- Micafungin was found to be non-inferior to caspofungin in treating candidemia and invasive candidiasis based on a randomized controlled trial of 595 patients (Pappas et al. 2007). Treatment success rates were similar between micafungin and caspofungin groups. - Another randomized controlled trial by Kuse et al. (2007) found micafungin to be non-inferior to liposomal amphotericin B in treating candidemia and invasive candidiasis based on intention-to-treat analysis of 537 patients, with similar treatment success rates of 89.6% for micafungin and 89.5% for liposomal

1. Echinocandins in Invasive Fungal
Infections:
Clinical Review

2. Agenda
•Trends in IFIs
Echinocandins in the management of IFIs
Guidelines & Recommendations
Clinical trial evidence
Conclusions

3. Trends in Invasive Fungal Infections
Proportion of Invasive Candidiasis
Kriengkauykiat et al Clinical Epidemiology 2011:3 175–191.

4. Proportion of Candidemia due to Candida species
Kriengkauykiat et al Clinical Epidemiology 2011:3 175–191.
Three-month mortality due to invasive
candidiasis in critically ill: 50%
Trends in Invasive Fungal Infections

5. Trends in the Invasive Fungal Infections
Proportion of Invasive Aspergillosis
Kriengkauykiat et al Clinical Epidemiology 2011:3 175–191.

6. Fungal isolates in different clinical samples (2007-2012)
(n=689)
Proportion of Invasive Fungal Infections
in India
Tyagi S et al International Journal of Basic and Applied Sciences, 3 (1) (2014) 26-29

7. ICU, intensive care unit; DIC Disseminated intravascular coagulation
Factors Predisposing to Invasive fungal Infections
Invasive Fungal
Infections
Invasive candidiasis
Host predisposition Colonization
Neutropenia ≥3 weeks Presence of central venous catheter
Environmental factors Hemodialysis
Surgery (complicated or repeated abdominal)
Clinical unstable presentation (acute renal failure,
shock, DIC)
Antianerobic antibiotic agents
Total parental nutrition or intralipid agents
Prolonged ICU stay
Kriengkauykiat et al Clinical Epidemiology 2011:3 175–191.

8. Developed in
response to
the need for
safe and
effective
antifungals
Inhibits 1,3-
beta-d-glucan
synthase
Favorable
activity in
vitro against
yeasts and
select moulds
Favorable
safety profile
Place of Echinocandins in the Management of Invasive Fungal
Infections
Turner MS et al Expert Opin Emerg Drugs. 2006 May;11(2):231-50.

9. Valuable first-line treatment option
Non-inferior to caspofungin, liposomal amphotericin B &
fluconazole
Superior to fluconazole & non-inferior to Itraconazole as
Prophylaxis
Once-daily dosage regimen
Fewer drug-drug interactions
Better tolerated
Place of Micafungin in Management of Invasive
Candida Infections

10. Echinocandins
recommended
as initial therapy
Caspofungin: loading dose 70
mg, then 50 mg daily
Micafungin: 100 mg
daily
Anidulafungin: loading
dose 200 mg, then 100
mg daily
 strong recommendation; moderate-quality evidence;   strong recommendation; high-quality evidence
Treatment of Candidemia in Neutropenic and Non-neutropenic**
Patients? IDSA 2016 Recommendation
Pappas PG et al Clin Infect Dis. 2016 Feb 15;62(4):e1-50.

11. Treatment of candidemia/invasive
candidiasis in Non-neutropenia:
Recommendations from Various Guidelines

12. Society First line Alternative I Alternative II
IDSA Fluconazole
-stable patient, azole
naïve
Echinocandins
-severe sepsis
-recent azole
exposure
AmB or lipid
formulations of AmB
(intolerance to others
or limited availability)
Voriconazole
ESCMID Echinocandins LipAmB, voriconazole fluconazole, lcAmB
European
Expert Opinion
Fluconazole
- stable patient
- susceptible isolate
Echinocandins
- severe sepsis
lipidformulations of
amphotericin B
AmB = amphotericin B, LipAmB= liposomal amphotericin B, lcAmB = lipid complex amphotericin B.
Treatment of candidemia/invasive candidiasis in Non-neutropenia
Recommendations from Various Guidelines
Paramythiotou E et al Molecules 2014;19:1085-1119.

13. Society First line Alternative I Alternative II
Canadian Clinical
Practice Guidelines
for Invasive
Candidiasis in
Adults
Fluconazole
-stable patient, azole naïve
-unstable patient with
C. parapsilosis
Echinocandins
-stable or unstable patient
-recent azole exposure
-avoid in C. parapsilosis
LipAmB or AmB
Joint
Recommendations
of the German
speaking
Mycological Society
Fluconazole
-stable patient
-susceptible isolate
Echinocandins
-critically ill septic patient
LipAmB
-critically ill,
septic patients
Voriconazole
AmB = amphotericin B, LipAmB= liposomal amphotericin B, lcAmB = lipid complex amphotericin B.
Treatment of candidemia/invasive candidiasis in Non-neutropenia
Recommendations from Various Guidelines
Paramythiotou E et al Molecules 2014;19:1085-1119.

14. Intervention SoR QoE Comment
Anidulafungin
200/100 mg
A I Consider local epidemiology, less drug–drug
interactions than caspofungin
Caspofungin 70/50
mg
A I Consider local epidemiology (C. parapsilosis)
Micafungin 100 mg A I Consider local epidemiology (C. parapsilosis), less drug–
drug interactions than caspofungin, consider EMA
warning label
Amphotericin B
liposomal 3 mg/kg
B I Similar efficacy as micafungin, higher renal toxicity than
micafungin
Voriconazole 6/3
mg/kg/daya,b
B I Limited spectrum compared to echinocandins, drug–
drug interactions, limitation of IV formulation in renal
impairment, consider therapeutic drug monitoring
Fluconazole 400–800
mga
C I Limited spectrum, inferiority to anidulafungin, may be
better than echinocandins against C. parapsilosis
EMA, European Medicines Agency. Comparative clinical trials did not prove a survival benefit of one treatment over another. Primary intention of treating
candidaemia is clearing the blood stream. aNot all experts agreed, SoR results from a majority vote. bThe licensed maintenance dosing is 4 mg/kg/day. Definition
of the strength of recommendation (ESCMID EFISG): Grade A: Strongly supports a recommendation for use Grade B: Moderately supports a
recommendation for use Grade C:Marginally supports a recommendation for use Grade D:Supports a recommendation against use.
Initial treatment of candidemia and invasive candidiasis
ESCMID Recommendations
Cornely OA et al Clin Microbiol Infect 2012; 18 (Suppl. 7): 19–37.

15. Intervention SoR QoE Comment
Amphotericin B lipid complex 5 mg/kg C I
Amphotericin B deoxycholate 0.7–1.0 mg/kg D IIa
Amphotericin B deoxycholate plus
fluconazole
D I Substantial renal and
infusion-related toxicity
Amphotericin B deoxycholate plus 5-
fluorocytosine
D II Efficacious, but increased
risk of toxicity in ICU
patients No survival
benefit
Efungumab plus lipid-associated
amphotericin B
D II
Amphotericin B colloidal dispersion D IIa
Itraconazole D IIa
Posaconazole D III
EMA, European Medicines Agency. Comparative clinical trials did not prove a survival benefit of one treatment over another. Primary intention of treating
candidaemia is clearing the blood stream. aNot all experts agreed, SoR results from a majority vote. bThe licensed maintenance dosing is 4 mg/kg/day. Definition
of the strength of recommendation (ESCMID EFISG): Grade A: Strongly supports a recommendation for use Grade B: Moderately supports a
recommendation for use Grade C:Marginally supports a recommendation for use Grade D:Supports a recommendation against use.
Initial treatment of candidemia and invasive candidiasis
ESCMID Recommendations
Cornely OA et al Clin Microbiol Infect 2012; 18 (Suppl. 7): 19–37.

16. Management of Candidemia/invasive candidiasis: ECIL, ESCMID, and
IDSA Recommendations
Leroux S et al Clin Microbiol Infect 2013; 19: 1115–1121.
ECIL ESCMID IDSA
Initial
targeted
treatment in
non-
neutropenic
patients
Caspofungin A I
Anidulafungin A I
Micafungin A I
L-AmB A I
AmB-d A Ia
Fluconazole A Id
Voriconazole A Ie
ABLC A II
ABCD A II
Itraconazole NR
Posaconazole NR
Caspofungin A I
Anidulafungin A I
Micafungin A I
L-AmB B I
Voriconazole B If
Fluconazole C If,g
ABLC C IIa
AmB-d D I
ABCD D IIa
Itraconazole D IIa
Posaconazole D III
Caspofungin A I
Anidulafungin A I
Micafungin A I
L-AmB A Ih
AmB-d A I
Fluconazole A Ii
Voriconazole A I
Itraconazole NR
Posaconazole NR
ABLC NR
ABCD NR
European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Diseases Society of America (IDSA), and the European Conference on
Infection in Leukaemia (ECIL). 5-Fu: 5-fluorocytosine, ABCD: amphotericin B colloidal dispersion, ABLC: amphotericin B lipid complex, AmB-d: amphotericin B
deoxycholate, CVC: central venous catheter, L-AmB: liposomal amphotericin B, NR: no recommendation, PICC: peripheral inserted central catheter, SoR: strength of
recommendation. aD III, by concomitant nephrotoxic drug and E III by renal impairment. bRather as step-down therapy. cLess critically ill patients, no azole
exposure. dNot in severely ill patients or in patients with previous azole prophylaxis. eNot in patients with previous azole prophylaxis. fNot all experts agreed, SoR
results from a majority vote. gMay be better than echinocandins against C. parapsilosis.

17. Strength of
recommen
dation ECIL until 2009 ESCMID IDSA/ECIL since 2009
A Strong evidence for efficacy and substantial
clinical benefit: strongly recommended
ESCMID strongly supports a
recommendation for use
Good evidence to support a
recommendation for or against use
B Strong or moderate evidence for efficacy,
but only limited clinical benefit: generally
recommended
ESCMID moderately supports a
recommendation for use
Moderate evidence to support a
recommendation for or against use
C Insufficient evidence for efficacy, or efficacy does not
outweigh possible adverse consequences (e.g. drug
toxicity or interactions) or cost of chemoprophylaxis or
alternative approaches: optional
ESCMID marginally supports a
recommendation for use
Poor evidence to support a
recommendation
D Moderate evidence against efficacy or for adverse
outcome: generally not recommended
ESCMID supports a
recommendation against use
NA
E Strong evidence against efficacy or for adverse
outcome: never recommended
NA NA
Quality of evidence
I Evidence from at least one well-executed randomized
trial
II Evidence from at least one well-designed clinical trial
without randomization; cohort or case-controlled
analytical studies (preferably from more than one
centre; multiple time-series studies; or
III Evidence from opinions of respected authorities
based on clinical experience, descriptive studies,
or reports from expert committees
ECIL, European Conference on Infection in Leukaemia; ESCMID, European Society of Clinical Microbiology and Infectious Diseases; IDSA, Infectious Diseases Society of America; NA, not applicable. Added Index proposed by the ESCMID only for level II of evidence:
r, meta-analysis or systematic review or randomized controlled trials; t, transferred evidence, i.e. results from different patient cohorts, or similar immune-status situation; h, comparator group is a historical control; u, uncontrolled trial; a, published abstract
(presented at an international symposium or meeting).
Leroux S et al Clin Microbiol Infect 2013; 19: 1115–1121.
Strength of Recommendations
Leroux S et al Clin Microbiol Infect 2013; 19: 1115–1121.

18. Study Design
• International, randomized, double-blind investigation
• Adults (n=595) with candidemia, or noncandidemic invasive candidiasis
• 85.1% candidemic; >50% with non-albicans Candida
Treatment protocol
• Micafungin (100 mg and 150 mg daily) & caspofungin (70 mg followed by
50 mg daily); randomization in 1:1:1 ratio
• Treatment for 14-28 days for up to 8 weeks
Pappas PG et al. Clinical Infectious Diseases 007; 45:883–93.
Micafungin vs. Caspofungin in the Treatment of Candidemia
and Invasive Candidiasis

19. Micafungin vs. Caspofungin in the Treatment of Candidemia
and Invasive Candidiasis
Efficacy outcome with Micafungin
Pappas PG et al. Clinical Infectious Diseases 007; 45:883–93.

20. Modified intent-to-treat population (MITT; n=595); micafungin 100 mg (n=191); micafungin 150 mg (n= 199);
caspofungin 70/50 mg (n=188)
Treatment success in modified intent-to-treat population
Micafungin vs. Caspofungin in the Treatment of Candidemia
and Invasive Candidiasis

21. Overall Clinical Success Rate
Micafungin vs. Caspofungin in the Treatment of Candidemia
and Invasive Candidiasis
Pappas PG et al. Clinical Infectious Diseases 2007; 45:883–93.

22. Key Points
Micafungin 100 mg and 150 mg non-inferior to standard
dosage of caspofungin in the treatment of candidemia and
invasive candidiasis

23. 537 patients enrolled and randomized
Micafungin group
264 patients received at least one
dose (intention-to-treat
population)
264 patients in intention-to-treat
population at follow-up
Liposomal amphotericin B group
267 patients received at least one dose
(intention-to-treat population)
267 patients in intention-to-treat
population at follow-up
Treatment allocation
and analysis sets
Follow-up, intention-
to-treat group
Study Design
Kuse ER et al. Lancet 2007; 369: 1519–27
Micafungin vs. Liposomal Amphotericin B in Candidemia and
Invasive Candidosis

24. Overall Clinical Success Rate
Kuse ER et al. Lancet 2007; 369: 1519–27
Inclusion Criteria
• Adults with clinical signs of systemic candida infection
• Positive candida cultures from blood or another sterile site
Treatment protocol
• Micafungin: 100 mg
• Liposomal amphotericin B: 3 mg per kg bodyweight
• Primary endpoint: overall treatment success
• Minimum duration of therapy: 14 days
• Maximum treatment period: 4 weeks
Micafungin vs. Liposomal Amphotericin B in Candidemia and
Invasive Candidosis

25. Treatment success in the intention-to-treat population
Kuse ER et al. Lancet 2007; 369: 1519–27
Treatment success with micafungin: 89.6%
Treatment success with liposomal amphotericin B: 89.5%
Micafungin vs. Liposomal Amphotericin B in Candidemia and
Invasive Candidosis

26. Adverse events in the intention-to-treat population
Micafungin vs. Liposomal Amphotericin B in Candidemia and
Invasive Candidosis
Kuse ER et al. Lancet 2007; 369: 1519–27
Micafungin associated with fewer treatment-related adverse events and serious adverse effects
leading to treatment discontinuation when compared with the liposomal amphotericin B.

27. Kuse ER et al. Lancet 2007; 369: 1519–27
Key Points
Micafungin non-inferior to liposomal amphotericin B
as first-line treatment of candidemia and invasive
candidosis
Better safety profile than liposomal amphotericin B

28. Micafungin versus caspofungin and liposomal amphotericin B
against non-albicans Candida (NAC) spp.
Study Design
• Post hoc analysis of two randomized phase III trials
• micafungin vs. caspofungin
• micafungin vs. liposomal amphotericin B
Treatment Protocol
• Micafungin 100 mg day 1 vs. LAMB 3 mg kg
• Micafungin 100 mg day 1 or 150 mg day 1 vs. caspofungin 70 mg on day 1,
then 50 mg day 1
• Data pooled for patients receiving micafungin 100 mg day 1 in the two-arm
and three-arm trials.

29. Clinical response defined as complete or partial resolution of symptoms. Mycological response defined as eradication or presumed eradication.
Treatment Success Rates
• 66% with Micafungin 150 mg
• 78% with Caspofungin
• 67% with LAMB Cornely OA et al Mycoses. 2014;57(2):79-89.
Efficacy of Micafungin in C. tropicalis infections

30. Cornely OA et al Mycoses. 2014;57(2):79-89.
Efficacy of Micafungin in C. parapsilosis infections
Clinical response defined as complete or partial resolution of symptoms. Mycological response defined as eradication or presumed eradication.
Treatment Success Rates
• 70% with Micafungin 150 mg
• 67% with Caspofungin
• 64% with LAMB

31. Cornely OA et al Mycoses. 2014;57(2):79-89.
Efficacy of Micafungin in C. glabrata infections
Clinical response defined as complete or partial resolution of symptoms. Mycological response defined as eradication or presumed eradication.
Treatment Success Rates
• 90% with Micafungin 150 mg
• 75% with Caspofungin
• 64% with LAMB

32. Efficacy of Micafungin in Candida krusei infections
Cornely OA et al Mycoses. 2014;57(2):79-89.
Clinical response defined as complete or partial resolution of symptoms. Mycological response defined as eradication or presumed eradication.
Treatment Success Rates
• 63% with Micafungin 150 mg
• 67% with Caspofungin
• 44% with LAMB

33. Key Points
Micafungin efficacious in the treatment of common NAC
species; C. parapsilosis, C. tropicalis and C. glabrata
Micafungin exhibits favorable treatment success rates, and
survival rates in the treatment of NAC spp.

34. Prevalence of Invasive fungal infections
• Candida species remain relevant cause of IFIs
Place of Echinocandins in invasive fungal infections
• Fungicidal against yeast
• Limited toxicity & minimal drug-drug interactions
Place of Micafungin in invasive fungal infections
• Efficacy & safety supported by comparative, randomized clinical trials
• Recommended in many clinical practice guidelines
Conclusion

35. Micafungin is an effective and safe
therapy in invasive fungal infections,
supported by randomized clinical trials,
and recommended by various guidelines
Take-Home Message

36. Thank you