Combination Antifungal Therapy

By

Amy Barnett,

Doctor of Pharmacy Candidate

University of Florida College of Pharmacy

Fungal Infections: high risk populations

• Neutropenic patients

• Solid organ transplant patients

• Diabetes Patients

• Immunocompromised

• Intensive care populations

• Premature infants

• Surgical populations

Most common fungal pathogens

• Candida

• Aspergillus

• Cryptococcus

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

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

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

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

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

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

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

Selected antifungal drug interactions for Candida

Table I. Combination In vitro In vivoAmphotericin B + flucytosine S, Add, I S, AddAmphotericin B + itraconazole Ant I, AntAmphotericin B + fluconazole Add, I, Ant I, AntAmphotericin B + terbinafine S, Add NDAmphotericin B + echinocandin S, Add, I IAmphotericin B + rifampicin S IFluconazole + echinocandin I NDFlucytosine + fluconazole S, I, Ant S, Add, IAdd = additive; Ant = antagonistic; I = indifferent; ND = insufficientdata available; S = synergistic.

Baddley, John W., et al. Drugs 2005;65(11):1461-1480

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.

Selected antifungal drug interactions for Cryptococcus

Table II. Combination In vitro In vivoAmphotericin B + flucytosine S, I S, IAmphotericin B + itraconazole I S, IAmphotericin B + fluconazole S, I A, IFlucytosine + fluconazole S, Add, I S, I

Add = additive; I = indifferent; S = synergistic.

Baddley, John W., et al. Drugs 2005;65(11):1461-1480

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.

Selected antifungal drug interactions for Aspergillus

Table III. Combination In vitro In vivoAmphotericin B + flucytosine S, Add, I S, Add, IAmphotericin B + itraconazole Ant AntAmphotericin B + fluconazole I, Ant IAmphotericin B + terbinafine Add, I IAmphotericin B + echinocandin S, Add, I S, Add, IAmphotericin B + rifampicin S, I AddExS triazole + echinocandin S, Add S, AddAmphotericin B + ExS triazole I NDItraconazole + nikkomycin Z S NDAdd = additive; Ant = antagonistic; ExS triazole = extendedspectrumazole (posaconazole, voriconazole or ravuconazole); I =indifferent; ND = insufficient data available; S = synergistic.

Baddley, John W., et al. Drugs 2005;65(11):1461-1480

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

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)

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.