How Can We Tailor Antifungal Therapy?

How Can We Tailor Antifungal Therapy? Russell Lewis Infections Diseases Unit Department of Medical Sciences and Surgery S.Orsola Malpighi Hospital University of Bologna

Most Common Infectious Diagnosis in Hematology Patients at S Orsola-Malpighi Hospital, 2007-2012 (n=1,712 episodes) Group % of cases No pathogen identified 45.9 Bacterial 41.9 Aspergillus (GM diagnosis-probable) 2.2 Invasive mold (possible) 1.9 Aspergillus + bacteria (GM diagnosis probable) 1.9 Mold proven 1.4 Invasive mold (possible) + bacteria 1.3 Bacterial + Yeast 0.8 CMV 0.6 Yeast 0.5 Non-CMV viral infection 0.4 8.7%

Crude Mortality of Invasive Fungal Infections in Hematology Patients, S Orsola Malpighi 2007-2012 100 Candida, n=20 Survival probability (%) 80 60 40 20 76% survival at 6 weeks* Proven or probable mold n=105 0 p=0.08 0 20 40 60 80 100 Days After Admission Includes mixed infections * 6-Week survival reported with voriconazole monotherapy=72.5% (Marr et al. ECCMID 2012)

This presentation focuses on general strategies to maximize the efficacy and safety of antifungal therapy Can we better target who (or who does not) need antifungal therapy? What should be our guiding principles of antifungal therapy for invasive mold disease? Can we avoid chronic toxicities of antifungals?

Guidelines provide little guidance of who really needs antifungal therapy High-risk High-risk for molds Consider prophylaxis Neutropenia > 10 days, comorbidities, persistent fever Remission-induction AML/MDS Allogeneic HSCT Freifeld et al. Clin Infect Dis 2011;52:e56-e93.

The incidence of aspergillosis varies considerably from one transplant center to the next 12-Month Cumulative Incidence (# aspergillus cases/# allogeneic HSCT transplants) TransNet Database 2001-2002 Cumulative Incidence 10 8 6 4 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Study site Morgan et al. Medical Mycology 2005;S49-58.

Clinical trials for invasive fungal infections may not reflect the patients you are treating Clinical trial (inclusion/exclusion criteria) EORTC/MSG Definitions Your institution? Goal: Homogeneous population, that gives drug best chance to work Greater diagnostic uncertainty, multiple comorbidities, prior treatments, co-infections, drug interactions, contraindications, terminal stages of underlying disease

Risk of invasive aspergillosis based on primary host factor INTERMEDIATE RISK LOW RISK HIGH RISK Chronic granulomatous disease Allogeneic HSCT with graft versus host disease Myelodysplastic syndrome treated with remission-induction chemotherapy Acute myeloblastic leukemia treated with remission-induction chemotherapy Lung or heart transplantation Small-bowel transplantation Liver transplantation Allogeneic HSCT without graft versus host disease Acute myeloblastic leukemia during consolidation phase Acute lymphoblastic leukemia Heart transplantation Chronic lymphocytic leukemia Myelodysplastic syndrome Multiple myeloma COPD with acute exacerbation AIDS Non-Hodgkin s lymphoma Autologous HSCT Kidney transplantation Solid tumor Autoimmune disorder Herbrecht et al. Ann NY Acad Sci 2012;1272:23-30.

Risk Factors Influencing Host Condition INNATE IMMUNE STATUS UNDERLYING CONDITION Toll-like receptor polymorphism C-type lectin receptor polymorphism Mannose binding lectin polymorphism Plasminogen polymorphism Other polymorphisms? PRIMARY HOST FACTOR Neutropenia Progressive cancer Graft versus host disease Anticancer chemotherapy Corticosteroids Anti-T-cell antibodies Hematological Malignancy Allogeneic HSCT SOT Climate Solid tumor Construction work Other immune disorder Place of residence Tobacco or cannabis use Contaminated food or spices Pets, plotted plants and gardening No HEPA filtration during hospitalizations ENVIRONMENTAL FACTORS Diabetes Iron overload Trauma, burns Renal impairment Metabolic acidosis Prior respiratory disease OTHER FACTORS Herbrecht et al. Ann NY Acad Sci 2012;1272:23-30.

Retrospective Review-Patient Characteristics Characteristics Hospitalization 2005-2008 n=1,709 episodes (%)* Median age (range) 52 (15-84) Sex, male 1,013 (59) Median no. of hospitalizations (range) 2 (1-12) Underlying malignancy (%) AML/MDS 527 (31) ALL 176 (10) CML 50 (3) CLL 19 (1) Lymphoma 490 (29) MM/ amyloidosis 418 (24) Aplastic anemia 13 (0.8) Non-neoplastic 16 (0.9) Allogeneic HSCT 203 (12) Autologous HSCT 584 (34) Stanzani et al. Submitted *At least 5 days of hospitalization

Risk Factors (n=12 of 17) Associated with Invasive Mold Disease by Univariate Analysis Risk factor No IMD (%) n=1650 IMD (%) n=59 P value At-risk profession (spore exposure) 168 (10) 10 (17) 0.05 Prior invasive mold disease 31 (2) 7 (12) < 0.001 Corticosteroids 312 (19) 16 (27) 0.06 Diabetes 156 (9) 10 (17) 0.03 High-risk malignancy 555 (34) 37 (63) < 0.001 Uncontrolled malignancy 755 (46) 47 (80) < 0.001 High-risk chemotherapy 512 (31) 37 (63) < 0.001 Neutropenia > 10 days 596 (36) 48 (81) < 0.001 Lymphocytopenia (< 50/mm 3 ) 415 (25) 31 (53) < 0.001 Acute GVHD, grade II-IV 47 (3) 5 (8) 0.02 Mucositis, Grade III-IV 206 (12) 14 (24) 0.004 Admitted to a room without HEPA filtration 587 (36) 29 (49) 0.01 Stanzani et al. Submitted

Risk factors Independently Associated Invasive Mold Disease In Multivariate Logistic Regression Variable Prolonged neutropenia IMD Incidence (%) β-coefficient Wald χ 2 P value 596 (41) 1.72 21.99 < 0.001 Previous IMD 31 (9) 1.71 12.42 < 0.001 Malignancy status 755 (50) 1.53 19.46 < 0.001 Lymphocytopenia 415 (31) 0.90 9.57 0.002 Hazard Ratio (95% CI) 5.60 (2.72 11.50) 5.55 (2.14 14.41) 4.64 (2.34 9.19) 2.45 (1.39 4.34) Points 4 4 3 2 Risk score (0-13 points) Stanzani et al. Submitted

A weighted risk score can screen-out patients unlikely to develop invasive mold disease Sensitivity 100 80 60 40 20 0 aroc=0.84 (95% CI 0.82-0.86) P<0.001 0 20 40 60 80 100 1-Specificity Percent 100 90 80 70 60 50 40 30 20 10 0 Criterion value Specificity Sensitivity 0 2 4 6 8 10 12 14 Risk Score Study Cohort Sens (95% CI) Spec (95% CI) PPV (95% CI) NPV (95% CI) 2005-2008 (n=1,709) 0.86 (0.77-0.95) 0.74 (0.73-0.75) 0.10 (0.07-0.13) 0.99 (0.99-1) Stanzani et al. Submitted

Risk Score Validation 2009-2012 n=1,746 episodes (855 patients) % Proven or Probable IMD 30 20 10 0 2005-2008 2009-2012 0.6 1.9 0.8 0.9 0-2 3-5 6-8 9-13 Score 686 535 669 629 7.3 5.1 16.8 26.5 345 143 350 98 =1,709 episodes =1,746 episodes Study Cohort aroc Sens (95% CI) Spec (95% CI) PPV (95% CI) NPV (95% CI) 2009-2012 (n=1,746) 0.76 (0.74-0.78) 0.69 (0.57-0.81) 0.76 (0.74-0.78) 0.10 (0.07-0.13) 0.98 (0.97-0.98) Stanzani et al. Submitted

Consistent NPV Across Various Primary Host Factors Validation cohort 2009-2012 Primary host factor (Risk score) AML (remission-induction), n=141 (median=7) AML (consolidation/salvage), n=285 (median=4) Lymphoma, n=390 (median=3) Allogeneic HSCT, n=227 (median=6) Autologous HSCT, n=344 (median=0) IMD Prevalence aroc Sensitivity Specificity PPV NPV 5.7% 0.65 0.87 (0.47-0.97) 2.1% 0.73 0.67 (22.3-95.7) 2.1% 0.79 0.75 (0.35-0.97) 11% 0.67 0.80 (0.59-0.93) 0.8% 0.53 1.0 (0.30-1.0) 0.28 (0.20-0.36) 0.05 (0.01-0.13) 0.93 (0.91-0.96) 0.32 (0.25-0.39) 0.06 (0.03-0.09) 0.06 (0.02-0.12) 0.05 (0.01-0.13) 0.20 (0.08-0.39) 0.22 (0.12-0.34) 0.009 (0.002-0.03) 0.95 (0.83-0.99) 0.99 (0.97-0.99) 0.99 (0.98-1.0) 0.93 (0.87-0.96) 1.0 (0.82-1.0) Stanzani et al. Submitted

What is the impact posaconazole prophylaxis? under utilized? Score < 6 Score > 6 10 P=0.30 10 n=448 % Cumulative Invasive Mold Disease 8 6 4 2 unnecessary? n=92 n=1298 8 6 4 2 n=108 ARR 6.1% P=0.008* 0 Pos No Pos 0 Pos No Pos *Posaconazole vs. itraconazole/fluconazole trial. ARR 6.0% Cornely et al., N Eng J Med 2007;356:348-359 Stanzani et al. Submitted

Pathogenesis of invasive molds and timing of antifungal treatment Radiographic signs inhaled conidia reach distal airspace macrophages and PMN block replication sub-clinical fungal proliferation disease detectable by high resolution CT extensive necrosis limits drug delivery dissemination and death Prophylaxis Large numbers of patients unnecessarily exposed to antifungals Preemptive requires sensitive surrogate markers (diagnostics) galactomannan? beta-glucan? PCR? Empiric Large numbers of patients unnecessarily treated, antifungals are administered late in the course of infection Pathogen-directed late in treatment course when fungal burden is high Risk of inappropriate therapy

Factors to consider when selecting antifungal therapy SPECTRUM PK PREDICTABILITY? SAFETY CONVIENENCE Lipid AMB Lipid AMB Fluconazole Fluconazole Posaconazole Echinocandin Echinocandin Voriconazole Voriconazole Fluconazole Posaconazole Posaconazole Echinocandin Voriconazole (IV) Voriconazole Echinocandin Fluconazole Voriconazole (PO) Lipid AMB Lipid AMB Posaconazole Chronic phase of treatment Acute phase of treatment Sometimes the best drug is not a single drug? The answer is always individualized to the patient, dynamic risks Does TDM improve PK confidence, equally important in acute and chronic phases?

This presentation focuses on general strategies to maximize the efficacy and safety of antifungal therapy Can we better target who needs (or does not need) antifungal therapy? Clinical risk score screening seems feasible as first step towards risk stratification What should be our guiding principles of antifungal therapy for invasive mold disease? Spectrum, activity and PK predictability in the acute treatment phase; then more balance towards safety and convenience in the chronic treatment phase Can we avoid chronic toxicities of antifungals?

Common Antifungal Toxicities Hepatic Renal toxicity CNS Photopsia Cutaneous?? All azoles Amphotericin B 5FC Echinocandins Amphotericin B; Cyclodextrans possibly toxic (IV voriconazole) Hyponatremia (azoles) Voriconazole Voriconazole Rash (all antifungals) Phototoxicity /malignancy? (voriconazole) GI Cardiac Infusion reactions Bone marrow suppression Itraconazole Posaconazole 5FC Cardiomyopathy (itraconazole, voriconazole, posaconazole) QTc prolongation (All azoles, especially with drug interactions) Amphotericin B Echinocandins Flucytosine Amphotericin B (anemia associated with decreased epoetin production)

Severe phototoxicity/ squamous cell carcinoma with voriconazole Risk factors Voriconazole treatment > 6-9 months Older patients Fair skin High sun exposures Profound immunosuppression Cowen et al. J Acad Dermatol 2010;62:31-37. Clancy & Nguyen. Curr Infect Dis Report 2011;13:536-543.

Severe phototoxicity with voriconazole- Not necessarily an idiosyncratic reaction? No absorbance at UVA or UVB spectrum N-Oxide Metabolite Absorbance in UVA and UVB range (320-400 nm), possibly acting as a chromophore for phototoxicity Strongly influenced by CYP2C19 genotype, enterohepatic circulation 4-hydroxy metabolite No absorbance in UVA and UVB range Scholz et al. B J Clin Pharm 2009;68:906-15. Murayama et al. Biochem Pharmacol 2007;73:1-7.

Drug Interactions with Triazole Antifungals Substrate Voriconazole Inhibitor Fluconazole Itraconazole Substrate Voriconazole Inhibitor Fluconazole Voriconazole Voriconazole 2C9 2C19 ENZYME SYSTEM 3A4 P-GP transporter Substrate Itraconazole Voriconazole Inhibitor Fluconazole Itraconazole Voriconazole Posaconazole Substrate Posaconazole Voriconazole Inhibitor Itraconazole Posaconazole Figure: P. Donnelly. Brüggemann et al. Clin Infec Dis 2009:48:1441-58.

Toxicodynamics of itraconazole: Implications for therapeutic drug monitoring n=216 chronically treated patients, 99 (46%) developing AE: Fluid retention (21%) 93% peripheral edema CHF symptoms GI intolerance (21%) 17.1 mg/l (bioassay) Lestner et al. Clin Infect Dis 2009;49:928-930. Is posaconazole similar?

I would like to acknowledge colleagues at S Orsola Malpighi Hospital Institute of Hematology, "Lorenzo e Ariosto Seràgnoli Marta Stanzani, M.D., Ph.D. Nicola Vianelli, M.D. Riccardo Ragionieri (database) Physicians, nurses, fellows involved in data collection Infectious Diseases Unit Pierluigi Viale, M.D., Ph.D.