Update on Invasive Fungal

Infections Management in a
Emergence of Anti Fungal
Resistance Era
Risk Factors for Fungal Infections
by Underlying Disease/Condition
Factors Involved in Development of
Opportunistic Fungal Infections

Barrier Quantitative or
disruption qualitative neutrophil
dysfunction
Candida spp Candida spp
Aspergillus (lung tx) Aspergillus and other moulds

Deficits in cell-mediated
Exposures immunity

Endemic mycoses Cryptococcus spp

Aspergillus and other moulds Endemic mycoses
Metabolic
Candida spp
Zygomycetes
Invasive Fungal Infection (IFI):
Who Is at Risk*?
Predisposing Conditions and Factors Mould Yeast
Hematopoietic stem cell transplant (HSCT)
 
 Allogeneic
 Nonmyeloablative allogeneic
 Autologous

Malignancy
 Acute leukemia  
 Other hematologic malignancy  
 Solid neoplasms  
Solid organ transplant (SOT)  
(risks vary with organ transplanted)

*A broad depiction of common conditions predisposing patients for increased risk of mould and yeast
infections; no single study published to date has surveyed the relative frequencies of systemic fungal
infections across different patient groups.
   : highest risk
  : high risk
 : at risk
Invasive Fungal Infections (IFI):
Who Is at Risk*?

Predisposing Conditions and Factors Mould Yeast

Critical care  

Concomitant lung disease/Critical care  

General surgery  
(risks vary by site, highest for GI and urology)
Corticosteroid use  

Diabetes mellitus/ketoacidosis  

*A broad depiction of common conditions predisposing patients for increased risk of mould and yeast
infections; no single study published to date has surveyed the relative frequencies of systemic fungal
infections across different patient groups.

   : highest risk
  : high risk
 : at risk
Systemic Candida Infections
 Systemic Candida Infections

Invasive fungal infections in humans

 Candida species are the most common cause
 Invasive candidiasis (IC) and candidaemia are
frequently encountered in the nosocomial setting,
particularly in the intensive care unit

C. albicans C. glabrata C. tropicalis C. parapsilosis

Pappas G et al. CID 2009; 48: 503-535, Guery BP, et al. ICM 2009;35: 55-62
Candida is now the third most common
cause of BSI in the ICU

Cause of nosocomial BSI in the ICU

40
(US; 1995-2002)
35.9%
35
Cause of infection (%)

30

25

20
16.8%
15
10.1% 9.8%
10
4.7%
5

0
CoNS Staph Candida Entero- Pseudo-
BSI=Blood stream infection.
coccus monas
ICU=Intensive care unit.
Wisplinghoff H et al. Clin Infect Dis. 2004;39:309-317.
 The incidence of systemic Candida
infection continues to increase
and mortality rates remain high

30 1.0

0.8

100,000 US population
100,000 US population
Incidence rate per

Mortality rate per

20
0.6

0.4
10

0.2

0 0
1996 1997 1998 1999 2000 2001 2002 2003
Year

Pfaller MA et al. Clin Microbiol Rev. 2007;20:133-163.

Candida BSI is associated with
a relatively high mortality rate
Crude mortality rate
(5 most common ICU pathogens, US; 1995-2002)

50 47.1% 47.9%
43.0%
40
34.4%
Crude mortality (%)

30 25.7%

20

10

0
CoNS Staph Candida Entero- Pseudo-
coccus monas
Wisplinghoff H et al. Clin Infect Dis. 2004;39:309-317.
More than 50% of cases of systemic Candida
infection are still caused by Candida albicans

Europe US
(1992-2001; N=775) (1992-2001; N=3683)

13% C glabrata 18%

14% C parapsilosis 13%

C albicans C albicans
58% 54%
8% C tropicalis 10%

3% C krusei 2%
5% Other spp 2%

Pfaller MA et al. Clin Microbiol Infect. 2004;10(suppl 1):11-23.

Diagnostic Tools for Candidiasis
Diagnostic tools for Candidiasis

 Absence of consensus except for candidemia

 Blood cultures: may be positive only after 3-5 days
 Diagnostic often delayed until dissemination
 Colonization: difficult to assess
Sens Spec PPV NPV
> 2 sites colonized <50% <50% <50% <50%
> 3 sites colonized <50% <50% <50% <50%
 Limited impact of biology (PCR/ anti-mannanes)

Wey et al. Arch Intern Med 1988, Voss et al. Infection 1997,
Pelz et al. J Int Care Med 2000, Blot et al. Am J Med 2002
Current Treatment Options
Current treatment options for candidemia*

 Fluconazole—most commonly used

 Amphotericin B (AMB) deoxycholate
 Lipid formulations of amphotericin
 Itraconazole
 Voriconazole

 Anidulafungin
 Caspofungin
 Micafungin

*See prescribing information of respective agents for complete information.

 In clinical studies, response to fluconazole
has been reported to be 56-70%

Rex et al, 1994 Phillips et al, 1997 Rex et al, 2003

100 100 100

79%
Success (% patients)

80 70% 80 80 69%
62%
57% 56%
60 60 60

40 40 40

20 20 20

0 0 0
Fluconazole Ampho B Fluconazole Ampho B Fluconazole Fluconazole
400 mg/day alone 400 mg/day alone 800 mg/day plus ampho B
n=103 n=103 n=42 n=42 n=107 n=112

Rex JH et al. N Engl J Med. 1994;331:1325-1330.

Phillips P et al. Eur J Clin Microbiol Infect Dis. 1997;16:337-345.
Rex JH et al. Clin Infect Dis. 2003;36:1221-1228.
 In clinical studies, mortality rates reported
with fluconazole were 33-39%

Rex et al, 1994 Phillips et al, 1997 Rex et al, 2003

Deaths through end of Deaths within 90 days of
follow-up (EOT + ~60 days) Day 60 mortality starting study therapy
100 100 100
Mortality (% patients)

80 80 80

60 60 60

40% 38% 39% 40%

40 33% 40 34% 40

20 20 20

0 0 0
Fluconazole Ampho B Fluconazole Ampho B Fluconazole Fluconazole
400 mg/day alone 400 mg/day alone 800 mg/day plus ampho B
n=103 n=103 n=50 n=53 n=107 n=112

Rex JH et al. N Engl J Med. 1994;331:1325-1330.

Phillips P et al. Eur J Clin Microbiol Infect Dis. 1997;16:337-345.
Rex JH et al. Clin Infect Dis. 2003;36:1221-1228.
Failure to respond to fluconazole is associated
with longer hospital and ICU stays
Fluconazole monotherapy (n=5653)
Fluconazole + OLAT (n=1517)
35
32 d
30
Mean length of stay (days)

25

20 18 d
15 d
15

10
7d
5

0
Mean hospital LOS Mean ICU LOS

OLAT=Other licensed antifungal therapy.

LOS=Length of stay.
Craver CW et al. Poster; 2006 ASHP.
Failure to respond to fluconazole is associated
with increased treatment costs

80
$76,329

60
Mean cost ($)

$38,980
40

20

0
Fluconazole Fluconazole
monotherapy + OLAT
n=5653 n=1517
Treatment cost
OLAT=Other licensed antifungal therapy.
Craver CW et al. Poster; 2006 ASHP.
Empirical therapy for suspected candidiasis in nonneutropenic patients
FLUCONAZOLE (loading dose of 800 mg [12mg/kg], then 400 mg [6 mg/kg]
daily),
CASPOFUNGIN (loading dose of 70 mg, then 50 mg daily),
ANIDULAFUNGIN (loading dose of 200 mg, then 100 mg daily), or
MICAFUNGIN (100 mg daily) is recommended as initial therapy .
An ECHINOCANDIN IS PREFERRED for patients who have had recent
azole exposure, whose illness is moderately severe or severe, or who are at
high risk of infection due to C. glabrata or C. krusei (B-III).
AmB-d (0.5–1.0 mg/kg daily) or LFAmB (3–5 mg/kg daily) are alternatives
Anidulafungin Profile
Echinocandin mechanism of action
involves a target specific for fungus
 Anidulafungin is a
noncompetitive inhibitor
of 1,3--D-glucan
synthase
 Enzyme is present in fungal,
but not mammalian cells
 -D-glucan is essential to
fungal cell wall integrity
 Without it, fungal cells
are osmotically fragile
and easily lysed
Anidulafungin molecular structure
is different from the other echinocandins

More stable
ring structure

Unique lipophilic
side chain

 Large volume
 Longer half-life of distribution
Anidulafungin achieves rapid killing
of Candida spp
1.0E+08

Control
1.0E+07
Fluconazole

1.0E+06 Ketoconazole
Log CFU/mL

Flucytosine
Itraconazole
1.0E+05

Anidulafungin
Concentrations used were the
1.0E+04
MIC of each antifungal agent

1.0E+03

Ampho B
1.0E+02
0 5 10 15 20 25
Time (hours)
No correlation between in vitro activity and clinical outcome has been established.
Zhanel G et al. Antimicrob Agents Chemother. 2001;45:2018-2022.
Anidulafungin is active against Candida glabrata

Candida glabrata exposed

for 48h to anidulafungin

Control

0.05 g/mL 0.7 g/mL

No correlation between in vitro activity and clinical outcome has been established.
Klepser ME et al. Antimicrob Agents Chemother. 1998;42:1387-1391.
 Anidulafungin is considerably more potent in vitro
than fluconazole

MIC profile of isolates from phase 3 study in candidemia

80

70
Anidulafungin
60 Fluconazole
No. of isolates

50

40

30

20

10

MIC (g/mL)
No correlation between in vitro activity and clinical outcome has been established.
Data on file. Pfizer Inc, New York, NY.
 Incubation period (24 vs 48 h) has a
significant impact on echinocandin MIC90

Species Anidulafungin Caspofungin Micafungin

24 h* 48 h‡ 24 h† 48 h‡ 24 h† 48 h‡

C albicans 0.12 0.03 0.06 0.5 0.03 0.03

C glabrata 0.12 0.12 0.06 1 0.03 0.06

C tropicalis 0.06 0.12 0.06 1 0.06 0.06

C krusei 0.06 0.12 0.25 2 0.12 0.25

C parapsilosis 2 2 1 2 2 2

C lusitaniae 0.5 0.25 0.25 2 0.25 2

No correlation between in vitro activity and clinical outcome has been established.
*Pfaller MA et al. J Clin Microbiol. 2005;43:5425-5427.
†Pfaller MA et al. J Clin Microbiol. 2006;44:3533-3538.
‡Ostrosky-Zeichner L et al. Antimicrob Agents Chemother. 2003;47:3149-3154.
Anidulafungin is highly active in vitro against
fluconazole-resistant* Candida species

Species Anidulafungin
(no. of isolates) MIC90 (g/mL)

C albicans (41) 0.06

C glabrata (110) 0.12

C krusei (146) 0.12

No correlation between in vitro activity and clinical outcome has been established.
*Resistance defined as fluconazole MIC 64 g/mL.
Pfaller MA et al. J Clin Microbiol. 2005;43:5425-5427.
Current recommended dosing delivers high blood
levels compared to typical MICs for Candida
200-mg loading dose
100-mg maintenance dose
6

5
Concentration (g/mL)

1 C albicans, C glabrata C tropicalis, C krusei

(MIC90: 0.12 g/mL) (MIC90: 0.06 g/mL)

0
0 1 2 3 4 5 13 14 15 16 17 18 19
Time (days)
No correlation between in vitro activity and clinical outcome has been established.
Adapted from Dowell JA et al. J Clin Pharmacol. 2004;44:590-598.
Anidulafungin has the longest half-life
of the available echinocandins
30
26.5 h
25
Beta half-life (hours)

20
14-17 h
15

9-11 h
10

0
Anidulafungin Micafungin Caspofungin
Comparisons do not imply interchangeability or comparable efficacy and safety.
See prescribing information of respective agents for complete information.
Eraxis [package insert]. New York, NY: Pfizer Inc; 2007.
Mycamine for Injection [package insert]. Tokyo, Japan: Astellas Pharma, Inc; 2006.
Cancidas for Injection [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2005.
 Animal studies demonstrate that anidulafungin
extensively distributes into critical body tissues

 In rats, tissue levels were 9- to 12-fold higher

than plasma

Tissue/plasma AUC ratio

Organ
for parent drug*

Liver 12.4

Kidney 10.7

Spleen 9.2

Lung 10.4

*Following a single IV bolus 5 mg/kg dose of 14C-anidulafungin in Fischer 344 rats.

Data on file. Pfizer Inc, New York, NY.
Anidulafungin has the greatest volume of
distribution of the available echinocandins

35 30-50 L
30 ~27 L
25
Vd (L)

20

15
8-10 L
10

0
Anidulafungin Micafungin Caspofungin

Comparisons do not imply interchangeability or comparable efficacy and safety.

See prescribing information of respective agents for complete information.
Dowell JA et al. J Clin Pharmacol. 2004;44:590-598.
Mycamine for Injection [package insert]. Tokyo, Japan: Astellas Pharma, Inc; 2006.
Stone JA et al. Antimicrob Agents Chemother. 2004;48:815-823.
Anidulafungin exhibits simple linear PK

120

100
Mean AUCSS (mgh/L)

80

60

40

20

0
0 50 100 150
Anidulafungin dose (mg)
Anidulafungin undergoes spontaneous chemical
degradation at physiologic conditions

Active molecule Chain breaks Inactive peptide converted

at physiologic to peptidic degradants
37°C and pH 7.4 and eliminated in feces

 Anidulafungin is the only echinocandin not hepatically

metabolized or renally excreted
 Because anidulafungin elimination is not dependent on
hepatic/renal function
 There are no known drug interactions of clinical significance
 There are no required dose adjustments
 Anidulafungin metabolism and elimination
differs from other echinocandins
Intravenous
only

OATP-1B1
Caspofungin N-acetylation
Slow chemical
degradation

Micafungin COMT

Anidulafungin
Biliary
elimination

Urine

OATP=Organic anion-transporting polypeptide.

COMT=Catechol-O-methyltransferase.
Anidulafungin is not metabolized by hepatocytes
120 Rat Human

100
% of anidulafungin remaining

80

60

40

20

0
0 1 2 3 4
Incubation time (hours)
Data points represent mean of triplicate incubations of 10 mol/L anidulafungin with hepatocytes.
Data on file. Pfizer Inc, New York, NY.
Stogniew M et al. 13th ECCMID. 2003. P-1223.
Anidulafungin does not inhibit CYP isoenzymes

Isoenzyme IC50
CYP3A >17.5 M
CYP2D6 >17.5 M
CYP2C9 >17.5 M
CYP1A2 >17.5 M
CYP2B6 >17.5 M
CYP2C8 12.0 M
CYP2C19 >17.5 M

Data on file. Pfizer Inc, New York, NY.

Anidulafungin has no known drug interactions

2.5

2.0
Clearance (L/h)

1.5

1.0

0.5

0.0
None Inhibitor Inducer Rifampin
n=77 n=140 n=40 n=27

 Anidulafungin is not an inhibitor, inducer, or substrate

of CYP450
Dowell JA et al. J Clin Pharmacol. 2004;44:590-598.
 Anidulafungin clearance unchanged
in impaired hepatic or renal function

Hepatic impairment Renal impairment*

3.0 3.0
Control (n=8) Control (n=8)
2.5 Mild (n=6) 2.5 Mild (n=6)
concentration (g/mL)

Moderate (n=6) Moderate (n=6)

Severe (n=6) Severe (n=6)
Anidulafungin

2.0 2.0

1.5 1.5

1.0 1.0

0.5 0.5

0 0
0 20 40 60 80 100 120 140 160 0 20 40 60 80 100 120 140 160
Time after study drug administration (h) Time after study drug administration (h)

*Anidulafungin is not dialyzable and may be administered without regard to timing of hemodialysis.
Vazquez JA. Clin Ther. 2005;27:657-673.
 Anidulafungin has least complex metabolism and
interaction profile of the available echinocandins
Caspofungin Micafungin Anidulafungin
Yes
(Arylsulfatase and
Hepatic Yes
catechol-O- No
metabolism? (N-acetylation)
methyltransferase; some
CYP3A hydroxylation)

CYP3A4
No Weak No
inhibitor?

Cyclosporine; Tacrolimus
Rifampin; Efavirenz;
Drug Sirolimus
Nevirapine; Phenytoin; No known interactions
Interactions? Nifedipine
Dexamethasone;
Carbamazepine

Yes
 Moderate to severe
Dose
hepatic insufficiency No No
adjustments?
and/or
 With CYP inducers

Comparisons do not imply interchangeability or comparable efficacy and safety.

See prescribing information of respective agents for complete information.
Cancidas [Summary of Product Characteristics]. Hoddesdon, Hertfordshire, UK: Merck Sharp & Dohme Limited; 2007.
Mycamine for Injection [package insert]. Tokyo, Japan: Astellas Pharma, Inc; 2006.
Ecalta [Summary of Product Characteristics]. Sandwich, Kent; UK: Pfizer Limited; June 2007. DRAFT.
 Efficacy of Anidulafungin in a
Single Pivotal Candidemia Study

Anidulafungin in indicated for the treatment of invasive candidiasis

in adult non-neutropenic patients. Anidulafungin has been studied
primarily in patients with candidemia and only in a limited number
of patients with deep tissue Candida infections or with abscess
forming disease.
Pivotal candidemia study
Anidulafungin demonstrated significantly greater
efficacy than fluconazole

Primary end point: treatment success at end of IV therapy

Required both clinical and microbiological response

100 Difference 15.4%

95% CI: 3.9-27.0
80
76%
Success rate (%)

60%
60

40

20

0
Anidulafungin Fluconazole
n=127 n=118

Reboli AC et al. N Engl J Med. 2007;356:2472-2482.

Pivotal candidemia study
Anidulafungin benefit was sustained
after end of treatment
Anidulafungin
Fluconazole
80 76%

60%
60
Success rate (%)

40

20

0
End of IV

Reboli AC et al. N Engl J Med. 2007;356:2472-2482.

Pivotal candidemia study
Anidulafungin had greater efficacy than fluconazole
in patients with Candida albicans infection

Anidulafungin
90 81% Fluconazole
80 71%
70 62%
Success (% patients*)

60%
60

50

40

30
Candida Non-albicans
20 albicans Candida

10

0
n=74 n=61 n=45 n=45

The majority of isolates were susceptible to fluconazole.

*Patients who had a single baseline pathogen.
Reboli AC et al. N Engl J Med. 2007;356:2472-2482.
Pivotal candidemia study
Anidulafungin global success compared to
fluconazole for non-albicans Candida infection*
Anidulafungin
Fluconazole
100 93%
90 83%
80 75%
70 64% 67%
56%
% Success

60
50% 50%
50

40

30

20

10
0
C glabrata C tropicalis C parapsilosis Other
n=16 n=22 n=14 n=8 n=11 n=12 n=4 n=3
*Patients who had a single baseline pathogen.
Reboli AC et al. N Engl J Med. 2007;356:2472-2482.
 Pivotal candidemia study
Microbiologic success* was numerically greater with
anidulafungin for C albicans, C glabrata, and C tropicalis†

Anidulafungin Fluconazole

C albicans C glabrata C tropicalis C parapsilosis

100 95%
87% 88%
81%
80 75%
69%
64%
60%
Success (%)

60

40

20

0
n=81 n=70 n=20 n=30 n=15 n=11 n=13 n=16

*Microbiologic success was defined as either documented (by blood culture) or presumed (based on clinical response)
eradication of all pathogens that were present at baseline.
†Patients may have had >1 pathogen at baseline, but the majority (94% anidulafungin; 90% fluconazole) had a

single pathogen.
Reboli AC et al. N Engl J Med. 2007;356:2472-2482.
Pivotal candidemia study
Anidulafungin was more effective than
fluconazole regardless of site of infection

100 Anidulafungin (N=127)

Fluconazole (N=118)
76%
80 73%
61%
Success rate (%)

60 53%

40

20

0
n=88/116 n=63/103 n=8/11 n=8/15
Candidemia only Other forms of
systemic candidiasis
Reboli AC et al. N Engl J Med. 2007;356:2472-2482.
Pivotal candidemia study
Fewer anidulafungin-treated patients had
positive blood cultures at days 3 and 7

Day 3 Day 7

Anidulafungin
Patients with positive blood culture (%)

30
Fluconazole

20.4%
20

12.1%
10.7%
10
5.2%

0
n=14/116 n=21/103 n=6/116 n=11/103

Data on file. Pfizer Inc, New York, NY.

Pivotal candidemia study
Anidulafungin was effective over a broad range
of APACHE II scores
Global success by APACHE II score
(MITT population)
100
Anidulafungin
Fluconazole
Successfully treated

75
patients (%)

50

25

0
0 10 20 30 40
Numbers of Patients
Anidulafungin 7 27 29 31 12 14
Fluconazole 4 33 35 26 12 8

Data on file. Pfizer Inc, New York, NY.

Pivotal candidemia study
All-causality adverse events reported
in >10% of patients on anidulafungin
Anidulafungin Fluconazole
N=131 N=125
Hypokalemia 25.2 19.2
Nausea 24.4 12.0
Diarrhea 18.3 18.4
Bacteremia 17.6 18.4
Pyrexia 17.6 18.4
Vomiting 17.6 9.6
Insomnia 15.3 9.6
UTI 14.5 17.6
Hypotension 14.5 14.4
Alk phos increased 11.5 11.2
Hypo Mg 11.5 11.2
Hypertension 11.5 4.0
Dyspnea 11.5 3.2
Edema 10.7 12.8
Reboli AC et al. N Engl J Med. 2007;356:2472-2482.
Pivotal candidemia study
All-causality adverse events reported
in >10% of patients on fluconazole

Anidulafungin Fluconazole
N=131 N=125
Anemia 9.2 16.0
Constipation 8.4 11.2
Pneumonia 6.1 15.2
Abdominal pain 6.1 12.8
Hyperkalemia 6.1 11.2
Hepatic enzyme increased 5.3 11.2
Back pain 5.3 10.4
Anxiety 4.6 10.4
Pulmonary edema 3.1 10.4
Thrombocytopenia 3.1 10.4
Reboli AC et al. N Engl J Med. 2007;356:2472-2482.
Pivotal candidemia study
Frequency of increased liver function tests
with anidulafungin comparable to fluconazole

Anidulafungin Fluconazole

ALT  4.6% 5.6%

(6/131) (7/125)

AST  1.5% 7.2%

(2/131) (9/125)

Alk phos  11.5% 11.2%

(15/131) (14/125)

Data on file. Pfizer Inc, New York, NY.

Pivotal candidemia study

14-day survival curve

 Fewer patients died in the anidulafungin arm than in the
fluconazole arm
1.00
Probability of survival

0.75

P=.0699

0.50

0.25 Anidulafungin Fluconazole

0.00
0 2 4 6 8 10 12 14
Time (days)
Reboli AC et al. N Engl J Med. 2007;356:2472-2482.
Data on file. Pfizer Inc, New York, NY.
Pivotal candidemia study

All-cause mortality for the study overall

40

31%
Overall study mortality

30
(% of patients)

23%

20

10

0
Anidulafungin Fluconazole
(n=127) (n=118)

Reboli AC et al. N Engl J Med. 2007;356:2472-2482.

Data on file. Pfizer Inc, New York, NY.
Anidulafungin: Summary of benefits

 Strong clinical data as demonstrated in the pivotal

candidemia study
 The only echinocandin statistically proven to show
greater efficacy than fluconazole (76% vs 60%; 95% CI:
3.9-27.0)
 Sustained efficacy at all time points
 Reduced persistence of infection at end of treatment
 Efficacy across a broad patient population
 Fewer deaths compared with fluconazole (23% vs 31%)
 Excellent safety; fewer discontinuations than fluconazole
 Unlike other echinocandins, no hepatic metabolism
 No known drug interactions
 No dosage adjustments in hepatic or renal insufficiency
Pfizer’s Antifungal Portfolio

Aspergillus infection / mixed

Candida Infection
fungal infection
Non-ICU SICU, ICU
Surgery Solid Tumor
Burn Trauma (ST) SOT* Hem. Mal. BMT*
Other

Better efficacy compared to fluconazole for Superior efficacy compared to

Candidemia/Invasive candidiasis ampho B in invasive aspergillosis
Broad spectrum Candida coverage with survival advantage
No dose adjustments in organ failure Demonstrated efficacy in serious
No known drug interactions Candida infections
Disclamer
These reference slides as parts of internal Pfizer Indonesia educational materials
Do not use it for external usage without Pfizer medical department permission