Proton Pump Inhibitors and Antifungals: How They Interfere With Absorption

When you’re on a proton pump inhibitor (PPI) like omeprazole for heartburn and suddenly need an antifungal for a serious infection, things can go wrong-fast. This isn’t just a theoretical concern. It’s a real, documented problem that’s caused treatment failures in hospitals across the U.S. and beyond. The issue? PPIs are quietly sabotaging the absorption of certain antifungal drugs, leaving patients vulnerable to infections that won’t go away.

Why Your Antifungal Might Not Be Working

Not all antifungals are affected the same way. The biggest problem happens with itraconazole, especially in capsule form. This drug needs a very acidic stomach environment to dissolve properly-pH below 3. But PPIs don’t just reduce acid; they shut it down completely. They block the proton pumps in your stomach lining, raising gastric pH from around 1-2 to 4-6. That’s enough to make itraconazole capsules sit there like a rock, barely dissolving, barely absorbed.

Studies show that when you take itraconazole capsules with a PPI, your blood levels drop by 50% to 60%. That’s not a small tweak-it’s a collapse. One study in JAMA Network Open found that the area under the curve (AUC), which measures total drug exposure over time, dropped by 60%. For someone with invasive aspergillosis or coccidioidomycosis, that’s the difference between survival and progression.

Not All Antifungals Are Created Equal

Fluconazole? No problem. It’s highly water-soluble and doesn’t care about stomach pH. Your levels stay steady whether you’re on omeprazole or not.

Voriconazole? It’s in the middle. Studies from the European Medicines Agency show a 22% drop in absorption with PPIs. It’s not as bad as itraconazole, but it’s still enough to worry about in serious infections.

Posaconazole is tricky. The delayed-release tablet form loses 40% of its absorption when taken with PPIs. But the oral suspension? Only a 15% drop. That’s why some hospitals switch patients to the suspension if they can’t stop their PPI.

And then there’s the solution form of itraconazole. Unlike capsules, it’s already dissolved in liquid. That means it skips the acid-dependent absorption step entirely. Studies show only a 10-15% reduction in levels with PPIs-far less than the capsule. So if you’re on a PPI and need itraconazole, ask your doctor: Is the solution version an option?

What About Other Acid Reducers?

H2 blockers like famotidine or ranitidine also reduce stomach acid-but not as much or as long. PPIs suppress acid for 12 to 24 hours. H2 blockers last 4 to 10 hours. That’s why switching from omeprazole to famotidine can boost itraconazole levels back up. One pharmacist in Massachusetts General Hospital documented a patient whose itraconazole trough levels jumped from 0.3 mcg/mL to 1.7 mcg/mL after making the switch.

Antacids? They cause short, sharp spikes in pH, but if you take them at least two hours before or after your antifungal, the impact is minimal. That’s why some providers recommend timing antacids separately-but it’s not a reliable fix for long-term PPI use.

Real-World Consequences

This isn’t just about numbers on a lab report. It’s about people getting sicker because their treatment didn’t work.

A 2022 survey of 1,247 hospital pharmacists found that 68% saw at least one itraconazole-PPI interaction every month. Twenty-three percent reported confirmed treatment failures-patients whose fungal infections worsened because drug levels were too low.

Medicare data shows 38.7% of patients prescribed itraconazole capsules also got a PPI in the same month. That’s nearly 4 in 10. Meanwhile, only 12.3% of those on itraconazole solution got a PPI. That gap tells you something: more providers are learning the hard way.

And the cost? The U.S. healthcare system wastes an estimated $287 million a year on failed antifungal treatments because of this interaction. That’s money spent on repeat hospitalizations, additional drugs, and longer stays-all preventable.

What Should You Do?

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

• Switch to itraconazole solution instead of capsules if possible.
• Use voriconazole or fluconazole if your infection allows it-both are less affected.
• Switch from PPI to famotidine and give itraconazole at least 10 hours after the H2 blocker.
• Take posaconazole delayed-release tablets with cola-the acidity helps absorption.
• Ask for therapeutic drug monitoring. For itraconazole, target levels are 0.5-1.0 mcg/mL in invasive infections. If you’re below that, your dose or timing needs adjustment.

The Surprising Twist: PPIs Might Help-Sometimes

Here’s where it gets weird. In test tubes, combining omeprazole with itraconazole actually kills more fungi-especially drug-resistant strains of Aspergillus fumigatus. A 2025 study in Frontiers in Pharmacology showed synergistic effects in 77.6% of tested fungal strains.

That’s not a mistake. Researchers think low-dose PPIs might make fungal cells more vulnerable to azoles. It’s being tested now in a phase I clinical trial at the NIH (NCT05678901), looking at whether low-dose omeprazole can help revive itraconazole’s power against resistant infections.

This doesn’t mean you should start mixing them at home. But it does mean the story isn’t over. What we thought was just a harmful interaction might become a clever new strategy-if proven safe.

New Options Are Coming

In 2023, the FDA approved a new itraconazole formulation called Tolsura. Unlike capsules, it’s designed to absorb regardless of stomach pH. Studies show only an 8% drop in absorption with PPIs-compared to 50% for the old capsules. That’s a game-changer.

The American Gastroenterological Association and IDSA are working on updated guidelines expected by the end of 2024. They’ll have to balance two truths: PPIs can ruin antifungal treatment, but stopping them might cause dangerous bleeding in high-risk patients.

Bottom Line

If you’re on a PPI and need an antifungal, don’t assume everything will work fine. This interaction is real, common, and dangerous. Fluconazole is your safest bet. Itraconazole capsules are risky. The solution form, voriconazole, or switching to famotidine are better options. Always ask about drug levels. And if your doctor says, “It’s fine,” ask them: “Do you know how much the absorption drops?”

This isn’t just about chemistry. It’s about making sure your treatment works. And sometimes, that means asking the right questions before you take that first pill.