Role of amphotericin B in management of IFI.pptx

Different antifungals, there use in hematology set up, recent guidelines.

1. Role of Amphotericin-B in management of IFI (Invasive Fungal Infections) Dr. Pritish Chandra Patra Consultant Clinical Hematology and Hemato -oncology Apollo Hospitals, Bhubaneswar

2. Candidiasis Aspergillosis Decreasing immunity Hematological Malignancy/ BMT Med ICU or Surgery ICU or SOT (except lung Tx) Candida ~ 70% Aspergillus ~ 25% Flückiger U, Marchetti O, Bille J, et al. Swiss Med Wkly. 2006;136(29-30):447-63. Invasive fungal Infection (IFI) Candida ~ 3 0% Aspergillus ~ 6 0% Leventakos K, Lewis RE and Kontoyiannis DP. Clin Infect Dis. 2010; 50(3):405–15.

3. Adapted from: Chakrabarti A, Sood P, Rudramurthy SM, et al. Intensive Care Med. 2015;41(2):285-95. Chakrabarti A, Sood P, Rudramurthy SM, et al. Intensive Care Med. 2015;41(2):285-95. SIHAM (Society for Indian Human and Animal Mycologists) Candidemia Network: An observational, prospective, multicentric, study undertaken at 27 medical and surgical ICUs across India Candida Species Causing Bloodstream Infection India

4. Overall incidence- 6.51 cases/1,000 ICU admission Acquisition occurred early after admission to ICU (median 8 days) Even infecting patients with lower APACHE II score at admission (median 17.0) 31 Candida species causing candidemia and a high rate of isolation of Candida tropicalis (41.6 %) Azole resistance seen in 11.8% of isolates Significantly higher presence of the relatively resistant C. auris and C. rugosa in public sector hospitals 30-day crude and attributable mortality rates of candidemia patients- 44.7% and 19.6%, respectively Chakrabarti A, Sood P, Rudramurthy SM, et al. Intensive Care Med. 2015;41(2):285-95. SIHAM Candidemia Network- Incidence, Characteristics and Outcome of ICU-Acquired Candidemia in India

5. Higher Susceptibility with AMB in SIHAM Candidemia Network Chakrabarti A, Sood P, Rudramurthy SM, et al. Intensive Care Med. 2015;41(2):285-95.

6. Antifungal Frequency of resistance Fluconazole 59(49.61%) Itraconazole 22(18.33%) Voriconazole 22(18.33%) Clotrimazole 20(16.66%) Amphotericin B 1(0.083%) Total of 258 yeasts isolated from various clinical specimens C. tropicalis 120 (65.21 %) predominated over Candida albicans 67 (26.69%) Fluconazole resistance was 50% for C. tropicalis Patel PH, Pethani JD, Shah PD, et al. IJSR.2013;2(3): 72-73. Adapted from: Patel PH, Pethani JD, Shah PD, et al. IJSR.2013;2(3): 72-73. Prevalence and Antifungal Susceptibility Profiles of Candida Tropicalis in a Tertiary Care Hospital Ahmedabad

7. Prolonged ICU stay Immunosuppressive agents Treatment with corticosteroids Chemotherapy Diabetes mellitus High disease severity score (APACHE II > 20) Advanced age Neutropenia Central venous catheter Renal replacement therapy Gastrointestinal surgery Malnutrition Total parenteral nutrition Multiple site colonization Prolonged antimicrobial use Burns over 50% of body sites Pancreatitis Major trauma Paramythiotou E, Frantzeskaki F, Flevari A, et al. Molecules. 2014;19(1):1085-119. Adapted from: Paramythiotou E, Frantzeskaki F, Flevari A, et al. Molecules. 2014;19(1):1085-119. Risk Factors Leading to Candida infections

8. The Spectrum of Pulmonary Aspergillosis Segal et al. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 173 2006 Lower power view shows arterial thrombosis, Solid arrow , vessel wall; dashed arrows ,intramural thrombus. Higher power magnification shows hyphae invading the arterial wall Invasive hyphae ( arrows ) within the thrombus

9. Invasive Aspergillosis-Risk factors It is estimated that 200 000 cases of Invasive aspergillosis occur worldwide per year 50% in hematological malignancies such as AML, ALL, allogenic HSCT recipient Cornelia Lass- Flörl , Manuel Cuenca-Estrella, Changes in the epidemiological landscape of invasive mould infections and disease,  Journal of Antimicrobial Chemotherapy , Volume 72, Issue suppl_1, 1 March 2017, Pages i5–i11, Common Risk factors 1. Environmental factors : Construction work, inadequate infection control 2.Emerging risk factors : COPD, liver cirrhosis critically ill, mechanical ventilation Risk factors associated with Immuno-compromised status 1.Prolonged/profound neutropenia 2. Prolonged steroids, T-cell immunosuppressants 3. Hematopoietic & solid organ transplant recipients 4. Primary immunodeficiency states: CGD 5.CMV infection

10. Prospective observational study; 11 tertiary care centers ICUs across India; April 2016 and September 2017 398 consecutive patients with proven or probable/putative IMIs (96 proven, 302 probable) Risk groups: Classical (neutropenia, malignancy, transplant recipients on immunosuppression) and non-classical (chronic obstructive pulmonary disease, diabetes, liver disease and glucocorticoids) Prevalence of 9.5 cases/1000 ICU admissions Mean ± SD APACHE II score: 14.3 ± 11.4. IMIs diagnosed at a median of 4 days after ICU admission Aspergillus spp.- the commonest (82.1%) isolates Mucorales detected in 14.4% subjects 42-day and 84-day mortality was 64.8% and 65.8%, respectively. Time to hospital mortality- significantly lower in non-classic risk factors vs classical High APACHE II score and IMI due to Mucormycosis : significant predictors of mortality Chakrabarti A et al. Journal of Critical Care 51 (2019) 64–70 Invasive Mould Infection in Indian ICUs

11. Pie charts showing the evolving epidemiology of invasive fungal infections by their prevalence in autopsies of patients with leukemia at M. D. Anderson Cancer Center, Houston, Texas The epidemiological characteristics of IFIs in leukemia patients continue to evolve Leventakos K, Lewis RE and Kontoyiannis DP. Clin Infect Dis. 2010; 50(3):405–15. IFI - Invasive Fungal Infection Epidemiology of IFIs in Neutropenics

12. Hsu LY, Lee DG, Yeh SP, et al. Clin Microbiol Infect. 2015;21(6):594.e7-11.. Adapted from: Hsu LY, Lee DG, Yeh SP, et al. Clin Microbiol Infect. 2015;21(6):594.e7-11.. Asia-Pacific Epidemiology of Invasive Fungal Diseases among Patients with Haematological Disorders: A Prospective Observational Study

13. 222 patients who had induction/ salvage chemotherapy for AML 2008 – 2013 AF Prophylaxis- 98% (AMB-d 68% & Posaconazole 23%) IFI seen in 86 patients (38.7%) Proven/Probable IFI - 12 (5.4%) Possible IFI – 74 (33.3%) Organisms isolated in proven IFI: Aspergillus (5) , Mucor (2) , Fusarium (3) , Geotrichum (1) , and Candida [ krusei (1) and glabrata (1)] in 2 cases High incidence of IFI during induction chemotherapy for acute myeloid leukaemia in developing countries Korula A, Abraham A, Abubacker FN, et al. Mycoses. 2017;60(10):686-691.

14. Mucormycosis- Pathophysiology “Invasion of blood vessels, resulting in tissue infarction and necrosis” Pathologic hallmark

15. Prakash et al. Microorganisms 2021, 9, 523. https://doi.org/10.3390/microorganisms9030523 Annual Incidence and Risk Factors of Mucormycosis in India

16. Clinical Forms of Mucormycosis in India Prakash et al. Microorganisms 2021, 9, 523. https://doi.org/10.3390/microorganisms9030523 ROCM- Rhino-orbital-cerebral mucormycosis- the commonest form (45–74%) Cutaneous (10–31%) Pulmonary (3–22%) Renal (0.5–9%) Gastrointestinal (2–8%) Disseminated infections (0.5–9%)

17. Prakash et al. Microorganisms 2021, 9, 523. https://doi.org/10.3390/microorganisms9030523 Clinical Forms & Risk Factors Association in Mucormycosis ROCM - Diabetes mellitus Pulmonary mucormycosis - SOT recipients, haematological malignancy, diabetes mellitus Cutaneous mucormycosis - Trauma

18. Patel A et al. Clinical Microbiology and Infection (2019) https://doi.org/10.1016/j.cmi.2019.11.021 Higher Survival with Combined Approach Higher survival probability with combined medical and surgical treatment

19. Patel A et al. Clinical Microbiology and Infection (2019) https://doi.org/10.1016/j.cmi.2019.11.021 Factors predicting Mortality in patients with Mucormycosis

20. Culture and sensitivity Histopathology (mainly for Molds) Radiological tests (mainly for Molds) Serological tests PCR Germ tube/Chrome agar PNA-FISH (peptide nucleic acid fluorescence in situ hybridization) MALDI-TOF (matrix-assisted laser desorption/ionization-time of flight) T2 Candida Limited availability & Not standardized Paramythiotou E, Frantzeskaki F, Flevari A, et al. Molecules. 2014;19(1):1085-119. Nadeem SG, Hakim ST and Kazmi SU. Libyan J Med. 2010;5:01-06. Sheppard DC, Locas MC, Restieri C, et al. J Clin Microbiol. 2008;46(10):3508-9. Pfaller MA, Wolk DM and Lowery TJ. Future Microbiol. 2016;11(1):103-17. Diagnostic Methods for Invasive Fungal Infection (IFI)

21. Disease Specimen Test Recommendation Candidemia Blood Blood culture Essential Investigation Serum Mannan / anti- mannan Recommended β – D glucan Recommended Septifast PCR No recommendation In house PCR No recommendation Disease Specimen Test Recommendation Invasive candidiasis Blood Blood culture Essential Investigation Serum Mannan / anti- mannan No Recommendation β – D glucan Recommended Septifast PCR No recommendation In house PCR No recommendation Tissue and sterile body fluids Direct microscopy and histopathology Essential Investigation culture Essential Investigation Cuenca-Estrella M, Verweij PE, Arendrup MC, et al. Clin Microbiol Infect. 2012;18 Suppl 7:9-18. Adapted from: Cuenca-Estrella M, Verweij PE, Arendrup MC, et al. Clin Microbiol Infect. 2012;18 Suppl 7:9-18. Adapted from: Cuenca-Estrella M, Verweij PE, Arendrup MC, et al. Clin Microbiol Infect. 2012;18 Suppl 7:9-18. Recommended Diagnostic Methods for Candida

22. Blood cultures (BCs) for Candida infection: The cornerstone of diagnosis But they have suboptimal sensitivity (30%–50%) Need long incubation time Moreover. in deep-seated candidiasis or in patients under fluconazole prophylaxis, BCs are often negative Newer culture methods have raised the sensitivity of Candida detection to almost 70%, but they require a minimum of 24 to 48 h to become positive and thus their result may come late in the course of the infection BCs positive for Aspergillus is extremely rare Isolation of Aspergillus from cultures of bronchial secretions, broncho alveolar lavage (BAL) or other body fluids or tissues, might represent colonisation rather than infection Paramythiotou E, Frantzeskaki F, Flevari A, et al. Molecules. 2014;19(1):1085-119 Inadequacy of Culture & Sensitivity Methods

23. Paramythiotou E, Frantzeskaki F, Flevari A, et al. Molecules. 2014;19(1):1085-119 Adapted from: Paramythiotou E, Frantzeskaki F, Flevari A, et al. Molecules. 2014;19(1):1085-119 Diagnostic Approach for Invasive Aspergillosis & Mucorales

24. Characteristics of the GM & BDG assays (galactomannan & 1,3- β- d-glucan) False + ve Pip+Taz RRT used for the presumptive diagnosis of IA Lamoth F. Galactomannan and 1,3- β- d-Glucan Testing for the Diagnosis of Invasive Aspergillosis. J Fungi (Basel). 2016 Jul 4;2(3):22.

25. GM & BDG assays Lamoth F. Galactomannan and 1,3- β- d-Glucan Testing for the Diagnosis of Invasive Aspergillosis. J Fungi (Basel). 2016 Jul 4;2(3):22.

26. IFI may be asymptomatic during early phase When present, symptoms are non-specific, e. g: fever, cough Microbial culture techniques have low sensitivity Invasive diagnostic procedures not always possible (neutropenic patient with hypercoagulable state, hemodynamically unstable) Radiological features non-specific for fungal infections Serological tests are not easily available and are not confirmatory PCR – not commonly used Paramythiotou E, Frantzeskaki F, Flevari A, et al. Molecules. 2014;19(1):1085-119. Hwang YY and Liang R. Expert Rev Anti Infect Ther. 2010;8(4):397-404. Pagano L, Caira M, Valentini CG, et al. Blood Reviews. 2010;24(2):51–61. Michallet M and Ito JI. J Clin Oncol. 2009;27(20):3398-3409 . IFI - Invasive Fungal Infection; PCR - Polymerase Chain Reaction Why Fungal Diagnosis is Difficult

27. Delay in start of antifungal treatment (hours) Hospital mortality (%) Patients with candidaemia (n = 157) Morrell M, Fraser VJ and Kollef MH. Antimicrob Agents Chemother. 2005;49(9):3640-5. Relationship between Timing of Initiation of Antifungal Treatment and Hospital Mortality Retrospective cohort study of 230 patients from 4 medical centers Garey KW, Rege M, Pai MP, et al. Clin Infect Dis. 2006;43(1):25-31.

28. Diagnosis-difficult Diagnosis-delayed Mortality-High To provide effective therapy, an early diagnosis must be made based on risk factors Invasive Fungal Infections

29. No disease Cultures (colonizer)/ antigen Signs and symptoms Cultures/ histopathology Sequelae Prophylaxis Pre-emptive Empiric Hospital mortality 31.8% Disease burden Treatment Morbidity/ mortality Inappropriate use of broad-spectrum antibiotics Catheters Neutropenia, corticosteroids Surgery, etc Risk of in-hospital mortality doubles if antifungal therapy is not started within 12 hours . * Glucan, PCR Morrell M, Fraser VJ and Kollef MH. Antimicrob Agents Chemother. 2005;49(9):3640-5. The Continuum of Invasive Candidiasis

30. Against the routine and universal administration of antifungal prophylaxis in critically ill patients (weak recommendation, moderate quality of evidence) Not recommend the use of pre-emptive antifungal therapy in critically ill patients (weak recommendation, low-quality evidence) Suggests that empirical antifungal therapy might be considered only in patients with septic shock and multi-organ failure (MOF ) who have more than 1 extra-digestive site (i.e. urine, mouth, throat, upper and lower respiratory tracts, skin folds, drains, operative site) with proven Candida species colonization (strong recommendation, low quality of evidence) Not recommended starting empirical antifungal therapy in patients without septic shock and MOF (strong recommendation, low quality of evidence) Recommends the promotion of antifungal stewardship programs in order to limit the use of empirical therapy (best practice statement) Martin‑ Loeches et al. Intensive Care Med (2019) 45:789–805 2019 ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients

31. Patient in hospital ≥ 7 days Antibiotic in last 7 days or Central venous catheter for 7 days Two of the following: TPN (days 1-3) Any dialysis (days 1-3) Major surgery (days -7-0) Pancreatitis (days -7-0) Steroid (days -7-3) Immunosuppressives (days -7-0) Candida colonization or β - glucan &/or Very low procalcitonin Start Early Antifungal Bassetti M, Peghin M and Timsit JF. J Antimicrob Chemother. 2016;71(suppl 2):ii13-ii22. Criteria to Start Early Antifungal Therapy

32. Early L-AMB Administration at Septic Shock Onset Associated with Early Shock Cessation L-AMB treatment initiation either at septic shock onset (early L-AMB group) or after the onset (delayed L-AMB group) Tashiro et al. Journal of Infection and Chemotherapy 27 (2021) 1471–1476

33. Comparison of the recommendations on the management of Candidaemia/invasive candidiasis Leroux et al. Clin Microbiol Infect 2013; 19: 1115–1121 ECIL: Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3) ESCMID: European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guideline for the diagnosis and management of Candida diseases 2012 IDSA: Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America

34. Mean peritoneal concentrations of the three echinocandins reported to be always below the mutant prevention concentrations In a recent worldwide surveillance study, only 10.3% C. albicans and < 1% other Candida species were susceptible to Anidulafungin as per MIC distribution in peritoneal fluid Echinocandin concentrations remain suboptimal in peritoneal fluid, leads to mutant selection and emergence of antifungal resistance in intraabdominal Candida Abdominal candidiasis has been pointed out as a hidden reservoir of echinocandin resistance, with 100% therapeutic failures despite source control interventions. Emerging Evidence in Support of First-line Liposomal Amphotericin B: To Avoid Treatment Failure & Emergence of Resistance with Echinocandin Intra-abdominal Candidiasis Pharmacokinetics of Echinocandins Suggestive of Potential Risk of Resistance and Treatment Failure Maseda et al. Critical Care (2023) 27:382

35. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62:e1. Hepatosplenic candidiasis

36. Treatment of CNS Candidiasis: IDSA Guidelines 2016 Pappas PG, Kauffman CA, Andes DR, et al. Clin Infect Dis. 2016;62(4):e1-50.

37. Treatment for Candida Endocarditis Pappas PG, Kauffman CA, Andes DR, et al. Clin Infect Dis. 2016;62(4):e1-50.

38. No disease Markers Signs & symptoms Full-blown disease Sequelae Prophylactic Preemptive Therapy Empirical Asymptomatic + colonization OR novel diagnostic High risk: Antibiotic + fever Evidence of infection + clinical disease Asymptomatic high-risk patient Disease Progression Rüping MJ, Vehreschild JJ and Cornely OA. Mycoses. 2008;51(Suppl 2):46-51. Bow EJ. Hematology Am Soc Hematol Educ Program. 2006:361-7. IFI - Invasive Fungal Infection IFI Management Strategies

39. Membrane function: Amphotericin B Cellwall synthesis: Echinocandins Ergosterol synthesis: Azoles MOA- Antifungals Georgopapadakou NH, Walsh T. Nature 1994; 264: 371

40. Paramythiotou et al. Molecules 2014, 19 , 1085-1119 Spectrum of Antifungals

41. Individualized approach that takes into consideration the rapidity and severity of infection and local epidemiology An aggressive and prompt attempt to establish a specific diagnosis with bronchoscopy and/or CT-guided biopsy for peripheral lung lesions Verified serum azole levels if TDM is available for patients receiving mold-active triazoles Antifungal therapy, empirically changed to an alternative class of antifungal with Aspergillus activity Other considerations: reduction of underlying immunosuppression if feasible, and susceptibility testing of any Aspergillus isolates recovered from the patient Patterson TF, Thompson GR 3rd, Denning DW, et al. Clin Infect Dis. 2016;63(4):e1-e60. IDSA - Infectious Diseases Society of America; Practice Guidelines for Aspergillosis: IDSA 2016

42. The preemptive approach: a logical extension of empiric antifungal therapy in defining a high-risk population with evidence of invasive fungal infection (e.g, pulmonary infiltrate or positive GM assay result) Often referred to as preemptive or biomarker-driven antifungal therapy , reduce unnecessary antifungal therapy Early initiation of antifungal therapy in patients with strongly suspected IPA is warranted while a diagnostic evaluation is conducted (strong recommendation; moderate quality evidence). Management of suspected or documented breakthrough IPA in the context of mold-active azole prophylaxis or empiric suppressive therapy is not defined by clinical trial data, but a switch to another drug class is suggested (weak recommendation; low-quality evidence). Patterson TF, Thompson GR 3rd, Denning DW, et al. Clin Infect Dis. 2016;63(4):e1-e60. Practice Guidelines for Aspergillosis: IDSA 2016

43. Empiric antifungal therapy for high-risk patients with prolonged neutropenia who remain persistently febrile despite broad-spectrum antibiotic therapy. Antifungal options: a lipid formulation of AmB (strong recommendation; high-quality evidence), an echinocandin ( caspofungin or micafungin) (strong recommendation; high-quality evidence), or voriconazole (strong recommendation; moderate quality evidence). Patterson TF, Thompson GR 3rd, Denning DW, et al. Clin Infect Dis. 2016;63(4):e1-e60. Practice Guidelines for Aspergillosis: IDSA 2016

44. Michallet M and Ito JI. J Clin Oncol. 2009;27(20):3398-3409. Walsh TJ, Teppler H, Donowitz GR, et al. N Engl J Med. 2004;351(14):1391-402. Walsh TJ, Pappas P, Winston DJ, et al. N Engl J Med. 2002;346(4):225-34. Because the overall voriconazole success rate was lower than that of L-AmB , and because “noninferiority” was not demonstrated, voriconazole did not receive FDA approval as empiric therapy.

45. Lipid Amphotericin B Formulations Ribbon-like particles Carrier lipids: DMPC, DMPG in 7:3 molar ratio Ampholip ABLC Ampho mul ABLE Disk-like particles ; S trong interaction between AmpB and oil droplets ( oil-in-water emulsion) – forms a reservoir of the monomeric form of AmpB DMPC- Dimyristoyl phospitidylcholine DMPG- Dimyristoyl phospitidylcglycerol HSPC-Hydrogenated soy phosphatidylcholine DSPG- Distearoyl phosphitidylcholine Am phonex L-AMB Intercalated into lipid bilayer; Unilaminar liposome Carrier lipids: HSPC, DSPG, cholesterol

46. Liposomal amphotericin B: Mechanism of Action Stone et al. Drugs (2016) 76:485–500

47. Reference Pathogen(s) Agent Response Survival Lipid AMB formulations vs. Conventional AMB When Used as First-Line Therapy In Prospective Randomized Trials Wingard. Clin Infect Dis 2002; 35:891-5 Leenders 1998 Mixed L-AMB Same Same Leenders 1997 Cryptococcus spp. L-AMB Same Same Anaisse 1995 Candida spp. ABLC Same Same Bowden 2002 Aspergillus spp. ABCD Same Same Hamill 1999 Cryptococcus spp. L-AMB Same Same Johnson 2002 H. capsulatum L-AMB Greater Greater Outcome

48. Reference Pathogen(s) Agent Infusion Renal Wingard. Clin Infect Dis 2002; 35:891-5 Leenders 1998 Mixed L-AMB Lower Lower Leenders 1997 Cryptococcus spp. L-AMB Lower Lower Anaisse 1995 Candida spp. ABLC Same Lower Bowden 2002 Aspergillus spp. ABCD Greater Lower Hamill 1999 Cryptococcus spp. L-AMB Lower Lower Johnson 2002 H. capsulatum L-AMB Lower Lower Toxicity Lipid AMB formulations vs. Conventional AMB When Used as First-Line Therapy In Prospective Randomized Trials

49. Comparison of Lipid AMB Formulations as Empiric Therapy for Febrile Neutropenia Wingard. Clin Infect Dis 2002; 35:891-5 Prentice 1997 L-AMB vs. AMB-D Similar Similar Lower L-AMB Lower L-AMB L-AMB 1-3 mg/kg/day White 1998 ABCD vs. AMB-D Similar Similar Higher ABCD Lower ABCD Infusion-related hypoxia > ABCD Walsh 1999 L-AMB vs. AMB-D Similar Similar Lower L-AMB Lower L-AMB Fewer breakthrough infection in L-AMB Wingard 2000 L-AMB vs. ABLC Similar Similar Greater for ABLC Greater for ABLC Primary endpoint-safety Fleming 2001 ABLC vs. L-AMB Similar for fungal Similar for fungal Higher ABLC Lower for L-AMB Mild abnormalities in LFT: L-AMB > ABLC Outcome Reference Agent Response Survival Infusion Renal Comments Toxicity

50. Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD010481.

51. Tissot F, Agrawal S, Pagano L, et al. Haematologica. 2017;102(3):433-444. Adapted from: Tissot F, Agrawal S, Pagano L, et al. Haematologica. 2017;102(3):433-444. ECIL-6 Recommendations for Initial First-Line Treatment of Candidemia

52. ABLC, amphotericin B lipid complex; ABPA, allergic broncho pulmonary aspergillosis; AmB, amphotericin B; AML, acute myelogenous leukemia; BID twice daily; CNS, central nervous system; GM, galactomannan; IA, invasive aspergillosis; IPA, invasive pulmonary aspergillosis; IV, intravenous; MDS, myelodysplastic syndrome; PO, oral; TID, 3 times daily. Patterson TF, Thompson GR 3rd, Denning DW, et al. Clin Infect Dis. 2016;63(4):e1-e60. Practice Guidelines for Aspergillosis: IDSA 2016

53. Tissot F, Agrawal S, Pagano L, et al. Haematologica. 2017;102(3):433-444. Adapted from : Tissot F , Agrawal S , Pagano L, et al. Haematologica . 2017;102(3):433-444.

54. Diagnostic Algorithm for Suspected Invasive Aspergillosis Segal et al. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 173 2006 Patient receiving mold-active azole prophylaxis or previous exposure- switch to another drug class. Voriconazole failed empiric febrile neutropenia treatment trial vs LAMB. Caspofungin is fungistatic for aspergillus. L-AMB is drug of choice in such cases.

55. Optimal Treatment Pathways for Mucormycosis in Adults Cornely et al. Lancet Infect Dis 2019. 19: e405–21

56. Optimal Treatment Pathways for Mucormycosis in Adults Cornely et al. Lancet Infect Dis 2019. 19: e405–21

57. Pagano L, Caira M, Valentini CG, et al. Blood Reviews. 2010;24(2):51–61. Adapted from: Pagano L, Caira M, Valentini CG, et al. Blood Reviews. 2010;24(2):51–61. Summary- Different Approaches in the Therapy of Invasive Fungal Infections

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