Proton Pump Inhibitors and Antifungals: How They Interfere With Absorption

When you take a proton pump inhibitor (PPI) like omeprazole for heartburn and an antifungal like itraconazole for a stubborn fungal infection at the same time, something unexpected can happen: the antifungal stops working as well as it should. This isn’t just a theoretical concern-it’s a real, documented problem that affects thousands of patients every year. The issue isn’t that the drugs clash in your bloodstream. It’s that the PPI changes the environment in your stomach, and that change blocks the antifungal from being absorbed properly.

Why Your Stomach Acid Matters for Antifungals

Most people think of stomach acid as just a nuisance that causes heartburn. But for certain antifungal drugs, it’s essential. Drugs like itraconazole and posaconazole are weak bases. That means they need a low pH-around 3 or lower-to dissolve properly in your stomach before they can be absorbed into your blood. PPIs shut down the acid-producing pumps in your stomach lining. Instead of a pH of 1-2, your stomach might sit at 4-6. That small change makes a huge difference.

At higher pH levels, itraconazole doesn’t dissolve. It just sits there, unchanged, and passes through your system without being absorbed. Studies show that when you take itraconazole capsules with a PPI, your blood levels of the drug drop by 50% to 60%. That’s not a minor reduction. It’s enough to turn a treatment that should work into one that fails.

Not All Antifungals Are Affected the Same Way

This isn’t a universal problem. Some antifungals don’t care about stomach pH at all. Fluconazole, for example, dissolves easily in water and gets absorbed no matter how acidic your stomach is. That’s why fluconazole is often the go-to choice when someone needs an antifungal and is already on a PPI.

But others are sensitive:

• Itraconazole capsules: 50-60% drop in blood levels with PPIs.
• Itraconazole solution: Only 10-15% drop-much safer to use with PPIs.
• Voriconazole: About 22-35% reduction in absorption.
• Posaconazole delayed-release tablets: 40% drop with PPIs.
• Posaconazole oral suspension: Only 15% drop-better than the tablet form.

Even the formulation matters. The liquid form of itraconazole has the drug already dissolved, so it doesn’t need stomach acid to break it down. That’s why hospitals often switch patients from capsules to the solution if they’re on long-term PPI therapy.

PPIs Are Worse Than Other Acid Reducers

Not all drugs that reduce stomach acid are equal. H2 blockers like famotidine (Pepcid) or ranitidine only lower acid for 4 to 10 hours. PPIs like omeprazole or pantoprazole suppress acid for 12 to 24 hours. That means PPIs create a longer, deeper change in your stomach environment.

One study found that omeprazole reduced itraconazole absorption by 57%, while famotidine cut it by only 41%. That’s a big difference. Antacids? They work fast but only last a few hours. If you take them two hours before or after your antifungal, the impact is minimal.

So if you’re stuck on a PPI and need an antifungal, switching to an H2 blocker might be a practical fix-especially if you’re on itraconazole capsules. But you still need to time it right. Take the antifungal at least 10 hours after the H2 blocker to avoid interference.

What Happens When the Antifungal Doesn’t Work

When antifungal levels drop too low, the infection doesn’t get treated. That’s not just frustrating-it’s dangerous. In patients with invasive aspergillosis or coccidioidomycosis, subtherapeutic levels can lead to treatment failure, hospital readmissions, or even death.

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) warns that low drug levels can actually make fungi resistant. If the drug is present but too weak to kill the fungus, it gives the fungus time to adapt. What was once a treatable infection becomes harder to manage.

Real-world data confirms this. A 2022 survey of over 1,200 hospital pharmacists found that 68% saw at least one case per month where a patient’s antifungal failed because of a PPI interaction. One pharmacist in Massachusetts General Hospital reported a patient with chronic pulmonary aspergillosis whose itraconazole levels jumped from 0.3 mcg/mL to 1.7 mcg/mL after switching from omeprazole to famotidine. That’s a fivefold increase-enough to turn a failing treatment into a successful one.

What Can You Do? Practical Solutions

If you’re on a PPI and need an antifungal, here’s what actually works:

1. Switch to fluconazole. If your infection allows it, this is the easiest fix. No interaction. No timing issues.
2. Use itraconazole solution instead of capsules. The solution bypasses the pH problem entirely.
3. Switch from PPI to H2 blocker. Use famotidine, and take your antifungal at least 10 hours after the H2 blocker.
4. Separate doses by 2 hours. For itraconazole solution, take it at least 2 hours before the PPI. For posaconazole tablets, take them with an acidic drink like cola-this can boost absorption by 35%.
5. Check blood levels. For serious infections like invasive aspergillosis, therapeutic drug monitoring is critical. Target levels for itraconazole are 0.5-1.0 mcg/mL. If you’re below that, your treatment isn’t working.

Many hospitals now have pharmacists review all antifungal prescriptions in patients on PPIs. That’s because the interaction is so common and so dangerous. A 2023 study showed that when pharmacists intervened, 82% of patients got their dosing right.

New Developments Are Changing the Game

There’s good news on the horizon. In 2023, the FDA approved a new version of itraconazole called Tolsura. Unlike the old capsules, Tolsura is designed to be absorbed regardless of stomach pH. Studies show it only drops 8% in absorption when taken with a PPI-compared to 50% for the old capsules. That’s a game-changer.

Even more surprising? Research published in Frontiers in Pharmacology in 2025 found that low-dose omeprazole and itraconazole, when combined in a lab, actually worked better together against resistant strains of Aspergillus fumigatus. The PPI itself seemed to help the antifungal penetrate fungal cells. That’s led to a new NIH clinical trial (NCT05678901) testing whether combining low-dose omeprazole with low-dose itraconazole could treat drug-resistant fungal infections.

So while we’ve spent decades treating this interaction as a problem, we might soon be using it as a tool.

Why This Matters More Than You Think

Over 150 million PPI prescriptions were filled in the U.S. in 2022. About 68% of those were generic omeprazole. Meanwhile, systemic antifungals are used in 5-7% of hospitalized patients. That means thousands of people are getting these two drugs together-often without anyone realizing the risk.

The financial cost is also huge. A 2021 study estimated that unnecessary PPI use with pH-dependent antifungals costs the U.S. healthcare system $287 million a year. That’s from wasted drugs, repeat hospital visits, and longer treatments.

And the problem isn’t going away. PPI use is projected to grow 14% annually in older adults, while fungal infections are becoming more common in immunocompromised patients. We’re not going to stop prescribing PPIs. But we need to be smarter about when and how we use them with antifungals.

Final Takeaway: Don’t Assume It’s Safe

If you’re taking a PPI and your doctor prescribes an antifungal, don’t assume it’s fine. Ask: Which antifungal? What formulation? Do I need to change anything? Many patients never get this conversation. That’s dangerous.

Fluconazole? Safe with PPIs. Itraconazole capsules? High risk. Itraconazole solution? Much safer. Tolsura? Best option if available. Posaconazole tablets? Watch out. Posaconazole suspension? Better.

And if you’re on a PPI for a condition like GERD or ulcers, ask your doctor if you still need it. Many people stay on PPIs long after they’re necessary. Stopping it might not just help your antifungal-it might help your whole body.

What to Do Next

If you’re currently taking both a PPI and an antifungal:

• Check which antifungal you’re on-capsules or solution?
• Look up whether your specific antifungal is pH-dependent.
• Ask your pharmacist or doctor if your dose needs adjustment.
• Don’t stop either drug without talking to your provider.
• If you’re on itraconazole capsules and a PPI, ask about switching to Tolsura or the solution.

This interaction is preventable. But only if you know it’s happening. Don’t let a simple stomach acid issue become a treatment failure.