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COMMON MYCOTIC
INFECTION
Dr. Awadh Al-Anazi
INTRODUCTION
 Last two decades witnessed marked changes in
pattern of fungal infections in humans.
 Fungi are separate group of higher organisms
distinct from both plants and animals.
- Fungal cells encased within rigid cell wall
composed of chitin and glucan while animals
have cell wall and in plants, cellulose is the
major component of cell wall.
- Fungi cannot make their organic food as plants
can, through photosynthesis.
 introduction(cont’d.)
- Fungi simpler in structure than both.
- No division of cell to organ or tissue.
 Basic structure unit
- Hyphae: chain of tubular, filament-like cells
- Independent single cell
 Classified based on appearance, rather than on
nutritional and biochemical appearances
FUNGI AS HUMAN PATHOGENS
 50,000 to 250,000 fungal spp. described
 500 associated with human disease
 No more than 100 spp. capable of causing
infection in normal individual.
 Remainder only able to cause disease in immunocompromised or debilitated people.
 Fungal infection classified into broad groups
according to initial site of infection.
CLASSIFICATION OF FUNGAL
INFECTION
•
Superficial
•
Cutaneous
•
Subcutaneous
•
Systemic
•
Opportunistic
 Superficial mycoses
- Pityriasis versicolor – pigmented lesion
on torso.
- Tinea nigra – gray to black macular lesion
on palms.
- Black piedra – dark gritty deposits on
hair.
- White piedra – soft whitish granules along
hair shaft.
- All diagnosed by microscopy and easily
treated by topical preparation.
Cutaneous infections
 Infections of skin and its appendages
(nails, hair)
 20 spp. Of dermatophytes cause ringworm.
 Subcutaneous mycoses
-Subcutaneous infections, over 35 spp. produce
chronic inflammatory disease of subcutaneous
tissue & lymphatics e.g. sporotrichosis:ulcerated lesion at site of inculasion followed by
multiple nodules, caused by dimorphic fungus
sporotrix schenckii.
 Systemic fungal infections
- Uncommon
- Natural immunity is high
- Physiologic barriers include:
- Skin and mucus membranes
- Tissue temperature: fungi grow better at
less than 37°C
- Redox potential – in vivo conditions too
reducing for most fungi.
▪ Coccidioidomycosis
▪ Histoplasmosis
▪ Blastomycosis
 Opportunistic Mycoses
- Do not normally cause disease in healthy people.
- Cause disease in immunocompromised people.
- Weakened immune function may occue due to:
▪ Inherited immunodeficiency disease
▪ Drugs that suppress immune system:
cancer chemotherapy, corticosteroids, drugs
to prevent organ TX. Rejection.
▪ Radiation therapy
▪ Infection (HIV)
▪ Cancer, diabetes, advanced age and malnutrition.
Most common opportunistic mycotic
infections:





Candidiasis
Aspergillosis
Cryptococcosis
Zygomycosis/mucormycosis
Pneumocystis carinii
Candidiasis
 C. Albicans is member of indigenous microbiol human flora:
- Found in GIT, respiratory tract, buccal cavity & vaginal
tract
- Growth usually suppressed by other organisms found in
these areas.
- GIT flora alteration by broad spectrum ABX or mucosal
injury leads to GIT invasion.
- Skin & mucus membranes are normally effective barrier
but damage by introduction of catheters or intravascular
devices can permit candida to enter blood stream.
- Vaginal candidiasis is the most common clinical infection.
- Local factors, e.g. pH & glucose conc. are of prime
importance in occurrence of this infection.
- In mouth, normal saliva reduces adhesion.
- Lactofemic also protective
Candidiasis (cont’d.)
Immune Response
 Hyphae too big for phagocytosis, but
 Damaged by PMNs and intracellular mechanisms
* Myeloperoxidase
* Glucuronidase
 Cytokine activated lymphocytes inhibit c. albicans growth.
 Resistance to invasive candida infection is mediated by
phagocytes, complement and antibody, although
 CMI plays major role
 Patients with defects in phagocytosis function and myeloperoxidase deficiency are at risk for disseminated/fatal
candidiasis.
Risk Factors for Candidiasis:
▪
▪
▪
▪
▪
▪
Post-operative status
Cytotoxic cancer chemotherapy
Antibiotic therapy
Burns
Drug abuse
GI damage
Chronic mucocutaneous candidiasis (CMC)
 CNC: group of overlaping syndromes that have
in common clinical pattern of persistent, severe
and diffuse cutaneous candidal infection, affecting
skin, nails and m. membranes.
 Immunologic studies of patients with CMC often
reveal Cmi defect, however, the defects
themselves vary widely.

Mucutaneous Candidiasis:
Response to fluconazole:
 Transfusion of candida-specific transfer factor
reported to be very successful (remission > 10
years) when combines with antifungal therapy.
 Availability of oral agents, especially, Azole antimicotics, dramatically changed life of patients with
CMC
Aspergillosis
 Contains hundred of species and occurs worldwide
 These species form the most commonly found fungi in any
environment.
 Major portal of entry: Respiratory tract
 Dissemination can occur from the lungs and involve:
- Other areas of the lung
- Brain
- GIT
- Kidneys
 CNS and nasal-orbital – cavities can occur without lung
involvement.
 Risk factors for invasive disease are:
- Neutropenia
- High doses of corticosteroids
Aspergillosis (cont’d.)
 Most common fatal infection seen in patients with chronic
granulomatous disease of childhood.
 Patients with this condition unable to form toxic oxygen
radicals after phagocytosis.
 Progressive and disseminated disease can complicate neoplastic diseases, esp. ac. Leukemia, BM and organ transplantation.
 In immunosuppressed host: Invasive pulmonary infection
usually with fever, cough and chest pain.
 May disseminate to brain, bone, skin and other organs.
 In immunocompetent host:: Localized pulmonary infection
and allergic sinusitis and allergic bronchopulmonary disease
(ABPA).
Cryptococcosis
 Cryptococcus neoformans
- Primary infection in lungs
- Cryptococcal meningitis is most common disseminated
manifestation.
- Can spread to skin, bone and prostate.
 Organism ubiquitous and infections occur worldwide.
 Diagnosis: - CSF microscopic exam diagnostic
- India staining
- Cryptococcal antigen in CSF and serum
Cryptococcosis (cont’d.)
 Immune response
- Phagocytosis by neutrophils is inhibited by presence of
capsule
- CMI primary defence
 About 30% of cryptococcus infections occur in patients
with lymphoma (CNS).
 Therapy: Ampho B & 5 FC
Fluconazole effective
Zygomycosis
 Due to Rhizopus, Rhizomucor, Absidia, mucor species, or
other class of zygomycetes.
 Causes invasive sinopulmonary infections
 Mucormycosis: Life-threatening form of zydomycosis known
as Rhinocerebral syndrome affecting diabetics with ketoacidosis.
 Other risk factors: DKA, neutropenia, steroids
WHAT DOES EMPIRICAL OR PRE-EMPTIVE MEAN?
Empirical
- Based on observation or experience, not on theory
- Regarding sense-data as valid information e.g. “an
empiric = a quack doctor”.
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
ARGUMENTS AGAINST LIBERAL
Empirical use of Antifungal:
 Introduces fake confidence by reducing the urge to
establish a correct diagnosis.
 Never shown to be unquestionably effective.
 Possible additional toxicity of antifungal with other
drugs.
 Because of toxicity and borderline indication lower
dosages of antifungal might be used.
 Brings in emotions, not science.
FDA approved drugs for empirical therapy
Drug
Dosing regimen used in controlled trials
Ampho B
0.6 – 1.0 mg/kg/day (IV)
__________________________________________________
Liposomal
3 mg/kg/day (IV)
Ampho B
__________________________________________________
Itraconazole
400 mg/day/or two days then 200 mg/d for
5-12 days (IV), followed by oral solution
400 mg/day for 14 days
__________________________________________________
Caspofungin
70 mg day 1, then 50 mg/daily
RD-BMT of Caspo.vs. L. Ampho B – NEJM 2004
The ideal empirical/pre-emptive strategy
USE ONLY
 Safe and effective antifungal drugs with spectrum adapted to
local ecology and optimally adjusted dosage; booster host
defense (CSF) first.
INCLUDE ONLY, BUT QUICKLY
 Patients with high probability of fungal disease, belonging to a
well defined high risk category
EXCLUDE CERTAINLY
 Patients with low risk profile or unlikely to have fungal disease
RELY EXCLUSIVELY ON
 Optimal batteries of clinical, radiologic and laboratory tests
AVOID ALWAYS
 Indiscriminate primary prophylaxis
ADOPT
 Early pre-emptive strategy. Secondary prophylaxis
WHY DO WE STILL USE EMPIRICAL ANTIFUNGAL
THERAPY?
Assumptions:
 Established invasive infections carry excessive
mortality rates.
 Prophylactic strategies are inefficient.
 Colonization and disease form an obligatory
continuum.
 Newer diagnostic tools yield “too little, too late”
 The “hard” data from the published randomized
studies are reliable and form “proof of principle”
Emotions and traditions
Empirical antifungal therapy
▪
▪
▪
▪
▪
Optimal timing
Optimal dosage
Optimal agent
Optimal spectrum
Optimal cost/benefit ratio
ADJUNCTIVE TREATMENT
 White blood cells transfusion
 Cytokines
- Gamma interferons enhances fungal hyphae
damage.
- Growth factors reduce IFI in leukemia patients
- GMCSF hepatosplenic candidiasis in patients
with acute leukemia.
*Organism (n=52)
GMCSF
Placebo (n=47)
ASP
¼ (25)
5/7 (71)
Candida
0/3
¾ (75)
Other
0/1
1/1 (100)
Total
1/8 (13)
9/12 (75%)
(P = 0.02)
Hyperbaric oxygen




Enhances cell-mediated fungal killing
Optimises tissue oxygenation
Reduces edema and acidosis
Promotes tissue survival
SURGICAL MANAGEMENT
Excision of well-defined fungal lesion associated with
superior outcome over medical therapy alone for:
 Fungal endocarditis valve replacement & antifungals better
survival than med. therapy alone.
 Endophthalmitis, bone & joint disease
 Early bleeding from mycotic lung sequestrum (primary
aspergilloma)
 Invasic fungal sinusitis
ROLE OF SURGERY LESS CLEARLY DEFINED FOR:
 Preventing bleeding in well-circumscribed mycotic lung
sequestrum.
 Cases refractory to medical therapy
 Prevention of future relapses in patients initially survived I.A.
who undergo further immunosuppression of their underlying
disease.
NEWER/NOVEL ANTIFUNGAL AGENTS
 Triazoles
- Voriconazole
- Posaconazole
- Ravuconazole
 Echinocardins
- Caspofungin
- Anidulafungin
- Micafungin
 Pneumocardins
 Pradimicins
 Benanomycins
 Nikkomycins
 Allylamines (e.g. terbinafine)
 Thiocarbamates
Candins

Good activity against Aspergillus and
Candida

Fungicidal in vitro

Novel mechanism of activity

Low potential for developing resistance

Well tolerated in humans

Potential for drug interactions
Average daily cost of Antifungals
Antifungals
Conv. AmphoB
Liposomal AmphoB
Lipid complex AmphoB
Fluconazole
Fluconazole
Itraconazole
Voriconazole
Voriconazole
Caspofungin
Dose
1 mg/kg
3 mg/kg
5 mg/kg
400 mg IV
200 mg PO
40 mg PO
40 mg IV
40 mg PO
70 mg IV
Euros
8
629
405
60
11
40
407
84
644
MAJOR ISSUES
 Unacceptable case fatality rates
 When to start treatment?
- Emperical or
- Diagnosis-guided
 Will higher doses of existing antifungals improve
survival?
 Definition of proven invasive fungal infection
 How will the clinical response be monitors?
Mode of action of antifungals
acetyl-CoA
allylamines
nucleic acid
synthesis
nucleosides
eg terbinafine
eg 5-flucytosine
squalenes
glucan synthesis
pneumocandins
azoles
eg caspofungin
eg fluconazole
lanosterol
chitin synthesis
nikkomycins
ergosterol
K+
Mg 2+
polyenes
eg amphotericin B
protein synthesis
azasordarins
Definite invasive fungal disease
Host
factor
+
Clinical
features
+
Tissue
+
Mycology
Do higher doses of Lipid AMB result
in greater survival?


Animal studies reveal non-parallelism
 Higher doses: mouse models:
 Invasive aspergillosis:
 Less survival : Abelcet
 Greater survival: Ambisome
 Systemic candidosis: greater survival (100%)
 Other factors impact on survival
 Clinical studies: greater survival with higher doses
 1 mg vs. 4 mg (Ellis CID 1998)
 Mean daily dose: 4.4 mg/kg; cumulative: 5.7 g
Lung tissue concentrations
 1 mg/kg: 1.8 mg/kg
 5 mg/kg: 10.3 mg/kg
Ellis J Med Micro. 2002; 51: 95-
Comparative spectrum of activity
Fungus

AMB FCZ ITZ VZ PCZ RCZ CF MF AF
Candida albicans
Candida tropicalis
Candida parapsilosis
Candida krusei
Candida glabrata
Cryptococcus neoformans
Histoplasma capsulatum
Blastomyces dermatitidis
Coccidiodes immitis
Paracocci brasiliensis
Pneumocystis carinii
Aspergillus fumigatus
Mucor spp
Rhizopus spp
Fusarium spp
Sentry Antimicrobial Surveillance
Programme 2000
Aspergillus spp. and other filamentous fungi
MIC 1 g/ml
Posaconazole
Voriconazole
Amphotericin B
Ravuconazole
Itraconazole
94%
91%
89%
88%
70%
Pfaller AAC April 2002; 46: 1032-1037
Before we start some observations
“Fluconazole and itraconazole represented fast
and useful progress along the azole learning
curve towards ideal compounds i.e.
 Broad spectrum of activity
 Low toxicity
 Ease of administration
Subsequent triazoles have emerged more
slowly and suggest the law of diminishing
returns may be operating against major
advances in triazole agents”
Odds ICAAC 2000
Will laboratory tests guide treatment?
Temperature (°C)
Treatment 4Prophylaxis Empirical
Pre-emptive
Specific
1
40
39
38
37
36
Disease
likelihood
Granulocytes (log10x109/L)
PCR +
Galactomannan+
Culture +
Tissue +
10
0
Remote
Possible Probable disease
Proven
1
0.1
-14
-7
0
7
14
21
28
35
Days after transplant
42
49
56
63
When to treat with the new
antifungals?
Antibody
How will the new antifungals be used?
PRETRANSPLANT
ENGRAFTMENT
Granulocytes (log10 1x 106/L) Temperature °C
Disease
likelihood
41
EARLY POSTENGRAFTMENT
Possible
Remote
LATE POSTENGRAFTMENT
Probable disease
Proven
40
39
38
Clinical
features
37
36
Persistent fever
High risk
Mucositis
Host factors
10
Mycological
evidence features
Tissue
evidence
1
Empirical
Treatment
Prophylaxis
0.1
-14
-7
0
Transplant
7
Days
14
21
Pre-emptive
28
6
8
10
Weeks
12
Specific
6
9
Months
12
How will the new antifungals be used?
Temperature °C
PRETRANSPLANT
ENGRAFTMENT
LATE POSTENGRAFTMENT
EARLY POST-ENGRAFTMENT
41
40
oral
39
oral
IV
38
37
itraconazole
voriconazole
posaconazole
Granulocytes (log10 1x 106/L)
36
10
Ambisome
itraconazole
caspofungin
voriconazole
posaconazole
1
itraconazole
voriconazole
posaconazole
0.1
-14
-7
0
7
Transplant Days
14
21
28
6
8
10
Weeks
12
6
9
Months
12
How will the clinical response to new
antifungals be monitored?

Antigen levels
 Reduction in Aspergillus GM levels
 Persistence of high GM levels: poor
prognosis
Suggests modification of antifungal
treatment
Glucan (Glucatell)
Mannan/anti-mannan (Platelia Candida)
Molecular methods: point-of-care-tests




Combination therapy





Additive or synergistic
Very poor clinical evidence (IDSA Guidelines,
2000)
Good animal data
New targets
New drug combinations
 AmBisome + caspofungin
 AmBisome + anidulafungin (invasive aspergillosis)
Invasive aspergillosis in allogeneic
stem cell transplant recipients:
increasing antigenemia is associated
with progressive disease
 37 allogeneic SCT recipients
 CAMB/LAMB/ITRA/VORI
 58 response episodes evaluated
 42 treatment failures
 16 complete or partial responses
 Treatment failures: galactomannan (GM)
 GM level 1.0 over baseline: predictive of treatment failure
Conclusion: serial determination of serum GM a useful tool for
assessing prognosis of IA in allogeneic SCT during treatment
Boutboul et al. CID 2002 (April 15th); 34: 939-943
The future of empiric antifungal
Major critical issues for future
antifungals







Spectrum of activity
Bioavailability
Pharmacokinetics
Side effects
Will prophylaxis with new azoles
induce amphotericin B resistance?
Interactions
Combinations
Why do we still use empirical
antifungal therapy?
Assumptions:





Established invasive infections carry
excessive mortality rates
Prophylactic strategies are inefficient
Colonization and disease form an obligatory
continuum
Newer diagnostic tools yield "too little, too
late"
The "hard" data from the published
randomized studies are reliable and form
"proof of principle"
HEM/20283M
Empirical antifungal
therapy
 Optimal timing
 Optimal dosage
 Optimal agent
 Optimal spectrum
 Optimal cost/benefit
ratio
HEM/90326M
Emotional
activity of
physician
Think
Add
about
empirical
antifungals antifungals
Realize
cost of
strategy
Add
growth
factors
Add
empirical
antibiotics
Start
empirical
antibiotics
24 hr
72 hr
96 hr
Duration of
neutropenic fever
Breakthrough infections
Fewer in voriconazole arm than
ambisome arm
Voriconazole
1.9%
Ambisome
5.0%
Adjusted for death – FDA analysis
Voriconazole
9.2% (38/415)%
Walsh et al, 2002
Ambisome
9.2% (39/422)%
Newer antifungal agents







Echinocandins
*caspo,anidula,
mika
Pneumocandins
Pradimicins
Benanomycins
Nikkomycins
Allylamines
Thiocarbamates
HEM/80652M
The ideal empirical/pre-emptive
strategy
USE ONLY

safe and effective antifungal drugs with spectrum adapted to
local ecology and optimally adjusted dosage; booster host
defense (CSF) first
INCLUDE ONLY, BUT QUICKLY

patients with high probability of fungal disease , belonging to a
well defined high risk category
EXCLUDE CERTAINLY

patients with low risk profile or unlikely to have fungal disease
RELY EXCLUSIVELY ON

optimal batteries of clinical, radiologic and laboratory tests
AVOID ALWAYS

indiscriminate primary prophylaxis
ADOPT

early pre-emptive strategy, secondary prophylaxis
HEM/90593M
Conclusions
 Potent in vitro activity: fungistatic vs. fungicidal
 Greater tissue penetration
 More appropriate pharmacokinetics
 Flexibility of dosing and formulations
 Induction of resistance: Should we be concerned?
 Longer treatment periods: define end points
 Activity to be shown in all clinically relevant
infections
 Earlier diagnosis
******************************************************
PREVENTION IS BETTER THAN CURE
 The essence of wisdom is the ability
to make the right decision on the
basis of inadequate evidence.
Alan Gregg