Trimethoprim-Sulfamethoxazole May Increase Risk for Hyperkalemia in the Elderly

Laurie Barclay, MD

July 07, 2010

July 7, 2010 — Use of trimethoprim-sulfamethoxazole (TMP-SMX) may increase risk for hyperkalemia requiring hospitalization in older adults, but there is no added risk when used in combination with beta-blockers, according to the results of 2 studies. The first is a nested case-control study reported online July 1 in the Journal of the American Society of Nephrology, and the second is a population-based study reported in the June 28 issue of the Archives of Internal Medicine.

"The simultaneous use of beta adrenergic receptor blockers (beta-blockers) and [TMP-SMX] may confer a high risk of hyperkalemia," write Matthew A. Weir, MD, from the University of Western Ontario in London, Canada, and colleagues. "Two nested case-control studies were conducted to examine the association between hospitalization for hyperkalemia and the use of TMP-SMX in older patients receiving beta-blockers."

The study cohort consisted of 299,749 adults at least 66 years of age who used beta-blockers and were identified using linked health administrative records from Ontario, Canada. These records also allowed data collection regarding medication use and hospital admissions for hyperkalemia.

From 1994 to 2008, 189 patients were hospitalized for hyperkalemia within 14 days of receiving a study antibiotic. Risk for hyperkalemia requiring hospital admission was 5-fold greater for TMP-SMX than for amoxicillin (adjusted odds ratio, 5.1; 95% confidence interval, 2.8 - 9.4). Ciprofloxacin, norfloxacin, and nitrofurantoin were not associated with risk for hyperkalemia requiring hospitalization.

The association of TMP-SMX with risk for hyperkalemia requiring hospitalization was greater at higher doses of TMP-SMX. Repetition of the primary analysis in a cohort of adults not using beta-blockers showed that the risk for hyperkalemia for TMP-SMX vs amoxicillin was not significantly different from that found among users of beta-blockers.

"Although TMP-SMX is associated with an increased risk of hyperkalemia in older adults, these findings show no added risk when used in combination with beta-blockers," the study authors write.

Limitations of this study include nonrandom allocation of study antibiotics leading to possible residual confounding; lack of information on risk factors such as dietary potassium intake, nonprescription medication use, and medication compliance; possible confounding by indication; and possible misclassification of exposure and outcome variables.

"Our study shows a significant, biologically plausible, dose-dependent risk of hyperkalemia among elderly users of TMP-SMX," the study authors conclude.

"Physicians should be cognizant of this risk and consider measurement of serum potassium in older patients treated with this antibiotic."

The population-based, nested case-control study by Tony Antoniou, BScPharm, PharmD, from the University of Toronto in Ontario, Canada, and colleagues aimed to determine the risk for hyperkalemia-associated hospitalization in elderly patients treated with TMP-SMX along with either an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB).

The study cohort consisted of residents of Ontario, Canada, who were at least 66 years of age and who were receiving continuous treatment with either an ACEI or an ARB. Cases were defined as patients with a hyperkalemia-associated hospitalization within 14 days of receiving a prescription for TMP-SMX, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin. Based on age, sex, and presence or absence of chronic renal disease and diabetes, up to 4 control patients were matched to each case.

Of 4148 hospitalizations involving hyperkalemia during the 14-year study period, 371 occurred within 14 days of antibiotic exposure. Use of TMP-SMX conferred a nearly 7-fold increased risk for hyperkalemia-associated hospitalization compared with amoxicillin (adjusted odds ratio, 6.7; 95% confidence interval, 4.5 - 10.0). The other antibiotics studied were not associated with increased risk.

Study limitations include use of administrative data, lack of information regarding other risk factors and outpatient events, lack of generalizability to younger patients with fewer risk factors for hyperkalemia, and lack of validation of the accuracy of hospital discharge coding for hyperkalemia.

"Among older patients treated with ACEIs or ARBs, the use of trimethoprim-sulfamethoxazole is associated with a major increase in the risk of hyperkalemia-associated hospitalization relative to other antibiotics," the study authors write. "Alternate antibiotic therapy should be considered in these patients when clinically appropriate."

Dr. Weir's study was supported by research funds from the Ontario Drug Policy Research Network and the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. The authors of this study have disclosed no relevant financial relationships. Dr. Antoniou has received unrestricted research grants from Glaxo-Smith-Kline Inc, Pfizer, and Merck Frosst, and a second author of this study, Dr. Loutfy, has received unrestricted research grants for other projects from, and has acted as a speaker and advisor for, Abbott Canada, Merck Frosst, Pfizer, Bristol-Myers Squibb, Tibotec, Boehringer Ingelheim, and Glaxo-Smith-Kline Inc. Please see the journal article for sources of support of the study authors.

J Am Soc Nephrol. Published online July 1, 2010.

Arch Intern Med. 2010;170:1045-1049. Abstract

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