Dificid Drug Interactions: What You Need to Know

If you've been prescribed Dificid (Fidaxomicin) for a C. diff infection, you may wonder whether it interacts with other medications you're taking. The good news is that Dificid has relatively few drug interactions compared to many other antibiotics — largely because it stays in your gut and is barely absorbed into your bloodstream.

That said, there are still some important interactions to be aware of. This guide covers what to avoid, what to watch out for, and what to tell your doctor before starting Dificid.

How Drug Interactions Work with Dificid

Most drug interactions happen when two medications affect each other's absorption, metabolism, or elimination from the body. Since Dificid has minimal systemic absorption — meaning very little of it enters your bloodstream — the risk of it interacting with medications that work throughout your body is low.

However, Dificid is a substrate of P-glycoprotein (P-gp), a transporter protein in the cells lining your gut. P-gp acts like a gatekeeper — it pumps certain drugs back out of cells. When another medication inhibits P-gp, it can increase the amount of Dificid that gets absorbed, potentially raising blood levels of Fidaxomicin and its active metabolite (OP-1118).

For a deeper understanding of how Dificid works in the body, see our guide on how Dificid works.

Medications That May Interact with Dificid

P-Glycoprotein (P-gp) Inhibitors

The most clinically significant interaction involves P-gp inhibitors. These medications can increase blood levels of Fidaxomicin by blocking the transporter that normally limits its absorption. The key P-gp inhibitors include:

• Cyclosporine (Neoral, Sandimmune, Gengraf) — This is the most well-studied interaction with Dificid. Cyclosporine is an immunosuppressant used after organ transplants and for autoimmune conditions. When co-administered with Dificid, plasma concentrations of Fidaxomicin increased approximately 2-fold and OP-1118 increased approximately 4-fold. However, in clinical trials, concomitant P-gp inhibitor use did not affect treatment outcomes or safety.
• Ketoconazole (Nizoral) — An antifungal medication that inhibits P-gp.
• Erythromycin — A macrolide antibiotic that is also a P-gp inhibitor.
• Clarithromycin (Biaxin) — Another macrolide antibiotic with P-gp inhibition.
• Verapamil (Calan, Verelan) — A calcium channel blocker used for high blood pressure and heart rhythm disorders.
• Dronedarone (Multaq) — Used to treat irregular heart rhythms (atrial fibrillation).
• Amiodarone (Cordarone, Pacerone) — Another antiarrhythmic medication.

What this means for you: While clinical trial data suggests that P-gp inhibitors did not significantly affect safety or treatment outcomes with Dificid, your doctor should be aware if you take any of these medications. They may want to monitor you more closely. In most cases, Dificid can still be used — but the decision should be made by your healthcare provider.

Live Vaccines

The Cholera Vaccine, Live (Vaxchora) should generally not be given while taking Dificid. Antibiotics can reduce the effectiveness of live oral vaccines by killing the live bacteria in the vaccine before your immune system can respond. If you need the cholera vaccine, discuss timing with your doctor.

Anti-Diarrheal Medications

While not a traditional "drug interaction," it's critical to mention: do not take anti-diarrheal medications like Loperamide (Imodium) or Bismuth Subsalicylate (Pepto-Bismol) without your doctor's explicit approval when you have C. diff. These medications can slow gut motility and potentially worsen C. diff infection by keeping the toxin in your intestines longer.

Supplements and OTC Medications to Watch

Dificid has very few known interactions with over-the-counter medications and supplements, but there are still some things to keep in mind:

Probiotics

Many C. diff patients want to take probiotics to restore gut health. While there's no direct drug interaction between Dificid and probiotics, the timing matters:

• Some doctors recommend waiting until after you finish your Dificid course to start probiotics
• Others may suggest taking them during treatment but separating the doses by a few hours
• The probiotic Saccharomyces boulardii is sometimes recommended alongside C. diff treatment, but always ask your doctor first

Antacids and Acid Reducers

Proton pump inhibitors (PPIs) like Omeprazole (Prilosec), Lansoprazole (Prevacid), and Pantoprazole (Protonix) are noteworthy — not because they interact with Dificid directly, but because PPI use is a known risk factor for C. diff infection. If you're taking a PPI, discuss with your doctor whether it should be continued during and after C. diff treatment.

Acetaminophen (Tylenol)

No known interaction with Dificid. Generally safe to take for headaches or pain during treatment.

NSAIDs (Ibuprofen, Naproxen)

No direct interaction with Dificid, but NSAIDs can irritate the stomach and intestinal lining. If your gut is already inflamed from C. diff, your doctor may recommend avoiding NSAIDs during treatment.

Food and Drink Interactions

Dificid has no significant food interactions. You can take it with or without food. There are no restrictions on specific foods or beverages.

That said, during a C. diff infection, your doctor may recommend:

• Avoiding spicy, greasy, or high-fiber foods that can irritate your gut
• Staying well hydrated — water, broth, and electrolyte drinks are important when dealing with diarrhea
• Limiting caffeine and alcohol — both can worsen diarrhea and dehydration
• Eating bland, easy-to-digest foods — like bananas, rice, toast, and applesauce (the BRAT diet)

These recommendations aren't about drug interactions — they're about supporting your recovery while Dificid does its job.

What to Tell Your Doctor Before Starting Dificid

Before starting Dificid, make sure your doctor knows about:

• All prescription medications you're taking — especially immunosuppressants like Cyclosporine, heart medications like Verapamil or Amiodarone, and antifungal drugs like Ketoconazole
• Over-the-counter medications — including antacids, PPIs, pain relievers, and anti-diarrheal drugs
• Supplements and herbal products — including probiotics
• Any allergies to macrolide antibiotics — such as Azithromycin, Clarithromycin, or Erythromycin
• Pregnancy or breastfeeding status
• Any recent vaccinations — especially live oral vaccines

Keeping your doctor fully informed helps them prescribe Dificid safely and effectively. Even though Dificid has fewer interactions than most antibiotics, the complete picture always matters.

Final Thoughts

Dificid has a favorable drug interaction profile thanks to its minimal systemic absorption. The main interaction to watch for involves P-glycoprotein inhibitors like Cyclosporine, which can increase Dificid blood levels — though clinical data suggests this doesn't significantly impact safety or effectiveness.

The most important rule: tell your doctor about everything you take — prescriptions, OTC drugs, supplements, and probiotics. And never take anti-diarrheal medications for C. diff without your doctor's approval.

If you've been prescribed Dificid and need help finding it, use Medfinder to locate a pharmacy with it in stock. For more information, explore our guides on Dificid side effects and what Dificid is.