The lactam antibiotics classification. Beta lactam antibiotics

Beta lactam antibiotics-LACTAM ANTIBIOTICS

S.V. Sidorenko, S.V. Yakovlev S.V. Sidorenko, S.V. Yakovlev

The article presents a detailed analysis of the most numerous group of antibacterial agents - beta-lactam antibiotics, their classification and microbiological characteristics. Recommendations for their use in clinical practice are given.

The paper presents a detailed analysis of the most numerous group of antibacterial agents, -lactam antibiotics, their classification and microbiological characteristics. Recommendations of their clinical use are given

S.V. Sidorenko, Department of Microbiology and Clinical Chemotherapy, Russian Medical Academy of Postgraduate Education S.V. Yakovlev, Department of Clinical Hematology and Intensive Care, Moscow Medical Academy. I.M. Sechenova S.V. Sidorenko, Department of Microbiology and Clinical Chemotherapy, Russian Medical Academy of Postgraduate Training S.V. Yakovlev, Department of Clinical Hematology and Intensive Care Therapy, I.M. Sechenov Moscow Medical Academy

1. Classification and microbiological characterization of beta-lactam antibiotics (bla)

UAVs are the basis of modern chemotherapy, as they occupy a leading or important place in the treatment of most infectious diseases. By the number of drugs used in the clinic, this is the largest group among all antibacterial agents. Their diversity is explained by the desire to obtain new compounds with a wider spectrum of antibacterial activity, improved pharmacokinetic characteristics and resistance to constantly emerging new mechanisms of microorganism resistance. The classification of modern UAVs (based on their chemical structure) and drugs registered in the Russian Federation are given in table 1.1.1. Mechanisms of action of UAVs and resistance of microorganisms to them

A common fragment in the chemical structure of BLA is the beta-lactam ring; the microbiological activity of these drugs is associated with its presence. A schematic representation of the mechanisms of action of UAVs and the resistance of microorganisms to them is given. on the image.

Due to the ability to bind to penicillin (and other UAVs), these enzymes received a second name - penicillin-binding proteins(PSB). PSB molecules are rigidly bound to the cytoplasmic membrane of a microbial cell; they carry out the formation of cross-links. The binding of BLAH to PSB leads to inactivation of the latter, cessation of growth, and subsequent death of the microbial cell. Thus, the level of activity of specific UAVs in relation to individual microorganisms is primarily determined by their affinity (affinity) for PSB. For practice, it is important that the lower the affinity of the interacting molecules, the higher concentrations of the antibiotic are required to suppress the function of the enzyme. Table 1. Classification of modern UAVs

I. Penicillins
1. Natural: benzylpenicillin, phenoxymethylpenicillin
2. Semi-synthetic
2.1. Penicillinase-stable	2.2. Aminopenicillins	2.3 Carboxypenicillins	2.4. Ureidopenicillins
methicillin	ampicillin	carbenicillin	azlocillin
oxacillin	amoxicillin	ticarcillin	mezlocillin
			piperacillin
II. Cephalosporins
1st generation	II generation	III generation	IV generation
parenteral	parenteral	parenteral	parenteral
cephalothin	cefuroxime	cefotaxime	cefpir
cephaloridine	cefamandol	ceftriaxone
cefazolin	cefoxitin*	cefodizyme
oral	cefotetan*	ceftizoxime
cephalexin	cefmetazole*	cefoperazone**
cefadroxil	oral	cefpyramide**
cephradine	cefaclor	ceftazidime**
	cefuroxime axetil	moxalactam
		oral
		cefixime
		cefpodoxime
		ceftibuten
III. Combined drugs		IV. Carbapenems	V. Monobactams
ampicillin/sulbactam		imipenem	aztreonam
amoxicillin/clavulanate		meropenem
ticarcillin/clavulanate
piperacillin/tazobactam
cefoperazone/sulbactam
Note: drugs with pronounced antianaerobic activity (cephamycins); *preparations with pronounced activity against P. aeruginosa and non-fermenting microorganisms.

However, to interact with PSB, the antibiotic must penetrate from the external environment through the external structures of the microorganism. In gram-positive microorganisms, the capsule and peptidoglycan are not a significant barrier to BL diffusion. The lipopolysaccharide layer of Gram-negative bacteria is an almost insurmountable barrier to UAV diffusion. The only way for BLA diffusion is the porin channels of the outer membrane, which are funnel-shaped structures of a protein nature, and are the main way of transporting nutrients into the bacterial cell. The next factor limiting the access of BLA to the target of action is beta-lactamase enzymes, which hydrolyze antibiotics. Beta-lactamases probably first appeared in microorganisms simultaneously with the ability to produce BLA as factors that neutralize the effect of synthesized antibiotic substances. As a result of interspecies gene transfer, beta-lactamases have become widespread among various microorganisms, including pathogens. In Gram-negative microorganisms, beta-lactamases are localized in the periplasmic space; in Gram-positive microorganisms, they freely diffuse into the environment. Practically important properties of beta-lactamases include: Substratum profile(the ability to preferentially hydrolyze certain UAVs, such as penicillins or cephalosporins, or both equally). Localization of coding genes(plasmid or chromosome). This characteristic defines the epidemiology of resistance. With plasmid localization of genes, a rapid intra- and interspecies spread of resistance occurs, with chromosomal localization, the spread of a resistant clone is observed. expression type(constitutive or inducible). At constitutive type, microorganisms synthesize beta-lactamase at a constant rate, with an inducible amount of the synthesized enzyme increases sharply after contact with an antibiotic (induction). sensitivity to inhibitors. Inhibitors include substances of a beta-lactam nature that have minimal antibacterial activity, but are capable of irreversibly binding to beta-lactamases and thus inhibiting their activity (suicidal inhibition). As a result, with the simultaneous use of BLA and beta-lactamase inhibitors, the latter protect antibiotics from hydrolysis. Dosage forms in which antibiotics and beta-lactamase inhibitors are combined are called combined, or protected, beta-lactams. Three inhibitors have been introduced into clinical practice: clavulanic acid, sulbactam and tazobactam. Unfortunately, not all known beta-lactamases are sensitive to their action. Among the variety of beta-lactamases, it is necessary to single out several groups that have the greatest practical significance. (Table 2). More information on the modern classification of beta-lactamases and their clinical significance can be found in the reviews.

Since peptidoglycan (target of action of BLA) is an essential component of a microbial cell, all microorganisms are more or less sensitive to antibiotics of this class. However, in practice, the real activity of UAVs is limited by their concentrations in the blood or the source of infection. If PBPs are not inhibited at concentrations of antibiotics that are actually achievable in the human body, then one speaks of the natural resistance of the microorganism. However, only mycoplasmas have true natural resistance to BLA, since they lack peptidoglycan, the target of antibiotics. In addition to the level of natural sensitivity (or resistance), the clinical efficacy of UAVs is determined by the presence of acquired resistance in microorganisms. Acquired resistance is formed by changing one of the parameters that determine the level of natural sensitivity of the microorganism. Its mechanisms can be: I. Decreased affinity of PSB for antibiotics. II. Reducing the permeability of the external structures of the microorganism. III. The appearance of new beta-lactamases or a change in the expression pattern of existing ones. These effects are the result of various genetic events: mutations in existing genes or the acquisition of new ones.

Beta-lactam antibiotics are antimicrobial agents that combine 4 groups of antibiotics of different origin and spectrum of antimicrobial activity, but united by one common feature - the content of the beta-lactam ring in the molecular formula.

The group of beta-lactams includes penicillin antibiotics, cephalosporins, carbapenems and mnobactams.

A similar chemical structure determines the general mechanism of antibacterial action, which consists in disrupting the synthesis of moray eels, the main building component of the prokaryotic membrane.

The development of cross-allergy or acquired resistance in bacteria due to a common structural component cannot be ruled out.

It is noted that the lactam ring is highly sensitive to the destructive effects of beta-lactamase proteins. Each of the representatives of the 4 classes is characterized by its degree of stability and may differ significantly in natural and semi-synthetic representatives.

Currently, lactam antibiotics are one of the most commonly used groups of antibiotics and are used universally for drug therapy of a wide range of diseases.

General classification of beta-lactam antibiotics:

Penicillins:
Cephalosporins, 5 generations.
Carbapenems.
Monobactams.

Full list

Penicillins
Natural		benzylpenicillin ®
		Phenoxymethylpenicillin ®
		Benzathine phenoxymethylpenicillin ®
Semi-synthetic	Antistaylococcal	oxacillin ®
	Aminopenicillins (spread spectrum)	ampicillin ®
		amoxicillin ®
	Carboxypenicillins (antipseudomonal)	carbenicillin ®
		ticarcillin ®
	Ureidopenicillins	azlocillin ®
		mezlocillin ®
		piperacillin ®
	inhibitor-protected
	Combined
Cephalosporins
1 generation	Injectable	cefalotin ®
		cephaloridine ®
		cefazolin ®
	Oral	cephalexin ®
		cefadroxil ®
		cephradine ®
2 generation	Injectable	cefuroxime ®
		cefamandol ®
		cefoxitin ®
		cefotetan ®
		cefmetazole ®
	Oral	cefaclor ®
		cefuroxime-axetil ®
3rd generation	Injectable	cefotaxime ®
		ceftriaxone ®
		cefodizyme ®
		ceftizoxime ®
		cefoperazone ®
		cefpyramide ®
		ceftazidime ®
		cefoperazone/sulbactam ®
	Oral	cefixime ®
		cefditoren
		cefpodoxime ®
		ceftibuten ®
4th generation	Injectable	cefpirom ®
		cefepime ®
5th generation	Injectable	ceftobiprol ®
		ceftaroline ®
		ceftolosan ®
Carbapenems
Infusions and intramuscular		imipenem ®
		meropenem ®
Monobactams
Infusions		aztreonam ®

Instructions for most of these drugs are on the website in the section "".

Penicillins

Penicillins are the first antimicrobial substances that were accidentally discovered by Alexander Fleming and revolutionized the world of medicine. The natural producer is Penicilla mushrooms. When the minimum inhibitory concentration is reached, beta-lactam antibiotics have bactericidal activity (destroy pathogenic microorganisms). Penicillin has low toxicity for mammals, since they lack the main target for exposure - peptidoglycan (murein ®). However, individual intolerance to the drug and the development of an allergic reaction are possible.

Due to the frequent use of penicillins, microorganisms have developed defense systems against the antibacterial effects of beta-lactams:

active synthesis of beta-lactamases;
rearrangement of peptidoglycan proteins.

Therefore, scientists have modified the chemical formula of the substance and in the 21st century, semi-synthetic penicillins, which are detrimental to a large number of gram-positive and gram-negative bacteria, have become widespread.

Discovery history

The British bacteriologist A. Fleming, as he himself later admitted, did not plan to revolutionize medicine with the discovery of antibiotics. However, he succeeded, and quite by accident. But, as you know, luck bestows only prepared minds, which he was. By 1928, he had already established himself as a competent microbiologist and conducted a comprehensive study of bacteria of the Staphylococcaceae family. However, A. Fleming did not differ in his predilection for the ideal order.

Having prepared Petri dishes with cultures of staphylococci for slaughter, he left them on his table in the laboratory and went on vacation for a month. Upon his return, he noticed that there was no bacterial growth where the mold had fallen from the ceiling onto the cup. On September 28, 1928, the greatest discovery in the history of medicine was made. It was possible to obtain the substance in its pure form by 1940, through the joint efforts of Fleming, Flory and Cheyne, for which they were awarded the Nobel Prize.

Indications for the use of penicillins

Penicillins are prescribed for a wide range of diseases:

purulent;
sinusitis;
otitis;
treatment of Helicobacter pylori infection (amoxicillin);
sepsis;
meningococcal infections;
osteomyelitis;
inflammatory processes;
diphtheria;
sexually transmitted infections (syphilis, gonorrhea);
pyoderma;
infections of the pelvic organs (prostatitis, adnexitis, etc.);
and (, scarlet fever, etc.);
malignant carbuncle.

Contraindications and side effects of penicillins

The main contraindication to the use of penicillins is individual intolerance and allergies to all lactam antimicrobial drugs. It is forbidden to inject into the lumen between the membrane of the spinal cord and the periosteum to people diagnosed with epilepsy.

Adverse symptoms include disorders of the gastrointestinal tract () and the central nervous system (weakness, drowsiness, irritability), and the oral cavity, as well as swelling.

It is noted that if the dosage and duration of treatment are observed, side effects are rare.

Important features of penicillins

Patients with pathologies of the functioning of the kidneys and liver are prescribed only if the benefit of the antibiotic significantly outweighs the possible risks. In the absence of relief of the symptoms of the disease after 48-72 hours after the start of treatment, the appointment of drugs of an alternative group is recommended.

Self-medication with lactam drugs is prohibited due to the rapid development of resistance of pathogenic strains to them.

Cephalosporins

The most extensive group of beta-lactams, leading in terms of the number of drugs. To date, 5 generations of drugs have been developed. Each subsequent generation is characterized by greater resistance to lactamases and an extended list of antimicrobial activity.

Of particular interest is the 5th generation, but many of the discovered drugs are still at the stage of preclinical and clinical trials. It is assumed that they will be active against a strain of Staphylococcus aureus, resistant to all known antimicrobial agents.

History of the discovery of cephalosporins

They were discovered in 1948 by the Italian scientist D. Brotzu, who was engaged in the study of typhus. He noted that in the presence of C. acremonium, no growth of S. typhi culture was observed on the Petri dish. Later, the substance was obtained in its pure form and is actively used in many areas of medicine and is being improved by microbiologists and pharmacological companies.

Indications for the use of cephalosporins

Drugs are prescribed by a doctor after isolation, identification of the causative agent of inflammation and determination of sensitivity to antibiotics. Self-treatment is unacceptable, this can lead to serious consequences for the human body and the spread of uncontrolled bacterial resistance. Cephalosporins are effective against staphylococcal and streptococcal infections of the dermis, bone tissue and joints, including MRSA (5th generation cephalosporins), respiratory tract infections, meningitis, sinusitis, tonsillitis, otitis media, intra-abdominal infections, genital infections, STDs (sexually transmitted diseases). ) etc.

Contraindications and side effects of cephalosporins

Contraindications are similar to penicillins. At the same time, the incidence of side effects is lower than in the previous group. Marks in the anamnesis of the patient about allergy to penicillins serve as a warning for use.

Before using injectable antibiotics, a test for allergic reactions (allergy tests) is performed.

Important Features

None of the cephalosporin drugs are compatible with alcohol. Violation of this rule can lead to acute and severe intoxication, damage to the liver and nervous system.

No correlation has been established between food intake and drug intake. When taking lactam antibiotics orally, it is recommended to drink it with plenty of water. Despite the fact that special studies aimed at establishing the safety of cephalosporins for pregnant women have not been conducted, nevertheless, it is successfully used for women in position. At the same time, no complications of the course of pregnancy and pathologies in the fetus were noted. However, it is forbidden to use antibiotics without a doctor's prescription.

Breastfeeding during treatment is stopped, as the substance passes into breast milk.

Carbapenems

Leaders in the degree of resistance to the action of lactamases. This fact explains the huge list of pathogenic bacteria for which carbapenems are detrimental. An exception is the NDM-1 enzyme found in E. coli and K. pneumoniae cultures. They exhibit bactericidal activity against representatives of the Enterohacteriaceae and Staphylococcaceae families, Pseudomonas aeruginosa and many anaerobic bacteria.

Toxicity does not exceed permissible limits, and their pharmacokinetic parameters are quite high. The effectiveness of the antimicrobial substance has been established and confirmed in the course of independent studies in the treatment of inflammation of varying severity and localization. The mechanism of their action, like all lactams, is aimed at inhibiting the biosynthesis of the bacterial cell wall.

The history of the discovery of carbapenems

After 40 years since the beginning of the "penicillin era", scientists have sounded the alarm about the growing levels of resistance and actively began work on the search for new antimicrobial agents, one of the results of which was the discovery of a group of carbapenems. First, they discovered imipenem, which met all the requirements for bactericidal substances. Since its discovery in 1985, more than 26 million patients have been cured by it. Carbapenems have not lost their significance at the present time, and there is no area of medicine where they would not be used.

Indications

The tool is indicated for hospitalized patients with infections of various organ systems, with:

hospital pneumonia;
sepsis;
meningitis;
fever
inflammation of the lining of the heart and soft tissues;
infections of the abdominal region;
osteomyelitis.

Contraindications and side effects of carbapenems

The safety of the substance has been confirmed by numerous studies. The incidence of negative symptoms (nausea, vomiting, rash, seizures, drowsiness, pain in the temporal region, stool disorder) is less than 1.8% of the total number of patients. Negative effects stop immediately when you stop taking the medicine. There are isolated reports of a decrease in the concentration of neutrophils in the blood during treatment with carbapenems.

Important features of carbapenems

Beta-lactam antibiotics have been successfully used for effective therapy for more than 70 years, however, it is necessary to strictly follow the doctor's prescriptions and instructions for use. Carbapenems are not compatible with alcohol and it is worth limiting its intake for 2 weeks after drug treatment. Revealed complete incompatibility with ganciclovir. With the combined use of these drugs, convulsions are observed.

Pregnant and breastfeeding women are prescribed for life-threatening pathologies.

Monobactams

A distinctive feature is the absence of an aromatic ring associated with the beta-lactam ring. Such a structure guarantees them complete immunity to lactamases. They have bactericidal activity to a greater extent against gram-negative aerobic bacteria. This fact is explained by the peculiarities of the structure of their cell wall, which consists in a thinner layer of peptidoglycan when compared with gram-positive microbes.

An important feature of monobactams is that they do not cause cross-allergy to other lactam antibiotics. Therefore, their use is permissible in case of individual intolerance to other lactam antibiotics.

The only drug that has been introduced into medical practice is aztreonam with a limited spectrum of activity. Aztreonam is considered a "young" antibiotic and was approved in 1986 by the Ministry of Food and Drug Administration.

Indications of monobactams

It is characterized by a narrow spectrum of action and belongs to the group of antibiotic drugs used in inflammatory processes caused by gram-negative pathogenic bacteria:

sepsis;
hospital and community-acquired pneumonia;
urinary tract infections, abdominal organs, dermis and soft tissues.

In order to achieve maximum results, combined therapy with drugs that destroy gram-positive microbial cells is recommended. Exclusively parenteral administration.

Contraindications and side effects of monobactams

Restriction to the appointment of aztreonam is only individual intolerance and allergies.

Undesirable reactions from the body are possible, manifested in the form of jaundice, abdominal discomfort, confusion, sleep disturbances, rashes and nausea. As a rule, they all disappear when therapy is stopped. Any, even the most insignificant negative reactions from the body - this is a reason to immediately consult a doctor and adjust the treatment.

Important features of monobactams

It is undesirable to prescribe to pregnant women, because the safety of monobactams has not been studied for this category of people. It is known that the substance can diffuse through the placenta into the fetal circulation. Therapy by women on HB is acceptable, the level of a bactericidal substance in breast milk does not exceed 1%.

Children are prescribed in cases where other drugs have not shown their therapeutic properties. Adverse symptoms are similar to those in adults. Be sure to carry out a dose adjustment with a decrease in the active component. Correction is also necessary for elderly patients, since their kidney function is already slowed down and the substance is excreted from the body to a much lesser extent.

With caution and only in cases of life-threatening patients are prescribed for pathology of the liver and kidneys.

On our site you can get acquainted with most groups of antibiotics, complete lists of their drugs, classifications, history and other important information. For this, a section "" has been created in the top menu of the site.

The classification of beta-lactam antibiotics includes 4 classes of drugs:

penicillins:

natural: benzylpenicillin, bicillins.

semi-synthetic: - narrow spectrum: methicillin, oxacillin, - broad spectrum: ampicillin, amoxicillin, - carboxypenicillins: carbenicillin, ticarcillin - are easily destroyed by β-lactamases. - ureidopenicillins: azlocillin, mezlocillin, piperacillin - are easily destroyed by β-lactamases. - potentiated penicillins (contain beta-lactamase inhibitors that protect the antibiotic from destruction by bacterial enzymes, but do not have bactericidal activity themselves). Beta-lactamase inhibitors include clavulanic acid, sulbactam, tazobactam. The most famous combinations of antibiotics and beta-lactamase inhibitors:

amoxicillin + clavulanic acid = amoxiclav, augmentin,

ampicillin + sulbactam = sultamicillin, unazine, ampiside, sulacillin Cephalosporins have 4 generations. The β-lactam ring of cephalosporins has a somewhat different structure than that of penicillins (the difference is associated with the areas surrounding the ring), and therefore is more resistant to the action of β-lactamases (compared to penicillins). Monobactams: aztreonam. Aztreonam is the only antibiotic of the 4 classes that is resistant to the New Delhi metallo-beta-lactamase, but degraded by some other beta-lactamases. The spectrum of action is narrower - it acts only on gram-negative bacteria and does not affect gram-positive (staphylo-, streptococci, etc.).

Carbapanems: imipenem, meropenem. These are expensive modern antibiotics with the widest spectrum of action of all known antibiotics. Resistant to a number of beta-lactamases, but not all. Useless for the treatment of MRSA infections. Used in intensive care units of hospitals to treat severe infections when other drugs are ineffective.

general characteristics

Penicillins, cephalosporins and monobactams are sensitive to the hydrolyzing action of special enzymes - β-lactamases produced by a number of bacteria. Carbapenems are characterized by a significantly higher resistance to β-lactamases.

Given the high clinical efficacy and low toxicity, β-lactam antibiotics form the basis of antimicrobial chemotherapy at the present stage, occupying a leading position in the treatment of most infections. Penicillin group

Produced by various types of fungus penicillium (Penicillium chrysogenum, Penicillium notatum, etc.). As a result of the vital activity of these fungi, various types of penicillin are formed.

One of the most active representatives of this group - benzylpenicillin - has the following structure:

Other types of penicillin differ from benzylpenicillin in that they contain other radicals instead of the benzyl group.

According to the chemical structure, penicillin is an acid, various salts can be obtained from it. The basis of the molecule of all penicillins is 6-aminopenicillanic acid, a complex heterocyclic compound consisting of two rings: thiazolidine and beta-lactam.

Preparations of the penicillin group are effective in infections caused by gram-positive bacteria (streptococci, staphylococci, pneumococci), spirochetes and other pathogenic microorganisms.

A characteristic feature of some semi-synthetic penicillins is their effectiveness against strains of microorganisms resistant to benzylpenicillin.

The resistance of resistant strains of microorganisms to the penicillin group is due to their ability to produce specific enzymes - beta-lactamases (penicillinase), hydrolyzing the beta-lactam ring of penicillins, which deprives them of antibacterial activity.

Recently, not only antibiotics resistant to the action of beta-lactamases have been obtained, but also compounds that destroy these enzymes.

Preparations of the penicillin group are not effective against viruses (causative agents of influenza, poliomyelitis, smallpox, etc.), Mycobacterium tuberculosis, the causative agent of amoebiasis, rickettsiae, fungi, and most pathogenic gram-negative microorganisms.

Preparations of this group have a bactericidal effect on microorganisms that are in the growth phase. The antibacterial effect is associated with the specific ability of penicillins to inhibit the biosynthesis of the cell wall of microorganisms. Their targets are transpeptidases, which complete the synthesis of cell wall peptidoglycan. Transpeptidases are a set of enzyme proteins localized in the cytoplasmic membrane of a bacterial cell. Individual beta-lactams differ in the degree of affinity for a particular enzyme, which is called penicillin-binding proteins.

Side effects: headache, fever, urticaria, rash on the skin and mucous membranes, joint pain, eosinophilia.

Antibiotics are a group of drugs with an etiotropic mechanism of action. In other words, these drugs act directly on the cause of the disease (in this case, the pathogen microorganism) and do it in two ways: they destroy microbes (bactericidal drugs - penicillins, cephalosporins) or prevent their reproduction (bacteriostatic - tetracyclines, sulfonamides).

There are a huge number of drugs that are antibiotics, but the most extensive group among them is beta-lactams. It is about them that will be discussed in this article.

Classification of antibacterial agents

According to the mechanism of action, these drugs are divided into six main groups:

Antibiotics that disrupt the synthesis of cell membrane components: penicillins, cephalosporins, etc.
Drugs that interfere with the normal functioning of the cell wall: polyenes, polymyxins.
Drugs that inhibit protein synthesis: macrolides, tetracyclines, aminoglycosides, etc.
Suppressing RNA synthesis at the stage of RNA polymerase action: rifampicins, sulfonamides.
Suppressing RNA synthesis at the stage of DNA polymerase action: actinomycins, etc.
DNA synthesis blockers: anthracyclines, nitrofurans, etc.

However, this classification is not very convenient. In clinical practice, the following division of antibacterial drugs is accepted:

Penicillins.
Cephalosporins.
Macrolides.
Aminoglycosides.
Polymyxins and polyenes.
Tetracyclines.
Sulfonamides.
Derivatives of aminoquinolones.
Nitrofurans.
Fluoroquinolones.

Beta-lactam antibiotics. Structure and mechanism of action

This is a group of drugs with a bactericidal effect and a fairly wide list of indications for use. Beta-lactam antibiotics include penicillins, cephalosporins, carbapenems, monobactams. All of them are characterized by high efficiency and relatively low toxicity, which makes them the most commonly prescribed drugs for the treatment of many diseases.

The mechanism of action of beta-lactam antibiotics is due to their structure. Excessive details are useless here, it is worth mentioning only the most important element, which gave the name to the entire group of drugs. The beta-lactam ring, which is part of their molecules, provides a pronounced bactericidal effect, which is manifested by blocking the synthesis of elements of the cell wall of the pathogen. However, many bacteria are able to produce a special enzyme that disrupts the structure of the ring, thereby depriving the antibiotic of its main weapon. That is why the use of drugs that do not have protection against beta-lactamase in the treatment is ineffective.

Now antibiotics of the beta-lactam group, protected from the action of a bacterial enzyme, are becoming more widespread. They include substances that block the synthesis of beta-lactamase, for example, clavulonic acid. This is how protected beta-lactam antibiotics (such as Amoxiclav) are created. Other bacterial enzyme inhibitors include Sulbactam and Tazobactam.

Drugs from the penicillin group: historical background

The drugs of this series were the first antibiotics, the therapeutic effect of which became known to people. For a long time they were widely used to treat various diseases and in the first years of use were almost a panacea. However, it soon became clear that their effectiveness was gradually declining, as the evolution of the world of bacteria does not stand still. Microorganisms are able to quickly adapt to a variety of complex conditions of existence, giving rise to generations of antibiotic-resistant bacteria.

The prevalence of penicillins has led to the rapid growth of strains of microbes insensitive to them, therefore, in their pure form, preparations of this group are now ineffective and almost never used. They are best used in combination with substances that enhance their bactericidal effect, as well as suppress the defense mechanisms of bacteria.

Penicillin preparations

These are beta-lactam antibiotics, the classification of which is quite extensive:

Natural penicillins (for example, "Benzylpenicillin").
Antistaphylococcal ("Oxacillin").
Extended-spectrum penicillins ("Ampicillin", "Amoxicillin").
Antipseudomonal ("Azlocillin").
Protected penicillins (combined with clavulonic acid, Sulbactam, Tazobactam).
Preparations that include several antibiotics of the penicillin series.

A brief overview of drugs belonging to the penicillin group

Natural penicillins are able to successfully suppress the activity of both gram-positive and gram-negative microorganisms. Of the latter, streptococci and the causative agent of meningitis are most sensitive to this group of beta-lactam antibiotics. The rest of the bacteria have now acquired defense mechanisms. Natural penicillins are also effective against anaerobes: clostridia, peptococci, peptostreptococci, etc. These drugs are the least toxic and have a relatively small number of undesirable effects, the list of which is reduced mainly to allergic manifestations, although in case of an overdose, the development of a convulsive syndrome and the appearance of symptoms of poisoning with side of the digestive system.

Of the antistaphylococcal penicillins, the beta-lactam antibiotic Oxacillin is of the greatest importance. This is a drug for narrow use, since it is intended primarily to combat Staphylococcus aureus. It is against this pathogen (including penicillin-resistant strains) that Oxacillin is most effective. Side effects are similar to those of other representatives of this group of drugs.

Extended-spectrum penicillins, in addition to gram-positive, gram-negative flora and anaerobes, are also active against pathogens of intestinal infections. Side effects are the same as those listed above, although these drugs are slightly more likely to cause digestive upset.

The beta-lactam antibiotic "Azlocillin" (a representative of the fourth group of penicillins) is intended to fight against. However, at present, this pathogen has shown resistance to drugs of this series, which makes their use not so effective.

Protected penicillins have already been mentioned above. Due to the fact that these drugs include substances that inhibit bacterial beta-lactamase, they are more effective in the treatment of many diseases.

The last group is a combination of several representatives of the penicillin series, mutually reinforcing each other's action.

Four generations of bacterial exterminators

Cephalosporins are also beta-lactam antibiotics. These drugs differ in the breadth of the spectrum of action and the insignificance of side effects.

There are four groups (generations) of cephalosporins:

The brightest representatives of the first generation are Cefazolin and Cefalexin. They are intended primarily for the fight against staphylococci, streptococci, meningococci and gonococci, as well as some gram-negative microorganisms.
The second generation is the beta-lactam antibiotic Cefuroxime. Its area of responsibility includes mainly gram-negative microflora.
"Cefotaxime", "Ceftazidime" are representatives of the third group of this classification. They are very effective against enterobacteria, and are also able to destroy the nosocomial flora (hospital strains of microorganisms).
The main drug of the fourth generation is Cefepim. It has all the advantages of the above medicines, in addition, it is extremely resistant to the action of bacterial beta-lactamase and has activity against Pseudomonas aeruginosa.

Cephalosporins and beta-lactam antibiotics in general are characterized by a pronounced bactericidal effect.

Of the adverse reactions to the administration of these drugs, various allergic reactions deserve the most attention (from minor rashes to life-threatening conditions, such as anaphylactic shock), in some cases, digestive disorders are possible.

Backup facility

Imipenem is a beta-lactam antibiotic belonging to the group of carbapenems. He, as well as the no less famous "Meropenem", in terms of the effectiveness of the impact on the microflora resistant to other drugs, can even be the third and fourth generations of cephalosporins.

A beta-lactam antibiotic from the group of carbapenems is a drug used in especially severe cases of diseases when pathogens cannot be treated with other drugs.

Backup number two

"Aztreonam" is the most prominent representative of monobactams, it is characterized by a rather narrow spectrum of action. This beta-lactam antibiotic is most effective against Gram-negative aerobes. However, it should be noted that, like Imipenem, Aztreonam is practically insensitive to beta-lactamases, which makes it the drug of choice for severe forms of diseases caused by these pathogens, especially when treatment with other antibiotics is ineffective.

Spectrum of action of beta-lactam antibiotics

Summing up the above, it should be noted that the drugs of these groups have an impact on a huge number of varieties of pathogens. The mechanism of action of beta-lactam antibiotics is such that it leaves no chance for microbes to survive: blockade of cell wall synthesis is a death sentence for bacteria.

Gram-positive and gram-negative organisms, aerobes and anaerobes... There is a highly effective preparation for all these representatives of the pathogenic flora. Of course, there are highly specialized drugs among these antibiotics, but most are still ready to fight several pathogens of infectious diseases at once. Beta-lactam antibiotics are able to resist even representatives of the nosocomial flora, which is the most resistant to treatment.

What are hospital strains?

We are talking about microorganisms that exist in medical institutions. The sources of their appearance are patients and medical staff. Latent, sluggish forms of diseases are especially dangerous. The hospital is an ideal place where carriers of all possible types of infectious diseases gather. And violations of sanitary rules and regulations are fertile ground for this flora to find a niche for existence, where it could live, multiply and acquire resistance to drugs.

The high resistance of hospital strains is primarily due to the fact that, having chosen a hospital institution as their habitat, bacteria get the opportunity to come into contact with various drugs. Naturally, the effect of drugs on microorganisms occurs randomly, without the purpose of destroying them, and in small doses, and this contributes to the fact that representatives of the hospital microflora can develop protection against destructive mechanisms for them, learn to resist them. This is how strains appear, which are very difficult to fight, and sometimes it seems impossible.

Antibiotics of the beta-lactam series, in one way or another, try to solve this difficult problem. Among them there are representatives who can quite successfully deal with even the most drug-insensitive bacteria. reserve. Their use is limited, and they are assigned only when it is really necessary. If these antibiotics are used unreasonably often, then most likely this will end in a drop in their effectiveness, because then the bacteria will have the opportunity to interact with small doses of these drugs, study them and develop ways of protection.

When are beta-lactam antibiotics prescribed?

Indications for the use of this group of drugs are primarily due to their spectrum of action. It is most advisable to prescribe a beta-lactam antibiotic for an infection whose pathogen is sensitive to the action of this drug.

Penicillins have proven themselves in the treatment of pharyngitis, tonsillitis, pneumonia, scarlet fever, meningitis, bacterial endocarditis, actinomycosis, leptospirosis, salmonellosis, shigellosis, infectious diseases of the skin and soft tissues. Do not forget about drugs that can fight Pseudomonas aeruginosa.

Cephalosporins have a similar spectrum of action, and therefore the indications for them are almost the same as for penicillins. However, it should be said that the effectiveness of cephalosporins, especially the last two generations, is much higher.

Monobactams and carbapenems are designed to fight the most severe and difficult to treat diseases, including those caused by hospital strains. They are also effective in sepsis and septic shock.

Unwanted action

As already mentioned, beta-lactam antibiotics (drugs belonging to this group are listed above) have a relatively small number of effects harmful to the body. Rarely occurring convulsive syndrome and symptoms of a disorder of the digestive system do not pose a threat to life. Serious allergic reactions to the introduction of drugs from among the beta-lactam antibiotics can become really dangerous.

Rashes, itching, rhinitis and conjunctivitis do not pose a threat to life, although they are very unpleasant. What really should be feared is such severe reactions as Quincke's edema (especially in the larynx, which is accompanied by severe suffocation up to the inability to breathe) and anaphylactic shock. Therefore, it is possible to administer the drug only after performing an allergy test.

Cross reactions are also possible. Beta-lactam antibiotics, the classification of which implies the presence of a large number of groups of drugs, are very similar in structure to each other, which means that if one of them is intolerant, all the others will also be perceived by the body as an allergen.

A few words about the factors that increase the resistance of bacteria

The gradual decrease in the effectiveness of antibacterial drugs (including beta-lactam antibiotics) is due to their unreasonably frequent and often incorrect prescription. An incomplete course of treatment, the use of small therapeutic doses do not contribute to recovery, but they give microorganisms the opportunity to "train", invent and develop methods of protection against drugs. So is it any wonder that the latter become ineffective over time?

Although now antibiotics are not dispensed in pharmacies without a prescription, you can still get them. And this means that self-medication and the problems associated with it (the use of the same drug all the time, unreasonable interruption of the course of therapy, incorrectly selected doses, etc.) will remain, creating conditions for the cultivation of resistant strains.

The hospital flora will not go anywhere either, having the opportunity to actively contact with various drugs and invent new ways to counteract them.

What to do? Do not self-medicate, follow the recommendations of the attending physician: take medicines for as long as necessary, and in the correct doses. Of course, it is more difficult to fight the nosocomial flora, but it is still possible. The tightening of sanitary standards and their strict implementation will reduce the likelihood of creating favorable conditions for the reproduction of resistant flora.

A few words in conclusion

A very extensive topic is beta-lactam antibiotics. Pharmacology (the science of drugs and their effect on the body) devotes several chapters to them, which include not only a general description of the group, but also contain a description of its most famous representatives. This article does not claim to be complete, it only tries to acquaint you with the main points that you simply need to know about these drugs.

Be healthy and do not forget: before using this or that antibiotic, carefully read the instructions and strictly follow the recommendations, and even better, consult a specialist.

b-Lactams were the first antibiotics to be used in medicine, and in fact they gave rise to the era of modern antibacterial chemotherapy. The first antibiotic is benzylpenicillin, which began to be used in clinical practice in 1941. In the late 50s, the first semi-synthetic penicillins were synthesized, in the early 60s, cephalosporins, and in the mid-80s, carbapenems.

Over the years, more than 70 antibiotics of this class have been synthesized, but currently about 30 drugs are actually used in medicine. Over more than half a century of history, many b-lactams have been excluded from practical use, but the remaining ones retain their leading positions in many areas of antimicrobial chemotherapy, although their positioning in some infectious diseases has changed. However, until now, antibiotics of this class are the most commonly prescribed both in outpatient practice and in the hospital. This review presents a modern view on the place of b-lactam antibiotics in antimicrobial chemotherapy with an emphasis on the features of antimicrobial activity and resistance of individual drugs and an indication of their preferential positioning in treatment regimens (means of choice or 1st line). An attempt was also made to present a weighted comparative characteristic of individual drugs that are similar in terms of the spectrum of antimicrobial activity.

b-Lactams (b-lactam antibiotics) include a large group of drugs having a b-lactam ring. These include penicillins, cephalosporins, carbapenems, monobactams. A separate group consists of combined preparations consisting of a b-lactam antibiotic (penicillins, cephalosporins) and a b-lactamase inhibitor (clavulanic acid, sulbactam, tazobactam) and called "inhibitor-protected b-lactams".

Antimicrobial activity

b-Lactams have a wide spectrum of antimicrobial activity, including gram-positive and gram-negative microorganisms. Mycoplasmas are naturally resistant to b-lactams. b-Lactams do not act on microorganisms that are localized inside cells, into which drugs do not penetrate well (chlamydia, rickettsia, legionella, brucella, etc.). Most b-lactams have no effect on anaerobes. Methicillin-resistant staphylococci are also resistant to all b-lactams.

Data on the natural activity of b-lactams against clinically significant microorganisms and indicative information on their acquired resistance to individual antibiotics are given in the table.

Mechanism of action and resistance

The individual properties of individual b-lactams are determined by:

affinity (affinity) for penicillin-binding proteins (PSB);
the ability to penetrate the external structures of microorganisms;
resistance to hydrolysis by b-lactamases.

The target of action of b-lactam antibiotics in a microbial cell is PSB, enzymes involved in the synthesis of the main component of the outer membrane of microorganisms (peptidoglycan); binding of b-lactams to PBP leads to inactivation of PBP, cessation of growth, and subsequent death of the microbial cell.

b-Lactams freely penetrate through the capsule and peptidoglycan into the cell of gram-positive microorganisms. b-Lactams do not pass through the outer membrane of gram-negative bacteria, and penetration into the cell is carried out through the porin channels of the outer membrane.

Access of b-lactam antibiotics to PSB is limited by enzymes - b-lactamases, which inactivate antibiotics. Special substances have been created that protect b-lactam antibiotics from the destructive action of b-lactamases (b-lactamase inhibitors). Dosage forms in which antibiotics and b-lactamase inhibitors are combined are called "inhibitor-protected b-lactams".

In addition to natural sensitivity (or resistance), the clinical efficacy of b-lactams is determined by acquired resistance, the mechanisms of which can be:

decreased affinity of PSB for b-lactams;
decrease in the permeability of the external structures of the microorganism for b-lactams;
the emergence of new b-lactamases or changes in the expression of existing ones.

Contraindications and warnings

allergic reactions

β-lactams are contraindicated only in case of documented hypersensitivity to them. Allergic reactions are more often observed with the use of penicillins (5-10%), less often with other b-lactams (1-2% or less). There is a risk of a cross-allergic reaction between b-lactams: with a history of allergy to benzylpenicillin, the likelihood of developing hypersensitivity to semi-synthetic penicillins is about 10%, to cephalosporins 2-5%, to carbapenems about 1%. If a history of severe hypersensitivity reactions to penicillin (anaphylactic shock, angioedema, bronchospasm) is indicated, the use of other b-lactams is not allowed; with moderate reactions (urticaria, dermatitis), it is possible to carefully prescribe cephalosporins and carbapenems under the guise of H1-histamine receptor blockers.

Pregnancy

If necessary, b-lactams can be used to treat infections in pregnant women, since they have not been shown to be teratogenic, mutagenic, or embryotoxic.

Impaired kidney function

Most β-lactams are not nephrotoxic and are safe at therapeutic doses, particularly in patients with kidney disease. Against the background of the use of oxacillin, in rare cases, the development of interstitial nephritis is possible. Indications of cephalosporin nephrotoxicity refer exclusively to early drugs (cephaloridine, cephalothin, cefapirin), which are no longer used.

Hepatotoxicity

A transient increase in the level of transaminases and alkaline phosphatase is possible with the use of any b-lactams. These reactions go away on their own and do not require discontinuation of the drug.

Reactions of the gastrointestinal tract

Nausea, vomiting and diarrhea may occur with all β-lactams. In rare cases, antibiotic-associated diarrhea caused by C. difficile may develop.

Hematological reactions

The use of certain cephalosporins and carboxypenicillins can lead to hemorrhagic syndrome. Some cephalosporins (cefamandol, cefotetan, cefoperazone, cefmetazole) have the ability to cause hypoprothrombinemia due to malabsorption of vitamin K in the intestine; bleeding is less common. Malnutrition, renal failure, liver cirrhosis, malignant tumors predispose to this reaction.

Carbenicillin and ticarcillin should be administered with caution before surgery due to the possibility of developing hemorrhagic syndrome associated with dysfunction of platelet membranes.

Impaired tolerance to alcohol

Disulfiram-like reactions when taking alcohol can cause some cephalosporins (cefamandol, cefoperazone). Patients treated with these antibiotics should be aware of the possibility of such a reaction.

natural penicillins

Benzylpenicillin

It is active mainly against gram-positive and gram-negative cocci: staphylococci (except those producing penicillinase), streptococci, pneumococci, E. faecalis (to a lesser extent), N. gonorrhoeae, N. meningitidis; shows high activity against anaerobes, C. diphtheriae, L. monocytogenes, T. pallidum, B. burgdorferi, Leptospira. In terms of its effect on the coccal flora, it surpasses other penicillins and cephalosporins of the I-II generation.

Acquired resistance

Currently, most strains of staphylococci (both community-acquired and hospital-acquired) produce penicillinase and are resistant to benzylpenicillin. Resistance of pyogenic streptococcus to benzylpenicillin has not been documented. The resistance of pneumococci to benzylpenicillin in the Russian Federation ranges from 10 to 20% and has increased in recent years. Clinically significant resistance of gonococci is more than 30%.

Main indications

In a non-infectious clinic, the use of benzylpenicillin is justified for streptococcal and meningococcal infections, as well as gas gangrene. In the treatment of bronchopulmonary infections, semi-synthetic penicillins have an advantage.

S. pyogenes infections (streptococcal tonsillitis, scarlet fever, erysipelas)
S. pneumoniae infections (community-acquired pneumonia, meningitis)
E. faecalis infections (in combination with gentamicin)
Treatment and prevention of clostridial infection (drug of choice)
Meningococcal infection (drug of choice)
Syphilis (means of choice)
Leptospirosis
Actinomycosis
As a means of empirical therapy:
- native valve infective endocarditis (in combination with gentamicin)
- abscess pneumonia (in combination with metronidazole)

Dosing

It is used intravenously and intramuscularly in a daily dose of 6 million units (streptococcal infections) to 24-30 million units (CNS infections).

Benzathinebenzylpenicillin

Prolonged dosage form of benzylpenicillin. Antimicrobial activity and resistance - see Benzylpenicillin

Features of pharmacokinetics

N,N-dibenzylethylenediamine salt of benzylpenicillin is a prolonged form of benzylpenicillin. When administered intramuscularly, it forms a depot, from which the active principle, benzylpenicillin, is released slowly (Tmax is reached after 12-24 hours), which is determined in the blood at low concentrations for a long time (up to 3 weeks). After intramuscular injection at a dose of 1.2 million IU, the average blood concentrations after 1 week are 0.1 mg / l, after 2 weeks - 0.02 mg / l, after 3 weeks - 0.01 mg / l.

Communication with plasma proteins 40-60%. It is excreted mainly by the kidneys.

Main indications

Syphilis
Scarlet fever (treatment and prevention)
Prevention of rheumatism

Phenoxymethylpenicillin

Features of antimicrobial activity

The spectrum of antimicrobial activity is similar to that of benzylpenicillin. Primary activity against gram-positive (staphylococci, streptococci) and gram-negative (N. gonorrhoeae, N. meningitidis) cocci, Treponema spp., H. influenzae, Cory-nebacterium spp.

Acquired resistance- see Benzylpenicillin

Main indications

Streptococcal tonsillitis in children
Prevention of endocarditis during dental procedures
Scarlet fever
Mouth and gum infections

Penicillinase-stable penicillins

Oxacillin

Features of antimicrobial activity

Active mainly against gram-positive cocci (Staphylococcus spp., S. pyogenes, S. pneumoniae, S. viridans, S. agalactiae); does not affect enterococci. In terms of natural activity against gram-positive cocci, it is inferior to natural penicillins. Does not show activity against gram-negative bacteria (except Neisseria spp.), anaerobes. Stable to staphylococcal b-lactamases.

Acquired resistance

The resistance rate of community-acquired strains of S. aureus is less than 5%, the frequency of oxacillin-resistant strains in hospitals varies between departments and in intensive care units can reach 50% or more.

Main indications

Currently, the use of oxacillin is advisable only for staphylococcal infections (mainly community-acquired).

Staphylococcal infections of various localization (means of choice)
Infections of suspected staphylococcal etiology:
uncomplicated infections of the skin and soft tissues (furuncle, carbuncle, pyoderma, etc.)
- mastitis
- infective endocarditis in intravenous drug users (the drug of choice)
- acute purulent arthritis (a drug of choice)
- catheter-associated angiogenic infection

Dosing

Intravenously, intramuscularly and inside; daily dose of 4-12 g (with an interval of 4-6 hours). The drug is preferably administered parenterally, since oral bioavailability is not very high. For oral administration, cloxacillin is preferred. In severe infections, the daily dose is 8-12 g (in 4-6 injections).

Cloxacillin

Features of antimicrobial activity

The spectrum of antimicrobial activity is close to oxacillin (see). Stable to staphylococcal b-lactamases.

Acquired resistance- see Oxacillin

Main indications

Staphylococcal infections of various localization, mild and moderate
Infections of suspected staphylococcal etiology:
- uncomplicated infections of the skin and soft tissues (furuncle, carbuncle, pyoderma, etc.)
- acute mastitis

Dosing

Inside 500 mg 4 times a day

Aminopenicillins

Amoxicillin

Broad spectrum semi-synthetic penicillin for oral use.

Features of antimicrobial activity

It has a wide spectrum of antimicrobial activity. Most active against gram-positive cocci (S. pyogenes, S. viridans, S. pneumoniae, penicillin-sensitive staphylococci), gram-negative cocci (N. gonorrhoeae, N. meningitidis), listeria, H. influenzae, gram-positive anaerobes, to a lesser extent - enterococci, H. pylori, some enterobacteria (E. coli, P. mirabilis, Shigella spp., Salmonella spp.).

Acquired resistance

Not stable to staphylococcal penicillinases, so most strains of S. aureus are resistant. The resistance of pneumococci and Haemophilus influenzae to amoxicillin in the Russian Federation is insignificant, the resistance of E. faecalis is 10-15%. The resistance of community-acquired strains of enterobacteria is moderate (10-30%), hospital strains are usually resistant.

Main indications

Currently considered as a means of choice for uncomplicated community-acquired respiratory infections in adults and children in outpatient practice; in these diseases is not inferior in effectiveness to inhibitor-protected aminopenicillins. Included in the main schemes of eradication therapy for gastric and duodenal ulcers.

Non-severe community-acquired infections of the upper and lower respiratory tract:
- pneumonia (means of choice)
- acute otitis media (remedy of choice)
- acute sinusitis (medicine of choice)
- streptococcal tonsillitis - tonsillitis (means of choice)
Intestinal infections (dysentery, salmonellosis)
In H. pylori eradication schemes
Prevention of endocarditis during dental interventions

Dosing

It is used orally (children in the form of a suspension). Multiplicity of application - 3 times a day. The recommended daily dose in adults is 1.5 g. Prevention of endocarditis - 3 g once.

Features of the dosage form: the dispersed dosage form of the antibiotic (solutab) is characterized by more complete absorption in the gastrointestinal tract compared to conventional dosage forms in the form of tablets and capsules, which is accompanied by the creation of higher serum concentrations in the blood, as well as a lower effect of the drug on the intestinal microflora.

Ampicillin

Broad spectrum semi-synthetic penicillin for parenteral and oral use.

Features of antimicrobial activity

The spectrum of natural activity is similar to amoxicillin. Acquired resistance - see Amoxicillin

Main indications

E. faecalis infections (the drug of choice)
Listeria and Haemophilus influenzae meningitis (in combination with aminoglycosides)
Lower respiratory tract infections:
- community-acquired pneumonia of moderate course (means of choice)
- exacerbation of chronic bronchitis
Secondary purulent meningitis in children and the elderly (in combination with third-generation cephalosporins)
Intestinal infections (shigellosis, salmonellosis)
Native valve infective endocarditis (in combination with gentamicin) (the drug of choice)

Dosing

It is applied parenterally and inside. The drug is characterized by low oral bioavailability, therefore, for oral administration, it is advisable to use amoxicillin, with the exception of intestinal infections.

The daily dose for intramuscular and intravenous administration is 4-12 g (with an interval of 4-6 hours): for respiratory infections - 4 g / day, for infections of the central nervous system and endocarditis - 8-12 g / day; inside (only for intestinal infections) - 0.5-1 g 4 times a day.

Carboxypenicillins

Carbenicillin

Broad spectrum antipseudomonas penicillin.

Features of antimicrobial activity

It is active against gram-positive and gram-negative microbes, including streptococci, pneumococci, neisseria, listeria, gram-positive anaerobes (clostridia, peptostreptococci), to a lesser extent - some types of enterobacteria, hemophilic bacillus, Pseudomonas aeruginosa (in antipseudomonal activity inferior to other antipseudomonas penicillins).

Acquired resistance

A high level is characteristic of staphylococci, enterobacteria, Pseudomonas aeruginosa, and therefore the use is limited to cases of infections with documented sensitivity of pathogens to an antibiotic.

Main indications

Infections caused by carbenicillin-sensitive strains of P. aeruginosa (in combination with aminoglycosides or fluoroquinolones).

Dosing

It is used as an intravenous infusion in large doses (5 g 5-6 times a day).

Be wary appoint when:

kidney dysfunction
history of bleeding
cardiovascular insufficiency
arterial hypertension

In cardiovascular or renal insufficiency, the use of carbenicillin can cause hypernatremia and hypokalemia.

Ureidopenicillins

This group includes piperacillin, azlocillin, mezlocillin, but only azlocillin remains important in medical practice.

Azlocillin

Features of antimicrobial activity

The spectrum of antimicrobial activity includes gram-positive and gram-negative microbes, as well as anaerobes. In relation to bacteria of the Enterobacteriaceae family, it is more active against E. coli, P. mirabilis, P. vulgaris. Highly active against H. influenzae and N. gonorrhoeae. Refers to antipseudomonal penicillins, and its activity is superior to carbenicillin.

Acquired resistance

Not stable to staphylococcal penicillinases, so most strains are resistant. Currently, many hospital strains of gram-negative bacteria are resistant to azlocillin.

Main indications

Carbenicillin-susceptible P. aeruginosa infections (in combination with aminoglycosides or fluoroquinolones)

Currently, indications for the use of carbenicillin are limited due to the high level of microbial resistance to the drug.

Dosing

It is used intravenously (drip, bolus), intramuscularly. The standard dose for adults is 2 g 3 times a day. In severe infections: a single dose of 4-5 g (even 10 g).

Be wary appoint: in the first trimester of pregnancy; when breastfeeding; with the simultaneous appointment of hepatoxic drugs and anticoagulants.

Inhibitor-protected penicillins

One of the methods of combating the resistance of microbes associated with the production of b-lactamase is the use of special substances of the b-lactam structure, which bind enzymes and thereby prevent their destructive effect on b-lactam antibiotics. These substances are called "b-lactamase inhibitors", and their combinations with b-lactam antibiotics are called "inhibitor-protected b-lactams".

There are currently 3 β-lactamase inhibitors in use:

Clavulanic acid
Sulbactam
Tazobactam

β-lactamase inhibitors are not used alone, but are used only in combination with β-lactams.

Inhibitor-protected penicillins include: amoxicillin/clavulanate, ampicillin/sulbactam, amoxicillin/sulbactam, piperacillin/tazobactam, ticarcillin/clavulanate.

These antibiotics are fixed combinations of semisynthetic penicillins (aminopenicillins, carboxypenicillins or ureidopenicillins) with β-lactamase inhibitors that irreversibly bind various β-lactamases and thus protect the penicillins from degradation by these enzymes. As a result, strains of microorganisms resistant to penicillins become sensitive to the combination of these drugs with inhibitors. The spectrum of natural activity of inhibitor-protected b-lactams corresponds to the penicillins contained in their composition; only the level of acquired resistance differs.

Inhibitor-protected penicillins are widely used in clinical practice, with amoxicillin / clavulanate, ampicillin / sulbactam and amoxicillin / sulbactam mainly for community-acquired infections, and ticarcillin / clavulanate and piperacillin / tazobactam - for hospital infections.

Amoxicillin/clavulanate

Features of antimicrobial activity

Clavulanic acid prevents the enzymatic inactivation of amoxicillin by the action of b-lactamases.

Active against gram-positive (streptococci, pneumococci, staphylococci, except oxacillin-resistant) and gram-negative (N. gonorrhoeae, N. meningitidis) cocci, listeria, H. influenzae, M. catarrhalis, anaerobes (including B. fragilis), less active against enterococci and some enterobacteria (E. coli, P. mirabilis, Klebsiella spp.).

Acquired resistance

Most community-acquired strains of S. aureus are susceptible. The resistance of S. pneumoniae, H. influenzae in the Russian Federation is negligible. In recent years, there has been an increase in the resistance of community-acquired uropathogenic strains of E. coli, which is currently about 30%. The resistance of Gram-negative enteric bacteria varies - community-acquired strains tend to be susceptible, while hospital-acquired strains are often resistant.

Main indications

The most well studied among the inhibitor-protected aminopenicillins in controlled clinical trials and therefore has the widest indications.

Community-acquired infections of the upper and lower respiratory tract:
- mild to moderate pneumonia
- pneumonia destructive and abscessing (means of choice)
- exacerbation of chronic bronchitis (means of choice)
- acute otitis media
- acute sinusitis
- exacerbation of chronic sinusitis (a means of choice)
- recurrent tonsillopharyngitis (a drug of choice)
- epiglottitis (means of choice)
Uncomplicated skin and soft tissue infections
Community Acquired Intra-Abdominal Infections (Medication of Choice)
Community-acquired gynecological infections of the pelvic organs (in combination with doxycycline):
- endometritis
- salpingoophoritis
Animal bite wounds (remedy of choice)
Prevention in abdominal surgery and obstetrics-gynecology (means of choice)

Dosing

Inside 375-625 mg 3 times a day or 1 g 2 times a day, intravenously 1.2 g 3 times a day. Prevention in surgery: intravenously 1.2 g 30-60 minutes before surgery.

Features of the dosage form: the dispersed dosage form of the antibiotic (solutab) is characterized by more uniform absorption in the gastrointestinal tract compared to conventional dosage forms of the drug, which provides more stable therapeutic concentrations of amoxicillin and clavulanic acid in the blood. As a result of increasing the bioavailability of clavulanic acid, the incidence of gastrointestinal side effects is reduced.

Ampicillin/sulbactam

Features of antimicrobial activity

Active against gram-positive (streptococci, staphylococci, except oxacillin-resistant) and gram-negative (N. gonorrhoeae, N. meningitidis) cocci, listeria, H. influenzae, M. catarrhalis, anaerobes (including B. fragilis), less active against enterococci and some enterobacteria (E. coli, P. mirabilis, Klebsiella spp.).

Acquired resistance- see Amoxicillin/clavulanate

Main indications

Skin and soft tissue infections
Community-acquired intra-abdominal infections
Community-acquired gynecological infections
Community-acquired destructive or abscess pneumonia
Prevention in abdominal surgery and obstetrics and gynecology

For infections of the upper respiratory tract and pneumonia, it is more appropriate to prescribe amoxicillin / clavulanate.

Dosing

Intravenously 1.5-3 g 4 times a day, orally 375-750 mg 2 times a day. Prevention in surgery: intravenously 3 g 30-60 minutes before surgery

Amoxicillin/sulbactam

Features of antimicrobial activity and resistance - see Ampicillin / sulbactam.

Main indications

Less studied than amoxicillin/clavulanate. Appointment is possible with community-acquired respiratory infections and uncomplicated infections of the skin and soft tissues, abdominal infections.

Dosing

Inside, 0.5 g 3 times a day, intravenously or intramuscularly, 1 g 3 times a day (calculation for amoxicillin).

Ticarcillin/clavulanate

Combination of the antipseudomonal carboxypenicillin ticarcillin and the b-lactamase inhibitor clavulanate.

Features of antimicrobial activity

Clavulanic acid prevents the enzymatic inactivation of ticarcillin by the action of b-lactamases. Active against gram-positive (streptococci, penicillin-sensitive pneumococci, oxacillin-sensitive staphylococci) and gram-negative (N. gonorrhoeae, N. meningitidis) cocci, listeria, H. influenzae, M. catarrhalis, anaerobes (including B. fragilis), P. aeruginosa, some species of Enterobacteriaceae.

Acquired resistance

Widespread in hospital strains of Enterobacteriaceae and P. aeruginosa.

Main indications

Community-acquired and non-severe hospital infections (aerobic-anaerobic) outside intensive care units:

pulmonary - abscess, empyema
intra-abdominal, pelvic

Dosing

Intravenously (infusion) for adults, 3.2 g 3-4 times a day.

Cephalosporins

All cephalosporins are derivatives of 7-aminocephalosporanic acid.

Depending on the spectrum of antimicrobial activity, cephalosporins are divided into 4 generations (generations).

I generation cephalosporins are active mainly against gram-positive microorganisms (staphylococci, streptococci, pneumococci). Some gram-negative enterobacteria (E. coli, P. mirabilis) are naturally sensitive to 1st generation cephalosporins, but acquired resistance to them is high. The drugs are easily hydrolyzed by b-lactamases. The spectrum of oral and parenteral cephalosporins is the same, although the activity is slightly higher in parenteral agents, among which cefazolin is the most active.

Second-generation cephalosporins are more active against gram-negative bacteria than first-generation cephalosporins and are more resistant to b-lactamase (cefuroxime is more stable than cefamandol). The preparations remain highly active against gram-positive bacteria.

Oral and parenteral agents do not differ significantly in terms of activity. One drug, cefoxitin, is active against anaerobic microorganisms.

III generation cephalosporins are predominantly active against gram-negative microorganisms and streptococci/pneumococci. Antistaphylococcal activity is low. III generation antipseudomonas cephalosporins (ceftazidime, cefoperazone) are active against P. aeruginosa and some other non-fermenting microorganisms. III generation cephalosporins are more resistant to β-lactamases, but are degraded by extended-spectrum β-lactamases and class C chromosomal β-lactamases (AmpC).

IV generation cephalosporins combine high activity of I-II generation cephalosporins against staphylococci and III generation cephalosporins against gram-negative microorganisms. Currently, IV generation cephalosporins (cefepime) have the widest spectrum of antimicrobial activity among cephalosporin antibiotics. IV generation cephalosporins in some cases are active against those strains of Enterobacteriaceae that are resistant to III generation cephalosporins.

Cefepime is completely resistant to hydrolysis of AmpC by b-lactamases and partially resists hydrolysis by extended-spectrum plasmid b-lactamases, exhibits high activity against P. aeruginosa (comparable to ceftazidime).

Thus, in cephalosporins from generation I to IV, activity against gram-negative bacteria and pneumococci increases, and activity against staphylococci slightly decreases from generation I to III; from generation I to IV, resistance to the action of b-lactamases of gram-negative bacteria increases.

All cephalosporins are practically devoid of activity against enterococci, inactive against gram-positive anaerobes and weakly active against gram-negative anaerobes.