Intended for healthcare professionals

CCBYNC Open access

Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study

BMJ 2011; 343 doi: (Published 12 September 2011) Cite this as: BMJ 2011;343:d5228
  1. Tony Antoniou, clinical pharmacy specialist12,
  2. Tara Gomes, epidemiologist13,
  3. Muhammad M Mamdani, director1345,
  4. Zhan Yao, analyst3,
  5. Chelsea Hellings, project manager3,
  6. Amit X Garg, professor36,
  7. Matthew A Weir, assistant professor of medicine6,
  8. David N Juurlink, division head137
  1. 1University of Toronto, Toronto, ON, Canada
  2. 2Department of Family and Community Medicine, St Michael’s Hospital, Toronto
  3. 3Institute for Clinical Evaluative Sciences, Toronto
  4. 4Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto
  5. 5King Saud University, Riyadh, Saudi Arabia
  6. 6Division of Nephrology, University of Western Ontario, London, ON, Canada
  7. 7Sunnybrook Research Institute, Toronto
  1. Correspondence to: T Antoniou, 410 Sherbourne Street, 4th Floor, Toronto, ON, Canada, M4X 1K2 tantoniou{at}
  • Accepted 22 July 2011


Objectives To characterise the risk of admission to hospital for hyperkalaemia in elderly patients treated with trimethoprim-sulfamethoxazole in combination with spironolactone.

Design Population based nested case-control study.

Setting Ontario, Canada, from 1 April 1992 to 1 March 2010.

Participants Cases were residents of Ontario aged 66 years or above receiving chronic treatment with spironolactone and admitted to hospital with hyperkalaemia within 14 days of receiving a prescription for either trimethoprim-sulfamethoxazole, amoxicillin, norfloxacin, or nitrofurantoin. Up to four controls for each case were identified from the same cohort, matched on age, sex, and presence or absence of chronic kidney disease and diabetes, and required to have received one of the study antibiotics within 14 days before the case’s index date.

Main outcome measures Odds ratio for association between admission to hospital with hyperkalaemia and receipt of a study antibiotic in the preceding 14 days, adjusted for conditions and drugs that may influence risk of hyperkalaemia.

Results During the 18 year study period, 6903 admissions for hyperkalaemia were identified, 306 of which occurred within 14 days of antibiotic use. Of these, 248 (81%) cases were matched to 783 controls. 10.8% (17 859/165 754) of spironolactone users received at least one prescription for trimethoprim-sulfamethoxazole. Compared with amoxicillin, prescription of trimethoprim-sulfamethoxazole was associated with a marked increase in the risk of admission to hospital for hyperkalaemia (adjusted odds ratio 12.4, 95% confidence interval 7.1 to 21.6). The population attributable fraction was 59.7%, suggesting that approximately 60% of all cases of hyperkalaemia in older patients taking spironolactone and treated with an antibiotic for a urinary tract infection could be avoided if trimethoprim-sulfamethoxazole was not prescribed. Treatment with nitrofurantoin was also associated with an increase in the risk of hyperkalaemia (adjusted odds ratio 2.4, 1.3 to 4.6), but no such risk was found with norfloxacin (adjusted odds ratio 1.6, 0.8 to 3.4)

Conclusions Among older patients receiving spironolactone, treatment with trimethoprim-sulfamethoxazole was associated with a major increase in the risk of admission to hospital for hyperkalaemia. This drug combination should be avoided when possible.


  • We thank Brogan, Ottawa, for use of their Drug Product and Therapeutic Class Database.

  • Contributors: TA, TG, DNJ, MMM, CH, AXG, and MAW were involved in the study concept and design. TG and ZY were responsible for data acquisition. All authors were involved in analysing and interpreting data. TA drafted the manuscript, and all authors critically revised it. TA, TG, and CH provided administrative, technical, or material support. TA is the guarantor.

  • Funding: TA is supported by a post-doctoral fellowship award from the Ontario HIV Treatment Network. AG is supported by a clinician scientist award from the Canadian Institutes of Health Research. This project was supported by research funds from the Ontario Drug Policy Research Network and by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. The opinions, results, and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred.

  • Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org_disclosure.pdf (available on request from the corresponding author). During the past three years, TA has received unrestricted research grants from GlaxoSmithKline, Merck, and Pfizer for different studies. All other authors declare no support from any company for the submitted work; no relationships with any companies that might have an interest in the submitted work in the previous 3 years; and no non-financial interests that may be relevant to the submitted work.

  • Ethical approval: This study was approved by the Research Ethics Board of the Sunnybrook Health Sciences Centre, Toronto.

  • Data sharing: No additional data available.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: and

View Full Text