1. Combination Antifungal Therapy By Amy Barnett, Doctor of Pharmacy Candidate University of Florida College of Pharmacy

2. Fungal Infections: high risk populations Neutropenic patients Solid organ transplant patients Diabetes Patients Immunocompromised Intensive care populations Premature infants Surgical populations

3. Most common fungal pathogens Candida Aspergillus Cryptococcus

4. Antifungal Classification Azoles –1st gen: fluconazole, itraconazole, ketoconazole –2nd gen: voriconazole Polyenes –Conventional AmphoB (Amphocin) –Liposomal AmphoB (AmBisome) –Colloidal AmphoB (Amphotec) –Lipid complex AmphoB (Abelcet) 5-Flucytosine Echinocandins –Caspofungin, anidulafungin, micafungin

5. Azoles Mechanism –Inhibits ergosterol biosynthesis by inhibition of 14-a-demethylase Adverse effects –Nausea; diarrhea; abdominal pain; rash; edema; CHF; pulmonary edema; inc LFTs Spectrum –Fluconazole: candida (not C.krusei), cryptococcus neoformins, histoplasma capsulatum –Itraconazole: above + aspergillus, coccidiodes immitis, paracocciodes, blastomycosis –Voriconazole: aspergillus, fusarium, scedosporium apiospermum, candida

6. Polyenes Mechanism –Binds directly to ergosterol to alter cell membrane activity Adverse effects –Fever, chills, phlebitis, anaphylaxis give APAP and benadryl prior to infusion –Increased creatinine (prevention:saline load), hypokalemia (prevention:IV K+ replacement or amiloride 5-10mg/day), renal tubular acidosis Spectrum –Broad spectrum: active against most fungal pathogens

7. 5-flucytosine Mechanism –FU  FUTP  inhibits protein synthesis –FU  FUM  interfere with DNA synthesis Adverse effects –Bone marrow suppression, CNS effects, GI upset, rash, inc LFTs, inc SCr/BUN Spectrum –Systemic candidiasis, cryptococcus –Used synergistically with AmphoB –Rapid resistance when used alone –Excellent CNS penetration

8. Echinocandins Mechanism –Non-competitive inhibitor of glucan synthase (critical component of the cell wall) Adverse effects –Pain at injection site, inc LFTs, flushing Spectrum –Aspergillus, candida

9. Studied Combinations Fluconazole + Ampho B –Candidemia Ampho B + 5-flucytosine –HIV-associated cryptococcal meningitis Ampho B + fluconazole + 5-flucytosine –HIV-associated cryptococcal meningitits Voriconazole + caspofungin –Aspergillus

10. Ampho B plus fluconazole N=219 non-neutropenic pts with candidemia Treatment groups: –Fluconazole + placebo –Fluconazole + AmphoB Doses: fluconazole 800 mg qd +/- AmphoB 0.6- 0.7mg/kg/day Results: Combination therapy was not antagonistic and trended toward improved success (p=0.043) and increased eradication from the bloodstream (p=0.02). Rex, John H., Peter G Pappas, et al. Clin Inf Diseases 2003;36:1221-8

11. Selected antifungal drug interactions for Candida Table I. Combination In vitro In vivo Amphotericin B + flucytosine S, Add, I S, Add Amphotericin B + itraconazole Ant I, Ant Amphotericin B + fluconazole Add, I, Ant I, Ant Amphotericin B + terbinafine S, Add ND Amphotericin B + echinocandin S, Add, I I Amphotericin B + rifampicin S I Fluconazole + echinocandin I ND Flucytosine + fluconazole S, I, Ant S, Add, I Add = additive; Ant = antagonistic; I = indifferent; ND = insufficient data available; S = synergistic. Baddley, John W., et al. Drugs 2005;65(11):1461-1480

12. AmphoB + fluconazole + 5- flucytosine N=64 pts HIV-associated cryptococcal meningitis Treatment Groups –AmphoB or –AmphoB + flucytosine or –AmphoB + fluconazole or –AmphoB + flucytosine + fluconazole Dosing: AmphoB 0.7mg/kg/day; flucytosine 100mg/kg/day; fluconazole 400mg/day Results: inc clearance with AmphoB + flucytosine regimen compared to AmphoB alone (p=0.006), AmphoB + fluconazole (p=0.02), or triple therapy (p=0.02). Brouwer, Annemarie E, et al. The Lancet 2004; 363:1764-1767.

13. Selected antifungal drug interactions for Cryptococcus Table II. Combination In vitro In vivo Amphotericin B + flucytosine S, I S, I Amphotericin B + itraconazole I S, I Amphotericin B + fluconazole S, I A, I Flucytosine + fluconazole S, Add, I S, I Add = additive; I = indifferent; S = synergistic. Baddley, John W., et al. Drugs 2005;65(11):1461-1480

14. Voriconazole + caspofungin N=87 transplant pts with Aspergillosis Treatment groups: –Voriconazole + caspofungin –AmphoB (as a control group) Doses: voriconazole 6mg/kg q12h x 1 day, then 4mg/kg q12h; caspofungin 70mg/day x 1 day, then 50mg/day; AmphoB 5-7.4mg/kg/d. Results: 90 day survival was significantly inc in transplant pts with renal failure (p=0.022) and those with A. fumigatus infection (p=0.019) compared to the control group. Singh, Nina, Ajit P Lamaye, et al. Transplantation 2006; 81(3): 320-326.

15. Selected antifungal drug interactions for Aspergillus Table III. Combination In vitro In vivo Amphotericin B + flucytosine S, Add, I S, Add, I Amphotericin B + itraconazole Ant Ant Amphotericin B + fluconazole I, Ant I Amphotericin B + terbinafine Add, I I Amphotericin B + echinocandin S, Add, I S, Add, I Amphotericin B + rifampicin S, I Add ExS triazole + echinocandin S, Add S, Add Amphotericin B + ExS triazole I ND Itraconazole + nikkomycin Z S ND Add = additive; Ant = antagonistic; ExS triazole = extendedspectrum azole (posaconazole, voriconazole or ravuconazole); I = indifferent; ND = insufficient data available; S = synergistic. Baddley, John W., et al. Drugs 2005;65(11):1461-1480

16. Advantages/Disadvantages of Combination Therapy Advantages: Additive or synergistic effects Increased spectrum of activity Decreased resistance Disadvantages: Antagonistic effects Increased risk of drug interactions Increased toxicity Increased cost Baddley, John W., et al. Drugs 2005;65(11):1461-1480

17. Conclusions Severe infections High risk patients More studies with more combinations –More consistent results –Combinations with other AmphoB formulations Micafungin + liposomal AmphoB (AmBisome) Anidulafungin + lipid complex AmphoB (Abelcet)

18. References Baddley, John W. and Peter G Pappas. Antifungal Combination Therapy: clinical potential. Drugs 2005; 65(11): 1461-1480. Brouwer, Annemarie, Adul Rajanuwong, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. The Lancet 2004; 363: 1764-1767. Kullberg BJ, JD Sobel, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial. The Lancet 2005;366:1435-42. Lacy, CF, et al. Lexi-Comp’s Drug Information Handbook. 13th ed. Rex, John H., Peter G Pappas, et al. A randomized and blinded multicenter trial of high- dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Inf Diseases 2003;35:1221-8 Singh, Nina, Ajit P Lamaye, et al. Combination voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: A prospective multicenter, observational study. Transplantation 2006; 81(3): 320- 326.