The use of aminoglycoside antibiotics is contraindicated in Antibacterial drugs of the aminoglycoside group: features of action and application. General description of the drug group

They bind to the GOI ribosome, thus inhibiting bacterial protein synthesis.

Pharmacology

Aminoglycosides are poorly absorbed when taken orally, but are well absorbed through the peritoneum, pleural cavity and joints (and should never be instilled into these body cavities) and damaged skin. Aminoglycosides are usually given intravenously. Aminoglycosides are well distributed in the extracellular fluid with the exception of the vitreous body, CSF, respiratory secretions and bile (especially in patients with obstruction of the bile ducts). Vitreous fiber injection is required to treat endophthalmitis. Introduction to the cerebrospinal fluid is often necessary to achieve sufficient levels of antibiotic in the cerebrospinal fluid for the treatment of meningitis.

Aminoglycosides are excreted by glomerular filtration in the kidneys and have a serum half-life of 2-3 hours; elimination half-life increases exponentially as glomerular filtration rate falls (eg, in renal failure, in the elderly).

Indications

Aminoglycosides are prescribed for severe gram-negative bacillary infections (especially those due to Pseudomonas aeruginosa). Aminoglycosides are active against most gram-negative aerobic and facultative anaerobic infections, but they lack activity against anaerobes and most gram-positive bacteria, with the exception of staphylococci; however, some gram-negative bacilli and methicillin-resistant staphylococci are resistant.

Aminoglycosides that are active in P. aeruginosa infection include tobramycin (especially), gentamicin, and amikacin. Streptomycin, neomycin, and kanamycin are not active against P. aeruginosa. Gentamycin and tobramycin have similar antibacterial spectra against Gram-negative bacilli, but tobramycin is more active against P. aeruginosa and gentamicin is more active against Serratia marcescens. Amikacin is often active against gentamicin- and tobramycin-resistant pathogens.
Aminoglycosides are rarely used in isolation, usually for plague and tularemia. They are usually given along with broad-spectrum 3-lactams for severe infection with Gram-negative bacillus species. However, due to increased resistance to aminoglycosides, fluoroquinolones may replace aminoglycosides in the initial empiric stages of treatment or if the pathogen is found to be susceptible to the accompanying antibiotic, the aminoglycoside may be discontinued after 2-3 days if there is no sensitivity to aminoglycosides in P. aeruginosa.

Gentamicin or, less commonly, streptomycin may be used with other antibiotics to treat streptococcal or enterococcal endocarditis. Enterococcal resistance to aminoglycosides has become a common problem. Since the treatment of enterococcal endocarditis requires prolonged use of a potentially nephrotoxic and ototoxic aminoglycoside plus an anti-cell wall drug (eg, penicillin, vancomycin) to achieve bactericidal synergy, the choice of aminoglycoside should be based on in vitro sensitivity assessment. Sensitivity to high levels of aminoglycosides in vitro alone predicts synergy when low-dose aminoglycoside treatment is combined with an anti-cell wall drug. If the strain is resistant to high levels of gentamicin and streptomycin, gentamicin is preferred because serum levels can be quickly determined and toxicity is reduced. High-level enterococcal resistance to gentamicin in vitro does not preclude susceptibility of these strains to high levels of streptomycin; in such cases, streptomycin should be used. Several therapeutic options are available for enterococcal endocarditis that is resistant to high levels of gentamicin and streptomycin; There is no synergistic anti-cell wall drug/aminoglycoside combination in endocarditis due to these strains, but prolonged courses of anti-cell wall drug alone or in combination with daptomycin or linezolid have had limited success.

The use of streptomycin is limited by resistance and toxicity. It is used along with other antibiotics to treat tuberculosis.

Due to toxicity, the use of neomycin and kanamycin is limited to local use in small amounts. Neomycin can be used for the eyes, ears, orally and rectally, and as a bladder douche method. Oral neomycin is used topically against intestinal flora to prepare the bowel before surgery and to treat hepatic coma.

Contraindications

Aminoglycosides are contraindicated in patients who are allergic to them.

Appointment during pregnancy and lactation

In pregnancy, aminoglycosides are classified as category D (there is evidence of a risk to humans, but the benefits of the clinical plan may outweigh the risk). Aminoglycosides readily pass into breast milk but are poorly absorbed orally. Thus, their use is considered possible during breastfeeding.

Negative impacts

All aminoglycosides have

• renal toxicity (often reversible),
• vestibular and auditory toxicity (often irreversible),
• the ability to prolong the effect of neuromuscular blockers.

Symptoms and signs of vestibular lesions are dizziness, nausea, vomiting, nystagmus and ataxia.

Risk factors for renal, vestibular and auditory toxicity are as follows:

• Frequent or very large doses.
• Very high levels of the drug in the blood.
• Long-term therapy (especially >3 days).
• advanced age,
• History of impaired renal function.
• Co-administration of vancomycin, cyclosporine, or amphotericin B.
• With renal toxicity, the simultaneous administration of contrast agents,
• With auditory toxicity - a history of hearing problems and the simultaneous appointment of loop diuretics.

Patients on aminoglycosides >2 weeks and those at risk for vestibular and auditory toxicity should be monitored by serial audiography. At the first sign of toxicity, the drug should be discontinued (if possible) or the dosage should be adjusted accordingly.

Aminoglycosides can prolong the effects of neuromuscular blockers (eg, succiniloline, a drug similar to curare) and increase weakness in disorders affecting neuromuscular transmission (eg, myasthenia gravis). Such effects are especially likely when the drug is given too quickly or serum levels are excessively high. The effect sometimes wears off faster if patients are given intravenous neostigmine or calcium. Other neurological effects include paresthesia and peripheral neuropathy.

Allergic reactions are uncharacteristic. High oral doses of neomycin may be poorly absorbed.

Choice of dosage

Since toxicity depends more on the duration of therapeutic levels than on peak levels, and since efficacy is more concentration dependent than time dependent, frequent administration of the drug is avoided. Preferably administered once a day intravenously for most diseases, except for enterococcal endocarditis. Intravenous aminoglycosides are administered slowly (30 minutes at a divided daily dosage or 30-45 minutes at a once daily dosage).

In patients with normal renal function, a single dose for gentamicin or tobramycin is 5 mg/kg (7 mg/kg if patients are critically ill) every 24 hours, and for amikacin, 15 mg/kg every 24 hours. If patients respond to higher dose of gentamicin clinically and renal function continues to be normal, the daily dose may be reduced to a lower dose after the first few days of treatment.

In critically ill patients, peak serum levels should be determined after the first dose. In all patients, peak and threshold levels are measured after the 2nd or 3rd dose (when the daily dose is divided) or when therapy lasts >3 days, and also after a dose change. Serum creatinine is measured every 2-3 days, and if it is stable, serum aminoglycoside levels should not be measured again. The peak concentration is the level 60 minutes after an intramuscular injection or 30 minutes after a 30-minute intravenous infusion. Threshold levels are measured 30 minutes before the next dose.

It is desirable to achieve peak serum levels of at least 10 times the MIC. The dosage is adjusted to achieve guaranteed therapeutic peak serum levels (to provide concentration-dependent activity) and non-toxic residual levels. For critically ill patients who are given higher initial doses, target peak serum levels are 16-24 mg/mL for gentamicin and tobramycin and 56-64 mg/mL for amikacin. For gentamicin and tobramycin, residual levels should be<1 мг/мл спустя 18-24 ч после первой дозы при одноразовом назначении и между 1 и 2 мг/ мл при разделенной ежедневной дозировке.

For patients with renal insufficiency, the loading dose is the same as for patients with normal renal function; usually increase the dosing interval rather than reduce the dose. Dosing guidelines are available based on serum creatinine or creatinine clearance, but they are not precise and measurement of blood levels is preferred.

If patients receive a high dose of a β-lactam (eg, piperacillin, ticarcillin) and an aminoglycoside, high serum β-lactam levels may inactivate the aminoglycoside. This has been proven in vitro in serum samples obtained to determine drug levels if the specimen was not immediately evaluated or frozen. If patients with renal insufficiency take both an aminoglycoside and a high-dose β-lactam, the serum level of the aminoglycoside may be lower because the in vivo interaction is prolonged.

Spectinomycin

Spectinomycin is a bacteriostatic antibiotic chemically related to aminoglycosides. Spectinomycin binds to the 30S subunit of the ribosome, thus inhibiting bacterial protein synthesis. Its activity is limited to gonococci. Spectinomycin is eliminated by glomerular filtration.

Indicators for appointment:

• gonococcal urethritis,
• Cervicitis.
• Proctitis.

Spectinomycin is not effective in gonorrheal pharyngitis. It is intended for those patients who cannot be treated with ceftriaxone, cefpodoxime, cefixime, or a fluoroquinolone.

Adverse events, including allergic reactions and fever, are rare.

The group of aminoglycosides is included in the category of antibiotics, in relation to which doctors have accumulated a lot of experience in the use. The drugs have a wide range of sensitive microorganisms, are effective in monotherapy, in combination with other antibiotics. They are used not only in the conservative treatment of internal organs, but also in surgery, urology, ophthalmology, otolaryngology. At the same time, the resistance of some bacteria, the possibility of side effects determines the need to carefully approach the choice of medication, timely identify contraindications, control the development of undesirable effects.

Spectrum of antimicrobial activity

A feature of aminoglycoside preparations is their high activity against aerobic bacteria.

Gram-negative enterobacteria are sensitive:

• coli;
• Proteus;
• klebsiela;
• enterobacter;
• serration.

Efficiency is also observed with respect to non-fermenting gram-negative rods: Acinetobacter, Pseudomonas aeruginosa.

Most staphylococci (gram-positive cocci) are also susceptible to these drugs. The most clinically significant effect is in relation to golden and epidermal.

At the same time, aminoglycosides do not act on microorganisms that exist in anoxic conditions (anaerobes). Bacteria that have the ability to penetrate into human cells, hiding from natural defense systems, are also insensitive to aminoglycosides. Methicillin-resistant staphylococci are also resistant to antibiotics. Therefore, their use is inappropriate for infections caused by pneumococci, anaerobes (bacteroids, clostridia), legionella, chlamydia, salmonella, shigella.

Modern systematization

The name "aminoglycosides" gave this group of antibiotics the presence in the molecule of amino sugars connected by glycosidic bonds with other structural elements.

There are various classification approaches. The most widely used are based on methods of preparation and microbial spectrum.

Depending on the sensitivity and resistance of the bacterial flora, 4 generations of aminoglycosides are isolated.

Classification of aminoglycosides and list of drugs:

• 1st generation: streptomycin, neomycin, monomycin, kanamycin;
• 2nd generation: gentamicin;
• 3rd generation: amikacin, netilmicin, sisomycin, tobramycin;
• 4th generation: isepamycin.

Also referred to as aminoglycosides is spectinomycin. It is a natural antibiotic produced by Streptomyces bacteria.

In addition to the general spectrum of sensitive microbes, each generation has its own characteristics. Thus, Mycobacterium tuberculosis is sensitive to 1st generation drugs, in particular, streptomycin and kanamycin, and amikacin is effective against atypical mycobacteria. Streptomycin is active against the causative agents of plague infection, tularemia, brucellosis, enterococci. Monomycin has less activity against staphylococci, while being more active in the presence of protozoa.

If the drugs of the 1st generation are ineffective when exposed to Pseudomonas aeruginosa, then the remaining antibiotics are highly active against this microbe.

In the 3rd generation, the spectrum of antimicrobial activity is significantly expanded.

Most effective for:

• Pseudomonas aeruginosa;
• klebsiela;
• mycobacterium tuberculosis;
• coli.

One of the most effective drugs with a low percentage of microbial resistance of the entire group of aminoglycosides is amikacin.

Amikacin is the drug of choice when urgent therapy is needed until the results of studies of the spectrum and sensitivity of the microbes that caused the disease are available.

The 4th generation includes isepamycin. Effective against citrobacter, listeria, aeromonads, nocardia. It can be used not only in the treatment of aerobic infections, but also in anaerobic, microaerophilic (with a need for a low oxygen content in the environment) flora.

A feature of spectinomycin is its high clinical efficacy against the causative agent of gonorrhea. Even those gonococci that are resistant to traditionally used penicillins are sensitive to this antibiotic. Also used for allergies to other antibacterial agents.

By origin, drugs are divided into natural and semi-synthetic. Both the first representative of this group (streptomycin), and neomycin, kanamycin, tobramycin are produced by actinomycetes (radiant fungi). Gentamicin - micromonospore fungi. By chemical transformation of these antibacterial agents, semi-synthetic antibiotics are obtained: amikacin, netilmicin, isepamycin.

Mechanisms for the formation of clinical effectiveness

Aminoglycosides are bactericidal antibiotics. By acting on sensitive microorganisms, drugs completely deprive them of their viability. The mechanism of action is due to a violation of protein synthesis on bacterial ribosomes.

The effect of treatment with aminoglycosides is determined by:

• spectrum of sensitive pathogens;
• features of distribution in tissues and excretion from the human body;
• post-antibiotic effect;
• ability to synergy with other antibiotics;
• formed resistance of microorganisms.

The antibacterial effect of drugs in this group is all the more significant, the higher the content of the drug in the blood serum.

The post-antibiotic phenomenon increases their effectiveness: the resumption of bacterial reproduction occurs only some time after the termination of contact with the drug. This helps to reduce therapeutic doses.

A positive feature of these drugs is an increase in the effect of treatment when used together with penicillin antibiotics and compared with the use of each drug separately. This phenomenon is called synergism and in this case is observed in relation to a number of aerobic microbes - gram-negative and gram-positive.

Over a long period of use of antibiotics of the aminoglycoside group (since the 40s of the last century), a significant number of microorganisms have formed resistance to them (resistance), which can be developed and natural. Bacteria that exist under anaerobic conditions are naturally resistant. Their intracellular transport system is unable to deliver the drug molecule to the target.

Mechanisms of acquired resistance formation:

• the influence of microbial enzymes on the antibiotic molecule, modifying and depriving it of antimicrobial activity;
• a decrease in the permeability of the cell wall for the drug molecule;
• a change in the structure of the protein target of the ribosome, which is affected by the antibiotic, as a result of a mutation.

At present, microorganisms have become resistant to most aminoglycosides of the 1st and 2nd generation. At the same time, significantly lower resistance is characteristic of drugs of other generations, which makes them more preferable for use.

Scope of clinical application

The use is indicated for severe, systemic infections. Most often, they are prescribed in combination with beta-lactams (cephalosporins, glycopeptides), antianaerobic agents (lincosamides).

Main indications for use:

• sepsis, including on the background of neutropenia;
• infective endocarditis;
• osteomyelitis;
• complicated infections of the abdominal cavity and small pelvis (peritonitis, abscesses);
• nosocomial pneumonia, including ventilator-associated;
• infections of the urinary system, complicated by purulent formation (paranephritis, carbuncle and apostomatosis of the kidney, pyelonephritis);
• meningitis (post-traumatic, postoperative);
• purulent processes against the background of neutropenia.

This group of antibiotics is also used in the treatment of infectious diseases.

The most effective is the use of:

• streptomycin (for plague, tularemia, brucellosis, tuberculosis);
• gentamicin (for tularemia);
• kanamycin (for tuberculosis).

Various routes of administration of aminoglycoside antibiotics are used, depending on the location of the focus of infection and the characteristics of the pathogen: intramuscularly, intravenously, in tablets. The introduction of the drug into the lymphatic system and endotracheally is used much less often due to the narrow therapeutic window.

Before extensive operations on the large intestine, it is necessary to destroy the local pathogenic microflora as much as possible. For this, tablets of neomycin, kanamycin are used, often in combination with macrolides (erythromycin).

Perhaps the use in ophthalmology for the local treatment of bacterial lesions of the conjunctiva of the eye, sclera, cornea. Special dosage forms are used - ear drops and ointments. As a rule, simultaneously with a hormonal anti-inflammatory drug. For example, gentamicin with betamethasone.

Aminoglycosides have a narrow therapeutic window, that is, the interval between the minimum therapeutic and side-effect-causing concentration.

The list of basic rules for the use of aminoglycosides:

• dose calculation is carried out on the basis of body weight, age of the patient, functional state of the kidneys;
• the method of administration depends on the location of the pathological focus;
• the regimen of drug administration is strictly observed;
• the concentration of the antibiotic in the blood is constantly monitored;
• the level of creatinine is controlled 1 time in 3-5 days;
• a hearing test is performed before (if possible) and after (mandatory) treatment.

Aminoglycosides are used in short courses. On average 7-10 days. If necessary, drugs are administered for a longer time (up to 14 days). However, it should be remembered that with prolonged use of drugs, side effects are more likely.

Unwanted Effects

Aminoglycosides are highly effective, as well as quite toxic antibiotics. It is not always possible to use them even in the presence of a sensitive microorganism.

Main contraindications:

• allergic reactions with past use;
• severe renal failure;
• damage to the auditory and vestibular apparatus;
• damage to nerve endings of an inflammatory nature (neuritis) and muscle tissue (myasthenia gravis);
• pregnancy at any time;
• breastfeeding period.

During pregnancy, the use is possible only for health reasons. When breastfeeding, drugs can affect the intestinal microflora of the infant and have a toxic effect on the growing body.

Drugs of the aminoglycoside group have a number of adverse effects:

• toxic effect on the organ of hearing and vestibular apparatus;
• negative impact on the renal tissue, deterioration of the urine filtration process;
• disruption of the nervous system;
• allergic reactions.

Toxic effects are more pronounced in children and the elderly. Gentamicin is not recommended for children under 14 years of age. For special indications and with caution, it is possible to use in newborns, premature babies. In these children, the functional activity of the kidneys is reduced, which leads to a sharp increase in the toxicity of drugs.

The likelihood of adverse effects in elderly patients is also high. In these patients, even with preserved kidney function, a toxic effect on the ears is possible. It is necessary to adjust the dosage, depending on the age of the patient.

Features of the effect of drugs on the ENT organs

The most pronounced negative effect of aminoglycosides on the upper respiratory tract during systemic use. Ototoxicity increases sharply with previous ear pathology. However, against the background of full health, irreversible changes can also develop.

Aminoglycosides in diseases of the upper respiratory tract are used as local therapy. The lack of significant absorption reduces the likelihood of toxic effects. Ear ointment, topical sprays are used. The preparations contain only an aminoglycoside (framycetin) or in combination with other medicines. The drug Sofradex consists of framycetin, gramicidin (a polypeptide antibiotic), the hormonal drug dexamethasone.

List of indications for local use of aminoglycoside preparations:

• acute nasopharyngitis;
• chronic rhinitis;
• diseases of the paranasal sinuses;
• otitis externa.

It is also possible to use it in surgical otolaryngology for the prevention of bacterial complications after operations.

Ototoxicity of aminoglycosides is determined by their ability to accumulate in the fluids of the inner ear.

Damage to the hair cells (the main receptor structures of the organ of hearing and balance), up to their complete destruction, causes the gradual development of complete deafness. Hearing is lost forever.

The activity of the vestibular apparatus is also disrupted. Dizziness appears, coordination of movements worsens, gait stability decreases. The least toxic for parenteral use is amikacin, the most - neomycin.

Thus, aminoglycosides are widely used in modern clinical medicine. At the same time, their safety is determined by a comprehensive examination of the patient, the selection of an adequate regimen and method of taking the drug. The possibility of using aminoglycosides in the treatment of diseases of the ENT organs should be decided by the doctor individually in each case, based on a comprehensive analysis of the nature and nature of the disease, age, state of the hearing and balance organs, and the body as a whole.

The appearance on the pharmacological market of new antibiotics with a wide range of effects, such as fluoroquinolones, cephalosporins, has led to the fact that doctors have become extremely rare in prescribing aminoglycosides (drugs). The list of medicines included in this group is quite extensive, and includes such well-known drugs as Gentamycin, Amikacin, Streptomycin. Streptomycin, by the way, is considered historically the first aminoglycoside. It is also the second known antibiotic after penicillin. Aminoglycosides, or rather, aminoglycoside preparations, remain to this day the most popular in intensive care and surgical departments.

Brief description of the group

Aminoglycosides are drugs (we will consider a list of drugs below) that differ in semi-synthetic or natural origin. This has a fast and powerful bactericidal effect on the body.

Medicines have a wide spectrum of action. Their antimicrobial activity is pronounced against gram-negative bacteria, but is significantly reduced in the fight against gram-positive microorganisms. And aminoglycosides are completely ineffective against anaerobes.

This group of drugs produces an excellent bactericidal effect due to the ability to irreversibly inhibit protein synthesis in sensitive microorganisms at the level of ribosomes. Medicines are active in relation to both multiplying and resting cells. The degree of activity of antibiotics depends entirely on their concentration in the patient's blood serum.

The group of aminoglycosides is used today rather limitedly. This is due to the high toxicity of these drugs. The kidneys and organs of hearing are most often affected by such drugs.

An important feature of these agents is the impossibility of their penetration into a living cell. Thus, aminoglycosides are completely powerless in the fight against intracellular bacteria.

Advantages and disadvantages

These antibiotics are widely used, as mentioned above, in surgical practice. And it is no coincidence. Doctors emphasize the many advantages that aminoglycosides have.

The effect of drugs on the body is distinguished by such positive aspects:

• high antibacterial activity;
• the absence of a painful reaction (with injection);
• rare occurrence of allergies;
• the ability to destroy multiplying bacteria;
• enhanced therapeutic effect when combined with beta-lactam antibiotics;
• high activity in the fight against dangerous infections.

However, along with the advantages described above, this group of medicines also has disadvantages.

The disadvantages of aminoglycosides are:

• low activity of drugs in the absence of oxygen or in an acidic environment;
• poor penetration of the main substance into body fluids (bile, cerebrospinal fluid, sputum);
• occurrence of many side effects.

Classification of medicines

There are several classifications.

So, given the sequence of introduction of aminoglycosides into medical practice, the following generations are distinguished:

1. The first drugs used to combat infectious diseases were Streptomycin, Monomycin, Neomycin, Kanamycin, Paromomycin.
2. The second generation includes more modern aminoglycosides (drugs). List of drugs: "Gentamicin", "Tobramycin", "Sizomycin", "Netilmicin".
3. This group includes semi-synthetic medicines, such as Amikacin, Isepamycin.

According to the spectrum of action and the emergence of resistance, aminoglycosides are classified somewhat differently.

Generations of medicines are as follows:

1. Group 1 includes such drugs: Streptomycin, Kanamycin, Monomycin, Neomycin. These medicines allow you to fight tuberculosis pathogens and some atypical bacteria. However, against the multitude and staphylococci, they are powerless.

2. The representative of the second generation of aminoglycosides is the drug "Gentamicin". It is distinguished by great antibacterial activity.

3. Better medicines. They have high antibacterial activity. Apply against klebisiella, enterobacter, it is the third generation of aminoglycosides (drugs). The list of medicines is as follows:

- "Sizomycin";

- "Amicin";

- "Tobramycin";

- Netilmicin.

4. The fourth group includes the drug "Isepamycin". It is distinguished by the additional ability to effectively fight cytobacter, aeromonas, and nocardia.

In medical practice, another classification has been developed. It is based on the use of drugs depending on the clinic of the disease, the nature of the infection, as well as the method of application.

Such a classification of aminoglycosides is as follows:

1. Drugs for systemic exposure, administered parenterally (injection) into the body. For the treatment of bacterial purulent infections occurring in severe forms, provoked by opportunistic anaerobic microorganisms, the following drugs are prescribed: Gentamicin, Amikacin, Netilmicin, Tobramycin, Sizomycin. Treatment of dangerous monoinfections based on obligate pathogens is effective when the drugs "Streptomycin", "Gentomycin" are included in the therapy. With mycobacteriosis, the medicines Amikacin, Streptomycin, Kanamycin are excellent.
2. Drugs that are used exclusively inside for special indications. These are: "Paromycin", "Neomycin", "Monomycin".
3. Medicines for topical use. They are used for the treatment of purulent bacterial infections in otorhinolaryngology and ophthalmology. For local exposure, the preparations "Gentamicin", "Framycetin", "Neomycin", "Tobramycin" have been developed.

Indications for appointment

The use of aminoglycosides is advisable for the destruction of a wide variety of aerobic gram-negative pathogens. Medicines can be used as monotherapy. Often they are combined with beta-lactams.

Aminoglycosides are prescribed for the treatment of:

• various localization;
• purulent postoperative complications;
• intra-abdominal infections;
• sepsis;
• pyelonephritis occurring in severe forms;
• infected burns;
• bacterial purulent meningitis;
• tuberculosis;
• dangerous infectious diseases (plague, brucellosis, tularemia);
• septic arthritis provoked by gram-negative bacteria;
• urinary tract infections;
• ophthalmic diseases: blepharitis, bacterial keratitis, conjunctivitis, keratoconjunctivitis, uveitis, dacryocystitis;
• otorhinolaryngological ailments: otitis externa, rhinopharyngitis, rhinitis, sinusitis;

Side effects

Unfortunately, during therapy with this category of drugs, the patient may experience a number of undesirable effects. The main disadvantage of medicines is high toxicity. That is why only a doctor should prescribe aminoglycosides to a patient.

Side effects may appear:

1. Ototoxicity. Patients complain of hearing loss, ringing, noise. Often they indicate stuffy ears. Most often, such reactions are observed in the elderly, in people who initially suffer from hearing impairment. Similar reactions develop in patients with long-term therapy or the appointment of high doses.
2. nephrotoxicity. The patient develops a strong thirst, the amount of urine changes (it can both increase and decrease), the level of creatinine in the blood rises, and glomerular filtration decreases. Similar symptoms are characteristic of people suffering from impaired functioning of the kidneys.
3. Neuromuscular blockade. Sometimes during therapy, breathing is depressed. In some cases, paralysis of the respiratory muscles is even observed. As a rule, such reactions are characteristic of patients with neurological diseases or impaired kidney function.
4. vestibular disorders. They are manifested by impaired coordination, dizziness. Very often, such side effects appear when the patient is prescribed the drug "Streptomycin".
5. neurological disorders. Paresthesia, encephalopathy may appear. Sometimes therapy is accompanied by damage to the optic nerve.

Very rarely, aminoglycosides cause allergic manifestations such as skin rash.

Contraindications

The described medicines have some limitations for use. Most often, aminoglycosides (whose names were given above) are contraindicated in such pathologies or conditions:

• individual hypersensitivity;
• violation of the excretory function of the kidneys;
• hearing disorders;
• the development of neutropenic severe reactions;
• vestibular disorders;
• myasthenia gravis, botulism, parkinsonism;
• oppressed breathing, stupor.

In addition, they should not be used for treatment if the patient's history had a negative reaction to any medication from this group.

Consider the most popular aminoglycosides.

"Amicin"

The drug has a pronounced bacteriostatic, bactericidal and anti-tuberculosis effect on the human body. It is highly active against many Gram-positive and Gram-negative bacteria. So testifies to the drug "Amikacin" instructions for use. Injections are effective in the treatment of staphylococci, streptococci, pneumococci, salmonella, Escherichia coli, mycobacterium tuberculosis.

The drug is not able to be absorbed through the gastrointestinal tract. Therefore, it is used only intravenously or intramuscularly. The highest concentration of the active substance is observed in the blood serum after 1 hour. The positive therapeutic effect persists for 10-12 hours. Due to this property, injections are performed twice a day.

• pneumonia, bronchitis, lung abscesses;
• infectious diseases of the peritoneum (peritonitis, pancreatitis, cholecystitis);
• diseases of the urinary tract (cystitis, urethritis, pyelonephritis);
• skin pathologies (ulcerative lesions, burns, bedsores,;
• osteomyelitis;
• meningitis, sepsis;
• tuberculosis infections.

Often this remedy is used for complications provoked by surgical intervention.

The use of the drug in pediatric practice is allowed. This fact confirms the instructions for use for the drug "Amikacin". For children from the first days of life, this medicine can be prescribed.

Dosages are determined solely by the doctor, depending on the age of the patient and his body weight.

1. For 1 kg of the patient's weight (both an adult and a child), 5 mg of the drug should be taken. With this scheme, a second injection is given after 8 hours.
2. If 7.5 mg of the drug is taken per 1 kg of body weight, then the interval between injections is 12 hours.
3. Pay attention to how the instructions for use recommend using Amikacin for newborns. For children who have just been born, the dosage is calculated as follows: per 1 kg - 7.5 mg. In this case, the interval between injections is 18 hours.
4. The duration of therapy can be 7 days (with intravenous injection) or 7-10 days (with intramuscular injections).

"Netilmicin"

This medicine is similar in its antimicrobial effect to Amikacin. At the same time, there are cases when "Netilmicin" was highly effective against those microorganisms in which the above medicine was powerless.

The drug has a significant advantage in comparison with other aminoglycosides. As the instructions for use indicate to the drug "Netilmicin", the drug has less nephro- and ototoxicity. The medicine is intended exclusively for parenteral use.

• with septicemia, bacteremia,
• for the treatment of a suspected infection caused by gram-negative microbes;
• with infections of the respiratory system, urogenital tract, skin, ligamentous apparatus, osteomyelitis;
• newborns in case of serious staphylococcal infections (sepsis or pneumonia);
• with wound, preoperative and intraperitoneal infections;
• in case of risk of postoperative complications in surgical patients;
• with infectious diseases of the gastrointestinal tract.

The drug "Gentamicin"

It is produced in the form of ointment, solution for injection and tablets. The drug has pronounced bactericidal properties. It provides a detrimental effect on many Gram-negative Campylobacter, Escherichia, Staphylococcus, Salmonella, Klebsiella.

The drug "Gentamicin" (tablets or solution), entering the body, destroys pathogens at the cellular level. Like any aminoglycoside, it provides a violation of protein synthesis of pathogens. As a result, such bacteria lose their ability to further reproduce and cannot spread throughout the body.

An antibiotic is prescribed for infectious diseases that affect various systems and organs:

• meningitis;
• peritonitis;
• prostatitis;
• gonorrhea;
• osteomyelitis;
• cystitis;
• pyelonephritis;
• endometritis;
• pleural empyema;
• bronchitis, pneumonia;

The drug "Gentamicin" is quite in demand in medicine. It allows you to cure patients of serious infections of the respiratory and urinary tract. This remedy is recommended for infectious processes involving the peritoneum, bones, soft tissues or skin.

Aminoglycosides are not intended for self-treatment. Do not forget that only a qualified doctor can choose the necessary antibiotic. Therefore, do not self-medicate. Trust your health to professionals!

Aminoglycosides are bactericidal-type antibiotics derived from various types of streptomycin fungi that have a common chemical component, similar antimicrobial, pharmacological and toxic characteristics.

They got their name due to the presence in the molecule of aminosaccharides connected by a glycosidic bond with an aglycone fragment. The structural element of aminoglycoside antibiotics is 2-deoxy-P-streptamine.

Antibiotics of this group are produced by radiant fungi Actinomyces (neomycin, kanamycin, tobramycin), Streptomyces (streptomycin), Micromonospora (gentamicin). Some aminoglycosides are obtained synthetically (amikacin).

Currently, the group of aminoglycosides includes the following antibiotics: streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomycin, biomycin, netilmicin, framycetin, paromomycin, etc. All of them have a wide antimicrobial spectrum of action, including the main representatives of gram-positive and gram-positive causative microorganisms. Some of them are active and highly effective in in-

infections caused by mycobacterium tuberculosis, Pseudomonas aeruginosa and protozoa. All representatives of this group of antibiotics have common pharmacological and pharmacokinetic properties.

The mechanism of action of aminoglycosides in relatively low concentrations is due to their binding to the 30S subunit of the ribosome of the microbial cell, which leads to a stop in protein synthesis (causes bacteriostasis), in large doses they disrupt the permeability and barrier functions of cytoplasmic membranes (bactericidal effect). All aminoglycosides are characterized by relatively high toxicity when administered parenterally, selective ototoxic, nephrotoxic effects and the ability to cause neuromuscular blockade.

In infections caused by gram-negative aerobic bacteria of the intestinal group, all aminoglycosides are used. In the treatment of tuberculosis infection, streptomycin and kanamycin are used, and in the treatment of plague, tularemia and brucellosis, streptomycin is used. For infections caused by Pseudomonas aeruginosa, gentamicin, tobramycin, sisomycin, netilmicin and amikacin. For staphylococcal infections, aminoglycosides are combined with beta-lactam antibiotics. Enterococcal infections are treated with a combination of an aminoglycoside with penicillin or ampicillin.

Neomycin, framycetin, kanamycin in recent years has been used to a limited extent and only orally or topically.

Pharmacokinetics

Aminoglycosides are bactericidal antibiotics for sensitive microorganisms. The mechanism of bactericidal action of aminoglyco-

zidov is still not entirely clear. It is assumed that the initial stage of their action is penetration through the cell wall by passive diffusion and, possibly, by active transport through oxygen-dependent mechanisms (aminoglycosides are relatively ineffective against anaerobes). After the aminoglycoside has entered the cell, it binds to specific receptor proteins on the 30S subunit of the bacterial ribosome. As a result, the formation of the initiating complex between messenger RNA and the 30S subunit of the ribosome is disrupted. Polysomes break down into non-functioning monosomes. Defects occur when reading from DNA, defective proteins are synthesized, which leads to a cessation of growth and development of the microbial cell. At high concentrations of aminoglycosides, damage to the cytoplasmic membrane occurs and the cell dies.

The aminoglycoside molecule, being highly polar, when administered orally from the digestive tract, is poorly absorbed, but can be absorbed in the presence of ulcerative processes in the gastrointestinal tract. Aminoglycoside does not enter the blood from the alveoli of the lungs if it is used in the form of inhalation. At least the entire accepted dose of aminoglycoside through the mouth is excreted by the gastrointestinal tract and only about 1% of the dose of the drug can be adsorbed. After intramuscular injection, the aminoglycoside is rapidly absorbed. Its maximum blood level is observed 30-90 minutes after injection, but only 10% of aminoglycosides bind to plasma proteins. The antibiotic is found in the peritoneal, pleural, cerebrospinal fluid, in the vitreous body of the eye and bile, penetrates the placental barrier, but does not pass through the blood-brain barrier. The largest number

The antibiotic activity is noted in the kidneys, then in the lungs. In the liver, brain, lymph nodes, aminoglycosides are not retained, with the exception of the adrenal cortex.

Aminoglycosides are excreted from the body in 12-24 hours, and about 70% of the administered amount is excreted by the kidneys and approximately 1% is excreted in the bile, the concentration in the biliary tract can be 30% of the blood level. The rest, 25-30%, undergoes various transformations in the body with the formation of products devoid of antimicrobial activity. The half-life of aminoglycosides from the body is 2-4 hours. Excretion of the drug by glomerular filtration is significantly reduced when renal function is impaired.

All aminoglycosides have varying degrees of ototoxicity and nephrotoxicity. Ototoxicity is manifested in hearing loss (damage to the cochlear apparatus), which is noted with high-grade tones, or vestibular disorders - dizziness, ataxia and loss of balance. Nephrotoxicity results in an increase in serum creatinine or a decrease in creatinine clearance. At high doses, aminoglycosides cause a curare-like effect with neuromuscular blockade leading to respiratory paralysis.

Clinical Application

Aminoglycosides are widely used against infections caused by Gram-negative bacteria or when sepsis is suspected. In the treatment of bacteremia or endocarditis caused by fecal streptococci or other gram-negative bacteria, aminoglycosides are administered along with penicillins, which increase pro-

the permeability of the microbial cell for aminoglycosides or contribute to the penetration of aminoglycosides into the cells of microorganisms.

Streptomycin in its pure form was first obtained by 3. Waksman and co-workers in 1942. In less than 2 years, the pharmacological activity was studied, and already in 1946, the drug was proposed for wide clinical use. Thanks to its widespread use, outstanding results have been obtained in the fight against tuberculosis, tularemia and other serious infections for which there was no specific therapy before. The antimicrobial activity of streptomycin is typical of all aminoglycosides, as are the mechanisms of resistance.

Streptomycin is used to treat various forms of TB, but is now rarely the first choice for TB treatment. In progressive forms of tuberculosis, miliary dissemination, meningitis or serious organ damage, the drug in combination with other antimicrobial agents is administered in doses of 0.5-1.0 g per day. In this mode, the drug is administered for weeks or months, initially daily, and then twice a week.

With plague, tularemia, and sometimes with brucellosis, streptomycin is administered intramuscularly at 1.0 g per day. However, treatment with streptomycin is most appropriate when the sensitivity of the infectious agent to the antibiotic has been laboratory proven. For some infections, such as infective endocarditis caused by fecal streptococci, some gram-negative bacteria, aerobes (Pseudomonas aeruginosa), and especially in immunocompromised patients, combined therapy with streptomycin and penicillin is indicated.

Among the side effects caused by streptomycin are: fever, skin lesions,

which are associated with hypersensitivity, disorders of the vestibular apparatus, hearing and dizziness. The frequency and severity of these disorders is proportional to the age of the patient, the level of antibiotic in the blood and the duration of treatment. However, after discontinuation of the drug, some improvement occurs.

Gentamicin was obtained in 1963. By chemical structure, it belongs to the group of aminoglycosides and is close to neomycin, kanamycin. The drug has a wide spectrum of action against gram-positive and gram-negative microorganisms (including Pseudomonas aeruginosa, Proteus, Escherichia coli, staphylococcus aureus). However, those microorganisms that are resistant to other aminoglycosides are not amenable to the action of gentamicin. In this case, there is cross-resistance. In recent years, the drug sisomycin has been obtained, which in its chemical structure is very similar to gentamicin.

Gentamicin is most often used for infections that do not respond to other, less toxic antibiotics. Most often, these are infections caused by Escherichia coli, Proteus, Pseudomonas aeruginosa, Salmonella. At a dose of 2-10 µg/ml, gentamicin inhibits in vitro many strains of staphylococci, colibacilli and gram-negative bacteria. Simultaneous use of carbenicillin or ticarcillin with gentamicin leads to a synergistic effect and an increase in bactericidal activity against strains of Pseudomonas aeruginosa, Proteus, Enterobacteriaceae, Klebsiella and fecal streptococci. However, penicillins and gentamicin cannot be used in an in vitro mixture.

Gentamicin is effective for infectious lesions of the urinary system (for cystitis, urethritis).

ritis, pyelonephritis), various forms of pneumonia, lung abscess, peritonitis, sepsis, osteomyelitis, endocarditis. It is most rational to prescribe gentamicin and tobramycin intramuscularly or intravenously for severe infections - sepsis or pneumonia caused by Pseudomonas aeruginosa, enterobacteria, proteus, klebsiella. In addition, with this pathology, patients have a sharp decrease in immunity, so the simultaneous use of aminoglycosides with cephalosporins or penicillins can save lives. In such cases, a dose of 5-7 mg/kg is administered intramuscularly 3 times a day in equivalent amounts.

Often, gentamicin is applied topically in the form of an ointment or solutions containing 0.1-0.3% gentamicin to treat infected wounds, burns, and skin lesions.

Side effects of gentamicin are typical, as for all other aminoglycosides. The drug has ototoxic and nephrotoxic effects. In high doses, gentamicin exhibits curare-like properties and disrupts neuromuscular conduction. Cases of hypersensitivity are described.

Sizomycin is a second-generation aminoglycoside antibiotic. It has a pronounced antibacterial (bacteriostatic, bactericidal) activity. It acts on most gram-positive and gram-negative microorganisms (Escherichia and Pseudomonas aeruginosa, Klebsiella, Proteus). The mechanism of action of sisomycin is similar to that of other aminoglycosides. The drug is poorly absorbed from the gastrointestinal tract, so it is usually used parenterally. High concentrations of sisomicin are created in the kidneys, lungs, liver, extracellular fluid. The drug, when administered parenterally, is in the body for a long time and is able to accumulate.

The main indications for its use are infections of the biliary and urinary tract, arthritis, peritonitis, sepsis, infectious and inflammatory diseases of the skin and soft tissues.

Tobramycin is a second-generation aminoglycoside antibiotic with a bactericidal type of action. It has an antibacterial spectrum similar to gentamicin, and at the same time has an effect on microorganisms resistant to other aminoglycoside antibiotics. Resistance to tobramyicin itself develops slowly.

After intramuscular injection, the maximum concentration of tobramycin is observed after 30-40 minutes, while it does not bind to blood proteins. The drug penetrates into the sputum, peritoneal and synovial fluid, the contents of the abscess. The half-life is 2 hours, within 8 hours 84% ​​of the antibiotic is excreted by the kidneys, creating its high concentrations in the urine.

Tobramycin is used for severe septicemia, infections of the gastrointestinal tract, for peritonitis, meningitis, burns, infections of the skeletal system and soft tissues. Doses of tobramycin should be selected strictly individually, depending on the weight of the patient. The course of treatment is from 7 to 10 days.

The side effects caused by tobramycin are identical to the side effects of other aminoglycosides, however, unlike other antibiotics of this group, it is the least toxic, as it penetrates the cells of the cochlear apparatus to a lesser extent.

Amikacin is a semi-synthetic aminoglycoside antibiotic and is a derivative of kanamycin. The drug has a high bactericidal activity against many gram-positive and gram-negative bacteria. Acts on bacteria

ria resistant to penicillin and methicillin. Amikacin is relatively resistant to enzymes that inactivate gentamicin and tobramycin.

After intramuscular administration, amikacin is rapidly adsorbed and its maximum serum concentration is determined after 1 hour. The half-life is 4-5 hours. Amikacin binds slightly to blood serum proteins, but it penetrates well into tissues, into the pleural fluid and passes through the placental barrier. Amikacin is excreted by the kidneys almost unchanged, and is completely excreted from the body within a day.

The drug is the drug of choice in the treatment of severe infections caused by gram-negative microorganisms. Amikacin is prescribed for infections of the respiratory system, lung abscesses, infections of the gastrointestinal tract, infections of the genitourinary system, infectious skin lesions, bedsores of various origins, osteomyelitis. Amikacin has been successfully used in systemic infections: neonatal sepsis, septicemia, endocarditis, peritonitis. Like other aminoglycosides, amikacin is ototoxic and nephrotoxic.

Netilmicin is an aminoglycoside antibiotic that was obtained in the USA in 1983. In terms of antimicrobial activity, the drug is similar to gentamicin and tobramycin. However, it is resistant to the destructive action of gentamicin- and tobramycin-resistant bacteria. It is highly active against gram-negative microorganisms (E. coli, Klebsiella, Enterobacter, Proteus, Salmonella, gonococci) and some gram-positive strains of staphylococcus that produce and do not produce penicillinase, and methicillin-resistant microorganisms.

Netilmicin is prescribed for bacteremia, septicemia, severe respiratory diseases,

infections of the kidneys and urinary tract, skin, soft tissues, bones and joints, gonorrhea. The principal indication for the drug is iatrogenic infections in immunocompetent and seriously ill patients with a high risk of gram-negative sepsis in a hospital setting. Netilmicin is less ototoxic and nephrotoxic compared to other aminoglycosides, but its use may cause palpitations, paresthesias, liver dysfunction, leukopenia, thrombocytopenia, and allergic reactions.

Neomycin is similar in chemical structure and antimicrobial activity to streptomycin. The drug was isolated by Z. Waksman in 1949, and it was introduced into medical practice in 1969. Another drug from this group, kanamycin, was obtained in 1957. This group also includes framycetin and paromomycin.

Neomycin has a bactericidal effect on most Gram-positive and Gram-negative microorganisms and Mycobacterium tuberculosis. Enterococci, streptococci, pneumococci and Pseudomonas aeruginosa are moderately sensitive to neomycin. In low concentrations, it causes bacteriostasis, penetrating into the microbial cell, binds to protein receptors on the 30S subunit of ribosomes, which leads to a stop in the synthesis of proteins of microorganisms. In high concentrations, the drug is capable of damaging the cytoplasmic membranes of a microbial cell, disorganizes the flow of metabolites inside the cell, followed by its death (bactericidal effect).

When administered orally, neomycin is slightly adsorbed from the gastrointestinal tract. The absorbed part of it is quickly excreted in the urine, and the non-absorbed residue is removed with the contents of the intestine unchanged and at the same time modifies the intestinal microflora.

Due to its high toxicity, parenteral administration of neomycin is dangerous due to possible kidney damage and ototoxicity. When applied topically, neomycin does not cause any local reactions, however, with long-term treatment, severe allergic reactions may occur. When prescribing neomycin by mouth, the development of candidiasis is noted. Neomycin is used to treat and prevent diseases of the skin and eyes (blepharitis, conjunctivitis, keratitis). Oral administration of the drug is advisable before operations on the large intestine or in the anus in order to prevent postoperative complications.

Framycetin is an aminoglycoside topical antibiotic. It is active against gram-positive and gram-negative bacteria that cause the development of infectious and inflammatory processes in the upper respiratory tract. It is applied topically in the form of intranasal injections in the treatment of rhinitis, sinusitis and the prevention of postoperative complications.

Kanamycin is a broad-spectrum aminoglycoside antibiotic. The drug is obtained biosynthetically. Chemically, kanamycin is a water-soluble substance, the molecule of which consists of two amino sugars and deoxystreptamine. Kanamycin is highly active against many gram-positive, gram-negative and acid-fast bacteria, as well as leptospira. Kanamycin has a bactericidal effect on most organisms sensitive to it, but on Mycobacterium tuberculosis it is bacteriostatic.

From the gastrointestinal tract, kanamycin is absorbed in small amounts. Kanamycin is rapidly adsorbed from muscle tissue and its maximum

concentration in the blood is detected after 1 hour. The drug penetrates into the pleural and peritoneal and synovial fluids, bronchial secretion and bile, crosses the placental barrier, but does not pass through the blood-brain barrier.

Inside, kanamycin is prescribed for infections of the gastrointestinal tract caused by salmonella or shigella, with preoperative preparation of patients before operations on the large intestine. Parenterally, kanamycin is administered for tuberculosis, staphylococcal and gram-negative infections, urinary tract infections, osteomyelitis, septicemia. But the drug should be used only in cases where infectious agents are resistant to other antibiotics.

Kanamycin has a pronounced nephrotoxic and ototoxic effect, which is directly dependent on the concentration and duration of stay of kanamycin in the body. Kanamycin, introduced in the postoperative period into the peritoneal cavity, being absorbed, can cause neuromuscular blockade.

Spectinomycin is a tricyclic amino-glycoside antibiotic that is active against many gram-positive and gram-negative microorganisms, with bacteriostatic and bactericidal activity. Penetrating inside the microbial cell, spectinomycin binds to the 30S subunit of ribosomes, blocks protein synthesis and stops the growth and development of microorganisms. In high concentrations, it is able to disrupt the structure and function of cytoplasmic membranes, causing the death of microbial cells. It acts mainly on gram-negative microorganisms, but the drug is used mainly as an alternative treatment

gonorrhea (generalized gonococcal infection, urethritis, prostatitis, cervicitis). The drug is especially indicated in cases of hypersensitivity to penicillin or when gonococci are resistant to penicillin and other agents.

Spectinomycin is rapidly absorbed when administered intramuscularly, does not bind to proteins in plasma and is not metabolized. Excreted by the kidneys unchanged. For the treatment of gonorrhea, a single dose of up to 2 g (40 mg / kg of body weight) is prescribed. Adverse reactions include pain at the injection site, nausea, and vomiting. The phenomena of nephrotoxicity are rare.