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Case report: Life-threatening hypoglycaemia associated with sulfadoxinepyrimethamine,a commonly used antimalarial drug
TRANSACTIONS OF THE ROYALSOCIETY OF TROPICALMEDICINE AND HYGIENE (2003) 97, 595-596
Case report: life-threatening hypoglycaemia associated with sulfadoxinepyrimethamine, a commonly used antimalarial drug R. M. F a i r h u r s t 1, B. S a d o u 2, A. G u i n d o 2, D . A . D i a U o 2, O. K. D o u m b o 2 a n d T. E. W e l l e m s 1 SLaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, M D 20892, USA; 2Malaria Research and Training Center, Faculty of Medicine, Pharmacy, and Odonwstornawlogy, University of Mall, Bamako, Mall Abstract Due to chloroquine resistance, several African countries have changed their first-line malaria treatment to sulfadoxine-pyrimethamine (SP). In this report, we present a case of hypoglycaemic coma associated with SP, an adverse reaction that is likely to be underreported and expected to occur with greater frequency as the use of SP increases. Keywords: malaria, hypoglycaemia, chemotherapy, sulfadoxine-pyrimethamine, Mall Case report In September 2002, a 3-year-old boy was brought to a rural health clinic in Mall for fever. The mother reported no other symptoms or signs of illness (e.g. headaches, lethargy, vomiting), chronic disease, recent medication use, or known drug allergies. Examination revealed axillary temperature 39.7°C, blood pressure 100/50 mmHg, pulse 158/rain, respiratory rate 32/rain, and weight 13 kg. There was no pallor, jaundice, oedema, dehydration, respiratory distress, splenomegaly, or diminished consciousness. Laboratory evaluation revealed haematocrit 0.39, haemoglobin 106 g / L and blood glucose 4.2 m m o l / L . Blood smears showed Plasmodium falciparum (294750 ring form s / m m 3, ~5% red cells infected). The child was treated for uncomplicated malaria with a standard course of chloroquine (CQ), given orally: 10 mg/kg on day 0, 10 mg/kg on day 1, and 5 mg/kg on day 2. Although no temperature elevations or symptoms were noted during the 14-d follow-up period, parasite densities on days 3, 7, and 14 were 900, 425, and 8 3 2 5 / m m 3, respectively, indicating type RII CQ-resistant infection. The child was treated on day 14 with sulfadoxine-pyrimethamine (SP; Fansidar, Hoffman-La Roche Inc., Nutley, NJ, USA), given orally: 3/4 tablet, based on ~25 mg/kg of the sulfadoxine component. N o quinine was given. Ninety minutes after ingesting SP, the child was found to be comatose with depressed respiratory rate (14/min) and brief periods of apnea. N o temperature elevation, meningeal signs, or seizures were noted. Blood glucose level could not be measured. The child was treated intravenously with 10% dextrose solution for presumptive sulfa-induced hypoglycaemia. After 250 m L were rapidly infused, the child's condition reversed completely without neurological sequelae. Discussion Sulfadoxine-pyrimethamine is supplied as a fixed combination tablet of 500 mg sulfadoxine and 25 mg pyrimethamine. In addition to warnings of blood cell dyscrasias, toxic epidermal necrolysis, and Stevens Johnson syndrome, Hoffman-La Roche Inc., the manufacturer of Fansidar, reports that: 'The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides' () (Figure). Sulfa-induced hypoglycaemia is extremely rare, idiosyncratic, and unrelated to dose or duration of
Address for correspondence: Rick M. Fairhurst, Laboratory of Malaria and Vector Research, NIAID/National Institutes of Health, Building 4, Room 126, 4 Center Drive, Bethesda, MD 20892-0425, USA; phone +1 301 496 4023, fax +1 301 402 2201, e-mail [email protected]
therapy. It can occur with all sulfonamides including sulfamethoxazole (Arem et el., 1993), an antibiotic frequently combined with trimethoprim for the treatment of diverse bacterial infections. It is unclear why our patient experienced coma that reversed rapidly after 10% dextrose infusion, as he had no clinical evidence of hypoglycaemia prior to receiving SP, showed no signs of severe malaria (White et el., 1987), and received no quinine, which is frequently associated with hypoglycaemia during malaria treatment (White et el., 1983). Hypoglycaemia is not commonly associated with SP treatment of uncomplicated malaria and whether malaria patients have increased risk of SPinduced hypoglycaemia is not known. Due to unacceptably high CQ resistance rates, SP has already supplanted CQ as first-line malaria therapy in 10 sub-Saharan African countries (Wongsrichanalai et el., 2002) with others considering the switch as well (Driessen et el., 2002); it has also been used in Asia and South America. To our knowledge, case reports of SPinduced hypoglycaemic coma occurring during the course of malaria treatment have not been reported. Given the increasingly large amounts of SP used for malaria treatment, this adverse reaction is likely to be underreported and can be expected to increase in frequency. Since hypoglycaemia occurs in both severe malaria and quinine treatment, determining whether Sulfadoxine NH2"-~
02
II
N~N
I
Chlorpropamide, a sulfonylurea C1
0
Figure. Chemical structures of sulfadoxine and chlorpropamide, an oral hypoglycaemic drug.
596 this reaction is due to SP may be problematic, especially since SP is often administered simultaneously with quinine. Sulfadoxine-pyrimethamine is well known for its delayed antimalarial activity, but intestinal absorption, and hence the hypoglycaemic reaction, can proceed rapidly. In addition to the more familiar serious adverse effects of sulfonamides (Bj6rkman & Phillips-Howard, 1991), physicians should be aware of hypoglycaemia so that they can treat the condition should it develop and warn their patients against future ingestion of all sulfacontaining drugs.
References Arem, R., Garber, A. J. & Field, J. B. (1993). Sulfonamideinduced hypoglycemia in chronic renal failure. Archives of InternalMedicine, 143, 827-829. Bj6rkman, A. & Phillips-Howard, P. A. (1991). Adverse reactions to sulfa drugs: implications for malaria chemotherapy. Bulletin of the WorldHealth Organization, 69, 297-304.
Book Review Evaluation of Certain Veterinary Drug Residues in Food. Fifty-eighth Report of the Joint FAO/ W H O Expert C o m m i t t e e on Food Additives. WHO Technical Report Series, No. 911. Geneva: World Health Organization, 2002.66 pp. ISBN 92-4-1209119. Ensuring that food derived from farm animals is safe to eat is an important, although specialized, discipline. The report starts with an outline of the principles of risk assessment and mentions a project to update these as well as methods used for measuring chemicals in food. The evaluation of certain drug residues in food continues the work of other reports in recommending acceptable daily intakes and maximum residues in various tissues. New data on 2 anthelminthics of major importance, doramectin and ivermectin are discussed as well as the benzimidazole, thiabendazole. Since this latter product is not sold for use in animals in the U K and presumably is disappearing in other
R.M. FAIRHURSTETAL. Driessen, G. J., van Kerkhoven, S., Schouwenberg, B. J., Bonsu, G. & Verhave, J. P. (2002). Sulphadoxine/pyrimethamine: an appropriate first-line alternative for the treatment of uncomplicated falciparum malaria in Ghanaian children under 5 years of age. TropicalMedicine and InternationalHealth, 7, 577-583. White, N. J., Warrell, D. A., Chanthavanich, P., Looareesuwan, S., Warrell, M. ]'., Kristma, S., Williamson, D. H. & Turner, R. C. (1983). Severe hypoglycemia and hyperinsulinemia in falciparum malaria. New England Journal of Medicine, 309, 61-66. White, N. J., Miller, K. D., Marsh, K., Berry, C. D., Turner, R. C., Williamson, D. H. & Brown, J. (1987). Hypoglycaemia in African children with severe malaria. Lancet, 1, 708-711. Wongsrichanalai, C., Pickard, A. L., Wernsdorfer, W. H. & Meshnick, S. R. (2002). Epidemiology of drug-resistant malaria. Lancet Infectious Dieases, 2, 209-218.
Received 30 January 2003; revised 14 April 2003; accepted for publication 17April 2003
markets, the detail involved is perhaps surprising. Insecticides considered are cyhalothrin, cypermethrin, ct-cypermethrin, and the organophosphate, phoxim. One production aid is mentioned, melengestrol acetate. Greatest detail is given for the first consideration of the cephalosporin antibacterial agent, cefuroxime. This includes the decision-tree for evaluating potential effects of veterinary drug residues on h u m a n intestinal flora and would be of interest to anyone involved in antibacterial residues. Other antibacterials considered are dihydrostreptomycin and streptomycin, lincomycin, neomycin, oxytetracycline and thiamphenicol. The report finishes with 15 references. An appendix provides a list of 156 reports and other documents of joint FAO/ WHO Expert Committee Meetings.
G. C. Coles
Department of Clinical Veterinary Science University of Bristol Langford House Langford, Bristol BS40 5DU, UK
Case report: life-threatening hypoglycaemia associated with sulfadoxinepyrimethamine, a commonly used antimalarial drug R. M. F a i r h u r s t 1, B. S a d o u 2, A. G u i n d o 2, D . A . D i a U o 2, O. K. D o u m b o 2 a n d T. E. W e l l e m s 1 SLaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, M D 20892, USA; 2Malaria Research and Training Center, Faculty of Medicine, Pharmacy, and Odonwstornawlogy, University of Mall, Bamako, Mall Abstract Due to chloroquine resistance, several African countries have changed their first-line malaria treatment to sulfadoxine-pyrimethamine (SP). In this report, we present a case of hypoglycaemic coma associated with SP, an adverse reaction that is likely to be underreported and expected to occur with greater frequency as the use of SP increases. Keywords: malaria, hypoglycaemia, chemotherapy, sulfadoxine-pyrimethamine, Mall Case report In September 2002, a 3-year-old boy was brought to a rural health clinic in Mall for fever. The mother reported no other symptoms or signs of illness (e.g. headaches, lethargy, vomiting), chronic disease, recent medication use, or known drug allergies. Examination revealed axillary temperature 39.7°C, blood pressure 100/50 mmHg, pulse 158/rain, respiratory rate 32/rain, and weight 13 kg. There was no pallor, jaundice, oedema, dehydration, respiratory distress, splenomegaly, or diminished consciousness. Laboratory evaluation revealed haematocrit 0.39, haemoglobin 106 g / L and blood glucose 4.2 m m o l / L . Blood smears showed Plasmodium falciparum (294750 ring form s / m m 3, ~5% red cells infected). The child was treated for uncomplicated malaria with a standard course of chloroquine (CQ), given orally: 10 mg/kg on day 0, 10 mg/kg on day 1, and 5 mg/kg on day 2. Although no temperature elevations or symptoms were noted during the 14-d follow-up period, parasite densities on days 3, 7, and 14 were 900, 425, and 8 3 2 5 / m m 3, respectively, indicating type RII CQ-resistant infection. The child was treated on day 14 with sulfadoxine-pyrimethamine (SP; Fansidar, Hoffman-La Roche Inc., Nutley, NJ, USA), given orally: 3/4 tablet, based on ~25 mg/kg of the sulfadoxine component. N o quinine was given. Ninety minutes after ingesting SP, the child was found to be comatose with depressed respiratory rate (14/min) and brief periods of apnea. N o temperature elevation, meningeal signs, or seizures were noted. Blood glucose level could not be measured. The child was treated intravenously with 10% dextrose solution for presumptive sulfa-induced hypoglycaemia. After 250 m L were rapidly infused, the child's condition reversed completely without neurological sequelae. Discussion Sulfadoxine-pyrimethamine is supplied as a fixed combination tablet of 500 mg sulfadoxine and 25 mg pyrimethamine. In addition to warnings of blood cell dyscrasias, toxic epidermal necrolysis, and Stevens Johnson syndrome, Hoffman-La Roche Inc., the manufacturer of Fansidar, reports that: 'The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides' (
Address for correspondence: Rick M. Fairhurst, Laboratory of Malaria and Vector Research, NIAID/National Institutes of Health, Building 4, Room 126, 4 Center Drive, Bethesda, MD 20892-0425, USA; phone +1 301 496 4023, fax +1 301 402 2201, e-mail [email protected]
therapy. It can occur with all sulfonamides including sulfamethoxazole (Arem et el., 1993), an antibiotic frequently combined with trimethoprim for the treatment of diverse bacterial infections. It is unclear why our patient experienced coma that reversed rapidly after 10% dextrose infusion, as he had no clinical evidence of hypoglycaemia prior to receiving SP, showed no signs of severe malaria (White et el., 1987), and received no quinine, which is frequently associated with hypoglycaemia during malaria treatment (White et el., 1983). Hypoglycaemia is not commonly associated with SP treatment of uncomplicated malaria and whether malaria patients have increased risk of SPinduced hypoglycaemia is not known. Due to unacceptably high CQ resistance rates, SP has already supplanted CQ as first-line malaria therapy in 10 sub-Saharan African countries (Wongsrichanalai et el., 2002) with others considering the switch as well (Driessen et el., 2002); it has also been used in Asia and South America. To our knowledge, case reports of SPinduced hypoglycaemic coma occurring during the course of malaria treatment have not been reported. Given the increasingly large amounts of SP used for malaria treatment, this adverse reaction is likely to be underreported and can be expected to increase in frequency. Since hypoglycaemia occurs in both severe malaria and quinine treatment, determining whether Sulfadoxine NH2"-~
02
II
N~N
I
Chlorpropamide, a sulfonylurea C1
0
Figure. Chemical structures of sulfadoxine and chlorpropamide, an oral hypoglycaemic drug.
596 this reaction is due to SP may be problematic, especially since SP is often administered simultaneously with quinine. Sulfadoxine-pyrimethamine is well known for its delayed antimalarial activity, but intestinal absorption, and hence the hypoglycaemic reaction, can proceed rapidly. In addition to the more familiar serious adverse effects of sulfonamides (Bj6rkman & Phillips-Howard, 1991), physicians should be aware of hypoglycaemia so that they can treat the condition should it develop and warn their patients against future ingestion of all sulfacontaining drugs.
References Arem, R., Garber, A. J. & Field, J. B. (1993). Sulfonamideinduced hypoglycemia in chronic renal failure. Archives of InternalMedicine, 143, 827-829. Bj6rkman, A. & Phillips-Howard, P. A. (1991). Adverse reactions to sulfa drugs: implications for malaria chemotherapy. Bulletin of the WorldHealth Organization, 69, 297-304.
Book Review Evaluation of Certain Veterinary Drug Residues in Food. Fifty-eighth Report of the Joint FAO/ W H O Expert C o m m i t t e e on Food Additives. WHO Technical Report Series, No. 911. Geneva: World Health Organization, 2002.66 pp. ISBN 92-4-1209119. Ensuring that food derived from farm animals is safe to eat is an important, although specialized, discipline. The report starts with an outline of the principles of risk assessment and mentions a project to update these as well as methods used for measuring chemicals in food. The evaluation of certain drug residues in food continues the work of other reports in recommending acceptable daily intakes and maximum residues in various tissues. New data on 2 anthelminthics of major importance, doramectin and ivermectin are discussed as well as the benzimidazole, thiabendazole. Since this latter product is not sold for use in animals in the U K and presumably is disappearing in other
R.M. FAIRHURSTETAL. Driessen, G. J., van Kerkhoven, S., Schouwenberg, B. J., Bonsu, G. & Verhave, J. P. (2002). Sulphadoxine/pyrimethamine: an appropriate first-line alternative for the treatment of uncomplicated falciparum malaria in Ghanaian children under 5 years of age. TropicalMedicine and InternationalHealth, 7, 577-583. White, N. J., Warrell, D. A., Chanthavanich, P., Looareesuwan, S., Warrell, M. ]'., Kristma, S., Williamson, D. H. & Turner, R. C. (1983). Severe hypoglycemia and hyperinsulinemia in falciparum malaria. New England Journal of Medicine, 309, 61-66. White, N. J., Miller, K. D., Marsh, K., Berry, C. D., Turner, R. C., Williamson, D. H. & Brown, J. (1987). Hypoglycaemia in African children with severe malaria. Lancet, 1, 708-711. Wongsrichanalai, C., Pickard, A. L., Wernsdorfer, W. H. & Meshnick, S. R. (2002). Epidemiology of drug-resistant malaria. Lancet Infectious Dieases, 2, 209-218.
Received 30 January 2003; revised 14 April 2003; accepted for publication 17April 2003
markets, the detail involved is perhaps surprising. Insecticides considered are cyhalothrin, cypermethrin, ct-cypermethrin, and the organophosphate, phoxim. One production aid is mentioned, melengestrol acetate. Greatest detail is given for the first consideration of the cephalosporin antibacterial agent, cefuroxime. This includes the decision-tree for evaluating potential effects of veterinary drug residues on h u m a n intestinal flora and would be of interest to anyone involved in antibacterial residues. Other antibacterials considered are dihydrostreptomycin and streptomycin, lincomycin, neomycin, oxytetracycline and thiamphenicol. The report finishes with 15 references. An appendix provides a list of 156 reports and other documents of joint FAO/ WHO Expert Committee Meetings.
G. C. Coles
Department of Clinical Veterinary Science University of Bristol Langford House Langford, Bristol BS40 5DU, UK