Chloramphenicol is an inhibitor of microbial protein synthesis and is bacteriostatic against most susceptible organisms. It binds reversibly to the 50S subunit of the bacterial ribosome (Figure 44–1) and inhibits peptide bond formation (step 2). Chloramphenicol is a broad-spectrum antibiotic that is active against both aerobic and anaerobic Gram-positive and Gram-negative organisms. It is active also against rickettsiae but not chlamydiae. Most Gram-positive bacteria are inhibited at concentrations of 1–10 mcg/mL, and many Gram-negative bacteria are inhibited by concentrations of 0.2–5 mcg/mL. H influenzae, Neisseria meningitidis, and some strains of Bacteroides are highly susceptible; for these organisms, chloramphenicol may be bactericidal.
Low-level resistance to chloramphenicol may emerge from large populations of chloramphenicol-susceptible cells by selection of mutants that are less permeable to the drug. Clinically significant resistance is due to production of chloramphenicol acetyltransferase, a plasmid-encoded enzyme that inactivates the drug.
The usual dosage of chloramphenicol is 50–100 mg/kg/d divided every 6 hours. It is no longer available in the USA as an oral formulation. The parenteral formulation is a prodrug, chloramphenicol succinate, which is hydrolyzed to yield free chloramphenicol, giving blood levels somewhat lower than those achieved with orally administered drug. Chloramphenicol is widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid, such that the concentration of chloramphenicol in brain tissue may be equal to that in serum. The drug penetrates cell membranes readily.
Most of the drug is inactivated either by conjugation with glucuronic acid (principally in the liver) or by reduction to inactive aryl amines. Active chloramphenicol, about 10% of the total dose administered, and its inactive degradation products are eliminated in the urine. A small amount of active drug is excreted into bile and feces. There are no specific dosage adjustments recommended in renal or hepatic insufficiency; however, the drug will accumulate and should be used with extra caution in these situations.
Newborns less than a week old and premature infants also clear chloramphenicol less well, and the dosage should be reduced to 25 mg/kg/d.
Because of potential toxicity, bacterial resistance, and the availability of many other effective alternatives, chloramphenicol is rarely used in the United States. It may be considered for treatment of serious rickettsial infections such as typhus and Rocky Mountain spotted fever. It is an alternative to a β-lactam antibiotic for treatment of bacterial meningitis occurring in patients who have major hypersensitivity reactions to penicillin.
Adults occasionally develop gastrointestinal disturbances, including nausea, vomiting, and diarrhea. These symptoms are rare in children. Oral or vaginal candidiasis may occur as a result of alteration of normal microbial flora.
Chloramphenicol commonly causes a dose-related reversible suppression of red cell production at dosages exceeding 50 mg/kg/d after 1–2 weeks. Aplastic anemia, a rare consequence (1 in 24,000 to 40,000 courses of therapy) of chloramphenicol administration by any route, is an idiosyncratic reaction unrelated to dose, although it occurs more frequently with prolonged use. Aplastic anemia tends to be irreversible and can be fatal, although it may respond to bone marrow transplantation or immunosuppressive therapy. Due to the severity of this reaction, a boxed warning has been added to its U.S. labeling.