Bone marrow with chloramphenicol

Risk for bone marrow depression ° Chloramphenicol given with ... 

It is important to monitor closely serum blood levels of chloramphenicol, particularly in patients with impaired liver or kidney function or when administering chloramphenicol with other drugs metabolized by the liver. Blood concentration levels exceeding 25 mcg/mL increase the risk of the patient developing bone marrow depression. 

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, (D(-)-threo-2-dichloroacetamido-1 -p-nitrophenylpropane-1,3-diol C H i Cl NjOj, molar mass 323.13). /Vote ingestion may cause a toxic effect on bone marrow, and contact with skin may cause an allergic response. 

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. 

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. 

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). 

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-... 

CHLORAMPHENICOL H2 RECEPTOR BLOCKERS -CIMETIDINE T adverse effects of chloramphenicol, e.g. bone marrow depression Additive toxicity Use with caution, monitor FBC regularly... 

Chloramphenicol causes two types of hematopoietic abnormality. The first is a dose-related toxic effect causing a bone marrow depression associated with inhibition of mitochondrial protein synthesis. Usually, discontinuing the antibiotic reverses this toxicity. 

Because serious and fetal blood dyscrasias can occur after the administration of chloramphenicol, it should be used only in serious infections for which less potentially dangerous drugs are ineffective or contraindicated. Chloramphenicol is contraindicated in patients with known hypersensitivity or intolerance to this drug, who have blood cell or bone marrow disorders, or who are undergoing dialysis and have other complications such as cirrhosis. 

Adverse effects include gastrointestinal upset which tends to be mild. Optic and peripheral neuritis occur with prolonged use (which should be avoided) but are uncommon. The systemic use of chloramphenicol is dominated by the fact that it can cause rare (between 1 18 000-100 000 courses) though serious bone marrow damage. This is of two types ... 

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. 

The pathogenesis of bone marrow aplasia after chloramphenicol is still uncertain. Compared with normal cells, bone marrow aspirates from patients with bone marrow aplasia are relatively resistant to the toxic effects of chloramphenicol in vitro. This has been... 

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). 

Linezolid has been associated with reversible myelosup-pression (14), which appears to be related to the duration of therapy, with a higher risk after more than 2 consecutive weeks of treatment (15). Myelosuppression with red cell hypoplasia has been reported in three patients taking linezolid 600 mg bd. The bone marrow changes were similar to those seen in reversible chloramphenicol toxicity. Another patient had sideroblastic anemia after taking linezolid for 2 months (16,17). 

There is evidence that thiamphenicol is more potent than chloramphenicol in causing the early dose-related and therefore predictable tjrpe of bone marrow toxicity. Many studies have shown that thiamphenicol in a dose of 1.5 g, and to a much lesser extent 0.75 g/day, causes an immediate disturbance of erythropoiesis in almost every case (6). Alterations in the bone marrow become most evident in patients with renal disease and in elderly subjects (probably because of reduced renal fimction). Leukocytes and thrombocjdes are only shghtly affected (7). 

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. 

It is incumbent on health professionals to avoid toxic drugs whenever possible. Antibiotics associated with CNS toxicities, usually when not dose-adjusted for renal function, include penicillins, cephalosporins, quinolones, and imipenem. Hematologic toxicities generally are manifested with prolonged use of nafcillin (neutropenia), piperacillin (platelet dysfunction), cefotetan (hypoprothrombinemia), chloramphenicol (bone marrow suppression, both idiosyncratic and dose-related toxicity), and trimethoprim (megaloblastic anemia). Reversible nephrotoxicity classically is associated with aminoglycosides... 

Dose-related erythroid suppression probably reflects inhibition of mitochondrial protein synthesis in erythroid precursors, which impairs iron incorporation into heme. Bone marrow suppression occurs regularly with plasma concentrations >25 pg/mL and is observed with large doses of chloramphenicol, prolonged treatment, or both. Dose-related bone marrow suppression may progress to aplasia if treatment is continued, but most cases of aplasia develop without prior dose-related marrow suppression. 

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). 

Chloramphenicol is not recommended for use with a patient who is undergoing radiation therapy or who has bone marrow depression. 

Chloramphenicol can have an adverse interaction with alfentanil (Alfenta) by increasing alfentanil levels in the patient. Chloramphenicol is known to increase bone marrow depression when given with anticonvulsants. 

The phenicols are transported into bacterial cells by passive or facilitated diffusion. They bind to the 505 subunit of the 705 bacterial ribosome and impair peptidyltransferase activity, thereby interfering with the incorporation of amino acids into newly formed peptides. Chloramphenicol also inhibits mitochondrial protein synthesis in mammalian bone marrow cells but does not significantly affect other intact cells. 

The second form of chloramphenicol toxicity in humans involves dose-dependent and reversible bone marrow suppression. With this toxicity, erythroid and myeloid precursors do not mature normally, serum iron concentration is increased, and phenylalanine concentrations are decreased. These signs of toxicity usually disappear when chloramphenicol is discontinued. Chronic dosing with thiamphenicol or florfenicol may also cause dose-dependent bone marrow suppression. 

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