Chloramphenicol - Clinical Tree

General information

Chloramphenicol is one of the older broad-spectrum antibiotics. It was introduced in 1948 and grew in popularity because of its high antimicrobial activity against a wide range of Gram-positive and Gram-negative bacteria, Rickettsiae , Chlamydia , and Mycoplasma species. It is particularly useful in infections caused by Salmonella typhi and Haemophilus influenzae . It is mainly bacteriostatic. It readily crosses tissue barriers and diffuses rapidly into nearly all tissues and body fluids.

The use of chloramphenicol and other older antibiotics in critically ill patients has been reviewed, with discussion of the possible usefulness of chloramphenicol in the treatment of VRE (vancomycin resistant enterococci) and MRSA (meticillin-resistant Staphylococcus aureus ) [ ].

The main route of elimination of chloramphenicol is metabolic transformation by glucuronidation. The microbiologically inactive metabolites are excreted rapidly and only a small proportion of unchanged drug is excreted in the urine. The usual daily dose is 50 mg/kg for adults and children over 2 months. The total dose should not exceed 3.0–3.5 g/70 kg. The statement that neither the dose nor the interval of chloramphenicol administration needs to be adjusted in patients with significant renal dysfunction [ ] probably has to be modified in view of recent findings [ ].

By 1950 it became evident that chloramphenicol could cause serious and fatal blood dyscrasias. Its use has therefore steadily fallen during the past 50 years. Since the risk of serious chloramphenicol toxicity is so small (1:18 000 or probably less) it is of more than historical interest. There are still many areas in which its benefits outweigh its risks. These include:

typhoid and paratyphoid fever;
other septic forms of Salmonella infections;
meningitis due to H. influenzae , Streptococcus pneumoniae , and Neisseria meningitidis when the patient is allergic to beta-lactam antibiotics or when the strains ( H. influenzae , Enterobacteriaceae) are resistant to aminopenicillins and cephalosporins;
brain abscess;
serious infections caused by Bacteroides fragilis (as an alternative to clindamycin or metronidazole).

Since chloramphenicol is still one of the cheapest antibiotics, this list of indications is longer in developing countries, where chloramphenicol may be more readily available than newer expensive antibiotics. However, most infections can be readily, safely, and effectively treated with alternative drugs. Therefore, the role of chloramphenicol in the treatment of infectious diseases is likely to diminish further.

Chloramphenicol and its metabolites act primarily on the 50S ribosomal subunit, with suppression of the activity of the enzyme peptidyltransferase. It inhibits mitochondrial membrane protein synthesis, leading to suppression of mitochondrial respiration and ultimately to cessation of cell proliferation [ ]. Analogous mechanisms may operate in the production of the reversible type of bone marrow depression, which is the most prominent toxic effect in patients taking chloramphenicol. Its potency to induce toxic effects on mitochondria in maturing or rapidly proliferating eukaryotic cells is very close to that for inhibiting prokaryotic cells (bacteria and blue-green algae). However, little progress has been made in elucidating the pathogenesis of irreversible bone marrow aplasia [ ].

General adverse effects and adverse reactions

Chloramphenicol has been associated with two serious but rare toxic effects, each with a high mortality. One is the “gray syndrome”, vasomotor collapse in neonates caused by excessive parenteral doses. The second is bone marrow aplasia, which is a hypersusceptibility reaction. Prolonged use can result in neuropathies. Mild gastrointestinal disturbances are common. Chloramphenicol can cause a Jarisch–Herxheimer reaction, for example in patients with louse-borne relapsing fever [ ]. Hypersensitivity reactions are commonly mild and more frequent with topical use (allergic contact dermatitis, rashes, glossitis). The late, severe type of bone marrow reaction may be of allergic origin. Tumor-inducing effects have not been described; a statement that chloramphenicol might cause cancer in the fetus appears to have been purely speculative.

Drug studies

Observational studies

The response to chloramphenicol has been assessed in cases of bacteremia due to vancomycin-resistant enterococci, of whom 65% received chloramphenicol [ ]. Among those in whom a response could be assessed, 61% had a clinical response and 79% had a microbiological response. Mortality was non-significantly lower in patients treated with chloramphenicol. In cases with central line-related bacteremia, there was no difference in mortality among those treated with chloramphenicol, line removal, or both. No adverse effect could be definitely attributed to chloramphenicol.

Organs and systems

Cardiovascular

The “gray syndrome” is the term given to the vasomotor collapse that occurs in neonates who are given excessive parenteral doses of chloramphenicol. The syndrome is characterized by an ashen gray, cyanotic color of the skin, a fall in body temperature, vomiting, a protuberant abdomen, refusal to suck, irregular and rapid respiration, and lethargy. It is mainly seen in newborn infants, particularly when premature. It usually begins 2–9 days after the start of treatment.

Inadequate glucuronyl transferase activity combined with reduced glomerular filtration in the neonatal period is responsible for a longer half-life and accumulation of the drug. In addition, the potency of chloramphenicol to inhibit protein synthesis is higher in proliferating cells and tissues. The most important abnormality seems to be respiratory deficiency of mitochondria, due, for example to suppressed synthesis of cytochrome oxidase. The dosage should be adjusted according to the age of the neonate, and blood concentrations should be monitored. In most cases of gray syndrome, the daily dose of chloramphenicol has been higher than 25 mg/kg [ , ]. Occasionally, treatment of older children and teenagers with large doses of chloramphenicol (about 100 mg/kg) has resulted in a similar form of vasomotor collapse [ ].

Nervous system

Peripheral neuropathy has been seen after prolonged courses of chloramphenicol [ ].

Retrobulbar optic neuritis and polyneuritis have been attributed to prolonged chloramphenicol therapy [ ].

Sensory systems

Vision

Optic neuropathy has been seen after prolonged courses of chloramphenicol [ ]. Alterations in color perception and optic neuropathy, in some cases resulting in optic atrophy and blindness, have been observed, especially in children with cystic fibrosis receiving relatively high doses for many months [ , ]. Most of these complications were reversible and were attributed to a deficiency of B vitamins.

Hearing

Local application of chloramphenicol can cause hearing defects. Asymmetrical hearing loss with lowered perception of high tones has been documented after treatment of chronic bilateral otitis media with chloramphenicol powder [ ]. Propylene glycol is often used as a vehicle for chloramphenicol ear-drops, and ototoxicity may be due to chloramphenicol and/or propylene glycol, which is itself strongly ototoxic. Ototoxic effects can also occur after systemic drug administration [ ].

Hematologic

The first death resulting from bone marrow aplasia induced by chloramphenicol eye-drops was described in 1955 [ ].

Among more than 200 million ocular chloramphenicol products dispensed in the UK in the past 10 years, only 11 cases of suspected chloramphenicol-induced blood dyscrasias (none fatal) were reported to the Committee on Safety of Medicines [ ]. However, under-reporting in this way, which may be as low as 6% [ ], suggests that the number of incidents could have been as many as 200.

Chloramphenicol causes two types of bone marrow damage [ ].

A frequent, early, dose-related, reversible suppression of the formation of erythrocytes, thrombocytes, and granulocytes (early toxicity).
A rare, late type of bone marrow aplasia, a hypersusceptibility reaction, which is generally irreversible, and has a high mortality rate (aplastic anemia) [ ].

Chloramphenicol inhibits mRNA translation by the 70S ribosomes of prokaryotes, but does not affect 80S eukaryotic ribosomes. Most mitochondrial proteins are encoded by nuclear DNA and are imported into the organelles from the cytosol where they are synthesized. Mitochondria retain the capacity to translate, on their own ribosomes, a few proteins encoded by the mitochondrial genome. True to its prokaryotic heritage, mitochondrial ribosomes are similar to those of bacteria, meaning that chloramphenicol inhibits protein synthesis by these ribosomes. Chloramphenicol-induced anemia is believed to result from this inhibition [ ]. Chloramphenicol can also cause apoptosis in purified human bone marrow CD34 + cells [ ].

Dose-related bone marrow suppression

The early, dose-related type of chloramphenicol toxicity is usually seen after the second week of treatment, and is characterized by inhibited proliferation of erythroid cells and reduced incorporation of iron into heme. The clinical correlates in the peripheral blood are anemia, reticulocytopenia, normoblastosis, and a shift to early erythrocyte forms. The plasma iron concentration is increased. Early erythroid forms and granulocyte precursors show cytoplasmic vacuolation. After withdrawal, complete recovery is the rule. Leukopenia and thrombocytopenia are less frequent.

Although there is no evidence that these abnormalities progress to frank bone marrow aplasia, continuation of chloramphenicol after the appearance of early toxicity is thought to be hazardous. Pre-existing liver damage (for example due to infectious hepatitis or alcoholism) and impaired kidney function can lead to reduced elimination of chloramphenicol and its metabolites, thereby aggravating marrow toxicity. As a rule, this is not the irreversible type.

Aplastic anemia

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 [ ]. 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 [ , ]. For example, there have been very few cases reported in blacks [ ]. 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.

When bone marrow aplasia was complete, the fatality rate approached 100%. As a rule, it has been found that the longer the interval between the last dose of chloramphenicol and the appearance of the first sign of a blood dyscrasia, the more severe the resulting aplasia. Nearly all patients in whom the interval was longer than 2 months died as a result of this complication. However, fatal aplastic anemia can also occur shortly after normal doses of chloramphenicol [ ].

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 explained by the hypothesis that during treatment with chloramphenicol, chloramphenicol-sensitive cells were eliminated, leaving behind only a chloramphenicol-insensitive population of blood cell precursors with poor proliferative capacity [ ]. Chloramphenicol can induce apoptosis in purified human bone marrow CD34 + cells; however, there was no protection from a variety of antioxidants on chloramphenicol-induced suppression of burst-forming unit erythroid and colony-forming unit granulocyte/monocyte in vitro [ ]. In contrast, a caspase inhibitor ameliorated the apoptotic-inducing effects of chloramphenicol.

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, nitrosochloramphenicol and chloramphenicol hydroxylamine. In human bone marrow, nitrosochloramphenicol inhibited DNA synthesis at 10% of the concentration of chloramphenicol required for the same effect, and proliferation of myeloid progenitors was irreversibly inhibited. The covalent binding of nitrosochloramphenicol to marrow cells was 15 times greater than that of chloramphenicol [ ]. This has lent support to the hypothesis that abnormal metabolism may contribute to the susceptibility to bone marrow aplasia. The production of reduced derivatives by intestinal microbes may contribute to toxicity, but oral administration of chloramphenicol is not essential for the development of aplastic anemia [ ]. There is evidence that genetic predisposition may play a role [ , ]. The wide geographical variations in the incidence of aplastic anemia may also reflect environmental factors.

For many years it had been said that there were no cases of aplastic anemia after parenteral administration of chloramphenicol; however, a few cases of aplastic anemia have been reported [ ]. There have also been reports of bone marrow hypoplasia after the use of chloramphenicol eye-drops [ , ].

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 [ ]. 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 liquid 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 topical chloramphenicol based on current data are not supported [ ].

In a study using general practitioner-based computerized data, 442 543 patients were identified who received 674 148 prescriptions for chloramphenicol eye-drops. Among these patients, there were three with severe hematological toxicity and one with mild transient leukopenia. The causal link between topical chloramphenicol and hematological toxicity was not further evaluated in detail [ ].

Over 40 cases of blood dyscrasias or aplastic anemia after the use of topical ocular chloramphenicol have been reported in the literature or to the National Registry of Drug-Induced Ocular Side Effects (Casey Eye Institute, Portland, Oregon, USA). Although there was no proof of causality, we feel, based on WHO criteria, that the association in these cases was probable. The medical literature contains many papers both for and against the use of chloramphenicol in ophthalmology [ , ].

Leukemia

In a small fraction of patients who survive the chronic type of bone marrow damage, myeloblastic leukemia develops [ , ]. In most instances this complication has appeared within a few months of the diagnosis of aplasia and was considered to be a sequel of chloramphenicol treatment. Sometimes the delay was shorter. The majority were either children or adults aged 50–70 years.

The occurrence of acute leukemia has been studied in relation to preceding use of drugs (before the 12 months preceding the diagnosis) in a case–control study of 202 patients aged over 15 years with a diagnosis of acute leukemia and age- and sex-matched controls [ ]. Among users of chloramphenicol or thiamphenicol the odds ratio for any use was 1.1 (0.6–2.2) whereas the odds ratio for high doses was 1.8 (0.6–5.3). Other systemic antibiotics showed no substantial relation with the occurrence of leukemia.

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