Antibiotics (Properties, Application, Interaction) - Posokhova K.A., Viktorov O.P. 2005

Aminoglycosides

Aminoglycosides are one of the oldest classes of Antibiotics. The first drug in this group, streptomycin, was introduced by S. Waksman in 1943, and its clinical use began in 1946. Over the decades that follow and to the present day, it has remained one of the most effective agents for treating tuberculosis.

The generic name "aminoglycosides" is used for this group of substances due to their shared chemical Structure: their molecules contain amino sugars linked by a glycosidic bond to an aglycone (the non-sugar moiety).

Depending on the time of discovery and Introduction into clinical practice, aminoglycosides (AGs) are divided into 3 groups:

1st generation: streptomycin, neomycin, monomycin, kanamycin.

2nd generation: gentamicin, tobramycin, sisomicin, netilmicin.

3rd generation: amikacin.

Original aminoglycoside drugs and their generics registered and approved for medical use in Ukraine are listed in Table 25.

Class="center">Table 25. Original aminoglycoside drugs and their generics registered and approved for medical use in Ukraine

Note. * - domestically produced AG drugs.

The MECHANISM OF ACTION of aminoglycosides involves the following aspects: a) they bind to the 30S ribosomal subunit during the initiation phase of Protein Synthesis, leading to the arrest of protein synthesis; b) they interact with the 30S ribosomal subunit during the elongation phase of the polypeptide chain, resulting in the synthesis of aberrant Proteins that impair Cell membrane permeability and other Functions essential for the normal viability of microorganisms; c) they inhibit METABOLISM/36.html">DNA Replication. To exert their antibacterial effect, aminoglycosides must bind to the membrane structures of the bacterial cell and respiratory Quinones. The latter ensure The transport of aminoglycosides into The Cell and their delivery to the Ribosomes.

THE SPECTRUM OF activity of aminoglycosides is broad. Table 26 presents the comparative antibacterial activity of certain 1st, 2nd, and 3rd generation drugs.

Aminoglycosides primarily inhibit gram-negative Bacteria (Escherichia coli, Salmonella, Klebsiella, particularly K. pneumoniae, Proteus, Yersinia, Brucella, Campylobacter, Helicobacter, Serratia, Shigella, etc.), although they also affect certain gram-positive microorganisms, notably staphylococci resistant to Other Antibiotics. Streptomycin, kanamycin, and amikacin are active against M. tuberculosis and certain atypical mycobacteria; 2nd-generation AGs (gentamicin, tobramycin, netilmicin) and 3rd-generation AGs (amikacin) are more active against P. aeruginosa. Currently, 77% of staphylococcal strains, 76% of Enterobacteriaceae strains, and 84% of pseudomonal strains are susceptible to amikacin.

Natural resistance to aminoglycosides is exhibited by microorganisms that lack respiratory quinones, notably anaerobes such as Clostridia and Bacteroides. Therefore, in severe Infections caused by mixed flora, aminoglycosides are typically combined with antianaerobic drugs—clindamycin, metronidazole—and Cephalosporins with antianaerobic activity (cefoxitin, cefotetan, cefmetazole).

Additionally, aminoglycosides exhibit a synergistic effect in combination with beta-lactams (Penicillins, cephalosporins, carbapenems) and fluoroquinolones, allowing them to be incorporated into complex empirical therapy regimens and individualizing Treatment. For instance, the inhibitory efficacy against Pseudomonas aeruginosa increases when gentamicin, tobramycin, amikacin, or netilmicin is combined with antipseudomonal cephalosporins (ceftAZidime, cefoperazone, cefepime, sulperazone—a combination of cefoperazone and the beta-lactamase inhibitor sulbactam).

Table 26. Antibacterial activity of certain 1st, 2nd, and 3rd generation aminoglycosides (V.P. Yakovlev, S.V. Yakovlev et al., 2003; with modifications)

Notes: "++" - highly susceptible; "+" - susceptible; "-" - resistant.

Aminoglycosides have no effect on S. pneumoniae; therefore, prescribing them for the empirical therapy of community-acquired Pneumonia, which is frequently caused by pneumococci, is inappropriate.

There are numerous Mechanisms of microbial resistance to aminoglycosides. The primary mechanism is enzymatic inactivation by specific Enzymes (acetyltransferases, adenylyltransferases, phosphotransferases), of which over 50 have been identified. Plasmid- and chromosome-mediated resistance pathways, modification of cellular targets for aminoglycosides, and impaired permeability across cell membranes also play a role. The spread of aminoglycoside resistance is facilitated by the growing prevalence of gram-negative strains that produce extended-spectrum beta-lactamases while remaining simultaneously resistant to multiple antibiotics.

At the same time, resistance to aminoglycosides develops more slowly compared to resistance to cephalosporins, particularly third-generation cephalosporins. Certain clinical strains of microorganisms may exhibit incomplete cross-resistance: Mycobacterium tuberculosis strains resistant to streptomycin may retain susceptibility to kanamycin, and gentamicin-resistant Pseudomonas aeruginosa strains may remain susceptible to amikacin.

Amikacin and netilmicin are considered the most potent aminoglycosides in modern clinical practice, as they are virtually resistant to all beta-lactamases and possess a very broad spectrum of activity.

Pharmacokinetics. Aminoglycosides are practically unabsorbed from the gastrointestinal tract. The absorption of aminoglycosides (neomycin, kanamycin), which are occasionally used for bowel decontamination, can increase sharply in the presence of inflammatory bowel disease. Absorption of aminoglycosides applied to damaged Skin, such as Burns, can lead to toxic effects. For the same reasons, aminoglycosides are not recommended for administration into the abdominal and pleural cavities or joints, as they are readily absorbed from these sites.

To achieve a systemic (resorptive) effect, aminoglycosides are administered intravenously (by drip infusion) or intramuscularly; to target intestinal microflora, they are given orally.

In Blood Plasma, aminoglycosides are 15–20% bound to proteins. The degree of plasma protein binding can increase significantly in hypomagnesemia or hypocalcemia. Plasma concentrations of aminoglycosides following the administration of identical doses can vary widely—from subtherapeutic to toxic levels (necessitating therapeutic drug monitoring during treatment).

The concentration of aminoglycosides in synovial and ascitic fluids is equal to that in plasma, while in many Tissues it reaches 30–50% of the blood level. High concentrations are found in highly perfused Organs (Liver, Lungs, Kidneys, and skeletal Muscles). They penetrate the blood-Brain barrier poorly, even in the presence of meningitis. To achieve a therapeutic effect in this condition, amikacin, gentamicin, and tobramycin are sometimes administered intrathecally. Aminoglycosides also cross the placental barrier.

Aminoglycosides are excreted unchanged via the kidneys through Glomerular Filtration, resulting in high concentrations in the urine. The half-life of all AGs in adults with normal renal function is 2–4 hours, in newborns 5–8 hours, and in children 2.5–4 hours. In renal failure, the half-life of aminoglycosides can increase to 70 hours or more.

Aminoglycosides have The ability to accumulate in renal tubular Cells. The concentration of aminoglycosides (with the exception of streptomycin) in the renal cortex is 100 times higher than their concentration in blood serum. Aminoglycosides can still be detected in renal tissue even 25 days after the cessation of treatment. On the one hand, this makes them exceptionally effective drugs for treating Urinary Tract infections, particularly Pyelonephritis; on the other hand, it creates a prerequisite for The Development of nephrotoxicity. It has been proven that at a urine pH of 7.5, the antibacterial activity of aminoglycosides is significantly higher than in an acidic environment. Therefore, their administration is recommended alongside a milk-and-plant diet and sodium bicarbonate (the latter at up to 10–15 g per day).

The antibacterial effect of aminoglycosides, which belong to concentration-dependent antibiotics, directly depends on their concentration at the site of infection. Accordingly, they exhibit the highest efficacy when administered in high doses. Therefore, it is more appropriate to administer aminoglycosides once daily at the full total daily dose: gentamicin, netilmicin, and tobramycin at 4–7 mg/kg, and amikacin at 15 mg/kg, with subsequent dose adjustment if necessary based on repeated drug concentration measurements in the blood. The dosages of aminoglycosides for adults and children are presented in Tables 27 and 28.

Table 27. Aminoglycoside dosages in adults (I.G. Bereznyakov, 2002)

Table 28. Aminoglycoside dosages in children aged 1 month to 12 years (I.G. Bereznyakov, 2002)

This method of administration leads to a significant increase in the area under the pharmacokinetic curve, resulting in a more prolonged action of high drug concentrations on pathogens and an extended post-antibiotic effect (the period during which an antibiotic continues to suppress microorganism viability after a brief exposure) of up to 5–7 hours (whereas with three-times-daily administration, the latter does not exceed 1–2 hours). It has also been established that to achieve maximum treatment efficacy with aminoglycosides, The ratio of the peak plasma concentration to the minimum inhibitory concentration (MIC) should exceed 8, although increasing this value to 10–12 does not lead to a further increase in drug efficacy.

A significant advantage of once-daily aminoglycoside administration is that it reduces drug accumulation in the renal cortex and, consequently, decreases nephrotoxicity.

At the same time, there are situations where the traditional multiple-daily dosing schedule for AGs should be preferred: in infective (primarily enterococcal) endocarditis, neutropenia, and cases with altered pharmacokinetics, such as severe burns.

Aminoglycosides are indicated for severe infections caused by susceptible Gram-negative bacteria or staphylococci. They are used in septicemia, abdominal Sepsis, pelvic infection-related sepsis, Peritonitis and intra-abdominal abscesses, complicated respiratory tract infections, complicated urinary tract infections, and frequently for the empirical therapy of severe bacterial infections. Aminoglycosides are also indicated for bacterial endocarditis caused by enterococci, streptococci, or staphylococci.

In the aforementioned cases, gentamicin, amikacin, and netilmicin are the drugs of choice; tobramycin is preferable for treating patients with infections caused by Pseudomonas aeruginosa; and amikacin should be reserved for infections caused by gentamicin-resistant microorganisms.

Neomycin and monomycin are used topically (for skin, eye, and ear infections); monomycin and kanamycin are also administered orally (for bowel sterilization prior to surgery or immunosuppressive therapy, in amebiasis, and as part of combination therapy for hepatic coma to reduce the microbial load in the gastrointestinal tract and, consequently, Ammonia Production).

Streptomycin and kanamycin are prescribed for patients with tuberculosis, tularemia, and plague.

Based on numerous studies, generalized clinical indications for The Use of aminoglycosides have been developed:

- Initial Stages of severe infectious processes of unknown Etiology (in combination with beta-lactam antibiotics);

- severe infections with a significant purulent-inflammatory component (peritonitis, sepsis, mediastinitis, soft tissue abscesses and phlegmons, etc.);

- exacerbations of chronic purulent-inflammatory Diseases and complications, including the development of secondary immunodeficiencies;

- Cytology/cytology/16.html">Early stages of secondary bacterial meningitis;

- urological practice (urinary concentrations of aminoglycosides significantly exceed the MIC for most urinary tract pathogens) — for severe forms of pyelonephritis and urinary tract infections caused by Gram-negative pathogens (provided other antibiotics are ineffective);

- prophylaxis of postoperative purulent complications (in combination with beta-lactam antibiotics, metronidazole, or other anti-anaerobic agents);

- skin and subcutaneous tissue infections in burn patients;

- septic Arthritis caused by Gram-negative pathogens;

- particularly dangerous infectious diseases (plague, tularemia).

Amikacin and netilmicin are preferred for the aforementioned processes. When isolating microorganism strains resistant to gentamicin, tobramycin, and sisomicin, netilmicin is the antibiotic of choice among aminoglycosides. Currently, the isolation rate of resistant pathogens does not exceed 8-12 %.

The duration of aminoglycoside therapy should not exceed 7-10 days. For bowel decontamination, they are used for 1-2 days.

Compared to first-generation aminoglycosides, gentamicin sulfate (garamycin) exhibits higher efficacy against staphylococci, Escherichia coli, and Brucella, and is also active against Pseudomonas aeruginosa. It is administered at a daily dose of 0.8-1.2 mg/kg of body weight, and up to 3.0 mg/kg for severe infections. The drug is administered intramuscularly, using either a ready-made solution in ampoules or an ex tempore solution prepared from powder in vials. Only the ampoule solution is administered via intravenous drip. The daily dose is divided into 2-3 injections.

For skin conditions, gentamicin sulfate is used as a 0.1 % ointment, applied to the affected areas 2-3 times daily.

Gentamicin tends to accumulate with repeated injections every 8 hours, and the risk increases in cases of renal impairment. Therefore, monitoring its serum concentration is necessary during treatment to prevent toxic effects.

In terms of antibacterial activity, amikacin surpasses gentamicin and other aminoglycosides, particularly against members of the Klebsiella and Providencia genera. It acts bactericidally. Peak serum concentrations are observed 1 hour after intramuscular administration. It binds to Plasma Proteins by 4-10 % and crosses the placental barrier. Approximately 90 % of the drug is excreted via the kidneys. Amikacin is indicated for bronchopulmonary diseases (Bronchitis, pneumonia, Pleurisy, empyema), endocarditis, meningitis, peritonitis, sepsis (including that caused by P. aeruginosa); genitourinary infections (pyelonephritis, cystitis, urethritis, prostatitis, epididymitis, parametritis), skin, soft tissue, bone, and joint infections (arthritis, Osteomyelitis), and infected burns, among others.

Amikacin is administered intramuscularly at a daily dose of 15 mg/kg (2-3 injections). In severe cases and for infections caused by P. aeruginosa, the drug is prescribed at 500 mg 3 times daily or 750 mg twice daily. In cases of obesity, ascites, or edema, the dosage of amikacin and other aminoglycosides should be calculated based on ideal body weight (see Appendix 12).

The drug exhibits lower toxicity compared to gentamicin or tobramycin.

Due to its high toxicity, neomycin sulfate is used topically and occasionally orally. Topically, the drug is prescribed for purulent skin conditions, infected wounds, Conjunctivitis, and keratitis in the form of solutions (5 mg per 1 ml) or ointments. The amount of 0.5 % ointment per application should not exceed 25-50 g, and 2 % ointment should not exceed 5-10 g. Oral administration of neomycin sulfate (0.1-0.2 g twice daily) is used for gastrointestinal disorders, particularly enteritis caused by microorganisms resistant to other antibiotics, and occasionally for bowel sterilization prior to gastrointestinal surgery.

The duration of aminoglycoside therapy should not exceed 7-10 days. For bowel decontamination, neomycin is used for 1-2 days.

The Adverse effects of aminoglycosides are quite serious. Most notably, they are characterized by ototoxicity, nephrotoxicity, and the ability to induce neuromuscular blockade.

Ototoxicity occurs in 10-25 % of patients and results from the intensive binding of aminoglycosides to phosphoinositides in the cell membranes of Inner ear structures. This manifests as irreversible disruption of the Structure and function of Hair cells and efferent fibers in the inner ear, leading to partial or complete Hearing loss. In early childhood, the onset of deafness consequently leads to mutism.

When using streptomycin and gentamicin, vestibular disorders—such as dizziness and gait disturbances—are typically the first manifestations of ototoxicity, whereas cochlear damage (deafness) develops later. Often, the earliest signs of ototoxicity include tinnitus (not always present) and a altered perception of high frequencies (>4000 Hz) on audiometry. As changes progress, patients begin to notice a decline in conversational speech comprehension. Ototoxic changes are frequently reversible, but residual effects usually persist for a long time, and sometimes deafness remains permanent, particularly if aminoglycosides are administered to patients with preexisting hearing impairment. There is a higher risk of ototoxicity with the parenteral use of monomycin, kanamycin, and amikacin. It can also occur with the topical application of neomycin—considered the most ototoxic aminoglycoside—if absorbed from wound surfaces, ulcers, etc.

The development of aminoglycoside ototoxicity is promoted by:

1) The use of high doses and, consequently, rising blood concentrations exceeding safe thresholds. Specifically, the ototoxic blood concentration is 35-40 mcg/ml for amikacin and kanamycin, and exceeds 10-12 mcg/ml for gentamicin and tobramycin.

2) The presence of otitis, meningitis, cranial trauma (including birth trauma), or intrapartum Hypoxia in the patient.

4) Exceeding the recommended duration of aminoglycoside treatment. Their use for 7-10 days is considered relatively safe. With prolonged administration (exceeding 2-3 weeks), the risk of toxic effects increases significantly.

5) Prior or concurrent use of other aminoglycosides.

6) Prior or concurrent administration of potent Diuretics (furosemide, ethacrynic acid, mannitol, thiazides).

7) Dehydration.

8) Advanced and senile age of the patient.

During aminoglycoside treatment and for 2-3 weeks after discontinuation, drugs that also exhibit ototoxic effects (other aminoglycosides, furosemide, ethacrynic acid, etc.) must not be used.

Nephrotoxicity is reported in 8-26 % of patients and occurs due to drug accumulation in the renal cortex, from which they may be excreted for up to 11 days after drug discontinuation.

Renal impairment during aminoglycoside therapy manifests as decreased filtration and secretion, impaired concentrating ability, proteinuria, and the development of non-oliguric renal failure. Renal damage is most dangerous with the use of gentamicin, amikacin, kanamycin, and tobramycin.

Risk factors for renal damage during aminoglycoside therapy include low blood pressure, dehydration, hypokalemia, concurrent or prior administration of loop diuretics (furosemide and ethacrynic acid), other aminoglycosides, cephalosporins, vancomycin, amphotericin B, nonsteroidal anti-inflammatory drugs, clindamycin, piperacillin, methoxyflurane, verapamil, intravenous radiocontrast agents, polyglucukin, and foscarnet. The risk of nephrotoxicity is higher in elderly patients. However, it is lower in infants under 3 months of age compared to adults, which is attributed to the immaturity of tubular epithelial cell uptake mechanisms for antibiotics in this age group. Certain factors contributing to the development of aminoglycoside nephrotoxicity are presented in Table 29.

Table 29. Factors contributing to the development of aminoglycoside nephrotoxicity (S.M. Kuznetsova, 2002)

Despite the significant hazards of nephrotoxic effects and the development of ACUTE RENAL FAILURE when aminoglycosides are combined with cephalosporins, this drug combination is currently used quite frequently in the empiric therapy of severe nosocomial infections to potentiate and broaden the spectrum of antibacterial activity. Naturally, such treatment is essentially a "therapy of despair".

When prescribing aminoglycosides to patients with renal impairment, dosage regimen adjustments are required (Tables 30, 31, and Appendix 12).

Table 30. Dosage intervals for gentamicin in patients with impaired renal function (O.P. Viktorov et al., 2002)

Table 31. Recommended aminoglycoside doses for patients with renal impairment (O.P. Viktorov et al., 2002; V.P. Yakovlev, S.V. Yakovlev, 2003)

The comparative oto- and nephrotoxicity of various aminoglycosides are presented in Table 32.

Table 32. Comparison of aminoglycoside toxicity (I.G. Bereznyakov, 2002)

Notes: "+" - minimal risk; "++" - moderate risk; "+++" - significant risk.

As shown in Table 32, amikacin and netilmicin are the safest agents.

The neurotoxicity of aminoglycosides is related to their ability to impair synaptic transmission (by inhibiting the release of Ca²⁺ and acetylcholine from presynaptic terminals). It manifests as profound Muscle weakness (even with short courses of aminoglycoside therapy), depression of respiratory Muscle contraction, and even respiratory arrest. The likelihood of this complication increases in patients receiving muscle relaxants, those with myasthenia gravis, Parkinson's disease, and with the concurrent use of magnesium preparations, antidepressants, or lincosamide antibiotics (lincomycin or clindamycin).

If symptoms of neuromuscular blockade develop during aminoglycoside therapy, intravenous administration of calcium chloride solution or anticholinesterase agents (neostigmine) is indicated, along with hemodialysis, peritoneal dialysis, and resuscitation measures if necessary.

Other Nervous system symptoms observed during aminoglycoside therapy include encephalopathy, generalized weakness, paresthesia, headache, muscle twitching, numbness, convulsions, drowsiness, and psychoses in children. Streptomycin administration may cause heartburn, numbness, or paresthesia in the facial and oral regions.

In order of increasing toxicity, aminoglycosides can be ranked as follows: sisomicin < netilmicin < gentamicin < tobramycin < amikacin < neomycin < streptomycin < monomycin < kanamycin.

Other adverse effects of aminoglycosides include rashes, fever, blood abnormalities (leukopenia, hemolytic anemia), hemorrhages (antagonism to blood clotting factor V), allergic reactions (cross-allergy to all agents in this group is characteristic), development of superinfections, and hypocalcemia, hypomagnesemia, and hypokalemia in children. Phlebitis may occur upon intravenous administration. Aminoglycosides can suppress The Immune System, which must be taken into account, especially during the acute phase of an infectious process.

Interactions. Combining aminoglycosides with other antibiotics is performed to broaden the spectrum of antibacterial activity and prevent the development of microbial resistance. The following aminoglycoside combinations are synergistic:

- with beta-lactam antibiotics - cefotaxime, ceftriaxone (in severe sepsis without neutropenia, with bacteriologically confirmed presence of gram-negative bacteria);

- with antianaerobic drugs - clindamycin, metronidazole (in the treatment of mixed pelvic infections);

- with antipseudomonal antibiotics - piperacillin, piperacillin/tazobactam, ceftazidime, sulperazone, cefepime (in confirmed Pseudomonas infection of various localizations).

Aminoglycosides must not be administered in the same syringe or intravenous infusion set with other antibiotics (penicillins, polymyxin B, cephalosporins) due to potential physicochemical incompatibility. Aminoglycosides should not be combined in an infusion set with aminophylline, as the latter possesses alkaline properties that cause antibiotic inactivation. Amikacin is pharmaceutically incompatible with Vitamins B and C, amphotericin, heparin, potassium chloride, nitrofurantoin, certain penicillins, chlorthiazide, cephalosporins, Tetracyclines, and erythromycin; gentamicin - with ampicillin, vitamin B₂, amphotericin B, benzylpenicillin, phenobarbital, prednisolone, diphenylhydantoin, diphenhydramine, and heparin; netilmicin - with penicillin.

Concomitant administration of aminoglycosides with diprasine, inhalational anesthetics, magnesium sulfate, lidocaine, procainamide, or chlorpromazine increases the risk of neuromuscular blockade. Nonsteroidal anti-inflammatory drugs may delay the elimination of aminoglycosides from the body, leading to manifestations of their specific adverse effects.

Regardless of the indications for aminoglycoside use, monitoring is required for respiratory function, audiograms and vestibulograms, diuresis, serum drug concentrations, and serum calcium and magnesium levels.