493 CO-TRIMOXAZOLE NEPHROTOXICITY
SIR,-In 1973 we reported deterioration in renal function in sixteen patients in relation to co-trimoxazole,’ and this stimulated considerable debate.2-6 The combination of trimethoprim and sulphamethoxazole is widely used and highly effective, but, like Bailey and Little,7 we find that this combination has replaced tetracyclines as the antibacterial agent most frequently responsible for hospital admissions of patients with sudden deterioration in renal function. The identification of the component which may cause a highly significant rise in serum-creatinine1,2,6 remains important because it is not practical to test renal function in every patient before giving such a widely used antibacterial agent. We have recently observed the simultaneous occurrence of a hypersensitivity rash and acute renal failure in four patients given co-trimoxazole, two of whom died (table). These findings suggest that hypersensitivity is one mechanism responsible for acute renal failure after co-trimoxazole. All four cases had underlying renal disease with renal impairment, and in two the renal biopsy at the time of the acute episode showed acute interstitial nephritis with prominent eosinophils. The first reports of nephrotoxic effects of co-trimoxazole appeared in 1969 when Hanley8 described one case of crystalluria and four cases of oliguria. Since that time several groups 1,2,4,6,7,9,10 have reported renal impairment in relation to co-trimoxazole. Others, however, have found no deterioration in renal function. Tasker et al. noted deterioration of renal function in only three of twenty patients treated with co-trimoxazole and attributed this to other causes. Rosenfeld et al." studied eighteen patients with neurogenic bladder and Hood et a1.5 twelve renal-transplant recipients and did not observe any renal function deterioration following co-trimoxazole. Conflict between these reports is probably more apparent than real since deterioration in renal function during co-trimoxazole therapy is infrequent, and in a prospective long-term crossover trial comparing co-trimoxazole and other antibacterial agents in fifteen patients we also found no evidence of deterioration in renal function. 12 Renal failure has been recognised as a complication of sulphonamide therapy for many years, and it seems clear that some patients develop renal failure as part of a hypersensitivity reaction to sulphonamides.13 Hypersensitivity skin reactions Kalowski, S., Nanra, R. S., Mathew, T. H., Kincaid-Smith, P. Lancet, 1973, i, 394. 2. Horn, B., Cottier, P. Schweiz. med. Wschr. 1974, 49, 1809. 3. Tasker, P. R. W., MacGregor, G. A., De Wardner, H., Thomas, R. D., Jones, N. F. Lancet, 1975, i, 1216. 4. Bailey, R. R., Little, P. J. Med. J. Aust. 1976, i, 914. 5. Hood, V. L., Hall, B. M., Horvath, J. S., Jones, B., Johnson, J. R., McGrath, B. P., Tillet, D. J. Aust. N. Z. Jl Med. 1976, 6, 86. 6. Shouval, D., Ligunsky, M., Ben-Sihay, D. Lancet, 1978, i, 244. 7 Bailey, R. R., Little, P. J. ibid. 1974, i, 712. 1.
8. 9
Hanley, T. Postgrad. med. J. 1969, 45, suppl. 85. Nanra, R. S., Andertson, J. L., Evans, M., Fairley, K. F., Kincaid-Smith, P. Med. J. Aust. 1975, i, 25. 10. Buchanan, N. Br. med. J. 1978, ii, 172. 11. Rosenfeld, J. B., Najensen, T., Grosswater, Z. Med. J. Aust. 1975, ii, 546. 12. McDonald, I., Hill, L., Kincaid-Smith, P. Unpublished. 13. Finlayson, W. B., Johnson, G. Lancet, 1978, ii, 682.
in 2% of patients receiving sulphonamides, and this may be dose related. 14,15 Stevens-Johnson syndrome (which occurred in two of the cases reported here) is a well-recognised adverse reaction to sulphonamides 16 and co-trimoxazole. 17,18 Our patients all received a dose of co-trimoxazole which was inappropriately high in relation to their renal function, hence accumulation of sulphonamides in the serum could have been a contributing factor. The two patients who died were elderly, and perhaps co-trimoxazole should be avoided in this group. While these cases cannot help to resolve the whole question of the reasons for the significant rise in serum-creatinine noted by various workers during co-trimoxazole administration, 1,2 ,6,77 it does identify one potentially serious group in which sulphonamide hypersensitivity was almost certainly responsible for both skin and renal lesions. Death in two of these patients and permanent impairment of renal function in other reports, 1,4 warrant re-emphasis of the potential nephrotoxicity of this widely used combination, particularly since full dosage is still frequently used even when renal function is impaired. The warning which the manufacturers give about reducing the dose when renal function is impaired is not sufficiently well known to prevent the occurrence of the serious complications described. Trimethoprim alone may well prove as effective as trimethoprim-sulphamethoxazole combinations, at least in urinary infections. Serious nephrotoxicity can be attributed to the sulphonamide component and provides an argument for the release of trimethoprim on its own for use in urinary-tract infections. occur
J. M. RICHMOND Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia
JUDITH A. WHITWORTH K. F. FAIRLEY PRISCILLA KINCAID-SMITH
MINIMUM EFFECTIVE DOSE OF CARBIMAZOLE
SiR,-Carbimazole is the most widely used antithyroid drug in Britain. The recommended starting dose in patients with hyperthyroidism is 30-60 mg daily in three or four divided doses, and when the patient is rendered euthyroid this can be reduced to a maintenance dose of 5-20 mg daily.l,2 In the treatment of thyrotoxicosis in pregnancy, the smallest dose sufficient to produce euthyroidism in the mother is preferable so that maternal hypothyroidism and fetal complications can be 14. The
Pharmacological Basis of Therapeutics, Goodman, (editors), p. 1196. New York, 1970. 15. Robinson, M. F., Campbell, G. R., Craswell, P. W. Clin
L.
S., Gilman, A.
Toxicol. 1972,
10,
411. 16. Australian
Drug Evaluation Committee. Med. J. Aust. 1972, i, 435 17. Kikuchi, S., Okazaki, T Lancet, 1978, ii, 580. 18. Bernstein, L. S., Cooper, J. ibid. 1978, i, 988. 1. Solomon, D. H., in Werner, S. C., Ingbar, S. H. (editors) The fundamental and clinical text; p. 816. 1978. 2. British National Formulary 1976-1978; p. 289
CLINICAL DETAILS IN FOUR PATIENTS WITH CO-TRIMOXAZOLE HYPERSENSITIVITY
Thyroid:
a
494 In some patients a daily dose of 10 mg carbimazole may be effective as 40 mg in the treatment of thyrotoxicosis. A dose of 40 mg carbimazole daily may have much greater influence on the effective iodide clearance in one patient than it has in another, and detailed kinetic analysis of thyroidal uptake of radioactive iodide is of value in explaining the variability of the response to antithyroid drugs commonly observed in clinical practice. In the treatment of thyrotoxicosis in pregnancy, the best initial dose seems to be 10-15 mg carbimazole daily (or 6-8 mg methimazole). The dosage of carbimazole used in the treatment of thyrotoxicosis is usually quoted as being similar to that of methimazole.’ However, carbimazole is rapidly converted to methimazole both in vivo and in vitro,6.7 and 10 mg carbimazole is hydrolysed to give about 6 mg of methimazole. as
Department of Medicine, Gardiner Institute, Western Infirmary, Glasgow G11 6NT; and Department of Clinical Physics and
Bio-Engineering, West of Scotland Health Boards,
Glasgow
L. C. K. LOW T. E. HILDITCH W. D. ALEXANDER
BETA-BLOCKER WITHDRAWAL SYNDROME
SIR,-We, like Dr Meinertz and colleagues (Feb. 3, p. 270) have seen an example of the "beta-blocker withdrawal syndrome" when metoprolol rather than propranolol was
abruptly stopped. Binding-rates
and clearance data.
avoided.3 Since there is
no information on the smallest effective dose of carbimazole, we present the following data.
Four untreated thyrotoxic patients with diffuse toxic goitre were treated for consecutive periods of one week with varying doses of carbimazole 12-hourly. Three patients were started at 5 mg per day for the first week and the dose was increased weekly to 10, 20, 30, and 40 mg per day during the subsequent weeks. The remaining patient received 40 mg per day and the dose was reduced weekly to 30, 20, and 10 mg per day. The kinetics of thyroidal uptake of intravenous 132I-iodide (50 µCi) was investigated before treatment and on the last day of each weekly treatment period. We measured plasma radioactivity and thyroidal uptake with an uptake counter, followed by a perchlorate discharge test (300 mg sodium perchlorate intravenously) after one hour. Each kinetic investigation was done 6 h after the oral dose of carbimazole in all patients. The thyroidal uptake and plasma radioactivity data were analysed to provide estimations of the binding-rate and effective iodide clearance.4,’
The variations in binding-rate and effective iodide clearexpressed as a percentage of the unidirectional clearance, for different doses of carbimazole are shown in the figure. At dose of 5 mg daily, the binding-rate is reduced from more than 0-150 min-’ before treatment to a mean value of 0.021 min1 in three patients (A, C, and D). In two (C and D), the effective clearance fell to 15-18° but in one (A) clearance remained high, being at the lower limit of the range when binding is not inhibited (75-100%). Higher doses of carbimazole resulted in further reduction of the binding-rate constant and effective iodide clearance. However, in only one patient (D), in whom both indices fell progressively with increasing dosage, was there any convincing change in the efficacy of carbimazole over the dose range of 10-40 mg/day. The results observed in patient A were uncharacteristic in that the effective iodide clearance remained relatively high even at a dose of 40 mg/ day. Kinetic analysis suggested that this was principally due to an unusually low exit-rate (0-008 min-1 compared with 0 - 024-0118 min-1 in the remaining three patients. ance,
3. 4. 5
Hamburger, J. I. Obstet. Gynec. 1972, 40, 114 Robertson, J. W. K., and others in Dynamic Studies with Radioisotopes Medicine, p. 199. International Atomic Energy Agency, Vienna, 1971. Hilditch,T. E. PH.D. thesis, University of Glasgow, 1978.
Blood-pressure and pulse record showing prolol was stopped. M=metoprolol ; L=labetalol.
increases after meto-
A 68-year-old woman was admitted for obesity and review of blood-pressure control. Her exercise tolerance was poor but she had no specific symptoms of ischaemic heart-disease. Metoprolol 200 mg daily was stopped as her blood-pressure was then normal (see figure). Within 24 h her heart-rate had increased. She then complained of palpitations and became very anxious. An E.C.G. showed a sinus tachycardia of 130/min,
in
6. Marchant, B., and others. J. clin. Endocr Metab 1972, 34, 847. 7 Skellern, G. G., and others Br. J. clin. Pharmac. 1974, 1, 265.
SIR,-In 1973 we reported deterioration in renal function in sixteen patients in relation to co-trimoxazole,’ and this stimulated considerable debate.2-6 The combination of trimethoprim and sulphamethoxazole is widely used and highly effective, but, like Bailey and Little,7 we find that this combination has replaced tetracyclines as the antibacterial agent most frequently responsible for hospital admissions of patients with sudden deterioration in renal function. The identification of the component which may cause a highly significant rise in serum-creatinine1,2,6 remains important because it is not practical to test renal function in every patient before giving such a widely used antibacterial agent. We have recently observed the simultaneous occurrence of a hypersensitivity rash and acute renal failure in four patients given co-trimoxazole, two of whom died (table). These findings suggest that hypersensitivity is one mechanism responsible for acute renal failure after co-trimoxazole. All four cases had underlying renal disease with renal impairment, and in two the renal biopsy at the time of the acute episode showed acute interstitial nephritis with prominent eosinophils. The first reports of nephrotoxic effects of co-trimoxazole appeared in 1969 when Hanley8 described one case of crystalluria and four cases of oliguria. Since that time several groups 1,2,4,6,7,9,10 have reported renal impairment in relation to co-trimoxazole. Others, however, have found no deterioration in renal function. Tasker et al. noted deterioration of renal function in only three of twenty patients treated with co-trimoxazole and attributed this to other causes. Rosenfeld et al." studied eighteen patients with neurogenic bladder and Hood et a1.5 twelve renal-transplant recipients and did not observe any renal function deterioration following co-trimoxazole. Conflict between these reports is probably more apparent than real since deterioration in renal function during co-trimoxazole therapy is infrequent, and in a prospective long-term crossover trial comparing co-trimoxazole and other antibacterial agents in fifteen patients we also found no evidence of deterioration in renal function. 12 Renal failure has been recognised as a complication of sulphonamide therapy for many years, and it seems clear that some patients develop renal failure as part of a hypersensitivity reaction to sulphonamides.13 Hypersensitivity skin reactions Kalowski, S., Nanra, R. S., Mathew, T. H., Kincaid-Smith, P. Lancet, 1973, i, 394. 2. Horn, B., Cottier, P. Schweiz. med. Wschr. 1974, 49, 1809. 3. Tasker, P. R. W., MacGregor, G. A., De Wardner, H., Thomas, R. D., Jones, N. F. Lancet, 1975, i, 1216. 4. Bailey, R. R., Little, P. J. Med. J. Aust. 1976, i, 914. 5. Hood, V. L., Hall, B. M., Horvath, J. S., Jones, B., Johnson, J. R., McGrath, B. P., Tillet, D. J. Aust. N. Z. Jl Med. 1976, 6, 86. 6. Shouval, D., Ligunsky, M., Ben-Sihay, D. Lancet, 1978, i, 244. 7 Bailey, R. R., Little, P. J. ibid. 1974, i, 712. 1.
8. 9
Hanley, T. Postgrad. med. J. 1969, 45, suppl. 85. Nanra, R. S., Andertson, J. L., Evans, M., Fairley, K. F., Kincaid-Smith, P. Med. J. Aust. 1975, i, 25. 10. Buchanan, N. Br. med. J. 1978, ii, 172. 11. Rosenfeld, J. B., Najensen, T., Grosswater, Z. Med. J. Aust. 1975, ii, 546. 12. McDonald, I., Hill, L., Kincaid-Smith, P. Unpublished. 13. Finlayson, W. B., Johnson, G. Lancet, 1978, ii, 682.
in 2% of patients receiving sulphonamides, and this may be dose related. 14,15 Stevens-Johnson syndrome (which occurred in two of the cases reported here) is a well-recognised adverse reaction to sulphonamides 16 and co-trimoxazole. 17,18 Our patients all received a dose of co-trimoxazole which was inappropriately high in relation to their renal function, hence accumulation of sulphonamides in the serum could have been a contributing factor. The two patients who died were elderly, and perhaps co-trimoxazole should be avoided in this group. While these cases cannot help to resolve the whole question of the reasons for the significant rise in serum-creatinine noted by various workers during co-trimoxazole administration, 1,2 ,6,77 it does identify one potentially serious group in which sulphonamide hypersensitivity was almost certainly responsible for both skin and renal lesions. Death in two of these patients and permanent impairment of renal function in other reports, 1,4 warrant re-emphasis of the potential nephrotoxicity of this widely used combination, particularly since full dosage is still frequently used even when renal function is impaired. The warning which the manufacturers give about reducing the dose when renal function is impaired is not sufficiently well known to prevent the occurrence of the serious complications described. Trimethoprim alone may well prove as effective as trimethoprim-sulphamethoxazole combinations, at least in urinary infections. Serious nephrotoxicity can be attributed to the sulphonamide component and provides an argument for the release of trimethoprim on its own for use in urinary-tract infections. occur
J. M. RICHMOND Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia
JUDITH A. WHITWORTH K. F. FAIRLEY PRISCILLA KINCAID-SMITH
MINIMUM EFFECTIVE DOSE OF CARBIMAZOLE
SiR,-Carbimazole is the most widely used antithyroid drug in Britain. The recommended starting dose in patients with hyperthyroidism is 30-60 mg daily in three or four divided doses, and when the patient is rendered euthyroid this can be reduced to a maintenance dose of 5-20 mg daily.l,2 In the treatment of thyrotoxicosis in pregnancy, the smallest dose sufficient to produce euthyroidism in the mother is preferable so that maternal hypothyroidism and fetal complications can be 14. The
Pharmacological Basis of Therapeutics, Goodman, (editors), p. 1196. New York, 1970. 15. Robinson, M. F., Campbell, G. R., Craswell, P. W. Clin
L.
S., Gilman, A.
Toxicol. 1972,
10,
411. 16. Australian
Drug Evaluation Committee. Med. J. Aust. 1972, i, 435 17. Kikuchi, S., Okazaki, T Lancet, 1978, ii, 580. 18. Bernstein, L. S., Cooper, J. ibid. 1978, i, 988. 1. Solomon, D. H., in Werner, S. C., Ingbar, S. H. (editors) The fundamental and clinical text; p. 816. 1978. 2. British National Formulary 1976-1978; p. 289
CLINICAL DETAILS IN FOUR PATIENTS WITH CO-TRIMOXAZOLE HYPERSENSITIVITY
Thyroid:
a
494 In some patients a daily dose of 10 mg carbimazole may be effective as 40 mg in the treatment of thyrotoxicosis. A dose of 40 mg carbimazole daily may have much greater influence on the effective iodide clearance in one patient than it has in another, and detailed kinetic analysis of thyroidal uptake of radioactive iodide is of value in explaining the variability of the response to antithyroid drugs commonly observed in clinical practice. In the treatment of thyrotoxicosis in pregnancy, the best initial dose seems to be 10-15 mg carbimazole daily (or 6-8 mg methimazole). The dosage of carbimazole used in the treatment of thyrotoxicosis is usually quoted as being similar to that of methimazole.’ However, carbimazole is rapidly converted to methimazole both in vivo and in vitro,6.7 and 10 mg carbimazole is hydrolysed to give about 6 mg of methimazole. as
Department of Medicine, Gardiner Institute, Western Infirmary, Glasgow G11 6NT; and Department of Clinical Physics and
Bio-Engineering, West of Scotland Health Boards,
Glasgow
L. C. K. LOW T. E. HILDITCH W. D. ALEXANDER
BETA-BLOCKER WITHDRAWAL SYNDROME
SIR,-We, like Dr Meinertz and colleagues (Feb. 3, p. 270) have seen an example of the "beta-blocker withdrawal syndrome" when metoprolol rather than propranolol was
abruptly stopped. Binding-rates
and clearance data.
avoided.3 Since there is
no information on the smallest effective dose of carbimazole, we present the following data.
Four untreated thyrotoxic patients with diffuse toxic goitre were treated for consecutive periods of one week with varying doses of carbimazole 12-hourly. Three patients were started at 5 mg per day for the first week and the dose was increased weekly to 10, 20, 30, and 40 mg per day during the subsequent weeks. The remaining patient received 40 mg per day and the dose was reduced weekly to 30, 20, and 10 mg per day. The kinetics of thyroidal uptake of intravenous 132I-iodide (50 µCi) was investigated before treatment and on the last day of each weekly treatment period. We measured plasma radioactivity and thyroidal uptake with an uptake counter, followed by a perchlorate discharge test (300 mg sodium perchlorate intravenously) after one hour. Each kinetic investigation was done 6 h after the oral dose of carbimazole in all patients. The thyroidal uptake and plasma radioactivity data were analysed to provide estimations of the binding-rate and effective iodide clearance.4,’
The variations in binding-rate and effective iodide clearexpressed as a percentage of the unidirectional clearance, for different doses of carbimazole are shown in the figure. At dose of 5 mg daily, the binding-rate is reduced from more than 0-150 min-’ before treatment to a mean value of 0.021 min1 in three patients (A, C, and D). In two (C and D), the effective clearance fell to 15-18° but in one (A) clearance remained high, being at the lower limit of the range when binding is not inhibited (75-100%). Higher doses of carbimazole resulted in further reduction of the binding-rate constant and effective iodide clearance. However, in only one patient (D), in whom both indices fell progressively with increasing dosage, was there any convincing change in the efficacy of carbimazole over the dose range of 10-40 mg/day. The results observed in patient A were uncharacteristic in that the effective iodide clearance remained relatively high even at a dose of 40 mg/ day. Kinetic analysis suggested that this was principally due to an unusually low exit-rate (0-008 min-1 compared with 0 - 024-0118 min-1 in the remaining three patients. ance,
3. 4. 5
Hamburger, J. I. Obstet. Gynec. 1972, 40, 114 Robertson, J. W. K., and others in Dynamic Studies with Radioisotopes Medicine, p. 199. International Atomic Energy Agency, Vienna, 1971. Hilditch,T. E. PH.D. thesis, University of Glasgow, 1978.
Blood-pressure and pulse record showing prolol was stopped. M=metoprolol ; L=labetalol.
increases after meto-
A 68-year-old woman was admitted for obesity and review of blood-pressure control. Her exercise tolerance was poor but she had no specific symptoms of ischaemic heart-disease. Metoprolol 200 mg daily was stopped as her blood-pressure was then normal (see figure). Within 24 h her heart-rate had increased. She then complained of palpitations and became very anxious. An E.C.G. showed a sinus tachycardia of 130/min,
in
6. Marchant, B., and others. J. clin. Endocr Metab 1972, 34, 847. 7 Skellern, G. G., and others Br. J. clin. Pharmac. 1974, 1, 265.
