Chloramphenicol

First isolated from Streptomyces venezuelae in 1947, this antibiotic has a very broad spectrum including Gram +ve, Gram -ve and a special use against typhoid. This agent is now produced by total synthesis.

Mechanism of action
It

inhibits protein biosynthesis in both Gram(+) and Gram(-)bacteria. It is a bacteriostatic agent.

Metabolism
Metabolism

is mainly through the formation of the C3-glucuronide metabolite that is the soluble excretable metabolite (Phase 2). The reduction of the nitro compound to the amine, dechlorination and the hydrolysis of the amide bond may also occur (Phase 1). All these metabolites are inactive.

Pharmacokinetic Properties
It

is well absorbed then well distributed to tissues. It shows about 60% protein binding. It has a bitter taste, which can be masked by the use of the palmitate ester at the 3-hydroxyl group in pediatric oral suspensions.

3-Hydroxyl group

Structure Activity Relationship

The

nitro group can be replaced with other electron withdrawing groups but activity declines.

Structure Activity Relationship

Structure Activity Relationship

The

aromatic ring is essential. Replacement of the phenyl group by other aromatic ring lead to loss of activity.

Structure Activity Relationship

Structure Activity Relationship

Removing

the chlorines or replacing them with other halogens reduces activity.

Structure Activity Relationship

 Replacement of

the primary or secondary alcohol by alkyl group decreases activity.

 Extending

the length or branching of the side chain leads to loss of activity.

Toxicity
It

can cause a dose-related bone marrow depression and may precipitate leukemia.

Toxicity
A

very small percent of patients (one in every 25,000 to 40,000 cases of therapy) may develop aplastic anemia and results from loss of both white and red cells precursors.

Aplastic anemia

 Heme

: C34H32O4N4FeOH

Toxicity
In

the newly born if this agent is given within the first 48 hours of life, Gray syndrome may arise due to the inability of formation of the 3glucuronide metabolite, resulting in toxic levels of the drug, and cyanosis resulting in cardiovascular collapse and death.

Resistance
Enzymes

that cause acetylation of the hydroxyl groups (especially the secondary alcohol), resulting in a decreased ability of binding to the ribosomes.

Acetylation of the secondary Alcohol