infusion, the rate of drug administration should be slowed down. Table 1 Dosing frequency in adult patients with normal renal function and a body weight of 70 kg or more*

*In patients weighing ≤70 kg, the prescribed dose should be proportionally reduced; **if it is necessary to prescribe low doses of the drug, it is recommended to use the drug in lower doses.

Due to the high antimicrobial effectiveness of the drug Tienam, it is not recommended to exceed the daily dose of 50 mg/kg/day or 4 g per day, whichever dose is lower. However, patients with cystic fibrosis and unimpaired renal function are prescribed up to 80 mg/kg of the drug per day, divided into several administrations, provided that they do not exceed 4 g per day. Tienam is successfully used as monotherapy in patients with cancer and weakened immunity with confirmed or suspected infections, such as sepsis. Treatment: dosages for adults with impaired renal function To determine the dose for patients with impaired renal function:

1. Select (see Table 1) the total daily dose, taking into account the characteristics of the infection.
2. Select the required dose reduction regimen (Table 2), taking into account the dose selected in the Table. 1 daily dose and creatinine clearance indicators for this patient.

Table 2 Scheme for reducing doses of Tienam for intravenous administration in adult patients with impaired renal function and a body weight of 70 kg or more*

*In patients weighing ≤70 kg, the prescribed dose should be proportionally reduced; **if it is necessary to prescribe low doses of the drug, it is recommended to use the drug in lower doses.

When used at a dose of 500 mg in patients with a creatinine clearance of 6–20 ml/min/1.73 m2, the risk of seizures significantly increases. Thiene for IV administration should not be prescribed to patients with creatinine clearance ≤5 ml/min/1.73 m2, unless these patients undergo hemodialysis within the next 48 hours. Hemodialysis When treating patients whose creatinine clearance is ≤5 ml/min/1.73 m2 and who undergo dialysis, doses recommended for use in patients with a creatinine clearance of 6–20 ml/min/1.73 m2 are used. Both imipenem and cilastatin are eliminated during hemodialysis. The patient must be administered Tienam immediately after the hemodialysis session and then administered every 12 hours after its completion. Patients on hemodialysis, and especially those with central nervous system disorders, need careful monitoring; It is recommended to prescribe Tienam to such patients only if the expected effect exceeds the probable risk of seizures (see PECULIARITIES OF APPLICATION). Currently, there is insufficient data regarding the use of Tienam in patients on peritoneal dialysis, therefore it is not recommended to use it for treatment in this category of patients. Creatinine and blood urea nitrogen levels may not accurately reflect the status of kidney function in older adults. In such patients, it is recommended to determine creatinine clearance for appropriate dose selection. Prevention: doses for adults To prevent postoperative infections, adults should be administered intravenously 1000 mg of Tienam during induction of anesthesia and 1000 mg after 3 hours. In case of high-risk surgery (for example, during surgery on the colon or rectum), two additional doses should be administered doses of 500 mg 8 and 16 hours after induction of anesthesia. There are no sufficient data regarding the prophylactic use of Tienam IV in patients with creatinine clearance ≤70 ml/min/1.73 m2. Treatment: doses for children (from 3 months of age) For children, the following dosage regimen is recommended:

• in children weighing 40 kg, the same doses are used as for adults;
• in children weighing ≤40 kg, doses are used at the rate of 15 mg/kg at 6-hour intervals.

The total daily dose should not exceed 2 g. It is not recommended to use the drug in children under 3 months of age or with impaired renal function (serum creatinine 2 mg/dL) due to insufficient clinical data. Tienam is not recommended for the treatment of meningitis. If meningitis is suspected, appropriate antibiotics should be prescribed. Tienam can be used to treat sepsis in children in the absence of suspicion of meningitis. Preparation of solution for intravenous administration

Preparation of Tienam solution in 20 ml bottles The contents of the bottle should be suspended and brought to 100 ml with the appropriate solution for infusion. It is recommended to add about 10 ml of the appropriate solution for infusion (solvents used: isotonic sodium chloride solution; 5–10% aqueous dextrose solution; 5% dextrose solution and 0.9% NaCl solution; 5% dextrose solution and 0.45% NaCl solution; 5% dextrose solution and 0.225% NaCl solution; 5% dextrose solution and 0.15 KCl solution; mannitol 5 and 10% solution p) to the bottle. Shake well and add the resulting suspension to the container with solution for infusion. Warning : the suspension is not a ready-made solution for infusion. Repeat the procedure, adding again 10 ml of solution for infusion so that the entire contents of the bottle are transferred to the solution for infusion. The resulting mixture must be shaken. until it becomes transparent. Solutions are stored at room temperature (25 °C) for 4 hours or at a temperature not exceeding 4 °C for 24 hours.

Medical errors when using antibacterial drugs of the carbapenem group

Introduction

Carbapenems are a unique class of antibiotics with an “ultra-broad” spectrum of antimicrobial activity. In their effectiveness against infections of various localizations, carbapenems are often superior to antimicrobial drugs of other groups used both as monotherapy and in combinations, which allows the successful use of this subclass of antibiotics for life-threatening infections. However, in recent years, the attitude towards carbapenems as deep reserve antibiotics has been changing, since inadequate initial antimicrobial therapy, especially in severe clinical cases of the disease, is accompanied by a statistically significant increase in mortality [1]. According to reports provided by the DSM Group, in 2013, the maximum growth rates in terms of sales volumes in the segment of medical institutions in the subgroup J01 - antibacterial drugs for systemic use - belonged to the antibiotics meropenem and thiene [2]. It is important to note that the antibiotic meropenem is among the top 20 brands by value of hospital purchases in Russia during the last years of 2014-2015. [3], but this is most likely due to the high cost of the drug, and, to a lesser extent, to the frequency of its use in comparison with other classes of beta-lactam antibiotics.

Due to the fact that carbapenems are indicated for severe infections caused by multidrug-resistant and mixed microflora [4], the consequences of medical errors (MO) when using antibacterial drugs (ABP) of this group can be especially serious, since incorrect use of an antibiotic is fraught with ineffective treatment, which, in this case, threatens the patient with dangerous complications, including death. In addition, inappropriate use of antibiotics leads to an increase in drug resistance in microorganisms, which can have significant consequences for global health.

The Rules of Good Pharmacovigilance Practice, a guide developed by the regulatory authorities of the member states of the Eurasian Economic Union, provide the following definition: a medicinal product (MD) error is any unintentional error by a healthcare worker, patient or consumer in the prescription, dispensing, dosage or administration/ taking the drug [5].

Considering the clinical significance of antibiotics, and carbapenems in particular, it is extremely important to obtain objective information about all possible effects of antimicrobial pharmacotherapy. Only constant monitoring of drugs in circulation allows us to get an adequate idea of ​​their safety profile. One of the main pharmacovigilance methods in many countries, including the Russian Federation, is the method of spontaneous reporting (SS). The method is based on healthcare specialists informing the authorized federal body (in the Russian Federation - Roszdravnadzor) about detected adverse reactions (ARs) of drugs. SS are entered into a national computer database, a detailed analysis of which allows not only to obtain valuable information about the safety of drugs, including antibiotics, when used in widespread clinical practice, but also to identify cases of their erroneous use, identify priority problems in this area and develop measures aimed at reducing the risks of antibacterial therapy.

Goal of the work

To study the structure of medical errors made when using antibiotics of the carbapenem group, based on an analysis of the national database of spontaneous reports of adverse reactions.

Materials and methods

The object of study in this work was spontaneous reports of adverse reactions that arose during the use of antihypertensive drugs of the carbapenem group, registered in the database of the Pharmacovigilance subsystem of the AIS of Roszdravnadzor for the period from 01/01/2012 to 08/01/2014.

Primary messages were subject to analysis, taking into account important information contained in some repeated messages. Duplicates and invalid CCs were excluded from the study.

To identify cases of medical errors associated with the prescription of antibiotics, we used instructions for the medical use of drugs approved in the Russian Federation, available on the website of the state register of medicines at the email address: https://grls.rosminzdrav.ru/, as well as standards of medical care and clinical recommendations for individual nosologies that were encountered in our study.

The work used a classification of human age periods based on the periodization adopted by the World Health Organization (WHO) in 2012 [6]. The following groups were identified: from birth to 17 years - children's age, from 18 to 44 years - young age, 45-59 years - middle age, 60-74 years - elderly, 75-89 years - senile age, and after 90 - long-lived.

The analysis included ABPs of the carbapenem group, registered in the Russian Federation, with the following international nonproprietary names (INN): meropenem, imipenem/cilastatin, ertapenem. In Russia, a drug with the INN doripenem has also been registered, but the AIS of Roszdravnadzor during the specified period of time did not receive any reports of adverse reactions when using this drug.

results

In total, the study included 161 primary CV reports of ADRs that arose during the use of carbapenem-based antihypertensive drugs. Information from repeated SS was taken into account in 22 cases. During the analysis, facts of committing MO when using antibiotics of the carbapenem group were identified in 40 reports, i.e. in 24.8% of cases. Of these, senders independently indicated errors when using the drug in 2 CCs (5.0%). 31 SS contained information about the commission of one medical error, 5 SS - about two medical errors, and one SS - about three. Thus, the total number of detected errors was 50.

In 50.0% of SS the patient's gender was indicated as female (20 SS), in 42.5% (17 SS) it was male. In 7.5% of cases (3 SS), information on this section was missing.

Errors in the use of these drugs occurred in people of different ages (Table 1). Most often, MOs were detected in children (27.5%), as well as in adults under 60 years of age (young and middle age - 25% each).

Carbapenems are drugs for the treatment of severe infections that require hospitalization of the patient, therefore 97.5% of all ADRs were registered in hospitals. However, one report indicated that the INN drug meropenem was used in an outpatient setting.

In total, 76 SS were received for drugs with the INN meropenem during the time interval we selected; cases of incorrect use of this antibiotic were identified in 20 SS (26.3%). The total number of detected MOs was 24 (Fig. 1).

The study included 71 reports on the development of adverse reactions when using drugs with the INN imipenem/cilastatin. MOs were detected in 18 (25.4%) of them. The total number of MOs was 24.

For drugs with the INN ertapenem, 14 SS were registered in the database, 2 of them contained information about MO (14.3%).

All groups of MOs we identified when using carbapenems are presented in Table. 2.

The most common type of errors we identified when using carbapenems were various violations of the dosage regimen (42.0%). Data on a lower frequency of antibiotic administration were presented in 10 CCs (20.0%), while in three of these cases the ineffectiveness of the therapy was reported. According to the approved instructions, in patients without impaired renal function, meropenem should be administered every 8 hours. 5 SS contained information about the unreasonable prescription of this drug 2 times a day, 1 SS - about a single daily administration of this antibiotic in the treatment of nosocomial pneumonia. The average therapeutic dose of imipenem/cilastatin in most cases should be divided into 3-4 administrations. We identified 4 cases of use of imipenem/cilastatin 2 times a day for severe infections. In terms of its dosage regimen, ertapenem compares favorably with the other two representatives of the carbapenem group, since in patients over the age of 13 years, the frequency of use of this drug is 1 time per day. There were no errors associated with incorrect frequency of administration of drugs with the INN ertapenem in our study.

Exceeding the recommended dose occurred in 14.0% of SS with MO (7 SS), the use of an unreasonably low dose of drugs - in 6.0% (3 SS). One of the received SS indicated a short duration of antibacterial therapy and did not provide any reasons for early discontinuation of the antimicrobial drug. Another notice states that the patient received imipenem/cilastatin for the indication of urosepsis for 2.5 months, while the causative agent of the disease is not specified, and there is no data on the patient’s medical history (in particular, information on the immune status). It should be noted that, according to existing recommendations, the duration of treatment with intravenous antibiotics, even in the most severe cases, should not exceed 4-6 weeks [7-9].

7 SS (14.0%) contained information about prescribing ABP in the presence of contraindications to its use. In 3 cases, the contraindication was severe hypersensitivity (anaphylactic and severe skin reactions) to penicillin antibiotics in the past. Ignoring anamnestic data in two patients led to the development of serious allergic reactions, one of which required prolongation of the patient’s hospitalization, the other posed a threat to the patient’s life. Four cases involved the use of meropenem in children under 3 months of age. It should be noted that another report stated that meropenem was prescribed to a child at the age of 26 days for the indication of meningitis, but in additional information there are explanations that three times cultures of the cerebrospinal fluid revealed the growth of Klebsiellae pneumoniae, sensitive only to meropenem and amikacin. Considering the results of the microbiological study, the prescription of this antibiotic is certainly justified, and this case was not classified as a medical error.

7 SS (14.0%) account for cases of untimely discontinuation of drugs in the event of an adverse reaction and late change of antibiotic in the absence of signs of its effectiveness. In particular, one report described that a 20-year-old man continued to receive meropenem for 10 days, despite an increase in leukocytosis. This tactic led to the development of sepsis in the patient. In another case, it is indicated that a 37-year-old patient with a burdened history of allergies (allergy to penicillins, cephalosporins) was prescribed meropenem. According to the instructions for medical use of the suspected drug with the INN meropenem, only severe hypersensitivity reactions to other beta-lactam antibiotics are contraindications to its use, so the prescription was not considered erroneous under this point. However, when the patient developed a skin rash, treatment with this drug was continued and two days later the patient developed angioedema, which, according to the reporter, posed a threat to her life.

5 SS were identified that contained information that carbapenem class antibiotics were used off-label. Thus, drugs with the INN imipenem/cilastatin were prescribed for the following conditions: fever, “hearing loss due to tubootitis,” meningoencephalitis, as well as for anti-inflammatory purposes. In the 1st SS on the development of adverse reactions when using a BPA with the active substance ertapenem, “amputation of the uterus and appendages” is indicated as the reason for its use, without specifying the risk or the presence of an infectious process.

According to generally accepted recommendations, the initial assessment of the effectiveness of ABT is carried out 48–72 hours after the start of treatment [10, 11]. In the first case, the conclusion about the lack of effectiveness of the drug meropenem (in the SS the reporter indicated only one adverse event - the ineffectiveness of the drug) was made within a day from the start of taking this antibiotic.

Another report contains information about changing meropenem if it is ineffective in a patient with meningoencephalitis to imipenem/cilastatin. Imipenem/cilastatin causes seizures more often than other beta-lactam antibiotics [12], and therefore, unlike meropenem and doripenem, imipenem is not indicated for infections of the nervous system. The incidence of seizures, according to various clinical studies, is 1.4% with imipenem, 0.5% with meropenem and 0.2% with doripenem [13]. According to current clinical guidelines for antibiotic therapy, imipenem/cilastatin should not be used to treat meningitis. In addition, although in vitro studies of the antimicrobial activity of carbapenems clearly show differences between the drugs [14], no differences in clinical efficacy between imipenem and meropenem were found in the vast majority of studies [1]. It should also be noted that MRSA, Enterococcus faecium, Stenotrophomonas maltophilia and metallo-β-lactamase-producing gram-negative microorganisms are resistant to all carbapenems [15]. In this regard, in this case, in the absence of a response to meropenem therapy, ineffectiveness of imipenem/cilastatin can also be expected.

Discussion of the results obtained

The total number of notifications received for antibiotics of the carbapenem class in our work was small - only 161 SS; there were no notifications about the development of adverse reactions for the modern carbapenem - doripenem. This is partly due to the relatively rare use of drugs in this group compared to other representatives of beta-lactams. It should also be noted that adverse reactions with carbapenems are difficult to detect. As noted earlier, these antibiotics are used for serious infections, against the backdrop of a serious condition of patients, and therefore many of the symptoms that arise during treatment can be regarded by doctors as manifestations/complications of the underlying disease, and not a consequence of the use of the drug. Back in 1976, DWVere was the first to describe the ability of adverse drug reactions to appear under the guise of disease, pointing out that the clinical situation can sometimes be so complex that its drug-related components go unnoticed [16].

Our analysis of the Russian SS database on ADRs arising from the use of carbapenem group ABPs for the period from 01/01/2012 to 08/01/2014 showed that the drug was prescribed with MO in 24.8% of cases. According to our data, the average rate of errors when using carbapenems is comparable to that when using cephalosporins (25.2%), but lower than when using penicillin antibiotics, for which errors were identified in 37.1% of prescriptions [17].

We have not found any work on the study of MO when using carbapenem antibiotics either in Russian or foreign literature. However, there are articles that provide information obtained by analyzing the SS and reflecting the overall frequency of MO when using all medications. Thus, according to the Norwegian Health Council, in 2007, 27% of all reports of adverse drug reactions contained information about medical errors [18]. Similar figures were obtained in Russia. In order to clarify the role of medical errors in the occurrence of adverse reactions, V.K. Lepakhin, E.A. Ovchinnikova et al. An analysis of spontaneous reports received by the Federal Center for the Study of Side Effects of Drugs for the period from 1997 to 2000 was carried out. It was found that drug complications due to medical errors accounted for 27.4%. The authors of the article also mention that most often the cause of adverse side effects as a result of physician errors were drugs from the group of antimicrobial drugs [19]. Thus, our data are consistent with the results obtained by other authors.

The leading place in terms of frequency of occurrence when using carbapenems is occupied by errors associated with a lower frequency of administration of the antimicrobial drug (20.0% of all MOs). All beta-lactams, including carbapenems, have time-dependent bactericidal activity, which is characterized by such an indicator as the time of exposure to the antibiotic necessary for the death of the microorganism. The main parameter determining the clinical and microbiological effectiveness of these drugs is the time during which the concentration of the antibiotic in the blood exceeds its minimum inhibitory concentration for a particular pathogen [20]. Therefore, to ensure the effectiveness of carbapenems, it is extremely important to observe the frequency of their administration. Violations of the dosage regimen are fraught with serious consequences, such as ineffective treatment and the formation of resistant strains of microorganisms.

In the course of our work, it was revealed that senders independently indicated errors in the use of the drug in only 2 SS out of 40 (5.0%), while the corresponding term in the NR description section was selected only in one of these messages, in the second notice information about the fact of the MO was contained in the CC section “additional information”. The data obtained from a detailed analysis of the SS suggests that most errors in the use of drugs remain unrecognized. Senders should be aware that when filling out a notification card in the “description of an adverse reaction” section, in addition to the term characterizing the identified ADR, it is necessary to indicate the term encoding the fact of a medical error. The electronic Pharmacovigilance database has a built-in dictionary that contains a range of such terms, and the sender can select the one that best suits the description of a particular situation. Practitioners should also be reminded of one of the basic international principles of the CC method: notification of an ADR cannot be the basis for punishing or prosecuting a doctor (in particular, it cannot be used as evidence in the event of legal claims in connection with medical errors). Errors in the use of drugs, like other problems associated with drug therapy, need to be identified and analyzed, since only in this way can methods for their prevention be developed.

Conclusion

Based on the analysis of the national database of spontaneous reports of ADRs, it was revealed that the share of notifications with MR when using ABPs of the carbapenem group is 24.8%. In 15.0% of these cases, 2 or more errors were made simultaneously while treating the patient.

The results obtained in the study indicate a low level (5.0%) of recognition of medicinal MOs by CC senders.

The proportions of SS with MO when using meropenem and imipenem/cilastatin are approximately the same and amount to 26.3% and 25.4% of cases, respectively. The smallest proportion of SS with MO was detected for drugs with the INN ertapenem - 14.3%.

The most common types of medical conditions (44.0%) when using carbapenems are various violations of the dose regimen. In most cases (20.0% of all identified MOs), ABP was administered in a lower frequency than required by the instructions for its medical use.

The method of analyzing spontaneous messages is a fairly effective way to identify errors in the use of medications. It is very important to send information about all cases of adverse reactions resulting from the incorrect use of drugs to the pharmacovigilance authorities for its recording, further analysis and development of measures to prevent such episodes. This will improve the effectiveness and safety of drug therapy and thereby improve the quality of medical care.

Side effects of the drug Thienam

Tienam is generally well tolerated. Adverse reactions rarely require discontinuation of treatment and are usually mild and transient; Severe side effects are rare. Among the known side effects, local ones are most often observed. Local manifestations (the same for different routes of administration): erythema, pain and infiltrates at the sites of drug administration, thrombophlebitis. Allergic reactions/skin manifestations : anaphylactic reactions, rash, pruritus, urticaria, erythema multiforme, Stevenson-Johnson syndrome, angioedema, toxic epidermal necrolysis (rare), exfoliative dermatitis (rare), candidiasis, fever (including drug-induced fever). Reactions from the gastrointestinal tract : nausea, vomiting, diarrhea, pigmentation of teeth and/or tongue. As with almost all other broad-spectrum antibiotics, pseudomembranous colitis may occasionally occur. Reactions from the hematopoietic system: eosinophilia, leukopenia, neutropenia, including agranulocytosis, thrombocytopenia, thrombocytosis, decreased hemoglobin levels, pancytopenia and increased prothrombin time. Some patients may have a positive direct Coombs test. Reactions from liver function: increased levels of transaminases, bilirubin and/or alkaline phosphatase; liver failure (rare), hepatitis (rare) and fulminant hepatitis (very rare). Reactions from renal function: oliguria/anuria, polyuria, acute renal failure (rare). It is difficult to assess whether Thienam affects renal function, since, as a rule, other factors predisposing to impaired renal function and the development of azotemia are simultaneously present. Increases in serum creatinine and blood urea nitrogen levels were detected. A change in the color of the urine has been noted, which does not pose any threat and should not be confused with hematuria. Reactions from the nervous system: when using the drug Tienam, like other β-lactam antibiotics, side effects such as myoclonus, mental disorders (including hallucinations), confusion and convulsions, paresthesia, and encephalopathy develop. Reactions from the senses: hearing loss, change in taste. Patients with granulocytopenia Nausea and/or vomiting caused by the use of Tienam occurs more often in patients with granulocytopenia than without it.

Special instructions for the use of Tienam

Some clinical and laboratory data are known that indicate partial cross-allergenicity of the drug Tienam and other β-lactam antibiotics, penicillins and cephalosporins. Severe reactions (including anaphylaxis) have been reported with most β-lactam antibiotics. Before starting drug therapy, the patient's medical history should be carefully examined for the presence of a hypersensitivity reaction to β-lactam antibiotics. If an allergic reaction develops during use of the drug, the drug must be discontinued and appropriate measures taken. The development of pseudomembranous colitis has been reported as a complication with the use of almost all antibiotics; its forms can range from mild to life-threatening. In this regard, antibiotics should be prescribed with caution to patients with a history of gastrointestinal diseases, especially colitis. It is important to remember the possibility of developing pseudomembranous colitis if a patient develops diarrhea during antibiotic treatment. Although available research evidence suggests that a toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis, other possible etiological factors should be kept in mind. CNS . As with therapy with other β-lactam antibiotics, CNS side effects such as myoclonus, confusion or convulsions have been described with Tienam, especially in cases where recommended doses have been exceeded depending on renal function and body weight. Typically, such disorders were noted in patients with damage to the central nervous system (brain injury or history of seizures) and/or in patients with impaired renal function, in whom accumulation of the drug in the body is possible. Therefore, in such patients it is necessary to carefully follow the recommended doses and dosage regimen. Therapy with anticonvulsants should be considered in patients with a history of seizures. If focal tremor, myoclonus or seizures occur during treatment with the drug, patients should undergo a neurological examination with the prescription of anticonvulsant therapy, if such treatment has not been prescribed before. If symptoms of central nervous system disorders persist, the dose of Tienam should be reduced or the drug should be discontinued. Thienam is not indicated for the treatment of patients with creatinine clearance ≤20 ml/min/1.73 m2, unless hemodialysis is required after 48 hours. In patients receiving hemodialysis, Tienam is recommended only in cases where the positive results of treatment outweigh the potential risk of developing seizures. During pregnancy and breastfeeding. Use during pregnancy has not been sufficiently studied, so the drug can be prescribed only if the expected benefit to the mother outweighs the possible risk to the fetus. Imipenem passes into breast milk. If it is necessary to use the drug in the mother, breastfeeding should be stopped. Children. Due to insufficient clinical data, it is not recommended to use Thienam in children under 3 months of age and in children with impaired renal function (serum creatinine 2 mg/dL). The ability to influence reaction speed when driving vehicles and working with other mechanisms. Given the risk of side effects such as myoclonus, hallucinations, confusion and convulsions, you should avoid driving and operating other machinery when using the drug.

Pharmacoeconomic assessment

Studies evaluating the pharmacoeconomic efficacy of various carbapenems were based on the results of the randomized clinical trials described above [45, 46].

In a study by S. Merchant et al., 2008 [50], the costs of treatment of NP-IVL (from a hospital point of view) were studied when using doripenem and imipenem. The duration of hospital treatment, stay in the ICU and mechanical ventilation were compared. The median length of hospital stay was shorter in the doripenem group (22 days) than in the imipenem group (27 days; p = 0.010). The median duration of mechanical ventilation was significantly lower for doripenem (7 vs. 10 days; p = 0.034). The median ICU stay did not differ between groups (12 vs. 13 days; Table 2). Clinical cure and mortality rates did not differ between groups. Similar data were obtained in a study by LJ McGarry (2010) [52].

T. Kongnakorn et al., 2010 [51], also compared the economic aspects of the use of doripenem and imipenem in the treatment of NP. Based on clinical studies, a pharmacoeconomic model was developed that included 10 thousand patients. The response to therapy, mortality, duration of hospital treatment and ICU stay, duration of mechanical ventilation, and the incidence of P. aeruginosa resistance were assessed. In the doripenem group, costs were reduced by an average of $7,000 per patient compared with imipenem—a 95% reduction in inpatient length of stay. In addition, the incidence of P. aeruginosa resistance to doripenem was 52% lower. These results indicate that the use of doripenem has pharmacoeconomic advantages over imipenem in the treatment of NP and NP-IVL.

The Russian pharmacoeconomic study (Yu.B. Belousov et al., 2008) compared doripenem with imipenem and meropenem in the treatment of NP-IVL [53]. Pharmacoeconomic analysis was carried out using the cost minimization method, based on data from foreign randomized clinical trials.

The following pharmacoeconomic advantages of doripenem compared to meropenem have been identified: depending on the prices of drugs in the regions, the total costs of treatment in the doripenem group are 1.2–1.4 times lower than the costs of treating patients in the meropenem group (Table 3 ), which translates into savings from 1.7 to 3.5 million rubles. per 100 patients treated, regardless of regional differences in the cost of meropenem. Savings on treating patients with doripenem are due to the difference in costs for the following expense items: the use of doripenem can reduce the cost of purchasing basic antibacterial drugs by 1.4–1.9 times, which translates into savings from 1.3 to 3.1 million rubles. per 100 patients treated; the use of doripenem makes it possible to reduce the cost of hospitalization of patients by 9.2% by reducing the duration of hospitalization, which amounts to 481,841 rubles. per 100 patients.

Pharmacoeconomic advantages of doripenem compared to imipenem/cilastatin (Table 3): when conducting an analysis using hospital purchase prices in some regions, as well as the average distributor price for imipenem/cilastatin, it was shown that the cost of treatment of NP-IV with doripenem is slightly higher than the cost of treatment with imipenem/ cilastatin. However, the data obtained largely depend on the cost of imipenem. In particular, in those regions where the cost of imipenem was 800 rubles. per package, the use of doripenem is less expensive due to the lower cost of concomitant antibiotic therapy and hospitalization, on the one hand, and the almost comparable cost of the main ABT, on the other. The possible additional cost of treatment with doripenem compared to imipenem/cilastatin is approximately 4,300 rubles. per patient is justified due to the high clinical effectiveness of doripenem and the low degree of development of treatment resistance.

The results of the study show that, compared with meropenem, the use of doripenem in the treatment of NP-IVP is pharmacoeconomically effective due to the lower cost of basic antibiotic therapy and hospitalization costs. This effect is consistent regardless of regional differences in the cost of meropenem packaging. The use of doripenem compared to imipenem/cilastatin is clinically and pharmacoeconomically justified, regardless of regional differences in the cost of imipenem packaging. In the case of a lower cost per package of imipenem, the additional cost of treatment with doripenem is minimal and is justified by the low risk of developing resistance to treatment with doripenem; In the case of a higher cost of packaging for imipenem, its use compared to doripenem leads to additional costs for concomitant ABT and hospitalization of patients.

Interactions of the drug Tienam

In patients receiving ganciclovir and Tienam simultaneously for intravenous infusion, generalized seizures were detected. These drugs should not be coadministered unless the expected benefit outweighs the potential risk. During post-marketing studies, decreased plasma levels of valproic acid have been reported when administered concomitantly with carbapenems, and in some cases, sudden onset seizures have been reported. When imepenem is used concomitantly with valproic acid, it is necessary to carefully monitor the level of valproic acid in the blood plasma.