CHLORAMPHENICOL

Chapter 4: CHLORAMPHENICOL


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I. History

Chloramphenicol was first isolated in 1948 from Streptomyces venezuela, derived from a soil sample (collected in Venezuela) and used later that year against an outbreak of epidemic typhus in Bolivia with great success. Filtrates of liquid cultures of the organism exhibited marked effectiveness against several gram-negative bacteria.; Pure crystalline antibiotic substance was isolated in 1948 and named"chloromycetin". After having determined its structural formula, it was prepared synthetically and by 1948 was made available in amounts sufficient for general therapy of a variety of infections. However, by 1950 it became known that the drug could cause serious and fatal human blood dyscrasias.; Furthermore, the availability of "ampicillin," which provided broad spectrum coverage without major toxicity, contributed to the subsequent decline in the use of chloramphenicol.

II. Chemistry

A. Structure(Fig. 6)

B. Chemical Characteristics

1. The levorotatory form is biologicaly active.

2. It is a white crystalline heat stable material with a bitter task.

3. It is slightly soluble in water. Dissolves in organic solvents such as propylene glycol and dimethylacetamide.

4. Esters of palmitate and succinate of chloramphenicol have been synthesized for IM, IV an subcutaneous injection. The Palmitate ester is tasteless and water soluble. It can be given orally to small animals such as cats.

III. Mechanism of Action

A. Chloramphenicol inhibits protein synthesis in bacteria and in cell-free systems.; It acts primarily on the 50s ribosomal subunit and suppresses the activity of peptidyl transferase, an enzyme that catalyzes peptide bond formation.

IV. Absorption

A. Readily absorbed from the gastrointestinal tract.

B. The oral route of administration provides better blood levels than the IM or subcautaneous route. Ruminants are an exception. Chloramphenicol is destroyed by the rumen microflora.

V. Biotransformation

A. It is metabolized mainly by the liver; 1. Reduction of the nitro group.; 2. Hydrolysis of the acetamide bond; 3. Glucuronide conjugation: New born animals and cats are deficient in this metabolizing enzyme. Therefore, dosage must be adjusted accordingly.

VI. Excretion

A. Chloramphenicol and its metabolites are rapidly excreted in the urine and feces.; B. 80 - 90% of an orally administered dose is excreted in the feces. 5-10% of the active form is excreted in the urine.

VII. Antibactrial Spectrum

A. A broad spectrum antibiotic. It is bacteriostatic.

1. Broad-spectrum of antibacterial activity effective against a variety of infective pathogens including Staphylococci, Salmonellae, Pasteurella, Bordetella, Haemophilus, Listeria, Mycoplasma, Leptospira, E. coli, coliform organisms, and rickettsia, many of which may be resistant to other antimicrobial agents.

2. Kinetic properties allow for the acheivement and maintenance of effective therapeutic concentrations in body fluids (such as CSF) and tissues, with a practicable dosage schedule in most species.

VIII. Distribution

A. Sixty percent of plasma chloramphenicol is bound to plasma proteins.

B. Chloramphenicol is unevenly distributed to all body tissues and fluids.

IX. Toxicity

A. Depression and anorexia

B. Bone marrow depression and anemia. (Seen mainly in humans.)

C. Interference with antibody formation.

D. Prolongation of anesthesia.

E. Blocks neuromuscular responses.

F. Hypersensitivity reactions.

G. Blood dyscrasia.

H. Depression of microsomal enzymes.

X. Clinical Uses

Although high doses of chloramphenicol, for several weeks may cause inappetence and severe depression and suppresion of hematopoiesis, the drug has not been proven to be toxic in animals. These signs are readily reversible in humans when the drug is withdrawn. A proper therapeutic regimen for a week or two can usually be provided without adverse reactions. The drug can be given to almost any species of animals, but it is most toxic in cats. In the U.S., the FDA has not approved the use of chloramphenicol in food animals.; A. Gastrointestinal infections; Chloramphenicol is most often the preferred drug against resistant Salmonella and E. coli infections of G.I. tract of such animals as cattle, swine, horse and cat.; B. CNS infections; Chloramphenicol is a valuable antibiotic for the treatment of susceptible infections of the CNS. There are many antibiotics such as ampicillin that are capable of attaining high CSF concentrations, but chloramphenicol ranks second only to sulfanilamide in its ability to diffuse into the CSF.; C. Urinary Tract Infections; There is some misconception about using chloramphenicol for urinary tracinfections that is based largely on the fact that most chloramphenicol (80-90%) is excreted in urine in an inactive form. However, whatever active portion (10-20%) of the drug is excreted via urinary tract seems to produce an effective therapeutic effect. It is considered to be a useful antibiotic for the treatment of susceptible urinary tract infections, especially in patients with subnormal renal functions.; D. Ophthalmic Infections; Many clinicians consider chloramphenicol to be the drug of choice for various ocular infections. It is effective because it penetrates ocular tissues very well and can be administered parenterally, topically, orally or by direct injection into the aqueous or vitreous humor or subconjunctivally. The admininstration of 1% chloramphenicol opthalmic ointments directly on the eye is of value and is ideal for treatment of conjunctivitis.; E. Skin Infections; Chloramphenicol has been reported to be effective against foot rot and Dermatophilus infection.