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Chloramphenicol Sodium Succinate

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Chloramphenicol Sodium Succinate

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

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 ribsomes. In vitro, chloramphenicol exerts mainly a bacteriostatic effect on a wide range of gram-negative and gram-positive bacteria. Bacteriological studies should be performed to determine the causative organisms and their susceptibilities to chloramphenicol.

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

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 procedure. Standardized procedures are based on a dilution method1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of chloramphenicol powder. The MIC values should be interpreted according to the following criteria:

For testing extraintestinal isolates of Salmonella species

MIC (μg/mL) Interpretation
< 8 Susceptible (S)
16 Intermediate (I)
> 32 Resistant (R)

For testing Haemophilus influenzaea

MIC (μg/mL) Interpretation
< 2 Susceptible (S)
4 Intermediate (I)
> 8 Resistant (R)
aThese MIC interpretative standards are applicable only to broth microdilution susceptibility tests with Haemophilus influenzae using Haemophilus Test Medium (HTM)1.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” 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 high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard chloramphenicol powder should provide the following MIC values:

Microorganism MIC (μg/mL)
Escherichia coli ATCC 25922 2-8
Haemophilus influenzaeb ATCC 49247 0.25-1
bThis MIC quality control range is applicable to only Haemophilus influenzae ATCC 49247 tested by broth microdilution procedure using Haemophilus Test Medium (HTM)1.

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30μg chloramphenicol to test the susceptibilty of microorgansims to chloramphenicol. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-μg chloramphenicol disk should be interpreted according to the following criteria:

For testing extraintestinal isolates of Salmonella species

Zone Diameter (mm) Interpretation
> 18 Susceptible (S)
13-17 Intermediate (I)
< 12 Resistant (R)

For testing Haemophilus influenzaec

Zone Diameter Interpretation
≥ 29 Susceptible (S)
26-28 Intermediate (I)
< 25 Resistant (R)
cThese zone diameter interpretative standards are applicable only to susceptibility tests performed by disk diffusion with Haemophilus influenzae using Haemophilus Test Medium (HTM)2.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30μg chloramphenicol disk should provide the following zone diameters in these laboratory test quality control strains:

Microorgansim Zone diameter (mm)
Escherichia coli ATCC 25922 21-27
Haemophilus influenzaed ATCC 49247 31-40
dThese zone diameter quality control limits are applicable to only Haemophilus influenzae ATCC 49247 tested by a disk diffusion method using Haemophilus Test Medium (HTM)2.

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Fourth Edition. Approved Standard NCCLS Document M7-A4, Vol. 17, No. 2, NCCLS, Wayne, PA, January, 1997.

2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests - Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1, NCCLS, Wayne, PA, January, 1997.

3. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing - Eighth Informational Supplement. Approved Standard NCCLS Document M100-S8, Vol. 18, No. 1, NCCLS, Wayne, PA, January, 1998.

Last reviewed on RxList: 8/12/2008
This monograph has been modified to include the generic and brand name in many instances.

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