Chloramphenicol aplastic anemia with

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. 

Although bone marrow aplasia has not been related with certainty to either the daily or the total dose of chloramphenicol or to the sex or age of the patients, it has occurred almost exclusively in individuals who were taking prolonged therapy, particularly if they were exposed to the drug on more than one occasion (24). The condition is rare, occurring about once in every 18 000-50 000 subjects in various countries. These variations may in part depend on ethnic factors (25,26). For example, there have been very few cases reported in blacks (27). Bone marrow aplasia due to chloramphenicol has usually resulted in aplastic anemia with pancytopenia other forms, such as red cell hypoplasia, selective leukopenia, or thrombocytopenia, are less common. 

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... 

The most important adverse effects are an immediate dose-related and reversible disturbance of erythropoiesis (2,3) and peripheral neuropathy. In contrast to chloramphenicol, aplastic anemia and the gray syndrome do not seem to occur with thiamphenicol. 

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... 

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 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. 

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). 

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... 

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. 

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... 

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). 

Froese EA. Chloramphenicol-associated aplastic anemia its occurrence in Africans and with parenteral administration. Cent Afr J Med 1978 24 58. 

West BC, DeVault G A Jr, Clement JC, Williams DM. Aplastic anemia associated with parenteral chloramphenicol review of 10 cases, including the second case of possible increased risk with cimetidine. Rev Infect Dis 1988 10(5) 1048-51. 

In a case-control surveillance of agranulocytosis and aplastic anemia conducted in the metropolitan area of Barcelona, where 178 cases of aplastic anemia were identified, nifedipine was associated with a significant relative risk of aplastic anemia, which translates into an absolute risk of 1.2 per patient-year. Among the 178 patients, 147 were interviewed and compared with 1295 controls. Six cases (4.1%) and 11 controls (0.8%) had been exposed to nifedipine during the window period, as aU of them had taken nifedipine for at least 7 months. The multivariate odds ratio was 4.6 (95% Cl = 1.5,15). AU six died within 5 months of diagnosis. The authors concluded that the risk of aplastic anemia associated with nifedipine is of a similar magnitude to that associated with chloramphenicol (1.7 per 100 000 patients) and that associated with phenylbutazone (2.2 per 100 000 patients) (21). 

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. 

The risk of aplastic anemia does not contraindicate the use of chloramphenicol in situations in which it may be life-saving. The drug should never be used in undefined situations or in diseases readily, safely, and effectively treated with other antimicrobial agents. 

Chloramphenicol. Chloramphenicol binds to the 508 ribosomal subunit of bacteria and prevents binding of the amino acid portion of the aminoacyl-tRNA, effectively inhibiting peptidyltransferase action. This antibiotic is used only for certain extremely serious infections, such as meningitis and typhoid fever. Chloramphenicol readily enters human mitochondria, where it inhibits protein synthesis. Cells of the bone marrow often fail to develop in patients treated with chloramphenicol, and use of this antibiotic has been linked to fatal blood dyscrasias, including an aplastic anemia. 

Reversible, dose-dependent bone marrow maturation arrest occurs with chloramphenicol. Serum iron concentration increases and blood levels of phenylalanine decrease. These actions are unrelated to the rare occurrence of aplastic anemia. The answer is (B). 

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