The authors suggest that the increased risk of sudden death observed in this study is related to hyperkalaemia resulting from a drug interaction between co-trimoxazole (trimethoprim) and spironolactone. The mechanism by which trimethoprim can precipitate hyperkalaemia in patients receiving spironolactone relates to inhibition of sodium channels in the luminal membrane of the distal tubule, which results in impaired potassium secretion and sodium reabsorption. They recommend that the risks of this drug interaction can be minimised or avoided through the use of alternative antibiotics, careful patient selection and monitoring, and limited duration of antibiotic treatment, when clinically appropriate.
Although ciprofloxacin has no known drug interaction with spironolactone, they postulate that the observed increased risk of sudden death may be explained by its proarrhythmic properties, variation in treatment indication or its use in patients with particularly severe urinary tract infections.
The authors do however go on to acknowledge the limitations of their study, which should be considered when interpreting the results. The study was based on analysis of administrative data, so there was no access to clinical information (including indication for antibiotic treatment, potassium levels, renal function, and whether antibiotics were dosed appropriately). In addition the population of the study was older adults (the findings may not be generalisable to younger patients) and cases had a greater co-morbidity burden relative to controls. As with all observational studies, the possibility of unmeasured confounders cannot be excluded.
Of note, the SPC for Aldactone® (spironolactone) does not list any specific interactions with co-trimoxazole/ trimethoprim or ciprofloxacin; it does however state that concomitant use of drugs known to cause hyperkalaemia with spironolactone may result in severe hyperkalaemia.
Stockley’s Drug Interactions states that there appears to have been no specific case reports of hyperkalaemia in patients taking trimethoprim with potassium-sparing diuretics (including spironolactone). In theory however the risk of hyperkalaemia would be increased by concurrent use, and it may therefore be prudent to monitor potassium levels.