When you take a proton pump inhibitor (PPI) like omeprazole for heartburn and an antifungal like itraconazole for a stubborn fungal infection, you might think you’re just managing two separate problems. But in your body, these drugs are having a silent, potentially dangerous conversation - one that can leave you with dangerously low levels of the antifungal you need to survive.

Why Your Antifungal Isn’t Working

Proton pump inhibitors don’t just reduce stomach acid - they turn your stomach into a near-neutral environment. Normally, your stomach pH hovers around 1 to 2, which is strong enough to break down most pills and dissolve drugs that need acid to be absorbed. But when you take a PPI, that pH climbs to 4 or even 6. That’s not just a small change. It’s enough to stop certain antifungals from dissolving at all.

The most affected drug? Itraconazole capsules. Studies show that when taken with a PPI, the amount of itraconazole that gets into your bloodstream drops by 50% to 60%. That’s not a minor dip. That’s the difference between a drug that works and one that doesn’t. For someone with invasive aspergillosis or coccidioidomycosis, this isn’t just inconvenient - it’s life-threatening. One study tracked a patient whose itraconazole blood levels jumped from 0.3 mcg/mL to 1.7 mcg/mL just by switching from omeprazole to famotidine. That’s more than a five-fold increase.

Not All Antifungals Are Created Equal

This isn’t a universal problem. Fluconazole? It doesn’t care about stomach pH. It dissolves easily in water, so even if your stomach is neutral, it still gets absorbed. Voriconazole? It’s affected, but only about 22% to 35% - still significant, but not as bad as itraconazole. Posaconazole is tricky: the delayed-release tablet loses 40% of its absorption with PPIs, but the older oral suspension doesn’t drop nearly as much.

The key difference? How the drug is formulated. Itraconazole capsules rely on acid to dissolve the solid particles inside. The liquid solution, on the other hand, already has the drug dissolved - so it doesn’t need stomach acid to work. That’s why the solution form only drops 10-15% in absorption with PPIs, not 60%. If you’re on itraconazole and you’re also on a PPI, the solution version is the safer choice.

What About Other Acid Reducers?

Not all acid-reducing drugs are the same. H2 blockers like famotidine or ranitidine only raise stomach pH for 4 to 10 hours. PPIs? They shut down acid production for 12 to 24 hours. That’s why PPIs cause much bigger drops in antifungal absorption. One study showed omeprazole cut itraconazole levels by 57%, while famotidine cut it by 41%. That’s a big gap.

Antacids like Tums or Maalox? They work fast and fade fast. If you take them at least two hours before or after your antifungal, they won’t interfere much. But if you’re popping antacids all day, you’re still creating a problem. The longer your stomach stays above pH 3, the worse it gets for drugs like itraconazole and posaconazole.

The Hidden Risk: Treatment Failure and Resistance

When antifungal levels drop too low, the fungus doesn’t die - it adapts. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) warns that subtherapeutic antifungal levels can turn a susceptible infection into a resistant one. That means the drug that should’ve cured you might not work at all next time - even if you take the full dose later.

Hospital pharmacists report seeing this firsthand. A 2022 survey found 68% of them encountered at least one itraconazole-PPI interaction every month. And 23% of those cases led to confirmed treatment failures. That’s not a rare mistake. It’s a pattern.

One patient in Massachusetts General Hospital had chronic pulmonary aspergillosis. His itraconazole levels were so low, his doctor thought the infection was getting worse. It turned out he was on omeprazole. Once they switched him to famotidine and gave him the itraconazole solution, his levels climbed into the therapeutic range. He didn’t need a new drug. He just needed the right combination.

What Should You Do?

If you’re prescribed itraconazole capsules and you’re on a PPI, here’s what you need to do:

• Ask your doctor if you can switch to itraconazole solution instead. It’s less affected by PPIs.
• If you must use capsules, stop the PPI if possible. If you can’t stop it - say, because you have a history of bleeding ulcers - switch to an H2 blocker like famotidine.
• Take itraconazole at least two hours before your PPI. Timing matters.
• For posaconazole delayed-release tablets, take them with a glass of cola. The acidity helps absorption.
• Ask for therapeutic drug monitoring. For itraconazole, the target level is 0.5-1.0 mcg/mL. If you’re below that, your treatment isn’t working.

New Hope: Better Formulations and Unexpected Synergies

There’s good news on the horizon. In 2023, the FDA approved a new version of itraconazole called Tolsura. It’s designed to absorb regardless of stomach pH. In trials, it only dropped 8% in absorption with PPIs - compared to 50% for the old capsules. That’s a game-changer.

Even more surprising? Research from 2025 found that when you combine low-dose omeprazole with itraconazole in a lab, they actually work better together against resistant strains of Aspergillus fumigatus. In 77.6% of tested fungal strains, the combo killed more fungus than either drug alone. This isn’t a mistake - it’s a discovery. The National Institutes of Health is now running clinical trials to see if this synergy can be used intentionally to treat drug-resistant fungal infections.

The Bigger Picture

About 15% of U.S. adults take PPIs long-term. Around 5-7% of hospitalized patients get systemic antifungals. That means thousands of people are getting these drugs together - often without anyone checking if it’s safe. The cost? Around $287 million a year in wasted drugs and failed treatments.

The solution isn’t just about switching pills. It’s about communication. Pharmacists need to flag these interactions. Doctors need to ask: “Are you on a PPI?” before prescribing itraconazole. Patients need to speak up: “I take omeprazole every morning.”

This isn’t a niche problem. It’s a common, preventable mistake that’s costing lives. But with better awareness, better formulations, and better timing - it doesn’t have to be.