Aplastic anemia chloramphenicol causing

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... 

The presence of antimicrobial drug residues in the edible tissues can cause allergies, toxic effects, changes in the intestinal microbial fauna and acquisition of drug resistance. Chloramphenicol residues in food consumed by humans can even result in aplastic anemia, which causes very serious bone marrow diseases. Nitrofuran antibiotics are known to cause cancer and many other diseases. It is for this reason that most countries that import fish products have banned the use of certain antibiotics (Sanandakumar, 2002). 

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. 

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 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. 

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 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. 

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. 

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. 

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. 

Some ADRs are caused by most or all medications in a class, while others are agent specific. Nausea, vomiting, and diarrhea have been observed with most antibiotics, yet only chloramphenicol and certain sulfonamide antibiotics have been consistently implicated as causes of aplastic anemia. Some pharmacological effects, such as sedation from an antihistamine, may be considered adverse effects when they are... 

Since thiamphenicol, which causes very few cases of aplastic anemia, differs from chloramphenicol by substitution of the para-nitro group by a methylsulfonyl group, interest has been focused on the para-nitro group and metabolites of that part of the molecule, nitrosochlor-amphenicol and chloramphenicol hydroxylamine. In human bone marrow, nitrosochloramphenicol inhibited DNA synthesis at 10% of the concentration of chloramphenicol required for the same effect, and prohferation of myeloid progenitors was irreversibly inhibited. The covalent binding of nitrosochloramphenicol to marrow cells was 15 times greater than that of chloramphenicol... 

There is controversy about the risk of aplastic anemia with topical chloramphenicol. In a prospective case-control surveillance of aplastic anemia in a population of patients who had taken chloramphenicol for a total of 67.2 million person-years, 145 patients with aplastic anemia and 1226 controls were analysed. Three patients and five controls had been exposed to topical chloramphenicol, but two had also been exposed to other known causes of aplastic anemia. Based on these findings, an association between ocular chloramphenicol and aplastic anemia could not be excluded, but the risk was less than one per million treatment courses (38). In another study, a review of the literature identified seven cases of idiosyncratic hemopoietic reactions associated with topical chloramphenicol. However, the authors failed to find an association between the epidemiology of acquired aplastic anemia and topical chloramphenicol. Furthermore, after topical therapy they failed to detect serum accumulation of chloramphenicol by high performance hquid chromatography. They concluded that these findings support the view that topical chloramphenicol was not a risk factor for dose-related bone marrow toxicity and that calls for abolition of treatment with... 

Of the two types of bone marrow toxicity that chloramphenicol can cause, it may cause the late type only in genetically predisposed patients. The overall risk of aplastic anemia after oral administration of chloramphenicol is 1 30 000 to 1 50 000, which is 13 times greater than the risk of idiopathic aplastic anemia in the population as a whole. Since topical administration achieves systemic effects by absorption through the conjunctival membrane or through drainage down the lacrimal duct, with eventual absorption from the gastrointestinal tract, the risk may be similar to that after oral administration. However, based on two case-control studies and a cohort study, the incidence of blood dyscrasias due to chloramphenicol eye-drops was estimated to be somewhat lower, namely 1 100 000 treated patients (40,66). 

Although the mechanism by which chloramphenicol causes aplastic anemia is not fully understood, all the available evidence suggests that the biochemical consequences of thiamphenicol administration and the risk of serious complications differ from those of chloramphenicol (1). 

Idiosyncratic aplastic anemia occurs only in humans exposed to chloramphenicol. The reaction is rare (1 in 30000) and not dose related. The toxic effects are related to the presence of the para-nitro group on the chloramphenicol molecule. Florfenicol lacks this group and is not associated with aplastic anemia in any species. Long-term chloramphenicol therapy (>14 days) is associated with dose-related anemia and pancytopenia through a decrease in protein synthesis in the bone marrow, especially in cats. Florfenicol may cause similar reversible suppression of the myeloid series in bone marrow, but this does not appear to be clinically significant during shortterm treatment regimens. 

Chloramphenicol causes both dose-dependent and dose-independent hematologic reactions. Fatal aplastic anemia occurs in genetically susceptible patients taking chloramphenicol on a long-term basis. Reversible and dose-dependent disturbances of hemopoiesis can also arise, and are characterized by the altered maturation of red blood cells, vacuolated nucleated red blood cells in the marrow, and reticulocytopenia. 

Chloramphenicol causes two distinct forms of toxicity in humans. The most serious form is an irreversible aplastic anaemia. This rare idiosyncratic response (the incidence is 25,000-60,000) may have an immunological component however, the meehanism of chloramphenicol-induced aplastic anemia remains unknown. Neither a dose-response relationship nor a threshold dose for the induction of aplastic anaemia has been established. Aplastic anemia is associated with reduced numbers of erythrocytes, leukocytes, and platelets (pancytopaenia), with resultant bleeding disorders and secondary infections. The condition tends to be irreversible and fatal. By comparison, leukemia may be a sequel of hypoplastic anemia. Because thiamphenicol and florfenicol lack the p-nitro moiety, they do not induce irreversible aplastic anemia in humans. 

Thiamphenicol is a semi-synthetic derivative of chloramphenicol. It can cause reversible bone marrow depression, but fatal aplastic anemia has not been reported in humans. Oral bioavailability in pre-ruminant calves is 60%. It is somewhat less lipid- and somewhat more water-soluble than chloramphenicol and therefore crosses cell membranes less readily. Hepatic metabolism is limited, and elimination is primarily as parent drug in the urine. Limited published data indicate that it has a high distribution volume in ruminants. It has been used in feed in pigs and chickens, but such usage is now limited. 

Chloramphenicol is a highly effective broad-spectrum antibiotic originally isolated from Streptomyces venezue-lae (Fig. 9). Nowadays, chloramphenicol is banned within the United States and the EC because it is believed to cause aplastic anemia. Other members of the amphenicol group are thiamphenicol and the recent one, florphenicol. These three antibiotics show strong UV absorption and can be determined directly, without any derivatization at 254 or 280 nm. Usually silica-gel plates and simple organic or aqueous-organic solvents are used. " ... 

Corbett, M. D. and B. R. Corbett. 1990. Biochemical studies on the putative nitroso metabolite of chloramphenicol a new model for the cause of aplastic anemia, p. 245-255. In P.C. Howard, S.S. Hecht and F.A. Beland (ed.), Nitroarenes occurrence, metabolism and biological impact. Plenum Press, New York. 

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