Chapter: Modern Pharmacology with Clinical Applications: Tetracyclines, Chloramphenicol, Macrolides, and Lincosamides

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Chloramphenicol

Chloramphenicol (Chloromycetin) is a nitrobenzene derivative that affects protein synthesis by binding to the 50S ribosomal subunit and preventing peptide bond formation.

CHLORAMPHENICOL

 

 

Mechanism of Action

 

Chloramphenicol (Chloromycetin) is a nitrobenzene derivative that affects protein synthesis by binding to the 50S ribosomal subunit and preventing peptide bond formation. It prevents the attachment of the amino acid end of aminoacyl-tRNA to the A site, hence the associ-ation of peptidyltransferase with the amino acid sub-strate. Resistance due to changes in the ribosome-binding site results in a decreased affinity for the drug, decreased permeability, and plasmids that code for en-zymes that degrade the antibiotic.

 

The drug-induced inhibition of mitochondrial pro-tein synthesis is probably responsible for the associated toxicity.

 

Antibacterial Spectrum

 

Chloramphenicol is a broad-spectrum antibiotic that is effective against gram-positive and gram-negative bac-teria, including Rickettsia, Mycoplasma, and Chlamydia spp. Chloramphenicol is also effective against most anaerobic bacteria, including Bacteroides fragilis.

 

Absorption, Distribution, Metabolism, and Excretion

 

Chloramphenicol is rapidly and completely absorbed from the gastrointestinal tract and is not affected by food ingestion or metal ions. Parenteral administration is generally reserved for situations in which oral therapy is contraindicated, as in the treatment of meningitis and septicemia or when vomiting prohibits oral administra-tion. The biological half-life of chloramphenicol is 1.5 to 3.5 hours. Although up to 60% of the drug is bound to serum albumin, it penetrates the brain and CSF and crosses the placental barrier.

 

Chloramphenicol is inactivated in the liver by glu-curonosyltransferase and is rapidly excreted (80–90% of dose) in the urine. About 5 to 10% of the administered drug is excreted unchanged. Renal elimination is by tu-bular secretion and glomerular filtration. Other degra-dation pathways are known to exist and may account for some of the toxicity seen in neonates and children.

Clinical Uses

 

The potentially fatal nature of chloramphenicol-induced bone marrow suppression restricts its use to a few life-threatening infections in which the benefits out-weigh the risks. There is no justification for its use in treating minor infections.

 

Chloramphenicol is no longer recognized as the treatment of choice for any bacterial infection. In almost all instances, other effective antimicrobial agents are available. Since effective CSF levels are obtained, it used to be a choice for treatment of specific bacterial causes of meningitis: Haemophilus influenzae, Neisseria menin-gitidis, and S. pneumoniae. Additionally, it was effective against H. influenzae–related arthritis, osteomyelitis, and epiglottitis. The development of β-lactamase-producing strains of H. influenzae increased the use of chloram-phenicol. However, with the advent of third-generation cephalosporins such as ceftriaxone and cefotaxime, chlo-ramphenicol use has significantly decreased. If the pa-tient is hypersensitive to β-lactams, chloramphenicol administration is appropriate therapy for meningitis caused by N. meningitidis and S. pneumoniae.

 

Chloramphenicol remains a major treatment of ty-phoid and paratyphoid fever in developing countries. However, with increasing resistance to ampicillin, tri-methoprim-sulfamethoxazole and, to some extent, chlo-ramphenicol, fluoroquinolones and some third-generation cephalosporins (e.g., ceftriaxone) have become the drugs of choice. Salmonella infections, such as osteomyelitis, meningitis and septicemia, have also been indications for chloramphenicol use. Nevertheless, antibiotic resistance patterns can be a problem. As noted previously, nonty-phoidal salmonella enteritis is not benefited by treatment with chloramphenicol or other antibiotics.

 

Chloramphenicol also is widely used for the topical treatment of eye infections. It is a very effective agent because of its extremely broad spectrum of activity and its ability to penetrate ocular tissue. The availability of safer, less irritating instilled ophthalmic antibiotics and the increase in fatal aplastic anemia associated with the use of this dosage form suggest that this agent might best be withdrawn.

 

Chloramphenicol is an alternative to tetracycline for rickettsial diseases, especially in children younger than 8 years, and alone or in combination with other antibi-otics, it has been used to treat vancomycin-resistant en-terococci. Another indication for chloramphenicol is in the treatment of serious anaerobic infections caused by penicillin-resistant bacteria, such as B. fragilis. Clinda-mycin and metronidazole are now preferred for treat-ment of anaerobic infections. Chloramphenicol, in com-bination with surgical drainage, is useful in treating cerebral abscesses caused by anaerobic bacteria, partic-ularly those that are resistant to penicillin.

 

Adverse Effects

 

Newborn infants, especially those born prematurely, cannot adequately conjugate chloramphenicol to form the glucuronide; they also have depressed rates of glomerular and tubular secretion. Because of these metabolic deficiencies, high levels of free chloram-phenicol may accumulate and cause a potentially fatal toxic reaction, the gray baby syndrome. This syndrome is characterized by abdominal distention, vomiting, pro-gressive cyanosis, irregular respiration, hypothermia, and vasomotor collapse. The mortality rate is high. The syndrome also has been observed in older children and is associated with high serum levels of chloramphenicol.

 

The presence of multiple metabolites in the serum of neonates treated with chloramphenicol suggests that the biotransformation of chloramphenicol takes place by multiple routes to include oxidation, reduction, and conjugation. The presence of particular metabolites does not appear to correlate with toxicity.

 

The most publicized adverse affects are those in-volving the hematopoietic system; they are manifested by toxic bone marrow depression or idiosyncratic aplas-tic anemia. The bone marrow depression is dose related and is seen most frequently when daily doses exceed 4 g and plasma concentrations exceed 25  μg/mL. The bone marrow depression is characterized by anemia, sometimes with leukopenia or thrombocytopenia, but it is reversible on discontinuation of chloramphenicol.

 

Aplastic anemia occurs in only about 1 in 24,000 to 40,000 cases of treatment. It is not a dose-related re-sponse and can occur either while the patient is taking chloramphenicol for days to months after completion of therapy. The aplastic or hypoplastic response involves all cellular elements of the marrow and is usually fatal. The mechanism is not known, but it occurs most fre-quently with oral or ocular administration.

 

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