339
COTRIMOXAZOLE AND FOLATE METABOLISM M. C. BATESON*
Gordon Hospital and Department of Therapeutics, Westminster
Hospital, London P. PENDHARKAR
J. P. L. A. HAYES
Department of Hœmatology Westminster Medical School, London
Cotrimoxazole 4 tablets daily (1 tablet = trimethoprim 80 mg and sulpha400 methoxazole mg) was given for a period of six to fourteen days to 13 inpatients, and serum-folate levels were measured before and one day after the course of treatment. The results were compared with those from 8 patients not receiving antibacterial therapy, tested on admission and one week later. Two assay techniques were used, one employing Lactobacillus casei and the other 125I-labelled folate isotope dilution. The microbiological technique showed a significant decline in folicacid levels in the serum after cotrimoxazole, and this decline was not seen in controls. By contrast, the radioisotope technique showed no significant alteration in serum-folate levels compared with controls. This suggests that cotrimoxazole does not depress true serum-folate and that many low microbiological results obtained during cotrimoxazole therapy reflect interference with the assay organism. There is insufficient evidence to incriminate cotrimoxazole as a significant cause of blood dyscrasias in excess of those which might occur on sulphonamide alone or even with other antibacterials.
Summary
Introduction MUCH has been written on the interference by cotrimoxazole with bone-marrow function and folate metabolism. This work has taken the forms of case-reports of blood dyscrasias,1-13 the assay of serum-folate in volun68 9 marrow biopteers and patients on cotrimoxazole,5 sies in patients on cotrimoxazole,2-59 and reports to th Committee for Safety of Medicines. Cases where standard doses of cotrimoxazole have been administered and some subsequent disturbance of folate metabolism or hxmatological change reported have included only one certain case of megaloblastic anaemia without other likelv caused This occurred after a year’s course of the drug *Present address
Department
of Medicine, Dundee
University.
and the serum-folate (bacterial) method was normal. Various changes such as anaemia, neutropenia, thrombocytopenia, and megaloblastosis of the marrow have been reported in patients on cotrimoxazole. Some workers have suggested that serum-folate levels fall on a sulphonamide/trimethoprim combination, 14-16 others that they remain normal. 17 Against reports in several patients of megaloblastic changes on cotrimoxazole must be set the finding in a controlled thirteen-week trial that 11 patients on cotrimoxazole did not have megaloblastosis, whereas 1 on placebo did.4We have assessed the validity of the microbiological technique of folate assay after the exhibition of cotrimoxazole by using the isotope dilution technique. 18-20 Methods
patients on standard courses of cotrimoxazole for urinary trior lower respiratory infections 4 tablets daily (1 tablet methoprim 80 mg and sulphamethoxazole 400 mg) for six to fourteen days had the following investigations immediately before and on the day after completing therapy: (a) Hb, white blood-cells, mean corpuscular volume (Coulter S), (b) platelets (Coulter ’Thrombocounter’) (c) Serum-vitamin-B12 (Euglena gracilis21) (d) Serum-folate (Lactobacillus casei) (e) red-bloodcell (R.B.c.) folate (L. casei) (j9 Serum folate (isotope dilution Bio Rad ’Quanta-Count’ Kit’9). 8 controls on no antibacterial or antifolate agents had the same investigations at a seven-day interval. Patients were generally studied immediately after hospital admission. To normal serum of a known folate activity were added serial dilutions of trimethoprim. The apparent serum-folate activity was then re-estimated. 13
=
Differences in ’folate levels were submitted to Student’s t tests, and correlation coefficients calculated (table i). 5 of the 13 trial patients had a final serum-folate (L. casei assay, twelve to twenty-four hours after the last dose of cotrimoxazole) less then lg/1; this was calculated as a value of 1 p.g/1. R.B.C. folate levels did not change.
paired
Results theradioisotope dilution technique there moderate fall in values for serum-folate in both the control patients and the patients on cotrimoxazole. A similar fall, of 25-30%, was seen in the microbiogically estimated results for the control patients. The initial radiofolate assay values correlate very well with the microbiological ones for both controls (r=0-76; and cotrimoxazole patients P
COTRIMOXAZOLE AND FOLATE METABOLISM M. C. BATESON*
Gordon Hospital and Department of Therapeutics, Westminster
Hospital, London P. PENDHARKAR
J. P. L. A. HAYES
Department of Hœmatology Westminster Medical School, London
Cotrimoxazole 4 tablets daily (1 tablet = trimethoprim 80 mg and sulpha400 methoxazole mg) was given for a period of six to fourteen days to 13 inpatients, and serum-folate levels were measured before and one day after the course of treatment. The results were compared with those from 8 patients not receiving antibacterial therapy, tested on admission and one week later. Two assay techniques were used, one employing Lactobacillus casei and the other 125I-labelled folate isotope dilution. The microbiological technique showed a significant decline in folicacid levels in the serum after cotrimoxazole, and this decline was not seen in controls. By contrast, the radioisotope technique showed no significant alteration in serum-folate levels compared with controls. This suggests that cotrimoxazole does not depress true serum-folate and that many low microbiological results obtained during cotrimoxazole therapy reflect interference with the assay organism. There is insufficient evidence to incriminate cotrimoxazole as a significant cause of blood dyscrasias in excess of those which might occur on sulphonamide alone or even with other antibacterials.
Summary
Introduction MUCH has been written on the interference by cotrimoxazole with bone-marrow function and folate metabolism. This work has taken the forms of case-reports of blood dyscrasias,1-13 the assay of serum-folate in volun68 9 marrow biopteers and patients on cotrimoxazole,5 sies in patients on cotrimoxazole,2-59 and reports to th Committee for Safety of Medicines. Cases where standard doses of cotrimoxazole have been administered and some subsequent disturbance of folate metabolism or hxmatological change reported have included only one certain case of megaloblastic anaemia without other likelv caused This occurred after a year’s course of the drug *Present address
Department
of Medicine, Dundee
University.
and the serum-folate (bacterial) method was normal. Various changes such as anaemia, neutropenia, thrombocytopenia, and megaloblastosis of the marrow have been reported in patients on cotrimoxazole. Some workers have suggested that serum-folate levels fall on a sulphonamide/trimethoprim combination, 14-16 others that they remain normal. 17 Against reports in several patients of megaloblastic changes on cotrimoxazole must be set the finding in a controlled thirteen-week trial that 11 patients on cotrimoxazole did not have megaloblastosis, whereas 1 on placebo did.4We have assessed the validity of the microbiological technique of folate assay after the exhibition of cotrimoxazole by using the isotope dilution technique. 18-20 Methods
patients on standard courses of cotrimoxazole for urinary trior lower respiratory infections 4 tablets daily (1 tablet methoprim 80 mg and sulphamethoxazole 400 mg) for six to fourteen days had the following investigations immediately before and on the day after completing therapy: (a) Hb, white blood-cells, mean corpuscular volume (Coulter S), (b) platelets (Coulter ’Thrombocounter’) (c) Serum-vitamin-B12 (Euglena gracilis21) (d) Serum-folate (Lactobacillus casei) (e) red-bloodcell (R.B.c.) folate (L. casei) (j9 Serum folate (isotope dilution Bio Rad ’Quanta-Count’ Kit’9). 8 controls on no antibacterial or antifolate agents had the same investigations at a seven-day interval. Patients were generally studied immediately after hospital admission. To normal serum of a known folate activity were added serial dilutions of trimethoprim. The apparent serum-folate activity was then re-estimated. 13
=
Differences in ’folate levels were submitted to Student’s t tests, and correlation coefficients calculated (table i). 5 of the 13 trial patients had a final serum-folate (L. casei assay, twelve to twenty-four hours after the last dose of cotrimoxazole) less then lg/1; this was calculated as a value of 1 p.g/1. R.B.C. folate levels did not change.
paired
Results theradioisotope dilution technique there moderate fall in values for serum-folate in both the control patients and the patients on cotrimoxazole. A similar fall, of 25-30%, was seen in the microbiogically estimated results for the control patients. The initial radiofolate assay values correlate very well with the microbiological ones for both controls (r=0-76; and cotrimoxazole patients P
