ESCMID Online Lecture Library. by author

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1 The antibacterial experience: indications for clinical use of antimicrobial combinations To prevent the emergence of resistant organisms (tuberculosis) To treat polymicrobial infections (abdominal complicated infections) To broaden the spectrum of initial therapy in high-risk settings (de-escalation therapy, febrile neutropenia?) To reduce toxicity (for example??) To exploit a synergistic effect in order to improve effectiveness PPID 6 Ed. Chapter 16. R. Moellering, G. Eliopoulos

2 WHAT WE CAN EXPECT FROM COMBINATION ANTIFUNGAL THERAPY Possible benefit Improved clinical efficacy and survival Increased spectrum of action Reduced resistance Possible disadvantage Possible risk of antagonism Possible increased toxicity and interactions Highly probable disadvantage Increased cost

3 A methodological algorythm for showing that combination therapy is more effective than monotherapy In vitro studies Animal models Clinical trials

4 In vitro studies Additive Combined effect is the sum of individual effects Synergistic Combined effect exceeds the sum of individual effects Neutral / indifferent Antagonistic

5 Drugs 2005

6 Animal models

7 Mortality (%) GUINEA PIG MODEL OF DISSEMINATED INVASIVE ASPERGILLOSIS Kirkpatrick et al. Antimicrob Ag Chemother Challenge A. fumigatus Days Controls CASPO 2.5 CASPO 1 AmB 2.5 VORI 5 CASPO 2.5+Vori 5 CASPO 1+Vori 5 12 animals each group doses are in mg/kg/day

8 Positive Cultures (%) any organ GUINEA PIG MODEL ORGAN CULTURES OF DISSEMINATED INVASIVE ASPERGILLOSIS Kirkpatrick et al. Antimicrob Ag Chemother /12 12/12 12/12 5/12 3/12 12/12 11/12 0 Control Cas 2.5 Cas 1.0 Cas Vori Cas Vori Vori 5 AmB **p<.0025

9 Combination Therapy in Treatment of Experimental Pulmonary Aspergillosis: Synergistic Interaction between an Antifungal Triazole and an echinocandin Vidmantas Petraitis, Ruta Petraitiene, Alia A. Sarafandi, Amy M. Kelaher, Caron A. Lyman, Heather E. Casler, Tin Sein, Andreas H. Groll, John Bacher, Nilo A. Avila, and Thomas J. Walsh J. Infectious Disease 15 June 2003

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12 Combination therapy for pulmonary aspergillosis (I): Petraitis V et al. Antimicrob. Agents Chemother. 2009;53:

13 Combination therapy for pulmonary aspergillosis (I): Petraitis V et al. Antimicrob. Agents Chemother. 2009;53:

14 Combination therapy for pulmonary aspergillosis (I): Petraitis V et al. Antimicrob. Agents Chemother. 2009;53:

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16 PROBLEMS IN EVALUATING DATA FROM ANIMAL MODELS Means for generating the invasive disease Time to treatment (at inoculation or at symptoms) Choice of dosages is crucial for efficacy, synergism and toxicity-relate failures Blood or tissue levels often different from those obtained in humans

17 Clinical studies and guidelines

18 Role of combination antifungal therapy for Crypto and Candida in recent guidelines of the IDSA Cryptococcosis Infection Role of combination Strength of recommendation HIV-associated meningitis Cryptococcal meningitis in transplant recipients Cryptococcal meningitis in patients without HIV/transplant Candidiasis Candidemia, osteoarticular, esophagitis CNS candidiasis Candida endophthalmitis Candida endocarditis Amphotericin B + flucytosine (L-AmB or ABLC) + flucytosine (L-AmB or ABLC) + flucytosine Amphotericin B + flucytosine Not recommended for routine managment LFAB ± flucytosine Amphotericin B + flucytosine (LFAB or amphotericin B) ± flucytosine A-I B-II B-III B-II B-III A-III B-III Courtesy Johann Maertens (modified)

19 Invasive aspergillosis

20 Challenges in the clinical study of antifungal combination therapy in IA Relative low incidence of invasive aspergillosis Slow enrollment and expense Host factors confounding the true efficacy of antifungal combinations Co-morbidities Activity of underlying disease Subtle and nonspecific clinical manifestations Concomitant bacterial/viral/infections Mixed fungal infections Type and severity of immunosuppression Recovery from immunosuppression Lack of a reliable laboratory surrogate marker for monitoring Lack of agreement on efficacy endpoints and appropriate comparator Courtesy Johann Maertens

21 Historical controlled study (retrospective review) comparing the outcomes (90 days survival) of patients with IA who failed initial therapy with AmB formulations and received either voriconazole Or voriconazole + caspofungin (CID 2004)

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23 Problems in evaluating the Small sample size Seattle study Historical control studies tend to underestimate results in control groups and to show larger treatment effects New diagnostic procedures have been introduced overtime, that might have lead to earlier diagnoses and consequent better therapeutic results Viscoli C. Editorial CID 2004

24 First line therapy for IA ECIL III 09 IDSA 08 BSH 08 Voriconazole A I (oral CIII) A I (1 line) Recommended L-AMB B I A I (1 line for some pts) Recommended ABLC B II - - ABCD D I - - D-AMB D I - Not recommended - A I Caspofungin C II Alternative Recommended Micafungin Alternative - Posaconazole Alternative - Itraconazole C III Alternative - Combinatio n Surgery (selected pts) D III Not recommended B II Discouraged A I C III B III B III

25 Salvage therapy ECIL III 2009 IDSA 2008 BSH 2008 L-AMB B III A II No recommendation ABLC B III Posaconazole B II B II Vorico B II Itraconazole C III B II Caspofungin B II B II Micafungin Combination therapy C II (Caspo + L-AMB or Caspo + Vori) B II B II The design of these trials is so heterogeneous that it is not possible to make a recommendation on the basis of their evidence.

26 ECCMID 2012

27 Combination study voriconazole and anidulafungin A prospective, randomized trial comparing the efficacy of anidulafungin and voriconazole in combination to that of voriconazole alone when used for primary therapy of proven or probable invasive aspergillosis (IA) 165 sites worldwide 454 Patients haematological malignancies (incl. HSCT) MITT proven or probable IA (possible cases upgraded <1wk) Statistical design not specified in the poster Population Vori/Anid Vori/Placebo Total Safety ITT MITT PP Marr KA et al. ECCMID 2012 abstract No. 47

28 Week 1 Study Treatment IV voriconazole + Blinded IV anidulafungin vs. IV voriconazole + Blinded IV anidulafungin placebo Week 2 IV/PO voriconazole + Blinded IV anidulafungin vs. IV/PO voriconazole + Blinded IV anidulafungin placebo Weeks 3 4 Option to continue either of the above or to switch to voriconazole monotherapy Investigator to decide (patient must be improving) Weeks 5 6 Voriconazole monotherapy for all subjects Marr KA et al. ECCMID 2012 abstract No. 48

29 Demographics (MITT) Vori/Anid Vori/Placebo n=142 n=135 Age (years),mean (SD) 52.2 (14.9) 51.6 (15.4) Gender, N (%) Male 74 (55) 82 (58) Female 61 (45) 60 (42) Race, N (%) White 99 (73) 98 (69) Other 36 (27) 44 (31) BMI, mean (SD) 24.0 (5.1) 24.0 (4.8) Host Factors, N (%) Allogeneic HSCT 44 (33) 42 (30) No Allogeneic HSCT 91 (67) 100 (70) Marr KA et al. ECCMID 2012 abstract No. 49

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34 Possible role of calcineurin inhibitors in invasive aspergillosis (IA) Calcineurin has a role in the fungal cell wall homeostasis, fungal growth and virulence The use of calcineurin-inhibitors (cyclosporin) was associated with a decrease in the incidence of IA in solid organ transplant recipients compared with conventional not immunosuppression cross-reacting with (Hoflin, human Ann Int calcineurin Med 1987, Singh, Clin Inf Dis 2003) These data have been confirmed in experimental models (Steinback, 2006) Calcineurin inhibition prevents the caspofunginassociated paradoxical effect (regrowth at high concentrations) The challenge is to develop a calcineurin-inhibitor