The longer I practice medicine, the more nervous I get about medications, especially when patients are already on other drugs for chronic diseases. I much prefer deprescribing.
A recent study on the common antibiotic cotrimoxazole, which is a combination of sulfamethoxazole and trimethoprim, and often referred to by its brand name, Bactrim or Septra, lends credence to the notion that combining drugs can be dangerous.
In a case-control study of more than 1.6 million patients over 17 years, researchers from Canada found that cotrimoxazole was associated with a three-fold increased risk of sudden death when used in older patients (age > 66) taking angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).
Steve Stiles covered the research on theHeart.org. Here is a link to the full article in the British Medical Journal. (A side note: The authors wrote the paper in the active voice. It was a pleasure to read.)
The Canadian researchers argued the association was plausible, and that the likely mechanism of sudden death involved high potassium levels (hyperkalemia). Their findings provide important messages to caregivers and patients alike.
In a general sense, this study gives me pause because cotrimoxazole carries such a benign reputation. “Go ahead and just cover him with some Bactrim. How can it hurt?â€ goes the (fast) thinking.
And be honest; did you know trimethoprim blocks the epithelial sodium channel (ENaC) in the distal nephron, thereby impairing potassium elimination? I would guess most caregivers who prescribe cotrimoxazole do not have a working knowledge of epithelial cells in the distal nephron. I did not.
But thatâ€™s the thing about drugs: they donâ€™t do just one thing. Trimethoprim is given to kill bacteria but it also acts like amiloride, (a potassium-sparing diuretic) in the kidney. In a young patient with good organ function, this is not significant. Young healthy patients have organ reserve.
Now consider older patients with lifestyle diseases, such as obesity, heart failure, diabetes and high blood pressure, conditions that impair organ function. Many of these patients take (guideline-directed) drugs called angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). ACE inhibitors and ARBs are used a lot. More than 250 million prescriptions are dispensed in the US each year.
These drugs, which act via the kidney, can increase potassium levels in up to 10% of patients. Diabetic patients require special consideration, as many of them are especially prone to high potassium levels.
So now you can see the problem. Cotrimoxazole is also a commonly used antibiotic, with up to 50 million prescriptions written each year. The authors have noted in previous work that cotrimoxazole combined with ACE/ARB drugs associated with a sevenfold increase in the risk of hospital admission for elevated potassium levels. Case reports have also confirmed life-threatening high potassium levels with the combination.
The finding of a threefold increased risk of death with cotrimoxazole over amoxicillin in older patients taking ACE inhibitors or ARBs teaches us to consider other antibiotics in these patients. That’s the easy lesson.
The story here is not just about the specifics of an important drug-drug interaction. Itâ€™s about the approach to treating people with diseases. Drugs are used too much. How many of those 250 million ACE/ARB prescriptions could have been avoided if exercise was seen asÂ a medicine,Â or if elderly patients had been deprescribed? Likewise, how many of the 50 million patients treated with cotrimoxazole had a viral, not bacterial, infection?
The default to pharmacologic treatment needs to change. Drugs have a place. I use them everyday. But they arenâ€™t free. They come with tradeoffs, and, the more drugs we use together in a patient, the more tradeoffs we should expect.
Finally, some would have electronic health records protecting us from prescribing drugs with dangerous interactions. This is magical thinking. Computers are fine. The problem lies with the humans that program the machines. If the goal of the computer is to capture every possible piece of billable data and alert us to every possible bad thing that could happen, the machine becomes part of the patient safety problem.
Be careful out there. Think about tradeoffs. Tradeoffs are truth.