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
Life threatening
• One of the deadliest among communicable diseases, along with lower
respiratory infections, tuberculosis and diarrheal diseases
Incidence
• Worldwide Incidence of 6/100 000 cases/year
increasing incidence every year along with increased mortality*
Impact
8-15% of nosocomial blood stream infections
Fourth most common isolate of patients of the intensive care unit
Mortality
• Kills up to 1.5 million people each year,
• Mortality rate around 50% but early diagnosis and appropriate treatment
save 80% of these patients
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. 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
1990s
1991
2000s
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

8. 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

9. Anti fungal Spectrum of Amphotericin B
Antifungal broad spectrum
fungal pathogens that are usually resistant to amphotericin B include
• The 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

10. 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
• Infusion-related toxicity :- This is thought to result from innate
immune production of proinflammatory cytokines

11. • 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

12. 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

13. 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

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

15. 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 Cmax 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
Cmax
The volume of drug distribution is significantly reduced with L-
AmB, allowing for greater drug concentration in plasma
Vd
AUC, area under curve; Cmax, maximum concentration; L-AmB, liposomal amphotericin B;
Vd, volume distribution.

16. 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 (μg/mL)
58 1.7 2.9
Mean AUC (μg/mL.h) 713 14 36
Mean Vd (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; Vd, volume distribution.
• Groll AH, et al. Klin Pediatr 1998;210:264‒73.
• There are biochemical and pharmacokinetic differences between different amphotericin B formulations

17. Effect of lipid structure on toxicity profile
L-AmB ABLC cAmB
Pharmacokinetics High Cmax , high AUC, low clearance1 Low Cmax and AUC, high
clearance1,4
Low Cmax and AUC, high clearance1
Uptake by RES
tissues
AmB mostly associated with liposomes in circulation; minimal
drug transfer to mammalian cells.2 Longer in circulation before
uptake by RES2
Taken up rapidly by cells of the
RES; results in release of
amphotericin into the
circulation and enhanced
tissue penetration3
Impact on
toxicity/efficacy
Reduced renal clearance due to intact liposomes (no
dissociated AmB)2
Less nephrotoxic profile than free AmB5
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
reactions3
Reduced nephrotoxicity rates
compared to cAmB1
Associated with toxicity problems due to
binding of AmB to mammalian cells2
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 damage2
Maximal tolerated doses (0.7–1.0
mg/kg/day) may be clinically suboptimal2
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
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.

18. 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
16.9
18.4
43.6
54.4
0
10
20
30
40
50
60
Fever Chills or rigors
Patients,
%
L-AmB (n=343) cAmB (n=344)
n=187
23.5
18.8
19.8
23.5
57.7
79.5
0
10
20
30
40
50
60
70
80
90
Fever Chills or rigors
Patients,
%
L-AmB 3 mg/kg/day (n=85) L-AmB 5 mg/kg/day (n=81) ABLC (n=78)
Infusion-related adverse reactions in cAmB and L-AmB1
Day 1 infusion-related adverse reactions in ABLC and L-AmB2
n=58
n=150
n=63
n=20
n=16
n=45
n=16
n=19
n=62
p<0.001
p≤0.001

19. 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
18.7
8.2
33.7
16.6
0
5
10
15
20
25
30
35
40
Serum creatinine >2x baseline Serum creatinine >3x baseline
Patients,
%
L-AmB (n-343) cAmB (n=344)
14.1
5.9
14.8
6.2
42.3
26.9
0
5
10
15
20
25
30
35
40
45
Serum creatinine >2x baseline Serum creatinine >3x baseline
Patients,
%
L-AmB 3 mg/kg/day (n=85) L-AmB 5 mg/kg/day (n=81) ABLC (n=78)
Nephrotoxicity in cAmB and L-AmB1 Nephrotoxicity in ABLC and L-AmB2
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

20. 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
12.9 12.3
32.1
0
5
10
15
20
25
30
35
Patients,
%
L-AmB 3 mg/kg/day (n=85) L-AmB 5 mg/kg/day (n=81) ABLC (n=78)
Drug discontinuations due to toxicity in ABLC and L-AmB
n=11 n=10
n=25
p<0.01

21. Safety and efficacy studies

22. 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

23. 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
58.3%
48.0% 47.5%
0
10
20
30
40
50
60
70
Patients,
%
Efficacy: Mycological success at week 2
L-AmB 3mg/kg/day (n=87)
LAmB 6mg/kg/day (n=86)
cAmB 0.7mg/kg/day (n=94)
n=35
n=36 n=29

24. 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 0 14 7 11 0 0.09
Mortality, n
(%)
13 (38.2) 7 (21.9) 0.19*
9.6
11.5
22.2
40.7
0
5
10
15
20
25
30
35
40
45
Fever/chills (p=0.11) Creatinine >2x baseline
(p<0.001)
Patients,
%
Fever/chills and creatinine increase in patients
taking L-AmB or cAmB
L-AmB cAmB
*When adjusted for malignancy status, p=0.03
n=5
n=12
n=6
n=22
p=0.11
p<0.001

25. 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;98:711‒18.
• L-AmB had significantly fewer adverse events in adults than cAmB
6%
11%
44%
0
10
20
30
40
50
DRAE Adults (n=134)
Patients,
%
Drug-related adverse events
L-AmB 1mg/kg/day L-AmB 3mg/kg/day cAmB 1mg/kg/day
0% 0%
16%
0
2
4
6
8
10
12
14
16
18
Severe DRAE Adults (n=134)
Patients,
%
Serious drug-related adverse events
L-AmB 1mg/kg/day L-AmB 3mg/kg/day cAmB 1mg/kg/day
p<0.01

26. 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)

27. 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)

28. 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
0
Probability
of
hospitalisation
cAmB
L-AmB
ABLC
11.5
7.2
2.4
0
5
10
15
Patients,
%
Patients experiencing severe nephrotoxicity (RIFLE failure)
cAmB ABLC L-AmB
n=20
n=5
n=2

29. 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 (40.0) 34 (42.0) 26 (33.3)
Emergent
fungal
infections
3 (3.6) 2 (2.5) 3 (3.8)
Death related
to fungal
infection
1 (1.2) 0 (0.0) 3 (3.8)
23.5
18.8
14.1 12.9
19.8
23.5
14.8 12.3
57.7
79.5
42.3
32.1
0
10
20
30
40
50
60
70
80
90
Fever (day 1) Chills/rigors (day 1) Nephrotoxicity* Toxicity-related
discontinuation
Patients,
%
Adverse events
L-AmB (3 mg/kg/day) L-AmB (5 mg/kg/day) ABLC (5 mg/kg/day)
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

30. 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

31. Spectrum of activity of antifungal agents

32. Spectrum of activity of antifungal agents
АmВ 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

33. 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
increasing prevalence
of C.galbrata, which is
less susceptible to
azoles1,3
Azole resistance was
reported in 3.2% of
A.fumigatus isolates in
Europe in 2009–20112
Echinocandin
resistance in Candida
spp. is increasing in
prevalence1,3
Minimal resistance
reported4–6
Azoles
Echinocandins
Polyenes
5.5–7.6% of azole-resistant
C.glabrata isolates may also
be resistant to an
echinocandin3
A 2012 study of 9,252 clinical
isolates of C. albicans found
that 99.8% remained
sensitive to amphotericin B8

34. Guidelines perspective

35. Key guidelines for the treatment of IFI: empiric treatment
Antifungal
Invasive Candidiasis Invasive Aspergillosis
IDSA 20161
Non-neutropenic patients in ICU
ESCMID/ECMM/ERS 20122 IDSA 20163
High-risk patients with prolonged
neutropenia
ESCMID/ECMM/ERS
20184
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)
CIa - 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: aLimited 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

36. Key guidelines for the treatment of IFI: invasive aspergillosis
Antifungal
ECIL 20171
Leukaemia/HSCT
patients
IDSA 20162
ESCMID/ECMM/ERS 20183
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

37. Key guidelines for the treatment of IFI: invasive candidiasis
Antifungal
ECIL 20171
Leukaemia/HSCT patients
IDSA 20162 ESCMID/ECMM/ERS 2012
Overall
population
Patients with
haematological
malignancies
Non-neutropenic patients Neutropenic patients
Non-neutropenic
patients3
Patients with haematological
malignancies and after HSCT4
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
evidenceΔ
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

38. Antifungal
ECIL 20171
Leukaemia/HSCT patients
ESCMID 20192
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

39. Antifungal therapy in IFI
Use 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

40. 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 guidelines1
 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 classes2
References:
1. 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.
2. 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.

41. Thank You!!!!!