I think you all remember the arrival of this group of drugs in clinical practice. It was like the era of antibiotics that had begun again, when seemingly hopeless patients were able to get back on their feet ... albeit with colossal, as it seemed to us then, financial costs(how naive we were, now for a tetracycline drug, we pay an amount greater than the cost of a day of carbapenem treatment for a patient).
Let's remember the place of each of the drugs in this group in our clinical practice.
V this moment In Russia, four drugs of the carbapenem group are registered, which are divided into antipseudomonal(due to some activity against Pseudomonas aeruginosa):
Imipenem
Meropenem
Doripenem
AND non-pyocyanic:
Ertapenem
On my own, I would like to note that all this “pseudomonism” and its absence are nothing more than a marketing ploy, since you must always remember that on your own, without the support of the antipseudomonal drugs that we talked about earlier, not a single carbapenem with P.aeruginosa won't do it.
At this point in time, carbapenems remain drugs with the widest possible spectrum of activity, while maintaining maximum safety of use, like all beta-lactams, since they have a common class effect and act on the cell wall of microorganisms, disrupting its formation (and how you remember, we are not Pinocchio, so that we have this very wall). In addition, no cases of crossover have been described. allergic reactions with a group of penicillins or cephalosporins. At the same time, carbapenems have maximum resistance to hydrolysis by extended-spectrum beta-lactamases (ESBLs), although at the moment there is a growing danger of the spread of carbapenemases in general and metal-beta-lactamases in particular, which destroy this group of drugs.
The basis of the spectrum of action of carbapenems is their pronounced gram-negative activity, since they are able to penetrate the wall of gram-negative bacteria faster than any beta-lactams. They are active against the family Enterobacteriaceae (Klebsiellaspp., Enterobacterspp., E.coli etc.), including ESBL-producing strains.
Also, carbapenems are active against gram-positive flora, namely pneumococci, gonococci, meningococci and staphylococci (excluding MRSA)
In addition, carbapenems are highly active against anaerobes, except for C.difficile.
Given the spectrum of ultra-wide action, a false illusion may be created that this group of drugs can be used as drugs a wide range actions, that is, in any more or less difficult situation, which, by the way, happened and is happening in some hospitals before today. Such an approach would be a huge mistake, since carbapenems can be seen as a tornado that destroys everything in its path. They will knock out not only pathogenic, but also saprophytic flora, and according to the principle “a holy place is never empty” after an effectively treated gram-negative infection, a gram-positive superinfection (most often caused by MRSA) will take its place, which is important not to overlook, to understand where it came from and start as much as possible rapid therapy with drugs with gram-positive activity.
I would also like to express my personal opinion about de-escalation therapy. I have nothing against starting therapy with carbapenems, a patient in serious condition to which they are shown, but I am against the replacement antibiotic therapy after receiving the results of microbiological examination, if cabrapenem therapy has given its result. Let's remember after how many days we receive data from a microbiological study - at the earliest after five, and in most cases after a week, if we do not have equipped software modern principles laboratories. When do we conduct clinical monitoring of the effectiveness of antibiotic therapy? In the case of carbapenems, after 48 hours. That is, after two days we must decide whether the therapy is effective or we overlooked something, or the patient's condition has changed due to the course of the main or exacerbation concomitant disease. In general, by the time data is received from the laboratory, one way or another, the microbe-causative agent will have already been destroyed by “carpet bombing” of carbapenem, or carbapenem in combination with an antistaphylococcal or antipseudomonal drug and no effective transition to another, cheaper antibacterial speech drug it can not be. If we have already begun to treat with carbapenems and they have shown their effectiveness, then it is necessary to end therapy with them too and not rush about with the choice.
A few words about each representative.
This drug is remarkable in that it has a long period half-life, which allows it to be driven once a day, which is very important. Since carbapenems, like all beta-lactam antibacterial drugs, are time-dependent drugs, which are extremely important to be administered strictly by the hour, otherwise the bactericidal concentration drops below the minimum and selection of resistant strains begins. In addition, it is simply convenient, unlike other carbapenems, which require 4 single, and prolonged intravenous administration. If the department is equipped with infusion pumps, the problem is not so acute, but when they are not there, and then four times the introduction becomes a problem, and the person is arranged in such a way that problems in his life are minimized (as well as costs) and thus situations are not rare when they try to switch to 3 or even 2 single injections. In case of severe infectious process such manipulations are not allowed. And this is where ertapenem is convenient, which is administered 1 g per day at a time. You can object to me and point out that this drug does not have antipseudomonal activity. But colleagues, the antipseudomonal activity of meropenem, imipenem and doripenem is such that it can (and should) be neglected, and if you suspect the presence of P.aeruginosa, you simply must additionally use amikacin or ciprofloxacin, as the most powerful antipseudomonal drugs, the main thing is to choose current dosage(the first we count on a kilogram of body weight, the second - based on the pathogen's IPC)
What testimony exist for the use of ertapenem:
Severe intra-abdominal infections
Severe community-acquired pneumonia
Severe urinary tract infections
Severe skin and soft tissue infections. Including diabetic foot without evidence of osteomyelitis
Acute infections in the pelvic area
Intra-abdominal infections moderate(cholicestitis, cholangitis, diverticulitis, splenic abscess and liver abscess) that do not require drainage or surgery.
2. Imipenem/cilastatin
It was with him that the solemn procession of carbapenems in Russia began. But how much marketing speculation was around him in the future, one of which is “the drug causes convulsions.” Imipenem increases convulsive readiness only in certain cases, which must be considered:
Infections of the central nervous system
Doses greater than 2 g per day
Age over 60 - 65 years
History of seizures or CNS lesions - stroke, TBI, epilepsy
And when do we we use:
Bacterial endocarditis
Septicemia
Cody and soft tissue infections (excluding MRSA)
Infections lower divisions respiratory tract including nosocomial pneumonia
· Gynecological infections
Intra-abdominal infections
Infections caused by polymicrobial flora
Complicated and uncomplicated infections urinary tract(pyelonephritis)
Can be used for:
§ Gas gangrene
§ Diabetic foot
§ Infections of bones and joints.
Dosing regimen:
Imipenem is used in a regimen of 250-500 mg 4 times a day intravenously by drip, preferably slowly for urinary tract infections
Infections of moderate severity - 500 mg intravenously drip slowly every 6 to 8 hours
· In severe and infections caused by Pseudomonas aeruginosa: 1 g IV drip every 6 to 8 hours.
When dosing, the condition of the kidneys should be taken into account and dose adjustment should be carried out in case of renal failure.
3. Meropenem
Unlike imipenem, it can be used for CNS infections without restrictions.
Indications to application.
LSR-002913/10-070410Tradename drug: Meropenem.
International non-proprietary name:
meropenem.Dosage form:
powder for solution for intravenous administration.Ingredients per bottle:
active substance- meropenem trihydrate - 1.140 g, in terms of meropenem - 1.0 g;
excipient: sodium carbonate.
Pharmacotherapeutic group:
antibiotic - carbapenem.ATX code: .
pharmachologic effect
Pharmacodynamics
Antibiotic from the group of carbapenems, intended for parenteral use. It has a bactericidal effect by inhibiting the synthesis of the bacterial cell wall. The bactericidal action of meropenem against a wide range of aerobic and anaerobic bacteria explained high ability meropenem to penetrate the bacterial cell wall, high level stability to most beta-lactamases and significant affinity for penicillin-binding proteins.
Interacts with receptors - specific penicillin-binding proteins on the surface of the cytoplasmic membrane, inhibits the synthesis of the peptidoglycan layer of the cell wall (due to structural similarity), inhibits transpeptidase, promotes the release of autolytic enzymes of the cell wall, which ultimately causes its damage and death of bacteria.
Bactericidal and bacteriostatic concentrations practically do not differ.
Activity spectrum
Gram-positive aerobes:
Enterococcus faecalis including vancomycin-resistant strains), Staphylococcus aureus (penicillin-area non-producing and penicillin-azoproducing [methicillin-susceptible]); Streptococcus agalactiae, Streptococcus pneumoniae (only penicillin-sensitive); Streptococcus pyogenes, Streptococcus spp. viridans groups.
Gram-negative aerobes:
Escherichia coli, Haemophilus influenzae (penicillinase-non-producing and penicillinase-producing), Klebsiella pneumoniae, Neisseria meningitidis, Pseudomonas aeruginosa, Proteus mirabilis.
anaerobic bacteria:
Bacteroides fragilis, Bacteroides thetaiotaomicron, Peptostreptococcus spp.
Meropenem is effective in vitro against the following organisms, but has not been clinically proven to be effective against these pathogens: Gram-positive aerobes:
Staphylococcus epidermidis (penicillin-azone-non-producing and penicillin-azoproducing [methicillin-susceptible]).
Gram-negative aerobes:
Acinetobacter spp., Aeromonas hydrophila, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Enterobacter cloacae, Haemophilus influenzae (ampicillin-resistant, penicillinase-non-producing strains), Hafnia alvei, Klebsiella oxytoca, Moraxella catarrhalis (penicillinase-non-producing and penicillinase-producing), Morganella morganii, Pasteurella multocida, Proteus vulgaris, Salmonella spp., Serratia marcescens, Shigella spp., Yersinia enterocolitica.
anaerobic bacteria:
Bacteroides distasonis, Bacteroides ovatus, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides vulgatus, Clostridium difficile, Clostridium perfringens, Eubacterium lentum, Fusobacterium spp., Prevotella bivia, Prevotella intermedia, Prevotella melaninogenica, Porphyromonas asaccharolytica, Propionibacterium acnes.
Pharmacokinetics
At intravenous administration 250 mg for 30 minutes, the maximum concentration (C max) is 11 μg / ml, for a dose of 500 mg - 23 μg / ml, for a dose of 1 g - 49 μg / ml. When the dose is increased from 250 mg to 2 g, the clearance of meropenem decreases from 287 to 205 ml/min.
With intravenous bolus administration over 5 minutes of 500 mg of meropenem, Cmax is 52 μg / ml, 1 g - 112 μg / ml. Communication with blood plasma proteins - 2%. It penetrates well into most tissues and body fluids, incl. v cerebrospinal fluid patients with bacterial meningitis, reaching concentrations exceeding those required to suppress most bacteria (bactericidal concentrations are created 0.5-1.5 hours after the start of the infusion). Penetrates in small amounts breast milk.
It undergoes insignificant metabolism in the liver with the formation of a single microbiologically inactive metabolite.
The half-life is 1 hour, in children under 2 years old - 1.5 - 2.3 hours. The pharmacokinetics of meropenem in children and adults is similar; in the dose range of 10-40 mg/kg observed linear dependence pharmacokinetic parameters.
Does not accumulate.
It is excreted by the kidneys - 70% unchanged within 12 hours. The concentration of meropenem in the urine, exceeding 10 μg / ml, is maintained for 5 hours after the administration of 500 mg.
In patients with kidney failure meropenem clearance correlates with creatinine clearance. In such patients, dose adjustment is necessary.
In elderly patients, a decrease in meropenem clearance correlates with age decline creatinine clearance. The half-life is 1.5 hours. Meropenem is excreted by hemodialysis.
Infectious-inflammatory diseases (monotherapy or in combination with other antimicrobial medicines) caused by pathogens susceptible to meropenem:
- infections of the lower respiratory tract (including pneumonia, including hospital ones);
- infections abdominal cavity(complicated appendicitis, peritonitis, pelvioperitonitis);
- infections urinary system(pyelonephritis, pyelitis);
- infections of the skin and soft tissues (including erysipelas, impetigo, secondarily infected dermatoses);
- infections of the pelvic organs (including endometritis);
- bacterial meningitis;
- septicemia;
- empiric treatment (as monotherapy or in combination with antiviral or antifungal drugs) for suspected infection in adult patients with febrile neutropenia.
Contraindications
History of hypersensitivity to meropenem or other beta-lactam antibiotics, childhood up to 3 months
Carefully
Co-administration with potentially nephrotoxic drugs. Persons with complaints from gastrointestinal tract(including with colitis).
Use during pregnancy and lactation
Meropenem should not be used during pregnancy unless the potential benefit justifies possible risk for the fetus.
Meropenem should not be used during lactation unless the potential benefit justifies the potential risk to the baby. If necessary, the use of the drug during lactation should consider stopping breastfeeding.
Dosage and administration
Intravenous bolus over at least 5 minutes or intravenous infusion over 15-30 minutes, using appropriate infusion solutions to dilute. The dose and duration of therapy should be adjusted according to the type and severity of the infection and the patient's condition.
Adults: 500 mg every 8 hours for pneumonia, urinary tract infections, infectious and inflammatory diseases of the pelvic organs, skin and soft tissue infections.
1 g 3 times a day for nosocomial pneumonia, peritonitis, septicemia, suspected bacterial infection in patients with symptoms of febrile neutropenia. In the treatment of meningitis, the recommended dose is 2 g every 8 hours.
With chronic renal failure the dose is adjusted depending on the creatinine clearance:
In patients with liver failure no need for dose adjustment.
In elderly patients with normal renal function or creatinine clearance of more than 50 ml / min dose adjustment is not required.
Children aged 3 months to 12 years the recommended dose for intravenous administration is 10-20 mg/kg every 8 hours, depending on the type and severity of infection, sensitivity pathogen and the patient's condition.
Adult doses should be used in children under 12 years of age weighing more than 50 kg.
For meningitis, the recommended dose is 40 mg/kg every 8 hours.
There is no experience of use in children with impaired renal function.
Preparation of solutions
Meropenem for intravenous bolus injection should be diluted with sterile water for injection (20 ml per 1 g of meropenem), while the concentration of the solution is about 50 mg/ml. The resulting solution is clear liquid(colorless or light yellow).
Meropenem for intravenous infusion may be diluted with a compatible infusion solution (50 to 200 ml).
Meropenem is compatible with the following infusion solutions:
- 0.9% sodium chloride solution
- 5% or 10% dextrose solution.
Side effect
From the side digestive system:
pain in the epigastric region, nausea, vomiting, diarrhea, constipation, anorexia, jaundice, cholestatic hepatitis, hyperbilirubinemia, increased activity of "liver" transaminases, alkaline phosphatase, lactate dehydrogenase; rarely - candidiasis of the oral mucosa, pseudomembranous colitis.
From the side of cardio-vascular system:
development or aggravation of heart failure, cardiac arrest, tachycardia or bradycardia, decrease or increase blood pressure, syncope, myocardial infarction, branch thromboembolism pulmonary artery.
From the urinary system: dysuria, edema, impaired renal function (hypercreatininemia, increased plasma urea concentration), hematuria.
Allergic reactions: itchy skin, skin rash, urticaria, multiforme exudative erythema(Stevens-Johnson syndrome), angioedema, anaphylactic shock.
From the nervous system: headache, dizziness, paresthesia, insomnia, drowsiness, irritability, agitation, anxiety, depression, impaired consciousness, hallucinations, epileptiform seizures, convulsions.
Laboratory indicators: eosinophilia, neutropenia, leukopenia, rarely - agranulocytosis, hypokalemia, leukocytosis, reversible thrombocytopenia, decreased partial thromboplastin time, anemia.
Local reactions: inflammation, phlebitis, thrombophlebitis, soreness at the injection site.
Others: positive direct or indirect Coombs test, hypervolemia, shortness of breath, vaginal candidiasis.
Overdose
Possible overdose during treatment, especially in patients with impaired renal function.
Treatment: carry out symptomatic therapy. Normally, the drug is rapidly eliminated through the kidneys. In patients with impaired renal function, hemodialysis effectively removes meropenem and its metabolite.
Interaction with other drugs
Drugs that block tubular secretion slow down excretion and increase plasma concentrations of meropenem.
May reduce plasma concentrations of valproic acid.
special instructions
Treatment of patients with liver diseases should be carried out under careful monitoring of the activity of "liver" transaminases and the concentration of bilirubin. In the course of treatment, the development of resistance of pathogens is possible, in connection with which long-term treatment carried out under constant control of distribution resistant strains.
In persons with diseases of the gastrointestinal tract, especially with colitis, it is necessary to consider the possibility of developing pseudomembranous colitis (a toxin produced by Clostridium difficile is one of the main causes of antibiotic-associated colitis), the first symptom of which may be the development of diarrhea during treatment.
When meropenem is used as monotherapy in critically ill patients with known or suspected Pseudomonas aeruginosa lower respiratory tract infection, regular meropenem susceptibility testing is recommended.
Experience with the drug in children with neutropenia, with primary or secondary immunodeficiency no.
Influence on the ability to drive a car and mechanisms
During the period of treatment, until the individual reaction to meropenem is clarified, patients should refrain from driving vehicles and other activities that require a high concentration of attention and speed of psychomotor reactions.
Release form
Powder for solution for intravenous administration 1.0 g. 1.0 g each active substance in bottles with a capacity of 20 ml of transparent colorless glass, sealed with rubber stoppers and crimped with aluminum caps with a plastic seal. 1 or 10 bottles, together with instructions for use, are placed in a cardboard box.
Storage conditions
List B. In a dry, dark place at a temperature not exceeding 25 ° C.
Keep out of the reach of children.
Best before date
2 years.
Do not use after the expiry date stated on the package.
Terms of dispensing from pharmacies
On prescription.
Producer/Packer
Gulfa Laboratories Ltd, India 610, Shah & Nahar, Dr. E. Moses Road Worley, Mumbai-400018, India
Packer/QC Releaser
or
CJSC Skopinsky Pharmaceutical Plant 391800, Russia, Ryazan region, Skopinsky district, s. Uspenskoe
Marketing Authorization Holder/Complaint Receiving Organization
CJSC MAKIZ-PHARMA, Russia 109029, Moscow, Avtomobilniy proezd, 6
Carbapenems are -lactam antibiotics that have the same principal mechanism of action as penicillin. However, carbapenems have a number of unique features:
they very quickly penetrate into the periplasmic space of the microbial cell, because have extremely small molecular sizes, are zwitterions, and use for transport not only porin channels, but also channels of D 2 proteins.
have a high affinity for penicillin-binding protein type 2 (this protein is found only in multiresistant cocci, enterococci and has a low affinity for other -lactam antibiotics).
drugs are resistant to the action of -lactamases, perhaps this is due to the fact that they have a different spatial arrangement of substituents in the 5 position of the -lactam ring (it is “reverse” compared to other -lactams)
Carbapenems are characterized by a “post-antibiotic effect” (i.e., the preservation of the bactericidal effect even after the elimination of the antibiotic from the blood) against both gram-positive and gram-negative microorganisms. In addition, these drugs block the synthesis of endotoxins in gram-negative bacteria, so endotoxin shock never develops during treatment with carbapenems.
spectrum of action. These are drugs with an ultra-broad spectrum of action, which covers almost all typical groups of microorganisms (to create such a spectrum of action, it was previously necessary to combine a III-generation cephalosporin with an aminoglycoside and metronidazole):
Gram-positive cocci and bacteria (except methicillin-resistant)
Gram-negative cocci and bacteria, including: all Neisseria, intestinal bacteria (Escherichia, Yersinia, Salmonella, Shigella, Klebsiella)
Haemophilus influenzae
Pseudomonas aeruginosa and Proteus (indole-positive and negative strains)
anaerobic clostridial and non-clostridial (putrid) infection
Carbapenems are the most active drugs against gram-positive and gram-negative flora, they are second only to fluoroquinolones in terms of strength of action. Carbapenems are resistant to atypical microorganisms (mycoplasmas, chlamydia, ureaplasma), acid-resistant bacteria (causative agents of tuberculosis, leprosy), corynebacteria, fecal enterococci.
The nature of the action: bactericidal.
secondary resistance to drugs develops extremely slowly and rarely. The exception is P.aeruginosa, S.aureus. However, carabapenems induce the production of -lactamase to other -lactam antibiotics. Therefore, the use of other -lactams after carbapenems or at the same time with them does not make sense (and carbapenems should be used only as a last resort, realizing that if it fails, further therapy will be very problematic!).
Unwanted effects: 1) pain and phlebitis at the injection site; 2) allergic reactions - rashes, eosinophilia (however, carbapenem rarely causes allergic reactions in persons sensitized to other -lactams); 3) superinfection, dysbacteriosis, candidiasis; 4) sometimes carbapenems cause urine to turn red; 5) nausea; 6) there are reports of isolated cases of hypotension, increased levels of liver enzymes, agranulocytosis.
Imipenem. It is the prototype of this group of medicines. Imipenem is rapidly degraded by renal dihydropeptidase type I, producing toxic products that can cause nephrotoxic reactions. In connection with this feature, imipenem is used only in combination with cilastatin, an inhibitor of renal dihydropeptidase type I (drug Tienam ). For injection, the powder is diluted in a buffer solution of bicarbonate and sodium chloride.
It is administered intramuscularly and intravenously, it penetrates well into all tissues and organs. It is excreted through the kidneys (50%) unchanged.
When used in high doses and in persons with impaired renal function, it can cause convulsions, encephalopathy, hypertonic and hypotonic muscle reactions, and muscle tremors. This is thought to be due to its competitive GABA receptor antagonism in the CNS.
Indications: 1) severe intra-abdominal infections, infections of the pelvic organs, including hospital-acquired (nosocomial) infections; 2) severe infections of soft tissues, bones; 3) sepsis, meningitis; 4) infections of the lower respiratory tract, genitourinary system; 5) infectious processes in persons with neutropenia.
Dosage: 0.25-0.5 3-4 times a day (up to 4.0 g / day) only intravenously, as a slow infusion.
VW: vials 0.25 and 0.5 for intravenous administration 60 ml; bottles 0.5 and 0.75 for i / m administration.
Indications: Same as for imipenem, in addition, meropenem is used to treat bacterial meningitis.
Dosage: 0.5-1.0-2.0 3 times a day in / in a bolus or as a slow infusion.
VW: bottles of 0.5 and 1.0
Generations of carbapenems
Two generations of carbapenems are known:
generation:
- imipenem,
- tienam,
- promaxin.
generation:
- meropenem (meronem).
Tienam and primaxin are a 1:1 combination of imipenem and cilastatin. Cilastatin is an inhibitor of dehydropeptidase I, an enzyme that breaks down imipenem in the kidneys. Meropenem is not destroyed by the named enzyme.
Pharmacodynamics of carbapenems
Carbapenems are beta-lactam antibiotics that disrupt the synthesis of the microbial wall at the time of mitosis. At the same time, their mechanism of action has a number of important features. They penetrate the microbial cell much better and faster than other beta-lactam preparations. For this, carbapenems use not only F-porin transmembrane proteins (like many other antibiotics: penicillins, cephalosporins, monobactams, tetracyclines, levomycetin), but also special D2 proteins, since their molecules are much smaller.
In addition, they have a very high affinity for penicillin-binding proteins (PBPs), of which 8 types have already been found. Moreover, they can also bind to such a hard-to-reach protein as PSB-2, synthesized by certain strains of microorganisms (for example, enterococci, pneumococci, etc.), resistant to many antibiotics. These features in the mechanism of action of carbapenems largely explain their large spectrum of action.
Pharmacological action of carbapenems:
The pharmacological effect of carbapenems is bactericidal. It should be noted that carbapenems have a pronounced post-antibiotic effect lasting 7-10 hours. At this time, the surviving microorganisms are not capable of division, and the macroorganism mobilizes its defensive forces completing the fight against infection. Unlike other beta-lactam antibiotics, only carbapenems have a post-antibiotic effect directed against Gr. "+", and against Gr. "-" bacteria. Another feature of the action of carbapenems is the ability to suppress the production and release of endotoxins Gr. flora, which prevents the occurrence of serious hemodynamic disorders.
Carbapenems are highly active antibiotics. Their average therapeutic concentrations are close to the MIC. These are the most active drugs against Gr. "+" flora and bacteroids, as for Gr. * – » flora, they are second only to fluoroquinolones. The suppression of fast-growing microorganisms occurs within 2-8 hours, and slowly dividing - within 8-20 hours.
The spectrum of action of carbapenems
The spectrum of action is ultra-wide, the largest among all anti-infection drugs. Carbapenems affect Gr. "+" microorganisms (aerobes and anaerobes), including enterococci, listeria and CI. difficile, although the sensitivity of the latter to these antibiotics is low (MIC > 8 µg/ml). In the spectrum of their action are Gr. "-" microorganisms (aerobes and anaerobes), including Serradia, Pseudomonas, Citrobacter, Acinetobacter and Enterobacter. In other words, the spectrum of action of carbapenems is able to cover such a list of microorganisms, for the elimination of which four are usually used. antibacterial drug such as a cephalosporin III generation, aminoglycoside, metronidazole and ampicillin.
Meropenem is less active (2-4 times) than thienam and primaxin against staphylococci (golden, epidermal, saprophytic, coagulase-negative), but more active (2-8 times) against Gr. "-" Enterobacteria and Pseudomonas.
However, it is necessary to name microorganisms that have a primary (natural, constitutive) resistance to carbapenems: chlamydia, mycoplasmas, corynebacteria, mycobacteria tuberculosis and leprosy, flavobacteria, a special stamp of enterococcus (Enterococcus faecium), varieties of pseudomonads (Ps. cepacia and Xanthomonas maltophilia), methicillin-resistant staphylococci and fungi.
Secondary (induced) resistance of microorganisms to carbapenems develops rarely and slowly. The only exceptions are Pseudomonas, Staphylococcus aureus, Staphylococcus aureus, and Acinetobacter. These microbes quickly develop resistance to these antibiotics. It should be emphasized that carbapenems themselves are not destroyed by either chromosomal or plasmid beta-lactamases, but induce the production of chromosomal beta-lactamases to all other beta-lactam antibiotics. Therefore, they cannot be combined with penicillins, cephalosporins and monobactams. For the same reason, it makes no sense to prescribe beta-lactams after the use of carbapenems.
Carbapenems for children - instructions for use
Carbapenems are administered only parenterally (in / in, in / m). Moreover, drugs intended for intravenous administration can only be administered intravenously. They are diluted in a buffer solution of sodium bicarbonate and administered as a bolus slowly, over 5-7 minutes. For infusion, drip administration, the drug is diluted either in an isotonic solution of sodium chloride or glucose and administered within 30-60 minutes.
The prepared drug should be stored in a refrigerator (+4 ° C) no longer than 24 hours before the injection; the use of carbapenems after this period is contraindicated. Preparations intended for intramuscular injection can only be administered intramuscularly. They are diluted with 1% lidocaine solution or special proprietary solution. A suspension is obtained, which is stored in the refrigerator for no longer than 4 hours until the moment of injection.
Bioavailability from muscles is more than 75%. 15-25% of thienam or primaxin and 2% of meropenem bind to plasma proteins. Therefore, after their introduction in the blood, high concentration free drug, ready to penetrate the tissues and have an effect. They have a large volume of distribution, but nevertheless, they are excreted from the body during hemodialysis, which must be remembered in case of an overdose. Meropenem penetrates the CNS better than others. The elimination half-life with intravenous administration is 1 hour (in newborns - 2 hours), with intramuscular injection- 2.6 hours
The frequency of prescribing drugs:
- with intravenous administration for tienam, primaxin - 4 times a day; meropenem - 3 times a day;
- at intramuscular injection- 2 times a day.
Imipenem in the brush border of the tubular epithelium of the proximal tubules of the kidneys under the influence of dehydropeptidase I is converted into nephrotoxic products. Therefore, pure imipenem is practically not used. In clinical practice, thienam and primaxin are used, which, as already mentioned, contain a dehydropeptidase I inhibitor. Meropenem, due to the peculiarity of its chemical structure, does not turn into substances toxic to the kidneys.
Excretion is carried out mainly in unchanged form by the kidneys (thienam, primaxin - 50%, meropenem - 70%) due to glomerular filtration and tubular secretion.
In renal failure, the use of drugs is as follows: it is necessary to change the dosing regimen for intravenous administration, if Cl cr< 80 мл/мин; при внутримышечном, если Cl кр < 30 мл/мин. Однако, следует отметить, что карбапенемы можно вводить даже при Cl кр < 5 мл/мин, если у больного каждые 48 ч проводят гемодиализ.
Interaction with other drugs
Carbapenems should not be co-administered with other unprotected beta-lactam antibiotics (antagonism occurs).
The use of carbapenems in the same syringe with other drugs is not recommended (chemical interaction).
Carbapenems have a wide latitude therapeutic effect These are low toxicity drugs.
- With the / m introduction - pain at the injection site; with intravenous - thickening of the veins, thrombophlebitis.
- Allergic reactions: rash, eosinophilia. It should be noted that cross-reactivity with other beta-lactam antibiotics is extremely rare.
- Superinfection (candidiasis).
- Nephrotoxicity (more often with imipenem).
- With intravenous administration of thienam or primaxin, but not meropenem, in patients with impaired renal function and central nervous system disease (meningitis, traumatic brain injury, stroke, epilepsy), weakness, tremor, muscle hypertonicity, paresthesia, encephalopathy, convulsions may occur.
- Other complications are described as isolated cases: arterial hypertension; increased activity of liver enzymes and serum bilirubin levels; pseudomembranous (or hemorrhagic) colitis; agranulocytosis, generalized pancytopenia.
Clinical and pharmacological group
Antibiotic of the carbapenem group
Release form, composition and packaging
0.5 g - bottles (1) - packs of cardboard.
0.5 g - bottles (10) - cardboard boxes.
0.5 g - bottles (50) - cardboard boxes.
Powder for solution for intravenous administration white or white with a yellowish tint.
Excipients: sodium carbonate.
1 g - bottles (1) - packs of cardboard.
1 g - bottles (10) - cardboard boxes.
1 g - bottles (50) - cardboard boxes.
pharmachologic effect
It has a bactericidal effect (suppresses the synthesis of the bacterial cell wall), easily penetrates the bacterial cell wall, and is resistant to the action of most beta-lactamases. It is practically not destroyed in the renal tubules by dehydropeptidase-1 (does not need to be combined with cilastatin, a specific inhibitor of dehydropeptidase-1) and, accordingly, nephrotoxic metabolic products are not formed, it has a high affinity for penicillin-binding proteins. Bactericidal and bacteriostatic concentrations practically do not differ. Interacts with receptors - specific penicillin-binding proteins on the surface of the cytoplasmic membrane, inhibits the synthesis of the peptidoglycan layer of the cell wall, inhibits transpeptidase, promotes the release of autolytic enzymes of the cell wall, which ultimately causes its damage and death of bacteria. The spectrum of antibacterial activity of meropenem includes the majority of clinically significant gram-positive and gram-negative aerobic and anaerobic strains of bacteria:
Gram-positive aerobes: Enterococcus faecalis (including vancomycin-resistant strains), Staphylococcus aureus (penicillin zone-non-producing and penicillin-producing); Streptococcus agalactiae, Streptococcus pneumoniae (only penicillin-sensitive); Streptococcus pyogenes, Streptococcus spp. viridans groups.
Gram-negative aerobes: Escherichia coli, Haemophilus influenzae (penicillinase-non-producing and psnicillinase-producing), Klebsiella pneumoniae, Neisseria meningitidis, Pseudomonas aeruginosa, Proteus mirabilis.
anaerobic bacteria: Bacteroides fragilis, Bacteroides thetaiotaomicron, Peptostreptococcus spp.
Effective in vitro against the following microorganisms:
Gram-positive aerobes: Staphylococcus epidermidis (penicillin-azone-non-producing and penicillin-azo-producing).
Gram-negative aerobes: Acinetobacter spp. Aeromonas hydrophila Campylobacter jejuni Citrobacter diversus Citrobacter freundii Enterobacter cloacae Proteus vulgaris, Salmonella spp., Serratia marcescens, Shigella spp., Yersinia enterocolitica.
anaerobic bacteria: Bacteroides distasonis, Bacteroides ovatus, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides vulgatus, Clostridium difficile, Clostridium perfringens, Eubacterium lentum, Fusobacterium spp.
Pharmacokinetics
With intravenous administration (in / in) of 250 mg over 30 minutes, the maximum concentration (Cmax) in plasma is 11 μg / ml, for a dose of 500 mg - 23 μg / ml, for a dose of 1.0 g - 49 μg / ml (absolute there is no pharmacokinetic proportional dependence on the administered dose for Cmax and the area under the concentration-time curve (AUC). With an increase in dose from 250 mg to 2.0 g, plasma clearance decreases from 287 to 205 ml / min. With an IV bolus of 500 mg over 5 minutes, Cmax - 52 μg / ml, 1.0 g - 112 μg / ml. Communication with blood plasma proteins - 2%.
It penetrates well into most tissues and body fluids, incl. into the cerebrospinal fluid (CSF) of patients with bacterial meningitis, reaching concentrations in excess of those required to suppress most bacteria (bactericidal concentrations are created 0.5-1.5 hours after the start of the infusion). In small quantities passes into breast milk.
It undergoes insignificant metabolism in the liver with the formation of a single inactive metabolite. The half-life (T1 / 2) is 1 hour, in children under 2 years old - 1.5 - 2.3 hours. In the dose range of 10-40 mg / kg in adults and children, a linear dependence of pharmacokinetic parameters is observed. Does not accumulate.
It is excreted by the kidneys - 70% unchanged within 12 hours. The concentration of meropenem in the urine, exceeding 10 μg / ml, is maintained for 5 hours after the administration of 500 mg. In patients with renal insufficiency, meropenem clearance correlates with creatinine clearance (CC), and dose adjustment is required. In elderly patients, a decrease in meropenem clearance correlates with an age-related decrease in CC. T1 / 2 - 1.5 hours. Meropenem is excreted during hemodialysis.
Indications
Infectious and inflammatory diseases (monotherapy or in combination with other antimicrobial drugs (PM)) caused by pathogens sensitive to meropenem:
Infections of the lower respiratory tract (including pneumonia, including hospital ones);
Intra-abdominal infections (including complicated appendicitis, peritonitis);
Infections of the urinary system (including pyelonephritis, pyelitis);
Infections of the skin and soft tissues (including erysipelas, impetigo, secondarily infected dermatoses);
Infections of the pelvic organs (including endometritis, pelvic peritonitis);
bacterial meningitis;
Septicemia, suspected bacterial infection in adults with febrile neutropenia (empiric treatment alone or in combination with antiviral or antifungal drugs).
Contraindications
Hypersensitivity to meropenem or other beta-lactam antibiotics in history;
Children's age up to 3 months.
Carefully
Simultaneous appointment with potentially nephrotoxic drugs, patients with colitis.
Dosage
Intravenous (IV) bolus or infusion.
Adults and children over 12 years old- 500 mg every 8 hours at pneumonia, urinary tract infections, infectious and inflammatory diseases of the pelvic organs, infections of the skin and soft tissues; 1.0 g every 8 hours at nosocomial pneumonia, peritonitis, suspected bacterial infection in patients with symptoms of febrile neutropenia, septicemia; 2.0 g every 8 hours at meningitis.
At
Meropenem is eliminated by hemodialysis. To restore the effective plasma concentration at the end of the hemodialysis procedure, it is necessary to enter the recommended for the corresponding pathology single dose meropenem.
Dose adjustment is not required in patients with liver failure, elderly patients with normal renal function (CC more than 50 ml / min).
Children aged 3 months to 12 years- 10-20 mg / kg every 8 hours, depending on the type and severity of the infection, the sensitivity of the pathogen and the condition of the patient. Children under 12 years old, but weighing more than 50 kg adult doses should be used. At meningitis- 40 mg/kg every 8 hours.
Experience with children with impaired renal function missing.
Preparation and administration of drug solutions:
For intravenous bolus injection, dilute with water for injection to a solution concentration of 50 mg / ml (10 ml for every 500 mg), inject over 5 minutes.
For intravenous infusion dilute in 50-100 ml compatible infusion solution(0.9% sodium chloride solution, 5-10% dextrose solution, 5% dextrose solution with 0.225% sodium chloride, 5% dextrose solution with 0.15% potassium chloride, 2.5 and 10% mannitol solution), inject into within 15-30 min.
Side effects
From the digestive system: pain in the epigastric region, nausea, vomiting, diarrhea, constipation, anorexia, jaundice; candidiasis of the oral mucosa; pseudomembranous colitis.
From the urinary system: dysuria, edema, impaired renal function (hypercreatininemia, increased plasma urea concentration), hematuria.
Allergic reactions: skin itching, skin rash, urticaria, erythema multiforme exudative, malignant exudative erythema (Stevens-Johnson syndrome), angioedema, anaphylactic shock.
From the nervous system: headache, dizziness, paresthesia, agitation, impaired consciousness, epileptiform seizures, convulsions.
Laboratory indicators: thrombocytosis, eosinophilia, thrombocytopenia, decrease in hemoglobin, hematocrit, leukopenia, shortening of prothrombin and partial thromboplastin time, leukocytosis, hypokalemia, hyperbilirubinemia, increased activity of ALT, ACT, alkaline phosphatase, LDH.
Local reactions: inflammation, phlebitis, thrombophlebitis, soreness, swelling at the injection site.
Others: false positive direct or indirect Coombs test, anemia, hypervolemia, vaginal candidiasis.
A causal relationship with the use of meropenem has not been established: syncope, hallucinations, depression, anxiety, irritability, insomnia, cholestatic hepatitis, heart failure, cardiac arrest, tachycardia, bradycardia, myocardial infarction, decrease or increase in blood pressure, thromboembolism of the pulmonary artery branches, shortness of breath.
If any of the side effects indicated in the instructions are aggravated, or you notice any other side effects not listed in the instructions, tell your doctor.
Overdose
Possible overdose during treatment, especially in patients with impaired renal function.
Treatment: carry out symptomatic therapy. Normally, the drug is rapidly eliminated through the kidneys. In patients with impaired renal function, hemodialysis effectively removes meropenem and its metabolite.
drug interaction
Drugs that block tubular secretion slow down excretion and increase plasma concentrations of meropenem.
May reduce plasma concentrations of valproic acid.
special instructions
Patients with a history of hypersensitivity to carbapenems, penicillins, or other beta-lactam antibiotics may be hypersensitive to meropenem.
Treatment of patients with liver diseases should be carried out under the control of the activity of "liver" transaminases and the concentration of bilirubin.
In the process of treatment, the development of resistance of pathogens is possible, and therefore long-term treatment is carried out under constant control of the spread of resistant strains. In persons with diseases of the gastrointestinal tract, especially colitis, it is necessary to consider the possibility of developing pseudomembranous colitis (a toxin produced by Clostridium difficile is one of the main causes of antibiotic-associated colitis), the first symptom of which may be the development of diarrhea during treatment.
For monotherapy of established or suspected lower respiratory tract infection severe course caused by Pseudomonas aeruginosa is recommended regular definition pathogen sensitivity.
There is no experience with the use of meropenem in neutropenic children with primary or secondary immunodeficiency.
Impact on ability to drive vehicles, mechanisms
During the period of use of the drug, care must be taken when driving vehicles and engaging in potentially dangerous species activities requiring increased concentration attention and speed of psychomotor reactions.
Pregnancy and lactation
The use of the drug during pregnancy is possible only in cases where the intended benefit to the mother outweighs the potential risk to the fetus.
If necessary, the use of the drug during lactation should decide on the termination of breastfeeding.
Application in childhood
Contraindicated in children under 3 months.
For impaired renal function
At chronic renal failure(CRF) the dose is adjusted depending on the CC:
For impaired liver function
Dose adjustment is not required in patients with hepatic impairment.
Use in the elderly
Dose adjustment is not required in elderly patients with normal renal function (CC more than 50 ml / min).
Terms of dispensing from pharmacies
On prescription.
Terms and conditions of storage
In a place protected from light at a temperature not exceeding 25 ° C. Keep out of the reach of children. Shelf life - 2 years.
After the expiration date of the drug, carefully open the unused vials, dissolve the contents in in large numbers water and drain into the sewer.
The description of MEROPENEM is based on officially approved instructions for use and approved by the manufacturer.
More often as a reserve drug, but in life-threatening infections may be considered as first line empirical therapy.
Mechanism of action
Carbapenems have a powerful bactericidal effect due to a violation of the formation of the bacterial cell wall. Compared to other β-lactams, carbapenems are able to penetrate the outer membrane of gram-negative bacteria faster and, in addition, exert a pronounced PAE against them.
Activity spectrum
Carbapenems act on many gram-positive, gram-negative and anaerobic microorganisms.
Staphylococci (except MRSA), streptococci, including S.pneumoniae(in terms of activity against ARP, carbapenems are inferior to vancomycin), gonococci, meningococci. Imipenem acts on E.faecalis.
Carbapenems are highly active against most gram-negative bacteria of the family Enterobacteriaceae(E. coli, Klebsiella, Proteus, Enterobacter, Citrobacter, Acinetobacter, Morganella), including against strains resistant to III-IV generation cephalosporins and inhibitor-protected penicillins. Slightly lower activity against proteus, serration, H.influenzae. Most strains P.aeruginosa initially sensitive, but in the process of using carbapenems, an increase in resistance is noted. Thus, according to a multicenter epidemiological study conducted in Russia in 1998-1999, resistance to imipenem in nosocomial strains P.aeruginosa in ICU was 18.8%.
Carbapenems have relatively little effect on B.cepacia, stable is S. maltophilia.
Carbapenems are highly active against spore-forming (except C.difficile) and non-spore-forming (including B. fragilis) anaerobes.
Secondary resistance of microorganisms (except P.aeruginosa) rarely develops to carbapenems. For resistant pathogens (except P.aeruginosa) is characterized by cross-resistance to imipenem and meropenem.
Pharmacokinetics
Carbapenems are used only parenterally. They are well distributed in the body, creating therapeutic concentrations in many tissues and secretions. With inflammation of the meninges, they penetrate the BBB, creating concentrations in the CSF equal to 15-20% of the level in the blood plasma. Carbapenems are not metabolized, they are excreted mainly by the kidneys in unchanged form, therefore, with renal failure, a significant slowdown in their elimination is possible.
Due to the fact that imipenem is inactivated in the renal tubules by the enzyme dehydropeptidase I and does not create therapeutic concentrations in the urine, it is used in combination with cilastatin, which is a selective inhibitor of dehydropeptidase I.
During hemodialysis, carbapenems and cilastatin are rapidly removed from the blood.
Adverse reactions
Allergic reactions: rash, urticaria, angioedema, fever, bronchospasm, anaphylactic shock.
Local reactions: phlebitis, thrombophlebitis.
GIT: glossitis, hypersalivation, nausea, vomiting, rare cases antibiotic-associated diarrhea, pseudomembranous colitis. Help measures: if nausea or vomiting occurs, the rate of administration should be reduced; with the development of diarrhea - use kaolin- or attapulgite-containing antidiarrheal drugs; if pseudomembranous colitis is suspected - the abolition of carbapenems, the restoration of water and electrolyte balance, if necessary, the appointment of metronidazole or vancomycin inside.
CNS: dizziness, impaired consciousness, tremor, convulsions (usually only when using imipenem). Relief measures: with the development of severe tremor or convulsions, it is necessary to reduce the dose of imipenem or stop it, as anticonvulsants benzodiazepines (diazepam) should be used.
Other: hypotension (more often with rapid intravenous administration).
Indications
Severe infections, predominantly nosocomial, caused by multiresistant and mixed microflora:
Bacterial infections in neutropenic patients.
neurotoxicity. Imipenem (but not meropenem) exhibits competitive antagonism with GABA, and therefore may have a dose-dependent CNS stimulatory effect, resulting in tremors or convulsions. The risk of seizures is increased in patients with traumatic brain injury, stroke, epilepsy, renal insufficiency and in the elderly. Imipenem is not used to treat meningitis.
Impaired liver function. Doses of carbapenems do not require adjustment in patients with liver disease, but appropriate clinical and laboratory monitoring is required.
Changes in laboratory parameters. During the use of carbapenems, a temporary increase in the activity of transaminases, alkaline phosphatase and lactate dehydrogenase is possible, as well as an increase in the content of bilirubin, urea, creatinine in the blood serum and, conversely, a decrease in hemoglobin and hematocrit.
Intravenous administration. In / in the introduction of imipenem should be carried out as a slow infusion. Doses of 0.125-0.5 g should be administered within 20-30 minutes, 0.75-1.0 g - within 40-60 minutes. With a more rapid introduction, the risk of developing nausea, vomiting, hypotension, phlebitis, thrombophlebitis increases. If nausea occurs, the rate of administration should be reduced. Meropenem can be administered either as an infusion or as a bolus (over 5 minutes).
Drug Interactions
Carbapenems should not be used in combination with other β-lactams (penicillins, cephalosporins or monobactams) due to their antagonism. It is not recommended to mix carbapenems in the same syringe or infusion set with other drugs.
Information for patients
During treatment, it is necessary to inform the doctor about changes in well-being, the appearance of new symptoms.
Table. Drugs of the carbapenem group.
Main characteristics and application features
| INN | Lekform LS | T ½, h * | Dosing regimen | Features of drugs |
|---|---|---|---|---|
| Imipenem/cilastatin | Since. d/inf. 0.5 g in a flask. Por.d / w / m in. 0.5 g in vial. |
1 | I/V Adults: 0.5-1.0 g every 6-8 hours (but not more than 4.0 g / day) Children: up to 3 months: see the section "The use of AMP in children"; older than 3 months with body weight: less than 40 kg - 15-25 mg / kg every 6 hours; more than 40 kg - as in adults (but not more than 2.0 g / day) V/m Adults: 0.5-0.75 g every 12 hours |
Compared to meropenem, it is more active against gram-positive cocci, but less active against gram-negative rods. It has broader indications, but is not used for meningitis. |
| Meropenem | Since. d/inf. 0.5 g; 1.0 g in a flask. |
1 | I/V Adults: 0.5-1.0 g every 8 hours; for meningitis 2.0 g every 8 hours Children over 3 months: 10-20 mg/kg every 8 hours; with meningitis, cystic fibrosis - 40 mg / kg every 8 hours (but not more than 6 g / day) |
Differences from imipenem: - more active against gram-negative bacteria; - less active against staphylococci and streptococci; - not inactivated in the kidneys; - does not have proconvulsant activity; - less likely to cause nausea and vomiting; - not used for infections of bones and joints, bacterial endocarditis; - not applicable to children under 3 months - can be given as a bolus over 5 minutes - no i/m dosage form |
* At normal function kidney
