Chloramphenicol is a nearly perfect antibacterial with one major flaw -- the production of aplastic anemia and other blood dyscrasias in a small percentage of patients treated. This bacteriostatic antibiotic is effective in a wide range of infectious diseases and distributes uniformly throughout the body. The FDA-CVM specifically disallows its use in food producing animals.
Structure and chemical characteristics
Originally isolated from Streptomyces venezuelae, chloramphenicol is now made synthetically. As shown in the accompanying figure, it contains a nitrobenzene ring, an amide bond, and an alcohol function. The presence of chlorides in biologically produced organic molecules is unusual. The nitrobenzene is relevant because it leads to the formation of aromatic amines which may be carcinogenic. The amide is hydrolyzed by some resistant bacteria leading to inactivation. The alcohol serves as a functional group facilitating the formation of esters that improve chloramphenicol's water solubility. Chloramphenicol base has low water solubility and high lipid (in organic alcohols) solubility. Its palmitate ester is similar, but the succinate ester has high water solubility.
Relatives of chloramphenicol have been developed, e.g., thiamphenicol, but have not received widespread application in the U.S.
Mechanism of action
Chloramphenicol binds reversibly with the large ribosomal subunit of bacteria and eukaryotes. The bacterial ribosome (and eukaryotic mitochondrial ribosome) is more sensitive, but protein synthesis is also decreased in patients receiving the drug as the concentration rises. It binds to the peptidyl transferase enzyme to inhibit transfer of the growing polypeptide to the next amino acid occupying the "Acceptor" site. The presence of chloramphenicol at this site may interfere with binding of lincosamides (e.g., clindamycin) and macrolides (e.g., erythromycin) which bind at or near the same site. This writer fails to see that this is an important problem because all are static in any case so overall inhibition of activity should not be a problem. However, it does point to the fact that one may be wasting drug and increasing the possibility of drug reactions by using a combination of these three drugs.
Except for rickettsial organisms, resistance to chloramphenicol is increasing. Resistance is due to deactivation of the drug by acetylation of the hydroxyl group, amidase hydrolysis of the amide group, or reduction of the nitro group. Enzymes coding for these reactions are normally found in some organisms rending them uniformly resistant. Normally sensitive organisms can become resistant through mutation (a slow, gradual process) or by transfer of resistance. Plasmids coding for acetyltransferase may be transferred by transduction. Plasmids exist that code for multiple drug resistance, e.g., to chloramphenicol, tetracycline, and streptomycin. In the absence of a plasmid, resistance develops slowly.
Selection pressure increases the frequency of plasmids coding for resistance. In pigs fed 20 ppm of chloramphenicol for some time, sensitive coliforms were replaced by resistant ones.
Chloramphenicol dose forms exist for oral, parenteral, and topical therapy (ophthalmic only). Because of the potential for development of hypersensitivity, chloramphenicol should be used in topical applications sparingly, paying special attention to protecting the person administering the drug.
Free chloramphenicol is rapidly absorbed after IV and PO administration, but is slowly absorbed from IM sites. Chloramphenicol is available in tablets, but because of chloramphenicol's poor water solubility, dissolution (and hence bioavailability) is not uniform. Tablets should be from reputable manufacturers with good quality control. Intramuscular injections of chloramphenicol are not recommended.
Chloramphenicol palmitate, prepared as a suspension, is intended for oral administration. The ester is hydrolyzed by lipases in the small intestine prior to absorption of the chloramphenicol. The palmitate ester is inactive. Bioavailability of this form is high and consistent.
Chloramphenicol succinate is a water soluble dose form intended for intravenous administration. This ester must be hydrolyzed to release active chloramphenicol. Hydrolysis occurs in plasma, liver, lungs, and kidneys. IM injection is not recommended because absorption and hydrolysis are inconsistent and incomplete.
Chloramphenicol should not be given orally to ruminating animals because it is almost completely inactivated by rumen bacteria. Chloramphenicol is inappropriate for use in animals intended for food because of potential health hazards to consumers. Chloramphenicol residues in food would be readily absorbed by the consumer and could lead to sensitization.
Chloramphenicol is ideally distributed throughout the body. CSF levels are 21-50% of those in plasma, but in the presence of inflammation, this may reach 89%. Liver (and bile), kidney (and urine), milk, and placentae all have high concentrations. Therapeutic concentrations are even reached in the eye.
Volume of distribution varies with species. For humans and horses it is approximately 1 L/kg. For the cat, values as high as 2.36 L/kg have been reported, but there is no obvious reason why it should be so high. Perhaps procedural problems in making the estimation led to an error. Protein binding is in the middle range, 25-60% in humans.
Chloramphenicol is eliminated primarily by biotransformation. In humans, as much as 90% is eliminated as the chloramphenicol glucuronide conjugate. The majority of the remaining 10% is eliminated in the kidney by glomerular filtration. This is sufficient to produce therapeutic concentrations in the urine. In other species, e.g., dog and rat, urinary elimination is still dominant, but increased amounts are elimination in bile as aromatic amines. Even in humans, as much as 10% may be eliminated unchanged in the bile, but much of this is reabsorbed and ultimately eliminated via the urine.
The glucuronide conjugate is formed by glucuronyl transferase in the liver. Conditions associated with decreased liver function may slow elimination and must be taken into account during therapy. Approximately 80% of the conjugated chloramphenicol is eliminated in the urine by active tubular secretion. Both hepatic biotransformation to form the conjugate and active transport in the kidney are poorly developed in neonates. As a result, chloramphenicol and its metabolites may accumulate to toxic concentrations if adult dose regimens are used. Gray baby syndrome is the shock-like condition produced by this accumulation.
Serum half-life of chloramphenicol varies from 0.9 hours in the horse to 5.1 hours in cats. In humans, the range is from 1.5 to 3.5 hours. As expected, anuria in humans has little impact on elimination, increasing it only to 3 to 4 hours.
Most adverse effects of chloramphenicol are easily handled, but the idiosyncratic blood dyscrasias which they cause place this drug in a special, reserved category.
Superinfection with resistant organisms is to be expected with this as with any broad spectrum drug.
Anorexia has been observed in dolphins, whales, and California sea lions after one to two days of treatment with chloraphenicol. Drug is administered by injecting it into fish used for food. A former student related that workers at the Mystic, CT aquarium have observed that it is very difficult to get the animals eating again. This is listed among the biological effects, because the author believes that a direct effect would be more rapidly reversed. The problem may well stem from alteration of intestinal flora, but there is no evidence to support this contention.
Hypersensitivity is not regarded as an important problem, although it does occur. Although the idiosyncratic blood dyscrasias may have an element of hypersensitivity as a cause, it is not currently thought to be the primary mechanism.
Reversible, dose-related anemia
A dose-related anemia is readily produced with chloramphenicol. In humans, the incidence of normocytic bone marrow depression increases as plasma chloramphenicol concentration increases beyond 25 mcg/ml (Soldin et.al.). Chloramphenicol given IV at doses of 15 mg/kg will produce plasma concentrations of 10 to 25 ug/ml. Usual therapeutic doses are in the range of 12.5 to 25 mg/kg q6h so one can see that the risk is real. This condition is more likely to occur if therapy is continued for 2 weeks or more.
Dogs have tolerated as much as 50 mg/kg q6h with no problem, but cats are more sensitive. A dose of 50 mg/kg, IM, q12h for 7 days has produced severe anorexia, depression, leucopenia, and bone marrow changes. Note the difference in dose interval between dog and cat.
Idiosyncratic blood dyscrasias
Idiosyncratic blood dyscrasias represent a major liability for chloramphenicol. These are defined as a diseased state of blood, usually referring to abnormal cellular elements of more or less permanent nature. It is this permanence and high probability of death that demands attention.
In humans, epidemiologic studies indicate that 1:11,000 to 1:40,000 patients receiving chloramphenicol will develop aplastic anemia. This is usually fatal in severe cases. It is estimated that 1:30,000 patients will develop leucopenia. Patients who recover from these conditions have an unusually high incidence of leukemia.
Conditions leading to this dyscrasia are not well understood, but twins show similar tendencies toward it indicating a genetic link. Multiple exposures and long exposures are also associated with increased incidence.
Teratogenic effects have been observed. Obviously this drug should be avoided in pregnant patients.
Gray Baby Syndrome
Gray baby syndrome is a condition of cardiovascular collapse that may occur in human infants less than one month old when they are overdosed with chloramphenicol. Signs may occur by day 2 of therapy on which the patient may vomit, refuse to nurse, and have irregular and rapid respiration. Abdominal distentions, cyanosis, and loose green stool may also be seen. By the second day, babies may be flaccid and ashen-gray in color. Up to 40% die by the 5th day. The condition is associated with serum concentrations greater than 40 mcg/ml (Soldin et al.). The problem is caused by lack of development of hepatic conjugating systems and renal transport systems leading to accumulation of chloramphenicol and its metabolites. When dose and schedule are properly adjusted for true elimination rate in the neonates, this toxicity does not occur. Although one might expect that such incidents do not occur nowadays, a case was reported in South Bend, IN in the middle 1980s. (Medical student report from personal knowledge).
Similar syndromes can be expected in animals because the drug metabolizing and renal secretory systems are not completely developed at birth. There is, however, species variation in the rate of maturation so the problem is greater in some species than others.
Drug interaction problems involving chloramphenicol stem from two basic properties. First, is the fact that therapeutic doses of chloramphenicol can depress hepatic biotransformation of other drugs. Second, is the problem of combining a bacteriostatic drug with cidal drugs. In the section on principles, it was stated that in most cases, it was difficult to see clinical evidence of antagonism when groups I and II drugs were combined. Patients with inadequate immune systems were the exception.
Combinations of chloramphenicol and ampicillin may lead to more treatment failures in the treatment of meningitis than using ampicillin alone. In some studies, patients who received the combination had poorer survival rates than those who received ampicillin. Feldman & Sweighaft (1979) found that ampicillin and chloramphenicol were antagonistic when tested against 13 of 21 strains of N. meningitidis\i and one of 21 strains of Streptococcus pneumoniae.
Conversely, it has been recommended that a combination of chloramphenicol and ampicillin be used until culture results are available when Haemophilus influenzae is the predicted pathogen because up to 15% of these are resistant to ampicillin (Kagan3rd). Feldman (1978) observed synergy between chloramphenicol and ampicillin in 6 of 13 ampicillin-sensitive strains and 5 of 8 ampicillin-resistant strains. In the absence of synergy, there was an additive effect. No antagonism was observed.
Chloramphenicol is not active against protozoans in contrast to the tetracyclines.
Chloramphenicol is universally active against anaerobic bacteria, rickettsiae, chlamydia, and mycoplasma. Note the extensive overlap with tetracyclines which would be preferred therapy when active, because of their lower toxicity.
Highly susceptible organisms have MICs in the range of 4 mcg/ml and those with MICs in the range of 16 mcg/ml are regarded as moderately sensitive. Using these criteria, a wide variety of bacteria are sensitive. Chloramphenicol may be preferred for many CNS infections and Bacteroides fragilis. It is second to the beta-lactams for other anaerobes. Most pseudomonads and enterobateriaceae are resistant.
Because of public health considerations, chloramphenicol should not be used in food producing animals.
- Feldman,W.E. 1978. Effect of ampicillin and chloramphenicol against Haemophilus influenzae. Pediatrics 61:406-9.
- Feldman, W.E., and T. Sweighaft. 1979. Effect of ampicillin and chloramphenicol against Streptococcus pneumoniae and Neisseria meningitidis. Antimicrobial Agents and Chemotherapy 15:240-2.
- KAGAN3rd. Chapter 10, pp 127-136.
- Sisodia, Chatur. 1980. Pharmacotherapeutics of chloramphenicol in veterinary medicine. JAVMA 176(10, part 2):1069-1071.
- Soldin, S.J., et.al., The high performance liquid chromatographic measurement of chloramphenicol and its succinate esters in serum. Journal?, Vol?, pp. 171-177, Yr?,
- Note the low water solubilitiy of chloramphenicol base and it high lipid solubility. Given that protein binding is moderate (meaning not much of a factor), predict its bioavailability after oral administration (assuming not biotransformation) and the relation between its plasma and intracellular concentrations (CSF, too).
- Why must chloramphenicol not be used in food producing animals.
- How does the antimicrobial (vs antibacterial, hint) spectrum of chloramphenicol differ from that of the tetracyclines?
- How does the mechanism of action of chloramphenicol compare to that of the aminoglycosides and beta-lactams? What two groups of antimicrobials bind to the same ribosomal subunit as chloramphenicol?
- What is the major route of elimination of chloramphenicol? How do poor renal function and poorly developed biotransforming enzymes and elimination\lr<120> systems affect chloramphenicol toxicity? Name a condition in neonates that stems from these deficiencies and failure to properly adjust dosage.
- What are the major adverse effects of chloramphenicol? How do these compare with respect to predictability and correlation with plasma drug concentration?