Liposomal amphotericin B in management of invasive fungal infections_Jan 23[2304].pptx

antifungal

1. Liposomal amphotericin B in management of invasive fungal infections

2. Disclaimer The presentations express the views and opinions of the presenter which were based on information and data available at the time Any patient cases and treatment options referred to are in the context of contemporary knowledge and medical practice in the field Please review the full Prescribing Information for complete data, including approved indication and usage, dosage, contraindications, warnings, and drug reactions The information in this presentation is for medical education purposes only

3. Epidemiology of Invasive fungal Infection on Lilienfeld- Toal M, Wagener J, Einsele H, Cornely OA, Kurzai O. Invasive Fungal Infection. Dtsch Arztebl Int. 2019 Apr 19;116(16):271-278.

4. Invasive fungal Infection- Rising trend The incidences of candidemia, systemic aspergillosis, cryptococcosis and zygomycosis in India have shown a steep rise.* The incidence of candidemia in India is 1-12 cases/1000 admissions. This is 20-30 times higher as compared to the developed world Bajwa S, Kulshrestha A. Fungal infections in intensive care unit: challenges in diagnosis and management.  Ann Med Health Sci Res . 2013;3(2):238-244. Extensive and inappropriate use of broad-spectrum antibiotic usage/immunosuppressants Improved knowledge of fungal disease Longer ICU stay Multiple Invasive procedure Infection control practices and hand hygiene heavy patient load high cost of disposables Increased Incidence due to

5. Fungi Fungi are unicellular or multicellular organisms with eukaryotic cell types. The cells have cell walls but are not organized into tissues. They do not carry out photosynthesis to obtain nutrients through absorption. Fungi can further be classified into yeasts and molds. Molds

6. Yeast and Molds Point of Distinction Mold Yeast Structure Multicellular with tubular, filamentous hyphae (branches) Mostly unicellular and existing either individually or with buds growing on them Predominance of Occurrence Any organic environment having a moist/ humid atmosphere and not exposed to harsh weather conditions Mostly occur naturally in oceans Method of Reproduction Production of sexual or asexual, airborne spores Budding or binary fission Appearance Threadlike, come in a wide variety of colors and hues Round or oval shaped, dull colored and mostly monochromatic

7. Classification of Fungi

8. Antifungal therapies over the last 60 years IV, intravenous. Nett JE, Andes DR. Infect Dis Clin North Am 2016;30(1):51 ‒ 83 . New antifungal agents have been developed over the last 60 years, but amphotericin B remains a suitable treatment in this field 2021 1958 1973 1990 s 1991 2000 s 2000 – 2010s Amphotericin B deoxycholate Azoles: First generation* Lipid formulations of amphotericin B Echinocandins Flucytosine Active against Candida ssp and Cryptococcus ssp Toxicity and resistance Azoles: Second generation** Broad spectrum of activity Nephrotoxicity and infusion-related reactions Oral formulations with good activity against yeasts CYP450 interactions Drug-drug interactions Broad spectrum of activity Less toxicity Active against Candida ssp and few drug-drug interactions IV formulations only Active against Candida ssp and Cryptococcus ssp CYP450 – interactions Drug-drug interactions * Fluconazole, Intraconazole ** Voriconazole, Pozaconazole , Isavuconazole

9. Amphotericin B Introduced in the late 1950s, polyenes represent the oldest family of antifungal drugs It remains a suitable antifungal due to its broad spectrum of activity, low resistance rate and good clinical and pharmacological action Amphotericin B has some side effects, such as nephrotoxicity and infusion reactions, which limit its use To overcome these, new formulations of amphotericin B were developed: Amphotericin B lipid complex Liposomal amphotericin B Amphotericin B colloidal dispersion, which has now been discontinued due to a high rate of infusion-related events Cavassin FB, et al. Infect Dis Ther 2021;10(1):115 ‒ 47. Amphotericin B remains the treatment of choice for many serious fungal infections in vulnerable hosts owing to its excellent spectrum of activity and its low resistance rates

10. Anti fungal Spectrum of Amphotericin B Antifungal broad spectrum fungal pathogens that are usually resistant to amphotericin B include T he organisms that cause chromoblastomycosis   Aspergillus terreus   Candida lusitaniae   Scedosporium   spp   Fusarium  spp Antiprotozoal Amphotericin B is used for life-threatening  protozoan infections  such as  visceral leishmaniasis [13]  and  primary amoebic meningoencephalitis

11. Mechanism of toxicity Amphotericin B molecules can form pores in the host membrane as well as the fungal membrane. This impairment in membrane barrier function can have lethal effects.  Ergosterol, the fungal sterol, is more sensitive to amphotericin B than cholesterol, the common mammalian sterol. Reactivity with the membrane is also sterol concentration dependent.  Bacteria are not affected as their cell membranes do not usually contain sterols I nfusion-related toxicity :- This is thought to result from innate immune production of proinflammatory cytokines

12. It is a liposomal formulation containing Amphotericin B intercalated into the lipid bilayer. It is a lyophilized sterile product for intravenous infusion Liposomal amphotericin B is a unique lipid formulation of amphotericin B Liposomes (for drug delivery) are spherical vesicles characterized by an aqueous core surrounded by a lipid bilayer. Liposomal Amphotericin B Stone et al. Drugs (2016) 76:485–500

13. Liposomal amphotericin B: Mechanism of Action Stone et al. Drugs (2016) 76:485–500 Penetrates the cell wall of both extracellular and intracellular forms of susceptible fungi. Achieves higher peak plasma levels ( Cmax ) & area under curve ( AUC) compared to conventional preparations due to small size and negative charge and avoids recognition by mononuclear phagocyte system. Less infusion related reactions

14. Tolerability of Liposomal Amphotericin B Generally Well tolerated A lower incidence of chills, hypertension , hypotension, tachycardia, hypoxia, hypokalemia, and various events related to decreased kidney function as compared to amphotericin B deoxycholate. A lower incidence of infusion-related fever (17% versus 44%), chills/rigors (18% versus 54%) and vomiting (6% versus 8%) on Day 1 as compared to amphotericin B deoxycholate-treated patients. Lower discontinuation rate as well as no dose adjustment compared to other preparations of Amphotericin B https://mycology.adelaide.edu.au/docs/therapeutic.pdf

15. Pharmacokinetic properties and the effect on toxicity of different lipid formulations

16. Pharmacokinetic parameters of L- AmB impact its toxicity 1. Adler-Moore J, Proffitt RT. J Antimicrob Chemother 2002;49( Suppl 1):21 ‒ 30; 2. Serrano DR, et al. Pharm Nanotechnol 2013;1:250 ‒ 8; 3. Groll AH, et al. Klin Pediatr 1998;210:264 ‒ 73 . Pharmacokinetic parameters suggest that amphotericin B remains associated with the liposome structure while in circulation when delivered as L- AmB The AUC of amphotericin given as L- AmB increased in a manner greater than the incremental increase in dose AUC A high C max ensures amphotericin delivered as L- AmB has a long circulation half-life and acts as a reservoir in plasma, from where it is distributed into tissues C max The volume of drug distribution is significantly reduced with L- AmB , allowing for greater drug concentration in plasma V d AUC, area under curve; C max , maximum concentration; L- AmB , liposomal amphotericin B; V d , volume distribution.

17. Biochemical and pharmacokinetic properties of L- AmB vs. ABLC and cAmB L- AmB ABLC cAmB Mole% (Mol%) AmB 10% 50% 34% Lipid Configuration Small unilamellar vesicles Ribbon-like Micelles Diameter (µm) 0.08 1.6‒11.0 <0.4 Mean maximum concentration ( μ g/mL) 58 1.7 2.9 Mean AUC ( μ g/mL.h) 713 14 36 Mean V d (L/kg) 0.22 131 1.1 Mean Clt (L/h/kg) 0.017 0.476 0.028 Relative nephrotoxicity ± ± ++ ABLC, amphotericin B lipid complex; AmB , amphotericin B; AUC, area under curve; cAmB , conventional amphotericin B; Clt , total clearance; L- AmB , liposomal amphotericin B; V d , volume distribution. Groll AH, et al. Klin Pediatr 1998;210:264 ‒ 73. There are biochemical and pharmacokinetic differences between different amphotericin B formulations

18. Effect of lipid structure on toxicity profile L- AmB ABLC cAmB Pharmacokinetics High C max , high AUC, low clearance 1 Low C max and AUC, high clearance 1,4 Low C max and AUC, high clearance 1 Uptake by RES tissues AmB mostly associated with liposomes in circulation; minimal drug transfer to mammalian cells. 2 Longer in circulation before uptake by RES 2 Taken up rapidly by cells of the RES; results in release of amphotericin into the circulation and enhanced tissue penetration 3 Impact on toxicity/efficacy Reduced renal clearance due to intact liposomes (no dissociated AmB ) 2 Less nephrotoxic profile than free AmB 5 Clinically achievable AUC values associated with near-complete suppression of galactomannan and (1→3) β- D-glucan levels (markers of therapeutic response in invasive pulmonary aspergillosis) 6 Associated with: Increased infusion related reactions 3 Reduced nephrotoxicity rates compared to cAmB 1 Associated with toxicity problems due to binding of AmB to mammalian cells 2 Infusion-related reactions include nausea, vomiting, chills, fever, BP alterations and hypoxia. 4 Most serious effect of this is nephrotoxicity, which can result in renal tubular damage 2 Maximal tolerated doses (0.7–1.0 mg/kg/day) may be clinically suboptimal 2 1. Groll AH, et al. Klin Pediatr 1998;210:264–73; 2. Hillery AM, et al Adv Drug Del Rev 1997;24:345‒63; 3. Mehta J, et al; The Open Transplant J 2011;5:23‒9; 4. Bassetti M, et al. Clin Drug Investig 2011;31(11):745 ‒ 58; 5. Adler-Moore JT, Proffitt RT. Clin Microbiol Infect 2008;14( Suppl 4):25–36; 6. Al- Nakeeb Z, et al.  Antimicrob Agents Chemother  2015;59(5):2735‒45. The structure of amphotericin B impacts its toxicity profile Groll /1998/ pg 7/col 2/para 4/ln 5-8 Groll /1998/ pg 6/col2/para 4/ln 19-22 Groll /1998/ pg 6/col 1/para 3/ln 7-11 Groll /1998/ pg 6/col 2/para 2/ln 1-2 Mehta/2011/ pg 4/col 2/para 3/ln 2-6 Mehta/2011/ pg 5/col 2/para 3/ln 8-9 Bassetti /2011/ pg 5/col 1/ pata 2/ln 4-10 ABLC, amphotericin B lipid complex; AmB , amphotericin B; AUC, area under curve; cAmB , conventional amphotericin B; Cmax, maximum concentration; L- AmB , liposomal amphotericin B; PD, pharmacodynamics; RES, reticuloendothelial system.

19. Infusion-related reactions in cAmB vs. L- AmB ABLC, amphotericin B lipid complex; cAmB , conventional amphotericin B; L- AmB , liposomal amphotericin B. 1. Walsh TJ, et al. New Engl J Med 1999;340(10):764 ‒ 71 ; 2. Wingard JR, et al. Clin Infect Dis 2000;31:1155 ‒ 63 . Patients treated with L- AmB experienced fewer infusion-related reactions than patients treated with cAmB or ABLC Infusion-related adverse reactions in cAmB and L-AmB 1 Day 1 infusion-related adverse reactions in ABLC and L-AmB 2 n=58 n=150 n=63 n=20 n=16 n=45 n=16 n=19 n=62 p< 0.001 p≤ 0.001

20. Nephrotoxicity cAmB vs. L- AmB ABLC, amphotericin B lipid complex; cAmB , conventional amphotericin B; L- AmB , liposomal amphotericin B. 1. Walsh TJ, et al. New Engl J Med 1999;340(10):764 ‒ 71 ; 2. Wingard JR, et al. Clin Infect Dis 2000;31:1155 ‒ 63 . Patients treated with L- AmB experienced less nephrotoxicity than those treated with cAmB or ABLC Nephrotoxicity in cAmB and L-AmB 1 Nephrotoxicity in ABLC and L-AmB 2 n=12 n=12 n=33 n=5 n=5 n=21 n=64 n=116 n=28 n=57 p< 0.001 p≤ 0.001

21. Drug discontinuation due to toxicity in lipid formulations of AmB ABLC, amphotericin B lipid complex; AmB , amphotericin B; L- AmB , liposomal amphotericin B. Wingard JR, et al. Clin Infect Dis 2000;31:1155 ‒ 63. More patients discontinued ABLC than L- AmB treatment due to toxicity Drug discontinuations due to toxicity in ABLC and L- AmB n=11 n=10 n=25 p< 0.01

22. Safety and efficacy studies

23. Efficacy and safety of amphotericin B lipid-based formulations Systematic review and meta analysis of 23 randomised controlled trials (n=2,677) The efficacy of all amphotericin B formulations was similar Lipid-based formulations of AmB vs cAmB provided fewer nephrotoxicity, fever, chills and vomiting adverse events AmB , amphotericin B. Steimbach LM, et al. Mycoses 2017;60(3):146 ‒ 54. Conventional amphotericin B presents a similar efficacy profile as lipid-based formulations, although the latter were associated with a safer profile Adverse event Odds ratio 95% confidence interval Nephrotoxicity 0.32 0.25 ‒ 0.41 Fever 0.49 0.26 ‒ 0.94 Chills 0.44 0.21 ‒ 0.92 Vomiting 0.64 0.46 ‒ 0.88 Nausea 0.88 0.65 ‒ 1.18

24. L- Amb vs. cAmB for treatment of AIDS-associated acute cryptococcal meningitis Randomised, double-blind trial of cAmB (0.7 mg/kg/day, n=87) or L- AmB (3 mg/kg/day, n=86, or 6 mg/kg/day, n=94) Efficacy was similar across all groups Overall mortality at 10 weeks was 11.6% Incidence of infusion-related reactions was significantly lower in both L- AmB groups compared to cAmB ( p <0.001) Significantly fewer patients who received the 3 mg/kg/day dosage of L- AmB developed nephrotoxicity, indicated by a doubling of the serum creatinine value, compared with recipients of cAmB ( p =0.004) AIDS, acquired immune deficiency syndrome; cAmB , conventional amphotericin B; L- AmB , liposomal amphotericin B. Hamil RJ, et al. Clin Infect Dis 2010;51(2):225 ‒ 32. L- AmB provides an equally efficacious alternative to cAmB in patients with AIDS and acute cryptococcal meningitis and, at a dosage of 3 mg/kg/day, is accompanied by significantly fewer adverse events n=35 n=36 n=29

25. L- Amb vs. cAmB for treatment of neutropenia-associated IFIs Randomised multicentre study comparing L- AmB (5 mg/kg/day, n=32) to cAmB (1 mg/kg/day, n=34) cAmB , conventional amphotericin B; L- AmB , liposomal amphotericin B; NE, not evaluable. Leenders AC, et al. Br J Haematol 1998;103(1):205 ‒ 12. In neutropenic patients with documented or suspected IFIs, L- AmB 5 mg/kg/day was superior to cAmB 1 mg/kg/day with respect to efficacy and safety AmB , n (n=34) L- AmB (n=32) p Response Complete Partial Failure NE Complete Partial Failure NE Response at day 14 2 6 25 1 5 10 15 2 0.03 Response at completion 6 13 15 14 7 11 0.09 Mortality, n (%) 13 (38.2) 7 (21.9) 0.19* *When adjusted for malignancy status, p =0.03 n=5 n=12 n=6 n=22 p= 0.11 p< 0.001

26. LAmB vs. cAmB for empirical treatment of pyrexia of unknown origin in neutropenic patients Prospective, multi-centre, comparative trial of 134 patients receiving either 1 mg/kg/day cAmB (n=39) or 1 mg/kg/day L- AmB (n=48) or 3 mg/kg/day L- AmB (n=47) cAmB , conventional amphotericin B; L- AmB , liposomal amphotericin B. Prentice HG, et al. Br J Haematol 1997;98:711 ‒1 8. L- AmB had significantly fewer adverse events in adults than cAmB p< 0.01

27. L- AmB vs. cAmB for patients with persistent fever and neutropenia Randomised, double-blind, multicentre trial of L- AmB (n=343) vs. cAmB (n=344) Patients taking L- AmB had less infusion-related fever (17 vs. 44%), chills or rigors (18 vs. 54%), and other reactions, including hypotension, hypertension, and hypoxia Survival outcomes in patients treated with L- AmB or cAmB are similar (93 vs.90%) but there were fewer proven breakthrough IFIs among patients treated with L- AmB (3.2 vs.7.8%, p=0.009) cAmB , conventional amphotericin B; CI, confidence interval; L- AmB , liposomal amphotericin B. Walsh TJ, et al. New Engl J Med 1999;340(10):764 ‒ 71 . Measure L- AmB (n=343) cAmB (n=344) No. patients Success rate (95 % CI) No. patients Success rate (95 % CI) Overall success 172 50.1 (45 ‒ 56) 170 49.4 (44 ‒ 55) Fever resolved during neutropenic period 199 58.0 (53 ‒ 63) 200 58.1 (53 ‒ 63) No breakthrough IFI 309 90.1 (86 ‒ 93) 307 89.2 (85 ‒ 92) Baseline fungal infection cured 9 81.8 (48 ‒ 98) 8 72.7 (39 ‒ 94) Survived 7 days after study drug initiation 318 92.7 (89 ‒ 95) 308 89.5 (86 ‒ 93) Study drug not prematurely discontinued due to toxicity or lack of efficacy 294 85.7 (82 ‒ 89) 280 81.4 (77 ‒ 85)

28. Renal outcomes in patients treated with four different formulations of amphotericin B Prospective study of 418 adult patients treated consecutively with cAmB (62%), L- AmB (27%), or other lipid AmB (11%) in haematology and oncology wards in 20 hospitals in Europe Of the patients initially treated with cAmB , 36% switched to lipid formulations of AmB , primarily because of increased serum creatinine levels (45.7%) or other amphotericin B–attributable AEs (41.3%) Predictors of nephrotoxicity included formulation type and duration of treatment Compared with patients without nephrotoxicity, patients with nephrotoxicity had a numerically higher mortality rate (24%), and their mean length of stay in the hospital was prolonged by 8.6 days Creatinine level increase developed in fewer patients receiving L- AmB than cAmB or ABLC/ABCD (5.36 vs. 35.14 vs.10.64%) Number of patients experiencing adverse events ABCD, amphotericin B colloidal dispersion; ABLC, amphotericin B lipid complex; cAmB , conventional amphotericin B; L- AmB , liposomal amphotericin B. Ullman A, et al. Clin Infect Dis 2006;43:e29‒38. Adverse event cAmB , n (%) (n=418) L- AmB , n (%) (n=112) ABLC or ABCD, n (%) (n=47) Creatinine level increase 91 (35.1) 6 (5.4) 5 (10.6) Hypokalaemia 66 (25.5) 9 (8.0) 5 (10.6) Chills 69 (22.8) 5 (4.5) 21 (44.7) Fever 22 (8.5) 3 (2.7) 4 (8.5)

29. Nephrotoxicity associated to different lipid formulations of AmB in the real world Retrospective cohort study of patients receiving cAmB (n=236), L- AmB (n=105) or ABLC (n=90) Use of L- AmB , as compared with cAmB , was found to be an independent protective factor for: Nephrotoxicity (OR, 0.18; 95% CI, 0.03 ‒ 0.64; p =0.006) Mortality (OR, 0.56; 95% CI, 0.32 ‒ 0.99; p =0.046) Length of hospital stay for patients treated with different formulations of AmB ABLC, amphotericin B lipid complex; cAmB , conventional amphotericin B; L- AmB , liposomal amphotericin B; RIFLE, Risk, Injury, Failure, Loss, and End-stage renal failure. Falci DR, et al. Mycoses 2015;58:104 ‒ 12. L- AmB was associated with better outcomes than other formulations, including severe nephrotoxicity and overall mortality 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Days 100 150 200 50 Probability of hospitalisation cAmB L- AmB ABLC n=20 n=5 n=2

30. ABLC vs. L- AmB in empirical treatment of febrile neutropenia Double-blind study comparing safety of L- Amb (3 mg/kg/day [n=85] or 5 mg/kg/day [n=81]) vs. ABLC (5 mg/kg/day [n=78]) in neutropenic patients with unresolved fever after 3 days of antibacterial therapy Therapeutic success was similar in all groups ABLC, amphotericin B lipid complex; L- AmB , liposomal amphotericin B. Wingard JR, et al. Clin Infect Dis 2000;31:1155 ‒ 63. Mortality was higher for patients treated with ABLC than for those treated with the 5 mg/kg dose of L- AmB (14.1 vs. 2.5%; p =0.009) L - AmB 3 mg/kg/day, n (%) ( n=85 ) L - AmB 5 mg/kg/day, n (%) ( n=81 ) ABLC 5 mg/kg/day, n (%) ( n=78 ) Successful response 34 ( 40 . ) 34 ( 42 . ) 26 ( 33 . 3 ) Emergent fungal infections 3 ( 3 . 6 ) 2 ( 2 . 5 ) 3 ( 3 . 8 ) Death related to fungal infection 1 ( 1 . 2 ) 0 ( .0) 3 ( 3 . 8 ) p≤ 0.001 p≤ 0.01 n=11 n=12 n=25 n=10 n=12 n=33 * Nephrotoxicty defined as 2x baseline creatinine value. n=16 n=19 n=62 n=45 n=16 n=20

31. Nephrotoxicity and other adverse events among inpatients receiving L- AmB or ABLC Retrospective analysis of patients with renal insufficiency or previous toxicity to cAmB , receiving ABLC (n=222) or L- AmB (n=105) ABLC, amphotericin B lipid complex; cAmB , conventional amphotericin B; L- AmB , liposomal amphotericin B; NS, not significant. Wade et al. Diagn Microbiol Infect Dis 2013;76:361 ‒ 7. L-AMB is associated with less nephrotoxicity, infusion reactions and hypomagnesemia than ABLC in patients at increased risk of nephrotoxicity % of patients L- AmB , % (n=85) ABLC, % (n=168) p 1.5 x Baseline creatinine value 29.4 39.3 0.122 2 x Baseline creatinine value 10.6 26.2 0.004 3 x Baseline creatinine value 3.5 10.7 0.056 Peak creatinine value (mg/dL) >1.5 36.5 53.0 0.013 >2.0 23.5 41.6 0.004 >2.5 16.5 29.2 0.027 >3.0 15.3 19.6 0.397 Infusion reaction requiring treatment 9.5 23.9 0.002 Hypomagnesemia during AmB therapy 28.1 44.3 0.033

32. Spectrum of activity of antifungal agents

33. Spectrum of activity of antifungal agents А m В 5FC FLU ITR VOR POS ISA CAS MICA ANI Candida albicans ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ Candida glabrata ++ ++ + + ++ ++ ++ + + + Candida parapsilosis ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ Candida tropicalis ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ Candida krusei ++ + _ + ++ ++ ++ ++ ++ ++ Candida lusitaniae - ++ ++ ++ ++ ++ ++ ++ ++ ++ Aspergillus fumigatus ++ - _ + ++ ++ ++ + + + Cryptococcus neoformans ++ ++ ++ ++ ++ ++ ++ - - - Mucorales ++ - - - - ++ ++ - - - Fusarium spp + - - + ++ ++ ++ - - - Scedosporium spp + - - + + + + - - - Blastomyces dermatitidis ++ - + ++ ++ ++ ++ - - - Coccidioides immitis ++ - ++ ++ ++ ++ ++ - - - Histoplasma capsulatum ++ - + ++ ++ ++ ++ - - - 5FC, flucytosine; AMB, amphotericin B; ANI, anidulafungin; CAS, caspofungin ; FLU, fluconazole; ISA, isavuconazole ; ITR, itraconazole; MICA, micafungin; POS, posaconazole ; VOR, voriconazole. Nett JE, Andes DR. Infect Dis Clin North Am 2016;30(1):51 ‒ 83. Amphotericin B demonstrates broad spectrum of activity against an array of yeast and filamentous fungal pathogens Acquired resistance to amphotericin B is uncommon despite its multiple decades of clinical use

34. Antifungal resistance Antifungal resistance is a growing problem associated with a changing epidemiology Resistance in Candida spp. is increasing and is associated with poorer outcomes Azole resistance is a growing phenomenon in Aspergillus spp. Pre-exposure to antifungals can cause an increased proportion of less susceptible species Liposomal amphotericin B is recommended for suspected resistant Aspergillus and breakthrough fungal infections after azoles and is the first choice for mucormycosis Increasing rates of acquired resistance to fluconazole in non- C.albicans species and i ncreasing prevalence of C.galbrata , which is less susceptible to azoles 1 , 3 Azole resistance was reported in 3.2% of A.fumigatus isolates in Europe in 2009–2011 2 Echinocandin r esistance in C andida spp. is increasing in prevalence 1 , 3 Minimal resistance reported 4 –6 Azoles Echinocandins Polyenes 5.5–7.6% of azole-resistant C.glabrata isolates may also be resistant to an echinocandin 3 A 2012 study of 9,252 clinical isolates of C. albicans found that 99.8% remained sensitive to amphotericin B 8

35. Guidelines perspective

36. Key guidelines for the treatment of IFI: empiric treatment   Antifungal Invasive Candidiasis Invasive Aspergillosis IDSA 2016 1 Non-neutropenic patients in ICU ESCMID/ECMM/ERS 2012 2 IDSA 2016 3 High-risk patients with prolonged neutropenia ESCMID/ECMM/ERS 2018 4 Caspofungin Strong recommendation/moderate quality evidence AI Strong recommendation/high quality of evidence AI Micafungin Strong recommendation/moderate quality evidence BII Strong recommendation/high quality of evidence BII Anidulafungin Strong recommendation/moderate quality evidence No data, not recommended - - Fluconazole Strong recommendation/moderate quality evidence (where resistance unlikely) CI a - DII AmBisome Strong recommendation/low quality evidence (where intolerance or resistance to other agents) AI Strong recommendation/high quality of evidence BI Voriconazole - BI Strong/moderate quality of evidence BII Itraconazole - BI - CII Amphotericin B lipid complex - BI - CI Amphotericin B colloidal dispersion - CI - CI Amphotericin B deoxycholate - DII - - AmBisome has a moderate-strong recommendation from ESCMID/ECMM/ERS and IDSA for the empiric treatment of IFIs Footnotes : a Limited use since fluconazole has no mould activity. Application requires appropriate work-up to rule out mould disease. Grades A–C reflect the strength of the recommendation, while levels I, II and III represent the quality of the available evidence. Full details of the classification systems are provided in the respective treatment guidelines. Abbreviations : ECMM: European Confederation of Medical Mycology; ERS: European Respiratory Society; ESCMID: European Society of Clinical Microbiology and Infectious Diseases; IDSA: Infectious Diseases Society of America; ICU: intensive care unit; NA: not applicable. Please refer to the notes section for details of the references cited Liposomal Amphotericin B

37. Key guidelines for the treatment of IFI: invasive aspergillosis Antifungal ECIL 2017 1 Leukaemia/HSCT patients IDSA 2016 2 ESCMID/ECMM/ERS 2018 3 Neutropenic patients (non-allo HSCT) Allo-HSCT patients (during neutropenia or w/o neutropenia) or other non-neutropenic patients Voriconazole AI* Strong recommendation/high quality of evidence AI AII Isavuconazole AI Strong recommendation/moderate quality of evidence AI AII AmBisome BI Strong recommendation/moderate quality of evidence BII BII Amphotericin B lipid complex BII Weak recommendation/low quality of evidence CIII CIII Amphotericin B colloidal dispersion CI Weak recommendation/low quality of evidence DI DII Caspofungin CII - CII CII Itraconazole CIII - CIII CII Voriconazole + Anidulafungin CI* - CI* CII* Voriconazole + Echinocandin - Weak recommendation/moderate quality of evidence - - Other combinations CIII - DIII DIII Recommendation against amphotericin B deoxycholate AI - - - Recommendation against primary therapy with echinocandin alone - Strong recommendation/moderate quality of evidence - - AmBisome has a strong recommendation with moderate quality of evidence from ESCMID/ECMM/ERS, ECIL and IDSA for the treatment of invasive aspergillosis, especially in azole-resistant species Footnotes : Grades A (strong)–C (weak) reflect the strength of the recommendation. Grade D in ESCMID/ECMM/ERS guidelines supports a recommendation against use. Levels I, II and III represent the quality of the available evidence. Full details of the classification systems are provided in the respective treatment guidelines. *Monitoring of serum levels of voriconazole is indicated. Abbreviations : ECIL: European Conference on Infections in Leukaemia; ECMM: European Confederation of Medical Mycology; ERS: European Respiratory Society; ESCMID: European Society of Clinical Microbiology and Infectious Diseases; IDSA: Infectious Diseases Society of America. Please refer to the notes section for details of the references cited Liposomal Amphotericin B

38. Key guidelines for the treatment of IFI: invasive candidiasis Antifungal ECIL 2017 1 Leukaemia/HSCT patients IDSA 2016 2 ESCMID/ECMM/ERS 2012 Overall population Patients with haematological malignancies Non-neutropenic patients Neutropenic patients Non-neutropenic patients 3 Patients with haematological malignancies and after HSCT 4 Micafungin AI AII Strong recommendation/high quality of evidence Strong recommendation/moderate quality of evidence AI AII Anidulafungin AI AII* Strong recommendation/high quality of evidence Strong recommendation/moderate quality of evidence AI BII Caspofungin AI AII Strong recommendation/high quality of evidence Strong recommendation/moderate quality of evidence AI AII AmBisome AI AII Strong recommendation/high quality of evidence † Strong recommendation/moderate quality of evidence § BI BII Amphotericin B lipid complex BII BII Strong recommendation/high quality of evidence † Strong recommendation/moderate quality of evidence § CII^ CII Amphotericin B colloidal dispersion BII BII Strong recommendation/high quality of evidence † Strong recommendation/moderate quality of evidence § DII^ CIII Amphotericin B deoxycholate CI CII - - DI DII Fluconazole AI CIII Strong recommendation/high quality of evidence ‡ Weak recommendation/low quality of evidence Δ CI CII Voriconazole AI BII Strong recommendation/moderate quality of evidence # Weak recommendation/low quality of evidence ◊ BI CII Itraconazole - - - - DII^ DIII Posaconazole - - - - DIII DIII AmBisome has a strong or moderate recommendation from ESCMID/ECMM/ERS, ECIL and IDSA for the treatment of invasive candidiasis Footnotes : Grades A (strong)–C (weak) reflect the strength of the recommendation. Grade D in ESCMID/ECMM/ERS guidelines supports a recommendation against use. Levels I, II and III represent the quality of the available evidence. Full details of the classification systems are provided in the respective treatment guidelines. * Not recommended for severely ill or unstable patients. † For patients who are intolerant/resistant to other antifungals. ‡ For patients that are not critically ill and where fluconazole resistance is unlikely. # Offers little advantage over fluconazole. § Less attractive because of toxicity. Δ Alternative for patients who are not critically ill and without prior azole exposure. ◊ Can be used where additional coverage against moulds is desired. ^ Strength of recommendation was not agreed upon by all experts, but from a majority vote. Abbreviations: ECIL: European Conference on Infections in Leukaemia; ECMM: European Confederation of Medical Mycology; ERS: European Respiratory Society; ESCMID: European Society of Clinical Microbiology and Infectious Diseases; HSCT: haematopoietic stem cell transplant; IDSA: Infectious Diseases Society of America. Please refer to the notes section for details of the references cited Liposomal AmB

39. Antifungal ECIL 2017 1 Leukaemia/HSCT patients ESCMID 2019 2 Overall population Patients with CNS involvement SOT patients AmBisome BII AII AIII AIII Amphotericin B lipid complex BII BII (Without CNS involvement) - AIII Isavuconazole - BII - - Amphotericin B colloidal dispersion CII - - - Amphotericin B deoxycholate CII DII (if alternative therapy available) DIII (Orbital mucormycosis) - - Posaconazole CIII BII (Tablet or IV) CII (Oral suspension) - - Combination therapy CIII - - - Escalation to full dose over days for any formulation of amphotericin B - DII - - Key guidelines for the treatment of IFI: mucormycosis AmBisome has a strong or moderate recommendation from ESCMID and ECIL for the treatment of mucormycosis and is considered the gold standard treatment Footnotes : Grades A (strong)–C (weak) reflect the strength of the recommendation. Grade D in ESCMID/ECMM/ERS guidelines supports a recommendation against use. Levels I, II and III represent the quality of the available evidence. Full details of the classification systems are provided in the respective treatment guidelines. Abbreviations : CNS: central nervous system; ECIL: European Conference on Infections in Leukaemia; ESCMID: European Society of Clinical Microbiology and Infectious Diseases; IV: intravenous; SOT: solid organ transplant. Please refer to the notes section for details of the references cited Liposomal Amphotericin B

40. Antifungal therapy in IFI U se of antifungal combinations with different mechanisms of action , have an established place in certain invasive fungal infections (IFIs) Fungi have the property of forming biofilms on various implanted medical devices which has important implications for treatment. The use of adjunctive treatment in the overall management is important. The duration of treatment is relatively prolonged as compared to most bacterial infections. Transition to oral agents which are less toxic and expensive is attempted whenever possible. Prophylactic, preemptive and empirical strategies have been proposed for IFIs as these have predictable occurrence, diagnostic difficulties and serious consequences associated with delayed treatment. Ayesha J Sunavala, Rajeev Soman Invasive Fungal Infections. API textbook of internal Medicine update 2017 P.76-80

41. Conclusion Considered “Gold standard” for the treatment of invasive fungal infections (IFI) owing to Broad spectrum of activity Reduced toxicity Low resistance rate Excellent clinical & pharmacological action It is strongly recommended as empirical therapy for presumed fungal infections By ECIL and BCSH guidelines 1 And the formulations are approved for use in paediatric patients (one month and above) 1 Continues to play an important role in the empiric management of IFI despite the recent availability of several other drugs in the azole and echinocandin classes 2 References: Aversa F, Busca A, Candoni A, Cesaro S, et. al. Liposomal amphotericin B ( AmBisome ®) at beginning of its third decade of clinical use. Journal of Chemotherapy . 2017 May 4;29(3):131-43.Accessed 13 Jan, 2022. Miceli MH, Chandrasekar P. Safety and efficacy of liposomal amphotericin B for the empirical therapy of invasive fungal infections in immunocompromised patients. Infection and drug resistance . 2012;5:9. Accessed 13 Jan, 2022.