Chloramphenicol

Pharmacological properties

chloramphenicol-chloramphenicol is a broad-spectrum bacteriostatic antibiotic. the effect is associated with a violation of the process of protein synthesis in a microbial cell at the stage of transfer of amino acids of tRNA to ribosomes. effective against many gram-positive and gram-negative bacteria: escherichia coli, shigella flexneri spp., shigella boydii spp., shigella sonnei spp., salmonella spp. (including salmonella typhi), acts on streptococcus spp. (including streptococcus pneumoniae), neisseria gonorrhoeae, neisseria meningitidis, a number of strains of proteus spp., some strains of pseudomonas aeruginosa; active against ricketsia spp., treponema spp., chlamydia spp. (including chlamydia trachomatis), pathogens of purulent infections, typhoid fever, dysentery, meningococcal infection, brucella, rickettsia, chlamydia, spirochete. does not affect mycobacterium tuberculosis, pathogenic protozoa and fungi. active against strains of bacteria resistant to penicillin, tetracyclines, sulfonamides. microorganism resistance develops slowly. the drug is inactive against acid-resistant bacteria, Pseudomonas aeruginosa, clostridia and protozoa.

The mechanism of action is due to inhibition of protein synthesis in the cells of microorganisms. At therapeutic concentrations it has a bacteriostatic effect. The resistance of microorganisms to the drug develops slowly and, as a rule, there is no cross-resistance to other chemotherapeutic agents. Due to its high toxicity, chloramphenicol is used to treat severe infections in which less toxic antibacterial agents are ineffective or contraindicated.

Pharmacokinetics Quickly and almost completely absorbed in the digestive tract. C_max in plasma is reached after 2-3 hours. The therapeutic concentration in the blood remains for 4-5 hours. Bioavailability after oral administration is 80%. It penetrates well into organs, tissues and body fluids, penetrates through the BBB, the placenta, into breast milk. 50-60% chloramphenicol binds to plasma proteins. The highest concentrations of chloramphenicol are determined in the liver and kidneys. In bile, up to 30% of the administered dose of chloramphenicol is observed. It penetrates well through the BBB: C_max in cerebrospinal fluid is achieved after 4-5 hours after a single oral administration. It is metabolized in the liver, 90% binds to inactive glucuronide. Chloramphenicol palmitate is hydrolyzed to a free state in the digestive system before absorption. Chloramphenicol sodium succinate is hydrolyzed to a free state in blood plasma, liver, lungs and kidneys. In the fetus and premature babies, the liver is not sufficiently developed to bind chloramphenicol, which leads to the accumulation of a toxic concentration of the active form of the drug and can lead to the development of gray syndrome. In the intestine under the action of intestinal bacteria, hydrolysis of chloramphenicol occurs with the formation of inactive metabolites.

It is excreted mainly with urine (mainly in the form of inactive metabolites), partially with bile (up to 30% of the dose) and feces.

T_½ in adults with normal renal and hepatic function, it is 1.5–3.5 hours, with impaired renal function - 3-4 hours, with severe impairment of liver function - 4.6–11 hours.

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to the drug: typhoid fever, paratyphoid fever, yersiniosis, brucellosis, shigellosis, salmonellosis, tularemia, rickettsiosis, chlamydia, purulent peritonitis, bacterial meningitis, biliary tract infections.

The drug is indicated for the ineffectiveness of other antimicrobials, given the possibility of developing pronounced side effects.

Application

Apply orally 30 minutes before meals; in case of nausea, vomiting - 1 hour after eating.

The dosage regimen should be set individually depending on the severity of the disease and the condition of the patient.

Adults use 250-500 mg 3-4 times a day. The daily dose is 2000 mg. In severe cases, the drug can be used orally at a dose of up to 4000 mg / day (maximum daily dose) under strict control of the blood condition and liver and kidney function. Distribute the daily dose into 3-4 doses.

For children aged 3–8 years, a single dose of 125 mg should be prescribed, for children over the age of 8 years — 250 mg. The frequency of administration is 3-4 times a day.

The course of treatment is 7-10 days. According to indications, subject to good tolerance and the absence of changes in the composition of peripheral blood, it is possible to prolong the course of treatment up to 2 weeks.

Contraindications

Hypersensitivity (allergy) to chloramphenicol, other amphenicol and / or other components of the drug. blood diseases, including inhibition of blood formation. severe impaired liver and / or kidney function. deficiency of the enzyme glucose-6-phosphate dehydrogenase. skin diseases (psoriasis, eczema, fungal diseases). porphyria. Levomycetin-darnitsa should not be prescribed for acute respiratory infections, tonsillitis, as well as for the prevention of bacterial infections.

Side effects

The most serious adverse reactions are aplastic anemia, inhibition of bone marrow function and gray syndrome.

It is also possible the development of adverse reactions from the following organs and systems.

From the nervous system and psyche: psychomotor disorders, moderate depression, confusion, headache, encephalopathy, delirium. Long-term use of high doses of the drug can lead to impaired taste, decreased hearing and visual acuity, the development of visual and auditory hallucinations, optical and peripheral neuritis (including paralysis of eyeballs). If these symptoms occur, discontinue use of the drug immediately.

From the digestive tract: dyspepsia, bloating, nausea, vomiting (the likelihood of developing when used within 1 hour after eating), diarrhea, irritation of the oral mucosa and throat, inhibition of intestinal microflora, dysbiosis, enterocolitis, stomatitis, glossitis.

From the hepatobiliary system: impaired liver function.

On the part of the blood system and lymphatic system: bone marrow depression, reticulocytopenia, decreased hemoglobin in the blood, anemia, leukopenia, granulocytopenia, thrombocytopenia, erythrocytopenia, pancytopenia, rarely - aplastic anemia, hypoplastic anemia, agranulocytosis, cytoplasia, and

On the part of the skin, subcutaneous tissue and immune system: allergic reactions, including those in the form of fever, skin rash, dermatosis; anaphylaxis reactions, including urticaria, angioedema, facial edema, Quincke edema, pruritus, hyperemia.

Others: it is possible to develop superinfection, including fungal, dermatitis (including perianal dermatitis), hyperthermia, collapse (in children).

There have been reports of the development of Yarish-Herxheimer reactions (bacteriolysis reaction) during the treatment of typhoid fever (more concerned with parenteral forms of chloramphenicol).

special instructions

Given the possibility of developing severe lesions of the blood forming organs as a result of the toxic effect of the drug, the composition of peripheral blood should be monitored during treatment and the state of the liver and kidneys should be monitored.

If leukopenia, thrombocytopenia, anemia, or other pathological changes in the blood appear, the drug should be immediately discontinued. Although constant monitoring of peripheral blood composition during treatment with chloramphenicol can reveal early changes in the blood system (leukopenia, reticulocytopenia, or granulocytopenia) before they become irreversible, this does not exclude the possibility of aplastic anemia due to the development of bone marrow depression. Aplastic anemia, thrombocytopenia and granulocytopenia usually occur after treatment is completed. Therefore, symptoms such as pallor of the skin, sore throat and fever, unusual bleeding, weakness (if they appear a few weeks or months after discontinuation of the drug) require emergency care.

In patients previously treated with cytotoxic drugs or using radiation therapy, the potential risks and expected benefits of treatment should be compared, given the possibility of developing serious side effects.

Treatment with antibacterial drugs leads to disruption of the normal flora of the large intestine and can lead to excessive growth of Clostridium difficile, the toxins of which are the main cause of pseudomembranous colitis. Pseudomembranous colitis occurs both directly during the use of the drug, and within 2 months after completion of antibiotic therapy. Cases of pseudomembranous colitis from mild to life-threatening have been reported with nearly all antibacterial drugs, including chloramphenicol. Therefore, it is important to clarify the diagnosis in patients with diarrhea after using antibacterial drugs. In the absence of the necessary treatment, toxic megacolon, peritonitis, shock can develop. It should be borne in mind that the development of colitis is most likely in severe diseases in elderly patients, as well as in debilitated patients.

The use of antibacterial drugs can lead to excessive growth of insensitive microorganisms, in particular fungi. If in the course of treatment infections develop caused by insensitive microorganisms, appropriate measures must be taken.

In patients with impaired liver or kidney function, an increase in the level of chloramphenicol in the blood plasma is possible, and the risk of toxic reactions to this drug may be higher, so the dose should be adjusted accordingly. It is advisable to periodically determine the concentration of the drug in the blood, checking the functions of the liver and kidneys.

Clinical experience did not reveal differences in responses to chloramphenicol treatment between patients of different age categories. However, taking into account the age-related features of the function of the kidneys, liver, cardiovascular system, the presence of concomitant diseases, the use of other drugs, it is necessary to determine the dose of the drug for elderly patients carefully, starting, as a rule, from the lower limit of the dosage range.

Levomycetin-Darnitsa should be prescribed with caution to patients with a tendency to allergic reactions.

The simultaneous use of ethanol leads to the development of a disulfiram-like reaction (skin hyperemia, tachycardia, nausea, vomiting, reflex cough, convulsions).

Uncontrolled administration of the drug and its use in mild forms of infectious processes, in acute respiratory diseases, or as a prophylactic to prevent bacterial infections, especially in pediatric practice, is unacceptable.

The appointment of chloramphenicol can provoke acute attacks of porphyria. The drug is dangerous for use in patients with porphyria.

Chloramphenicol can affect the development of the immune response; it cannot be prescribed during active immunization.

Repeated courses of treatment with chloramphenicol should be avoided, treatment should not last longer than necessary to obtain positive results without the risk of complications or relapse of the disease.

Use with caution in cardiovascular diseases.

Use during pregnancy and lactation. The use of chloramphenicol is contraindicated during pregnancy. During treatment, breast-feeding should be discontinued.

Children. Use in children over the age of 3 years. For the treatment of children over the age of 3 years, the drug should be prescribed with caution and only in the absence of alternative therapy.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Until the patients individual reaction to the drug is clarified, one should refrain from driving vehicles or other mechanisms, given that during the treatment with chloramphenicol, disorders of the nervous system can be observed.

Interactions

Long-term use of chloramphenicol, which is an inhibitor of liver enzymes, in the preoperative period or during surgery can reduce clearance and increase the duration of action of alfentanil.

Chloramphenicol suppresses the enzyme system of cytochrome P450, therefore, while its use with antiepileptic drugs (phenobarbital, phenytoin), indirect anticoagulants (dicumarin, warfarin), a weakening of the metabolism of these drugs, a slowdown in excretion, an increase in their plasma concentration and toxicity are noted.

Oral hypoglycemic drugs (chlorpropamide, tolbutamide). When used with chloramphenicol, an increase in the effect of oral antidiabetic drugs is noted (due to the suppression of metabolism in the liver and an increase in their concentration in blood plasma), which requires dose adjustment.

Phenobarbital, rifampicin, rifabutin reduce the concentration of chloramphenicol in blood plasma by accelerating its metabolism in the liver.

With simultaneous use with paracetamol, an elongation of T may be observed_½ chloramphenicol.

Phenytoin. With simultaneous use, both a decrease and an increase in the concentration of chloramphenicol in the blood plasma are possible.

Cyclosporine - with simultaneous use with chloramphenicol, an increase in the level of cyclosporin in blood plasma is possible. With the simultaneous use of these drugs, it is necessary to monitor the concentration of cyclosporine.

Cyclophosphamide - simultaneous use prolongs T_½ cyclophosphamide from 7.5 to 11.5 hours

Tacrolimus - with simultaneous use with chloramphenicol, they may increase the level of tacrolimus in blood plasma. With simultaneous use, the dose of tacrolimus must be adjusted.

Chloramphenicol reduces the antibacterial effect of penicillins and cephalosporins.

Macrolides (erythromycin, oleandomycin, clindamycin), lincosamides (lincomycin), polyene antibiotics (nystatin, levorin) - with the simultaneous use of chloramphenicol with these drugs, there is a mutual weakening of the action due to the fact that chloramphenicol can displace these drugs from a bound state or prevent them with the 50S subunit of bacterial ribosomes. Therefore, their simultaneous use should be avoided.

Cycloserine - simultaneous use enhances the neurotoxicity of chloramphenicol.

Medicines that suppress hematopoiesis (sulfonamides, cytostatics, cimetidine, ristomycin), radiation therapy - simultaneous use can increase the risk of inhibition of bone marrow function and the severity of its manifestations. Therefore, their simultaneous use should be avoided.

Estrogen-containing oral contraceptives - prolonged simultaneous use can lead to a decrease in the reliability of contraception and an increase in the frequency of breakthrough bleeding.

Preparations of iron, folic acid, cyanocobalamin - chloramphenicol can reduce the effectiveness of these drugs.

Ethanol - with the simultaneous use of ethanol, it is possible to develop a disulfiram-like reaction (hyperemia of the skin, tachycardia, nausea, vomiting, reflex cough, convulsions).

Overdose

Severe complications from the hematopoietic system, as a rule, are associated with the use of the drug for a long time in high doses (more than 3 g / day) - pale skin, sore throat and fever, bleeding and hemorrhage, fatigue or weakness.

Overdose symptoms: gray syndrome (cardiovascular syndrome in young children), with relative overdose (the cause of development is the accumulation of chloramphenicol, due to the immaturity of liver enzymes, and its direct toxic effect on the myocardium) - a bluish-gray skin color, decreased body temperature, irregular breathing , decrease in nervous reactions, cardiovascular failure, circulatory collapse, acidosis, inhibition of myocardial conduction, coma and death. Gray syndrome can also develop in patients with impaired liver and kidney function and is a consequence of the cumulation of the drug. Gray syndrome occurs when the concentration of chloramphenicol in blood plasma is 50 μg / ml.

Treatment: drug withdrawal and symptomatic therapy, gastric lavage, saline laxative, activated charcoal, high cleansing enema. In severe cases - symptomatic therapy, hemosorption.

Storage conditions

In the original packaging at a temperature not exceeding 25 ° C.