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.
Comments:
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?” 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 that’s the thing about drugs: they don’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. It’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 as a medicine, 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 aren’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.
JMM
Lisa says
So is the QT prolonging potential of Bactrim caused by it’s ability to promote hyperkalemia?
Anthony Pearson, MD, FACC says
Agree totally! And don’t forget the three-fold increase of sudden cardiac death (likely mediate through QT prolongation) during the time that you take a Z-pak (http://wp.me/p30zF0-98)
Dr. Www says
Shhh! Careful, John! You’re starting to sound like a doctor. What are you thinking? (Those “stakeholders” are getting pissed… I mean, don’t trust computers? Please! Get in together, will you? Otherwise that leadership position might have to go to someone else…)
Steve Goldstein says
A few years back, I had a confirmed UTI (P. mirabilis). I didn’t want to take Cipro because of possible side effects (including Achilles Tendon rupture), so the doc Rxed Bactrim instead. I was on Sotalol and Pradaxa (afib) at the time. I developed lesions on my tongue (blood gorged papules) and peeling skin on my genitals. I had never taken ACE/ARBs. Now, following second ablation, I am on Tikosyn and Pradaxa. I have tolerated Z-paks following dental surgery, but I keep my fingers crossed when I take it.
Lisa Bloomquist says
Thank you for the thoughtful and insightful post! I think that most people, doctors and patients alike, think that all antibiotics are as benign as amoxicillin. They’re not. Thank you for bringing attention to the dangers of cotrimoxazole. If you ever feel like covering the dangers of fluoroquinolones, I know that everyone going through fluoroquinolone toxicity syndrome would appreciate the attention and acknowledgement. Antibiotics aren’t “supposed” to cause multi-symptom, chronic illness. They’re not “supposed” to do the same thing to GABA-A receptors as protracted benzodiazepine withdrawal. They’re “supposed” to be out of your system within hours, or at least days, after they’re taken, so they “shouldn’t” cause long-term illness. They “should” only damage bacteria, while leaving eukaryotic cells unscathed, but they damage mitochondria too (of course they do, mitochondria are ancient bacterium – Did anyone think that disrupting the process of DNA replication and reproduction in bacteria wouldn’t mess up mitochondrial DNA?). But short-sighted physicians (and others), who don’t look at multi-symptom, chronic illness as a possible effect of a class of antibiotics (FQs are chemo drugs masquerading as antibiotics) think that they have a better safety record than sulfa drugs. Sigh. Sorry for going off on my tangent about FQs. It’s a good post about another antibiotic to avoid and I appreciate the warning.
pgyx says
I admit I entered medical school suspicious of medications’ ability to restore or maintain true health. But as I’ve learned more and more about pharmacology, I’m amazed that we don’t see more major drug interactions and side effects in folks who take multiple medications. Between sedentary lifestyles, rich foods, and the medicalization of symptoms otherwise treatable by lifestyle changes, it is a rare patient over 40 who takes two or fewer medications.
I also wonder how best to disseminate details of drug interactions and adverse effects to practicing physicians as I’ve noticed several instances of recently publicized interactions (e.g., thiazide diuretics depressive effect on insulin secretion with resulting increased blood glucose) that are well-described in much older editions of medical physiology and pharmacology texts. These really should come as no surprise, but again and again they do.
Thank you for pointing out to your patients and readers that many conditions are better treated by lifestyle changes. No one wants to pay much for this kind of preventive care, so you essentially donate your time and energy to do this.
Steven Davidson says
I learned a long time ago that as we age and loss neurons we also lose nephrons and thus many drugs eliminated through the kidneys behave differently in the elderly–never learned about the epithelial sodium channel in the distal tubule–did learn about the caution on prescribing in the elderly from my dad and Morton Ward early (ca. 1950) self-taught practitioners of geriatric medicine.
You’ve written a wonderful piece. I came to it from your tweet. Thank you.
Jane-Alexandra Krehbiel says
I laughed when I read your first paragraph. Thirty years ago as a young nurse I was quite comfortable administering drugs as ordered, and upper ranges of drugs when I was given a range via protocols. We were helping patients with effective dose ranges. Of course, with each passing year I have become incrementally more cautious with everyone from infants to the elderly in hospitals or in public health settings. I ask for clarification more, and I have refused to administer certain drugs without better evaluation. Every drug which works to effect positive change can have potentially disastrous results when poorly selected or administered during a vulnerable period of time for a particular patient.
Thanks for a great post, and for helping me to feel less like a dinosaur.
Ken Grauer says
JOHN – Just reading all of the above wonderful comments is true vindication for your excellent post on antibiotic used/drug interactions. Unfortunately – I suspect readers of your column like me are “part of the choir” – so the task that remains is to convey these important messages to our “non-choir” colleagues in the medical community. KEEP UP the GREAT work John!