Aminoglycosides from the perspective of modern practice in the treatment of respiratory tract infections

AMINOGLICOSIDES

MODERN ANTIMICROBIAL CHEMOTHERAPY

MODERN ANTIMICROBIAL CHEMOTHERAPY

L.S. Strachunsky, S.N. Kozlov. Guide for doctors

Antibacterial drugs

The main clinical significance of aminoglycosides is their activity against gram-negative bacteria. Aminoglycosides have a faster bactericidal effect than β-lactams, very rarely cause allergic reactions, but are much more toxic compared to β-lactams. Aminoglycosides are classified by generation (Table 4).

Table 4. Classification of aminoglycosides

GENERAL PROPERTIES

Activity spectrum

Warnings

A. Pneumococci are resistant to aminoglycosides

Therefore, it is a mistake to use them for community-acquired pneumonia.

B.

Streptococci, including the group of viridans streptococci, are generally insensitive to aminoglycosides. But when used together with penicillin, pronounced synergism is observed. Therefore, when treating, for example, bacterial endocarditis, a combination of benzylpenicillin (or ampicillin) with gentamicin (or streptomycin) is used.

IN.

Despite the fact that Salmonella and Shigella
in vitro
, these antibiotics cannot be used to treat shigellosis and salmonellosis due to low efficiency. This is due to poor penetration of aminoglycosides into human cells, where Shigella and Salmonella are localized. To avoid unnecessary testing and to avoid misleading clinicians when interpreting susceptibility results, it is not recommended to test susceptibility to Shigella and Salmonella aminoglycosides.

Pharmacokinetics

They are practically not absorbed into the gastrointestinal tract (prescribed orally for selective decontamination of the gastrointestinal tract before operations on the large intestine or in patients in the ICU). They are well absorbed when administered intramuscularly, intraperitoneally and intrapleurally. Compared to β-lactams and fluoroquinolones, they pass through various tissue barriers (BBB, GOB) worse and create lower concentrations in bronchial secretions and bile. High levels are observed in kidney tissue. They are not metabolized in the liver and are excreted unchanged in the urine. T1/2 of all drugs is 2-3.5 hours. In newborns, due to the immaturity of the kidneys, T1/2 increases to 5-8 hours.

Adverse reactions

• Ototoxicity (vestibulotoxicity, cochleatoxicity).
• Nephrotoxicity.
• Neuromuscular blockade.

Risk factors for the development of adverse reactions

• Elderly age.
• High doses.
• Long-term use (more than 7-10 days).
• Hypokalemia.
• Dehydration.
• Lesions of the vestibular and auditory apparatus.
• Kidney failure.
• Concomitant use of other nephrotoxic and ototoxic drugs (amphotericin B, polymyxin B, furosemide, etc.).
• Simultaneous administration with muscle relaxants.
• Myasthenia.
• Rapid intravenous administration of aminoglycosides or their large doses into the abdominal and pleural cavity.

Measures to prevent adverse reactions

• Do not exceed the maximum daily dose if it is not possible to determine the concentration of aminoglycosides in the blood.
• Monitor renal function before prescribing aminoglycosides and then every 2-3 days by determining serum creatinine and calculating creatinine clearance.
• Observe the maximum duration of therapy - 7-10 days, with the exception of bacterial endocarditis - up to 14 days, tuberculosis - up to 2 months.
• Do not prescribe two aminoglycosides at the same time or replace one drug with another if the first aminoglycoside has been used for 7-10 days. A repeat course can be carried out no earlier than after 4-6 weeks.
• Monitor hearing and vestibular apparatus (patient survey, audiometry if necessary).

Help measures

First of all, drug withdrawal. Hearing impairment is usually irreversible, while kidney function is gradually restored. When neuromuscular blockade develops, calcium chloride is administered intravenously as an antidote.

Drug interactions

Synergy

when combined with penicillins or cephalosporins (but not when administered in the same syringe!).

Antagonism

with β-lactam antibiotics and heparin when mixed in one syringe due to physicochemical incompatibility.

Increased toxic effects

when combined with other nephrotoxic and ototoxic drugs (polymyxin B, amphotericin B, furosemide, etc.).

Indications

• Infections of various localizations caused by gram-negative bacteria from the Enterobacteriaceae
  (Escherichia coli, Klebsiella, Enterobacter, etc.) and non-fermenting bacteria (Acinetobacter,
  S. maltophilia
  , etc.) - aminoglycosides of the II-III generations.
• Pseudomonas aeruginosa infection - aminoglycosides of II-III generations.
• Enterococcal infections - gentamicin or streptomycin must be combined with penicillin or ampicillin.
• Tuberculosis - streptomycin, kanamycin, amikacin - must be combined with other anti-tuberculosis drugs.
• Zoonotic infections: plague, brucellosis (streptomycin); tularemia (streptomycin, gentamicin).

Dosing principles for aminoglycosides

Due to the fact that severe adverse reactions may develop when using aminoglycosides, and also taking into account the peculiarities of their pharmacokinetics (excretion through the kidneys unchanged), special attention should be paid to the correct calculation of doses of aminoglycosides. There are two key points to take into account:

• the dose of aminoglycosides (not only in children, but also in adults!) should be calculated based on body weight;
• the dose should be adjusted based on the individual characteristics of the patient: age, kidney function, localization of infection.

Factors determining the dose of aminoglycosides

Frequency of administration

Traditionally, aminoglycosides were administered 2-3 times daily. However, numerous studies have shown that in many cases the entire daily dose of aminoglycosides can be administered once daily.

. With a single administration regimen, clinical efficacy is not reduced, and the frequency of adverse reactions may even decrease.

A single dose is used for most indications. The exceptions are endocarditis, meningitis, and the neonatal period.

For a single administration, aminoglycosides are best administered intravenously by drip over 15-20 minutes, since it is difficult to administer a large volume of the drug intramuscularly.

Therapeutic drug monitoring

For aminoglycosides, a relationship has been established between their concentration in the blood, the antimicrobial effect and the incidence of ototoxicity and nephrotoxicity. At the same time, the pharmacokinetics of aminoglycosides has large individual variations. As a result, when medium doses of drugs are administered, approximately half of patients experience subtherapeutic concentrations.

Table 5. Therapeutic serum concentrations of aminoglycosides

When conducting therapeutic drug monitoring, the following is determined:

Establishing a peak concentration not lower than the threshold value (Table 5) indicates that the dose of aminoglycoside used is sufficient, while its high levels do not pose a danger to the patient. The value of the residual concentration exceeding the therapeutic level indicates the accumulation of the drug and the danger of developing toxic effects. In this case, reduce the daily dose

or
lengthen the interval between single doses
. With a single administration of the entire daily dose, it is sufficient to determine only the residual concentration.

CHARACTERISTICS OF INDIVIDUAL DRUGS

STREPTOMYCIN

The first aminoglycoside antibiotic. It has high cochleatoxicity and especially vestibulotoxicity, but is the least nephrotoxic of the aminoglycosides. Microflora resistance to it quickly develops.

Indications

Currently limited to the following diseases:

• tuberculosis;
• bacterial endocarditis caused by viridans streptococci or enterococci (in combination with penicillin or ampicillin);
• brucellosis, tularemia, plague (in combination with tetracycline).

Dosage

Adults and children

Parenteral - 15 mg/kg/day (no more than 2.0 g/day) in 1-2 administrations.

For tuberculosis

Adults

Intramuscularly - 1.0 g 2 times a week.

Children

Intramuscularly - 20 mg/kg/day 2 times a week.

Release forms

Bottles of 0.25 g, 0.5 g, 1.0 g and 2.0 g of powder for the preparation of solution for injection.

NEOMYCIN

One of the most ototoxic drugs. Parenteral administration is prohibited. Sometimes used internally for selective decontamination of the gastrointestinal tract before operations on the large intestine and locally (included in some ointments in combination with glucocorticoids). Not used in children.

Dosage

Adults

Orally - 0.5 g every 6 hours for 1-2 days.

Release forms

Tablets of 0.1 g and 0.25 g; 0.5% and 2% ointment.

KANAMYCIN

Outdated drug. Unlike aminoglycosides of the second generation, it acts on M. tuberculosis

, but is inferior to them and amikacin in activity against nosocomial strains of gram-negative flora. Does not affect Pseudomonas aeruginosa.

It has high ototoxicity and nephrotoxicity.

Retains its value in tuberculosis as a second-line drug. It can be used orally for the same indications as neomycin.

Dosage

Adults

Orally - 2-3 g every 6 hours; parenterally - 15 mg/kg/day in 1-2 administrations.

Children

Parenteral - 15 mg/kg/day in 1-2 administrations.

Release forms

Tablets of 0.125 g and 0.25 g; bottles of 0.5 g and 1.0 g of powder for the preparation of solution for injection.

GENTAMICIN

Garamycin

The main aminoglycoside of the second generation. Acts on Pseudomonas aeruginosa.

Compared to streptomycin, it is more nephrotoxic, but less ototoxic.

Indications

• Nosocomial pneumonia (with low level of resistance).
• UTI infections.
• Intra-abdominal and pelvic infections (in combination with antianaerobic drugs).
• Bacterial endocarditis (in combination with penicillin or ampicillin).
• Sepsis (in combination with β-lactams).
• Tularemia.

Warnings

Currently, due to the widespread (often unjustified) use of gentamicin, many nosocomial microorganisms, primarily Pseudomonas aeruginosa and Klebsiella, have acquired resistance to the drug.

A serious mistake is the use of gentamicin for community-acquired pneumonia, since gentamicin, like other aminoglycosides, does not act on pneumococci.

Dosage

Adults and children

Parenteral - 3-5 mg/kg/day in 1-2 administrations.

Newborns

Parenteral - 5-7.5 mg/kg/day in 2-3 administrations.

Release forms

Bottles of 0.08 g of powder for the preparation of solution for injection; ampoules of 1 ml and 2 ml of 4% solution (40 mg/ml); 0.1% ointment.

TOBRAMYCIN

Nebtsin, Brulamytsin

Compared to gentamicin, it is more active against Pseudomonas aeruginosa, but in most cases there is co-resistance to both drugs. Does not affect enterococci. Less nephrotoxic.

Indications

• Nosocomial pneumonia.
• UTI infections.
• Intra-abdominal and pelvic infections (in combination with antianaerobic drugs).
• Sepsis (in combination with β-lactams).

Dosage

Adults and children

Parenteral - 3-5 mg/kg/day in 1-2 administrations.

Release forms

Ampoules of 1 ml and 2 ml of 4% solution (40 mg/ml).

NETILMICIN

Netromycin

Active against some nosocomial strains of gram-negative bacteria resistant to gentamicin. Compared to gentamicin, it has slightly less ototoxicity and nephrotoxicity.

Indications

• Nosocomial pneumonia.
• UTI infections.
• Intra-abdominal and pelvic infections (in combination with antianaerobic drugs).
• Bacterial endocarditis (in combination with ceftriaxone).
• Sepsis (in combination with β-lactams).

Dosage

Adults and children

Parenteral - 4-6.5 mg/kg/day in 1-2 administrations.

Release forms

Solution for injection in 2 ml bottles containing 0.05 g or 0.15 g of netilmicin.

AMICACIN

Amikin

Effective against many strains of gram-negative bacteria (including P.aeruginosa

), resistant to gentamicin and other second generation aminoglycosides.
Active against M. tuberculosis
. Does not affect enterococci.

Compared to gentamicin, it is slightly less nephrotoxic.

Indications

Used to treat infections caused by multidrug-resistant gram-negative microflora. The most preferred among aminoglycosides for the empirical treatment of nosocomial infections.

• Nosocomial pneumonia.
• UTI infections.
• Intra-abdominal and pelvic infections (in combination with antianaerobic drugs).
• Sepsis (in combination with β-lactams).
• Tuberculosis (II line drug).

Dosage

Adults and children

Parenteral - 15-20 mg/kg/day in 1-2 administrations.

Release forms

Solution in ampoules containing 0.1 g, 0.25 g and 0.5 g of amikacin; solution in vials containing 1.0 g of amikacin.

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Last modified date: 05/24/2004 18:56

Aminoglycosides from the perspective of modern practice in the treatment of respiratory tract infections

The emergence of aminoglycoside antibiotics dates back to the discovery of streptomycin, the first drug active against Mycobacterium tuberculosis, by Selman Waksman's research group in 1943 [1]. For such an outstanding discovery, Waksman was awarded the Nobel Prize in 1952, which was presented by Fr.

Subsequently, based on natural structures produced by various representatives of actinomycetes (natural antibiotics), and among their semisynthetic derivatives, a large group of antibacterial drugs was developed, which formed the class of aminoglycosides. Currently, there are three generations of aminoglycosides (

). The first generation includes streptomycin, neomycin, kanamycin and monomycin, the use of which is currently limited due to their toxicity. The second generation consists of gentamicin, tobramycin, sisomycin and netilmicin. Amikacin and isepamycin are part of the third generation of aminoglycosides.

The name of this group of antibiotics is due to the molecular structure, which is based on amino sugars linked by a glycosidic bond to the aglycone part of the molecule (Fig. 1).

The mechanism of action of aminoglycosides is associated with irreversible inhibition of protein synthesis at the ribosome level in microorganisms sensitive to them. Unlike other protein synthesis inhibitors, aminoglycoside antibiotics do not have a bacteriostatic, but rather a bactericidal effect. Aminoglycosides of the II and III generations have a wide spectrum of antimicrobial action, primarily against most gram-negative microorganisms of the Enterobacteriaceae family (Escherichia coli, Proteus spp., Klebsiella spp., Enterobacter spp., Serratia spp., etc.), as well as non-fermentative gram-negative rods (Pseudomonas aeruginosa, Acinetobacter spp.) [2, 3, 4]. Aminoglycosides also show activity against Staphylococcus aureus, except for methicillin-resistant (MR) strains. Individual representatives of the class differ in activity and spectrum of action. In particular, first generation aminoglycosides (streptomycin, kanamycin) exhibit the greatest activity against M. tuberculosis, monomycin is effective against some protozoa. All second and third generation aminoglycosides are active against P. aeruginosa, with tobramycin exhibiting the highest activity. Sizomycin is characterized by greater activity than gentamicin against Proteus spp., Klebsiella spp., Enterobacter spp. (

).

One of the most effective aminoglycosides is amikacin, which is associated with resistance to the action of enzymes that inactivate other aminoglycosides, so the antibiotic can remain active against P. aeruginosa strains resistant to tobramycin, gentamicin and netilmicin [2, 5, 12]. Another representative of the third generation, isepamycin, is additionally active against Aeromonas spp., Citrobacter spp., Listeria spp. and Nocardia spp.

All representatives of the aminoglycoside class are inactive against S. pneumoniae, S. maltophilia, B. cepacia and anaerobes (Bacteroides spp., Clostridium spp., etc.). Moreover, it should be remembered that aminoglycoside resistance of S. pneumoniae, S. maltophilia and B. cepacia is used in the identification of these microorganisms. Aminoglycosides are active in vitro against Shigella, Salmonella, and Legionella, but their use for these infections is unacceptable, since they are clinically ineffective against pathogens localized intracellularly [2].

In some cases, aminoglycosides have a post-antibiotic effect, which depends on the strain of the microorganism and the concentration of the drug at the site of infection.

All aminoglycosides are characterized by almost identical pharmacokinetics (

). Antibiotic molecules are highly polar compounds, and therefore are poorly soluble in lipids and, when taken orally, are practically not absorbed from the gastrointestinal tract (less than 2% enters the systemic circulation). As a result, the main route of administration of aminoglycosides is parenteral (except neomycin). The binding of aminoglycosides to blood proteins is low and varies for different antibiotics from 0 to 30% (for example, tobramycin practically does not bind to proteins). The time to reach Cmax with intramuscular administration is 1–1.5 hours. Aminoglycosides practically do not undergo biotransformation and are excreted unchanged by the kidneys through glomerular filtration, creating high concentrations in the urine. The rate of excretion depends on the age, renal function and concomitant pathology of the patient (for example, with fever it increases, the drug is eliminated at a high rate in drug addicts, at a lower rate in pregnant women, with a decrease in renal function, the rate of excretion slows down significantly). The half-life of all aminoglycosides in adults with normal renal function is 2–4 hours; in renal failure, the period may increase to 70 hours or more. Peak concentrations of aminoglycosides vary between patients and depend on body weight, volume of fluid and adipose tissue, and the patient's condition. For example, in patients with extensive burns or ascites, the volume of distribution of aminoglycosides is increased. On the contrary, with dehydration or muscular dystrophy it decreases.

Aminoglycosides are capable of creating high concentrations in organs with good blood supply: liver, lungs, kidneys; on the contrary, low concentrations are observed in sputum, bronchial secretions, bile, and breast milk. Aminoglycosides pass poorly through the blood-brain barrier, but when the meninges are inflamed, their permeability increases.

Taking into account the peculiarities of the pharmacokinetics of aminoglycosides, as well as the potential specific toxicity of this class of antibiotics, it is necessary to correctly calculate the dose of the drugs used. The dose of aminoglycosides (not only in children, but also in adults!) should be calculated based on body weight, taking into account the individual characteristics of the patient (age, kidney function, localization of infection).

Factors determining the dose of aminoglycosides are [2]:

• Patient's body weight.

Doses for adults and children over 1 month: streptomycin, kanamycin, amikacin 15–20 mg/kg/day in 1–2 administrations; gentamicin, tobramycin - 3-5 mg/kg/day in 1-2 injections; netilmicin - 4–6.5 mg/kg/day in 1–2 administrations.

• Obesity/wasting. If the ideal body weight is exceeded by 25% or more, the dose calculated for the actual body weight should be reduced by 25%. In debilitated patients, on the contrary, the dose should be increased by 25%.
• Age. It is necessary to reduce the dose of aminoglycosides in the elderly, as they experience an age-related decrease in glomerular filtration rate.
• Kidney function. If renal function is impaired, it is necessary to reduce the daily dose using the method of calculating endogenous creatinine clearance. Calculation of clearance must be carried out before prescribing the drug and repeated every 2–3 days. A decrease in creatinine clearance by more than 25% from the initial level indicates a possible nephrotoxic effect of aminoglycosides; a decrease of more than 50% is an indication for discontinuation of aminoglycosides. For renal failure, the first single dose of gentamicin, tobramycin and netilmicin is 1.5–2 mg/kg, amikacin - 7.5 mg/kg. Subsequent single doses are determined by the formula: 1st dose (mg) ´ CC/100, where CC is creatinine clearance in ml/min/1.73 m2.
• Severity and location of infection. For meningitis, pneumonia, sepsis, maximum doses are prescribed; for pyelonephritis, bacterial endocarditis - average doses. Particularly high doses are administered to patients with cystic fibrosis and burns, since the distribution of aminoglycosides is significantly impaired in them, but it is desirable to determine the concentration of aminoglycosides in the blood.

Modern practice of using aminoglycosides involves administering the drug once a day, which is justified both from a microbiological point of view (dose-dependent, rapidly onset bactericidal effect; long-term post-antibiotic effect) and from a clinical point of view (less toxicity of aminoglycosides with a single administration with similar effectiveness of therapy) [2 , 3]. Currently, once daily administration of aminoglycosides is used for most indications (with the exception of endocarditis and meningitis). For a single dose, aminoglycosides are best administered intravenously over 15–20 minutes.

It is extremely important that aminoglycosides are characterized by variability in pharmacokinetic parameters. When the same dose is administered, potentially toxic blood levels (10–14 μg/ml) for natural aminoglycosides can be detected on average in 10% of patients; concentrations below those required for adequate therapy are detected in 25% of patients or more [3]. In this regard, the most preferable are semisynthetic drugs - amikacin and netilmicin, which have the least variability of indicators. In addition, this group of drugs is characterized by a narrow safety corridor, i.e., a slight gap between the effective and toxic levels of concentrations in the blood. In this regard, the only means of optimizing treatment with aminoglycosides is continuous pharmacokinetic monitoring, which eliminates the creation of toxic or subtherapeutic levels of the drug in the blood (

).

When carrying out therapeutic monitoring, the following is determined: 1) the peak concentration of aminoglycosides in the blood serum - 60 minutes after intramuscular administration of the drug or 15 minutes after the end of intravenous administration; 2) residual concentration - before administering the next dose. Establishing a peak concentration not lower than the threshold value indicates the sufficiency of the aminoglycoside dose used, while its high levels do not pose a danger to the patient. The value of the residual concentration exceeding the therapeutic level indicates the accumulation of the drug and the danger of developing toxic effects. In this case, reduce the daily dose or lengthen the interval between single doses. With a single administration of the entire daily dose, it is sufficient to determine only the residual concentration [2].

Aminoglycosides are drugs with a low level of overall toxicity. However, they are characterized by specific adverse reactions, namely oto- and nephrotoxicity. The incidence of these reactions varies depending on the drug. Clinical studies have shown that the incidence of nephrotoxic events with netilmicin is 2.8%, amikacin - 8.5%, gentamicin - 11.1% and tobramycin - 11.5% [9]. Ototoxic reactions were observed in 2.3% of patients treated with netilmicin, 7.7% with gentamicin, 9.7% with tobramycin, and 13.8% with amikacin [9]. Ototoxicity manifests itself both in the form of vestibular disorders (more often with the use of streptomycin, gentamicin, tobramycin) and in the form of hearing impairment (amikacin, netilmicin). Hearing impairment and damage to the vestibulocochlear nerve may be irreversible; the likelihood of these reactions increases with increasing dosage of the drug, with long courses of treatment, in elderly patients and patients with underlying hearing impairment. Impaired renal function with the use of aminoglycosides, on the contrary, is most often reversible. Gentamicin is highly nephrotoxic; the safest drugs are amikacin and netilmicin. In some cases, the use of aminoglycosides is accompanied by impaired neuromuscular conduction, the development of paresthesia, and peripheral neuropathies.

From the point of view of preventing the development of adverse reactions, the previously noted control of the main pharmacokinetic parameters, which should be limited to specified limits, is of greatest importance (Tables 3 and 4). The simultaneous use of aminoglycosides with other drugs that are eliminated from the body by renal excretion is also a risk factor that affects the frequency or severity of adverse reactions. Aminoglycosides are not recommended for use with amphotericin B, cisplatin, muscle relaxants and vancomycin.

For a long time, aminoglycosides have been widely used antibacterial drugs and are included in the standards for the treatment of infections of various localizations (

). At the present stage, the practical importance of this group of antibiotics is primarily associated with the treatment of nosocomial infections caused predominantly by gram-negative microorganisms. The main indications for the use of second and third generation aminoglycosides are severe infections: sepsis, septic endocarditis, osteomyelitis, skin and soft tissue infections, nosocomial pneumonia, generalized forms of wound and burn infections, peritonitis, postoperative purulent complications, kidney and genitourinary tract infections, etc. In most cases, aminoglycosides are prescribed in combination with beta-lactam and antianaerobic antibiotics. It should be noted that only amikacin can serve as a means of empirical therapy, since more than 70% of strains of gram-negative bacteria remain highly sensitive to it. The administration of other aminoglycosides is recommended after confirmation of sensitivity to gentamicin or a specific antibiotic of the isolated pathogens.

Resistance of microorganisms to aminoglycosides

Unfortunately, more than half a century of use of aminoglycosides, including for unfounded indications (community-acquired respiratory tract infections, etc.), has led to the emergence and spread of strains of microorganisms resistant to them [10]. In particular, in Russia the level of resistance to aminoglycosides, primarily to gentamicin, exceeds that in most other countries [11].

The formation of resistance to aminoglycosides is primarily due to enzymatic inactivation of antibiotics through modification [11, 12]. Modified molecules lose the ability to bind to ribosomes and suppress the protein synthesis of microorganisms. Three groups of aminoglycoside-modifying enzymes (AMPs) are known: acetyltransferases (AAS), which attach a molecule of acetic acid, phosphotransferases (APN), which attach a molecule of phosphoric acid, and nucleotidyl or adenylyltransferases (ANT), which attach a molecule of adenine nucleotide (

). In general, it is gentamicin that is a substrate for a significantly larger amount of AMP than other aminoglycosides of the second and third generations, which determines the high level of resistance to this antibiotic. On the contrary, the possibility of modifying amikacin determines the smallest amount of AMP among aminoglycosides, therefore a number of bacteria resistant to gentamicin, netilmicin and other drugs of this group remain sensitive to it.

According to data on antibiotic resistance in Russia for the period 2002–2004, extremely high resistance of nosocomial strains of P. aeruginosa and Klebsiella pneumoniae was observed to gentamicin, amounting to 74.9% and 76.5%, respectively -

,

[13]. The most active against these pathogens is amikacin, to which up to 35.8% of K. pneumoniae and 42.9% of P. aeruginosa strains are insensitive.

In another study (Micromax), conducted in hospitals in Moscow, Smolensk and Yekaterinburg, the frequency of isolation of amikacin-insensitive strains of P. aeruginosa and K. pneumoniae was 11% and 10.8%, respectively [14]. In this regard, it is extremely important to be guided by local data on antibiotic resistance of pathogens.

The use of aminoglycosides in the treatment of respiratory tract infections

Due to the fact that aminoglycosides do not have activity against the main causative agent of community-acquired respiratory tract infections - S. pneumoniae, they cannot be used for the treatment of community-acquired pneumonia (both in outpatient and inpatient practice) and other community-acquired infections of the upper and lower respiratory tract . Perhaps the only clinical situation that justifies the administration of aminoglycosides is severe community-acquired pneumonia caused by P. aeruginosa. In this case, ceftazidime, cefepime, cefoperazone/sulbactam, ticarcillin/clavulanate, piperacillin/tazobactam, carbapenems (meropenem, imipenem) or ciprofloxacin are used, either in monotherapy or in combination with aminoglycosides of the II–III generation (the use of amikacin is preferable) [15].

Lung abscess and pleural empyema

Potential causative agents of lung abscess are anaerobic microorganisms - Fusobacterium nucleatum, Peptostreptococcus spp., Bacteroides spp. or associations of anaerobic and aerobic bacteria (primarily representatives of the Enterobacteriacea family - K. pneumoniae and K. oxytoca) [16]. Russian experts recommend the use of inhibitor-protected aminopenicillins (amoxicillin/clavulanate, ampicillin/sulbactam) or cefoperazone/sulbactam as the drugs of choice. In the absence of these antibiotics or their ineffectiveness, carbapenems, inhibitor-protected penicillins (ticarcillin/clavulanate, piperacillin/tazobactam) or combinations of clindamycin with aminoglycosides of the second and third generation can be used [17].

In the etiology of pleural empyema, the leading role is occupied by gram-negative bacteria (15–32%) and anaerobes (5–19%). S. aureus accounts for 7 to 15% of cases, S. pneumoniae is isolated in 5–7% of patients, and H. influenzae is even less common. In 20–25% of cases, microbial associations are found, primarily anaerobes and aerobes, represented by gram-negative bacteria [18]. Antibacterial therapy should, if possible, be carried out purposefully, i.e., taking into account data from microbiological examination of the contents of the pleural cavity. For acute post-pneumonic pleural empyema caused by S. pneumoniae and S. pyogenes, cephalosporins of the 2nd–4th generations are used as monotherapy as the drugs of choice. Alternatives include lincosamides or vancomycin. For staphylococcal acute post-pneumonic empyema, oxacillin or cefazolin is used; lincosamides, fusidic acid, vancomycin and linezolid are considered as alternatives. In the case of acute post-pneumonic pleural empyema caused by Haemophilus influenzae, the drugs of choice are III or IV generation cephalosporins. An alternative to them are “protected” aminopenicillins (amoxicillin/clavulanate, ampicillin/sulbactam) or fluoroquinolones.

In the etiology of subacute and chronic pleural empyema, the leading role is played by anaerobic streptococci and bacteroides, often in association with microorganisms of the Enterobacteriaceae family. The first-line drugs in this case are “protected” aminopenicillins - amoxicillin/clavulanate or ampicillin/sulbactam. As alternative drugs, lincosamide in combination with an aminoglycoside of the II or III generation, or cephalosporins of the II–IV generation, or carbapenems (imipenem, meropenem), or ticarcillin/clavulanate or piperacillin/tazobactam are recommended [17]. With pleural empyema, as a rule, it is impossible to cure the patient without surgical intervention, and in most cases thoracotomy drainage is required, thoracoscopy and decortication are used less often.

Nosocomial pneumonia

Nosocomial pneumonia (NP) ranks second among all nosocomial infections (13–18%) and is the most common infection (≥ 45%) in intensive care units (ICU) [19, 23]. NP develops on average in 0.5–1% of all hospitalized patients and in 10–20% of those hospitalized in the ICU. A special category of NP in patients on mechanical ventilation (ventilator-associated pneumonia - VAP) develops in 9–27% of the total number of intubated patients. In terms of mortality, NP is the leader among nosocomial infections, causing deaths on average in 30 to 70% of patients [20, 21].

NP is most often caused by aerobic gram-negative microorganisms - P. aeruginosa, E. coli, K. pneumoniae and Acinetobacter spp. (

). Recently, there has been an increase in the frequency of detection of S. aureus, including MRSA [21]. Most cases of NP have a polymicrobial etiology [22]. The incidence of multidrug-resistant pathogens depends on the patient population (most often in patients with severe chronic diseases, risk factors for developing pneumonia and late onset of pneumonia > 5 days), hospital and type of department, which indicates the urgent need to obtain local data.

When choosing antibiotics for empirical antibacterial therapy of NPs, it is necessary to focus primarily on local data on antibiotic resistance of pathogens. It must be remembered that these data need to be updated periodically, as bacterial resistance may change over time depending on the composition and frequency of antibiotic use.

Currently, a recommended approach to antibiotic therapy for NPs depends on the timing of the disease. For early NP (≤ 5 days) that developed in patients without risk factors, third and fourth generation cephalosporins, amoxicillin/clavulanate, levofloxacin, moxifloxacin, ciprofloxacin and ertapenem are used as monotherapy.

On the contrary, in patients with late (> 5 days) NP or in the presence of risk factors for multidrug-resistant pathogens, combination therapy is recommended - an antipseudomonas cephalosporin or carbapenem or cefoperazone/sulbactam in combination with amikacin or a fluoroquinolone with pseudomonas activity.

Aminoglycosides are also used in combination with a carbapenem for NP of established etiology, in particular caused by E. coli, K. pneumoniae, other gram-negative microorganisms (Enterobacter spp., Morganella spp., Serratia spp.), P. aeruginosa or Acinetobacer spp. (

).

The traditional duration of NP therapy is 14–21 days, but modern management of patients with CAP involves reducing the duration of antibiotic therapy to 7 days in case of effective initial empirical therapy [21]. When using aminoglycosides for combination empiric therapy, their use may be discontinued after 5–7 days in patients with clinical response to treatment.

In conclusion, it should be noted once again that the use of aminoglycosides for the treatment of community-acquired respiratory tract infections is unacceptable; for hospital-acquired infections, aminoglycosides (netilmicin, amikacin) should be used only in certain clinical situations and only in combination with other antibacterial drugs.

Literature

1. Nobel laureates. Available at: https://thenobel.info/? PREMIYa_PO_MEDICINE: Zelmzman_Vaksman.
2. Reshedko G.K., Khaikina E.V. Group of aminoglycosides. Practical guide to anti-infective chemotherapy / Ed. L. S. Strachunsky, Yu. B. Belousov, S. I. Kozlov. M., 2007; With. 88–94.
3. Fomina I. P. Modern aminoglycosides. Importance in infectious pathology and features of action // Russian Medical Journal. 1997; 5 (21): 1382–1391.
4. Siegenthaler WE, Bonetti A., Luthy R. Aminoglycoside antibiotics in infectious diseases // Am J Med. 1986; 80:2–14.
5. Ushkalova E. A. Netilmitsin in modern medical practice // Farmateka. 2006; No. 5 (120). Available at: https://www.pharmateca.ru/cgi-bin/statyi.pl?sid=1262&mid=1085056570&magid=101&full=1.
6. Simon C., Stille W. Antibiotika - Therapie in Klinik und Praxis. Schattaner, Stuttgart, New York, 1989; 153–168.
7. Yakovlev S.V., Yakovlev V.P. Modern antimicrobial therapy in tables // Consilium medicum. 2007; No. 1.
8. Brahams D. Lancet. 1995; 1: 1395–1396.
9. Cone LA A survey of prospective, controlled clinical trials of gentamicin, tobramycin, amikacin, and netilmicin // Clin Ther. 1982; 5 (2): 155–162.
10. Rachina S. A., Fokin A. A., Ishmukhametov A. A., Denisova M. N. Analysis of outpatient consumption of antimicrobial drugs for systemic use in various regions of the Russian Federation // KMAH. 2008; No. 1 (vol. 10): 59–69.
11. Reshedko G.K. Mechanisms of resistance to aminoglycosides in nosocomial gram-negative bacteria in Russia: results of a multicenter study // KMAH. 2001; 3 (2): 111–132.
12. Sidorenko S. V., Eidelshtein M. V. Mechanisms of resistance of microorganisms. In the book: Practical guide to anti-infective chemotherapy // Ed. L. S. Strachunsky, Yu. B. Belousov, S. N. Kozlov. M., 2007; With. 23.
13. Reshedko G.K., Ryabkova E.L., Kozlov R.S. Modern aspects of epidemiology, diagnosis and treatment of nosocomial pneumonia // KMAH. 2008; 10 (2): 143–153.
14. Sidorenko S. V., Strachunsky L. S., Akhmedova L. I. et al. Results of a multicenter study of the comparative activity of cefepime and other antibiotics against pathogens of severe hospital infections (Micromax program) // Antibiot Chemoter. 1999; 44 (11): 7–16.
15. Chuchalin A. G., Sinopalnikov A. I., Strachunsky L. S. et al. Community-acquired pneumonia in adults. Practical recommendations for diagnosis, treatment and prevention. M.: OOO Publishing House M-Vesti, 2006. 76 p.
16. Hammond JM, Potgieter PD, Hamslo D. et al. The etiology and antimicrobial susceptibility patterns of microorganisms in acute community-acquired lung abscess // Chest. 1995; 108:937–941.
17. Strachunsky L. S., Kozlov S. N. Modern antimicrobial chemotherapy. Guide for doctors. M.: Borges; 2002.
18. Bartlett JG, Thadepalli H., Gorbach SL, Finegold SM Bacteriology of empyema // Lancet. 1999; 2: 338–340.
19. Richards M., Thursky KM, Buising K. Epidemiology, Prevalence and Sites of Infections in Intensive Care Units // Semin Respir Crit Care Med. 2003; 24:3–22.
20. Stevens RM, Teres D., Skillman JJ, Feingold DS Pneumonia in an intensive care unit. A 30-month experience // Arch Intern Med. 1974; 134: 106–111.
21. Hospital-acquired Pneumonia Guideline Committee of the American Thoracic Society and Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated and healthcare-associated pneumonia // Am J Respir Crit Care Med. 2005; 171:388–416.
22. Lynch JP Hospital-acquired pneumonia: risk factors, microbiology, and treatment // Chest. 2001; 119(2):373–384.
23. Chuchalin A. G., Sinopalnikov A. I., Strachunsky L. S. et al. Nosocomial pneumonia in adults: practical recommendations for diagnosis, treatment and prevention // KMAH. 2005; 7 (1): 4–31.

A. A. Zaitsev , Candidate of Medical Sciences A. I. Sinopalnikov , Doctor of Medical Sciences, Professor of the State Institute of Internal Medicine of the Ministry of Defense of the Russian Federation, Moscow

Battle with bacteria: Part II

We continue the series of articles devoted to antibacterial drugs. In them we briefly describe their mechanism of action, features of use and key rules of administration. This time we will talk about drugs that are obtained from actinobacteria of the genus Streptomyces. This knowledge will help you use antibiotics consciously and responsibly, as well as help your family and friends do the same.

bacterial cell

Bacteria are single-celled living creatures. Not all bacteria in the human body are harmful; moreover, most of them are useful: they produce substances the body needs, process unnecessary compounds, safely “train” the immune system, and so on. Pathogenic bacteria (aka pathogens) differ only in that their vital processes lead to the accumulation of harmful substances (toxins) in the host’s body. These toxins affect the cells of our body, causing unpleasant, painful and even life-threatening symptoms. This logic is true for all bacterial pathogens, from everyday respiratory pathogens to deadly ones (such as plague).

In creating weapons against pathogenic bacteria, man showed remarkable ingenuity.

Different antibacterial drugs “hit” different parts of the bacterial cell, destroying it (bactericidal effect) or preventing it from multiplying (bacteriostatic effect).

In a previous article, we looked at beta-lactams, a large family of antibacterial drugs that target the cell wall. The molecules of these drugs “wedge” themselves into the process of building the cell wall and prevent the different layers of which it consists from connecting. As a result, the cell wall is destroyed and the cell dies. Accordingly, beta-lactam antibiotics have a bactericidal effect.

Today we will talk about antibiotics that inhibit the synthesis of proteins necessary for the life of a bacterial cell.

Aminoglycosides

In the world of bacteria, as elsewhere in nature, there is competition for territory. To have an advantage in the war with their neighbors, some bacteria use “chemical weapons” - antibacterial substances that kill competitors but do not harm their creators. An example of such a substance is streptomycin, produced by the actinobacterium Streptomyces griseus. Streptomycin is the first representative of a group of antibacterial drugs called aminoglycosides.

Aminoglycosides interfere with the production of proteins necessary for bacteria by affecting ribosomes. Ribosomes are small “factories” of proteins inside a living cell (including bacteria). Resembling a slightly flattened ball, the ribosome consists of a small and a large subunit. The small subunit reads genetic information from messenger RNA (“reads the assembly instructions”), and the large subunit “assembles” the protein from amino acids according to these instructions.

The aminoglycoside molecule attaches to the small subunit of the ribosome and prevents it from “reading” genetic information from RNA. Without instructions, the ribosome stops working, and the protein remains “unfinished.”

Aminoglycosides include drugs such as gentamicin, neomycin, tobramycin, framycetin, as well as streptomycin, kanamycin, netilmicin, spectinomycin and amikacin.

Macrolides

Unlike their “relatives” aminoglycosides, compounds collectively called “macrolides” are attached to the large subunit of the ribosome - the same one that sequentially “assembles” chains of protein molecules from individual amino acids. This also causes the protein creation process to stop, and the bacterial cell stops reproducing (bacteriostatic effect).

These antibiotics are obtained from the bacterium Streptomyces erythreus, a microorganism belonging to the same genus as the natural producer of aminoglycosides, Streptomyces griseus.

Macrolides are considered one of the safest antibiotics. They also do not cause so-called “cross-allergy” with beta-lactams, which allows them to be used in case of individual intolerance to the latter. The comparative safety of macrolides is not a reason to use them yourself. We remind you of the importance of medical consultation when using antibacterial agents!

Examples of macrolides include azithromycin, josamycin, clarithromycin, midecamycin, roxithromycin, spiramycin and erythromycin.

Tetracyclines

Another class of substances that affect the small “reader” subunit of the ribosome are tetracyclines produced by the actinobacterium Streptomyces aureofaciens. They have a very wide spectrum of activity, but are strictly contraindicated for pregnant women, as they have a significant negative effect on the fetus, suppressing bone growth due to the binding of calcium cations. They should also not be used by women during lactation and children under eight years of age.

The effectiveness of tetracyclines against pathogens, as well as their toxicity to humans, is associated with their ability to penetrate well into cells, as well as with a high level of resorption (reabsorption).

Tetracyclines include doxycycline, minocycline, tetracycline itself and tigecycline.

Antibacterial "special forces"

In the world of bacteria, generations replace each other incredibly quickly, which means that natural selection occurs instantly by the standards of multicellular organisms. This is the basis for the phenomenon of pathogen resistance to antibiotics: the active use of one or another class of antibacterial drugs leads to the fact that bacteria adapt to their action, developing protective mechanisms. For example, many pathogens secrete the enzyme beta-lactamase, a substance that neutralizes beta-lactam antibiotics by destroying their active molecular fragment, the beta-lactam ring.

Pathogen resistance leads to a sharp decrease in the effectiveness of treatment and additional stress on the body due to the need to use several drugs at once. But among antibiotics there is a “special force” - drugs to which resistance develops extremely slowly. They are often used to treat severe infections under strict medical supervision. Examples of such specialty drugs are oxazolidinones and amphenicols.

The oxazolidinones include linezolid, and among the amphenicols, the drug chloramphenicol stands out.

Lincosamides

Finally, it is worth mentioning a couple of antibiotics that disrupt protein synthesis in bacterial cells. Each of them has its own spectrum of activity, but they have a common mechanism of action - “switching off” the large subunit of the ribosome.

Lincosamides are natural antibacterial drugs secreted by the actinobacterium Streptomyces lincolnensis. Among the features of lincosamides, we can mention resistance to the acidic environment of the stomach and good absorption in the gastrointestinal tract.

They are used for such severe conditions as sepsis and lung abscess, as well as during the treatment of purulent skin lesions.

The most famous representative is lincomycin.

Rules for taking antibiotics

When taking antibiotics, it is very important to follow the course prescribed by your doctor or indicated in the instructions for use. You shouldn’t focus on the symptoms - it’s become easier, which means you can quit so as not to “be poisoned again.” Antibiotic courses have been developed by scientists and tested in clinical studies: they allow you to achieve the concentration of the drug in the body that will effectively stop the infection. If you stop taking it ahead of time, the “unkilled” pathogens will adapt, and it will be even more difficult to cope with them.

The second rule is that you should not self-medicate with antibiotics, especially those listed in this article (if you somehow manage to buy them without a prescription). Don't be fooled by the natural origins of these antibacterial drugs. Not everything “natural” and “natural” is obviously safer than synthetic. Nature learned to kill effectively long before the advent of man with his microscopes and chemistry.

Taking most antibiotics does not depend on food intake or time of day. But at the same time, it is very important before you start using a drug that is new to you, carefully read the instructions for use, namely, the “Contraindications” section. At particular risk are pregnant women, nursing mothers, children under 12 years of age, as well as people with kidney and liver diseases.

Mark Volkov, editor of the online magazine for pharmacists and medical workers “Katren-Style”
Photo depositphotos.com The author’s opinion may not coincide with the opinion of the editors