New Paradigm in Invasife

Fungal Infections
Budi Enoch SpPD
RSUD dr Abdul Aziz
 Introduction

Fungal infections have become

increasingly more frequent

Immunocompromised patients
organ
AIDS
transplantation

Increased use of invasive instruments

urinary catheters
 Fungal Infections
Terminology and Microbiology
 Traditionally, fungal infections have been classified into specific
categories based on both anatomic location and epidemiology.
 The most common general anatomic categories are
mucocutaneous and deep organ infection; the most common
general epidemiologic categories are endemic and opportunistic.
 Although mucocutaneous infections can cause serious morbidity,
they are rarely fatal.
 Deep organ infections also cause severe illness in many cases and,
in contrast to mucocutaneous infections, are often fatal.
 The endemic mycoses (e.g., coccidioidomycosis) are infections
caused by fungal organisms that are not part of the normal human
microbial flora and are acquired from environmental sources.
 In contrast, opportunistic mycoses are caused by organisms (e.g.,
Candida and Aspergillus) that commonly are components of the
normal human flora and whose ubiquity in nature renders them
easily acquired by the immunocompromised host
 Three other terms frequently used in clinical discussions of fungal
infections are yeast, mold, and dimorphic fungus.
 Yeasts are seen as rounded single cells or as budding organisms.
Candida and Cryptococcus are traditionally classified as yeasts.
 Molds grow as filamentous forms called hyphae both at room
temperature and in invaded tissue. Aspergillus, Rhizopus [the
species that causes mucormycosis (zygomycosis)], and fungi
commonly infecting the skin to cause ringworm and related
cutaneous conditions are classified as molds. Variations occur
within this classification of yeasts and molds. For instance, when
Candida infects tissue, both yeasts and filamentous forms may
occur (except with C. glabrata, which forms only yeasts in tissue);
in contrast, Cryptococcus exists only in yeast form.
 Dimorphic is the term used to describe fungi that grow as yeasts or
large spherical structures in tissue but as filamentous forms at
room temperature in the environment. Classified in this group are
the organisms causing blastomycosis, paracoccidioidomycosis,
coccidioidomycosis, histoplasmosis, and sporotrichosis
 EPIDEMIOLOGY

• The incidence of fungi infection has increased dramatically over 20 year-period

by 207%

• Candida species are the most common cause of infection in patients icu,
accounting for 85% of all documented mycosis :
 C. albicans is responsible for approximately 45- 58%
 C. non albicans ( C. krusei and C. glabrata ) has emerged and
increase to about 44%

• Fungi are the fourth leading pathogen in nosocomial infections in the USA
 Diagnosis
 The definitive diagnosis of any fungal infection
requires histopathologic identification of the
fungus invading tissue, accompanied by evidence
of an inflammatory response.
 The identification of an inflammatory response
has been especially important with regard to
Aspergillus infection. Aspergillus is ubiquitous and
can float from the air onto biopsy material.
 Therefore, in rare but important instances, this
fungus is an ex vivo contaminant during
processing of a specimen for microscopy, with a
consequent incorrect diagnosis.
 The stains most commonly used to identify fungi
are periodic acid–Schiff and Gomori
methenamine silver
 Increases in the prevalence of
systemic Candida infections
3.5
(episodes/10,000 patient-days/year)

3.0
Incidence of candidaemia

2.5

2.0

1.5

1.0

0.5 Europe
EuropeData
Data

0
1999 2000 2001 2002 2003

Year Bassetti M, et al. BMC Infect Dis 2006; 6:21

Invasive Fungal Disease

*Includes Pseudallescheria boydii and other non-specified species

Menzin J et al. Am J Health-Syst Pharm 2009;66:1711-1717

Presented at ESICM
Congress 2010, 12 Okt
Risk Factors for Invasive Candidiasis

 Host Factors  Medical

◦ Age extremes
◦ Neutropaenia
◦ Renal Failure
◦ Trauma/burns
◦ Bowel perforation
◦ Candida colonisation
Interventions
◦ Chemotherapy
◦ Dialysis
◦ Central venous catheter
◦ Nasogastric tube
◦ Prior antibiotic use
◦ Prior surgery; especially
GIT
◦ Parenteral nutrition
◦ ICU stay > 7 days

Smith D et al. Crit Care Med 2010;38:S380-387

Different step of treatment strategies of IFI
 Relationship between hospital mortality and the
timing of antifungal treatment

35
Hospital mortality (%)

30
25
20
15
10
5
0
< 12 12–24 24–48 > 48

Delay in start of antifungal treatment (hours)

Morrell M, et al. Antimicrob Agents Chemother 2005; 49:3640–5 13

 Increased hospital costs associated
with candidemia

Category Cost ($) % of total cost

Total 44,536 100

Length of hospital stay 37,681 84.6

Antifungal therapy 4,710 10.5

Diagnostic procedures 1,513 3.4

Adverse drug reactions 610 1.4

Clin. Infect. Dis. 1998;27:781-788.

Treatment Fungal Infections
 Since fungal organisms are eukaryotic
cells that contain most of the same
organelles (with many of the same
physiologic functions) as human cells, the
identification of drugs that selectively kill
or inhibit fungi but are not toxic to human
cells has been highly problematic.
 Far fewer antifungal than antibacterial
agents have been introduced into clinical
medicine.
 Selection of Appropriate Antifungal Agents

 The appropriate antifungal injection must have

the following factors, such as:
 Good tolerability

 Reliable efficacy

 Limited drug interaction

 Simple drug administration

 Cost effectiveness

16
 Therapeutic Options
Ampho B Deoxycholate
Liposomal Ampho B (Ambisome)
Polyenes
Polyenes Ampho B Colloidal Dispersion (ABCD)
Ampho B Lipid Complex (ABLC)

Azoles Itraconazole, Fluconazole, Voriconazole

Azoles
Posaconazole, Ravuconazole

Echinocandins Caspofungin, Micafungin, Anidulafungin

Antimetabolite Flucytosine

17
 Fungal Cell Wall Targets
Fungal cell Cell membrane and cell wall

Mannoproteins

b-(1,6)-glucan
b-(1,3)-glucan

Chitin

Phospholipid bilayer
POLYENES ECHINOCANDINS
of cell membrane

b-(1,3)-glucan synthase
Ergosterol

Ergosterol
Ergosterol
Synthesis
Synthesis DNA/RNA Synthesis
AZOLES
Pathway
Pathway
FLUCYTOSINE
Squalene

18
 The echinocandins are a
new class of antifungal
agents.
 Noncompetitive inhibitors
of the synthesis of beta-
1,3-glucan, which is an
essential constituent of
the candida cell wall.
 Inhibition of the synthesis
of beta-1,3-glucan
disrupts the structure of
the growing cell wall,
resulting in osmotic
instability and the death
of susceptible yeast cells.
 Summary of Profile Anti Fungal
Drug
Interaction Major
Antifungal Inhibition of
Spectrum Mechanism of Action & Adverse Adjustment Dosage
Injection CYP-450
Contraindic Event
ation
-Inh. synthesis 1,3-b-D-
Micafungin Candida Spp glucan. Headache/Fever no need to mild-severe renal impairement
Aspergillus Spp - Disruption fungal cell wall. No + Nausea No need to mild-moderate hepatic impairement
Candida Spp -Inh. synthesis ergosterol. Visual DisturbanceShould be avoid (CCl<50ml/min)
Voriconazole
Aspergillus Spp, poor - Disruption fungal cell for hepatic impairement Standard loading dose
against Zygomycetes membrane. Yes +++ GI Symptom followed by half of maintenance dose

Candida Spp (Candida

glabrata associated with
variable resistance,
-Inh. synthesis ergosterol. Headache, Abnormal liver function should be closely
Candida krusei is always
Fluconazole nausea, monitored, adjustment 50% for moderate renal
resistance), Inactive
abdominal pain impairement
against molds
(Zygomycetes, Aspergillus)
- Disruption fungal cell
dimorphic fungi membrane. Yes ++
Candida, Aspergillus, -Binds to ergosterol
Amfotericin-B Zygomycetes, Criptococcus -Increase membrane Nephrotoxic Renal and Hepatic should be closely monitored
and dimorphic fungi) permeablility. Yes +++

20
20
 Dosis Mycamine
INDIKASI DOSIS
Pediatrik* Dewasa Dewasa
<16 tahun dan dan
(termasuk elderly
neonatus)** elderly ≤ 40 > 40 kg
kg
Profilaksis infeksi jamur 1 mg/kg BB/hari 1 mg/kg 50 mg
candida pada pasien BB/hari
Transplantasi sumsum tulang

Terapi candidemia, acute 2 mg/kg BB/ hari 2 mg/kg BB/ 100 mg

disseminated candidiasis, hari
candidiasis peritonitis dan
abscesses

Esophageal Candidiasis - 3 mg/kg BB/ 150 mg

hari
Keterangan :
* Dosis Mycamine untuk pediatrik > 40 kg menggunakan dosis dewasa > 40 kg
** Dosis CNS candidiasis pada neonatus dapat ditingkatkan menjadi 4 mg/ kg BB/hari
** Pada bayi dengan berat badan < 15 kg penggunaan pelarut infus tidak perlu 100 ml , cukup 2 ml/kg BB
Cara Pemberian Mycamine :
1. Ambil 5 ml NaCl fisiologis (atau glukosa/dekstrosa 5%) dari kantung infus 100 ml untuk melarutkan 1
dry vial Mycamine 50 mg. Jangan dikocok untuk mencegah busa
2. Masukkan sejumlah volume tertentu (sesuai indikasi dan dosisnya) dari Mycamine yang sudah
dilarutkan ke dalam sisa volume dari kantung infus tadi. Infus drip sekali sehari selama 1 jam
 Clinical Efficacy Against IC
Drug Response Author
%
Caspofungin 73.4
Mora-Duarte et al
Ampho B deoxycholate 61.7
Micafungin 89.6
Liposomal Ampho B 89.5 Ruhnke et al
Anidulafungin 75.6
Reboli et al
Fluconazole 60.2
Voriconazole 65
Ampho B 71 Kullberg et al
deoxycholate/fluconazole
Fluconazole 70
Rex et al
Ampho B deoxycholate 79
22
 Guidelines selected to specific
group
 Definite treatment
1. Non neutropenic patients
2. Neutropenic patients
 Empirical treatment

1. Non neutropenic patient

2. Neutropenic patient
 Guidelines for the treatment of
invasive candidiasis: IDSA
Condition or Therapy
treatment group
Primary Alternative
Recommendation Rank* Recommendation Rank*

Non-neutropenic patients
Candidaemia Fluconazole or an A-I Lipid formulation of AmB A-I
(targeted therapy) echinocandin† (LFAmB) or AmB-d or
voriconazole
Suspected candidiasis As for candidaemia; B-III LFAmB or AmB-d B-III
(empirical therapy) echinocandin or
fluconazole preferred†
Neutropenic patients
Candidaemia Echinocandin or LFAmB A-II Fluconazole‡ or B-III
(targeted therapy) voriconazole
Suspected candidiasis LFAmB or caspofungin A-I Fluconazole¶ or B-I
(empirical therapy§) or voriconazole (B-I for itraconazole ¶

voriconazole)
*See following slide for definitions. An echinocandin is favoured for moderately severe to severe illness and in patients with recent azole exposure, and
†

as initial therapy in patients with or suspected to have C. glabrata infection; fluconazole is preferred as initial therapy in patients with or suspected to
have C. parapsilosis infection, if no prior azole exposure. ‡Fluconazole should be reserved for patients without prior azole exposure who are not
critically ill. §Empirical therapy should be initiated following ≥ 4 days’ fever despite antibiotics. ¶Azoles should not be used for empirical therapy in
patients who have received an azole for prophylaxis.

Pappas PG, et al. Clin Infect Dis 2009; 48:503–35

 Empirical Therapy of Invasive Candidiasis or Candidemia

Fluconazole
Loading dose NO
800 mg/ day iv
then 400 mg/day iv - Hemodynamically unstable
Including : - Septic / Neutropenia
- No risk of infection C.glabrata - Recent Azole exposure
**
- No risk of concomitant
Endocardial YES
and CNS Candidiasis #
MYCAMINE
100 mg/day IV

Note : ** Risk of C.glabrata infection: elderly, cancer and diabetes

patients ; # Echinocandin
(endocardial candidiasis), L- Amphotericin B (endocardial and CNS
candidiasis)

Adapted from Pappas et al. Treatment Guidelines for Candidiasis.CID

2009
 Treatment of Invasive Candidal Infections: Systematic
Review and Meta-analysis
Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD
Mayo Clin Proc 2008; 83(9): 1011-1021

 Fluconazole not recommeded as single empirical drug for

patients with severe infections
 Comparable efficacy for caspofungin and micafungin vs
amphotericin B formulations
 Echinocandins have comparable safety profile to
azoles/polyenes
 Echinocandins may be considered first-line treatment for
empirical treatment of candidemia
 Liposomal amphotericin B equally good alternative if organ
function permits
 Treatment-related adverse events with a significantly
lower incidence* for micafungin compared with L-AmB

Micafungin (n = 316)
30
L-AmB (n = 321)
Patients (%)

20

10

a ia rs t
emi e x g o s ed v en
ala P yr Ri rea d e
k c e
po e in e lat
Hy inin on- r
t i
ea us
Cr In f

*p < 0.05,
Cornely OA, et al. 47th ICAAC. Chicago, IL, USA, 17–20 Sep 2007; Poster M-1175; Fisher’s exact
Kuse ER, et al. Lancet 2007; 369:1519–27 test
 Topical Antifungal Agents
 Many classes of compounds have been used to treat the
common fungal infections of the skin.
 Among the azoles used are clotrimazole, econazole,
miconazole, oxiconazole, sulconazole, ketoconazole,
tioconazole, butoconazole, and terconazole.
 In general, topical treatment of vaginal candidiasis has been
successful. Since there is considered to be little difference in
the efficacy of the various vaginal preparations, the choice of
agent is made by the physician and/or the patient on the basis
of preference and availability.
 Fluconazole given orally at 150 mg has the advantage of not
requiring repeated intravaginal application.
 Nystatin is a polyene that has been used for both
oropharyngeal thrush and vaginal candidiasis.
 Useful agents in other classes include ciclopirox olamine,
haloprogin, terbinafine, naftifine, tolnaftate, and undecylenic
acid.
Thank You