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. 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

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
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

7. 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

8. 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

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 `
~ 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)

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 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

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
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

16. 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:

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
Adrenal (HPA) axis
Hypothalamus
CRH
Pituitary
ACTH
Adrenal
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
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:

21. Neptune, Fontana di Trevi
Thank you
Neptune, Fontana di Trevi

22. Addendum

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:

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