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

Tetracyclines

Tetracyclines have been used in clinical practice for over 50 years. Nevertheless, they have not lost their significance, although multiple drug resistance among microflora has been frequently observed over the last decade (driven by their long-term continuous use in clinical and outpatient settings, as well as their agricultural use as veterinary drugs and feed additives).

Tetracycline Antibiotics are divided into two groups:

1. Natural - biosynthetic: oxytetracycline, tetracycline, demeclocycline.

2. Semisynthetic - doxycycline, metacycline, minocycline.

Original tetracycline preparations and their analogs approved for use in Ukraine are presented in Table 21.

Class="center">Table 21. Tetracycline preparations approved for use in Ukraine

All tetracyclines exhibit bacteriostatic activity. They inhibit the binding of aminoacyl-tRNA to the A-site of the ribosome on the 30S ribosomal subunit (acting as Polypeptide chain elongation inhibitors), thereby suppressing Protein Synthesis.

The antimicrobial spectrum of natural and semisynthetic tetracyclines is broad (Table 22). They are active against a range of gram-positive and gram-resistant Bacteria, rickettsiae, legionellae, Mycoplasmas, and chlamydiae. Notable tetracycline-resistant microorganisms include enterococci, corynebacteria, P. aeruginosa, P. cepacia, S. maltophilia, Acinetobacter, Citrobacter, Enterobacter, Proteus (indole-positive), Serratia, Mycobacterium tuberculosis and M. leprae, C. difficile, Haemophilus influenzae type b, Protozoa (except amebae), and Fungi. Doxycycline is active against H. pylori.

Table 22. Antibacterial activity of tetracyclines (S.M. Navashin, P.S. Navashin, 1993)

Against gram-positive cocci (staphylococci, pneumococci, group A pyogenic streptococci), the efficacy of tetracyclines is comparable to that of benzylpenicillin, and they frequently remain active against strains resistant to benzylpenicillin. Enterococci are moderately sensitive to tetracyclines, whereas clostridia, listeriae, actinomycosis agents, and anthrax pathogens are sensitive. Among hospital strains, tetracycline-resistant staphylococci are isolated in 30–60% of cases. In outpatient settings, microorganisms often retain their susceptibility, making these antibiotics suitable for treating moderately severe infections (tonsillitis, otitis media, Prevention of exacerbations in Chronic Bronchitis, etc.). The spread of tetracycline-resistant group A streptococci (15–60%, depending on the geographic region) is linked to the widespread use of this drug class. Resistant pneumococci occur at a frequency of 2–>30%.

Many gram-negative bacteria, particularly most enterobacteria, are sensitive to tetracyclines. These antibiotics are active against gram-negative cocci (gonococci, meningococci), Haemophilus influenzae, yersiniae, francisellae, brucellae, and others. Activity against pseudomonads, acinetobacters, and legionellae is higher for doxycycline compared to biosynthetic preparations. Beta-lactamase-producing gonococci are moderately sensitive to tetracyclines (MIC 1–2 mcg/mL). The isolation rate of such strains worldwide ranges from 6–60%. When the MIC of tetracyclines against gonococci exceeds 1 mcg/mL, Gonorrhea Treatment with these antibiotics is generally ineffective. Furthermore, in such microorganisms, reduced susceptibility to tetracyclines is combined with resistance to Penicillins, erythromycin, and chloramphenicol.

Among Escherichia and Salmonella species, tetracycline-resistant strains are isolated in 20–70% of cases. Enterobacteria resistant to tetracyclines are concurrently insensitive to streptomycin, ampicillin, chloramphenicol, and sulfonamides. With prolonged use of tetracyclines in chronic bronchitis, H. influenzae also develops resistance to them. Tetracyclines exhibit complete cross-resistance: microbial strains non-susceptible to one antibiotic in the group are equally non-susceptible to all others.

Pharmacokinetics. When administered orally, tetracyclines are rapidly absorbed: doxycycline up to 90%. Optimal absorption conditions occur on an empty Stomach; doxycycline absorption decreases by 20% after a meal, and tetracycline by 50%. Divalent and trivalent cations (calcium, aluminum, iron), milk, and dairy products reduce tetracycline absorption. The tendency to form complexes that reduce absorption is lower for doxycycline and metacycline (see below).

The half-life (T_1/2) of oxytetracycline and tetracycline is 8–9 hours, while metacycline and doxycycline have a prolonged duration of action, with a T_1/2 of 14 hours and 16–20 hours, respectively.

Due to their lipophilicity, tetracyclines readily penetrate various body Tissues and fluids. Their concentration in the Lungs, skeletal and smooth Muscles of various Organs, and prostate tissue reaches 50–70% of plasma concentration; in pleural, peritoneal, and synovial exudates, pericardial fluid, and renal tissue, it reaches 100%; and in CEREBROSPINAL FLUID, it is 10% (up to 15–25% in meningitis). They readily cross the placental barrier, achieving fetal tissue levels equal to 25–50% of maternal Blood concentrations. Their concentration in breast milk equals that in maternal blood. Doxycycline levels in the Liver, Gallbladder, and Bile duct tissues exceed serum levels by 8–10 times, and in the endometrium and ovarian tissue by 2–2.5 times.

Upon parenteral administration, 60–70% of tetracycline and oxytetracycline and 35–40% of doxycycline are excreted in the urine. They are also partially excreted via bile, achieving concentrations 10–20 times higher than blood levels. Doxycycline undergoes enterohepatic recirculation.

The duration of maintaining therapeutic concentrations of these antibiotics in the blood and, consequently, their dosing frequency for patients are as follows: for oxytetracycline and tetracycline, 4–6 hours (administered 4 times daily); for metacycline, 12 hours (administered twice daily); and for minocycline and doxycycline, approximately 24 hours, allowing for once- or twice-daily administration.

In renal failure, the elimination of tetracyclines is delayed, which may lead to drug accumulation. Doxycycline accumulation does not typically occur, even in patients with anuria, because 60–65% of it is eliminated via extrarenal pathways. For Infections caused by tetracycline-sensitive microflora complicating chronic renal failure, doxycycline is the drug of choice (The Use of other drugs in this group may lead to a further increase in serum creatinine and urea). If hemodialysis, peritoneal dialysis, or Forced diuresis is required—Procedures that normally accelerate drug elimination—the dose of doxycycline

may remain unadjusted, as these clearance Methods do not significantly reduce its effective concentration in the body.

Tetracyclines tend to accumulate within microbial Cells, where intracellular concentrations can exceed extracellular levels by 10 to 100 times. Consequently, they are highly effective against intracellular pathogens, including chlamydial and mycoplasmal infections.

Clinical Use. Since their Introduction into clinical practice in the late 1940s, tetracyclines have enjoyed considerable popularity among physicians, long remaining the drugs of choice in the treatment of cholera, epidemic typhus, rickettsiosis, brucellosis, plague, tularemia, and infections with intracellular localization (Table 23).

Table 23. Indications for tetracycline use

Due to The Development of resistance to tetracyclines among a significant number of MICROORGANISMS AND THE emergence of more modern, broad-spectrum antibacterial agents (including those effective against intracellular pathogens of infectious processes), the range of indications for this group of antibiotics has narrowed. Nevertheless, their use remains appropriate for the following infectious conditions:

1. Particularly dangerous infections: cholera, plague, anthrax, brucellosis, tularemia, borreliosis.

2. Rickettsial infections (epidemic typhus, spotted fever, Q fever).

3. Osteomyelitis, infectious Arthritis (including gonococcal Etiology).

4. Chlamydiosis. Tetracyclines are especially important in reactive arthritis, particularly Reiter's Syndrome (urethro-oculo-synovial syndrome), where chlamydial infection (C. trachomatis) plays a leading etiologic role.

5. Mycoplasma pneumonia.

6. Urogenital infections caused by chlamydia, mycoplasmas, and gonococci.

7. Skin infections (including severe forms of acne) and soft tissue infections.

8. Trachoma, psittacosis, lymphogranuloma venereum.

9. PEPTIC ULCER DISEASE of The Stomach and duodenum (doxycycline).

10. Asymptomatic and invasive (intestinal) amebiasis.

Tetracyclines, most commonly doxycycline, continue to be used for respiratory tract infections caused by susceptible microorganisms (H. influenzae, Staphylococcus spp., mixed microbial flora), both for treating acute conditions and for the seasonal prophylaxis of chronic bronchitis. Doxycycline is effective against mixed aerobic-anaerobic infections, making it useful in postoperative purulent complications, including in combination with Aminoglycosides. Given their pharmacokinetics, tetracyclines are employed in gynecological infections (endometritis, parametritis, salpingitis, inflammation of the Ovaries and cervix, etc.), as well as in acute CHOLECYSTITIS AND CHOLANGITIS caused by susceptible pathogens. Tetracycline and oxytetracycline are effective in acute and chronic Urinary Tract infections caused by enterobacteria and enterococci. Doxycycline is indicated for the treatment of acute prostatitis and acute exacerbations of chronic prostatitis.

In gonorrhea, doxycycline is prescribed when the patient has an allergy to beta-lactam antibiotics. However, it is inactive against strains of the pathogen that produce beta-lactamases. Intravenous administration of doxycycline provides a favorable therapeutic effect in meningitis caused by ampicillin-resistant, penicillinase-producing strains of H. influenzae.

The bacteriostatic nature of tetracyclines precludes their use in the acute phase of severe postoperative complications and Sepsis. However, they are highly effective as follow-up therapy.

Tetracyclines are not indicated when the microflora is susceptible to penicillin, as the latter exerts a bactericidal effect and has low toxicity.

Tetracycline (oxytetracycline) is prescribed at 0.25-0.5 g every 6 hours, metacycline at 0.3-0.6 g every 12 hours, and doxycycline initially at 0.2 g, followed by 0.1 g every 24 hours. For acute gonorrhea, doxycycline is used at a daily dose of 200 mg for 3 days. In the treatment of meningitis caused by H. influenzae, it is administered intravenously at a daily dose of 50 mg/kg. It should be kept in mind that rapid intravenous administration of the drug (due to the chelation of blood calcium) can trigger Heart Failure and collapse.

When prescribing tetracyclines, one must always take into account literature data on the level of microbial resistance and ongoing surveillance data within a specific region or healthcare facility, as bacterial resistance to tetracyclines has increased substantially in modern times. In particular, 90% of Vibrio cholerae strains in Ukraine exhibit acquired resistance to these antibiotics.

The incidence of adverse reactions associated with tetracyclines ranges from 7% to 30%. The most characteristic adverse effects during tetracycline therapy include overall systemic or organ-specific toxicity, allergic reactions (anaphylactic Shock, cutaneous reactions, including photodermatitis), complications related to the suppression of saprophytic microflora (dysbiosis, superinfections, hypovitaminosis), and impaired bone and tooth development.

The toxicity of tetracyclines is related to their lack of selective action: they simultaneously affect the growth and division of microbial cells and, to a lesser extent, host cells. Tetracyclines primarily damage rapidly dividing cells, leading to Bone Marrow suppression (thrombocytopenia, leukopenia, anemia), impaired Spermatogenesis, and gastrointestinal and dermatological disorders.

Hepatotoxicity is one of the most severe complications of tetracycline therapy. It typically occurs when the drugs are used in high doses or in patients with impaired renal excretion. Clinically, this manifests as jaundice, flushing, vomiting, elevated transaminase activity, Hyperbilirubinemia, azotemia, and prolonged prothrombin time. This complication is more likely and particularly dangerous in pregnant women and children, especially during the prepubertal period. It has been proven that the risk of hepatotoxic effects exists when tetracyclines are used at a daily dose exceeding 1 g. Consequently, synthetic tetracycline derivatives are safer in this regard, as they are administered in lower daily doses.

The teratogenic activity of tetracyclines has been established, manifesting as skeletal malformations, Osteogenesis Imperfecta, hepatic and renal tissue damage, reduced body weight, and an increased rate of fetal demise. Using tetracyclines during Pregnancy poses a risk of abnormal dental development in the fetus, accompanied by dental enamel hypoplasia, malformed canines, yellow or brown discoloration, and an increased susceptibility to caries. Even short courses of tetracycline therapy during pregnancies exceeding 14 weeks or in infants during their first months of life can lead to such consequences. Prolonged use of high doses of tetracyclines in children under 8 years of age not only disrupts dental mineralization but may also cause dental hypoplasia. To prevent damage to permanent anterior Teeth, tetracyclines should not be prescribed to pregnant women during the last 2 months of gestation or to children under 4 years of age; for other teeth, to children under 8; and for third molars, to children under 12.

Tetracyclines, particularly metacycline and doxycycline, are excreted into breast milk during Lactation, which can cause jaundice, dysbiosis, impaired synthesis of B-complex Vitamins and vitamin K, delayed ossification of tubular bones, and stunted GROWTH AND DEVELOPMENT of the Skeleton and tooth enamel in the newborn.

The use of tetracyclines during pregnancy and lactation is generally considered contraindicated.

Gastrointestinal disorders (loss of appetite, nausea, diarrhea, etc.) induced by tetracyclines result both from direct irritation of the gastrointestinal mucosa (stomatitis, glossitis, esophagitis, pruritus, etc.) and from dysbiosis and superinfections. To prevent complications associated with the suppression of normal microflora during prolonged tetracycline therapy, patients should concurrently receive a complex of B-complex vitamins, Vitamin C, and biological bacterial products such as lactobacterin, bifidumbacterin, linex, symbioflor, etc.

Photodermatitis (phototoxic reactions) develops in 1-10% of patients receiving tetracyclines. These reactions are triggered by sun exposure not only during therapy but also several days to months after initiation, and are characterized by erythema and edema of sun-exposed skin areas resembling sunburn. They feature a slow resolution (ranging from 2-4 weeks to several months) and residual hyperpigmentation. Metacycline does not cause photosensitization. Tetracyclines can also cause allergic skin reactions, including generalized exanthema, urticaria, and maculopapular, erythematous, or exfoliative polymorphic skin lesions.

The catabolic (anti-anabolic) effect of tetracyclines (disruption of protein synthesis) leads to hypotrophy, reduced resistance to infections, and impaired neuromuscular transmission. It is particularly dangerous in premature newborns, infants, pregnant women, elderly patients, patients undergoing prolonged hormone therapy, and those suffering from hypotrophy and myasthenia gravis.

The nephrotoxic effect of tetracyclines is typically caused by the presence of degradation products (anhydro- and epi-forms) in the preparations, which damage the tubular epithelium (Fanconi Syndrome). To prevent Kidney damage, one should bear in mind that using tetracycline preparations that have been stored for a long time, especially after their expiration date, is strictly unacceptable. Nephrotoxic effects may also be observed when tetracyclines are administered in high doses.

Intramuscular injections of tetracycline are painful due to its irritating effect, while rapid intravenous administration may lead to phlebitis and thrombophlebitis.

Tetracyclines are contraindicated in children under 8 years of age (prescribed only for life-saving indications), during pregnancy, in liver disease, renal failure, and myasthenia gravis. Tetracyclines should not be prescribed concurrently with agents that possess oto- and/or nephrotoxic effects, Diuretics, antacids, or anti-anemic drugs.

When treating with tetracyclines, one must consider the possibility of changes in their pharmacokinetics and pharmacodynamics when interacting with other medicinal products (Table 24).

Table 24. Results of the interaction of doxycycline, methacycline, and tetracycline with certain medicinal products (L.V. Derimedved et al., 2002)

Specifically, the absorption of tetracyclines decreases when they are used concurrently with preparations containing divalent and trivalent ions of calcium, manganese, aluminum, zinc, and iron As a result of direct interaction in the intestinal lumen, leading to The formation of chelate complexes. This may cause blood antibiotic levels to drop below the therapeutic range. To prevent negative consequences of this pharmacokinetic interaction, the interval between the administration of tetracyclines, on the one hand, and antacids, antidiarrheal, and iron-containing preparations, on the other, should be at least 3 hours.

The action of tetracyclines may be diminished due to accelerated inactivation when combined with Inducers of the microsomal enzyme system, such as diphenylhydantoin, carbamazepine, rifampicin, cordiamine, etc. Tetracyclines can potentiate the anticoagulant effect of indirect anticoagulants, the Muscle relaxation caused by peripheral muscle relaxants, and the hypoglycemic effect of antidiabetic drugs (particularly sulfonylurea derivatives), while reducing the efficacy of oral contraceptives.

Combining tetracyclines with certain diuretics (furosemide, ethacrynic acid) increases the risk of nephrotoxicity. There is evidence of intracranial hypertension (pseudotumor cerebri syndrome) developing when tetracyclines are used concomitantly with retinol preparations (such a drug combination can be encountered in the treatment of acne vulgaris).

Tetracyclines can enhance the effect of peripheral muscle relaxants (d-tubocurarine, pipecuronium, suxamethonium, etc.). The impairment of neuromuscular transmission by tetracyclines is attributed to the ability of these agents to form chelate compounds with Calcium Ions, which are necessary for acetylcholine release. The myoparalytic effect of tetracyclines can be mitigated by the intravenous administration of calcium salts.

Tetracyclines must not be administered in the same syringe with heparin, glucocorticosteroids, barbiturates, macrolides, and many other agents, as chemical interactions occur between them.

Food components can significantly impact the absorption, bioavailability, and pharmacological activity of tetracyclines. In particular, calcium caseinate found in milk reduces the absorption and blood concentration of tetracycline by 50–60%. To prevent the Adverse effects of such pharmacokinetic interactions, the interval between taking tetracyclines and consuming milk should be 2–3 hours.

When prescribing tetracyclines, to prevent the formation of highly toxic nitrosamines and carcinogenic amines, patients are advised to avoid consuming sausages, ham, and other products preserved with nitrites and nitrates.

In patients who regularly consume alcohol, the elimination half-life of doxycycline is shortened, and its antibacterial activity may drop below the therapeutic level.