FLUCONAZOLE

1. What’s New in Antifungal Therapy
P.H. Chandrasekar, M.D.
Chief, Division of Infectious Diseases
Wayne State University School of Medicine, Detroit, MI

2. Introduction

3. Maximizing the Benefits of Antifungal Therapy

4. Antifungal Treatment Development

5. Know the Spectrum of Activity1
1Andes D, Curr Med Res Opin, 2013; 29: 13-18

6. Know the Pathogenesis of Invasive Mycoses
and Timing of Antifungal Treatment

7. Know the Distribution1
1 Groll AH,e t al. Adv Pharmacol, 1998; 44:343-500

8. Know the Common Adverse Effects1
1 Lewis RE. Mayo Clin Proc, 2011; 86:805-817

9. Early Diagnosis and Treatment are Important1
1 Chamilos G, et al. Clin Infect Dis, 2008; 47:503-509

10. Factors Contributing to Antifungal Failure Are
Frequently Multiple and Interrelated

11. Consider the Phase of the Disease
1 Lewis, RE. Am J Ther, 2012; 19: 51-63.

12. General PK/PD Considerations1,2
1 Wiederhold, N. Current Fungal infection Reports. 2010; 4:70-77
2 Andes D. Antimicrob Agents Chemother. 2003;47:1179-1186

13. Drug-Drug Interactions: Azoles

14. Therapeutic Drug Monitoring1,2
1 Lewis RE. Am J Ther. 2012; 19:51-63
2 Andes, D, et al. Antimicrob Agent Chemother. 2009; 53:24-34

15. Advances in Antifungal Therapy:
Posaconazole1
1 http://www.merck.com/product/usa/pi_circulars/n/noxafil/noxafil_pi.pdf Accessed May 27, 2014

16. Advances in Antifungal Therapy:
Isavuconazole1,2
• Novel broad-spectrum triazole agent; once-daily oral and IV
formulations available
• Granted FDA fast-track status and received QIDP and orphan
drug designation for invasive aspergillosis and mucormycosis
(zygomycosis)
• Currently in phase 3 of clinical development
1 Falci DR, Pasqualotto AC. Infect Drug Resist. 2013; 6:163-174
2 http://www.basilea.com/Development/Isavuconazole. Accessed may 27, 2014.

17. Isavuconazole: Spectrum of Activity1,2
1 Falci DR, Pasqualotto AC. Infect Drug Resist. 2013; 6:163-174.
2 Andes D. Curr Med Res Opin. 2013;29 (Suppl 4):13-18.

18. Isavuconazole: Pharmacokinetic Properties1
1 Falci Dr, Pasqualotto AC. Infect Drug Resist. 2013; 6:163-174.

19. Isavuconazole: Phase 3 Clinical Trials

20. Invasive Aspergillosis: Voriconazole +
Anidulafungin1
1 Marr KA, et al. 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2012). Poster LB2812.

21. First 2 wks: AmB + 5 flucytosine vs AmB
Combination: Better survival, Adv Events ≡
IDSA Guidelines: AmB + 5FC or Flucon + 5-FC (less optimal)
AmB clears crypto faster in CSF
Flucytosine Needs to be made more widely available
AmB Needs to be made more widely available
Cryptococcal Meningitis: 2 Drugs vs 1 Drug
1 NEJM, 2013

22. Treatment for Crypto meningitis: AmB + Flucon → Flucon
Antiretroviral treatment: 1-2 wks after diagnosis
or
5 wks after diagnosis
Mortality (26 wks): 45% v 30% (early v delayed treatment)
Mortality higher, if csf < 5 WBC (early v delayed treatment)
Incidence of cryptococcal IRIS ≡ (early v delayed treatment)
Conclusion: Delayed start of ART improved survival
Cryptococcal Meningitis/HIV Treatment
Timing
N Engl J Med 2014
Study in Africa

23. • Flucon/Itracon; Flucytosine; AmB-convent & lipid forms
• Flucon-most avail; Flucyt. – least available
• AmB – 49% of countries; Itracon – 93.5% of countries
• Flucon- improper formulation (single dose), expensive
• Prices - >> daily wage of many
Bottom line: Inequality in access; poor formulation; high price
Antifungal Drugs
Availability/Pricing (163 countries)
Kneale M et al, Manchester/Switzerland (GAFFI)

24. • Invasive fungal infections continue to increase in frequency
globally
• Several drugs are available but the maldistribution and cost
need to be addressed
• A good knowledge of fungal infections and available drugs is
crucial to minimize abuse of these drugs.
Summary