Antibiotics (Properties, Administration, Interactions) - Posokhova K.A., Viktorov O.P. 2005

Lincosamides

The lincosamide group of drugs includes lincomycin and clindamycin (a chlorinated derivative of lincomycin).

Lincomycin was introduced into clinical practice in 1962. Later, through modification of its molecule, clindamycin was synthesized, which exhibits higher antibacterial activity and bioavailability compared to lincomycin.

MECHANISM OF ACTION. Both drugs exert a bacteriostatic effect by inhibiting microbial Protein Synthesis through binding to the 50S ribosomal subunits and halting the incorporation of Transfer RNA into ribosome-mRNA complexes. At higher concentrations, they exhibit a bactericidal effect against staphylococci, streptococci, and anaerobes. They possess a post-antibiotic effect against susceptible microorganisms, which is likely related to their prolonged binding to microbial Ribosomes. These Antibiotics facilitate phagocytosis and the intracellular destruction of Bacteria, while reducing The production of bacterial endotoxins, thereby preventing The Development of endotoxic Shock.

THE SPECTRUM OF action encompasses most gram-positive aerobic cocci (clindamycin's activity is 5–8 times higher than that of lincomycin), including group A, B, C, and G streptococci, S. pneumoniae, staphylococci (including penicillinase-producing and methicillin-susceptible strains of S. aureus), among others, with the exception of E. faecalis and E. faecium. Moderate activity of lincosamides, which is of no major practical significance, has been noted against M. catarrhalis, H. influenzae, N. meningitidis, and N. gonorrhoeae. Of greatest practical importance is the high activity of these drugs against a range of gram-positive and gram-negative anaerobes, particularly Actinomyces spp., B. fragilis, B. melaninogenicus, Peptostreptococcus spp., Peptostreptococcus spp. [sic: Peptococcus spp.], C. perfringens, and C. tetani. They are inactive against enterobacteria, legionellae, Mycoplasma pneumoniae, and C. difficile.

Pharmacokinetics. The antibiotics are well absorbed in the gastrointestinal tract (the bioavailability of lincomycin is 30–50%, and that of clindamycin is approximately 90%). Food intake reduces the bioavailability of lincomycin to 5%, but does not affect the absorption of clindamycin. They penetrate all Body Fluids and Tissues (Bone tissue, sputum, pleural and peritoneal fluid, Bile, etc.), achieve high concentrations in sites of inflammation and destruction (abscesses, empyema, trophic ulcers), and do not cross the Blood-Brain barrier (BBB).

Lincomycin and, particularly, clindamycin have The ability to actively transport into polymorphonuclear leukocytes and macrophages. Consequently, the intracellular concentration of clindamycin exceeds the extracellular concentration by 40-fold.

The drugs are metabolized primarily in The Liver and excreted by the Kidneys. In hepatic and renal impairment, dosages need to be reduced only when high doses of the drugs are administered.

Indications for use. The Clinical significance of lincosamides is primarily determined by their activity in infectious processes caused by mixed aerobic-anaerobic flora, staphylococci (including certain methicillin-resistant strains), and beta-lactamase-producing anaerobic flora.

Lincosamides are indicated for Infections caused by anaerobic microorganisms, which are frequently the pathogens responsible for nosocomial (hospital-acquired) infections. In such cases, the drugs are used in combination with other antibacterial agents. They are indicated for anaerobic infections caused by penicillin-resistant microorganisms in orodental Sepsis; in recurrent tonsillopharyngitis, otitis media, and sinusitis; in aspiration Pneumonia, lung abscesses, and Pleural Empyema; in intra-abdominal sepsis and gynecological infections (not sexually transmitted and typically caused by penicillin-resistant anaerobes); as well as in staphylococcal Bone and joint infections, and Skin and soft tissue infections.

They are used in Toxoplasmosis in AIDS patients (in combination with pyrimethamine) and in tropical malaria caused by chloroquine-resistant strains of P. falciparum (in combination with quinine).

In cases where The Nature and localization of the infection indicate a high probability of gram-negative flora (chronic otitis media, abdominal sepsis, penetrating abdominal trauma, etc.), lincosamides must be combined with aztreonam or Aminoglycosides.

The Use of clindamycin in severe Lower Respiratory Tract infections is presented in Table 20.

The daily dose of lincomycin for adults is 1.8 g (up to 2.4 g in severe infections). Clindamycin is administered in a daily dose of 1.2–1.8 g (up to 2.7 g in severe cases) divided into 3–4 injections. When administered intramuscularly, it is not recommended to exceed 600 mg per single injection. Orally, clindamycin is used at 300–450 mg every 6 hours. The drugs are mostly administered intravenously (slowly, preferably as an infusion); in this case, the bacteriostatic concentration of the antibiotic in the blood (as well as after oral administration) is maintained for 5–6 hours. They are administered 4 times a day. To achieve therapeutic concentrations in the CEREBROSPINAL FLUID, clindamycin can be administered intrathecally.

Class="center">Table 20. Use of clindamycin in lower respiratory tract infections

Adverse effects of lincosamides. Nausea, vomiting, abdominal pain, and diarrhea are observed in 10–30% of cases when using lincosamides. Pseudomembranous colitis develops in 1–2% of patients (especially when lincosamides are used concomitantly with aminoglycosides), characterized by a severe and sometimes fatal course. In such cases, metronidazole (orally 400 mg 3 times daily) is used to eradicate C. difficile, and vancomycin (125 mg 4 times daily) for enterococci, for 7–10 days; sometimes these drugs are combined. The risk of gastrointestinal complications increases if the patient has a history of Ulcerative Colitis, Crohn's disease, or antibiotic-associated colitis.

Intravaginal administration of the drugs frequently leads to cervicitis, vaginitis, and vulvovaginitis (35% in pregnant women, 16% in non-pregnant women).

Lincosamides may cause liver dysfunction, jaundice, and transient granulocytopenia or thrombocytopenia.

Rapid intravenous administration of these drugs, particularly lincomycin, may cause neuromuscular blockade with respiratory depression and arrest, as well as cardiovascular disorders (hypotension accompanied by nausea, vomiting, arrhythmias, and cardiac arrest). Management in such cases involves intravenous administration of physostigmine and calcium preparations. Intravenous administration may cause pain and potential thrombophlebitis at the injection site.

Lincosamides are not contraindicated during Pregnancy and Lactation. They can be used in children, including premature infants. Relative contraindications for their use include gastrointestinal disorders, including a history thereof (nonspecific ulcerative colitis, Crohn's disease, antibiotic-induced enterocolitis). Lincosamides are not recommended for neuroinfections.

Drug interactions. Synergism is observed when lincosamides are combined with:

- ceftazidime (against aerobic-anaerobic flora);

- primaquine (against P. carinii);

- pyrimethamine or telithromycin (against T. gondii);

- chloroquine (against P. falciparum);

- with ketolides (in toxoplasma-induced encephalitis).

The combined use of lincosamides with beta-lactams, rifampicin, and aminoglycosides can be employed in the empirical therapy of pulmonary abscess, destructive (necrotizing) pneumonia, as well as intra-abdominal and gynecological infections.

Lincosamides may be combined with benzylpenicillin, antipseudomonal cephalosporins, aztreonam, aminoglycosides, fluoroquinolones, rifampicin, and telithromycin.

It is not advisable to combine lincosamides with macrolides and chloramphenicol, as they share similar antibacterial Mechanisms of action. Furthermore, competition for binding to Plasma Proteins occurs between them, which diminishes the antibacterial efficacy of lincosamides.

Lincosamides can inhibit the METABOLISM of Muscle relaxants, general anesthetics, and opioid analgesics, thereby potentiating their effects and creating a dangerous risk of neuromuscular blockade and respiratory arrest.

Antidiarrheal agents containing kaolin and attapulgite can significantly impair the absorption of lincosamides from the gastrointestinal tract. Therefore, an interval of at least 4 hours should be maintained between their administration.