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Steroids, Aspergillus, and Antifungals Russell E. Lewis, Pharm.D., FCCP, BCPS Associate Professor University of Houston College of Pharmacy & The University.

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Presentation on theme: "Steroids, Aspergillus, and Antifungals Russell E. Lewis, Pharm.D., FCCP, BCPS Associate Professor University of Houston College of Pharmacy & The University."— Presentation transcript:

1 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

2 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?

3 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)

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

5 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

6 Glucocorticoids are used to control inflammation in allergic bronchopulmonary aspergillosis Mild disease Minimal fibrosis Minimal muscle thickness Minimal mucus Effect of glucocorticoid on airway remodeling Chronic disease with airway remodeling Increased fibrosis Fungal spores Increased inflammatory cells Increased muscle thickness Increased mucus 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 Image courtesy of NIAID/ NIH Gilley, Godblatt and Judson. Aspergillosis: From Diagnosis to Prevention 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

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

8 What are the effects of glucocorticoids on immunity? Neutrophils Increased susceptibility to bacterial and fungal infections Monocytes/ macrophages Increased susceptibility to some intracellular bacterial and fungal infections prednisone Lymphocytes Increased susceptibility to intracellular bacterial pathogens, fungi and viruses 1.Suppressed cell-mediated immunity 2.“Mask” symptoms of infection CD4 + CD8 + T-lymphocytes X X communication

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

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

11 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

12 How does your body act on medications? If drug is already water soluble, it is filtered by kidneys Passed in urine Some drugs can be passed in stool without modification 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: 1.Oxidative reactions (CYP enzymes) 2.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

13 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

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

15 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 Aspergillus cytochrome P450 lanosterol a-demethylase (Erg11) Human cytochrome P450 3A4 (responsible for metabolizing 35% of all drugs used therapeutically in humans) non-specific broad(er) spectrum

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

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

18 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 Hypothalamus Pituitary Adrenal Adrenal (HPA) axis CRH ACTH your cortisol “thermostat”

19 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

20 Do steroids have a direct effect on Aspergillus? Sterol (10 -6 M)Growth increase relative to control P value Hydrocortisone44%0.03 Ergosterol30% β-oestradiol8%0.277 Progesterone3%0.937 Testosterone15%0.211 Ng et al. Microbiology 1994;140: Modest effect in the test tube, but the importance (relative to immunosuppression in the body) is not well understood

21 Thank you Neptune, Fontana di Trevi

22 Addendum

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25 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:

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