Antibiotics
Aiya Almogaber, PharmD
Older adults who take trimethoprim-sulfamethoxazole (TMP-SMX) while on digoxin are at a much higher risk of dangerous adverse effects compared with those who take amoxicillin, according to research published in the July 2024 issue of the Journal of Human Pharmacology and Drug Therapy. In fact, the study found that patients on TMP-SMX were almost six times more likely to need a hospital visit for digoxin toxicity.
“These results stress the importance of careful antibiotic selection in this population,” said lead author Flory Tsobo Muanda, MD, PhD, assistant professor at Western University in London, Ontario, Canada.
The research focused on the 30-day risk of digoxin toxicity, which can lead to adverse effects such as nausea, dizziness, or life-threatening heart complications. Researchers analyzed over 47,000 patients aged 66 years and older who were continuously using digoxin and had been newly prescribed either TMP-SMX or amoxicillin.
Of the study patients, 10,273 were prescribed TMP-SMX and 37,688 received amoxicillin. The results were clear: 0.48% of those taking TMP-SMX developed digoxin toxicity, while only 0.08% of those on amoxicillin experienced the same issue. Although the percentages seem small, this translates to a significant difference in real terms: One patient would be expected to experience digoxin toxicity for every 200 patients prescribed TMP-SMX compared to just one in over 1,000 for those prescribed amoxicillin.
Why TMP-SMX could increase risk
According to the study, TMP-SMX interferes with the renal secretion of digoxin, which results in higher concentrations of digoxin in the bloodstream. This is particularly concerning for older adults, whose kidney function often diminishes with age, making them more susceptible to drug interactions that depend on renal clearance.
The study findings also seem to highlight a gap in clinical practice. Although the digoxin product monograph recommends reducing the dose of digoxin by 15% to 30% when it is co-prescribed with TMP-SMX, only 5% of patients in the study had their digoxin dose reduced.
“Biological plausibility does not necessarily mean a drug–drug interaction will result in a clinical outcome in humans, and vice versa,” said Muanda.
This lack of dose adjustment may have contributed to the significantly higher rate of toxicity observed in patients on TMP-SMX compared with those on amoxicillin. The findings suggest that closer monitoring of serum digoxin levels is essential when TMP-SMX is prescribed, especially in older adults who are at higher risk for toxicity.
By contrast, amoxicillin does not significantly interfere with the renal clearance of digoxin, which may explain why patients prescribed amoxicillin had a much lower incidence of toxicity.
Limitations
Some cases of toxicity might have been missed, especially if they were less severe and didn’t require hospitalization, mainly because the researchers couldn’t directly measure the levels of digoxin in patients’ blood. Instead, they looked at hospital records to see how many patients were admitted with digoxin toxicity.
Another limitation of the study is that the researchers only followed patients for 30 days, so it’s unclear whether the risks persisted over a longer period of time. More research is needed to fully understand how TMP-SMX affects digoxin levels after more than 30 days.
“I foresee a growing focus on studying drug–drug interactions in vulnerable populations, such as those with chronic kidney disease or older adults, where these interactions may have more severe consequences,” said Muanda. “This could lead to updated prescribing guidelines and increased awareness of the risks associated with commonly used medications.”
What this means for patients
The findings reinforce the need for careful management when prescribing antibiotics to older adults on digoxin. TMP-SMX is a useful antibiotic for many infections, but for patients on digoxin, clinicians should consider safer alternatives, such as amoxicillin. If TMP-SMX must be used, clinicians should monitor digoxin levels closely and adjust the dose if needed to prevent potential toxicity.
“While I initially thought this drug–drug interaction might not be harmful, I wasn’t entirely surprised by the finding,” said Muanda. “This interaction has biological plausibility, and our results support this mechanism.” ■