Carbapenem drugs. Carbapenems: spectrum of action, indications, side effects. Prescription of universal antibiotics

10. CLINICAL AND PHARMACOLOGICAL CHARACTERISTICS OF CARBAPENEMS

Carbapenems (from the English carbon - “carbon” and penems - “a type of beta-lactam antibiotics”) - group beta-lactam antibiotics, in which the sulfur atom in the thiazolidine ring of the penicillin molecule is replaced by a carbon atom. Carbapenems have a wide spectrum of antibacterial activity, including gram-positive and gram-negative aerobes and anaerobes.

Mechanism of action

Like all beta-lactam antibiotics, carbapenems inhibit penicillin-binding proteins of the bacterial wall, thus disrupting its synthesis and leading to the death of bacteria (bactericidal type of action).

The following carbapenems are currently used in clinical practice: imipenem+cilastatin, meropenem, ertapenem, doripenem.

Pharmacokinetics

Carbapenems are acid labile and can only be used parenterally. They are well distributed in the body, creating therapeutic concentrations in many tissues and secretions. When the membranes of the brain are inflamed, they penetrate the blood-brain barrier.

T½ --1 hour (with intravenous administration). They are not metabolized and are excreted primarily by the kidneys unchanged, therefore, in case of renal failure, their elimination may be significantly delayed.

Pharmacodynamics

Carbapenems are resistant to destruction by bacterial beta-lactamases, which makes them effective against many microorganisms, such as Pseudomonas aeruginosa, Serratia spp. and Enterobacter spp., which are resistant to most

beta-lactam antibiotics.

Spectrum of action of carbapenems includes virtually all clinically significant pathogenic microorganisms:

1. Gram-negative aerobes: including: Acinetobacter spp, Bordetella spp, Brucella melitensis, Campylobacter spp, Citrobacter spp, Enterobacter spp, Escherichia coli, Gardnerella vaginalis, Haemophilus influenzae (including beta-lactamase producing strains), Haemophilus ducreyi, Haemophilus parainfluenzae, Hafnia alvei, Klebsiella

spp, Moraxella spp, Morganella morganii, Neisseria gonorrhoeae (including penicillinase-producing strains), Neisseria meningitidis, Proteus spp, Pseudomonas spp, Salmonella spp, Serratia spp, Shigella spp, Yersinia spp.

2. Gram-positive aerobes: Bacillus spp, Enterococcus faecalis, Erysipelothrix rhusiopathiae, Listeria monocytogenes, Nocardia spp, Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis (including penicillinase-producing strains), Staphylococcus saprophyticus,

Streptococcus spp. group B, Streptococcus spp. groups C, G, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans.

3. Gram-negative anaerobes: Bacteroides spp, Bacteroides fragilis, Fusobacterium spp, Veillonella spp.

4. Gram-positive anaerobes: Actinomyces spp, Bifidobacterium spp, Clostridium spp, Lactobaccilus spp, Mobilincus spp, Peptococcus spp, Peptostreptococcus spp.

5. Others: Mycobacterium fortuitum, Mycobacterium smegmatis.

Microorganisms resistant to carbapenems:

Methicillin-resistant staphylococci (MRSA);

Clostridium difficile;

some strains of Enterococcus faecalis and most strains of Enterococcus faecium;

some strains of Pseudomonas cepacia;

Burkholderia cepacia and Pseudomonas aeruginosa may have acquired resistance

Imipenem/cilastatin (tienam)

The first of the class of carbapenems, it has a wide spectrum of antibacterial action. Active against gram-positive cocci, less active against gram-negative rods. Not used for meningitis (has proconvulsant activity). Disadvantages include pronounced inactivation in the body due to hydrolysis of the beta-lactam ring by the kidney enzyme dehydropeptidase-1. In this regard, it is not used as a stand-alone drug, but only together with a specific renal dehydropeptidase inhibitor, cilastatin.

Meropenem

Shows high activity against gram-negative microbes. In vitro, it is more active than imipenem against the Enterobacteriaceae family, as well as against strains resistant to ceftazidime, cefotaxime, ceftriaxone, piperacillin and

gentamicin. Meropenem is significantly more active than imipenem against Haemophilus influenzae, Moraxella catarrhalis and Neisseria spp. Regarding the effect on gram-negative bacteria, meropenem is not inferior to ciprofloxacin and is superior in effectiveness to third-generation cephalosporins and gentamicin. High

Meropenem has activity against streptococci.

Not used for infections of bones and joints, bacterial endocarditis. Not destroyed by renal dehydropeptidase. It does not have convulsive activity and is used for meningitis.

Doripenem

Compared to imipenem and meropenem, it is 2–4 times more active against Pseudomonas aeruginosa. Doripenem penetrates well into the tissues of the uterus, prostate, gall bladder and urine, as well as retroperitoneal fluid, reaching concentrations there that exceed the minimum inhibitory concentration. Doripenem is excreted mainly unchanged by the kidneys.

Ertapenem

Unlike other carbapenems, ertapenem has no effect on Pseudomonas and Acinetobacter, common pathogens of nosocomial infections.

Daily doses and frequency of use of carbopenems

Note:

In patients with impaired renal function, doses of carbapenems should be reduced in accordance with the instructions for use.

Clinical indications for the use of carbapenems

Imipenem/cilastatin

1. Lower respiratory tract infections (including nosocomial infections, abscess)

2. Urinary tract infections (complicated and uncomplicated),

3. Intra-abdominal infections

4. Skin and soft tissue infections

5. Bacterial septicemia caused by Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Escherichia coli, Pseudomonas aeruginosa, bacteria of the genera Enterobacter, Klebsiella, Serratia, Bacteroides, including B. fragilis.

6. Bone and joint infections

7. Infections of the pelvic organs in women

8. Endocarditis caused by Staphylococcus aureus (penicillinase-producing strains).

9. Polymicrobial infections caused by S. pneumoniae (pneumonia, septicemia), S. pyogenes (skin and its appendages) or S. aureus strains (non-penicillinase-producing).

NB! Imipenem is not indicated for meningitis because the safety and effectiveness of imipenem in this disease have not been established.

Meropenem

Bacterial meningitis (only from 3 months of age) caused by Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis.

Side effects of carbapenems

1. Allergic reactions (cross-reaction with beta-lactam antibiotics)

2. Reactions at the injection site: post-infusion complications (phlebitis, thrombophlebitis), pain, infiltrates

3.Gastrointestinal tract: nausea, vomiting, diarrhea

4. Central nervous system often - headache, less often dizziness, drowsiness, insomnia, convulsions, impaired consciousness

5. Infrequent side effects: impaired renal function, liver function, taste disturbance (thienam), cavity candidiasis (meropenem, ertapenem), neutropenia, leukopenia, thrombocytopenia (meropenem, ertapenem).

Of particular note neurotoxicity (high epileptogenicity) of imipenem , which limits its use in bacterial meningitis. Other carbapenems do not have neurotoxic properties.

Contraindications to the use of carbapenems

– Hypersensitivity to any of the components of all carbapenems.

– History of allergy to beta-lactam antibiotics, since cross-allergy is possible up to the development of anaphylactic shock.

– Imipenem/cilastatin is contraindicated in patients with creatinine clearance less than 5 ml/min/1.73 m2, unless hemodialysis is prescribed.

– Meropenem, ertapenem is contraindicated under the age of 3 months.

– Doripenem is contraindicated in people under 18 years of age.

Interaction of carbapenems with other drugs

Carbapenems are able to potentiate the effect of penicillins on gram-positive flora, aminoglycosides on gram-negative flora, clindamycin and metronidazole on anaerobic microflora.

Preferanskaya Nina Germanovna
Associate Professor, Department of Pharmacology, Faculty of Pharmacy, First Moscow State Medical University named after. THEM. Sechenova, Ph.D.

The group of cephalosporins includes drugs based on 7-aminocephalosporanic acid. All cephalosporins, like othersβ-lactam antibiotics,characterized by a single mechanism of action. Individual representatives differ significantly in pharmacokinetics, severity of antimicrobial action and stability to beta-lactamases (Cefazolin, Cefotaxime, Ceftazidime, Cefepime, etc.). Cephalosporins have been used in clinical practice since the beginning of 1960; they are currently divided into four generations and, depending on their use, into drugs for parenteral and oral administration.

1st generation drugs most active against gram-positive bacteria, not resistant to beta-lactamases - Cephalexin ( Keflex), Cefazolin(Kefzol), Cefaclor, Cefadroxil(Biodroxil).

2nd generation drugs exhibit high activity against gram-negative pathogens, retain activity against gram-positive bacteria and increase resistance to betalactamases - Cefamandole, Cefaclor(Ceclor), Cefuroxime(Aksetin, Zinacef), Cefuroxime axetil (Zinnat).

3rd generation drugs highly active against a wide range of gram-negative microorganisms, not inactivated by many beta-lactamases (excluding extended spectrum and chromosomal) - Cefotaxime(Klaforan), Cefoperazone(Cephobid), Ceftriaxone(Azaran, Rocephin), Ceftazidime(Fortum), Ceftibuten(Tsedex), Cefixime(Suprax).

4th generation drugs have a high level of antimicrobial activity against gram-positive and gram-negative bacteria, resistant to hydrolysis by chromosomal beta-lactamases - Cefepime(Maxipim, Maxicef), Cefpir(Katen).

Combined cephalosporins help increase and maintain the effective concentration of the antibiotic and enhance the antimicrobial activity of the drug: Cefoperazone + Sulbactam(Sulperazon, Sulperacef).

Cephalosporins with more pronounced resistance to beta-lactamases (cefazolin, cefotaxime, ceftriaxone, ceftazidime, cefepime, etc.). Oral cephalosporins (cefuroxime axetil, cefaclor, cefixime, ceftibuten) are active against microorganisms that produce beta-lactamases.

General approaches to the use of cephalosporins:

• infections caused by pathogens that are not sensitive to penicillins, for example, Klebsiella and Enterobacteriaceae;
• in case of allergic reactions to penicillin, cephalosporins are the first-line reserve antibiotics, but 5-10% of patients experience cross-allergic sensitivity;
• for severe infections, use in combination with semisynthetic penicillins, especially acylureidopenicillins (azlocillin, mezlocillin, piperacillin);
• can be used during pregnancy and do not have teratogenic or embryotoxic properties.

Indications for use include community-acquired infections of the skin and soft tissues, urinary tract infections, infections of the lower and upper respiratory tract and pelvic organs. Cephalosporins are used for infections caused by gonococci; ceftriaxone, cefotaxime, and cefixime are used to treat gonorrhea. In the treatment of meningitis, drugs that penetrate the blood-brain barrier (cefuroxime, ceftriaxone, cefotaxime) are used. 4th generation cephalosporins are used to treat infections associated with immunodeficiency conditions. During the use of cefoperazone and for two days after treatment with this antibiotic, you should avoid drinking alcoholic beverages to avoiddevelopment of a disulfiram-like reaction. Alcohol intolerance occurs due to blockade of the enzyme aldehyde dehydrogenase, toxic acetaldehyde accumulates and a feeling of fear, chills or fever occurs, breathing becomes difficult, and the heartbeat increases. There is a feeling of lack of air, a drop in blood pressure, and the patient suffers from uncontrollable vomiting.

Carbapenems

Carbapenems have been used in clinical practice since 1985; drugs in this group have a wide spectrum of antimicrobial activity; “gr+” and “gr-” bacteria are sensitive to them, including Pseudomonas aeruginosa. The main representatives are Imipenem, Meropenem and combination drug Tienam(Imipenem + Cilastatin). Imepenem is destroyed in the renal tubules by the enzyme dehydropeptidase. I , therefore it is combined with cilastatin, which inhibits the activity of this enzyme. The drugs are resistant to beta-lactamases and penetrate well into body tissues and fluids. They are used for severe infections caused by polyresistent and mixed microflora, complicated infections of the urinary system and pelvic organs, skin and soft tissues, bones and joints. Meropenem used to treat meningitis. Carbapenems cannot be combined with other β-lactam antibiotics due to their antagonism, and also mixed in the same syringe or infusion system with other drugs!

Interaction of β-lactam antibiotics with other drugs

In Russia they apply IMPENEM And PEROPENEM (MERONEM), in Japan - also biapenem and panipenem. Oral carbapenems, sanfethrinem and faropenem, are being studied.

The first drug of the carbopenem group, imipenem, appeared in clinical practice in 1980. It is produced by microorganisms Streptomyces cattleya. Meropenem is a stable derivative of imipenem. To date, more than 40 natural and synthetic representatives of carbapenems are known.

They are characterized by higher resistance to the action of bacterial b-lactamases compared to penicillins and cephalosporins, have a wider spectrum of activity and are used for severe infections of various locations. More often they are used as reserve drugs, but for life-threatening infections they can be considered as first-priority empirical therapy.

Imipenem causes eradication of predominantly gram-positive bacteria, while meropenem largely suppresses gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter, Bacteroides, causative agents of glanders and melioidosis.

Carbapenems, like other antibiotics of the β-lactam group, have a bactericidal effect by disrupting the synthesis of the cell wall of microorganisms. They penetrate cell wall porins more easily than other β-lactams, since they have positive and negative charges in the molecule, a changed position of the sulfur atom and a branched side chain.

The therapeutic effect of carbopenems does not depend on the maximum concentration, but on the time it is maintained above the minimum constant concentration (MCC) for a given pathogen. It is necessary to maintain a constant concentration of antibiotics in the blood at a level of 2–4 times the MIC values. In this regard, the main importance is not the size of the single dose, but the frequency of injections. Carbapenems typically have a long post-antibiotic effect against gram-negative bacteria. They prevent the release of bacterial endotoxins, which cause infectious-toxic shock and other hemodynamic disorders.

The advantage of meropenem is the ability to penetrate macrophages and enhance their phagocytic activity. Under the influence of meropenem, the destruction of phagocytosed microorganisms is accelerated.

Natural resistance to carbapenems is characteristic of flavobacteria; acquired resistance occurs rarely (identified only in 7 strains of Pseudomonas aeruginosa).

Spectrum of activity. Carbapenems are active against gram-positive, gram-negative and anaerobic microorganisms.

Staphylococci (except methicillin-resistant), streptococci, gonococci, meningococci, pneumococci are sensitive to carbapenems (carbapenems are inferior to vancomycin in their activity against pneumococci).

Highly active against most gram-negative microorganisms (Escherichia coli, Klebsiella, Proteus, Enterobacter, Citrobacter, Morganella), including strains resistant to III-IV generation cephalosporins and inhibitor-protected penicillins. Slightly lower activity against Proteus and serration.

Carbapenems are highly active against spore-forming and non-spore-forming anaerobes.

However, carbapenems are inactivated by carbapenemases. Carbapenemases are produced by Shigella, Acinebacter, Pseudomonas aeruginosa and other bacteria. There are known outbreaks of hospital infections caused by gram-negative microorganisms that secrete carbapenemases.

Secondary resistance of microorganisms to carbapenems rarely develops. Resistant microorganisms are characterized by cross-resistance to all drugs.

Combination drug IMIPENEM/CILASTATIN (TIE-NAM) injected into a vein by drip, since when injecting a bolus, nausea and vomiting occur.

Carbapenems bind to blood proteins to a minimal extent (2%) and penetrate into all tissues and environments of the body, including cerebrospinal fluid and necrotic pancreatic tissue. 70% of their dose is excreted unchanged in the urine. Antibiotics are removed from the body by hemodialysis.

Carbapenems are necessary for the empirical treatment of severe community-acquired and hospital-acquired infections caused by multidrug-resistant microflora. In most cases, monotherapy with carbapenems replaces the combined use of 3 drugs - a third generation cephalosporin, an aminoglycoside and metronidazole. The effectiveness of treatment with carbapenems is 70–90%.

Indications for use are as follows:

Hospital-acquired pneumonia (including in patients with artificial ventilation);

Pulmonary sepsis in cystic fibrosis;

Complicated urinary tract infections;

Community-acquired and hospital-acquired intra-abdominal infections (80% of cases are destructive lesions of the abdominal organs, 20% are surgical interventions and injuries);

Gynecological and obstetric infections;

Infections of the skin, soft tissues, bones and joints;

Diabetic foot;

Neutropenic fever;

Endocarditis, sepsis;

Meningitis and brain abscess (prescribe only meropenem);

Prevention of infectious complications of anesthesia and perioperative infections.

In 20% of patients, imipenem injections are accompanied by side effects - nausea, vomiting, diarrhea, allergic reactions (in 50% of cases they are cross-reactions with other β-lactams). In diseases of the central nervous system and renal failure, there is a risk of tremors and seizures due to antagonism with GABA. Meropenem is much better tolerated - it does not cause dyspeptic disorders or convulsions.

Carbapenems are contraindicated in case of hypersensitivity to β-lactam antibiotics, pregnancy, and infants under 3 months. Breastfeeding is avoided during the treatment period.

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Carbapenems in modern clinical practice

Summary

Bacterial resistance represents a serious problem in antibacterial therapy and in this regard can have severe social consequences. According to Reuters, about 70,000 patients with nosocomial infections died in the United States in 2004, and half of them were caused by flora resistant to the antibiotics commonly used to treat such infections. Data have been published showing a higher mortality rate in patients with infections caused by resistant flora. There are reports of additional costs to the health care system associated with resistance of nosocomial flora, which, according to some estimates, range from 100 million to 30 billion dollars per year.

The main mechanisms of resistance of microorganisms are the production of enzymes that inactivate antibiotics; disruption or change in the structure of receptors that antibiotics need to contact to suppress bacterial growth; a decrease in the concentration of antibiotics inside bacteria, associated with the impossibility of their entry into bacterial cells due to impaired permeability of the outer membrane or active removal using special pumps.

Antibiotic resistance is observed everywhere and has an unfavorable upward trend. To date, in addition to resistance to a specific drug or group of drugs, multidrug-resistant bacteria have been isolated, i.e. resistant to the main groups of antibacterial drugs (β-lactams, aminoglycosides, fluoroquinolones), and pan-resistant, against which, according to microbiological studies, there are no active antibiotics.

The history of the creation of antibacterial drugs was directly related to the solution of certain clinical problems: the search for drugs with high natural activity to suppress streptococci (penicillin, ampicillin), staphylococci (oxacillin), gram-negative flora (aminoglycosides); overcoming side effects (allergy to natural penicillins); increased penetration of antibiotics into tissues and cells (macrolides, fluoroquinolones). However, the use of antibiotics has led to the activation of microflora protection processes against them. Therefore, when developing drugs that are currently widely used in the clinic, the task of overcoming the natural and acquired resistance of nosocomial flora has become urgent. The most prominent representatives of this relatively new generation of drugs are carbapenems.

Development of carbapenems and their structural and functional features

Like penicillins and cephalosporins, carbapenems are naturally occurring. The first carbapenem, thienamycin, is a product of Streptomyces cattleya. The basic structure of thienamycin and subsequent carbapenems, like penicillins, is a five-membered β-lactam ring. The chemical feature of carbapenems that distinguishes them from penicillins is the replacement of carbon with nitrogen in the 1st position and the presence of double bonds between 2 and 3 carbon atoms, high resistance to hydrolysis of the β-lactam ring in the 6th position and the presence of a thio group in the 2nd position five-membered ring. It is believed that the last of these differences is associated with the increased antipseudomonal activity of carbapenems.

The first of the carbapenems, imipenem, appeared in clinical practice in 1986. To increase the stability of this drug against renal dihydropeptidase-1, imipenem was combined with an inhibitor of this enzyme, cilastatin, which significantly improved its pharmacokinetics in the kidneys.

Meropenem appeared in clinical practice in 1996. The main chemical difference from imipenem was the presence of a transhydroxyethyl group in the 6th position, which determined the stability of the drug to the action of various β-lactamases and the unique microbiological and pharmacological characteristics. The appearance of a side dimethylcarbamylpyrrolidinthio group in the 2nd position of the five-membered ring sharply increased the activity of the drug against Pseudomonas aeruginosa and other important gram-negative bacteria. The methyl group in the 1st position created stability of the drug against the action of renal dihydropeptidase-1, which made it possible to use the drug without cilastatin.

Ertapenem became the third drug in the carbapenem family in 2001. Like meropenem, it is stable to renal dihydropeptidase-1 and various β-lactamases. The chemical difference of this drug was the replacement of the methyl group with a benzoic acid residue in the 2nd position of the five-membered ring, which sharply increased its binding to plasma proteins. This figure reaches 95%, for imipenem - 20% and 2% for meropenem. As a result, the half-life of the drug from plasma increased, and it became possible to administer it once a day. Modification of the chemical structure had a negative impact on its activity against non-fermentative Gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. In Psedomonas aeruginosa, it is proposed that a significant change in charge, increase in molecular weight and lipophilicity impaired the penetration of ertapenem through the membrane porin channel (OprD), which is a critical portal for the penetration of carbapenems.

In 2010, a new carbapenem appeared - doripenem. Its chemical structure resembles meropenem and ertapenem, differing in the presence of a sulfagroup in the 2nd position of the five-membered ring. This change resulted in increased activity against Staphylococcus aureus, while activity against gram-positive flora was not significantly changed compared to meropenem.

Mechanism of action and significance of penicillin-binding proteins

Carbapenems, like other β-lactam antibiotics, are bactericidal inhibitors of cell wall synthesis due to their binding to penicillin binding proteins (PBPs). PBPs are cytoplasmic cell wall proteins that complete the synthesis of peptidoglycan, the skeleton of the cell wall. Carbapenems bind to all major PBPs of Gram-negative bacteria. The main difference between the binding of carbapenems and other β-lactams to PBP is the high affinity for PBP-1a and -1b of Pseudomonas aeruginosa and E. coli, which leads to rapid killing of bacteria and increases the number of dead bacteria. Among carbapenems, in turn, there are differences in affinity for PSB-2 and -3 gram-negative bacteria. Imipenem has a greater affinity for PSB-2 compared to PSB-3. This causes the bacteria to acquire a spherical or ellipsoidal shape before lysis occurs. However, the affinity for Pseudomonas aeruginosa PSB-2 and -3 is the same. The affinity of meropenem and ertapenem for PSB-2 and -3 E. coli is significantly higher than that of imipenem. Similarly, the affinity for Pseudomonas aeruginosa PSB-2 is higher for meropenem than for imipenem, but for PSB-3 it is 3-10 times higher. Meropenem and doripenem have the same affinity for PSB-2, -3. At the same time, there are individual differences between microbial strains in the affinity of PBP to various carbapenems.

Pharmacodynamic features of carbapenems

They depend more on the frequency of drug administration than on the concentration in the blood, which distinguishes them from aminoglycosides and fluoroquinolones, the effectiveness of which is directly related to the concentration of the drug in plasma. The maximum bactericidal effect of carbapenems is observed when plasma concentrations exceed the minimum inhibitory concentration (MIC) by 4 times. Unlike carbapenems, the effectiveness of aminoglycosides and fluoroquinolones increases in proportion to their plasma concentration and can be limited only by the maximum permitted single dose of the drug.

The most important pharmacodynamic indicator of carbapenems is the ratio of the time when the drug concentration exceeds the MIC to the time between drug administrations. This indicator is expressed as a percentage (T > MIC%). Theoretically, it would be ideal to maintain carbapenem concentrations throughout 100% of the dosing interval. However, this is not necessary to achieve optimal clinical outcome. Moreover, this interval varies among different β-lactam antibiotics. To achieve the bacteriostatic effect of an antibiotic, an indicator of 30-40% is required for penicillins and cephalosporins and 20% for carbapenems. To achieve the maximum bactericidal effect, it is necessary to achieve 60-70% for cephalosporins, 50% for penicillins and 40% for carbapenems. Although penicillins, cephalosporins, and carbapenems kill bacteria by the same mechanism, differences in T > MICs reflect differences in the rate of killing, which is slowest for cephalosporins and fastest for carbapenems. The molecular reasons for the difference in this process between cephalosporins and carbapenems may be the different affinities of these drugs for PBP-1a and -1b.

Another important characteristic of these drugs is the duration of the postantibiotic effect (PAE). PAE is the effect of a drug that continues after it is removed from the system. Among β-lactams, PAE is most often observed in carbapenems. PAE of imipenem against some microbes, including P. aeruginosa, lasts 1-4.6 hours. It should be noted that this indicator can vary significantly among strains belonging to the same genus. Meropenem has a PAE similar to imipenem. The duration of PAE of ertapenem against gram-positive bacteria is 1.4-2.6 hours. In doripenem, PAE against S.aureus, K.pneumoniae, E.coli and P.aeruginosa was observed for about 2 hours, and only against strains of S.aureus and P.aeruginosa.

Spectrum of activity and clinical efficacy

Carbapenems have the widest spectrum of activity among all antibacterial drugs. They are active against gram-positive and gram-negative microbes, including aerobes and anaerobes. The MIC50 indicator allows one to evaluate their natural activity and resistance; in this indicator they are similar to fluoroquinolones and aminoglycosides. Some bacteria lack natural sensitivity to carbapenems, such as S. maltophila, B. cepacia, E. faecium and methicillin-resistant staphylococci. There are certain differences between carbapenems in natural activity, which may be due to impaired penetration of drugs through the cell membrane and the activity of efflux pumps. Data on the comparative activity of all 4 drugs against the same clinical strains of microbes are very limited. However, there are experimental data from global comparative studies of the activity of these drugs, which are also not exhaustive. For example, in one of them there is no comparative assessment of certain MIC values: the minimum concentration for doripenem and meropenem was 0.008 μg/ml, for ertapenem - 0.06 μg/ml, and for imipenem - 0.5 μg/ml, so 3023 strains E. coli comparison of MIC90 was possible only with the above indicators. However, there is direct comparison of the MICs of doripenem, meropenem and imipenem against Enterobacteriaceae, P. aeruginosa, Haemophylus influenza and Bordetella pertussis, which indicate their similar natural activity in terms of MIC50, which was similar or differed by one to twofold dilution. Only against Proteus mirabilis, the activity of meropenem was 4 times higher than the activity of doripenem, and both drugs turned out to be significantly more active than imipenem; the same trends persisted with respect to MIC90. All three drugs were equally active against penicillin-sensitive and penicillin-resistant S. pneumoniae. Resistance associated with modification of penicillin-binding proteins had a significant effect on the activity of carbapenems: MIC50 and MIC90 of penicillin-resistant strains were 32-64 times higher than those of sensitive strains, while MIC90 remained below 1 μg/ml. Doripenem had similar activity to imipenem against S. aureus and E. faecalis. Against ceftazidime-sensitive Enterobacteriaceae that do not produce extended-spectrum β-lactamases (ESBLs), the activity of ertapenem, meropenem and doripenem was equal to or superior to that of imipenem. However, the activity of ertapenem was significantly lower against non-fermenting gram-negative flora (P.aeruginosa, A.baumannii). Against S. pneumoniae, S. aureus, S. epidermidis and E. faecalis, the activity of carbapenems was approximately the same, including ertapenem. Against gram-positive and gram-negative anaerobes, the activity of carbapenems was also the same with an MIC50 of 1 μg/ml and lower.

Carbapenems and resistance mechanisms

Resistance to β-lactams is present in gram-negative and gram-positive microorganisms. Gram-positive bacteria do not have resistance mechanisms associated with changes in the properties of the outer membrane, or enzymes capable of destroying carbapenems. The emergence of resistance in Gram-positive bacteria is associated with changes in penicillin-binding proteins (PBPs), such as the emergence of PBP-2a with low affinity for all β-lactams in methicillin-resistant S. aureus (MRSA). In gram-negative bacteria, the presence of an outer membrane and various β-lactamases led to the emergence of resistance associated with the production of inactivating enzymes (β-lactamases), disruption of the PBP structure, and decreased accumulation of the drug in the periplastic space due to a decrease in the permeability of outer membrane porin proteins or efflux pumps , removing various antibiotics from microbial cells. Of these, the production of β-lactamases and a decrease in cellular permeability are of greatest importance.

Extended spectrum and AmpC class beta-lactamases

The production of β-lactamases is the most common mechanism of resistance in Gram-negative bacteria. The location of the hydroethyl group at position 6 determines the high stability of carbapenems compared to cephalosporins and penicillins to hydrolysis by β-lactamases, especially cephalosporinases (ESBLs and AmpC). Therefore, the real difference between carbapenems and other β-lactam antibiotics is their stability to the action of ESBLs and AmpC.

AmpC is a cephalosporinase with a broad spectrum of activity that destroys penicillins (including protected ones) and most cephalosporins. A necessary condition for the destruction of antibiotics is a high level of production of this enzyme by the microbe. In P.aeruginosa and many enterobacteria (E.coli, K.pneumoniae), the chromosomes contain information about the synthesis of AmpC, but synthesis begins under certain conditions - upon contact with an antibiotic. This nature of the formation and release of the enzyme is called inducible. However, if there is a congenital predisposition to hyperproduction of the enzyme, its depression may occur as a result of mutation. Cephalosporinases AmpC are present on plasmids of some enterobacteriaceae, most often they are found in K. pneumoniae and E. coli. Some plasmid-borne AmpC may have an inducible phenotype. Regardless of whether AmpC is chromosomal or plasmid, its overproduction in Enterobacteriaceae and P. aeruginosa leads to resistance to almost all β-lactams. However, many Enterobacteriaceae - hyperproducers of AmpC remain sensitive to cefepime and carbapenems, and most P.aeruginosa - hyperproducers of AmpC are sensitive to imipenem, meropenem and doripenem.

ESBL production is a second mechanism of β-lactam resistance. The production of these enzymes leads to resistance to penicillins and cephalosporins. The source of these enzymes for enterobacteria turned out to be Kluyvera spp. . It should be noted that this type of β-lactamases can be suppressed by β-lactamase inhibitors (sulbactam, tazobactam, clavulanic acid), so protected penicillins and cephalosporins can retain their activity against ESBL producers. However, carbapenems are considered the drugs of choice for the treatment of infections caused by ESBL-producing Enterobacteriaceae. It was shown that E. coli and K. pneumoniae remain sensitive to all carbapenems, with the exception of ertapenem, and MIC90 does not change significantly. The MIC90 of ertapenem in ESBL producers is approximately 4 times higher than in wild strains.

Carbapenemases

In addition to ESBLs and AmpC, some bacteria have enzymes (carbapenemases), information about which is encoded on the chromosome or plasmids. Such enzymes can be produced by some enterobacteria, P.aeruginosa and Acinetobacter spp. Carbapenemases pose a challenge to the treatment of severe infections with carbapenems, but a direct correlation between carbapenemase production and carbapenem resistance has not been identified. One explanation for this fact is the difference in the hydrolytic activity of carbapenemases towards different substrates, which are various carbapenem preparations. Other reasons may be a simultaneous decrease in penetration through the bacterial wall (changes in the structure of porin proteins) or the inaccessibility of target penicillin-binding proteins (presence of carbapenemases in the periplastic space). If carbapenemase production is present in clinical situations, carbapenems should not be used to treat infections caused by such microbes.

Porin-associated resistance

Reduced penetration into the bacterial cell is one of the mechanisms of resistance to carbapenems in enterobacteria. The most well-studied resistance in P.aeruginosa is associated with changes in the structure of the porin OprD, which passively captures basic amino acids and short peptides, but also serves as a channel for carbapenems. It is this mechanism of resistance that is characteristic of carbapenems and does not affect sensitivity to other β-lactam ABs. In P.aeruginosa, this mechanism is associated with a number of genetic mechanisms and leads to an increase in the MIC of imipenem by 4-16 times, meropenem by 4-32 times, and doripenem by 8-32 times. Despite the apparent benefit of imipenem, its MIC rises above the level considered sensitive (4 μg/ml), while the MICs of doripenem and meropenem remain below 4 μg/ml.

P. aeruginosa resistance associated with efflux

Potentially resistant P.aeruginosa has genes on its chromosome that encode information about several efflux pumps that remove various antibiotics from the cell. The most studied are Mex-OprM, MexCD-OprJ, MexEF-OprN and MexXY. These pumps are capable of pumping out various drugs from the cytoplasm and periplastic space of the cell. As a result of the study of these pumps, prospects have opened for the development of new antibacterial drugs that can control the process of their operation. Taking this into account, it became clear that it was necessary to separately consider their role in resistance to imipenem, meropenem and doripenem in P.aeruginosa.

The pumps that remove imipenem are not exactly installed. However, it has been shown that with high expression of two efflux pumps (MexCD-OprJ and MexEF-OprN), there is a significant decrease in the sensitivity of P.aeruginosa to imipenem. This mechanism has been shown not to involve a combination of the β-lactamase activities of AmpC and OprD. At the same time, high expression of MexCD-OprJ and MexEF-OprN leads to a significant decrease in sensitivity to imipenem due to decreased expression of OprD.

Unlike imipenem, meropenem is a suitable substrate for efflux pumps: it has been shown to be cleared from cells by MexAB-OprM, MexCD-OprJ and MexEF-OprN. According to other studies, only overproduction of MexAB-OprM determines resistance to meropenem. The influence of this mechanism explains the difference in resistance to imipenem and meropenem in P. aeruginosa strains that have such pumps. It is important to note that increased production of MexAB-OprM does not necessarily result in an increase in BMD above the sensitivity level, but does indicate a likely interaction of this mechanism with others (eg, OprD-associated resistance) and is therefore of important clinical significance. With regard to doripenem, it has been shown that it is a substrate for MexAB-OprM, MexCD-OprJ and MexEF-OprN efflux pumps; more detailed information is not available in the literature. Thus, the interaction of mechanisms related to clearance, permeability impairment, β-lactamase activity, and PBP availability leads to clinically significant carbapenem resistance.

Dosing and clinical pharmacokinetics

All carbapenems are water-soluble substances and are administered intravenously or intramuscularly due to low absorption from the gastrointestinal tract. The main dosages of drugs are presented in table. 1.

The amount of protein binding is an important indicator of the pharmacokinetics and antibacterial activity of drugs. Pharmacodynamic analysis of antibacterial drugs requires taking into account protein binding and discussing the kinetics of the “free” drug. As shown in table. 1, protein binding of imipenem (20%), doripenem (8%) and meropenem (3%) varies significantly. Changing the structure of ertapenem significantly increased dose-dependent protein binding: up to 95% at plasma concentrations below 100 mg/l and 85% above 300 mg/l. High protein binding results in longer elimination: the half-life of ertapenem is 4 hours compared to 1 hour for other carbapenems. The pharmacokinetic profile of the “free” drug after administration of a 500 mg dose shows its equivalence with imipenem, meropenem and ertapenem. In this case, predominantly renal clearance of the drug is observed in imipenem, meropenem and doripenem.

Due to its long half-life, ertapenem is the only carbapenem that is administered once daily (500 mg or 1 g). Meropenem is administered at 500 mg or 1 g after 8 hours, and imipenem at 500 mg or 1 g after 6-8 hours. A decrease in renal clearance requires a reduction in drug dosage, however, when using ertapenem, this clearance should be below 30 ml/min, when using meropenem - below 51 ml/min. The convulsive potential of imipenem requires special attention when choosing the dosage of the drug, taking into account renal function and body weight. Imipenem dosage reduction should begin after clearance decreases below 70 ml/min and in patients weighing less than 70 kg.

As stated earlier, the effectiveness of carbapenems depends on the duration of the intervals between drug administrations when its concentration is above the MIC. Optimization of pharmacodynamic parameters can be achieved by administering a higher dose, shortening the period between doses and increasing the duration of drug infusion. The most attractive method is to increase the duration of infusion, because... this makes it possible to optimize pharmacodynamic parameters without significantly increasing economic costs. However, the duration of infusion is limited by the stability of the drug in solution: meropenem and imipenem at room temperature should be administered within 3 hours; The stability of doripenem reaches 12 hours. Currently, continuous infusion of carbapenems may be considered for meropenem and doripenem. However, the maximum permitted dosage for meropenem is 6 g of the drug per day, and for doripenem - 1.5 g/day. To optimize pharmacodynamic parameters, it is necessary to use the maximum dose and prolonged infusion of the drug. Pharmacodynamic modeling showed that the use of meropenem at a dose of 6 g per day and a 3-hour infusion creates conditions for the suppression of flora, which is interpreted in microbiological testing as resistant (up to 64 μg/ml). The possibility of using doripenem in such situations is limited by its low permitted daily dose (1.5 g).

Carbapenems and seizures

All β-lactams have the potential to cause seizures, especially if inappropriately dosed in settings with impaired renal function or low body weight, certain chronic pathologies, or increased seizure activity. An increase in seizure activity was identified during the phase III clinical trial of imipenem, and later - meropenem and ertapenem. Various mechanisms can lead to seizures, but for carbapenems the main mechanism is inhibition of GABAa receptors. The side chain at position 2 of the 5-membered ring of carbapenems has been shown to be responsible for this complication. Moreover, at the highest concentration (10 mmol/l), imipenem suppresses 95% of GABA receptors that bind 3H-muscimol, meropenem suppresses 49%, and doripenem suppresses 10%. This mechanism explains the occurrence of seizures in 1.5-6% of patients receiving imipenem. In a retrospective dose-response study, low body weight, decreased renal function, a history of seizures, the presence of other central nervous system pathology, and high doses of imipenem/cilastatin were shown to be considered risk factors for seizures. An excess dose of imipenem/cilastatin is one that exceeds the recommended daily dose by 25% and the usual dose in patients with impaired renal function or concomitant CNS pathology. Careful control of the dosage of the drug allowed to reduce the incidence of seizures to the level observed with the use of meropenem and ertapenem (~0.5%).

Conclusion

Carbapenems currently remain the most reliable drugs for the treatment of nosocomial infections in severe patients, especially in cases of infections caused by resistant flora. Taking into account current trends in the growth and spread of resistance in nosocomial flora, carbapenems are the main drugs for the treatment of infections caused by resistant gram-negative microbes (enterobacteria, P. aeruginosa, Acinetobacter spp.). The permitted daily doses and the possibility of prolonged infusion allow us to consider meropenem as the only drug whose pharmacodynamics can be optimized to suppress flora, which, from a microbiological point of view, is determined to be resistant to meropenem and other carbapenems.

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group carbapenems are beta-lactam antibiotics with a very broad spectrum of action. These drugs are more resistant than penicillins and cephalosporins to the action of beta-lactamases of bacterial cells and have a bactericidal effect by blocking cell wall synthesis.

Carbapenems are active against many Gr(+)- and Gr(-) microorganisms. This applies, first of all, to enterobacteria, staphylococci (except for methicillin-resistant strains), streptococci, gonococci, meningococci, as well as Gr(-) strains resistant to the last two generations of cephalosporins and protected penicillins. In addition, carbapenems are highly effective against spore-forming anaerobes.

All drugs in this group are used parenterally. Quickly and for a long time they create therapeutic concentrations in almost all tissues. In meningitis, they are able to penetrate the blood-brain barrier. The advantage of all carbapenems is that they are not metabolized and are excreted by the kidneys in their original form. The latter must be taken into account when treating patients with renal failure with carbapenems. In this case, the elimination of carbapenems will be significantly slowed down.

Carbapenems are reserve antibiotics, used in case of ineffectiveness of treatment, for example, younger generation cephalosporins. Indications: severe infectious processes of the respiratory, urinary systems, pelvic organs, generalized septic processes, and so on. Use with caution in case of renal failure (individual dose adjustment), liver pathology, neurogenic disorders. The use of carbapenems during pregnancy is not recommended. Contraindicated in case of individual intolerance to carbapenems, as well as in parallel use of beta-lactams of other groups. Cross-allergic reactions with penicillin and cephalosporin drugs are possible.

Imipenem- has high activity against Gr(+) and Gr(-) flora. However, for the treatment of severe infections caused by gram-negative microorganisms, it is better to use meropenem. It is not used to treat meningitis, but is used in the treatment of joint and bone infectious pathologies, as well as for the treatment of bacterial endocarditis. Dosage: adults - intravenously 0.5-1.0 g every 6-8 hours (but not more than 4.0 g/day); children over 3 months with a body weight less than 40 kg - intravenously 15-25 mg/kg every 6 hours. Release form: powder for the preparation of intravenous injections in 0.5 g bottles.

Meropenem- more active than imipenem against gram-negative flora, while meropenem has weaker activity against gram-positive flora. It is used to treat meningitis, but is not used in the treatment of joint and bone infectious pathologies, as well as for the treatment of bacterial endocarditis. It is not inactivated in the kidneys, which makes it possible to treat severe infectious processes developing there. Contraindicated in children under three months of age. Release form: powder for infusion of 0.5 or 1.0 g in bottles.