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 aid the physician in selecting an antibacterial drug for treatment. Dilution Techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized (broth and/or agar). 1,3 The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method. 2,3 This procedure uses paper disks impregnated with 30 mcg chloramphenicol to test the susceptibility of bacteria to chloramphenicol. The disc diffusion breakpoints should be interpreted according to the criteria provided in Table 1. Table 1. Susceptibility Test Interpretive Criteria for Chloramphenicol Pathogen Minimum Inhibitory Concentrations (mcg/mL) Zone Diameters (mm) S I R S I R Salmonella spp. < 8 16 > 32 > 18 13 to 17 < 12 Haemophilus influenzae < 2 4 > 8 ≥ 29 26 to 28 < 25 A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. 1,2,3 Standard chloramphenicol powder should provide the following range of MIC values noted in Table 2. For the disc diffusion technique using the 30 mcg disk, the criteria in Table 2 should be achieved. Table 2. Quality Control Parameters for Chloramphenicol QC Strain Minimum Inhibitory Concentrations (mcg/mL) Zone Diameters (mm) Escherichia coli ATCC 25922 2 to 8 21 to 27 Haemophilus influenzae ATCC 49247 0.25 to 1 31 to 40 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 aid the physician in selecting an antibacterial drug for treatment. Dilution Techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized (broth and/or agar). 1,3 The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method. 2,3 This procedure uses paper disks impregnated with 30 mcg chloramphenicol to test the susceptibility of bacteria to chloramphenicol. The disc diffusion breakpoints should be interpreted according to the criteria provided in Table 1. Table 1. Susceptibility Test Interpretive Criteria for Chloramphenicol Pathogen Minimum Inhibitory Concentrations (mcg/mL) Zone Diameters (mm) S I R S I R Salmonella spp. < 8 16 > 32 > 18 13 to 17 < 12 Haemophilus influenzae < 2 4 > 8 ≥ 29 26 to 28 < 25 A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. 1,2,3 Standard chloramphenicol powder should provide the following range of MIC values noted in Table 2. For the disc diffusion technique using the 30 mcg disk, the criteria in Table 2 should be achieved. Table 2. Quality Control Parameters for Chloramphenicol QC Strain Minimum Inhibitory Concentrations (mcg/mL) Zone Diameters (mm) Escherichia coli ATCC 25922 2 to 8 21 to 27 Haemophilus influenzae ATCC 49247 0.25 to 1 31 to 40