No Evidence As Yet. Georg Maschmeyer. Dept. of Hematology, Oncology & Palliative Care Klinikum Ernst von Bergmann Potsdam, Germany

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1 Is Combined Antifungal Therapy More Efficient than Single Agent Therapy? No Evidence As Yet Georg Maschmeyer Dept. of Hematology, Oncology & Palliative Care Klinikum Ernst von Bergmann Potsdam, Germany

2 Where We Stand: Current Guidelines Johnson MD & Perfect JR, Curr Fungal Infect Rep 2010;4:87-95

3 Fluconazole vs Fluconazole + D-AmB for Candidemia in Non-neutropenic Patients p = 0.08 Rex JH et al (MSG), Clin Infect Dis 2003;36:1221-8

4 Where We Stand: Reviews on Aspergillosis The currently available antifungals used in various combination approaches have not demonstrated clear improvement over monotherapy. The combination of L-AMB and echinocandins offered no advantage in terms of improving response or reducing mortality over either drug alone. Hence, this combination will only add to the cost of therapy without any improvement in outcome in patients with hematological malignancies. Steinbach WJ et al (Duke), Med Mycol 2011;49:S77-81 Mihu CN et al (MDACC), Cancer 2010;116:5290-6

5 Antifungal Combination Therapy: Considerations PRO CON Increased activity More rapid response Broader spectrum Prevention of resistance development Better tissue distribution Reduced toxicity? (Reduced dosage?) Potential antagonism Drug interactions Increased toxicity? Higher costs

6 Aspergillus - in vitro Studies Combination AmB + 5FC AmB + Rifampin AmB + azoles Echino + AmB or azole Caspo + calcineurin inhibitors or rapamycin Results no consensus: synergy (antagonism) strain, method, dose dependent no antagonism variable results azole preexposure strong antagonism (indifference) - synergy no antagonism synergy Johnson MD et al, Antimicrob Agents Chemother 2004;48: Steinbach WJ et al, Clin Infect Dis 2003;37(Suppl 3):S

7 Antifungal Drug Interactions for Aspergillus 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 = extended spectrum azole (posaconazole, voriconazole or ravuconazole); I = indifferent; ND = insufficient data available; S = synergistic Baddley JW et al, Drugs 2005;65:

8 AmB ± Itraconazole against A. fumigatus Kontoyiannis DP et al, Antimicrob Agents Chemother 2000; 44: ITRA 0 ng/ml ITRA 5 ng/ml In-vitro Antagonism! ITRA 10 ng/ml ITRA 20 ng/ml

9 Evaluable patients LipoAMB: n = 101 ITC and LipoAMB: n = 11 Kontoyiannis DP et al, Cancer 2005;103:2334-7

10 Sequential Azole => AmB Therapy in Invasive Aspergillosis (Voriconazole + AmB: no data available) Steinbach WJ et al, Clin Infect Dis 2003;37(Suppl3):S

11 L-AmB/Ravuconazole Against Invasive Pulmonary Aspergillosis in Neutropenic Rabbits: Antagonism 100 Survival day 13 (%) % 60% 20% % Control L-AmB 1.5 mg/kg Ravu 5 mg/kg L-AmB + Ravu Meletiadis J et al (NCI), J Infect Dis 2006;194:

12 Caspofungin + AmB in Leukemia Pts with Refractory Pulmonary Aspergillosis n = 30, pretreated with D-AmB or L-AmB (± Itra) for a median of 12 days 6 proven, 4 probable, 20 possible Favorable response (CR/PR): 60% CR in 5/6 with proven IPA Survival and hospital discharge: 17/18 in responders, 3/12 non-responders (p < 0.001) (The Good are good...!) Aliff TB et al (MSKCC), Cancer 2003;97:

13 Caspofungin + L-AmB for Salvage Treatment of IA in Patients with Hematologic Malignancies Retrospective evaluation of patients treated with caspo + L-AmB for 7 days Documented (23) or possible (25) IA Response in pts with progressive documented IA: 18% No additive toxicity Kontoyiannis DP et al (MDACC), Cancer 2003;98:292-9

14 Salvage Antifungal Therapy: Voriconazole or Combination? Safety: no difference in bilirubin, AST or serum creatinine levels p = Historical control group Marr KA et al (FHCRC), Clin Infect Dis 2004;39:

15 Combination Salvage Antifungal Therapy: 1-Year Follow-Up Overall survival rate for the 2 groups was equivalent 1 year after infection Marr KA et al (FHCRC), Clin Infect Dis 2004;40:1075-6

16 Micafungin Alone and in Combination for Treatment of Invasive Aspergillosis Phase II, primary or salvage, alone or in combination n = 283 (9-84 years), probable or proven IA 36% completed treatment, 57% died Response: 45% (mono), 35% (combo) Denning DW et al, J Infect 2006;53:337-49

17 Voriconazole + Caspofungin vs L-AmB n = 87 organ transplant pts with aspergillosis Treatment cohorts: Voriconazole + caspofungin (n = 40; ) L-AmB (control group = 47; ) 90 day survival 67.5 vs 51% (p = 0.12) Historical cohorts No survival benefit Singh N et al, Transplantation 2006;81:320-6

18 Combistrat : Combination vs High Dose Prospective, randomized, multicenter pilot study in invasive aspergillosis (n=30), first-line treatment L-AmB (3 mg/kg) + caspofungin vs L-AmB 10 mg/kg L-AmB + Caspo L-AmB HD Mean age in years 56 (16-75) 62 (25-72) Gender (M/F) 11/4 10/5 Underlying malignancy (n) -AML -ALL -Other (CLL, MPS) Median treatment duration in days Caillot D et al, Cancer 2007;110:2740-6

19 Combistrat : Response L-AmB HD Kombination Caillot D et al, Cancer 2007;110:2740-6

20 Combistrat : No Survival Benefit Caillot D et al, Cancer 2007;110:2740-6

21 Other Combination Partners? Granulocyte transfusions G(M)-CSF Deferasirox? (negative study, ICAAC 2011) IFN-gamma, IL-12, anti-il-4,... Quinolone, rifampin, macrolide... Cyclosporin A, other calcineurin inhib s

22 Murine Pulmonary Mucormycosis Treated with Fluconazole plus Trova- or Ciprofloxacin Sugar AM & Liu XP (Boston), Antimicrob Agents Chemother 2000;44:2004-6

23 Clinical Study of Combination Therapy of Aspergillosis? To show a 10% improvement in survival over that achieved with voriconazole alone will require 570 evaluable patients and enrollment of >800 subjects (assuming that 70% of enrollees are evaluable) Wheat LJ (editorial), J Infect Dis 2003;187:1832-3

24 Conclusions There is no indication to give combination therapy first-line to patients with invasive fungal infection, except cryptococcal meningitis Preclinical tests do not reliably predict clinical outcome Combinations of AmB and an azole should be avoided in mold infections Prospective randomized studies will show whether combination treatment for IA is beneficial or not

25 N = 460 Salvation is Near!