DR RITA OLADELE CLINICAL MYCOLOGIST

CMUL/LUTH

MANAGEMENT OF INVASIVE FUNGAL INFECTIONS IN THE NIGERIA SETTING

Direct microscopy

TRENDS IN FUNGAL DISEASES

• Increasing cases of invasive fungal infections• Poor diagnostic tools• Replacement of sensitive species by resistant ones

Invasive fungal infections• Candida Endogenous

(mostly)

• Aspergillus Exogenous• Cryptococcus• Zygomycetes• Rare filamentous species

•Histoplasmosis Reactivation•Blastomycosis•Coccidioidomycosis•Paracoccidioidomycosis

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%).

0%

2%

4%

6%

8%

10%

12%

14%

16%

Polyenes/no prophylaxisRat

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Proven Proven / suspected

Data from the control arms of RCTs on antifungal prophylaxis, n=3597

(Glasmacher et al., JCO 2003)

Incidence of invasive fungal infections in neutropenic patients with haematological malignancies

Inci

dence

in a

uto

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es

0%

5%

10%

15%

20%

25%

1978-82

1983-87

1988-92

Invasive mycoses:• 76% responsible for death

• 19% of patients with AIDS

Frankfurt (Germany), Groll et al. 1996 25% of patients with AML

Candida spp. 49%, Aspergillus spp. 51%

Mortality from invasive Aspergillus infections

0

10

20

30

40

50

60

70

80

90

100

Leuk./Lymph. alloSCT Kidney-Tx Lung/Heart-Tx Liver-Tx AIDS/HIV

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%

Mortality from invasive Candida infections

0

10

20

30

40

50

60

70

80

90

100

Surgery ICU Solid tumor Haem. Malig. HIV Premature birth Tort

oran

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Development of antifungals

mod. nach R. Lewis, ICAAC 2002

Amphotericin B

Abelcet Amphotec

liposomalesNystatin

Ketoconazol

Fluconazol

Voriconazol

PosaconazolRavuconazol

AmBisome

5-Flucytosin

Itraconazol

Micafungin

Caspofungin

Nystatin

PyrimidinanalogaPolyene Azole Echinocandine

Anidulafungin

Amphotericin B

Abelcet Amphotec

liposomalesNystatin

Ketoconazol

Fluconazol

PosaconazolRavuconazol

AmBisome

5-Flucytosin

Micafungin

Nystatin

PyrimidinanalogaPolyenes Azoles Echinocandins

Anidulafungin

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The (small) world of antifungals

Membrane function:Amphotericin B

Cellwall synthesis:Echinocandins

Ergosterol synthesis:Azoles

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.

Presentation overview

Risk stratification Antifungal prophylaxis Empirical antifungal therapy Therapy of proven invasive

mycoses

Copyright ©2009 Ferrata Storti Foundation

Cornely, O. A. et al. Haematologica 2009;94:113-122

Table 1. Infectious Diseases Society of America, United States Public Health Service Grading System for ranking recommendations

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%).

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

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).

Risk groups for invasive fungal infections in cancer patients

Low riskAutologous bone marrow /stem cell transplant (SCT)Childhood ALL (except for P. jirovecii)Lymphoma

Intermediate– low – risk

Moderate neutropenia 0.1-0.5 G/l < 3 weeksLymphocytes < 0.5 G/l + antibioticsOlder age Central venous catheter

Intermediate– high – risk

Colonized > 1 site OR heavy at one siteNeutropenia < 0.5 to > 0.1 G/l >3 to <5 weeksAML TBI Allogeneic matched sibling donor SCT

High risk

Neutrophils <0.1 G/l > 3 weeks OR <0.5 G/l > 5 weeksColonized by Candida tropicalis Unrelated or mismatched donor SCT GVHDCorticosteroids: > 1mg/kg & neutroph. < 1 G/l >1 week Corticosteroids: > 2mg/kg > 2 weeksHigh-dose cytarabine Fludarabine?

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Why do we need empiricalantifungal 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

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

Predicting who will become infected……...

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.

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

Definition of proven infectionsEORTC/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 factorsE.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).

Treatment indication according to risk groups for invasive fungal infections

Low riskNo primary antifungal prophylaxisEmpirical antimycotic therapy rarely necessaryTreat proven / probable infections

Intermediate– low – risk

No primary antifungal prophylaxis (in most circumstances)Empirical antimycotic therapy usually indicated

Intermediate– high – risk

Antifungal prophylaxis recommendedEmpirical antimycotic therapy recommended

High risk

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

Bob Dylan hospitalized with chest infectionMay 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.

ASPERGILLOSIS AT AUTOPSY - RISK GROUPS Vogeser et al Eur J Clin Microbiol Infect Dis 1999;18; 42-45

aspergillosis1187 autopsies 1993 - 199648 (4%) aspergillosis

Hematologic malignancy

Hematopoietic stem cell transplant

Solid organ transplant

Solid tumor

Steroids unknown

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

Community-acquired pneumonia

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

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

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

• Persistently febrile (40 oC)• bloodcultures 14 Sept:

Candida• more bloodcultures 15 Sept: C. albicans• liver function improved• abnormalities chest X -ray

better• respiratory failure improved

16 September

Fluconazole

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 lavageE. faecalis 4+A. fumigatus +HSV +

23/9Neurological signs & symptoms

CT cerebrum: multiple abscesses24/9

Biopsy…………….A. fumigatus

R/ AmB Amoxicillin Aciclovir

23/9HIV-No apparent host defence defects

29/9No improvement-interferon, donor granulocytes, steroids

30/9R/ Ambisome + rifampin

03/10Neurological and clinical deterioration

CT cerebrum: no improvement

07/10Died

Disseminated aspergillosis

Voriconazole Adult >40 kg Dosing Regimen• Intravenous formulation:– Loading dose (first 24 hours) = 6 mg/kg q12h.– Maintenance doses serious Candida = 3 mg/kgq12h. 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 mLbd Aspergillus, Scedosporium, Fusarium, other moulds. = 200mg or 5 mL bdPaediatric 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/kgq12h have been used) ? dosing intervals.• Oral formulation:– Maintenance doses = 200 mg bd• Adolescents

Treatment of adult patients withcandidemia or invasive candidiasisThursky et al. 2008. Internal Medicine Journal 38:496-520.(1) Unknown or yet to be identified Candida species, not haemodynamicallyunstable, not neutropenic, and no risk factors associated with azoleresistantCandida spp.(2) Candida species known (or likely) to be susceptibility for fluconazole.Fluconazole (A)Caspofungin (B) ORVoriconazole (B) ORLipid-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) ORLipid-AmB (C)Voriconazole (B) ORAmB-D (B)

Treatment of definite, probable andpossible invasive AspergillosisThursky et al. 2008. Internal Medicine Journal 38:496-520.(1) Invasive pulmonary aspergillosis(2) Infection with Aspergillus isolates known to be resistant to AmBVoriconazole IV 6 mg/kg bdfor 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)ORAmB-D 1.0-1.5 mg/kg/day (C).Caution with voriconazole if concomitant use of a cytochrome P450 inducers, vincaalkaloids, tacrolimus or significant hepatic dysfunction.Conventional AmB should be avoided in patients at risk of nephrotoxicity, or withpre-existing renal impairment.AmB resistant isolates include A. terreus, A. nidulans and A. ustus

Treatment of definite, probable andpossible invasive AspergillosisThursky et al. 2008. Internal Medicine Journal 38:496-520.CNS or disseminated diseaseVoriconazole IV 6 mg/kg bd for 24hours (loading dose) then 4 mg/kgIV bd or 200-300 mg po bd(maintenance (D)An intra-vitreal injection of AmB(10 μg) is recommended forendopthmalmitis.Liposomal AmB3 mg/kg/day (D)L-AmB is preferred due its ability to achieve higher concentrations in the blood andbrain than AmB and other lipid formulations.