Systemic Fungal Infection:

Candidiasis

Rudi Wisaksana
Internal Medicine Department
Hasan Sadikin Hospital
Bandung
 Fungal problems
▪ The incidence of fungal infections is
increasing
▪ The spectrum of fungal disease is changing
▪ Selection of fungi is a reality
▪ Resistance of fungi is on the rise
▪ Cross resistance is increasingly recognized
INCREASE IN FUNGAL INFECTIONS

• Better diagnosis
• More broadspectrum antibiotics
• Higher age of patient population
• More complex interventions
(e.g.transplants)
• More intensive cytotoxic therapy
• More immunosuppressive therapy
• Less mortality from other causes
• More high risk patients
 SYSTEMIC FUNGAL INFECTIONS
AND GROUPS AT RISK
▪ Prolonged deep neutropenia (>7 days;<500/mm )
3

▪Stem Cell Transplants (allo>>>auto)

▪ Solid Organ Transplants
▪ AIDS patients
▪High Risk Environment
▪ Prolonged antibiotic and/or corticosteroid use
 Terminology
■ Anatomic
■ Mucocutaneus: Serious morbidity, rarely fatal
■ Deep organ infection: Severe illness, fatal

■ Epidemiologic
■ Endemic: Environmental sources
■ Opportunistic: Normal human microbial flora
 Signs and symptoms
■ No specific signs
■ Resemble bacterial infections:
■ Septic shock
■ Severe sepsis
■ Multi organ failure
■ Signs appear early but diagnosis is late

Depends on the organ infected

 Diagnosis

■ Proven: the finding of fungal element in biopsy

materials or isolation of the fungus from sterile site
(blood, spinal fluid, etc)
■ Probable: symptoms of systemic infections, risk
factors and isolation of the fungus from un-sterile
site
■ Possible: no fungus isolated, only symptoms of
systemic infection/sepsis and risk factors
Proven Diagnosis
 Probable

Possible
 Etiology of deep fungal infection
Anatomic Epidemiologic

Histoplasmosis Deep organ Endemic

Coccidiomycosis Mucocutaneus, Deep Endemic
infection
Blastomycosis Deep infection Endemic
Cryptococcosis Deep infection Endemic
Candidiasis Mucocutaneus, Deep Opportunistic
infection
Aspergilosis Deep Infection Opportunistic
Mucormycosis Deep infection Endemic
Pneumocystis Deep infection Endemic
 Invasive candidosis
■ Mostly caused by C. albicans,
■ shift toward non albicans species:
■ C. tropicalis
■ C prapsillosis
■ C. krusei, etc.

■ The species that causes infection is

different from country to country, from
hospital to hospital even from ward to ward.
 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 Data

0
1999 2000 2001 2002 2003

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

 Distribution of principal Candida species in Europe

C. glabrata is now the second most commonly isolated Candida species in

Europe C. albicans
C. glabrata
C. parapsilosis
C. tropicalis
C. krusei
C. guilliermondii
C. lusitaniae
C. kefyr
Other species
Unidentified Candida sp.
> 1 Candida spp.
Tortorano AM, et al. Eur J Clin Microbiol Infect Dis 2004; 23:317–22
 Relationship between hospital mortality and the
timing of appropriate 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)

■ Initiation of therapy > 12 h after the first positive blood sample was
associated with a greater risk of mortality than appropriate therapy given
within 12 h
Morrell M, et al. Antimicrob Agents Chemother 2005; 49:3640–5
 47th Annual ICAAC* 2007

▪ 5,715 patients with presumed septic shock in ICUs of 22 hospitals

▪ Candida were determined to be responsible in 7.8% cases (n = 443),
▪ Septic shock was more likely fungal than a bacterial with catheter-
associated infections, systemic disseminated infections, leukemia and
lymphoma, organ transplant, or metastatic cancer.
▪ Systemic fungal infections, which often lead to septic shock, are
associated with mortality rates much higher than bacterial infections.
▪ Onset of hypotension in patients with likely/confirmed infections should
be a signal that septic shock was underway and that antimicrobial
therapy should be started right away.
 Importance of Candida infection in hospital

▪ Candidemia is the fourth leading cause of

nosocomial bloodstream infections after
coagulase-negative staphylococci,
Staphylococcus aureus, and Enterococcus
species

▪ Among Candida species, C. albicans

remains the most common species causing
invasive infection

▪ Candidemia is associated with high mortality

and morbidity
Pfaller MA and Diekema DJ. Clinical Microbiology Reviews 2007.
 Risk factors for Candidosis

1. colonization of skin and mucous membranes

with Candida
2. alteration of natural host barriers (wounds,
surgery) the colonized Candida might enter
the blood stream when microbes balance
disturbed (antibiotics) and the barrier alter
(central/peripheral catheter)
3. Neutropenia (hematology disorders)
 Risk For Systemic Candidiasis
High Risk Nonspecific Risk

Colonization of multiple body sites Age (young and old)

Broad-spectrum antibiotic therapy Diabetes mellitus
Immunosuppression Renal failure
Neutropenia Recent surgery
Burns on >50% body surface area Urinary catheter
Perforation of digestive tract Vascular access
Major abdominal surgery Prolonged ICU stay

Urinary tract surgery in presence of candiduria Multiple transfusions

Major trauma
Total parenteral nutrition Meersseman W, Lagrou K, Maertens
Hemodialysis/hemofiltration J, Van Wijngaerden E. Invasive
aspergillosis in the intensive care
APACHE II score >20
unit. Clin Infect Dis. 2007;45(2):205-
Central venous catheter
216.
Candiduria (>105 cfu/mL)
 Diagnosis
■ Biopsy:
■ Definitive diagnosis
■ problems in tissue sampling in most critically ill patients

■ Blood culture:
■ Definitive diagnosis but
■ sensitivity only 50-60%; positive in the late stage

■ Culture of un-sterile site,

■ the results goes to probable or possible diagnosis.
■ Candida colonization index.
 Diagnosis
■ Serology:
■ Antigen detection: Cell wall mannan, galactomannan and β-(1,3)- D-
glucan,
■ antibodies detection: directed against these antigens in blood or
other body fluids.
Sensitivity and specificity:
■ mannan 40% and 98%
■ anti-mannan antibodies, 53%
■ Combination of AG and AB detection 94% & 80 - 90%
■ β- (1,3)-D-glucan
■ Sensitivities: 69-97%,
■ Specificities: 87 - 100%,
■ PPV & NPV: 59% - 96% and 75% to 97%,

Yera et al., Eur J Clin Microbiol Infect Dis 2001, 20: 864-70. Sendid et al., J Med Microbiol 2002, 51:433-42.
Sendid et al., J Clin Microbiol 1999, 37:1510-7.
 ANTIFUNGAL
STRATEGIES
■ Prophylaxis
■ Empirical use
■ Pre-emptive use
■ Treatment
 WHAT DOES EMPIRICAL or PRE-
EMPTIVE MEAN?
Empirical :
▪ based on observation or experiment , not on theory
▪ regarding sense-data as valid information

Pre-emptive :
▪ to make a bid in an auction high enough to prevent further bidding
▪to obtain by acting in advance of others
▪to occupy public land in order to lay claim to it
▪to purchase goods before they are formally put on sale
▪to go on the offensive in order to avert an enemy attack
Oxford Dictionary
 Concepts of antifungal
strategies
Likelihood of Fungal Disease Treatment
-
➢Remote 0-4% Prophylaxis

➢Possible 5-15% Empirical

➢Probable 15-35% Pre-emptive

➢Proven 100% Treatment

+
 Will laboratory tests guide treatment?
Empiric Pre-
Treatme Prophylax al emptive
Specifi
nt 4
1
is c
4
0
3
Temperature

9
3
8
3
CT
7
3
(°C)

6
PC +
R
Galactomanna + Cultur + Tissu +
Granulocytes (log10x109/L)

1 n e e
Disease
00 Remot Possibl Probable Prove
likelihood e e disease n
1

0.
1
- - 0 7 1 2 2 3 4 4 5 6
14 7 4 Days1after 8 5 2 9 6 3
transplant
 Candida Colonization Index

■ The index is the ratio of body sites colonized

with genotypically identical strains of Candida
over the total number of body sites investigated;
a value of >0.5 indicates invasive candidiasis.

Pittet D, Monod M, Suter PM, Frenk

E, Auckenthaler R. Candida
colonization and subsequent infections
in critically ill surgical patients. Ann
Surg. 1994;220(6):751-758.
Candida Score

❑ Clinical sepsis = 2 points;

❑ Surgery = 1 point;
❑ TPN = 1 point;
❑ Multi-focal colonization = 1 point;
Total = 5 points
❑ Points > 2.5 sensitivity 81% and specificity 74%
❑ OR = 7.75 * [95% CI 4.74, 12.66]
* Intend to treat as initial Empiric antifungal

Leon et al. CCM 2006.34

 S.T.A.R
STart Antifungal Rx

Pittet D, Anaissie E, Solomkin JS. When to start antifungal

therapy in the non-neutropenic critically ill? In: Year Book of
Intensive Care and Emergency Medicine. De. JL Vincent.
Springer. Berlin.1996;567-77
JL Vincent, E Anaissie, H Bruining et al. Epidemiology,
diagnosis and treatment of systemic Candida infection in
surgical patients under intensive care. Intens Care Med
1998;24:206-216
 Antifungal Agents: The last 50 years

# of drugs
L-AmB
ABCD
ABLC
Terbinafine
Itraconazole
Fluconazole
Ketoconazole
Miconazole
5-FC
 Candidemia in Non Neutropenic Patients

Recommendation for adult patients :

■ Fluconazole :
■ loading dose 800 mg ( 12 mg/kgBW) followed by 400
mg (6 mg/KgBW) daily
■ Echinocandin :
■ Caspofungin : loading dose 70 mg then 50 mg daily
■ Anidulafungin : loading dose 200 mg then 100 mg daily
■ Micafungin :100 mg daily
 Candidemia in Non Neutropenic Patients

■ Patients who less critical ;

■ the recommendation is Fluconazole
■ For moderately severe to severe illness patients or patients
who had recent azole exposure ;
■ The recommendation : Echinocandin
■ Transition from Echinocandin → Fluconazole :
■ isolates to be susceptible to Fluconazole ( Candida Albicans ) and
clinically stable
 Candidemia in Non Neutropenic Patients

■ C. Glabrata infections : Echinocandin is prefered

■ Transition to fluconazole or voriconazole is not
recommended without confirmation of isolate susceptibility
■ Patients who have initially received fluconazole or
voriconazole and clinically improved → culture results
negative → continuing use of Echinocandin is recommended
■ Infection due to Candida parapsilosis → fluconazole if
initially received echinocandin → clinically improved →
continue the therapy
 Candidemia in Non Neutropenic Patients

■ Voriconazole administered at a dosage of 400 mg (6

mg/kg) twice daily for 2 doses and then 200 mg
(3mg/kgBW) twice daily → effective for candidemia
■ Offer little advantages over fluconazole →
recommended as step down oral therapy for selected
cases of candidiasis → C. Krusei and or
voriconazole susceptible C. Glabrata
 Candidemia in Non Neutropenic Patients

■ Recommended duration of therapy or

candidemia :
■ Without obvious metastatic complications :
■ 2 weeks after documented clearance of candida
from the blood stream and resolution of
symptoms attributable to candidemia

IV catheter removal → strong recommended for non

nitropenic candidemia
 Candidemia in Neutropenic Patients

■ Recommendation → for most of patients : Echinocandin

■ Caspofungin 70 mg loading dose then 50 mg daily
■ Micafungin 100 mg daily
■ Anidulafungin 200 mg then 100 mg daily
■ Less critical and no azole exposure before: fluconazole
■ Voriconazole : can be used in situation → additional molds
coverage is desired
■ For C. Glabrata : Echinocandin is prefered
■ C. parapsilosis : fluconazole
■ C. C. Krusei : Voriconazole or Echinocandin
 Empiric Antifungal Therapy

■ Therapy antifungal considered in critically ill

patients with risk factor for invasive
candidiasis and no other known cause of fever
; based on
■ Clinical assessment of risk factors
■ Serologic marker of invasive candidiasis
■ And/or culture data from nonsterile sites
 Empiric Therapy for Suspected Invasive
Candidiasis
■ In Non Neutropenic :
■ Fluconazole : loading dose 800 mg then 400 mg daily
■ Caspofungin : loading dose 70 mg then 50 mg daily
■ Anidulafungin : loading dose 200 mg then 100 mg daily
■ Micafungin : 100 mg daily
■ Echinocandin is preferred for patients who have had
recent azole exposure, whose illness moderately severe
or severe
 Empiric Therapy for Suspected Invasive
Candidiasis
■ In Neutropenic
■ LF AmB
■ Caspofungin
■ Voriconazole
■ Fluconazole loading dose 800 mg then 400 mg daily
■ Itraconazole 200 mg 2x/ day
■ Am-B → high risk of toxicity → to avoid use L Am-B
■ Azole should not be used for empirical therapy in
patients who have received an azole for prophylaxis ( B
– II )
 Empiric Antifungal Therapy for
Disseminated Candidiasis
Is the patient hemodynamically UNSTABLE or neutropenic?

Yes No

Avoid fluconazole: use of

polyene, echinocandin, or Is C. glabrata or C. krusei likely to be the cause?
voriconazole preferred Yes No

Avoid fluconazole: use of Use of fluconazole

polyene or echinocandin
preferred, use of voriconazole is
an alternative option
Spellberg BJ CID 2006;42:244
 Chosing the drug
■ If you’re really sick...echinocandin or L-AMB*
■ If you’ve been on azoles...echinocandin or L-AMB*
■ If you’re stable with likely albicans...fluconazole
■ Candida on line...echinocandin or L-AMB*