Haemotoxicity of chloramphenicol succinate in the CD-1 mouse and Wistar Hanover rat

Abstract

1 Chloramphenicol has been widely used in the treatment of serious infections including typhoid fever and meningitis. However, the drug is haemotoxic in man inducing firstly, a reversible, dose-dependent anaemia which develops during treatment, secondly, an often fatal aplastic anaemia with pancytopenia and acellular marrow, and thirdly, leukaemia.

2 We investigated the haemotoxicity of chloramphenicol succinate (CAPS) in female CD-1 mice in repeat dose studies, to compare the response with the reversible anaemia reported in man. Studies in male Wistar Hanover rats were also carried out.

3 CAPS was gavaged daily to mice at dose levels from 800–2000 mg/kg for seven days. Values were significantly reduced for reticulocytes at 1700 and 2000 mg/ kg, and for erythrocytes (RBC), haematocrit (HCT), and haemoglobin (Hb) at 2000 mg/kg. Platelet and white blood cell (WBC) counts were unaffected.

4 Mice were dosed with CAPS at 1400 mg/kg for 10 days and sampled at 1, 4 and 15 days after the last dose. At day 1 post dosing, RBC, HCT and Hb values were significantly reduced, but returned to normal (or above normal) by day 4 or 15.

5 CAPS from 2000–4000 mg/kg was gavaged to rats daily for 19 days. Hb values were significantly lower at 3600 and 4000 mg/kg; reticulocytes were not reduced. WBC and platelet counts, in general, were unaffected.

6 Levels of apoptosis in marrow mononuclear cells were increased in CAPS-treated mice, but not in CAPS-treated rats. Serum biochemistry parameters, in general, showed few changes of toxicological significance.

7 We conclude that the administration of CAPS to CD-1 mice induced haematological changes showing close parallels with the chloramphenicol-induced reversible anaemia seen in man.

Keywords

chloramphenicol succinate haemotoxicity mouse rat aplastic anaemia

References

Volini IF et al. Hemopoietic changes during administration of chloramphenicol (chloromycetin) . Journal of the American Medical Association 1950; 142: 1333–1355 .

Reynolds JEF . Martindale. The Extra Pharmacopoeia, 29th Edition. The Pharmaceutical Press, London , 1989.

Chaplin S . Bone marrow depression due to mianserin, phenylbutazone, oxyphenbutazone, and chloramphenicol–part II . Adverse Drug Reactions and Acute Poisoning Reviews 1986; 3: 181–196 .

Young NS , Alter BP . Aplastic Anemia: Acquired and Inherited. WB Saunders, Philadelphia , 1994.

IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans. Chloramphenicol. Volume 50. pp.169–193. IARC, Lyon , 1990.

FAO/WHO Expert Committee on Food Additives . Chloramphenicol. In: Toxicological Evaluation of Certain Veterinary Drug Residues in Food (WHO Food Additives Series 23). pp.1–71. World Health Organisation, Geneva , 1988.

Krakoff IH , Karnofsky DA , Burchenal JH . Effects of large doses of chloramphenicol on human subjects . The New England Journal of Medicine 1955; 253: 7–10 .

Scott JL , Finegold SM , Belkin GA , Lawrence JS . A controlled double blind study of the haematologic toxicity of chloramphenicol . The New England Journal of Medicine 1965; 272: 1137–1142 .

Rich ML , Ritterhoff RJ , Hoffmann RJ . A fatal case of aplastic anaemia following chloramphenicol (chloromycetin) therapy . Annals of Internal Medicine 1950; 33: 1459–1467 .

10.

Welch H , Lewis CN , Kerlan I . Blood dyscrasias. A nationwide survey . Antibiotics and Chemotherapy 1954; 4: 607–623 .

11.

Wallestein RO et al. Statewide study of chloramphenicol therapy and fatal aplastic anaemia . Journal of the American Medical Association 1969; 208: 2045–2050 .

12.

Yunis AA , Bloomberg GR . Chloramphenicol toxicity, clinical features and pathogenesis . Progress in Haematology 1964; 4: 138–159 .

13.

Brauer MJ , Dameshek W . Hypoplastic anaemia and myeloblastic leukemia following chloramphenicol therapy. Report of three cases . The New England Journal of Medicine 1967; 277: 1003–1005 .

14.

Andrews CM , Spurling NW , Turton JA . Characterisation of busulphan induced myelotoxicity in B6C3F1 mice using flow cytometry . Comparative Haematology International 1993; 3: 102–115 .

15.

Andrews CM , Williams TC , Turton JA . Long-term haematological alterations in female B6C3F1 mice treated with busulphan . Comparative Haematology International 1998; 8: 125–136 .

16.

Holt DE et al. The myelotoxicity of chloramphenicol: in vitro and in vivo studies: II: in vivo myelotoxicity in the B6C3F1 mouse . Human and Experimental Toxicology 1998; 17: 8–17 .

17.

Morley A , Blake J . An animal model of chronic hypoplastic marrow failure. I. Late marrow failure after busulphan . Blood 1974; 44: 49–56 .

18.

Morley A , Trainor K , Remes J . Residual marrow damage: possible explanation for idiosyncrasy to chloramphenicol . British Journal of Haematology 1976; 32: 525–531 .

19.

Morley AA , Trainor KJ , Seshadri RS . Chronic hypoplastic marrow failure and residual injury . Blood Cells 1978; 4: 253–266 .

20.

Yallop D et al. Chloramphenicol is haemotoxic at high dose levels in the mouse but not in the rat . Human and Experimental Toxicology 1998; 17: 53–53 .

21.

Spurling NW , Burton LK , Pilling T . Canine factor–VII deficiency: experience with a modified Thrombotest method in distinguishing between phenotypes . Research in Veterinary Science 1974; 16: 228–239 .

22.

Godsafe PA , Singleton BK . The use of the whole blood Thrombotest time (1/51) as a routine monitor of vitamin K-dependent blood coagulation factor levels in the rat . Comparative Haematology International 1992; 2: 51–55 .

23.

Pazdernik TL , Corbett MD . Role of chloramphenicol reduction products in aplastic anaemia . Pharmacology 1980; 20: 87–94 .

24.

Robin E et al. Induction of lymphomas in mice by busulphan and chloramphenicol . Cancer Research 1981; 41: 3478–3482 .

25.

Bhoopalam N et al. Busulphan and chloramphenicol induced T cell lymphoma: cell surface characteristics and functional properties . Clinical and Experimental Immunology 1986; 64: 646–655 .

26.

Hara H , Kohsaki M , Noguchi K , Nagai K . Effect of chloramphenicol on colony formation from erythrocytic precursors . American Journal of Haematology 1978; 5: 123–130 .

27.

Vácha J , Pospiŝil M , Velovský V . The toxic effect of chloramphenicol on erythropoiesis in X-irradiated mice . Chemotherapy 1981; 27: 131–138 .

28.

Firkin FC , Sumner MA , Bradley TR . The influence of chloramphenicol on the bone marrow haemopoietic stem cell compartment . Experimental Haematology 1974; 2: 264–268 .

29.

Gruhzit OM , Fisken RA , Reutner TF , Martino E . Chloramphenicol (chloromycetin), an antibiotic. Pharmacological and pathological studies in animals . Journal of Clinical Investigation 1949; 28: 943–952 .

30.

Fritz H , Hess R . The effect of chloramphenicol on the prenatal development of rats, mice and rabbits . Toxicology and Applied Pharmacology 1971; 19: 667–674 .

31.

Rosenbach LM , Caviles AP , Mitus WJ . Chloramphenicol toxicity: reversible vacuolization of erythroid cells . The New England Journal of Medicine 1960; 263: 274–278 .

32.

Saidi P , Wallerstein RO , Aggeler PM . Effect of chloramphenicol on erythropoiesis . Journal of Laboratory and Clinical Medicine 1961; 57: 247–256 .

33.

Scott JL , Finegold SM , Belkin GA , Lawrence JS . A controlled double-blind study of the hematologic toxicity of chloramphenicol . The New England Journal of Medicine 1965; 272: 1137–1142 .

34.

Schrober R , Kosek JC , Wolf PL . Chloramphenicolinduced vacuoles. Their ultrastructure in bone marrow pronormoblasts and immature myeloid cells . Archives of Pathology 1972; 94: 298–302 .

35.

Morris TH . Antibiotic therapeutics in laboratory animals . Laboratory Animals 1995; 29: 16–36 .

36.

Alison PM , Mummah Schendel LL , Kindberg CC . Effects of vitamin K-deficient diet and antibiotics in normal human volunteers . Journal of Clinical Medicine 1987; 110: 180–188 .

37.

Reddy J , Bailey RR . Vitamin K deficiency developing in patients with renal failure treated with cephalosporin antibiotics . New Zealand Medical Journal 1980; 92: 378–379 .

38.

Bengmark S , Goransson G , Soucas E . Defects in hemostasis produced by antibiotics. An in vivo study in the rat . European Surgical Research 1981; 13: 290–298 .

39.

Smith RM et al. Chloromycetin: biological studies . Journal of Bacteriology 1948; 55: 425–448 .

40.

Philpott NJ et al. Increased apoptosis in aplastic anaemia bone marrow progenitor cells: Possible pathophysiologic significance . Experimental Haematology 1995; 23: 1642–1648 .

41.

Holt DE et al. The myelotoxicity of chloramphenicol: in vitro and in vivo studies: I. In vitro effects on cells in culture . Human and Experimental Toxicology 1997; 16: 570–576 .

42.

Mandal B , Hazra N , Maity CR . Metabolic and enzymatic changes in rats following high doses of tetracycline, chloramphenicol and trimethoprim . Annals of the National Academy of Medical Sciences (India) 1982; 18: 146–156 .

43.

Rubin D , Weisberger AS , Botti RE , Storaasli JB . Changes in iron metabolism in early chloramphenicol toxicity . Journal of Clinical Investigation 1958; 37: 1286–1292 .

44.

Suhrland LG , Weisberger AS . Chloramphenicol toxicity; in liver and renal disease . Archives of Internal Medicine 1963; 112: 747–754 .

45.

Yunis A . Drug-induced bone marrow injury . Advances in Internal Medicine 1969; 15: 357–376 .