Chloramphenicol

CLINICAL PHARMACOLOGY: Chloramphenicol administered orally is absorbed rapidly from the intestinal tract. In controlled studies in adult volunteers using the recommended dosage of 50 mg/kg/day, a dosage of 1 g every 6 hours for 8 doses was given. Using the microbiological assay method, the average peak serum level was 11.2 mcg/mL one hour after the first dose. A cumulative effect gave a peak rise to 18.4 mcg/mL after the fifth dose of 1 g. Mean serum levels ranged from 8 to 14 mcg/mL over the 48-hour period. Total urinary excretion of chloramphenicol in these studies ranged from a low of 68% to a high of 99% over a three-day period. From 8% to 12% of the antibiotic excreted is in the form of free chloramphenicol; the remainder consists of microbiologically inactive metabolites, principally the conjugate with glucuronic acid. Since the glucuronide is excreted rapidly, most chloramphenicol detected in the blood is in the microbiologically active free form. Despite the small proportion of unchanged drug excreted in the urine, the concentration of free chloramphenicol is relatively high, amounting to several hundred mcg/mL in patients receiving divided doses of 50 mg/kg/day. Small amounts of active drug are found in bile and feces. Chloramphenicol diffuses rapidly, but its distribution is not uniform. Highest concentrations are found in liver and kidney, and lowest concentrations are found in brain and cerebrospinal fluid. Chloramphenicol enters cerebrospinal fluid even in the absence of meningeal inflammation, appearing in concentrations about half of those found in the blood. Measurable levels are also detected in pleural and in ascitic fluids, saliva, milk, and in the aqueous and vitreous humors. Transport across the placental barrier occurs with somewhat lower concentration in cord blood of neonates than in maternal blood. Microbiology Mechanism of Action Chloramphenicol is a broad-spectrum antibiotic originally isolated from Streptomyces venezuelae . It inhibits bacterial protein synthesis by interfering with the transfer of activated amino acids from soluble RNA to ribosomes. In vitro, chloramphenicol exerts mainly a bacteriostatic effect on a wide range of gram-negative and gram-positive bacteria. Antimicrobial Activity Chloramphenicol has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Aerobic gram-negative microorganisms Haemophilus influenzae Salmonella species, including Salmonella typhi Other microorganisms Lymphogranuloma-psittacosis group Rickettsia Susceptibility Testing Methods When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should ai

ADVERSE REACTIONS: Blood Dyscrasias The most serious adverse effect of chloramphenicol is bone marrow depression. Serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia) are known to occur after the administration of chloramphenicol. An irreversible type of marrow depression leading to aplastic anemia with a high rate of mortality is characterized by the appearance weeks or months after therapy of bone marrow aplasia or hypoplasia. Peripherally, pancytopenia is most often observed, but in a small number of cases only one or two of the three major cell types (erythrocytes, leukocytes, platelets) may be depressed. A reversible type of bone marrow depression, which is dose related, may occur. This type of marrow depression is characterized by vacuolization of the erythroid cells, reduction of reticulocytes and leukopenia, and responds promptly to the withdrawal of chloramphenicol. An exact determination of the risk of serious and fatal blood dyscrasias is not possible because of lack of accurate information regarding 1) the size of the population at risk, 2) the total number of drug-associated dyscrasias, and 3) the total number of non-drug associated dyscrasias. In a report to the California State Assembly by the California Medical Association and the State Department of Public Health in January 1967, the risk of fatal aplastic anemia was estimated at 1:24,200 to 1:40,500 based on two dosage levels. There have been reports of aplastic anemia attributed to chloramphenicol which later terminated in leukemia. Paroxysmal nocturnal hemoglobinuria has been reported. Gastrointestinal Reactions Nausea, vomiting, glossitis and stomatitis, diarrhea and enterocolitis may occur in low incidence. Neurotoxic Reactions 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 withdrawn. Hypersensitivity Reactions Fever, macular and vesicular rashes, angioedema, urticaria, and anaphylaxis may occur. Herxheimer’s reactions have occurred during therapy for typhoid fever. "Gray Syndrome" Toxic reactions including fatalities have occurred in the premature and neonate; the signs and symptoms associated with these reactions have been referred to as the “gray syndrome.” One case of gray syndrome has been reported in a neonate born to a mother having received chloramphenicol during labor. One case has been reported in a 3-month-old infant. The following summarizes the clinical and laboratory studies that have been made on these patients: a) In most cases therapy with chloramphenicol had been instituted within the first 48 hours of life. b) Symptoms first appeared after 3 to 4 days of continued treatment with high doses of chloramphenicol. c) The symptoms appeared in the following order: (1) abdominal distension with or without emesis; (2) progressive pallid cyanosis; (3) vasomotor collapse, frequently accompanied by irregular respiration; (4) death within a few hours of onset of these symptoms. d) The progression of symptoms from onset to exitus was accelerated with higher dose schedules. e) Preliminary blood serum level studies revealed unusually high concentrations of chloramphenicol (over 90 mcg/mL after repeated doses). f) Termination of therapy upon early evidence of the associated symptomatology frequently reversed the process with complete recovery.

Blood Dyscrasias The most serious adverse effect of chloramphenicol is bone marrow depression. Serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia) are known to occur after the administration of chloramphenicol. An irreversible type of marrow depression leading to aplastic anemia with a high rate of mortality is characterized by the appearance weeks or months after therapy of bone marrow aplasia or

CONTRAINDICATIONS: Chloramphenicol is contraindicated in individuals with a history of previous hypersensitivity and/or toxic reaction to it. It must not be used in the treatment of trivial infections or where it is not indicated, as in colds, influenza, infections of the throat; or as a prophylactic agent to prevent bacterial infections.