Penicillins (penicillina)- a group of antibiotics produced by many types of molds of the genus Penicillium, active against most gram-positive, as well as some gram-negative microorganisms (gonococci, meningococci and spirochetes). Penicillins are classified as so-called. beta-lactam antibiotics (beta-lactams).
Beta-lactams are a large group of antibiotics, which have in common the presence of a four-membered beta-lactam ring in the structure of the molecule. Beta-lactams include penicillins, cephalosporins, carbapenems, and monobactams. Beta-lactams are the largest group of antimicrobial drugs used in clinical practice, occupying a leading place in the treatment of most infectious diseases.
Historical information. In 1928, the English scientist A. Fleming, who worked at St. Mary's Hospital in London, discovered the ability of a filamentous green mold fungus (Penicillium notatum) cause the death of staphylococci in cell culture. A. Fleming called the active substance of the fungus, which has antibacterial activity, penicillin. In 1940, in Oxford, a group of researchers led by H.W. Flory and E.B. Cheyna isolated significant amounts of the first penicillin from culture in pure form. Penicillium notatum. In 1942, the outstanding domestic researcher Z.V. Ermolyeva received penicillin from a mushroom Penicillium crustosum. Since 1949, virtually unlimited quantities of benzylpenicillin (penicillin G) have become available for clinical use.
The penicillin group includes natural compounds produced by various types of molds. Penicillium, and a number of semi-synthetic ones. Penicillins (like other beta-lactams) have a bactericidal effect on microorganisms.
The most common properties of penicillins include: low toxicity, a wide range of dosages, cross-allergy between all penicillins and some cephalosporins and carbapenems.
Antibacterial effect beta-lactams are associated with their specific ability to disrupt the synthesis of bacterial cell walls.
The cell wall of bacteria has a rigid structure; it gives microorganisms their shape and protects them from destruction. Its basis is a heteropolymer - peptidoglycan, consisting of polysaccharides and polypeptides. Its cross-linked network structure gives the cell wall strength. Polysaccharides include amino sugars such as N-acetylglucosamine, as well as N-acetylmuramic acid, which is found only in bacteria. Associated with amino sugars are short peptide chains, including some L- and D-amino acids. In gram-positive bacteria, the cell wall contains 50-100 layers of peptidoglycan, in gram-negative bacteria - 1-2 layers.
About 30 bacterial enzymes are involved in the process of peptidoglycan biosynthesis; this process consists of 3 stages. It is believed that penicillins disrupt the late stages of cell wall synthesis, preventing the formation of peptide bonds by inhibiting the enzyme transpeptidase. Transpeptidase is one of the penicillin-binding proteins with which beta-lactam antibiotics interact. Penicillin-binding proteins—enzymes that take part in the final stages of bacterial cell wall formation—in addition to transpeptidases, include carboxypeptidases and endopeptidases. All bacteria have them (for example, Staphylococcus aureus there are 4 of them, Escherichia coli- 7). Penicillins bind to these proteins at different rates to form a covalent bond. In this case, inactivation of penicillin-binding proteins occurs, the strength of the bacterial cell wall is disrupted and the cells undergo lysis.
Pharmacokinetics. When taken orally, penicillins are absorbed and distributed throughout the body. Penicillins penetrate well into tissues and body fluids (synovial, pleural, pericardial, bile), where they quickly reach therapeutic concentrations. The exceptions are the cerebrospinal fluid, the internal media of the eye and the secretion of the prostate gland - here the concentrations of penicillins are low. The concentration of penicillins in the cerebrospinal fluid may vary depending on the conditions: normally it is less than 1% of the serum concentration, and during inflammation it can increase to 5%. Therapeutic concentrations in the cerebrospinal fluid are created during meningitis and the administration of drugs in high doses. Penicillins are quickly eliminated from the body, mainly by the kidneys through glomerular filtration and tubular secretion. Their half-life is short (30-90 min), the concentration in urine is high.
There are several classifications Medicines belonging to the penicillin group: by molecular structure, by sources of production, by spectrum of activity, etc.
According to the classification presented by D.A. Kharkevich (2006), penicillins are divided as follows (classification is based on a number of characteristics, including differences in production routes):
I. Penicillin preparations obtained by biological synthesis (biosynthetic penicillins):
I.1. For parenteral administration (destroyed in the acidic environment of the stomach):
Short acting:
benzylpenicillin (sodium salt),
benzylpenicillin (potassium salt);
Long-lasting:
benzylpenicillin (novocaine salt),
Bicillin-1,
Bicillin-5.
I.2.
phenoxymethylpenicillin (penicillin V).
II. Semi-synthetic penicillins
II.1. For parenteral and enteral administration (acid-resistant):
Penicillinase-resistant:
oxacillin (sodium salt),
nafcillin;
Wide spectrum of action:
ampicillin,
amoxicillin.
II.2. For parenteral administration (destroyed in the acidic environment of the stomach)
Broad spectrum of action, including Pseudomonas aeruginosa:
carbenicillin (disodium salt),
ticarcillin,
azlocillin.
II.3. For enteral administration (acid-resistant):
carbenicillin (indanyl sodium),
carfecillin.
According to the classification of penicillins given by I.B. Mikhailov (2001), penicillins can be divided into 6 groups:
1. Natural penicillins (benzylpenicillins, bicillins, phenoxymethylpenicillin).
2. Isoxazolepenicillins (oxacillin, cloxacillin, flucloxacillin).
3. Amidinopenicillins (amdinocillin, pivamdinocillin, bacamdinocillin, acidocillin).
4. Aminopenicillins (ampicillin, amoxicillin, talampicillin, bacampicillin, pivampicillin).
5. Carboxypenicillins (carbenicillin, carfecillin, carindacillin, ticarcillin).
6. Ureidopenicillins (azlocillin, mezlocillin, piperacillin).
The source of production, spectrum of action, as well as combination with beta-lactamases were taken into account when creating the classification given in the Federal Guide (formulary system), issue VIII.
1. Natural:
benzylpenicillin (penicillin G),
phenoxymethylpenicillin (penicillin V),
benzathine benzylpenicillin,
benzylpenicillin procaine,
benzathine phenoxymethylpenicillin.
2. Antistaphylococcal:
oxacillin.
3. Extended spectrum (aminopenicillins):
ampicillin,
amoxicillin.
4. Active in relation Pseudomonas aeruginosa:
Carboxypenicillins:
ticarcillin.
Ureidopenicillins:
azlocillin,
piperacillin.
5. Combined with beta-lactamase inhibitors (inhibitor-protected):
amoxicillin/clavulanate,
ampicillin/sulbactam,
ticarcillin/clavulanate.
Natural (natural) penicillins - These are narrow-spectrum antibiotics that affect gram-positive bacteria and cocci. Biosynthetic penicillins are obtained from the culture medium on which certain strains of molds are grown (Penicillium). There are several varieties of natural penicillins, one of the most active and persistent of them is benzylpenicillin. In medical practice, benzylpenicillin is used in the form of various salts - sodium, potassium and novocaine.
All natural penicillins have similar antimicrobial activity. Natural penicillins are destroyed by beta-lactamases, and therefore are ineffective for the treatment of staphylococcal infections, because in most cases, staphylococci produce beta-lactamases. They are effective primarily against gram-positive microorganisms (incl. Streptococcus spp., including Streptococcus pneumoniae, Enterococcus spp.), Bacillus spp., Listeria monocytogenes, Erysipelothrix rhusiopathiae, gram-negative cocci (Neisseria meningitidis, Neisseria gonorrhoeae), some anaerobes (Peptostreptococcus spp., Fusobacterium spp.), spirochete (Treponema spp., Borrelia spp., Leptospira spp.). Gram-negative microorganisms are usually resistant, with the exception of Haemophilus ducreyi And Pasteurella multocida. Penicillins are ineffective against viruses (causative agents of influenza, polio, smallpox, etc.), mycobacterium tuberculosis, the causative agent of amebiasis, rickettsia, and fungi.
Benzylpenicillin is active mainly against gram-positive cocci. The antibacterial action spectra of benzylpenicillin and phenoxymethylpenicillin are almost identical. However, benzylpenicillin is 5-10 times more active than phenoxymethylpenicillin against sensitive Neisseria spp. and some anaerobes. Phenoxymethylpenicillin is prescribed for moderate infections. The activity of penicillin preparations is determined biologically by their antibacterial effect on a specific strain of Staphylococcus aureus. The activity of 0.5988 mcg of chemically pure crystalline sodium salt of benzylpenicillin is taken as a unit of action (1 unit).
Significant disadvantages of benzylpenicillin are its instability to beta-lactamases (with enzymatic cleavage of the beta-lactam ring by beta-lactamases (penicillinases) to form penicillanic acid, the antibiotic loses its antimicrobial activity), insignificant absorption in the stomach (requiring injection routes of administration) and relatively low activity against most gram-negative microorganisms.
Under normal conditions, benzylpenicillin preparations penetrate poorly into the cerebrospinal fluid, but with inflammation of the meninges, permeability through the BBB increases.
Benzylpenicillin, used in the form of highly soluble sodium and potassium salts, acts for a short time - 3-4 hours, because is quickly eliminated from the body and requires frequent injections. In this regard, poorly soluble salts of benzylpenicillin (including novocaine salt) and benzathine benzylpenicillin were proposed for use in medical practice.
Prolonged forms of benzylpenicillin, or depot penicillins: Bicillin-1 (benzathine benzylpenicillin), as well as combined drugs based on them - Bicillin-3 (benzathine benzylpenicillin + benzylpenicillin sodium + benzylpenicillin novocaine salt), Bicillin-5 (benzathine benzylpenicillin + benzylpenicillin novocaine salt ), are suspensions that can only be administered intramuscularly. They are slowly absorbed from the injection site, creating a depot in muscle tissue. This allows you to maintain the concentration of the antibiotic in the blood for a significant time and thus reduce the frequency of drug administration.
All benzylpenicillin salts are used parenterally, because they are destroyed in the acidic environment of the stomach. Of the natural penicillins, only phenoxymethylpenicillin (penicillin V) has acid-stable properties, although to a weak extent. Phenoxymethylpenicillin differs in chemical structure from benzylpenicillin in the presence of a phenoxymethyl group in the molecule instead of a benzyl group.
Benzylpenicillin is used for infections caused by streptococci, including Streptococcus pneumoniae(community-acquired pneumonia, meningitis), Streptococcus pyogenes(streptococcal tonsillitis, impetigo, erysipelas, scarlet fever, endocarditis), with meningococcal infections. Benzylpenicillin is the antibiotic of choice in the treatment of diphtheria, gas gangrene, leptospirosis, and Lyme disease.
Bicillins are indicated primarily when it is necessary to maintain effective concentrations in the body for a long time. They are used for syphilis and other diseases caused by Treponema pallidum (yaws), streptococcal infections (excluding infections caused by group B streptococci) - acute tonsillitis, scarlet fever, wound infections, erysipelas, rheumatism, leishmaniasis.
In 1957, 6-aminopenicillanic acid was isolated from natural penicillins and the development of semisynthetic drugs began on its basis.
6-Aminopenicillanic acid is the basis of the molecule of all penicillins (“penicillin core”) - a complex heterocyclic compound consisting of two rings: thiazolidine and beta-lactam. A side radical is associated with the beta-lactam ring, which determines the essential pharmacological properties of the resulting drug molecule. In natural penicillins, the structure of the radical depends on the composition of the medium in which they grow Penicillium spp.
Semi-synthetic penicillins are obtained by chemical modification by adding various radicals to the 6-aminopenicillanic acid molecule. In this way, penicillins were obtained with certain properties:
Penicillinase (beta-lactamase) resistant;
Acid-resistant, effective when administered orally;
Possessing wide range actions.
Isoxazolepenicillins (isoxazolyl penicillins, penicillinase-stable, antistaphylococcal penicillins). Most staphylococci produce a specific enzyme beta-lactamase (penicillinase) and are resistant to benzylpenicillin (80-90% of strains are penicillinase-forming Staphylococcus aureus).
The main antistaphylococcal drug is oxacillin. The group of penicillinase-resistant drugs also includes cloxacillin, flucloxacillin, methicillin, nafcillin and dicloxacillin, which due to high toxicity and/or low effectiveness have not found clinical use.
The spectrum of antibacterial action of oxacillin is similar to that of benzylpenicillin, but due to the resistance of oxacillin to penicillinase, it is active against penicillinase-forming staphylococci that are resistant to benzylpenicillin and phenoxymethylpenicillin, as well as resistant to other antibiotics.
In terms of activity against gram-positive cocci (including staphylococci that do not produce beta-lactamase), isoxazolepenicillins, incl. oxacillin are significantly inferior to natural penicillins, therefore, for diseases caused by microorganisms sensitive to benzylpenicillin, they are less effective compared to the latter. Oxacillin does not show activity against gram-negative bacteria (except Neisseria spp.), anaerobes. In this regard, drugs of this group are indicated only in cases where it is known that the infection is caused by penicillinase-forming strains of staphylococci.
The main pharmacokinetic differences between isoxazolepenicillins and benzylpenicillin:
Rapid, but not complete (30-50%) absorption from the gastrointestinal tract. These antibiotics can be used both parenterally (IM, IV) and orally, but 1-1.5 hours before meals, because they have low resistance to hydrochloric acid;
High degree of binding to plasma albumin (90-95%) and the impossibility of removing isoxazolepenicillins from the body during hemodialysis;
Not only renal, but also hepatic excretion, no need to adjust the dosage regimen for mild renal failure.
The main clinical value of oxacillin is the treatment of staphylococcal infections caused by penicillin-resistant strains Staphylococcus aureus(except infections caused by methicillin-resistant Staphylococcus aureus, MRSA). It should be taken into account that strains are common in hospitals Staphylococcus aureus, resistant to oxacillin and methicillin (methicillin - the first penicillinase-resistant penicillin, discontinued). Nosocomial and community-acquired strains Staphylococcus aureus, resistant to oxacillin/methicillin, are usually multidrug-resistant - they are resistant to all other beta-lactams, and often also to macrolides, aminoglycosides, and fluoroquinolones. The drugs of choice for MRSA infections are vancomycin or linezolid.
Nafcillin is slightly more active than oxacillin and other penicillinase-resistant penicillins (but less active than benzylpenicillin). Nafcillin penetrates the BBB (its concentration in the cerebrospinal fluid is sufficient for the treatment of staphylococcal meningitis), is excreted primarily in bile (the maximum concentration in bile is much higher than the serum concentration), and to a lesser extent by the kidneys. Can be used orally and parenterally.
Amidinopenicillins - These are penicillins with a narrow spectrum of action, but with predominant activity against gram-negative enterobacteria. Amidinopenicillin preparations (amdinocillin, pivamdinocillin, bacamdinocillin, acidocillin) are not registered in Russia.
Penicillins with an extended spectrum of activity
In accordance with the classification presented by D.A. Kharkevich, semi-synthetic broad-spectrum antibiotics are divided into the following groups:
I. Drugs that do not affect Pseudomonas aeruginosa:
Aminopenicillins: ampicillin, amoxicillin.
II. Drugs active against Pseudomonas aeruginosa:
Carboxypenicillins: carbenicillin, ticarcillin, carfecillin;
Ureidopenicillins: piperacillin, azlocillin, mezlocillin.
Aminopenicillins - broad-spectrum antibiotics. All of them are destroyed by beta-lactamases of both gram-positive and gram-negative bacteria.
Amoxicillin and ampicillin are widely used in medical practice. Ampicillin is the founder of the aminopenicillin group. In relation to gram-positive bacteria, ampicillin, like all semisynthetic penicillins, is inferior in activity to benzylpenicillin, but superior to oxacillin.
Ampicillin and amoxicillin have similar action spectra. Compared to natural penicillins, the antimicrobial spectrum of ampicillin and amoxicillin extends to sensitive strains of enterobacteria, Escherichia coli, Proteus mirabilis, Salmonella spp., Shigella spp., Haemophilus influenzae; act better than natural penicillins on Listeria monocytogenes and sensitive enterococci.
Of all the oral beta-lactams, amoxicillin has the greatest activity against Streptococcus pneumoniae, resistant to natural penicillins.
Ampicillin is not effective against penicillinase-forming strains Staphylococcus spp., all strains Pseudomonas aeruginosa, most strains Enterobacter spp., Proteus vulgaris(indole positive).
Combination drugs are available, for example Ampiox (ampicillin + oxacillin). The combination of ampicillin or benzylpenicillin with oxacillin is rational, because the spectrum of action with this combination becomes wider.
The difference between amoxicillin (which is one of the leading oral antibiotics) and ampicillin is its pharmacokinetic profile: when taken orally, amoxicillin is absorbed more quickly and well in the intestine (75-90%) than ampicillin (35-50%), bioavailability does not depend on food intake . Amoxicillin penetrates better into some tissues, incl. into the bronchopulmonary system, where its concentrations are 2 times higher than those in the blood.
The most significant differences in the pharmacokinetic parameters of aminopenicillins from benzylpenicillin:
Possibility of administration internally;
Insignificant binding to plasma proteins - 80% of aminopenicillins remain in the blood in free form - and good penetration into tissues and body fluids (with meningitis, concentrations in the cerebrospinal fluid can be 70-95% of concentrations in the blood);
The frequency of administration of combined drugs is 2-3 times a day.
The main indications for prescribing aminopenicillins are infections of the upper respiratory tract and ENT organs, kidney and urinary tract infections, gastrointestinal infections, eradication Helicobacter pylori(amoxicillin), meningitis.
A feature of the undesirable effect of aminopenicillins is the development of an “ampicillin” rash, which is a maculopapular rash of a non-allergic nature, which quickly disappears when the drug is discontinued.
One of the contraindications to the administration of aminopenicillins is infectious mononucleosis.
Antipseudomonas penicillins
These include carboxypenicillins (carbenicillin, ticarcillin) and ureidopenicillins (azlocillin, piperacillin).
Carboxypenicillins are antibiotics that have a spectrum of antimicrobial action similar to aminopenicillins (except for the effect on Pseudomonas aeruginosa). Carbenicillin is the first antipseudomonal penicillin, and is inferior in activity to other antipseudomonal penicillins. Carboxypenicillins act on Pseudomonas aeruginosa (Pseudomonas aeruginosa) and indole-positive Proteus species (Proteus spp.) resistant to ampicillin and other aminopenicillins. The clinical significance of carboxypenicillins is currently decreasing. Although they have a wide spectrum of action, they are inactive against most strains Staphylococcus aureus, Enterococcus faecalis, Klebsiella spp., Listeria monocytogenes. Almost do not pass through the BBB. The frequency of administration is 4 times a day. Secondary resistance of microorganisms quickly develops.
Ureidopenicillins - These are also antipseudomonas antibiotics, their spectrum of action coincides with carboxypenicillins. The most active drug from this group is piperacillin. Of the drugs in this group, only azlocillin retains its importance in medical practice.
Ureidopenicillins are more active than carboxypenicillins against Pseudomonas aeruginosa. They are also used in the treatment of infections caused by Klebsiella spp.
All antipseudomonas penicillins are destroyed by beta-lactamases.
Pharmacokinetic features of ureidopenicillins:
Administered only parenterally (i.m. and i.v.);
Not only the kidneys, but also the liver take part in excretion;
Frequency of application - 3 times a day;
Secondary bacterial resistance develops rapidly.
Due to the emergence of strains with high resistance to antipseudomonas penicillins and the lack of advantages over other antibiotics, antipseudomonas penicillins have practically lost their importance.
The main indications for these two groups of antipseudomonas penicillins are nosocomial infections caused by susceptible strains Pseudomonas aeruginosa, in combination with aminoglycosides and fluoroquinolones.
Penicillins and other beta-lactam antibiotics have high antimicrobial activity, but microbial resistance can develop to many of them.
This resistance is due to the ability of microorganisms to produce specific enzymes - beta-lactamases (penicillinases), which destroy (hydrolyze) the beta-lactam ring of penicillins, which deprives them of antibacterial activity and leads to the development of resistant strains of microorganisms.
Some semisynthetic penicillins are resistant to beta-lactamases. In addition, to overcome acquired resistance, compounds have been developed that can irreversibly inhibit the activity of these enzymes, the so-called. beta-lactamase inhibitors. They are used to create inhibitor-protected penicillins.
Beta-lactamase inhibitors, like penicillins, are beta-lactam compounds but have minimal antibacterial activity on their own. These substances irreversibly bind to beta-lactamases and inactivate these enzymes, thereby protecting beta-lactam antibiotics from hydrolysis. Beta-lactamase inhibitors are most active against beta-lactamases encoded by plasmid genes.
Inhibitor-protected penicillins are a combination of a penicillin antibiotic with a specific beta-lactamase inhibitor (clavulanic acid, sulbactam, tazobactam). Beta-lactamase inhibitors are not used alone, but are used in combination with beta-lactams. This combination makes it possible to increase the stability of the antibiotic and its activity against microorganisms that produce these enzymes (beta-lactamases): Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Escherichia coli, Klebsiella spp., Proteus spp., anaerobes, incl. Bacteroides fragilis. As a result, strains of microorganisms resistant to penicillins become sensitive to the combined drug. The spectrum of antibacterial activity of inhibitor-protected beta-lactams corresponds to the spectrum of the penicillins they contain, only the level of acquired resistance differs. Inhibitor-protected penicillins are used to treat infections of various locations and for perioperative prophylaxis in abdominal surgery.
Inhibitor-protected penicillins include amoxicillin/clavulanate, ampicillin/sulbactam, amoxicillin/sulbactam, piperacillin/tazobactam, ticarcillin/clavulanate. Ticarcilin/clavulanate has antipseudomonal activity and is active against Stenotrophomonas maltophilia. Sulbactam has its own antibacterial activity against gram-negative cocci of the family Neisseriaceae and families of non-fermenting bacteria Acinetobacter.
Indications for the use of penicillins
Penicillins are used for infections caused by pathogens sensitive to them. They are mainly used for upper respiratory tract infections, in the treatment of sore throat, scarlet fever, otitis, sepsis, syphilis, gonorrhea, gastrointestinal infections, urinary tract infections, etc.
Penicillins should only be used as directed and under the supervision of a physician. It must be remembered that the use of insufficient doses of penicillins (as well as other antibiotics) or stopping treatment too early can lead to the development of resistant strains of microorganisms (this is especially true for natural penicillins). If resistance occurs, therapy with other antibiotics should be continued.
The use of penicillins in ophthalmology. In ophthalmology, penicillins are used topically in the form of instillations, subconjunctival and intravitreal injections. Penicillins do not pass well through the blood-ophthalmic barrier. Against the background of the inflammatory process, their penetration into the internal structures of the eye increases and their concentrations reach therapeutically significant levels. Thus, when instilled into the conjunctival sac, therapeutic concentrations of penicillins are determined in the corneal stroma; when applied topically, they practically do not penetrate into the moisture of the anterior chamber. With subconjunctival administration, drugs are detected in the cornea and the humor of the anterior chamber of the eye, and in the vitreous body - concentrations below therapeutic ones.
Solutions for local application prepare ex tempore. Penicillins are used to treat gonococcal conjunctivitis (benzylpenicillin), keratitis (ampicillin, benzylpenicillin, oxacillin, piperacillin, etc.), canaliculitis, especially caused by actinomycetes (benzylpenicillin, phenoxymethylpenicillin), abscess and orbital phlegmon (ampicillin/clavulanate, bactam, phenoxymethylpenicillin and etc.) and other eye diseases. In addition, penicillins are used to prevent infectious complications in injuries of the eyelids and orbit, especially when a foreign body penetrates into the orbital tissue (ampicillin/clavulanate, ampicillin/sulbactam, etc.).
The use of penicillins in urological practice. In urological practice, inhibitor-protected drugs are widely used among penicillin antibiotics (the use of natural penicillins, as well as the use of semi-synthetic penicillins as drugs of choice is considered unjustified due to the high level of resistance of uropathogenic strains.
Side and toxic effects of penicillins. Penicillins have the lowest toxicity among antibiotics and a wide range of therapeutic effects (especially natural ones). Most serious side effects associated with hypersensitivity to them. Allergic reactions are observed in a significant number of patients (according to various sources, from 1 to 10%). Penicillins are more likely than drugs from other pharmacological groups to cause drug allergies. In patients who have had a history of allergic reactions to the administration of penicillins, with subsequent use these reactions are observed in 10-15% of cases. Less than 1% of people who have not previously experienced such reactions have an allergic reaction to penicillin when given again.
Penicillins can cause an allergic reaction at any dose and in any dosage form.
When using penicillins, both immediate and delayed allergic reactions are possible. It is believed that an allergic reaction to penicillins is associated mainly with an intermediate product of their metabolism - the penicillin group. It is called a large antigenic determinant and is formed when the beta-lactam ring ruptures. Small antigenic determinants of penicillins include, in particular, unchanged penicillin molecules and benzyl penicilloate. They are formed in vivo, but are also determined in penicillin solutions prepared for administration. It is believed that early allergic reactions to penicillins are mediated mainly by IgE antibodies to small antigenic determinants, delayed and late (urticaria) - usually by IgE antibodies to large antigenic determinants.
Hypersensitivity reactions are caused by the formation of antibodies in the body and usually occur within a few days of starting penicillin use (times can range from a few minutes to several weeks). In some cases, allergic reactions manifest themselves in the form of skin rash, dermatitis, and fever. In more severe cases, these reactions are manifested by swelling of the mucous membranes, arthritis, arthralgia, kidney damage and other disorders. Possible anaphylactic shock, bronchospasm, abdominal pain, cerebral edema and other manifestations.
A severe allergic reaction is an absolute contraindication to future administration of penicillins. The patient must be explained that even a small amount of penicillin that enters the body with food or during a skin test can be fatal to him.
Sometimes the only symptom of an allergic reaction to penicillins is fever (which can be constant, remitting or intermittent in nature, sometimes accompanied by chills). Fever usually disappears 1-1.5 days after stopping the drug, but sometimes it can last for several days.
All penicillins are characterized by cross-sensitization and cross-allergic reactions. Any preparations containing penicillin, including cosmetics, and food products, may cause sensitization.
Penicillins can cause various side and toxic effects of a non-allergic nature. These include: when taken orally - irritating effects, incl. glossitis, stomatitis, nausea, diarrhea; with intramuscular injection - pain, infiltration, aseptic muscle necrosis; with intravenous administration - phlebitis, thrombophlebitis.
There may be an increase in reflex excitability of the central nervous system. When using high doses, neurotoxic effects may occur: hallucinations, delusions, dysregulation of blood pressure, convulsions. Seizures are more likely in patients receiving high doses of penicillin and/or in patients with severely impaired liver function. Due to the risk of severe neurotoxic reactions, penicillins cannot be administered endolumbarally (with the exception of benzylpenicillin sodium salt, which is administered extremely carefully, for health reasons).
When treated with penicillins, the development of superinfection, candidiasis of the oral cavity, vagina, and intestinal dysbiosis is possible. Penicillins (usually ampicillin) can cause antibiotic-associated diarrhea.
The use of ampicillin leads to the appearance of an “ampicillin” rash (in 5-10% of patients), accompanied by itching and fever. This side effect most often occurs on the 5th-10th day of using large doses of ampicillin in children with lymphadenopathy and viral infections or with concomitant use of allopurinol, as well as in almost all patients with infectious mononucleosis.
Specific adverse reactions when using bicillins are local infiltrates and vascular complications in the form of Aune syndrome (ischemia and gangrene of the limbs when accidentally introduced into an artery) or Nicolau syndrome (embolism of pulmonary and cerebral vessels when it enters a vein).
When using oxacillin, hematuria, proteinuria, and interstitial nephritis are possible. The use of antipseudomonal penicillins (carboxypenicillins, ureidopenicillins) may be accompanied by the appearance of allergic reactions, symptoms of neurotoxicity, acute interstitial nephritis, dysbacteriosis, thrombocytopenia, neutropenia, leukopenia, eosinophilia. When using carbenicillin, hemorrhagic syndrome is possible. Combined drugs containing clavulanic acid can cause acute liver damage.
Use during pregnancy. Penicillins pass through the placenta. Although adequate and strictly controlled safety studies in humans have not been conducted, penicillins, incl. inhibitor-protected, are widely used in pregnant women, with no complications recorded.
In studies on laboratory animals, when penicillins were administered in doses 2-25 (for different penicillins) higher than therapeutic ones, fertility disorders and effects on reproductive function were not found. Teratogenic, mutagenic, embryotoxic properties were not detected when penicillins were administered to animals.
In accordance with the internationally recognized FDA (Food and Drug Administration) recommendations, which determine the possibility of using drugs during pregnancy, drugs of the penicillin group for their effect on the fetus belong to FDA category B (reproduction studies in animals did not reveal any adverse effects of drugs on the fetus, but adequate and There are no strictly controlled studies in pregnant women).
When prescribing penicillins during pregnancy, one should (as with any other drugs) take into account the duration of pregnancy. During therapy, it is necessary to strictly monitor the condition of the mother and fetus.
Use during breastfeeding. Penicillins pass into breast milk. Although no significant complications have been reported in humans, the use of penicillins by nursing mothers can lead to sensitization of the child, changes in intestinal microflora, diarrhea, the development of candidiasis and the appearance of skin rashes in infants.
Pediatrics. No specific pediatric problems have been reported with the use of penicillins in children, but it should be borne in mind that insufficiently developed renal function in newborns and young children can lead to the accumulation of penicillins (therefore, there is an increased risk of neurotoxicity with the development of seizures).
Geriatrics. No specific geriatric problems have been reported with the use of penicillins. However, it should be remembered that in older people, age-related renal dysfunction is more likely, and therefore dose adjustment may be required.
Impaired kidney and liver function. In case of renal/liver failure, cumulation is possible. In case of moderate and severe insufficiency of renal and/or liver function, dose adjustment and an increase in the periods between administrations of the antibiotic are required.
Interaction of penicillins with other drugs. Bactericidal antibiotics (including cephalosporins, cycloserine, vancomycin, rifampicin, aminoglycosides) have a synergistic effect, bacteriostatic antibiotics (including macrolides, chloramphenicol, lincosamides, tetracyclines) have an antagonistic effect. Caution must be exercised when combining penicillins active against Pseudomonas aeruginosa. (Pseudomonas aeruginosa), with anticoagulants and antiplatelet agents (potential risk of increased bleeding). It is not recommended to combine penicillins with thrombolytics. When combined with sulfonamides, the bactericidal effect may be weakened. Oral penicillins may reduce the effectiveness of oral contraceptives due to disruption of the enterohepatic circulation of estrogen. Penicillins can slow down the elimination of methotrexate from the body (inhibit its tubular secretion). When ampicillin is combined with allopurinol, the likelihood of skin rash increases. The use of high doses of benzylpenicillin potassium salt in combination with potassium-sparing diuretics, potassium supplements or ACE inhibitors increases the risk of hyperkalemia. Penicillins are pharmaceutically incompatible with aminoglycosides.
Due to the fact that long-term oral administration of antibiotics can suppress the intestinal microflora that produces vitamins B1, B6, B12, PP, it is advisable to prescribe B vitamins to patients to prevent hypovitaminosis.
In conclusion, it should be noted that penicillins are a large group of natural and semi-synthetic antibiotics that have a bactericidal effect. The antibacterial effect is associated with a violation of the synthesis of cell wall peptidoglycan. The effect is due to the inactivation of the enzyme transpeptidase, one of the penicillin-binding proteins located on the inner membrane of the bacterial cell wall, which takes part in the later stages of its synthesis. The differences between penicillins are associated with the characteristics of their spectrum of action, pharmacokinetic properties and the range of undesirable effects.
Over several decades of successful use of penicillins, problems associated with their misuse have arisen. Thus, prophylactic administration of penicillins at risk of bacterial infection is often unjustified. Incorrect treatment regimen - incorrect selection of dose (too high or too low) and frequency of administration can lead to the development of side effects, decreased effectiveness and the development of drug resistance.
Thus, currently most strains Staphylococcus spp. resistant to natural penicillins. In recent years, the frequency of detection of resistant strains has increased Neisseria gonorrhoeae.
The main mechanism of acquired resistance to penicillins is associated with the production of beta-lactamases. To overcome the widespread acquired resistance among microorganisms, compounds have been developed that can irreversibly inhibit the activity of these enzymes, the so-called. beta-lactamase inhibitors - clavulanic acid (clavulanate), sulbactam and tazobactam. They are used to create combined (inhibitor-protected) penicillins.
It should be remembered that the choice of one or another antibacterial drug, incl. penicillin should be determined, first of all, by the sensitivity of the pathogen that caused the disease to it, as well as the absence of contraindications to its use.
Penicillins were the first antibiotics to be used in clinical practice. Despite the variety of modern antimicrobial agents, incl. cephalosporins, macrolides, fluoroquinolones, penicillins still remain one of the main groups of antibacterial agents used in the treatment of infectious diseases.
Drugs
Drugs - 1869 ; Trade names - 83 ; Active ingredients - 11
| Active ingredient | Trade names |
PART I
Chapter 1
INVENTION OF PENICILLIN
Fate favors only prepared minds.
Louis Pasteur
INVISIBLE ENEMIES
For many centuries and further millennia, millions of people died from enemies invisible to the naked eye. These enemies are microbes. The history of mankind is a history of large and small wars, but it is safe to say that far more people fell victim to microscopic bacteria than in all wars combined. Suffice it to recall the terrifying epidemics of smallpox, plague, or at least influenza, which in the Middle Ages literally mowed down up to half of the population of Europe and even more. To this list we must add wound infection and fatal complications of minor household injuries that are harmless by today’s standards. It is known that in the 16th century. average duration human life was about 30 years. What does it mean for a modern person to cut himself with a bread knife in the kitchen or step on a nail? A nuisance, nothing more. And at the beginning of the twentieth century. (by historical standards - quite recently) such a trifle could easily take the victim to the grave.
FIRST STEP TO VICTORY
The situation has changed significantly thanks to the English surgeon D. Lister, who established that infectious complications leading to enormous postoperative mortality are caused by microorganisms introduced into the wound from the outside. In 1867, he developed and theoretically substantiated a method of combating them, called antiseptics. The essence of the method is to destroy microbes that have entered the wound. However, the discovery of an English (more precisely, Scottish) microbiologist radically changed the situation A. Fleming(1881–1955), which, like many other great discoveries, was not without absurd but happy accidents, which, however, in no way detracts from the scientist’s merits. He managed to isolate the first antibiotic, penicillin, from seemingly ordinary mold. The most significant achievements in the treatment of infectious diseases at the turn of the century were the first vaccines, as well as the doctrine of phagocytes by I. I. Mechnikov. All of them were based on the mobilization of natural forces human body to fight the disease. Leading doctors and bacteriologists of that time reasonably assumed that further progress in medicine would be associated with attempts to strengthen or somehow supplement the properties of the human immune system.
SAVIOR OF HUMANITY
Alexander Fleming was born in Great Britain in Ayrshire in the family of farmer Hugh Fleming from his second wife Grace. When the boy was 7 years old, his father died, and his mother had to manage the farm herself. A. Fleming attended a small rural school located near their farm, and later Kilmarnock Academy. He showed an early interest in natural history. At the age of 13, he went to London, where he began working as a clerk. At the same time, young A. Fleming attended classes at the Polytechnic Institute on Regent Street, and in 1900 he joined the London Scottish Regiment. A. Fleming earned a reputation as an excellent shooter and athlete; by that time the Boer War had already ended, and he did not have the chance to serve outside of Great Britain. A year later, he received an inheritance of 250 pounds sterling from his uncle - a hefty sum at that time - and, following the advice of his older brother, who worked as a doctor in London, he took part in a national competition for admission to medical school. He distinguished himself in the examinations, receiving the highest scores, and became a scholarship student at the medical school that existed at St. Mary's Hospital. A. Fleming studied surgery and, having successfully passed his exams, became a member of the Royal College of Surgeons in 1906. One of the most distinguished scientists at St. Mary's Hospital was Professor Almroth Wright, a renowned bacteriologist and immunologist. Since 1906, A. Fleming worked in the bacteriological laboratory under his leadership; in 1908 he received his BA and MS degrees from the University of London. During World War I he served as a captain as an army doctor in France under A. Wright. In war as in war, the issue of immunization was not even raised; there were much more pressing problems: thousands of wounded died from blood poisoning, tetanus and gangrene. In a futile attempt to save them, surgeons used antiseptic agents. A. Fleming, having carefully studied infected wounds, proved the complete unsuitability of antiseptics for therapy in these cases. Moreover, he found that carbolic acid, used as the main antiseptic in the treatment of open wounds, destroys white blood cells, thereby destroying the body's protective barrier and promoting the survival of bacteria in the wound. A little more than 10 years remained before the main discovery of A. Fleming’s life.
A NEW INVENTION IS THE MERIT OF MANY
Penicillin should not be considered the only merit of A. Fleming; back in 1922, he made his first important discovery - he isolated a substance from human tissue that had the ability to quite actively dissolve certain types of microbes. This discovery was made almost by accident while trying to isolate bacteria that cause the common cold. Professor A. Wright, under whose leadership A. Fleming continued his research work, named the new substance lysozyme (lysis - destruction of microorganisms). True, it turned out that lysozyme is ineffective in the fight against the most dangerous pathogenic microbes, although it successfully destroys relatively less dangerous microorganisms. Thus, the use of lysozyme in medical practice did not have very broad prospects. This prompted A. Fleming to further search for antibacterial drugs that are effective and, at the same time, as harmless as possible to humans. It must be said that back in 1908, he conducted experiments with a drug called “salvarsan,” which the laboratory of Professor A. Wright was among the first in Europe to receive for comprehensive research. This drug was created by the talented German scientist P. Ehrlich (Nobel Prize jointly with I.I. Mechnikov, 1908). He was looking for a drug that would kill pathogens but be safe for the patient, the so-called magic bullet. Salvarsan was a fairly effective antisyphilitic drug, but had toxic side effects on the body. These were only the first small steps towards the creation of modern antimicrobial and chemotherapeutic drugs. It is known that back in the 15th–16th centuries. In folk medicine, green mold was used to treat festering wounds. For example, Alena Arzamasskaya, an associate of Stepan Razin, and the Russian Joan of Arc knew how to treat with it. Attempts to apply mold directly to the wound surface yielded, oddly enough, good results. Based on the doctrine of antibiosis (suppression of some microorganisms by others), the foundations of which were laid by L. Pasteur and our great compatriot I. I. Mechnikov, A. Fleming in 1929 established that the therapeutic effect of green mold is due to a special substance secreted by it in environment.
IS EVERYTHING GENIUS DISCOVERED BY CHANCE?
Let's try to recreate the chain of almost incredible accidents and coincidences that preceded the great discovery. The root cause was, oddly enough, A. Fleming’s sloppiness. Absent-mindedness is characteristic of many scientists, but it does not always lead to such positive results. So, A. Fleming did not clean the cups from the studied cultures for several weeks, and as a result, his workplace was littered with fifty cups. True, during the cleaning process he scrupulously examined each cup for fear of missing something important. And I didn’t miss it. One fine day, he discovered fluffy mold in one of the cups, which suppressed the growth of the staphylococcus culture sown in this cup. It looked like this: the chains of staphylococci around the mold disappeared, and in place of the yellow cloudy mass, drops resembling dew were visible. Having removed the mold, A. Fleming saw that “the broth on which the mold had grown acquired a distinct ability to inhibit the growth of microorganisms, as well as bactericidal and bacteriological properties against many common pathogenic bacteria.” The mold spores were apparently brought in through a window from a laboratory where mold samples taken from the homes of asthma patients were being cultured to produce desensitizing extracts. The scientist left the cup on the table and went on vacation. The London weather played a role: colder temperatures favored the growth of mold, and subsequent warming favored the growth of bacteria. If at least one event had occurred from a chain of random coincidences, who knows when humanity would have learned about penicillin. The mold that infected the staphylococcal culture belonged to a rather rare species of the genus Penicillium – P. notatum, which was first found on rotted hyssop (a subshrub containing essential oil and used as a spice); It is interesting that in the Bible we find an incredibly precise indication of the properties of this plant. Here is a fragment of Psalm 50, which, by the way, A. Fleming also remembered: “Purge me with hyssop, and I will be clean; Wash me, and I will be whiter than snow.” First mention of antibacterial therapy?
ADVANTAGES OF THE NEW INVENTION
Further research revealed that, fortunately, even in large doses, penicillin is non-toxic to experimental animals and is capable of killing very resistant pathogens. There were no biochemists at St. Mary's Hospital, and as a result, penicillin could not be isolated into an injectable form. This work was carried out in Oxford by H. W. Flory and E. B. Chain only in 1938. Penicillin would have sunk into oblivion if A. Fleming had not previously discovered lysozyme (this is where it really came in handy!). It was this discovery that prompted Oxford scientists to study the medicinal properties of penicillin, as a result of which the drug was isolated in its pure form in the form of benzylpenicillin and tested clinically. Already the very first studies of A. Fleming gave a whole series invaluable information about penicillin. He wrote that it is “an effective antibacterial substance that has a pronounced effect on pyogenic (i.e., causing the formation of pus) cocci and bacilli of the diphtheria group. Penicillin, even in large doses, is not toxic to animals. It can be assumed that it will be an effective antiseptic when applied externally to areas affected by microbes sensitive to penicillin, or when administered internally.”
THE MEDICINE HAS BEEN RECEIVED, BUT HOW TO USE IT?
Similar to the Pasteur Institute in Paris, the vaccination department at St. Mary's Hospital, where A. Fleming worked, existed and received research funding through the sale of vaccines. The scientist discovered that during the preparation of vaccines, penicillin protects cultures from staphylococcus. This was a small but significant achievement, and A. Fleming made extensive use of it, weekly ordering the production of large batches of penicillium-based broth. He shared samples of culture Penicillium with colleagues in other laboratories, but, oddly enough, A. Fleming did not take such an obvious step, which was taken 12 years later by H. W. Flory and was to establish whether experimental mice would be saved from a fatal infection if treat them with injections of penicillin broth. Looking ahead, let's say that these mice were extremely lucky. A. Fleming only prescribed the broth to several patients for external use. However, the results were very, very contradictory. The solution was not only difficult to purify in large quantities, but also proved unstable. In addition, A. Fleming never mentioned penicillin in any of the 27 articles or lectures he published in 1930–1940, even when they dealt with substances that cause the death of bacteria. However, this did not prevent the scientist from receiving all the honors due to him and the Nobel Prize in Physiology or Medicine in 1945 G.
It took a long time before scientists concluded that penicillin was safe for both humans and animals.
WHO FIRST INVENTED PENICILLIN?
What was happening in the laboratories of our country at this time? Have domestic scientists really been sitting with their hands folded? Of course this is not true. Many have read V. A. Kaverin’s trilogy “Open Book”, but not everyone knows that the main character, Dr. Tatyana Vlasenkova, had a prototype - Zinaida Vissarionovna Ermolyeva (1898-1974), an outstanding microbiologist, creator of a number of domestic antibiotics. In addition, Z. V. Ermolyeva was the first Russian scientist to begin studying interferon as an antiviral agent. A full member of the Academy of Medical Sciences, she made a huge contribution to Russian science. The choice of profession of 3. V. Ermolyeva was influenced by the story of the death of her favorite composer. It is known that P.I. Tchaikovsky died after contracting cholera. After graduating from the university, Z. V. Ermolyeva was left as an assistant at the department of microbiology; at the same time she headed the bacteriological department of the North Caucasus Bacteriological Institute. When a cholera epidemic broke out in Rostov-on-Don in 1922, she, ignoring the mortal danger, studied this disease, as they say, on the spot. Later, she conducted a dangerous experiment with self-infection, which resulted in a significant scientific discovery. During the Great Patriotic War, observing the wounded, Z.V. Ermolyeva saw that many of them were dying not directly from their wounds, but from blood poisoning. By that time, research from her laboratory, completely independent of the British, had shown that some molds inhibit the growth of bacteria. Z.V. Ermolyeva, of course, knew that in 1929 A. Fleming obtained penicillin from mold, but could not isolate it in its pure form, because the drug turned out to be very unstable. She also knew that for a long time our compatriots were still at the level traditional medicine, healers noticed the healing properties of mold. But at the same time, unlike A. Fleming, fate did not indulge Z.V. Ermolyev with happy accidents. In 1943, W. H. Flory and E. Chain were able to establish the production of penicillin on an industrial scale, but to do this they had to organize production in the USA. Z.V. Ermolyeva, who at that time was the head of the All-Union Institute of Experimental Medicine, set herself the goal of obtaining penicillin exclusively from domestic raw materials. We must pay tribute to her perseverance - in 1942 the first portions of Soviet penicillin were obtained. The greatest and undeniable merit of Z.V. Ermolyeva was that she not only obtained penicillin, but also managed to establish mass production of the first domestic antibiotic. It should be taken into account that the Great Patriotic War was going on, and there was an acute shortage of the simplest and most necessary things. At the same time, the need for penicillin was growing. And Z.V. Ermolyeva did the impossible: she managed to ensure not only quantity, but also quality, or rather, the strength of the drug. Our penicillin was 1.4 times more effective than the Anglo-American one, which was confirmed by Professor W. H. Flory himself. How many wounded people owe their lives to her cannot even be roughly calculated. The creation of Soviet penicillin became a kind of impetus for the creation of a number of other antibiotics: the first domestic samples of streptomycin, tetracycline, chloramphenicol and ecmolin - the first antibiotic of animal origin isolated from the milk of sturgeon fish. A message appeared relatively recently, the authenticity of which is still difficult to vouch for. Here it is: penicillin was discovered even before A. Fleming by a certain medical student Ernest Augustine Duchenne, who in his dissertation described in detail a surprisingly effective drug he discovered for combating various bacteria that have a detrimental effect on the human body. E. Duchenne was unable to complete his scientific discovery due to a transient illness that resulted in death. However, A. Fleming had no idea about the young researcher’s discovery. And only quite recently in Leon (France) a dissertation by E. Duchenne was accidentally found. By the way, a patent for the invention of penicillin has not been issued to anyone. A. Fleming, E. Chain and W. H. Flory, who received one Nobel Prize between them for its discovery, flatly refused to receive patents. They considered that a substance that has every chance of saving all of humanity should not be a source of profit, a gold mine. This scientific breakthrough is the only one of this magnitude for which no one has ever claimed copyright. It is worth mentioning that, having defeated many common and dangerous infectious diseases, penicillin extended human life by an average of 30–35 years!
THE BEGINNING OF ANTIBIOTIC ERA
So, a new era has begun in medicine - era of antibiotics. “Like cures like” - this principle has been known to doctors since ancient times. So why not fight some microorganisms with the help of others? The effect exceeded our wildest expectations; In addition, the discovery of penicillin marked the beginning of the search for new antibiotics and sources of their production. At the time of their discovery, penicillins were characterized by high chemotherapeutic activity and a wide spectrum of action, which brought them closer to ideal drugs. The action of penicillins is aimed at certain “targets” in microbial cells that are absent in animal cells.
Reference. Penicillins belong to a broad class of gamma-lactam antibiotics. This also includes cephalosporins, carbapenems and monobactams. What is common in the structure of these antibiotics is the presence of a 3-lactam ring, (3-lactam antibiotics form the basis of modern chemotherapy for bacterial infections.
ANTIBIOTICS ATTACK BACTERIA DEFEND,
BACTERIA ATTACK ANTIBIOTICS DEFEND
Penicillins have bactericidal properties, that is, they have a detrimental effect on bacteria. The main target of action is the penicillin-binding proteins of bacteria, which are enzymes of the final stage of bacterial cell wall synthesis. Blocking peptidoglycan synthesis by an antibiotic leads to disruption of cell wall synthesis and ultimately to the death of the bacterium. In the process of evolution, microbes have learned to defend themselves. They secrete a special substance that destroys the antibiotic. This is also an enzyme with the intimidating name (3-lactamases), which destroys the (3-lactam ring of the antibiotic. But science does not stand still, new antibiotics have appeared containing so-called inhibitors ((3-lactamases - clavulanic acid, clavulanate, sulbactam and tazobactam Such antibiotics are called penicillinase-protected.
GENERAL FEATURES OF ANTIBACTERIAL DRUGS
Antibiotics– these are substances that selectively suppress the vital activity of microorganisms. By “selective influence” we mean activity exclusively in the interaction of microorganisms while maintaining the viability of host cells and the effect not on all, but only on certain genera and types of microorganisms. For example, fusidic acid has high activity against staphylococci, including methicillin-resistant ones, but has no effect on GABHS pneumococci. Closely related to selectivity is the idea of the broad spectrum of activity of antibacterial drugs. However, from today's perspective, the division of antibiotics into broad-spectrum and narrow-spectrum drugs seems arbitrary and is subject to serious criticism, largely due to the lack of criteria for such a division. It is incorrect to assume that drugs wide range actions are more reliable, effective, stronger, and the use of narrow-spectrum antibiotics contributes less to the development of resistance, etc. This does not take into account acquired resistance, as a result of which, for example, tetracyclines, which in the first years of use were active against Most clinically significant microorganisms have now lost a significant part of their spectrum of activity, in fact, due to the formation of acquired resistance in pneumococci, staphylococci, gonococci, and enterobacteria. III generation cephalosporins, as a rule, are considered as drugs with a wide spectrum of activity, despite the fact that they do not act on MRSA, many anaerobes, enterococci, listeria, atypical pathogens, etc. It is most rational to consider antibiotics from the point of view of clinical effectiveness for infections of a specific organ localization, since clinical evidence of effectiveness acquired in well-observed (comparative, randomized, prospective) clinical experiments is undoubtedly more significant than a conventional label such as “an antibiotic of a broad (or narrow) spectrum of activity.” Traditionally, antibacterial drugs are divided into natural (actually antibiotics, for example penicillin), semi-synthetic (products of modification of natural molecules, for example amoxicillin or cefazolin) and synthetic (for example, sulfonamides, nitrofurans). Currently, this division has lost its relevance, since a number of natural antibiotics are obtained by synthesis (chloramphenicol), and some drugs (fluoroquinolones), called “antibiotics,” are synthetic compounds. It is necessary to distinguish antibiotics from antiseptics, which act indiscriminately on microorganisms and are used to destroy them in living tissues, and disinfectants, intended for the indiscriminate destruction of microorganisms outside a living organism (for disinfecting care items, surfaces, etc.). Antibiotics are the largest group of drugs. For example, in Russia, 30 different groups of antibiotics are currently used, and the number of drugs is approaching 200. All antibiotics, despite the differences in chemical structure and mechanisms of action, are connected by a number of unique features. Firstly, the uniqueness of antibiotics lies in the fact that, unlike most other drugs, their target receptor is not located in the tissues of the human body, but in the cell of a microorganism. Secondly, the dynamism of antibiotics is not long-term, but decreases over time, which is due to the development of drug resistance (resistance). Antibiotic resistance is an indispensable biological phenomenon, and it is almost impossible to prevent it. Thirdly, antibiotic-resistant microorganisms pose a threat not only to the patient from whom they were isolated, but also to many other people, even those separated by time and space. As a result, the fight against antibiotic resistance has now become global. The division of antibiotics, like other drugs, into groups and classes is well known. Such a division is of great importance from the point of view of understanding the spectrum of activity, pharmacokinetic characteristics, the nature of adverse drug reactions, etc. However, it is a mistake to consider all drugs included in one group (class, generation) as interchangeable. There can be significant differences between drugs of the same generation that differ by only one molecule. For example, among third-generation cephalosporins, only ceftazidime and cefoperazone have clinically important activity against Pseudomonas aeruginosa. As a result, even if data on the sensitivity of Pseudomonas aeruginosa to cefotaxime or ceftriaxone are acquired, these drugs should not be used to treat this infection, since the results of clinical trials confirm a high rate of ineffectiveness. The second example is the difference in the pharmacokinetics of antibacterial drugs: first generation cephalosporins (cefazolin) are not allowed to be used in the treatment of bacterial meningitis due to poor permeability through the BBB. The isolation of bactericidal and bacteriostatic antibiotics is of primary practical importance in the treatment of severe infections, especially in patients with impaired immunity, when bactericidal drugs must be prescribed. Of the pharmacokinetic characteristics, the most significant when choosing a drug are the periods of partial elimination and bioavailability (which is typical for drugs for internal use). Therefore, despite the many common features that antibacterial drugs have in common, when prescribing them, it is necessary to take into account the properties of each drug and the consequences of their clinical use, identified in well-tested clinical trials.
The discovery of penicillin extended human life by an average of 30-35 years old. Scientists in their studies have shown how antibiotics fight pathogenic bacteria.
When I got up on the morning of September 28, 1928, I certainly did not plan to make any breakthrough in medicine with my creation of the world’s first killer bacteria or antibiotic,” these words were noted in the diary of Alexander Fleming, the man who discovered us penicillin.
At the beginning of the 19th century, the idea of using microbes in the fight against the microbes themselves appeared. Scientists already in those distant times understood that in order to combat complications from wounds, it was necessary to find a way to paralyze microbes that cause further complications, and that it was possible to neutralize microorganisms with their help. In particular, Louis Pasteur realized that the anthrax bacilli could be destroyed by exposure to certain other microbes. Around 1897, Ernest Duchesne used the mold, i.e., the characteristics of penicillin, to treat typhus in guinea pigs.
It is believed that penicillin was actually invented on September 3, 1928. By this period, Fleming was already popular and known as a brilliant researcher. At that time, he was studying staphylococci, but his laboratory could often be found in an unkempt state, which turned out to be the reason for the discovery.
On September 3, 1928, Fleming returned to his laboratory after being away for a month. He tried to collect all the staphylococci, and then he came across one plate on which mold fungi had formed, and the colonies of staphylococci on it were destroyed, and there were practically no other colonies. The researcher took with him the mushrooms that formed on the plate with his cultures, attributed them to the genus Penicillium, and called the isolated substance penicillin. Upon further study, he noticed that penicillin had an effect on staphylococci and other pathogens that cause pneumonia, scarlet fever, diphtheria and meningitis. But this remedy could not fight typhoid and paratyphoid.
Publication of Fleming's discovery.
Fleming published a report on his new discovery in 1929 in a British journal, which was dedicated to experimental pathology. In the same year, he was still engaged in research and soon discovered that working with penicillin was difficult, production was quite slow, and, moreover, penicillin was not able to take root in the human body for very long to destroy bacteria. Also, the scientist was unable to extract and purify the active substance. Until the beginning of 1942, the scientist tried to improve the new invention, but until 1939 he was not able to develop an impeccable culture. In 1940, the Anglo-German biochemist Howard Walter Florey and Ernst Boris Chain actively tried to purify and obtain penicillin, and after some period of time they produced the necessary amount of penicillin in order to treat the wounded.
Already at the beginning of the 1941s, penicillin was obtained in the required quantities for a positive dose. The first person to be saved by a completely new antibiotic was a 15-year-old boy who had blood poisoning. In 1945, Fleming, Cheyne and Florey were awarded the Nobel Prize in Medicine or Physiology "for the discovery of penicillin and its beneficial effects in all infectious diseases."
Penicillin in medicine.
During World War II, the United States was already producing penicillin, which saved a huge number of US soldiers and neighboring countries from amputation. Over time, the method of creating an antibiotic was improved, and since 1952, fairly affordable penicillin began to be used on a global scale.Penicillin helps fight various diseases: osteomyelitis, syphilis, pneumonia, puerperal fever. It also helps prevent the formation of infections after burns and wounds - in former times, all these diseases were fatal. With the development of pharmacology, antibacterial agents of other categories were isolated and synthesized, and when other types of antibiotics were obtained, they were able to fight such a deadly disease as tuberculosis.
For a couple of decades, antibiotics were a panacea for any disease, but Alexander Fleming himself said that there is no need to use penicillin before diagnosing the disease, and there is no need to use the antibiotic for a short period and in small doses, because under these conditions bacteria can develop resistance . Most experts believe that antibiotics are ineffective in fighting disease, but patients themselves are also to blame for this because they do not always take antibiotics as prescribed or in the required doses.
“The problem of resistance is quite large and affects everyone. This leads to great concern among scientists; we may once again return to the pre-antibiotic era, since all microbes will be resistant, not a single antibiotic will be able to act on them. Our careful actions have resulted in the fact that we will no longer use quite powerful drugs. It will be simply impossible to treat tuberculosis, AIDS, HIV, and malaria,” added Galina Kholmogorova.
That is why when treating with antibiotics it is necessary to be quite responsible and follow the following rules:
- you cannot take them without the advice of doctors;
- do not stop the started course of treatment;
- remember that they do not help with viral infections.
Antibiotics are one of the most remarkable inventions of the 20th century in the field of medicine. Modern people are not always aware of how much they owe to these medicinal drugs. Humanity in general very quickly gets used to the amazing achievements of its science, and sometimes it takes some effort to imagine life as it was, for example, before the invention of television, radio or steam locomotive. Just as quickly, a huge family of various antibiotics entered our lives, the first of which was penicillin.
Today it seems surprising to us that back in the 30s of the 20th century, tens of thousands of people died every year from dysentery, that pneumonia in many cases was fatal, that sepsis was a real scourge of all surgical patients, who died in large numbers from blood poisoning, that typhus was considered a most dangerous and intractable disease, and pneumonic plague inevitably led the patient to death. All these terrible diseases (and many others that were previously incurable, such as tuberculosis) were defeated by antibiotics.
Even more striking is the impact of these drugs on military medicine. It’s hard to believe, but in previous wars, most soldiers died not from bullets and shrapnel, but from purulent infections caused by wounds. It is known that in the space around us there are myriads of microscopic organisms, microbes, among which there are many dangerous pathogens. Under normal conditions, our skin prevents them from penetrating into the body. But during the wound, dirt entered the open wounds along with millions of putrefactive bacteria (cocci). They began to multiply with colossal speed, penetrated deep into the tissues, and after a few hours no surgeon could save the person: the wound festered, the temperature rose, sepsis or gangrene began. The person died not so much from the wound itself, but from wound complications. Medicine was powerless against them. In the best case, the doctor managed to amputate the affected organ and thereby stopped the spread of the disease.
To deal with wound complications, it was necessary to learn to paralyze the microbes that cause these complications, to learn to neutralize the cocci that got into the wound. But how to achieve this? It turned out that you can fight microorganisms directly with their help, since some microorganisms, in the process of their life activity, release substances that can destroy other microorganisms. The idea of using microbes to fight germs dates back to the 19th century. Thus, Louis Pasteur discovered that anthrax bacilli are killed by the action of certain other microbes. But it is clear that solving this problem required enormous work - it is not easy to understand the life and relationships of microorganisms, it is even more difficult to understand which of them are at enmity with each other and how one microbe defeats another. However, the hardest thing was to imagine that the formidable enemy of the cocci had long been well known to man, that he had been living side by side with him for thousands of years, reminding himself every now and then. It turned out to be ordinary mold - an insignificant fungus that is always present in the air in the form of spores and willingly grows on anything old and damp, be it a cellar wall or a piece of bread.
However, the bactericidal properties of mold were known back in the 19th century. In the 60s of the last century, a dispute arose between two Russian doctors - Alexei Polotebnov and Vyacheslav Manassein. Polotebnov argued that mold is the ancestor of all microbes, that is, that all microbes come from it. Manassein argued that this was not true. To substantiate his arguments, he began to study green molds (penicillium glaucum in Latin). He sowed mold on a nutrient medium and was amazed to note that where the mold grew, bacteria never developed. From this Manassein concluded that mold prevents the growth of microorganisms.
Polotebnov later observed the same thing: the liquid in which mold appeared always remained transparent, and therefore did not contain bacteria.
Polotebnov realized that as a researcher he was wrong in his conclusions. However, as a doctor, he decided to immediately investigate this unusual property of such an easily accessible substance as mold. The attempt was successful: the ulcers, covered with an emulsion containing mold, healed quickly. Polotebnov made an interesting experiment: he covered deep skin ulcers of patients with a mixture of mold and bacteria and did not observe any complications in them. In one of his articles in 1872, he recommended treating wounds and deep abscesses in the same way. Unfortunately, Polotebnov’s experiments did not attract attention, although many people died from post-wound complications in all surgical clinics at that time.
The remarkable properties of mold were rediscovered half a century later by the Scot Alexander Fleming. From his youth, Fleming dreamed of finding a substance that could destroy pathogenic bacteria, and persistently studied microbiology. Fleming's laboratory was located in a small room in the pathology department of one of the large London hospitals. This room was always stuffy, cramped and chaotic. To escape the stuffiness, Fleming kept the window open all the time. Together with another doctor, Fleming was engaged in research on staphylococci. But without finishing his work, this doctor left the department. Old dishes with cultures of microbial colonies were still on the shelves of the laboratory - Fleming always considered cleaning his room a waste of time.
One day, having decided to write an article about staphylococci, Fleming looked into these cups and discovered that many of the cultures there were covered with mold. This, however, was not surprising - apparently mold spores had been brought into the laboratory through the window. Another thing was surprising: when Fleming began to examine the culture, in many cups there was no trace of staphylococci - there was only mold and transparent, dew-like drops. Has ordinary mold really destroyed all pathogenic microbes? Fleming immediately decided to test his guess and placed some mold in a test tube with nutrient broth. When the fungus developed, he introduced various bacteria into the same cup and placed it in a thermostat.
Having then examined the nutrient medium, Fleming discovered that light and transparent spots had formed between the mold and the colonies of bacteria - the mold seemed to constrain the microbes, preventing them from growing near them.
Then Fleming decided to make a larger experiment: he transplanted the fungus into a large vessel and began to observe its development. Soon the surface of the vessel was covered with “felt” - a fungus that had grown and gathered in tight spaces. “Felt” changed its color several times: first it was white, then green, then black. The nutrient broth also changed color - it turned from transparent to yellow. “Obviously, mold releases some substances into the environment,” Fleming thought and decided to check whether they had properties harmful to bacteria. New experience has shown that the yellow liquid destroys the same microorganisms that the mold itself destroyed. Moreover, the liquid had extremely high activity - Fleming diluted it twenty times, but the solution still remained destructive for pathogenic bacteria.
Fleming realized that he was on the verge of an important discovery. He abandoned all his affairs and stopped other research.
The mold Penicillium notatum now completely absorbed his attention. For further experiments, Fleming needed gallons of mold broth - he studied at what day of growth, at what temperature and on what nutrient medium the action of the mysterious yellow substance would be most effective in destroying microbes. At the same time, it turned out that the mold itself, as well as the yellow broth, turned out to be harmless to animals. Fleming injected them into a rabbit's vein, abdominal cavity white mouse, washed the skin with broth and even dropped it into the eyes - no unpleasant phenomena were observed. In a test tube, a diluted yellow substance - a product secreted by mold - inhibited the growth of staphylococci, but did not disrupt the functions of blood leukocytes.
Fleming called this substance penicillin. From then on, he constantly thought about an important question: how to isolate the active substance from a filtered mold broth? Alas, this turned out to be extremely difficult. Meanwhile, it was clear that introducing an unrefined broth into a person’s blood, which contained a foreign protein, was certainly dangerous. Fleming's young colleagues, like him, doctors and not chemists, made many attempts to solve this problem. Working in makeshift conditions, they spent a lot of time and energy but achieved nothing. Every time after purification was undertaken, penicillin decomposed and lost healing properties. In the end, Fleming realized that this task was beyond his capabilities and that the solution should be left to others.
In February 1929, he made a report at the London Medical Research Club about the unusually strong antibacterial agent he had found. This message did not attract attention. However, Fleming was a stubborn Scot. He wrote a long article detailing his experiments and published it in a scientific journal. At all congresses and medical conventions, he one way or another made a reminder of his discovery. Gradually, penicillin became known not only in England, but also in America. Finally, in 1939, two English scientists - Howard Fleury, professor of pathology at one of the Oxford institutes, and Ernst Chain, a biochemist who fled Germany from Nazi persecution - paid close attention to penicillin.
Chayne and Fleury were looking for a topic to collaborate on. The difficulty of isolating purified penicillin attracted them. A strain (a culture of microbes isolated from certain sources) sent there by Fleming turned out to be at Oxford University. It was with this that they began to experiment. In order to turn penicillin into a drug, it had to be combined with some substance soluble in water, but in such a way that, being purified, it would not lose its amazing properties. For a long time, this problem seemed insoluble - penicillin quickly destroyed in an acidic environment (which is why, by the way, it could not be taken orally) and did not last long in an alkaline environment; it easily went into ether, but if it was not placed on ice, it was destroyed in it too . Only after many experiments was it possible to filter the liquid secreted by the fungus and containing aminopenicillic acid in a complex way and dissolve it in a special organic solvent in which potassium salts, which are highly soluble in water, were not soluble. After exposure to potassium acetate, white crystals of the potassium salt of penicillin precipitated. After doing many manipulations, Chain received a slimy mass, which he finally managed to turn into a brown powder. The very first experiments with it had an amazing effect: even a small granule of penicillin, diluted in a proportion of one in a million, had a powerful bactericidal property - deadly cocci placed in this environment died within a few minutes. At the same time, the drug injected into the vein of the mouse not only did not kill it, but had no effect on the animal at all.
Several other scientists joined Cheyne's experiments. The effect of penicillin was extensively studied on white mice. They were infected with staphylococci and streptococci in doses more than lethal. Half of them were injected with penicillin, and all of these mice remained alive. The rest died within a few hours. It was soon discovered that penicillin destroys not only cocci, but also gangrene pathogens. In 1942, penicillin was tested on a patient who was dying of meningitis. Very soon he recovered. The news of this made a great impression. However, it was not possible to establish production of the new drug in warring England. Fleury went to the USA, and here in 1943 in the city of Peoria, Dr. Coghill's laboratory began the industrial production of penicillin for the first time. In 1945, Fleming, Fleury and Chain were awarded the Nobel Prize for their outstanding discoveries.
In the USSR, penicillin from the mold Penicillium crustosum (this fungus was taken from the wall of one of the Moscow bomb shelters) was obtained in 1942 by Professor Zinaida Ermolyeva. There was a war going on. Hospitals were overcrowded with wounded people with purulent lesions caused by staphylococci and streptococci, complicating already severe wounds. The treatment was difficult. Many wounded died from purulent infection. In 1944, after much research, Ermolyeva went to the front to test the effect of her drug. Before the operation, Ermolyeva gave all the wounded an intramuscular injection of penicillin. After this, most fighters’ wounds healed without any complications or suppuration, without fever. Penicillin seemed like a real miracle to seasoned field surgeons. He cured even the most seriously ill patients who were already suffering from blood poisoning or pneumonia. In the same year, factory production of penicillin was established in the USSR.
Subsequently, the family of antibiotics began to expand rapidly. Already in 1942, Gause isolated gramicidin, and in 1944, an American of Ukrainian origin, Waksman, received streptomycin. The era of antibiotics began, thanks to which millions of people were saved in subsequent years.
It is curious that penicillin remained unpatented. Those who discovered and created it refused to receive patents - they believed that a substance that could bring such benefits to humanity should not serve as a source of income. This is probably the only discovery of this magnitude for which no one has claimed copyright.
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