fungal management

1. MANAGEMENT OF INVASIVE
FUNGAL INFECTIONS IN THE
NIGERIA SETTING
DR RITA OLADELE
CLINICAL MYCOLOGIST
CMUL/LUTH

2. Direct microscopy

3. TRENDS IN FUNGAL DISEASES
• Increasing cases of invasive
fungal infections
• Poor diagnostic tools
• Replacement of sensitive
species by resistant ones

4. Invasive fungal infections
• Candida Endogenous (mostly)
• Aspergillus Exogenous
• Cryptococcus
• Zygomycetes
• Rare filamentous species
•Histoplasmosis Reactivation
•Blastomycosis
•Coccidioidomycosis
•Paracoccidioidomycosis

5.  Chamilos et al (2006)
 reported autopsy-proven IFI in patients with
HM from a single institute during three
 separate four year periods, 1989-93, 1994-98
and 1999-2003. There was a declining
 rate of autopsies (67%-34%-26%) but IFI were
found in 314 of 1017 autopsies and
 most were not diagnosed in life (75%).

7. Incidence of invasive fungal infections in
neutropenic patients with haematological malignancies
25% Proven Proven / suspected
Rate of invasive fungal infections
16%
Incidence in autopsies
20% 14%
12%
15% 1978-82
10%
1983-87
8%
10% 1988-92
6%
5% 4%
2%
0% 0%
Invasive mycoses: Polyenes/no prophylaxis
• 76% responsible for death Data from the control arms of RCTs on
antifungal prophylaxis, n=3597 (Glasmacher et
•19% of patients with AIDS al., JCO 2003)
Frankfurt (Germany), Groll et al.
1996 25% of patients with AML Candida spp. 49%, Aspergillus spp. 51%

8. Mortality from invasive
Aspergillus infections
%
100
90
Lin et al., CID 2001; 32: 358
80
70
60
50
40
30
20
10
0
Leuk./Lymph. alloSCT Kidney-Tx Lung/Heart-Tx Liver-Tx AIDS/HIV

9. Mortality from invasive
Candida infections
%
100
Tortorano et al., EJCMID 2004; 23: 317
90
80
70
60
50
40
30
20
10
0
Surgery ICU Solid tumor Haem. Malig. HIV Premature birth

10. Development of antifungals
Polyenes
Polyene Pyrimidinanaloga Azoles
Azole Echinocandins
Echinocandine
Nystatin Amphotericin B 5-Flucytosin Ketoconazol
Fluconazol Itraconazol
AmBisome Abelcet
Abelcet Amphotec
Voriconazol Caspofungin
liposomales
Nystatin Anidulafungin
Ravuconazol Posaconazol
Posaconazol Micafungin
mod. nach R. Lewis, ICAAC 200

11. The (small) world of
antifungals
Membrane function: Cellwall synthesis:
Amphotericin B
Echinocandins
Ergosterol synthesis:
Azoles

12. Antifungal Activity
(█ > 75% sensible, █ 50%, █ < 5%; mixed colours: differing results;
modified after O'Brien et al., ASH Edu 2003)
Erreger AmB Fluco Itra Vori Caspo Flucyt.
C. albicans
C. parapsilosis
C. tropicalis
C. glabrata
C. krusei
A. fumigatus
A. flavus
A. terreus
Zygomycetes
Fusarium spp.

13. Presentation
overview
 Risk stratification
 Antifungal prophylaxis
 Empirical antifungal therapy
 Therapy of proven invasive mycoses

14. Table 1. Infectious Diseases Society of America, United States Public Health Service Grading System for ranking
recommendations
Cornely, O. A. et al. Haematologica 2009;94:113-122
Copyright ©2009 Ferrata Storti Foundation

15. Evidence based
 Chamilos et al (2006)
 reported autopsy-proven IFI in patients with
HM from a single institute during three
 separate four year periods, 1989-93, 1994-98
and 1999-2003. There was a declining
 rate of autopsies (67%-34%-26%) but IFI were
found in 314 of 1017 autopsies and
 most were not diagnosed in life (75%).

16. Evidence based
 fungal infection and the decrease of IFI attributable
mortality. In a longitudinal observation survival benefit
extended beyond the period of fluconazole treatment (75
days) and was accompanied by a lower incidence of
intestinal graft versus host disease.19
 Moreover, fluconazole has been reported to protect from
cyclophosphamide toxicityUpton A, McCune JS, Kirby
KA, Leisenring W, McDonald G, Batchelder A, et al.
 Fluconazole coadministration concurrent with
cyclophosphamide conditioning may reduce regimen-
related toxicity postmyeloablative hematopoietic cell
transplantation. Biol Blood Marrow Transplant
2007;13:760-4

17. Evidences still
 The clinical relevance of the development of resistance
during fluconazole prophylaxis is still a matter of debate,
 while a general shift towards higher rates of strains
exhibiting primary resistance have been clearly shown in
the intensive care setting.
 favorable safety profile and patient compliance rate of
fluconazole resulted in discontinuation rates of less than
8%. There is good evidence (Level A I) that primary
prophylaxis with fluconazole 400 mg/d reduces the
incidence of invasive candidiasis and the mortality rate
after allogeneic hematopoietic stem cell transplant.
 For patients with acute leukemia prophylaxis with
fluconazole 400 mg/d cannot be recommended with similar
strength (Level C I). Doses less than 400 mg/d have not
been effective in well designed trials (Level E I).

19. Risk groups for invasive fungal
infections in cancer patients
rentice HG, Kibbler CC, Prentice AG, BJH 2000; 110: 273
Autologous bone marrow /stem cell transplant (SCT)
Low risk Childhood ALL (except for P. jirovecii)
Lymphoma
Moderate neutropenia 0.1-0.5 G/l < 3 weeks
Intermediate
Lymphocytes < 0.5 G/l + antibiotics
– low – risk
Older age  Central venous catheter
Colonized > 1 site OR heavy at one site
Intermediate
Neutropenia < 0.5 to > 0.1 G/l >3 to <5 weeks
– high – risk
AML  TBI  Allogeneic matched sibling donor SCT
Neutrophils <0.1 G/l > 3 weeks OR <0.5 G/l > 5 weeks
Colonized by Candida tropicalis
Unrelated or mismatched donor SCT  GVHD
High risk
Corticosteroids: > 1mg/kg & neutroph. < 1 G/l >1 week
Corticosteroids: > 2mg/kg > 2 weeks
High-dose cytarabine  Fludarabine?

20. Why do we need empirical
antifungal therapy?
 High incidence and fatality rates for invasive
fungal infections
 Insufficient diagnostics
 Culture-based methods
 Helpful only with Candida, but even then 10% false
negative
 Almost never diagnostic for invasive Aspergillus
infections
 Non-culture based methods (GM, PCR)
 Still high false negative rate
 Many invasive fungal infections are diagnosed
too late or only at autopsy
 Late treatment greatly reduces success rates

21. The options available
 Four classes of drugs for the treatment of
invasive fungal infections exist: polyenes,
triazoles,echinocandins and nucleoside
analogues.
 Conventional amphotericin B (CAB), liposomal
amphotericin B, amphotericin B lipid complex
(ABLC),B colloidal dispersion (ABCD)
 , fluconazole, itraconazole, voriconazole,
posaconazole,
 caspofungin , anidofulgins
 flucytosine

22. Predicting who will
become
infected……...

23. Evidences
 Fluconazole has activity against many yeasts but limited activity against
moulds.19 Reduced
 susceptibility to fluconazole is also seen with C. krusei and C. glabrata. C.
tropicalis has been
 reported to have reduced susceptibility to fluconazole in international
studies but this is rarely
 seen in Australia. Itraconazole has anti-Aspergillus activity and variable
activity against other
 moulds. Voriconazole has activity against most yeasts and moulds;
zygomycetes and
 Scedosporium prolificans are important exceptions. Zygomycetes are
susceptible to
 posaconazole. S. prolificans is resistant in vitro to all available
Caspofungin has poor activity
 against Cryptococcus neoformans, Scedosporium species, Fusarium
species and zygomycetes.antifungal drugs.

24. Development of empirical
antimycotic therapy
 Period I (1982-1988)
 Conventional amphotericin B vs. no therapy / placebo
 Pizzo et al. 1982, EORTC 1988
 Significant reduction of breakthrough infections if both studies combined
 Period II (1993-1998)
 Conventional amphotericin B vs. fluconazole or liposomal AmB
 Defervescence as main outcome, mostly no statistically signif. differences
 Only one study (Prentice 1997) with a significant difference
 Period III (1998-2001)
 Introduction of the composite outcome score (Walsh et al., COS)
 Conventional AmB vs. liposomal AmB, fluconazole, itraconazole, ABCD
 No significant differences
 Period IV (2000-today)
 Continued use of the composite outcome score (COS)
 Liposomal AmB vs. ABLC, voriconazole, caspofungin

25. Definition of proven
infections
EORTC/MSG criteria:
 Proven: Culture / histology from a normally sterile body site
 Probable: Requires host, clinical AND microbiological factors
E.g.: Neutropenic patient with a typical lesion in HR-CT AND two
positive galactomannan antigen results
 Possible: Requires host, clinical OR microbiological factors
E.g.: Same patient without two positive GM antigen results
These criteria are made for clinical trials and should not be used
for clinical decision making
 Of 22 patients with IPA at autopsy only 2 were classified as
proven, 6 as probable, 13 as possible. 64% had no
microbiological or major clinical criteria before death (Subira et
al., AH 2003).

26. Treatment indication according to
risk groups for invasive fungal
infections
No primary antifungal prophylaxis
Low risk Empirical antimycotic therapy rarely necessary
Treat proven / probable infections
Intermediate No primary antifungal prophylaxis (in most circumstances)
– low – risk Empirical antimycotic therapy usually indicated
Intermediate
– high – risk
Antifungal prophylaxis recommended
Empirical antimycotic therapy recommended
High risk

27. Prophylaxis
 Patients receiving chemotherapy for acute
leukaemia may have the
 same risk of IFI as allogeneic
haematopoietic stem cell transplant
 patients.
 Prophylaxis of IFI should be confined to
high risk patients
 The two most common organisms in all
studies are Candida and Aspergillus spp

28. Bob Dylan hospitalized with chest infection
May 28, 1997 Web posted at: 10:07 p.m. EDT
NEW YORK (CNN) -- Singer Bob Dylan has been hospitalized with a
"potentially fatal" chest infection, according to a statement from his
record label.
The rock/folk legend, who turned 56 on Saturday, was admitted
over the weekend with severe chest pains, the Columbia Records
statement said Wednesday.
He was diagnosed with histoplasmosis, which causes swelling of the
sac that surrounds the heart, the statement said. Columbia did not
say where he contracted it or whether the disease was associated
with an underlying disorder such as HIV positivity.

29. ASPERGILLOSIS AT AUTOPSY - RISK GROUPS
Vogeser et al Eur J Clin Microbiol Infect Dis 1999;18; 42-45
1187 autopsies 1993 - 1996
aspergillosis 48 (4%) aspergillosis
Steroids unknown Hematologic
malignancy
Solid tumor
Hematopoietic stem
cell transplant
Solid organ
transplant

31. The final advice that I can give ya,
Whether your name is Lester or Lydia,
Or whether you live in L.A. or Moskovia,
Try to watch out for all those fungal conidia.
Adapted from:Barranco C.P. J Med Vet Mycol, 1994, 32, 477-479

32. Community-acquired pneumonia

33. Male, 45 year-old farmer, no relevant history
Since 1 month “malaise”
Admission to another hospital with pneumonia
Transfer due to respiratory insufficiency
High fever, CRP 307, LC 1.8
Chest X-ray: bilateral infiltrates

34. 11 September
• Laboratory: ASAT 852, ALAT 514,
creatinin 394, WBC 8.5 (left shift)
• gram negative rods (E. coli) in
bloodcultures and bronchial secretions
• Rx/ ciprofloxacin

35. 11 September
• Laboratory: ASAT 852, ALAT 514,
creatinin 394, WBC 8.5 (left shift)
• gram negative rods (E. coli) in
bloodcultures and bronchial secretions
• Rx/ ciprofloxacin

36. 16 September
• Persistently febrile (40 oC)
• bloodcultures 14 Sept: Candida
• more bloodcultures 15 Sept:
C. albicans Fluconazole
• liver function improved
• abnormalities chest X -ray better
• respiratory failure improved

37. 22 September
• Persistent febrile;fundoscopy normal
• CRP 163, WBC 15.2: 86% neutrophils
• No more clinical or radiological
improvement (Cipro d. 11;Fluco d. 6)
Bronchoalveolar lavage
E. faecalis 4+
A. fumigatus +
HSV +

38. 23/9
Neurological signs & symptoms
CT cerebrum: multiple abscesses
24/9
Biopsy…………….A. fumigatus
R/ AmB
Amoxicillin
Aciclovir

39. 23/9
HIV-
No apparent host defence defects
29/9
No improvement
-interferon, donor granulocytes, steroids
30/9
R/ Ambisome + rifampin

40. 03/10
Neurological and clinical deterioration
CT cerebrum: no improvement
07/10
Died
Disseminated aspergillosis

41. Voriconazole Adult >40 kg Dosing Regimen
• Intravenous formulation:
– Loading dose (first 24 hours) = 6 mg/kg q12h.
– Maintenance doses serious Candida = 3 mg/kg
q12h. Aspergillus, Scedosporium, Fusarium, other moulds
= 4 mg/kg q12h
• Oral formulation:
– Loading dose (first 24 hours) = 400 mg or 10 mL q12h
– Maintenance doses. serious Candida = 200 mg or 5 mL
bd Aspergillus, Scedosporium, Fusarium, other moulds. = 200
mg or 5 mL bd
Paediatric dosing 2 to <12 years (EU)
• No oral or IV loading dose recommended
• Intravenous formulation:
– Maintenance doses 7 mg/kg q12h (up to 12 mg/kg
q12h have been used) ? dosing intervals.
• Oral formulation:
– Maintenance doses = 200 mg bd
• Adolescents

42. Treatment of adult patients with
candidemia or invasive candidiasis
Thursky et al. 2008. Internal Medicine Journal 38:496-520.
(1) Unknown or yet to be identified Candida species, not haemodynamically
unstable, not neutropenic, and no risk factors associated with azoleresistant
Candida spp.
(2) Candida species known (or likely) to be susceptibility for fluconazole.
Fluconazole (A)
Caspofungin (B) OR
Voriconazole (B) OR
Lipid-AmB B (C) OR AmB-D (A).
(1) Unknown or yet to be identified Candida species, haemodynamically unstable,
neutropenic, or risk factors associated with azole-resistant Candida spp.
(2) Candida species known (or likely) to be resistant to fluconazole.
Caspofungin (B) OR
Lipid-AmB (C)
Voriconazole (B) OR
AmB-D (B)

43. Treatment of definite, probable and
possible invasive Aspergillosis
Thursky et al. 2008. Internal Medicine Journal 38:496-520.
(1) Invasive pulmonary aspergillosis
(2) Infection with Aspergillus isolates known to be resistant to AmB
Voriconazole IV 6 mg/kg bd
for 24 hours (loading dose)
then 4 mg/kg IV bd or 200-
300 mg po bd (maintenance)
(B)
Liposomal AmB 3 mg/kg/day (B)
OR
AmB-D 1.0-1.5 mg/kg/day (C).
Caution with voriconazole if concomitant use of a cytochrome P450 inducers, vinca
alkaloids, tacrolimus or significant hepatic dysfunction.
Conventional AmB should be avoided in patients at risk of nephrotoxicity, or with
pre-existing renal impairment.
AmB resistant isolates include A. terreus, A. nidulans and A. ustus

44. Treatment of definite, probable and
possible invasive Aspergillosis
Thursky et al. 2008. Internal Medicine Journal 38:496-520.
CNS or disseminated disease
Voriconazole IV 6 mg/kg bd for 24
hours (loading dose) then 4 mg/kg
IV bd or 200-300 mg po bd
(maintenance (D)
An intra-vitreal injection of AmB
(10 μg) is recommended for
endopthmalmitis.
Liposomal AmB
3 mg/kg/day (D)
L-AmB is preferred due its ability to achieve higher concentrations in the blood and
brain than AmB and other lipid formulations.