CHLORAMPHENICOL
General Monograph,
Antibiotic
Pharmacology: Chloramphenicol, which was originally isolated from Streptomyces venezuelae and is now synthetically produced, exerts mainly a bacteriostatic effect on a wide range of gram-positive and gram-negative organisms and is active against Rickettsia, Chlamydia (psittacosis-lymphogranuloma organisms), and Mycoplasma. It is particularly effective against H. influenzae, S. pneumoniae, S. typhi and Neisseria species. The palmitate and sodium succinate esters are inactive until hydrolyzed to free chloramphenicol which occurs rapidly in vivo. The mechanism of action of chloramphenicol is through inhibition of protein synthesis by binding to the 50S ribosomal subunit. There is some evidence that chloramphenicol inhibits protein synthesis in rapidly proliferating mammalian cells which may be the cause of reversible bone marrow depression. Both natural and acquired resistance to chloramphenicol has been seen in strains of P. aeruginosa, Staphyloccus, and Enterobacteriacea particularly Shigella, Salmonella, and Escherichia. The type of resistance exhibited by gram-negative organisms involves acetylation of chloramphenicol, which is a plasmid-mediated trait.
Pharmacokinetics: Chloramphenicol palmitate is hydrolyzed in the gastrointestinal tract and rapidly absorbed as free chloramphenicol. The peak serum level after an oral dose of chloramphenicol occurs in 1 to 3 hours. Chloramphenicol sodium succinate is hydrolyzed to free chloramphenicol following i.v. administration, presumably by esterases in the liver, kidneys and lungs. The rate and extent of hydrolysis and renal elimination of the succinate ester are subject to a high degree of interindividual variation.
Chloramphenicol is approximately 60% bound to serum proteins and is widely distributed in the body. CSF concentrations range from 21 to 50% of serum concentrations with uninflamed meninges and 45 to 89% of serum concentrations with inflamed meninges. The drug crosses the placenta and is distributed into breast milk.
Chloramphenicol is metabolized in the liver, mainly by conjugation with glucuronic acid; only about 5 to 15% of an oral dose is excreted unchanged in the urine. The half-life of chloramphenicol is 1.5 to 4 hours in adults with normal renal and hepatic function. The plasma half-life is increased in patients with markedly reduced hepatic function. In patients with impaired renal function, the half-life of chloramphenicol itself is not significantly altered although the half-life of the inactive metabolites may be prolonged. Following i.v. administration, patients with renal impairment may achieve higher chloramphenicol concentrations due to decreased renal excretion of the succinate ester.
Since the processes for glucuronide conjugation and renal excretion in neonates may be immature, the half-life of the drug in neonates less than 3 days old may be in excess of 24 hours and about 10 hours for infants 10 to 16 days old. In these cases the dosage and administration interval should be adjusted using measured serum concentrations.
Plasma concentrations of chloramphenicol are not affected by peritoneal dialysis and only small amounts of the drug are removed by hemodialysis.
Indications: The use of chloramphenicol should be reserved for the treatment of serious infections caused by susceptible organisms when less toxic antimicrobials are ineffective or contraindicated.
Chloramphenicol is used in the acute treatment of typhoid fever caused by S. typhi, as well as invasive salmonellosis. It should not be used to eliminate the carrier state.
Chloramphenicol is used as an alternate for the treatment of bacterial meningitis caused by H. influenzae, S. pneumoniae and N. meningitidis when a cephalosporin or penicillin is not suitable. It is also used to treat brain abscesses caused by B. fragilis or other susceptible organisms.
Chloramphenicol is used as an alternative in the treatment of rickettsial infections, such as typhus or Rocky Mountain spotted fever, when tetracyclines cannot be given. It can also be used to treat severe H. influenzae infections other than meningitis, e.g., epiglottitis.
Chloramphenicol may be used locally in the treatment of superficial infections of the eye, external ear or skin, when caused by susceptible organisms.
Chloramphenicol is contraindicated in individuals with a history of previous hypersensitivity or toxic reaction to it.
Warnings: Serious and sometimes fatal reactions have occurred in patients taking chloramphenicol, even during short-term systemic therapy or after long-term local application. These include blood dyscrasias such as aplastic anemia, hypoplastic anemia, thrombocytopenia and granulocytopenia. While hematologic studies may detect early peripheral blood changes, they are not useful in predicting irreversible bone marrow depression which precedes the development of aplastic anemia.
A severe and potentially fatal reaction known as the gray syndrome has occurred in premature and newborn infants receiving large doses of chloramphenicol. Most commonly, chloramphenicol therapy had been initiated in the first 48 hours after birth; however, it has occurred in children as old as 2 years and in infants born to mothers who received chloramphenicol in the final stages of labor. Symptoms include failure to feed, abdominal distention, vomiting, blue-gray skin color, hypothermia, irregular breathing and cardiovascular collapse. Death can occur within hours. The syndrome has been attributed to excessive serum concentrations of chloramphenicol due to immature hepatic and renal elimination processes. If the syndrome is detected early and chloramphenicol is stopped, the infant may recover completely.
Chloramphenicol must not be used when less toxic agents may be expected to be effective.
Precautions: It is essential that hematologic studies be conducted prior to and frequently during therapy with chloramphenicol. The drug should be discontinued if reticulocytopenia, leukopenia, thrombocytopenia, anemia or other hematologic abnormalities occur (see Warnings).
Chloramphenicol has a narrow therapeutic index. In infants, or in patients with renal or hepatic impairment, plasma concentrations should be monitored and maintained in the range of 5 to 20 µg/mL.
Ocular symptoms such as a bilateral decrease in visual acuity or central scotomas may herald the onset of chloramphenicol-induced optic neuritis which rarely may result in blindness. Chloramphenicol must be discontinued immediately if optic or peripheral neuritis occurs.
Natural or plasmid-mediated resistance to chloramphenicol is known to occur in strains of staphylococci, Salmonella, Shigella, E. coli and rarely, H. influenzae.
As with other antibiotics, therapy with chloramphenicol may result in the overgrowth of nonsusceptible organisms including bacteria, viruses or fungi.
Repeated courses of chloramphenicol should be avoided whenever possible.
Otic preparations should not be used in patients with a perforated tympanic membrane.
When chloramphenicol is used topically in combination with corticosteroids, the signs of suprainfection may be masked.
Pregnancy: Chloramphenicol readily crosses the placenta. Birth defects in humans have not been documented; however, it should not be used in pregnancy at term or during labour because of potential toxicity in premature or full-term infants, including gray syndrome (see Warnings).
Lactation: Chloramphenicol is excreted in human breast milk and should not be used in nursing mothers because of the possibility of adverse effects (bone marrow depression) in the infant.
Neonates: Caution should be used in therapy of premature and full-term infants to avoid toxicity including gray syndrome (see Warnings). Serum drug levels should be monitored.
Drug Interactions : Hepatic drug clearance: Chloramphenicol inhibits hepatic microsomal enzymes and may interfere with the metabolism of alfentanil, chlorpropamide, phenobarbital, phenytoin, tolbutamide, warfarin or other drugs metabolized by the microsomal system. Dosages of these drugs may need to be adjusted accordingly. Conversely, drugs such as rifampin or phenobarbital which induce microsomal enzymes may increase the metabolism and reduce serum concentrations of chloramphenicol.
Anticoagulants: Chloramphenicol may prolong the prothrombin time in patients receiving anticoagulant therapy by interfering with vitamin K production by intestinal bacteria.
Anemia agents: Concurrent therapy with chloramphenicol may delay the clinical response to iron preparations, Vitamin B12 or folic acid in the treatment of anemias.
Antibacterial agents: Chloramphenicol has been reported to antagonize the bactericidal activity of penicillins and aminoglycosides in vitro and some clinicians recommend that these antibiotics not be used concomitantly. However, in vivo antagonism has not been demonstrated and chloramphenicol has been used successfully with ampicillin or penicillin G or aminoglycosides with no apparent decrease in activity.
Radiation Therapy or Myelosuppressive Drugs: Concomitant administration of chloramphenicol may result in additive bone marrow suppression.
Adverse Effects: Hematologic: Serious and sometimes fatal blood dyscrasias including aplastic anemia, hypoplastic anemia, thrombocytopenia and granulocytopenia have occurred during systemic or topical therapy with chloramphenicol. Two types of bone marrow suppression may occur. One is dose-related and generally reversible, tending to occur when serum levels exceed 25 µg/mL. Aplastic anemia, however, is an irreversible, idiosyncratic reaction occurring in approximately 1 in 25 000 to 40 000 patients treated and is not related to dose or duration of therapy. The onset of aplastic anemia may not occur until weeks or months following the discontinuation of chloramphenicol. See Warnings and Precautions.
Gastrointestinal: nausea, vomiting and diarrhea. Following oral administration, disturbances of the oral and intestinal flora may cause stomatitis, glossitis and enterocolitis. An unpleasant taste has been reported following rapid i.v. administration.
CNS: Headache, mild depression, mental confusion and delirium have been described in patients receiving chloramphenicol.
Optic and peripheral neuritis have been reported, usually following long-term therapy. If this occurs, the drug should be promptly discontinued.
Hypersensitivity: Fever, macular and vesicular rashes, angioedema and urticaria may occur, especially after topical use. Herxheimer-like reactions have occurred during therapy for typhoid fever.
Gray Syndrome: A toxic reaction which can occur in premature and newborn infants receiving large doses of chloramphenicol. It is characterized by abdominal distention, vomiting, blue-gray skin color, hypothermia, irregular breathing and cardiovascular collapse, followed by death in few hours or days. If chloramphenicol is stopped early after the onset of symptoms, the infant may recover completely (see Warnings and Precautions).
Local: Transient burning or stinging may occur upon instillation of ophthalmic preparations.
Symptoms: Hypersensitivity reactions including anaphylaxis may occur. Nausea and vomiting may occur, particularly after oral ingestion. Metabolic acidosis may occur after acute or chronic ingestion and may precede the onset of hypotension, hypothermia and abdominal distention. Sustained high serum levels may be associated with many other adverse effects (see Warnings, Precautions and Adverse Effects).
Treatment: Management of anaphylaxis may require the use of antihistamines, epinephrine, oxygen supplementation, airway management and i.v. fluids, depending on the severity of the reaction.
In cases of recent oral ingestion, induction of emesis or administration of activated charcoal with or without a cathartic may be indicated in certain cases.
Dosage: Where possible, chloramphenicol should be administered orally.
Oral and I.V.: Adults: 50 mg/kg/day in divided doses at 6 hour intervals. Patients with infections due to moderately resistant organisms or CNS infections may require higher doses of up to 100 mg/kg/day to achieve therapeutic serum or CSF levels, but the dose should be decreased as soon as possible to 50 mg/kg daily. Adults with impairment of hepatic or renal function may have reduced ability to metabolize and excrete the drug. In instances of impaired metabolic processes, dosages should be adjusted appropriately (see Precautions).
Children: Dosage of 50 mg/kg/day divided at 6 hour intervals is effective against most susceptible organisms. Severe infections (e.g., septicemia or meningitis): up to 100 mg/kg/day divided at 6 or 12 hour intervals.
Children with impaired hepatic or renal function require dosage adjustment with serum level monitoring where possible.
Infants: Premature infants or full-term infants up to 2 weeks of age: 6.25 mg/kg every 6 hours. Full-term infants over 2 weeks of age: 12.5 mg/kg every 6 hours or 25 mg/kg every 12 hours. Appropriate dosing is extremely important in neonates with immature metabolic processes as severe toxicity such as gray syndrome may occur (see Warnings and Precautions).
I.M. administration is controversial because studies have reported varying serum levels.
Local: Ophthalmic: Preparations (e.g., a thin strip of ointment approximately 1 cm long or 1 drop of solution) may be applied in the conjunctival sac every 3 hours for the first 48 hours, at which time the dosing interval may be increased.
Otic: Instil 2 or 3 drops into the ear canal every 6 to 8 hours.
Topical: Cream may be applied to the skin 3 or 4 times daily.
CHLORAMPHENICOL General Monograph, Antibiotic
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