The prescribing of co-trimoxazole with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) results in a sevenfold increase in the risk of hospital admission with hyperkalemia relative to amoxicillin, Case reports have shown that this drug interaction can cause life threatening hyperkalemia, In older patients receiving ACE inhibitors or ARBs, co-trimoxazole was associated with an increased risk of sudden death; this may reflect sudden death from unrecognized severe hyperkalemia, When patients receiving ACE inhibitors or ARBs require an antibiotic, clinicians should either select antibiotics that do not contain trimethoprim or limit the dose and duration of trimethoprim based therapies, while closely monitoring the serum potassium concentration. A Deadly Drug Interaction Often Ignored by Doctors and Pharm Joe Graedon is a pharmacologist who has dedicated his career to making drug information understandable to consumers. After some digging, I found that at least one of the antibiotics, Bactrim, likely does indeed induce thiamine deficiency by potently blocking both thiamine transporters. The case story that compelled my investigation into Bactrim included clear symptoms of both wet and dry beriberi, marked by serious dysautonomic function. I had never taken ACE/ARBs. "If there's a problem with a drug interaction, it's only going to be exacerbated in a population of older adults with heart problems," he said. Drugs are used too much. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. To prevent model over-fitting, we adjusted for an extensive array of covariates associated with the risk of sudden death by using a disease risk index in our adjusted analysis. Lessons to be had. First published on February 2, 2015 / 3:49 PM. DNA synthesis and repair. Their findings provide important messages to caregivers and patients alike. MF drafted the manuscript, which was critically revised for important intellectual content by all authors. Most of the patients who died were over age 85. The trouble is, physicians and pharmacists often ignore and override drug interaction alerts, especially those they deem relatively unimportant. Because trimethoprim induced hyperkalemia may take longer to manifest clinically, we replicated our analyses using a 14 day period between antibiotic prescription and sudden death. All rights reserved. Thank you for writing this. "One of the consequences of a high potassium level is getting these irregular heart rhythms that can be quite dangerous and cause sudden deaths," Antoniou said. The cases and controls were very different (the sudden-death cases were more likely to have heart failure, renal failure, and more co-morbidities). Ciprofloxacin also had a smaller but still significant increased risk of sudden death compared to those taking amoxicillin (1.29, CI of 1.03 to 1.62). The otherness of potential drug targets holds true to this day. Of these deaths, 1,110 occurred within seven days of a prescription for one of the study antibiotics, GeriPal reports. But they arent free. We thank Brogan Inc, Ottawa, for use of their Drug Product and Therapeutic Class Database. Bactrim is also sold under the names: Septra, Sulfatrim, Septrin, Apo-Sulfatrim, SMZ-TMP and cotrimoxazole. The solution is simple, Antoniou said: If a heart patient is taking spironolactone, they should be prescribed a different antibiotic if one is needed. Methods: A few weeks back we published a case story of young man who developed serious cardiac and neurological symptoms after beginning a course of two antibiotics, Bactrim and Keflex. Co-trimoxazole induced hyperkalemia is common,13 18 can occur quickly,13 19 and can be life-threatening.20 We examined whether treatment with co-trimoxazole was associated with a higher risk of sudden death than other antibiotics used for urinary tract infection in patients receiving angiotensin converting enzyme inhibitors or angiotensin receptor blockers. When trimethoprim was originally discovered and yet still, medicine believed that bacteria were somehow entirely separate from the organism in which they resided. Antoniou, who is also a clinical epidemiologist at the non-profit Institute for Clinical Evaluative Sciences, was prompted to conduct his research after reading reports of high potassium levels associated with this particular drug interaction. I would guess most caregivers who prescribe cotrimoxazole do not have a working knowledge of epithelial cells in the distal nephron. 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 wouldnt mess up mitochondrial DNA?). Finally, we were unable to reliably determine the dose of trimethoprim, precluding a dose-response analysis. Im stopping this medication ASAP and taking a full dose of thiamine today. Parker Waichman was there for my family when one of our family members was desperately in need of assistance. Each of the two drugs that make up Bactrim block microbial folate synthesis precipitating complete folate deprivation in bacteria, capable of resulting in folate deficiency non-bacterial cells. We used administrative data and did not have access to serum potassium or creatinine concentrations, adherence to treatment, non-prescription drug use, and other risk factors for sudden death. In the primary analysis, trimethoprim/sulfamethoxazole was associated with a significantly increased risk of sudden death compared to amoxicillin (odds ratio1.38, 95% confidence interval 1.09 to 1.76 after adjustment). Using the same data, they found that of the 11,968 patients who died of sudden death while receiving potassium-elevating spironolactone, 328 died within 14 days of exposure to certain antibiotics: trimethoprim-sulfamethoxazole, amoxicillin, ciprofloxacin, norfloxacin or nitrofurantoin. The authors hypothesize that it is due to trimethoprims ability to raise potassium levels. We are not funded and accept limited advertising. CastBox Results Of 39 879 sudden deaths, 1027 occurred within seven days of exposure to an antibiotic and were matched to 3733 controls. I will be more in tune and reading your blog for sure. Thank you very much for your job . I recognized it immediately as a need for thiamine. Youre starting to sound like a doctor. ACP Journal Club. 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. Many of these patients take (guideline-directed) drugs called angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). doi: 10.1136/bmj.d5228. The results showed that, in this specific patient population, 3 of every 1000 individuals taking either ACE inhibitors or ARBs who then begin treatment with trimethoprim/sulfamethoxazole will die suddenly within 7 to 14 days. It confirms what I had suspected that it was the Bactrim. In the primary analysis, co-trimoxazole was associated with a significantly increased risk of sudden death within seven days relative to amoxicillin (unadjusted odds ratio 1.83, 95% confidence interval 1.50 to 2.24), and this result persisted after adjustment using the disease risk index (1.38, 1.09 to 1.76). In reality, however, there are a number of serious side effects associated with it including: A review published in 2011, identified 925 papers on the adverse effects of trimethoprim and sulfamethoxazole through 2011. I use them everyday. I much prefer deprescribing. In other words, it was easier and more economically prudent not to question potential problems in the research or the assumptions driving said research than risk losing a useful and lucrative antibiotic. In fact, mixing medicines is very much like playing Russian roulette. This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Trimethoprim-sulfamethoxazole-induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system: a population-based study. 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. Two more issues on the treatment of Sudden Death in the young person, A malignant arrhythmia from an antibiotic? Doctors also can limit the length of antibiotic treatment. National Library of Medicine weight gain or loss. Although other combinations of sulfonamides are available with trimethoprim, TMP-SMX is by far the most widely used. Trimethoprimsulfamethoxazole and risk of sudden death among patients taking spironolactone. In contrast, we observed no increased risk of sudden death with the other antibiotics (table 3). Thanks for a great post, and for helping me to feel less like a dinosaur. Contributors: MF, EMM, TG, MMM, and DNJ were responsible for study concept and design. The most common cause of sudden cardiac death in young people is this genetic condition that causes the heart muscle to grow too thick. The story here is not just about the specifics of an important drug-drug interaction. This additive adverse effect would also be expected with any other drug known to cause hyperkalaemia, such as other potassium-sparing diuretics and angiotensin-converting enzyme inhibitors, they say. Most people do not need to worry about high potassium levels, says Antoniou. Objective To determine whether the prescription of co-trimoxazole with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker is associated with sudden death. As a structural analog to PABA, sulfamethoxazole binds to and blocks a key enzyme in the folate pathway (dihydropteroate synthetase) thereby inhibiting the conversion of PABA and downstream metabolites critical for folate synthesis and metabolism. We speculate that this association reflects sudden death from co-trimoxazole induced hyperkalemia in a vulnerable group of patients. Dear Doctor, I would like to express the deepest gratitude to you for writing and updating this website. Although trimethoprim inhibits dihydrofolate reductase in bacteria, it is estimated that an approximately 50,000 times increased concentration of the drug is required to inhibit the human form of this enzyme.. HHS Vulnerability Disclosure, Help It is estimated that roughly 20 million prescriptions are filled for this drug each year. This particular study gathered data for more than 17 years, from 1994 through 2012, and included patients aged 66 years or older who were being treated with either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and then suddenly died within 7 or 14 days of starting treatment as an outpatient with an oral antibiotic. Each case was matched with up to four controls on age, sex, chronic kidney disease, and diabetes. They come with tradeoffs, and, the more drugs we use together in a patient, the more tradeoffs we should expect. I think that most people, doctors and patients alike, think that all antibiotics are as benign as amoxicillin. They simply prevent bacterial replication. PMC Alternate antibiotic therapy should be considered in these patients when clinically appr In other words, an awful lot of people are vulnerable to this potentially deadly drug combination. My phone calls were always returned quickly and all of my questions were answered in a thorough manner. The laws of nature no longer hold true. I just finished a five day course of 800mg bactrim DS for a uti. I was on Sotalol and Pradaxa (afib) at the time. What? His symptoms immediately reminded me of beriberi induced by an acute thiamine deficiency. In a young patient with good organ function, this is not significant. Antibiotics arent supposed to cause multi-symptom, chronic illness. Now, we have computers as close as our smart phones. I believe these aspects of the drug may underlie many its adverse reactions in addition to, and perhaps compounding, those associated with its propensity to induce hyperkalemia. Fill out the form below to receive a free confidential consultation. The primary analysis examined the association between sudden death and receipt of a prescription for co-trimoxazole, norfloxacin, nitrofurantoin, or ciprofloxacin in the preceding seven days. We speculate that the increased risk of sudden death during treatment with co-trimoxazole reflects unrecognized arrhythmic death due to hyperkalemia, a well described complication of the use of trimethoprim in this setting. What it means is that when an older person dies suddenly while taking co-trimoxazole while on a medication like lisinopril or valsartan, no one will figure out why. These really should come as no surprise, but again and again they do. 2014; Pompei et al. The findings are published Feb. 2 in CMAJ (Canadian Medical Association Journal). It protects the heart by blocking a hormone that causes salt and fluid buildup. Insufficient consumption and/or ingestion of pharmaceutical compounds that block intestinal thiamine transporters responsible for bringing thiamine into the cells, pose a serious health risk that includes death. We have been alarmed about incompatible drug combinations for more than 40 years. 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. [2] Antoniou T, Gomes T, Mamdani M et al. And the researchers did not know why the individuals had been prescribed the antibiotics.But the results point toward greater caution in prescribing Bactrim to those taking ACE-inhibitors and ARBs, and closer monitoring of potassium levels in those patients. cardiac electrophysiologist, cyclist, learner, Changing the use of DrJohnM Facebook page for disease education, Staying Alive Start The Heart Foundation taking off in Louisville, Death-denial is something doctors can change. Whereas nitrofurantoin and norfloxacin are limited to the treatment of urinary tract infection, amoxicillin, co-trimoxazole, and ciprofloxacin are sometimes used for infections at other sites. We found that use of co-trimoxazole was associated with an increased risk of sudden death in older patients taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers. 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