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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.

Nausea, vomiting, glossitis and stomatitis, diarrhea and enterocolitis may occur in low incidence.

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  If this occurs, the drug should be promptly withdrawn.

Fever, macular and vesicular rashes, angioedema, urticaria, and anaphylaxis may occur.  Herxheimer’s reactions have occurred during therapy for typhoid fever.

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.

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

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.

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.