Among older individuals, the commonly used antibiotic trimethoprim-sulfamethoxazole (TMP-SMX) is associated with the development of hyperkalemia requiring hospitalization, researchers found.
The relationship was independent of the concomitant use of beta-blockers, Amit Garg, MD, PhD, of the University of Western Ontario in London, and colleagues reported online in the Clinical Journal of the American Society of Nephrology.
"Our study shows a significant, biologically plausible, dose-dependent risk of hyperkalemia among elderly users of TMP-SMX," they wrote. "Physicians should be cognizant of this risk and consider measurement of serum potassium in older patients treated with this antibiotic."
Action Points
- Explain to interested patients that this study did not find that combining trimethoprim-sulfamethoxazole and a beta-blocker magnified the risk of developing hyperkalemia.
The use of beta-blockers has become increasingly common over the past decade, and "their role in hyperkalemia through inhibition of cellular adrenergic receptor-dependent potassium translocation has been extensively studied," according to the researchers.
TMP-SMX also is commonly used, accounting for 30% of all antibiotics prescribed for urinary tract infections. It has also been associated with hyperkalemia. Trimethoprim is structurally related to the potassium-sparing diuretic amiloride and has been shown to block sodium channels in the distal nephron, which reduces potassium secretion.
Garg and his colleagues hypothesized that coadministration of TMP-SMX and a beta-blocker would be associated with an even greater risk of hyperkalemia than administration of either drug alone.
Using health administrative records from Ontario for 1994 to 2008, the researchers identified 299,749 beta-blocker users ages 66 and older.
During the study period, 189 individuals were hospitalized for hyperkalemia within 14 days of receiving one of five study antibiotics -- amoxicillin, TMP-SMX, ciprofloxacin, norfloxacin (Noroxin), or nitrofurantoin.
The patients were matched by age, sex, history of chronic kidney disease, and history of diabetes with 641 beta-blocker users who were not admitted for hyperkalemia.
Amoxicillin was used as the reference drug because it has not been associated with hyperkalemia.
Compared with use of amoxicillin, use of TMP-SMX was associated with higher odds of being hospitalized with hyperkalemia (OR 5.1, 95% CI 2.8 to 9.4) after adjustment for comorbidities, number of prescriptions, socioeconomic status, congestive heart failure, coronary artery disease, previous episodes of hyperkalemia, and use of medications that may affect serum potassium concentrations.
The association was strongest at the higher, double-strength dose of TMP-SMX compared with the single-strength dose (OR 6.6 versus 3.4).
The absolute risk of hospitalization for hyperkalemia was 6.9 per 1,000 prescriptions for TMP-SMX and 2.9 for amoxicillin.
There was no greater chance of hyperkalemia hospitalization with the other three antibiotics.
When the primary analysis was repeated in a group of patients who were not taking beta-blockers, TMP-SMX was still associated with hospitalization for hyperkalemia (OR 5.8, 95% CI 4.7 to 7.3). The odds ratio was not significantly different than that found in patients who were using beta-blockers (P=0.65).
"This indicated the risk of hyperkalemia was attributable to TMP-SMX alone, rather than its combination with beta-blockers," the researchers wrote.
Despite the risk, TMP-SMX remains a useful antibiotic, they said.
"We recognize the importance of TMP-SMX in the modern antibiotic armamentarium and do not suggest curtailing its use," they wrote. "Rather, it is likely that some cases of severe morbidity associated with TMP-SMX may be prevented through simple measures such as serum potassium testing."
They acknowledged some limitations of the study, including the nonrandom allocation of antibiotics, the possibility that TMP-SMX was used for more severe infections, and the reliance on administrative databases and diagnostic codes to define the study outcome. In addition, information regarding dietary potassium intake, nonprescription medication use, and medication compliance was not available.
Disclosures
The study was supported by research funds from the Ontario Drug Policy Research Network and 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). Garg was supported by a clinician-scientist award from the Canadian Institutes of Health Research (CIHR). His co-authors reported support from the Clinician Investigator Program at the University of Western Ontario, MOHLTC, a CIHR New Investigator Award, a CIHR fellowship, and clinician-scientist funding from the Department of Medicine of the University of Western Ontario.
All of the researchers reported that they had no conflicts of interest.
Primary Source
Clinical Journal of the American Society of Nephrology
Weir M, et al "Beta-blockers, trimethoprim-sulfamethoxazole, and the risk of hyperkalemia requiring hospitalization in the elderly: a nested case-control study" Clin J Am Soc Nephrol 2010; DOI: 10.2215/CJN.01970310.