Pantoprazole for candida infections

Practice
By
Dr Esther Lau and Prof Lisa Nissen
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Promising findings give hope in the fight against azole-resistant Candida. 

The human microbiome comprises the microorganisms that live on and within the human body. In a state of ‘health’, a delicate equilibrium is maintained, but things go awry when this balance is disrupted. Candida is yeast that lives on our body in small amounts. It is kept in check by the body’s microbiome, so it does not usually cause problems, but if this becomes off-balanced, then it can overgrow and cause infection (candidiasis).1 For the most part, localised candidiasis (e.g. thrush, vaginal yeast infections, nappy rash) can be managed with over-the-counter antifungal medicines. However, in some cases, candidiasis can be invasive and cause severe infections that target the entire body in susceptible people (e.g. those who are immunocompromised or in hospital).1,2

Management of candidaemia (the most common presentation of invasive candidiasis) is complex and needs expert advice to guide treatment. The choice of antifungal is based on a range of factors (e.g. whether the person is critically ill, the likelihood of the causative agent, local microbiology and susceptibility).3 Fluconazole – an ‘azole’ that impairs ergosterol synthesis, leading to breakdown of fungal cell membranes to cause cell leakage4 – may be used for non-critically ill people with Candida albicans or those unlikely to be infected with a fluconazole- resistant Candida species.3 Other options include echinocandins (changes cell membrane permeability inhibiting synthesis of 1,3-beta-D-glucan in the fungal cell wall5), or amphotericin B (irreversibly binds to ergosterol, leading to changes in the permeability of the fungal cell wall and leakage of intracellular component6) if there are problems with resistance.3

Azoles are often used because they are inexpensive, have limited issues with toxicity, and can be administered orally.7

Unfortunately, there continues to be increasing resistance to various antifungals, particularly azoles, and one of the mechanisms is thought to be due to the up-regulation of several efflux pumps.8 In the race against antimicrobial resistance, the efflux pumps are important drug targets. One medicine gaining increasing recognition for effects as efflux pump inhibitors, and therefore, the potential to help in the fight against multidrug- resistant strains of microbes are the proton-pump inhibitors (PPIs). 

PPIs such as pantoprazole work in the stomach by binding to the proton pump (hydrogen/potassium ATPase enzyme system) to stop acid secretion.9 PPIs are, of course, most commonly known for use in the prevention and management of gastrointestinal conditions such as peptic ulcer disease, gastro-oesophageal reflux disease, and as part of the regimen for treating H. pylori, and for Zollinger- Ellison syndrome.9

A relatively recent in vitro study investigated pantoprazole and haloperidol for their effects in reversing the azole resistance of different Candida species.8 Clinical specimens were collected from different sources in the clinical laboratories of two university hospitals in Egypt. A total of 122 clinical isolates were identified, with over half (n = 70) being Candida albicans.8 Overall, 16 isolates were ‘azole’ resistant (to fluconazole) and overexpressed the efflux pump genes CDR1, MDR1 and ABC2, with the majority (n = 15) also showing biofilm formation activity.8 Pantoprazole reduced the minimum inhibitory concentration (MIC) of fluconazole in the resistant isolates by 3–5 fold, and significantly reduced the expression levels of efflux pump genes CDR1 (from 1.97 to 0.55) and MDR1 (from 2.45 to 1) when compared with a sensitive standard strain that served as the control (p <0.0001).8

Haloperidol showed similar effects with most of the strains but was less effective compared to pantoprazole.8 The reason for this difference was revealed in the structure activity relationships and molecular docking, which found pantoprazole showed higher blockade activity due to more stable and higher affinity binding to the active site of the efflux pumps.8

These findings are certainly promising in the face of alarming rates of reporting of multidrug-resistant organisms, particularly given the difficulties with developing new antimicrobials. However, it has been cautioned that in vitro studies of fungal susceptibility must be interpreted with caution due to the impact different methods have on MIC values, and the lack of correlation between in vitro and in vivo results.10 Nevertheless, further work continues to be necessary to better understand the clinical utility and repurposing of existing medicines as one of the many strategies to help in the battle against antimicrobial resistance.

References

  1. Cleveland Clinic. Candida Albicans: Infections, Symptoms & Treatments: Cleveland Clinic; 2022. At: https://my.clevelandclinic.org/health/diseases/22961-candida-albicans
  2. Centers for Disease Control and Prevention. About Invasive Candidiasis: U.S. Department of Health & Human Services; 2021. At: www.cdc.gov/fungal/diseases/candidiasis/invasive/definition.html
  3. Antibiotic Expert Group. Therapeutic guidelines: Directed therapy for bloodstream infections, including sepsis and septic shock. Melbourne: Therapeutic Guidelines Limited; 2022.
  4. Australian Medicines Handbook. Australian Medicines Handbook – Azoles: Australian Medicines Handbook Pty Ltd; 2023.
  5. Australian Medicines Handbook. Australian Medicines Handbook – Echinocandins Australian Medicines Handbook Pty Ltd; 2023.
  6. Australian Medicines Handbook. Australian Medicines Handbook – Amphotericin B: Australian Medicines Handbook Pty Ltd; 2023.
  7. Whaley SG, Berkow EL, Rybak JM, et al. Azole antifungal resistance in candida albicans and emerging non-albicans candida species. Front Microbiol 2016;7(2173).
  8. El-Ganiny AM, Kamel HA, Yossef NE, et al. Repurposing pantoprazole and haloperidol as efflux pump inhibitors in azole resistant clinical candida albicans and non-albicans isolates. Saudi Pharm J 2022;30(3):245–55.
  9. Australian Medicines Handbook. Australian Medicines Handbook – Pantoprazole: Australian Medicines Handbook Pty Ltd; 2023.
  10. Australian Medicines Handbook. Australian Medicines Handbook – Fungal susceptibility: Australian Medicines Handbook Pty Ltd; 2023.