Most people who have been through a C. diff infection know the story: you took an antibiotic, it disrupted your gut bacteria, and C. diff took hold. Antibiotics are the most well-known risk factor for C. diff, and for good reason. But a sweeping new study published this spring in the journal Gut suggests the picture is more complicated than that. Dozens of commonly prescribed medications that millions of Americans take every day may increase the risk of developing C. diff.

For patients, caregivers, and anyone who has lived through this infection, this research raises important questions. And for those who have wondered, ‘Why did I get C. diff when I wasn’t even on a major antibiotic?’ it may offer some answers.

What the Study Found

Researchers from Karolinska Institutet in Sweden and Antwerp University in Belgium conducted one of the largest studies of its kind, examining the medical records of nearly 43,000 people diagnosed with C. diff between 2006 and 2019. They published their findings in Gut, a leading gastroenterology journal. The research team matched each patient with up to ten people who had not developed C. diff, using Sweden’s national health registries, which are among the most complete health data sources in the world.

The goal was to understand how both antibiotic and non-antibiotic medications affected a person’s risk of first contracting C. diff. The researchers focused specifically on drugs with suspected microbiome-modulating activity, meaning medications that might affect the balance of bacteria living in your gut.

Their findings confirmed what we already knew about antibiotics. They also uncovered something new: a long list of non-antibiotic drugs was linked to significantly higher C. diff risk.

The Antibiotics We Already Know About, and Some Surprises

Antibiotics associated with the highest C. diff risk included lincosamides (including clindamycin), combinations of penicillins, sulfonamides combined with trimethoprim, and cephalosporins.

Clindamycin has long been considered one of the most dangerous antibiotics for C. diff, and this study reinforces that finding. PLF community member Dana, a 54-year-old from Ohio, learned this the hard way. She had taken clindamycin for an ear infection in August 2024 without knowing it was known to raise C. diff risk. Six weeks later, she found herself in an emergency room with severe stomach pain and abnormal liver enzyme levels. She was eventually diagnosed with C. diff and treated with vancomycin.

“I had taken clindamycin for an ear infection, not knowing that the medication was known to cause C. diff.” — Dana M., Ohio

You can read Dana’s full story on our website: Dana’s C. diff Story.

Interestingly, the study found no significant association between tetracyclines and increased C. diff risk after adjusting for other factors, making them the only antibiotic class without an elevated risk signal.

This is a nuance worth discussing with your doctor if you ever need an antibiotic.

The Non-Antibiotic Drugs: A Longer List Than Expected

This is where the study breaks new ground. Among non-antibiotic drugs, the researchers found an increased risk of C. diff for antidiarrheal medications, corticosteroids (steroids), proton pump inhibitors (PPIs), nervous system drugs, including antidepressants and antiepileptics, constipation medications, histamine H2-receptor antagonists, and beta-blockers. Here is what some of those mean in plain terms.

Proton Pump Inhibitors (PPIs)

PPIs are drugs like omeprazole (Prilosec), pantoprazole (Protonix), and esomeprazole (Nexium). They reduce stomach acid and treat conditions like GERD and ulcers. The study found that PPI use was associated with nearly double the odds of developing C. diff, confirming what previous research has also suggested.PLF community member Marsha, a 69-year-old from California, had been on proton pump inhibitors for at least twenty-five years before she was diagnosed with C. diff. Her story illustrates how long-term PPI use, combined with antibiotic treatment for another condition, may have created conditions for C. diff to take hold. Read Marsha’s full story here.

“Doctors should have all patients tested for C. diff who are on PPIs, are older, or have any likely reason they might be C. diff colonized before putting them on antibiotics for non-urgent reasons.” — Marsha M., California

Corticosteroids

Steroids like prednisone are used to treat everything from asthma to arthritis to inflammatory bowel disease. The study found that corticosteroid use was linked to more than double the odds of developing C. diff, a finding consistent with earlier research. Researchers believe steroids may raise risk by suppressing the immune system and by altering gut bacteria in ways that make C. diff harder to fight off.

Antidiarrheal Medications

Antidiarrheal drugs showed the highest elevated odds of any non-antibiotic drug class in the study. The researchers acknowledge that this is partly explained by reverse causality, meaning some patients may have already been experiencing early C. diff symptoms and reached for anti-diarrheal medications before being officially diagnosed. But the association remained significant even when looking at drug use further back in time, suggesting there may be a real relationship worth watching.

This is a reminder that if you are experiencing prolonged or unusual diarrhea, using anti-diarrheal drugs to push through the symptoms may delay a C. diff diagnosis. PLF community member Peggy shared that her doctor advised her to take Imodium while waiting for her test results, something she later learned was not recommended for C. diff patients.

Antidepressants, Beta-Blockers, and Other Nervous System Drugs

The study also found elevated C. diff risk associated with antidepressants, anti-epileptic and psycholeptic medications, and beta-blockers. Researchers are careful to note that some of these associations may reflect the underlying health conditions being treated rather than the drugs themselves. Still, they point to emerging evidence that many of these drug classes interact with the gut microbiome in ways that are not yet fully understood.

Two Drugs That May Actually Be Protective

Not all the news points toward higher risk. The study found that lipid-modifying drugs, a class that includes statins like atorvastatin and simvastatin, were associated with a lower risk of C. diff. Aspirin also appeared to be associated with reduced risk. These findings align with some prior research and give scientists useful leads for future investigation.

Why Does This Happen? It Is All About the Gut Microbiome

The common thread connecting all of these drugs is the gut microbiome, the trillions of bacteria, fungi, and other microorganisms that live in your digestive tract. A healthy microbiome acts as a barrier against C. diff. When that balance is disrupted by antibiotics, illness, or other medications, C. diff can move in, multiply, and release toxins that cause disease.

The researchers note that evidence from large drug-microbiome studies has revealed that far more drugs affect gut microbiome composition than previously believed. One study found that 24 percent of more than 1,000 tested drugs inhibited the growth of at least one bacterial strain. Understanding how everyday medications affect the gut is a relatively new field, and this study is one of the most comprehensive looks at how that risk relates specifically to C. diff.

What This Means for You

This study is observational, meaning it identifies associations rather than definitive causes. If you are taking a PPI, a steroid, or an antidepressant, that does not mean you will get C. diff. Many people take these medications without ever developing an infection.

But if you have additional C. diff risk factors, including a history of C. diff, older age, recent hospitalization, or current antibiotic use, it is worth having a conversation with your doctor about your overall risk. Questions you might consider asking:

• Do I need this antibiotic, and if so, which one carries the lowest C. diff risk?
• Am I still on a PPI for a reason, or is it time to reassess?
• Are there lower-risk alternatives for any of my current medications?
• Should I be taking a probiotic while on antibiotics?

The study’s authors call for “prudent prescribing and regular medication review” for many drugs, including analgesics, corticosteroids, PPIs, and most antibiotic classes, given their widespread use and associations with C. diff risk.

The Bigger Picture: Advocating for Informed Prescribing

At the Peggy Lillis Foundation, we have long argued that C. diff is preventable and that prevention requires informed decision-making by both patients and providers. Research like this gives us an important new tool. By understanding which medications carry elevated risk, clinicians can make more careful prescribing decisions, and patients can become more active partners in their own care.

Every person who gets C. diff is someone’s mother, father, sibling, or friend. Dana, Marsha, and thousands more who have shared their stories with PLF are living proof that this infection can strike anyone, often in ways they never anticipated.

The more we understand about what puts people at risk, the better equipped we are to protect them.

Learn More

Read the full research paper in Gut (BMJ)

About C. diff: What You Need to Know

C. diff Treatment Options

Patient Stories from the PLF Community

Dana’s Story: Clindamycin and C. diff

Marsha’s Story: PPIs and C. diff