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Sulfamethoxazole-trimethoprim interactions to avoid

Many of the drug interactions related to sulfa-methoxazole-trimethoprim are linked to increasing the serious side effects of other medications
By | Jan. 9, 2024
Rx prescription pad and Rx pill bottle: Sulfamethoxazole-trimethoprim interactions

Key takeaways

  • Sulfamethoxazole-trimethoprim, known also as brand name Septra, Cotrimoxazole, or Bactrim DS, can heighten the levels of the cardiac antiarrhythmic Tikosyn (dofetilide), antirheumatic agent Trexall (methotrexate), and antiepileptic Dilantin (phenytoin), leading to arrhythmias, anemia, and sedation, respectively.

  • Oral hypoglycemics for diabetes, particularly sulfonylureas, can be amplified by SMX-TMP, leading to hypoglycemia.

  • The vitamin K antagonist blood thinner Jantoven (warfarin) interacts with SMX-TMP, resulting in thinner blood and an increased risk of hemorrhage.

  • Potassium levels can get dangerously high, termed hyperkalemia, in the setting of this combination sulfa antibiotic when used concurrently with other drugs that raise potassium, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone antagonists.

  • Calling attention to these potential interactions in advance of starting SMX-TMP is ideal, but certainly, if you experience symptoms of a drug interaction, such as bleeding, hypoglycemia, palpitations, dizziness, or lethargy, while on this drug, you should get medical attention immediately.

In this article:

Sulfamethoxazole-trimethoprim combines two drugs to form a potent antibiotic, recommended for use against urinary tract infection, methicillin-resistant staph aureus (MRSA) bacterial infections, pneumocystis pneumonia, and bronchitis exacerbations in chronic obstructive pulmonary disease (COPD). Such diverse use of this sulfonamide makes it likely you have or will be prescribed it. Recognizing the drug’s pitfalls is important, so you can be safe when taking sulfamethoxazole-trimethoprim, abbreviated SMX-TMP. Among the potential downsides, drug interactions rank near the top in terms of critical information for you to know. 

SMX-TMP interacts with certain diabetes meds, antihypertensives, and anticoagulant warfarin, among others. These drug interactions could result in life-threatening heart arrhythmias, hypoglycemia (low blood sugar), or bleeding. Knowing these risks in advance is vital, and a plan should be formed between you and your healthcare team to keep you safe. Here, we will endeavor to get you the information you need.

Sulfamethoxazole-trimethoprim drug interactions

Many of the drug interactions related to sulfa-methoxazole-trimethoprim are related to magnifying the other med’s serious side effects. This comes as a result of SMX-TMP either increasing the other drug’s concentration or mechanism of action.

Tikosyn

A classic double-edged sword, dofetilide is an antiarrhythmic, used for treating heart rhythm disorders, that can actually induce arrhythmias, even life-threatening ones, like Torsades de Pointes. Levels of the drug in our bloodstream play a role in determining how much adverse effect risk is present. Unfortunately, sulfamethoxazole-trimethoprim can increase Tikosyn levels in a dangerous fashion.

Based on the high-risk nature of this interaction, it is usually best to avoid SMX-TMP when taking dofetilide. You should confirm this by speaking to the prescribing healthcare provider.

Trexall

Trexall (methotrexate) is both a chemotherapeutic used in cancer treatment and a disease-modifying immunosuppressant agent used in treating autoimmune conditions like rheumatoid arthritis. While quite effective, methotrexate therapy must be closely monitored due to toxicities, according to the Food and Drug Administration (FDA). SMX-TMP can increase the risk of methotrexate adverse reactions, particularly when it comes to bone marrow suppression, which leads to anemia and low platelets (clotting cells). This issue might arise from folic acid inhibition, something methotrexate, sulfamethoxazole, and trimethoprim all do.

Your doctor can talk to you about whether sulfamethoxazole-trimethoprim should be avoided altogether. If not, dosing may need to be modified or lab monitoring intensified. Looking for a different immunosuppressant to replace methotrexate could be difficult too, and keep in mind that cyclosporine, another drug used for autoimmune conditions, interacts with SMX-TMP too.

Dilantin

Preventing seizures is obviously the foremost goal of epilepsy management. Dilantin can be quite effective at doing so, but to best balance this benefit with the ever-present risk of adverse effects, phenytoin dosing is carefully done utilizing blood level measurement. Those blood levels can spike with concurrent SMX-TMP use. The results can be perilous, including lethargy, confusion, and unsteadiness. Besides this direct interaction between the two meds, sulfamethoxazole, and phenytoin are among the highest-risk drugs for precipitating Stevens-Johnson syndrome, a serious drug reaction including skin rash.

Combining phenytoin with sulfamethoxazole-trimethoprim may not be wise, and altering phenytoin dosing to permit the sulfa drug’s use could be risky as well. Reach out to your team of healthcare professionals about this interaction if you are prescribed both, and if you are feeling symptoms of this interaction, get medical care immediately.

Jantoven

Jantoven (warfarin) thins the blood by blocking vitamin K from helping to build blood-clotting proteins. Since our vitamin K is mainly derived from good bacteria in our intestinal tract, it makes sense that antibiotics that kill those good bacteria will make warfarin’s anticoagulant job easier by reducing vitamin K supply. As a result, blood can become overly thin, leading to bleeding, when antibiotics are used with warfarin. Combination tablets of SMX and TMP are no exception to this rule. In fact, it might be the worst offender, because the combo may also boost warfarin concentrations in the body too. 

Excess bleeding risk is worrisome enough that finding an alternative to SMX-TMP may be worth your while. Your medical provider can guide you on finding an alternative antibiotic or reducing the dose of warfarin during your treatment course of sulfamethoxazole-trimethoprim.

Oral hypoglycemics

Keeping blood glucose levels in check is a basic tenet of diabetes care. Of course, you want to make sure your sugar does not go too high, but just as importantly, you don’t want glucose levels to drop dangerously low. Hypoglycemia is a risk with some drugs for diabetes, most notably insulin, sulfonylureas, and repaglinide. By potentiating hypoglycemia, sulfamethoxazole with trimethoprim can make matters worse if you are taking sulfonylurea or repaglinide. Examples of sulfonylureas include:

To avoid hypoglycemia from this drug-drug interaction, your healthcare provider may want you to change to a different antimicrobial or monitor your blood sugar closely. Make sure this plan is discussed with your medical team because low blood sugar can be deadly. If your sugar levels are dropping related to these drugs, enact your emergency hypoglycemia treatment plan and get medical attention right away.

Angiotensin-converting enzyme inhibitors

This drug interaction is straightforward. ACE inhibitors are antihypertensives that can cause elevated potassium levels during treatment for high blood pressure. Trimethoprim, one component of SMX-TMP, raises potassium too. As a result, hyperkalemia can result, with potassium levels going high enough to risk dangerous heart arrhythmias. Accordingly, you should talk to your doctor about potassium monitoring or alternatives to SMX-TMP if you are taking an ACE inhibitor, like the following examples.

Angiotensin receptor blockers

Like ACE inhibitors, ARBs are a class of antihypertensives that bump up potassium levels by increasing retention of the electrolyte by our kidneys. Thanks to the trimethoprim component, putting any ARB with sulfamethoxazole-trimethoprim can have additive effects on potassium concentrations. Check with your healthcare team about whether a different antibiotic option is advisable or lab work should be done. Reducing dietary potassium intake may be another strategy. Examples of ARBs include:

Aldosterone antagonists

Also known as mineralocorticoid receptor antagonists, aldosterone antagonists mainly function as diuretics in the setting of congestive heart failure or antihypertensives for blood pressure control. Their mechanism of action leads to potassium retention and, therefore, can cause hyperkalemia (elevated potassium levels). Concomitant SMX-TMP use can potentiate that problem. If you are taking Aldactone (spironolactone) or Inspra (eplerenone), ask your healthcare provider if additional potassium monitoring or an alternative to sulfamethoxazole-trimethoprim is recommended.

Sulfamethoxazole-trimethoprim food interactions

While it does not have any direct interactions with food, sulfamethoxazole-trimethoprim does heighten the risk of hyperkalemia in those who are susceptible, whether that is due to other medications or kidney disease. Couple that with a diet high in potassium, and you can imagine the trouble that arises. Bananas, oranges, milk, fish, and nuts are just some of the potassium-rich foods that could be problematic in this scenario.

Likewise, folic acid deficiency in the diet could exacerbate problems with anemia in the setting of SMX-TMP and methotrexate usage. You can keep adequate folic acid in your diet by eating eggs, broccoli, beans, oranges, and bananas, for example.

Other sulfamethoxazole-trimethoprim interactions

There are still more interactions of importance to call your attention to. These involve alcohol and underlying health conditions.

Sulfamethoxazole-trimethoprim and alcohol

As you may know, alcohol can produce flushing, headache, and nausea. Sulfamethoxazole can amplify those toxic effects, meaning that alcohol should be avoided during a treatment course of SMX-TMP.

Sulfamethoxazole-trimethoprim and kidney disease

Renal insufficiency, or impaired kidney function, often leads to high levels of potassium due to reduced elimination of the electrolyte in the urine. For that reason and because it is excreted from the body in urine, SMX-TMP can be troublesome in the setting of renal insufficiency. Sulfamethoxazole-trimethoprim dosing is typically adjusted downward based on the level of kidney function. 

Sulfamethoxazole-trimethoprim and G6PD deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic disorder affecting half a billion people in the world. With G6PD enzyme dysfunction, our red blood cells are fragile, with different factors capable of making them break. Medications can be one of the predisposing factors that lead to hemolysis or cell breakage. Cases have been reported with sulfamethoxazole, so caution is needed.

Sulfamethoxazole-trimethoprim and breastfeeding

If a mother is taking sulfamethoxazole-trimethoprim, her breastfeeding infant would be exposed to a small amount of the drug in breast milk. This could be problematic if the infant has G6PD deficiency or has high bilirubin levels since the drug could complicate either of these situations. Sulfamethoxazole-trimethoprim can displace bilirubin, leading to complications in jaundiced newborns. Your healthcare provider may recommend avoidance of the drug while breastfeeding in these specific situations.

How to minimize sulfamethoxazole-trimethoprim interactions

From disease states and alcohol to a variety of medications, SMX-TMP has a diverse assortment of interactions. Avoiding them comes down to direct communication with your healthcare providers. You should ensure that they know about all the prescription drugs, over-the-counter medications, and supplements that you take, and it is worthwhile reviewing your health history, alcohol intake habits, and past allergic reactions with anyone prescribing you medication. Providing this information can help healthcare professionals catch drug interactions before negative reactions occur.

When to talk to a healthcare provider about sulfamethoxazole-trimethoprim interactions

It is now time to speak to your medical team about interactions with sulfamethoxazole-trimethoprim. You now know some of the important ones, but the list of interactions is too extensive to be comprehensive here. When you are prescribed SMX-TMP or a new medication while already taking the sulfa antibiotic, ask about drug interactions and the influence of any underlying health conditions. Speaking up, rather than assuming that all safety checks are complete, is a great way for you to enhance your safety when receiving medical treatment.