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

Chloramphenicols (Phenicols)

Representatives of this group of Antibiotics include chloramphenicol (levomycetin), synthomycin, and thiamphenicol.

Levomycetin has been used in clinical practice for about 60 years.

MECHANISM OF ACTION. It affects Protein Synthesis in microbial Cells by inhibiting the enzyme peptidyl transferase, which promotes the elongation of the polypeptide chain on Ribosomes. It exhibits bacteriostatic activity against most microorganisms. It has a bactericidal effect on certain Bacteria (S. pneumoniae, N. meningitidis, H. influenzae).

THE SPECTRUM OF antibacterial activity is broad. It is active against gram-positive (staphylococci and streptococci) and gram-negative cocci (gonococci, meningococci), many bacteria (Escherichia coli, Haemophilus influenzae, salmonellae, shigellae, klebsiellae, serratiae, yersiniae, proteus), rickettsiae, spirochetes, and chlamydiae. It shows activity against strains of pathogens resistant to penicillin, streptomycin, and sulfonamides.

Recent literature reports low susceptibility and frequent resistance (20-60% of cases) to levomycetin in A number of shigella and salmonella strains, particularly S. typhimurium, which is obviously associated with the prolonged, often uncontrolled use of the drug. In gram-positive cocci, meningococci, and neisseriae, the level of resistance to chloramphenicol does not exceed 1%.

Pharmacokinetics. The bioavailability of levomycetin, which is a highly lipophilic compound, is greater when administered orally than via parenteral administration of its esters, reaching 90%. The latent period upon oral administration is 20 min. It easily penetrates Body Fluids and Tissues, including across the Blood-Brain barrier. The highest concentrations of the drug are found in The Liver and Kidney tissues, as well as in urine. In pleural, peritoneal, and synovial fluids, it reaches concentrations of 30-50% of the serum level, and in the CEREBROSPINAL FLUID, 20-50% (50-90% in meningitis). Up to 90% of the drug is metabolized in the liver via reduction and glucuronidation. Levomycetin is excreted primarily through the Kidneys: 5-15% in unchanged form and 80% as inactive metabolites. In patients with impaired liver function, the T_1/2 of levomycetin can increase to 5-11 hours (normally it is 1.5-3 hours). Due to the immaturity of liver and renal Functions in newborns, especially premature infants, the T_1/2 of levomycetin can increase up to 24 hours (in the first days after birth), up to 10 hours (at the age of 10 days to 4 weeks), and up to 6-7 hours (at an older age).

Indications for use. Systemic levomycetin (oral, intramuscular, intravenous) is used only as a reserve drug when less toxic antibiotics are ineffective or contraindicated. It may be used for:

- bacterial Meningitis caused by H. influenzae, N. meningitidis, S. pneumoniae, including in newborns and premature infants;

- brain abscess caused by B. fragilis and other susceptible pathogens;

- typhoid fever, paratyphoid fever, and dysentery, provided that 80% of the strains of these pathogens in the given region are susceptible to levomycetin;

- brucellosis, tularemia, plague;

- epidemic typhus and other rickettsioses;

- severe purulent-septic processes, including those in the Abdominal cavity AND small pelvis;

- anaerobic infections, gas gangrene;

- Rocky Mountain spotted fever, Q fever.

Levomycetin is sometimes prescribed topically for purulent-inflammatory Skin and soft tissue conditions, nipple fissures in nursing mothers, and bacterial eye infections (trachoma, Conjunctivitis, blepharitis, keratitis).

The drug is administered orally at a dose of 0.25-0.75 g every 6 hours. For parenteral administration, it is used as chloramphenicol sodium succinate. The latter compound is pharmacologically inactive. For its antimicrobial action to manifest, preliminary Hydrolysis is required to release active levomycetin, which takes place in Blood Plasma, liver, kidneys, and Lungs. The rate of hydrolysis, which determines the intensity of its antimicrobial effect, varies significantly, especially in newborns and young children. Therefore, if levomycetin must be prescribed to them, its plasma level should be monitored every 48 hours and must not exceed acceptable values (25-30 mg/L).

Side effects. Levomycetin exerts a toxic effect on the hematopoetic system. Hypochromic anemia may develop due to the suppression of heme synthesis (3-5 days after Treatment initiation), accompanied by reticulocytopenia, decreased Hemoglobin levels, and elevated serum iron concentration. Levomycetin can also cause neutropenia and thrombocytopenia (which usually develop on the 10th-14th day of treatment). These hematological reactions are dose-dependent (occurring upon drug overdose when the serum level exceeds 25-30 mg/L) and are generally reversible.

An extremely severe complication of levomycetin use is fatal aplastic anemia, which results in death in the majority of patients (its incidence ranges from 1:24000 to 1:40000). It develops abruptly, sometimes after a single dose of the antibiotic, or several weeks (months) after discontinuation (most commonly after 2-5 weeks). This complication is believed to be associated with genetic characteristics of levomycetin METABOLISM (resulting in toxic metabolites that damage the Bone Marrow).

In erythrocyte glucose-6-phosphate dehydrogenase deficiency, chloramphenicol can trigger intense hemolysis. To prevent blood-related complications, a blood test must be performed every 3 days during its administration.

High doses of levomycetin in newborns, especially premature infants, and occasionally in older children, can cause severe cardiovascular failure known as "gray baby syndrome" (gray collapse syndrome). Its development is based on the accumulation of chloramphenicol in the child's body due to age-related deficiency of the hepatic glucuronoconjugation system (reduced glucuronyl transferase activity) and impaired renal excretion. Symptoms include metabolic acidosis, abdominal distension, vomiting, diarrhea, hypotension, hypothermia, respiratory distress, and gray skin discoloration. Death, resulting from severe hemodynamic disorders, occurs within 24-48 hours in 40-60% of such children. Resuscitation, hemoperfusion, and exchange transfusion are indicated. Hemodialysis is of little efficacy.

Administration of levomycetin provokes The Development of dysbiosis, superinfection, pseudomembranous colitis, and toxic hepatitis.

High doses of the drug can cause psychomotor disorders (confusion, visual and auditory hallucinations). A decrease in visual and auditory acuity, retrobulbar optic neuritis, and peripheral neuritis (limb Muscle weakness, tingling, burning sensation, muscle pain) may be observed.

Uncontrolled use of levomycetin, its prescription for mild infections, and its prophylactic use are unacceptable. In children under 3 years of age, it may be used only for life-saving indications. Levomycetin is contraindicated during Pregnancy and Lactation. Despite lacking teratogenic effects, it is not administered to pregnant women due to the high probability of myelotoxic effects in the fetus and the development of "gray syndrome" in the newborn. Levomycetin is contraindicated in liver and kidney diseases, erythrocyte glucose-6-phosphate dehydrogenase deficiency, and hematopoietic disorders.

Interactions. Some undesirable results of levomycetin interactions with other drugs are presented in Table 33.

Unlike levomycetin, synthomycin is not a levorotatory isomer, but rather the D,L-form (racemate) of threo-1-para-nitrophenyl-2-dichloroacetylamino-1,3-propanediol. Its spectrum of antimicrobial activity is identical to that of levomycetin. The drug is used exclusively topically in the form of liniments and other dosage forms for pustular skin lesions, infected wounds, Burns, ulcers, and similar conditions.

Class="center">Table 33. Interaction of levomycetin with other medicinal products (V.P. Yakovlev, S.V. Yakovlev et al., 2003)