Aplastic anemia, chloramphenicol

As mentioned above, in order to protect the health of consumers, few countries permit the use of chloramphenicol in food-producing animals. In addition to epidemiological studies in humans showing that treatment with chloramphenicol is associated with the induction of aplastic anemia, chloramphenicol is a genotoxin in vivo and may cause adverse effects in humans (discussed further in Chapter... 

Both chloramphenicol and thiamphenicol cause reversible bone marrow suppression (9). The irreversible, often fatal, aplastic anemia, however, is only seen for chloramphenicol (9). This rare (1 in 10,000—45,000) chloramphenicol toxicity has been linked to the nitroaromatic function (1,9). Thiamphenicol, which is less toxic than chloramphenicol in regard to aplastic anemia, lacks potency as can be seen in Table 1, and thiamphenicol has never found much usage in the United States. An analogue of thiamphenicol having antimicrobial potencies equivalent to chloramphenicol was sought. Florfenicol (2) was selected for further development from a number of closely related stmctures. 

Toxic Effects on the Blood-Forming Tissues Reduced formation of erythrocytes and other elements of blood is an indication of damage to the bone marrow. Chemical compounds toxic to the bone marrow may cause pancytopenia, in which the levels of all elements of blood are reduced. Ionizing radiation, benzene, lindane, chlordane, arsenic, chloramphenicol, trinitrotoluene, gold salts, and phenylbutazone all induce pancytopenia. If the damage to the bone marrow is so severe that the production of blood elements is totally inhibited, the disease state is termed aplastic anemia. In the occupational environment, high concentrations of benzene can cause aplastic anemia. 

Chloramphenicol was the first orally active, broad-spectrum antibiotic to be used in the clinic, and remains the only antibiotic which is marketed in totally synthetic form. Its initial popularity was dampened, and its utilization plummeted when it was found that some patients developed an irreversible aplastic anemia from use of the drug. Of the hundreds of analogues synthesized, none are significantly more potent or certain to be safer than chloramphenicol itself. Two analogues have been given generic names and fall into this chemical classification. It was found early in the game that activity was retained with p-substituents, and that... 

The answer is c. (Hardman, pp 1134-1135.) Hematologic toxicity is by far the most important adverse effect of chloramphenicol The toxicity consists of two types (1) bone marrow depression (common) and (2) aplastic anemia (rare) Chloramphenicol can produce a potentially fatal toxic reaction, the gray baby syndrome, caused by diminished ability of neonates to conjugate chloramphenicol with resultant high serum concentrations. Tetracyclines produce staining of the teeth and phototoxicity... 

Chloramphenicol (CAP) is a broad-spectrum antibiotic that was widely used in veterinary medicine. Since 1994 the use of CAP is banned in the EU because of certain toxicological problems (i.e., aplastic anemia and the grey baby syndrome ) observed in its administration to humans [ 107] that have prompted the establishment of a zero tolerance for the presence of these residues in meat and animal products. As a consequence, many efforts have been made to develop sensitive methodologies capable of detecting CAP residues or its metabolites. 

Chloramphenicol has a broad spectrum of antimicrobial activity, including Gram-positive, Gram-negative, aerobic, and anaerobic bacteria, spirochaeta, mycoplasma, chlamydia, and so on however, it can cause pronounced suppression of blood flow, which is accompanied by reticulocytopenia, granulocytopenia, and in severe cases, aplastic anemia. 

Serious and fatal blood dyscrasias occur after short-term and prolonged therapy with chloramphenicol. Aplastic anemia, which later terminated in leukemia, has been reported. Chloramphenicol must not be used when less potentially dangerous agents are effective. It must not be used to treat trivial infections or infections other than indicated, or as prophylaxis for bacterial infections. 

Chloramphenicol Hematological events (including aplastic anemia) have been reported. 

Mostly chloramphenicol is well tolerated with only mild gastrointestinal disturbances. However this antibiotic inhibits mitochondrial protein synthesis in red blood cell precursors in the bone marrow and thus may cause dose-dependent anemia. This dose dependent reaction should not be confused with the idiosyncratic aplastic anemia which is dose-independent and usually fatal. The onset of this idiosyncrasy which has an incidence of about 1 20 000-1 50 000 may be during the treatment or weeks to months after therapy. 

Chloramphenicol also is widely used for the topical treatment of eye infections. It is a very effective agent because of its extremely broad spectrum of activity and its ability to penetrate ocular tissue. The availability of safer, less irritating instilled ophthalmic antibiotics and the increase in fatal aplastic anemia associated with the use of this dosage form suggest that this agent might best be withdrawn. 

The most publicized adverse affects are those involving the hematopoietic system they are manifested by toxic bone marrow depression or idiosyncratic aplastic anemia. The bone marrow depression is dose related and is seen most frequently when daily doses exceed 4 g and plasma concentrations exceed 25 jig/mL. The bone marrow depression is characterized by anemia, sometimes with leukopenia or thrombocytopenia, but it is reversible on discontinuation of chloramphenicol. 

Aplastic anemia occurs in only about 1 in 24,000 to 40,000 cases of treatment. It is not a dose-related response and can occur either while the patient is taking chloramphenicol for days to months after completion of therapy. The aplastic or hypoplastic response involves all cellular elements of the marrow and is usually fatal. The mechanism is not known, but it occurs most frequently with oral or ocular administration. 

Chloramphenicol Gray baby syndrome, aplastic anemia... 

Chloramphenicol commonly causes a dose-related reversible suppression of red cell production at dosages exceeding 50 mg/kg/d after 1-2 weeks. Aplastic anemia, a rare consequence (1 in 24,000 to 40,000 courses of therapy) of chloramphenicol administration by any route, is an idiosyncratic reaction unrelated to dose, although it occurs more frequently with prolonged use. It tends to be irreversible and can be fatal. 

Chloramphenicol Prevents bacterial protein synthesis by binding to the 50S ribosomal subunit Bacteriostatic activity against susceptible bacteria Use is rare in the developed world because of serious toxicities Oral, IV hepatic clearance (half-life 2.5 h) dosage is 50-100 mg/kg/d in four divided doses Toxicity Dose-related anemia, idiosyncratic aplastic anemia, gray baby syndrome... 

In some drug reactions, several of these hypersensitivity responses may present simultaneously. Some adverse reactions to drugs may be mistakenly classified as allergic or immune when they are actually genetic deficiency states or are idiosyncratic and not mediated by immune mechanisms (eg, hemolysis due to primaquine in glucose-6-phosphate dehydrogenase deficiency, or aplastic anemia caused by chloramphenicol). 

Thiamphenicol is a synthetic chloramphenicol analogue with a molecular structure that appears to preserve tlie antibacterial properties, decrease markedly the metabolism by the liver, enhance kidney excretion, and eliminate tlie occurrence of aplastic anemia, although it is probably more liable to cause dose-dependent reversible depression of the bone marrow (15). These properties make it preferable in certain cases to chloramphenicol (36, 37). 

Exceptions, however, to this situation may occur for some drugs, particularly those possessing inherent properties that can threaten human health. One such example is chloramphenicol, which has been implicated as the causative agent in many cases of fatal aplastic anemia, a condition reported to be non-dose-related and potentially could be induced by even extremely low levels of this antibiotic in food (30). Thus, the establishment of a safe level in chloramphenicol residue exposure from food animal tissues can be precluded. 

Although there have been no reported cases of aplastic anemia attributable to consumption of chloramphenicol residues through food, the possibility of such an event is not remote. Use of chloramphenicol in cattle is thought to be responsible for the death of a Kansas rancher. The rancher was diagnosed as having aplastic anemia 4 months after he began treating his cattle with chloramphenicol... 

Chloramphenicol (CAP), florfenicol (FLO), and thiamphenicol (TAP) are broad-spectrum antibiotics suitable for the treatment of a variety of infectious organisms (5). Chloramphenicol, which could produce aplastic anemia in a small percentage of humans, is not approved for use in food-producing animals in the United States (129). Florfenicol is allowed for the treatment of bovine respiratory diseases in the United States. The FDA has set a level of 10 /Ug/L in milk (130). The maximum residue level of CAP is set by the EU at 10 yug/kg (15). In Table 6, the different HPLC methods can be found. 

The most serious problem associated with chloramphenicol is the potential for bone marrow aplasia, which can lead to aplastic anemia and possibly death.16,83 Chloramphenicol is also associated with other blood dyscrasias such as agranulocytosis and thrombocytopenia. Because of these risks, chloram-... 

Florfenicol (IX) was patented by Schering-Plough as a broad spectrum antibiotic with Gram-positive and Gram-negative activity comparable to chloramphenicol (X). Chloramphenicol had become severely restricted in use, owing to its propensity to cause blood dyscrasia (aplastic anemia) in some patients. 

Anemias Hemolytic anemia occurs in patients with low levels of glucose 6-phosphate dehydrogenase3 (see p. 351). Other types of anemia occurring as a side effect of chloramphenicol include reversible anemia, which is apparently dose-related and occurs concomitantly with therapy, and aplastic anemia, which is idiosyncratic and usually fatal. [Note Aplastic anemia is independent of dose and may occur after therapy has ceased.]... 

Blood dyscrasias, mostly dose independent, are among the most important allergic-type adverse reactions to drugs. Aplastic anemia is a serious but rare (presumably) idiosyncratic reaction. It has been reported in association with chloramphenicol, quinacrine, phenylbutazone, mephenytoin, gold compounds, and potassium chlorate. Hemolytic anemia, thrombocytopenia, and agranulocytosis may result from an unusual, acquired sensitivity to a variety of widely used drugs including aminopyrine, phenylbutazone, phenothiazines, propylthiouracil, diphenylhydantoin, penicillins, chloramphenicol, sulfisoxazole, and tolbutamide. 

Topical application of chloramphenicol solution or ointment is effective against most bacterial infections of the external eye. However, because aplastic anemia has also occurred after topical ocular use of chloramphenicol, its use must be limited to infections for which less toxic antibiotics prove ineffective. 

FIGURE 16.3 Chemical structures of chloramphenicol and thiamphenicol. Thiamphenicol, in which the nitroso group of chloramphenicol is replaced by a methylsulfone group, retains antibiotic activity, but does not cause the aplastic anemia that is a major concern with chloramphenicol therapy. 

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