Steroids, Aspergillus, and Antifungals Russell E. Lewis, Pharm.D., FCCP, BCPS Associate Professor University of Houston College of Pharmacy & The University of Texas M.D. Anderson Cancer Center UH Anti-Infective Research Laboratories

Outline How do steroids and antifungals act on your body (pharmacology)...how does your body act on these drugs (pharmacokinetics)? What are the benefits/risks associated with taking these medications alone or in combination? Do steroids directly affect Aspergillus?

Key point #1 Humans and Aspergillus use similar enzyme pathways to synthesize: Sterols for their cell membrane Humans: cholesterol Fungi: ergosterol Steroids specifically for humans: Sex steroids (e.g., testosterone, estrogen) Mineralocorticoids (e.g., aldosterone) Glucocorticoids (e.g., cortisone) Soluble metabolites of drugs (i.e. how drugs are eliminated in humans)

Overview of steroid synthesis adrenal glands 2-AcetylCoA mevalonate Mineralocorticoids Drugs designed to target one of these pathways have the potential to affect multiple pathways squalene lanosterol cholesterol Kidneys (regulation of sodium and potassium) Aldosterone in Aspergillus Deoxy- corticosterone Glucocorticoids Liver, pancreas, other tissue (glucose production, metabolism) Progestagens Progesterone 11-deoxycortisol Cortisol Immune system (feedback mechanism to control inflammation) ergosterol Androgens Testosterone Estradiol Sex steroids

Glucocorticoids (steroids) Glucocorticoids (Glucose+ cortex+ steroid) Cortisol is the glucocorticoid synthesized in our body that regulates a variety of important cardiovascular, metabolic, and immunologic functions Important for adapting to stress Part of the feedback mechanism in the immune system that turns immune activity (inflammation) down Synthetic glucocorticoids (e.g., prednisone) can be prescribed to suppress a damaging immune response

Glucocorticoids are used to control inflammation in allergic bronchopulmonary aspergillosis Mild disease Fungal spores Prednisone 30 mg per day (0.5 mg/kg) 1-2 weeks; then alternate days for 6-8 weeks Decrease daily prednisone dose by 5-10 mg every 2 weeks Minimal fibrosis Minimal mucus Minimal muscle thickness Goals of treatment: Preserve lung function through suppression of inflammation to Aspergillus antigens and the inflammatory response of asthma with the lowest possible (cumulative) exposure to steroids Increased fibrosis Increased mucus Increased inflammatory cells Increased muscle thickness Chronic disease with airway remodeling Effect of glucocorticoid on airway remodeling Image courtesy of NIAID/ NIH Gilley, Godblatt and Judson . Aspergillosis: From Diagnosis to Prevention. 2009

What are the possible risks of staying on high doses of prednisone for prolonged periods? Hypothalamus CRH Pituitary Muscle weakness Ocular ACTH cataracts glaucoma Adrenal Adrenal (HPA) suppression (your cortisol set point) Diabetes mellitus Cardiovascular Hypertension Hyperlipidemia Artherosclerosis high blood sugars Gastointestinal Peptic ulcer disease Gastritis Psychological Euphoria Depression Insomnia Psychosis Infections what are the specific risks? Thinning skin/ Fat re-distribution Decreased bone density Osteoperosis/necrosis Increased risk of fracture Growth inhibition

What are the effects of glucocorticoids on immunity? Suppressed cell-mediated immunity “Mask” symptoms of infection Neutrophils Increased susceptibility to bacterial and fungal infections Monocytes/ macrophages Increased susceptibility to some intracellular bacterial and fungal infections prednisone T-lymphocytes X X CD4+ CD8+ communication Lymphocytes Increased susceptibility to intracellular bacterial pathogens, fungi and viruses communication

What is the “threshold” glucocorticoid dose for invasive aspergillosis? Ribaud et al, Clin Infect Dis;1999;28:322

Inhaled corticoisteroids reduce the risk of side effects because of less drug delivery to the systemic circulation ` ~ 10-20% inhaled Mouth and pharynx Lungs ~ 80-90% swallowed (↓spacer/mouth wash) Systemic circulation GI tract Liver Adverse effects Inactivation in liver, including CYP 3A4 (first pass metabolism)

Key point #2 Synthetic glucocorticoids (e.g., prednisone) are often the most effective therapy for preserving lung function in patients with allergic/inflammatory responses in the lung due to Aspergillus ....however, their long term use can be associated with side effects, including severe infections Therefore, the goal is to use the minimally effective dose (oral or inhaled) that provides benefit

How does your body act on medications? If drug is not water soluble, it must be chemically modified in the liver to make the drug more water soluble Two major types of chemical modifications to make drugs more water soluble: Oxidative reactions (CYP enzymes) Synthetic (water soluble molecule added) Drug interactions can occur if a patient is taking two or more medications that: • Are metabolized through the same pathway • Block these pathways • Induce (accelerate) these pathways If drug is already water soluble, it is filtered by kidneys Some drugs can be passed in stool without modification Passed in urine

Antifungals used to treat aspergillosis Amphotericin B (intravenous only) Must be administered intravenously Typically reserved for patients who have not responded to other therapies Can be toxic to the kidneys Echinocandins (intravenous only) caspofungin micafungin, anidulafungin Azoles (can be given by mouth) itraconazole voriconazole posaconazole highest potential for drug interactions

Azole antifungals work by inhibiting an enzyme in fungi that is responsible for making cell membrane sterol called ergosterol.... The newer (triazole) antifungals

Azole antifungals work by inhibiting an enzyme in fungi that is responsible for making cell membrane sterol called ergosterol.... ...but they can also can inhibit human liver enzymes that metabolize drugs, leading to drug-drug interactions Human cytochrome P450 3A4 (responsible for metabolizing 35% of all drugs used therapeutically in humans) non-specific Aspergillus cytochrome P450 lanosterol a-demethylase (Erg11) broad(er) spectrum

An example of liver metabolizing drug interaction with voriconazole-inhibition voriconazole inhibits the metabolism of cyclosporin resulting cyclosporin + voriconazole cyclosporin + placebo Clin Pharmacol Ther 2002; 71:226-234.

An example of liver metabolizing drug interaction with voriconazole-induction phenytoin accelerates the metabolism (clearance) of voriconazole resulting in ineffective bloodstream concentrations

What is the risk of administering oral azole antifungals with inhaled corticoisteroids? Administration of high doses of synthetic steroids (e.g., prednisone, inhaled budenoside) for prolonged periods may suppress the body’s cortisol “set point” Because some steroids are metabolized in the gut and liver, the co-administration of an azole antifungal can reduce the metabolism of some steroids by 30-60%, resulting in higher steroid bloodstream concentrations and greater than expected suppression of the cortisol “set point” Your doctor can lower your steroid dose and monitor blood tests to make sure your steroid dose is not too high Adrenal (HPA) axis Hypothalamus CRH Pituitary ACTH Adrenal your cortisol “thermostat”

Key point #3 If your doctor has prescribed you an azole antifungal, be aware that you are at higher risk for experiencing drug-drug interactions-including steroid medications This risk can be reduced by adjusting the doses of your other medications, and with blood tests In some patients, antifungal therapy can lesson the dependence on steroids

Do steroids have a direct effect on Aspergillus? Sterol (10-6 M) Growth increase relative to control P value Hydrocortisone 44% 0.03 Ergosterol 30% 0.183 17β-oestradiol 8% 0.277 Progesterone 3% 0.937 Testosterone 15% 0.211 Modest effect in the test tube, but the importance (relative to immunosuppression in the body) is not well understood Ng et al. Microbiology 1994;140:2475-2479.

Neptune, Fontana di Trevi Thank you Neptune, Fontana di Trevi

Addendum

All formulations are inhibited by CYP 3A4. Clinicians should be aware of the need to use lower doses of most inhaled corticosteroids with co-administration of CYP3A4 inhibitors Kelly WH. Annals of Pharmacotherapy 2009;43:519-27.

Kelly WH. Annals of Pharmacotherapy 2009;43:519-27.