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
Eyes
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.
Ears
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. 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 prokar-yotic 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 paranitro 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 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.
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 whereas the odds ratio for high doses was 1.8 (0.6-5. Other systemic antibiotics showed no substantial relation with the occurrence of leukemia.
Gastrointestinal
Mild gastrointestinal disturbances are common in patients taking chloramphenicol. In 51 children with Mediterranean spotted fever randomized for 7 days to either clarithromycin, 15 mg/kg/day orally in two divided doses, or chloramphenicol, 50 mg/kg/day orally in four divided doses, the two drugs were equally well tolerated and there were no major adverse effects; there was vomiting in two patients treated with clarithromycin and in one treated with chloramphenicol. None of the patients required drug withdrawal.
Skin
Hypersensitivity occurs about four times more often after topical than after oral use. In fact, there has been a continuous increase in chloramphenicol hypersensitivity, owing to the use of dermatological formulations. Allergic contact dermatitis and macular or vesicular skin rashes are usually limited to skin areas previously exposed to the drug. Contact conjunctivitis has also been reported. A case of a facial contact dermatitis due to chloramphenicol with cross-sensitivity to thiamphenicol has been reported.
Immunologic
Systemic reactions with collapse, bronchospasm, angioedema, and urticaria occur rarely.
Infection risk
The number and types of microorganisms that constitute the normal microflora of the alimentary, respiratory, and genital tracts change during therapy with chloramphenicol. Superinfections can then develop with Staphylococcus aureus, Pseudomonas, Proteus, and fungi. The changes in intestinal flora may be partly responsible for a reduction in the synthesis of vitamin K-dependent clotting factors, especially in patients with severe illnesses and malnutrition or during the administration of oral anticoagulants.
Chloramphenicol: Long-Term Effects
Drug tolerance
There have been reports of chloramphenicol-resistant H. influenzae from various countries, but there have been few cases. Outbreaks of chloramphenicol-resistant S. typhi have been observed in several countries.
High-level chloramphenicol-resistant strains of N. meningitidis serogroup B were isolated from 11 patients in Vietnam and one patient in France. Resistance was due to the presence of the catP gene on a truncated transposon that has lost mobility because of internal deletions.
Salmonella typhimurium DT104 is usually resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline. An outbreak of 25 culture-confirmed cases of multidrug-resistant S. typhimurium DT104 has been identified in Denmark. The strain was resistant to the above-mentioned antibiotics and nalidixic acid and had reduced susceptibility to fluoroquinolones. A swineherd was identified as the primary source. The DT104 strain was also found in cases of salmonellosis in Washington State, and soft cheese made with unpasteur-ized milk was identified as an important vehicle of its transmission.
A high rate of resistance of non-typhoid Salmonella to commonly used antimicrobial agents was found in Taiwan; 67% of the isolated strains were resistant to chloramphenicol.
Streptococcus pneumoniae was isolated in 30% of 40 HIV-infected and 50% of 162 HIV-negative children living in a Romanian orphanage. Multidrug-resistant streptococci were highly prevalent, and 21% of the isolates were resistant to chloramphenicol.
Esterases in serum from rabbits and to a lesser extent humans can convert diacetyl chloramphenicol back to an active antibiotic. Therefore, in vitro findings may not accurately reflect the level of chloramphenicol resistance by chloramphenicol acetyltransferase-bearing bacteria in vivo, when growth media supplemented with serum are used.
The flo gene that confers resistance to chloramphenicol and the veterinary antibiotic florfenicol have previously been identified in Photobacterium piscicida and Salmonella enterica serovar typhimurium DT104. Florfenicol-resistant isolates of Escherichia coli were tested and found to contain large flo-positive plasmids, suggesting that several of these isolates may have a chromosomal flo gene. The E. coli flo gene also specifies non-enzymatic cross-resistance to both florfenicol and chloramphenicol. Florfenicol resistance has emerged among veterinary isolates of E. coli incriminated in bovine diarrhea.
Chloramphenicol: Side Effects
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 main route of elimination of chloramphenicol is metabolic transformation by glucuronidation. The micro-biologically 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 pneumo-niae, 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.
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.
General adverse effects
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.
Chloramphenicol: Organs and Systems
Chloramphenicol: Long-Term Effects
Second-Generation Effects
Teratogenicity
In the large population-based dataset of the Hungarian Case Control Surveillance of Congenital Abnormalities, of 38 151 pregnant women who had babies without any defects and 22 865 pregnant women who had neonates or fetuses with congenital abnormalities, 51 and 52 had been treated with oral chloramphenicol respectively. Treatment during early pregnancy presented little, if any, teratogenic risk to the fetus.
Fetotoxicity
Chloramphenicol penetrates the fetal circulation and should therefore be avoided during the last phase of pregnancy. The gray syndrome has been observed in babies born to mothers who had received chloramphenicol in the final stage of pregnancy.
Lactation
Chloramphenicol has been found in relatively large amounts in breast milk. It should therefore be avoided during breast-feeding.
Susceptibility Factors
Age
In children, a high cumulative dose seems to be an important risk factor. As leukopenia can occur in the early phase of treatment, a complete blood count every third day is recommended.
Renal disease
Impaired kidney function, with reduced clearance of chloramphenicol, may be a risk factor for toxicity.
Hepatic disease
Liver damage, with reduced clearance of chloramphenicol, may be a risk factor for toxicity.
Other features of the patient
In a retrospective study of 30 consecutive children with sepsis treated with oral chloramphenicol, weight, albumin, and white blood cell count were the most important determinants for chloramphenicol distribution volume, whereas age, white blood cell count, and serum creatinine were most important for drug clearance. A preexisting blood dyscrasia is generally considered to be an absolute contraindication to the use of chloramphenicol.
Drug Administration
Drug administration route
In 1993 the American National Register of Drug Induced Ocular Side Effects received reports of 23 patients with blood dyscrasias that could have been related to topical ocular administration of chloramphenicol.
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.
It is difficult to justify subjecting patients to this small potential risk, in view of the availability of other antibiotics for use in the eye. In the USA the Physician’s Desk Reference emphasizes with repeated warnings the importance of not using ocular chloramphenicol unless there is no alternative, and this warning should be respected on both sides of the Atlantic.
Allergic reactions to chloramphenicol eye-drops include conjunctivitis, keratitis, and palpebral and periocular eczema.
Erythema multiforme caused by local treatment with chloramphenicol eye-drops has been described. The possible role of an allergic mechanism in this reaction was suggested, based on a positive mast cell degranulation test.
Chloramphenicol: Drug-Drug Interactions
Ciclosporin
A possible interaction between ciclosporin and chloramphenicol has been observed.
A morbidly obese 17-year-old Hispanic girl, who had a cadaveric renal transplantation 5 years before, took ciclosporin and prednisone for stabilization. She was treated with chloramphenicol 875 mg qds and ceftazi-dime 2 g tds for vancomycin-resistant enterococcal sinusitis. There was a substantial and sustained increase in ciclosporin concentrations after chloramphenicol was added. Normalization was achieved after withdrawal of chloramphenicol.
Cyclophosphamide
Chloramphenicol inhibits the biotransformation of cyclophosphamide.
Cytochrome P450
Chloramphenicol can interfere with the elimination of drugs that are inactivated by hepatic metabolism, probably through a mechanism involving inhibition of microsomal enzymes. The mechanism has been claimed to be inactivation of microsomal enzymes via an intermediate reactive metabolite that binds covalently to the protein moiety of cytochrome P450. Assuming such a mechanism, chloramphenicol would be expected to interact with the metabolism of other drugs dealt with by cytochrome P450.
Oral anticoagulants
Chloramphenicol inhibits the biotransformation of oral anticoagulants.
Paracetamol (acetaminophen)
Paracetamol altered the pharmacokinetics of chloramphenicol in some studies but not in others.
In six adults the half-life of chloramphenicol, 1 g intravenously was increased from 3.3 to 15 hours by paracetamol 100 mg intravenously.
In contrast, in five children aged 2.5-5 years paracetamol 50 mg/kg/day for several days significantly lowered the Cmax of chloramphenicol, increased its apparent volume of distribution and clearance, and slightly shortened its half-life.
Other studies have failed to show any interaction in children or adults.
Phenobarbital
Phenobarbital can increase the rate of chloramphenicol metabolism and so lead to abnormally low serum chloramphenicol concentrations. In 17 children receiving chloramphenicol succinate alone, mean peak and trough serum concentrations were 25 and 13 µg/ml respectively. In six patients phenobarbital reduced these concentrations to 17 and 7.5 µg/ml respectively.
Phenytoin
The ability of chloramphenicol to inhibit the biotransformation of phenytoin is well established and clinically relevant.
Conversely, phenytoin can increase the rate of chloramphenicol metabolism and so lead to abnormally low serum chloramphenicol concentrations, as has been anec-dotally reported. However, contrary to expectation, in another study serum chloramphenicol concentrations rose during concomitant phenytoin therapy.
Rifampicin
Rifampicin can increase the rate of chloramphenicol metabolism and so lead to abnormally low serum chloramphenicol concentrations.
Tacrolimus
Inhibition of tacrolimus clearance has been observed in an adolescent renal transplant recipient who was treated with standard doses of chloramphenicol for vancomycin-resistant enterococci. Toxic concentrations of tacrolimus were observed on the second day of chloramphenicol treatment, requiring an 83% reduction in the dose of tacrolimus.
A significant interaction has also been reported in an adult.
A 47-year-old white man with a cadaveric liver transplant took chloramphenicol for a urinary tract infection due to a vancomycin-resistant Enterococcus and inadvertently received 1850 mg qds (roughly twice the maximum recommended dose). On day 4 he had a 12-hour trough tacrolimus concentration of over 60 µg/ml, and complained of fatigue, lethargy, headache, and tremor, symptoms consistent with tacrolimus toxicity.
It was suggested that the underlying mechanism might be inhibition of CYP3A4 by chloramphenicol.
Tolbutamide
Chloramphenicol inhibits the biotransformation of tolbutamide.
Warfarin
An interaction of warfarin with ocular chloramphenicol (5 mg/ml; 1 drop qds in each eye), which led to an increase in INR, has been suspected in an 83-year-old white woman. The authors suggested that the effect may be due to chloramphenicol inhibition of hepatic microsomal CYP2C9, since the pharmacologically active enantiomer 5-warfarin is metabolized by this enzyme).