Cephalosporins and carbapenems. New antibiotics in clinical practice Group of carbapenems

Carbapenems (imipenem and meropenem) are β-lactams. Compared with penicillins And cephalosporins, they are more resistant to the hydrolyzing action of bacterial β-lactamase, including ESBL, and have a wider spectrum of activity. Used for severe infections of various locations, including nosocomial, often as reserve drugs, but for life-threatening infections they can be considered as first-priority empirical therapy.

Mechanism of action. Carbapenems have a powerful bactericidal effect due to disruption 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 more quickly and, in addition, have a pronounced PAE against them.

Spectrum of activity. Carbapenems act on many gram-positive, gram-negative and anaerobic microorganisms.

Staphylococci are sensitive to carbapenems (except MRSA), streptococci, including S. pneumoniae(carbapenems are inferior in activity against ARP vancomycin), gonococci, meningococci. Imipenem acts on E. faecalis.

Carbapenems are highly active against most gram-negative bacteria of the family Enterobacteriaceae(Escherichia coli, Klebsiella, Proteus, Enterobacter, Citrobacter, Acinetobacter, Morganella), including strains resistant to cephalosporins III-IV generation and inhibitor-protected penicillins. Slightly lower activity against Proteus, serration, H.influenzae. Most strains P. aeruginosa initially sensitive, but during the use of carbapenems an increase in resistance is observed. Thus, according to a multicenter epidemiological study conducted in Russia in 1998-1999, resistance to imipenem in nosocomial strains P. aeruginosa in the ICU was 18.8%.

Carbapenems have a relatively weak effect on B.cepacia, is stable S.maltophilia.

Carbapenems are highly active against spore formers (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 parenterally only. They are well distributed in the body, creating therapeutic concentrations in many tissues and secretions. During 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 and are excreted primarily by the kidneys unchanged, therefore, in case of renal failure, their elimination may be significantly delayed.

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 quickly removed from the blood.

Indications:

• 1. Severe infections, mainly nosocomial, caused by multidrug-resistant and mixed microflora;
• 2. NPD infections(pneumonia, lung abscess, pleural empyema);
• 3. Complicated UTI infections;
• 4. Intra-abdominal infections;
• 5. Pelvic organ infections;
• 6. Sepsis;
• 7. Skin and soft tissue infections;
• 8. And infections of bones and joints(imipenem only);
• 9. Endocarditis(imipenem only);
• 10. Bacterial infections in patients with neutropenia;
• 11. Meningitis(meropenem only).

Contraindications. Allergic reaction to carbapenems. Imipenem/cilastatin should also not be used if you have an allergic reaction to cilastatin.

Carbapenems have an ultra-wide spectrum of action and a bactericidal effect. Carbapenems are prescribed if the 4th generation of cephalosporins does not work.

1st generation - imipenem - is destroyed by dehydropeptidase-1 of the kidneys, therefore it is combined with the dehydropeptidase-1 inhibitor cilastatin 1:1; combination drugs - tienam, primaxin

2nd generation – meropenem

Administered intravenously, intramuscularly 2-4 times a day, penetrate well into cavities and tissues, incl. in the liquid.

Spectrum of action

Range of action: ultra-wide – replace a combination of 2-4 antibiotics. The 2nd generation is more active against enterobacteria and pseudomonas. Natural resistance in chlamydia, mycoplasmas, corynebacteria, mycobacteria tuberculosis and leprosy, some types of pseudomonads, because the antibiotic does not penetrate inside the cell.

Indications for use

Indications: reserve antibiotics for severe infectious diseases of an aerobic-anaerobic nature. In the postoperative period, in gynecology, with sepsis, meningitis, complicated UTI infections, neonatal intensive care, 2nd generation + meningitis caused by multidrug-resistant Gr-bacteria.

Side effects

Side effects: carbapenems are relatively low toxic -

• allergic reactions are possible,
• local irritant effect,
• thrombophlebitis,
• dyspepsia,
• candidiasis,
• rarely - nephrotoxicity, tremor, muscle hypertonicity, paresthesia, pseudomembranous colitis.

I think you all remember the arrival of this group of drugs into clinical practice. It was like the antibiotic era that had just begun again, when patients who seemed hopeless were able to get back on their feet... albeit at what seemed to us then to be colossal financial costs (how naive we were, now for a tetracycline drug we pay more than the cost of treating a patient with carbapenems per day).

Let's remember the place of each of the drugs in this group in our clinical practice.

Currently, four drugs of the carbapenem group are registered in Russia, which are divided into antipseudomonas(due to some activity against Pseudomonas aeruginosa):

· Imipenem

Meropenem

Doripenem

AND non-pseudomonas:

Ertapenem

On my own behalf, I would like to note that all this “pseudomonas aeruginosa” and its absence is nothing more than a marketing ploy, since we must always remember that on our own, without the support of antipseudomonal drugs, which we talked about earlier, not a single carbapenem with P.aeruginosa won't cope.

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 general class effect and act on the cell wall of microorganisms, disrupting its formation (and how you remember, we are not Pinocchio, so we have this very wall). In addition, not a single case of cross-allergic reactions with a group of penicillins or cephalosporins has been described. At the same time, carbapenems have maximum resistance to hydrolysis by extended spectrum beta-lactamases (ESBLs), although at the moment there is an increasing 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 strains producing ESBLs.

Carbapenems also show activity against gram-positive flora, namely pneumococci, gonococci, meningococci and staphylococci (excluding MRSA)

In addition, carbapenems are highly active against anaerobes, except C.difficile.

Considering the ultra-broad spectrum of action, a false illusion may be created that this group of drugs can be used as broad-spectrum drugs, that is, in any more or less complex situation, which, by the way, has happened and is happening in some hospitals to this day. This approach would be a huge mistake, since carbapenems can be viewed 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 the main thing is not to overlook, 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 regarding de-escalation therapy. I have nothing against initial therapy with carbapenems for a patient in serious condition for whom they are indicated, but I am against changing antibacterial therapy after receiving the results of a microbiological study if therapy with carbapenems has yielded results. Let's remember how many days later we receive microbiological research data - at the earliest in five, and in most cases in a week, if we do not have a laboratory equipped according to modern principles. When do we conduct clinical monitoring of the effectiveness of antibacterial therapy? In the case of carbapenems, after 48 hours. That is, within two days we must decide whether the therapy is effective or whether we missed something, or whether the patient’s condition has changed due to the course of the underlying disease or an exacerbation of a concomitant disease. In general, by the time data is received from the laboratory, one way or another, the pathogenic microbe will already be destroyed by the “carpet bombing” of carbapenem, or carbapenem in combination with an antistaphylococcal or antipseudomonas drug, and there is no talk of any effective transition to another, cheaper antibacterial drug it can not be. If we started treating with carbapenems and they showed their effectiveness, then we need to end the therapy with them too and not rush around with the choice.

A few words about each representative.

This drug is notable for the fact that it has a long half-life, which allows it to be administered once a day, which is very important. Since carbapenems, like all betalactam antibacterial drugs, are time-dependent drugs, which are extremely important to administer strictly on the clock, otherwise the bactericidal concentration drops below the minimum and the selection of resistant strains begins. In addition, it is simply convenient, unlike other carbapenems, which require 4-time, long-term intravenous administration. If the department is equipped with infusion pumps, the problem is not so acute, but when they are not there, even the four-time administration becomes a problem, and a person is designed to reduce problems in his life as much as possible (as well as costs) and thus situations are not uncommon when they try switch to 3 or even 2-time administration. In the case of a severe infectious process, such manipulations are not permissible. And this is where ertapenem comes in handy, 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 powerful antipseudomonal drugs, the main thing is to choose the current dosage (we first We count per kilogram of body weight, the second - based on the MIC of the pathogen)

What readings 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 signs of osteomyelitis

Acute infections in the pelvic area

· Intra-abdominal infections of moderate severity (cholicestitis, cholangitis, diverticulitis, splenic abscess and liver abscess) that do not require drainage or surgical intervention.

2. Imipenem/cilastatin

It was with him that the solemn procession of carbapenems in Russia began. But how many marketing speculations surrounded it in the future, one of which was “the drug causes convulsions.” Imipenem increases seizure activity only in certain cases that must be taken into account:

Central nervous system infections

Doses more than 2 g per day

· Age over 60 - 65 years

History of seizures or central nervous system lesions - stroke, head injury, epilepsy

And when will we we use:

Bacterial endocarditis

· Septicemia

Cody and soft tissue infections (except MRSA)

Lower respiratory tract infections, including nosocomial pneumonia

· Gynecological infections

· Intra-abdominal infections

Infections caused by polymicrobial flora

· Complicated and uncomplicated urinary tract infections (pyelonephritis)

Can be used for:

§ Gas gangrene

§ Diabetic foot

§ Infections of bones and joints.

Dosage regimen:

· Imipenem is used in a regimen of 250 - 500 mg 4 times a day intravenously, preferably slowly, for urinary tract infections

Moderate infections - 500 mg intravenously slowly every 6 to 8 hours

· For severe infections caused by Pseudomonas aeruginosa: 1 g intravenously every 6 to 8 hours.

When dosing, the condition of the kidneys should be taken into account and the dose should be adjusted in case of renal failure.

3. Meropenem

Unlike imipenem, it can be used for CNS infections without restrictions.

Indications for use.

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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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Antibiotic tablets are substances that inhibit the growth of microorganisms and, as a result, kill them. Used to treat infectious pathologies. Can be 100% natural or semi-synthetic. So, what drugs are antibiotics?

Prescription of universal antibiotics

Prescribing the described medications is justified in the following cases:

1. Therapy is selected based on clinical symptoms, i.e. without identifying the pathogen. This is relevant for active illnesses, for example, meningitis - a person can die in just a couple of hours, so there is no time for complex measures.
2. The infection has not one, but several sources.
3. The microorganism that causes the disease is resistant to narrow-spectrum antibiotics.
4. A set of preventive measures is carried out after the operation.

Classification of universal antibiotics

The medicines we are considering can be divided into several groups (with names):

• penicillins – Ampicillin, Amoxicillin, Ticarcillin;
• tetracyclines - these include the drug of the same name;
• fluoroquinolones – Ciprofloxacin, Levofloxatin, Moxifloxacin; Gatifloxacin;
• aminoglycosides – Streptomycin;
• amphenicols – Levomycetin;
• carbapenems - Imipenem, Meropenem, Ertapenem.

This is the main list.

Penicillins

With the discovery of benzylpenicillin, scientists came to the conclusion that microorganisms could be killed. Despite the fact that, as they say, “a lot of water has already flown under the bridge,” this Soviet antibiotic has not been discounted. However, other penicillins were created:

• those that lose their qualities when passing through the acid-base environment of the gastrointestinal tract;
• those that do not lose their qualities when passing through the acid-base environment of the gastrointestinal tract.

Ampicillin and Amoxicillin

Special attention should be paid to antibiotics such as Ampicillin and Amoxicillin. In terms of action they are practically no different from each other. Able to cope with:

• gram-positive infections, in particular staphylococci, streptococci, enterococci, listeria;
• gram-negative infections, in particular, Escherichia coli and Haemophilus influenzae, salmonella, shigella, pathogens of whooping cough and gonorrhea.

But their pharmacological properties are different.

Ampicillin is characterized by:

• bioavailability – no more than half;
• the period of elimination from the body is several hours.

The daily dose varies from 1000 to 2000 mg. Ampicillin, unlike Amoxicillin, can be administered parenterally. In this case, injections can be done both intramuscularly and intravenously.

In turn, Amoxicillin is characterized by:

• bioavailability – from 75 to 90%; does not depend on food intake;
• The half-life is several days.

The daily dose varies from 500 to 1000 mg. The duration of treatment is five to ten days.

Parenteral penicillins

Parenteral penicillins have one important advantage over Ampicillin and Amoxicillin - the ability to cope with Pseudomonas aeruginosa. It leads to the formation of purulent wounds and abscesses, and is also the cause of cystitis and enteritis - infections of the bladder and intestines, respectively.

The list of the most common parenteral penicillins includes Ticarcillin, Carbenicillin, Piperacillin.

The first is prescribed for peritonitis, sepsis, septicemia. Effective in the treatment of gynecological, respiratory and skin infections. Prescribed to patients whose immune system is in an unsatisfactory state.

The second is prescribed in the presence of microorganisms in the abdominal cavity of the genitourinary system and bone tissue. Administered intramuscularly and, in difficult cases, intravenously through a dropper

The third is prescribed for pus in the abdominal cavity, genitourinary system, bone tissue, joints and skin.

Improved penicillins

Ampicillin and Amoxicillin become useless in the presence of beta-lactamases. But the great minds of mankind found a way out of this situation - they synthesized improved penicillins. In addition to the main active substance, they contain beta-lactamase inhibitors, these are:

1. Amoxicillin with added clavulanic acid. Generics – Amoxiclav, Flemoclav, Augmentin. Sold in injections and in oral form.
2. Amoxicillin with the addition of sulbactam. In pharmacies it is called Trifamox. Sold in tablets and in oral form.
3. Ampicillin with the addition of sulbactam. In pharmacies it is called Ampisid. Sold by injection. It is used in hospitals for diseases that are difficult for an ordinary person to recognize.
4. Ticarcillin with added clavulanic acid. In pharmacies it is called Timentin. Sold in a form for oral administration.
5. Piperacillin with tazobactam added. In pharmacies it is called Tacillin. Delivered by infusion drip.

Tetracyclines

Tetracyclines are not susceptible to beta-lactamases. And in this they are one step higher than penicillins. Tetracyclines destroy:

• gram-positive microorganisms, in particular staphylococci, streptococci, listeria, clostridia, actinomycetes;
• gram-negative microorganisms, in particular Escherichia coli and Hemophilus influenzae, salmonella, shigella, pathogens of whooping cough, gonorrhea and syphilis.

Their peculiarity is that they pass through the cell membrane, which allows them to kill chlamydia, mycoplasma and ureaplasma. However, they do not have access to Pseudomonas aeruginosa and Proteus.

Tetracycline is commonly found. Also on the list is Doxycycline.

Tetracycline

Undoubtedly, tetracycline is one of the most effective antibiotics. But he has weaknesses. First of all, insufficient activity with a high probability of changes in the intestinal microflora. For this reason, you should choose tetracycline not in tablet form, but in ointment form.

Doxycycline

Doxycycline, compared to tetracycline, is quite active with a low probability of changes in intestinal microflora.

Fluoroquinolones

The first fluoroquinolones, such as Ciprofloxacin, Ofloxacin, Norfloxacin, could not be called universal antibiotics. They were only able to cope with gram-negative bacteria.

Modern fluoroquinolones, Levofloxacin, Moxifloxacin, Gatifloxacin, are universal antibiotics.

The disadvantage of fluoroquinolones is that they interfere with the synthesis of peptidoglycan, a kind of building material of tendons. As a result, they are not permitted to persons under 18 years of age.

Levofloxacin

Levofloxacin is prescribed for the presence of microorganisms in the respiratory tract, bronchitis and pneumonia, infections in the ENT organs, otitis and sinusitis, infections in the skin, as well as for diseases of the gastrointestinal tract and urinary tract.

The duration of treatment is seven, sometimes ten, days. Dose – 500 mg at a time.

In pharmacies it is sold as Tavanik. Generics are Levolet, Glevo, Flexil.

Moxifloxacin

Moxifloxacin is prescribed for the presence of microorganisms in the respiratory tract, ENT organs, skin, and also as a prophylaxis after surgery.

Duration of treatment is from seven to ten days. Dose – 400 mg at a time.

It is sold in pharmacies as Avelox. There are few generics. The main active ingredient is included in Vigamox - eye drops.

Gatifloxacin

Gatifloxacin is prescribed for the presence of microorganisms in the respiratory tract, ENT organs, urogenital tract, as well as serious eye diseases.

Dose – 200 or 400 mg once.

In pharmacies it is sold as Tabris, Gaflox, Gatispan.

Aminoglycosides

A prominent representative of Aminoglycosides is Streptomycin, a drug that every person has heard of at least once in their life. It is indispensable in the treatment of tuberculosis.

Aminoglycosides are able to cope with most gram-positive and gram-negative bacteria.

Streptomycin

It is efficient. With its help, you can cure not only tuberculosis, but also diseases such as plague, brucellosis and tularemia. As for tuberculosis, localization is not important when using streptomycin. Sold in injections.

Gentamicin

It is gradually becoming a thing of the past, as it is very, very controversial. The fact is that there was hearing damage, up to complete deafness, which the doctors did not expect at all. In this case, the toxic effect is irreversible, i.e. Once you stop taking it, nothing is returned.

Amikacin

Amikacin is prescribed for peritonitis, meningitis, endocarditis, and pneumonia. Sold in ampoules.

Amphenicols

This group includes Levomycetin. It is prescribed for typhoid and paratyphoid fever, typhus, dysentery, brucellosis, whooping cough, and intestinal infections. Sold in the form of injections and ointments.

Carbapenems

Carbapenems are intended to treat severe infections. They are able to cope with many bacteria, including those resistant to all the antibiotics listed above.

Carbapenem is:

• Meropenem;
• Ertapenem;
• Imipenem.

Carbapenems are administered using a special dispenser.

Now you know the names of antibiotics, which drugs are antibiotic tablets and which are not. Despite this, under no circumstances should you self-medicate, but seek help from a specialist. Remember that taking these medications incorrectly can seriously harm your health. Be healthy!