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6/28/2012


Rhonda E. Colombo, MD
Assistant Professor
DOM, Section of Infectious Diseases
Georgia Health Sciences University




Increase awareness of risk factors associated
with development of invasive fungal infections
(IFIs)
Review clinical features of select fungal infections
Highlight current diagnostic approaches &
challenges
Discuss key features of available antifungal
agents, including spectrum and common toxicities
Provide a brief overview of adjunctive treatment
measures for certain fungal infections
Increasing incidence
◦
◦
◦
◦
Majority caused by Candida spp.
Aspergillosis = 2nd most common
Cryptococcus
Emerging fungal infections
 Fusarium, Zygomycetes, Scedosporium, etc

Challenges
◦ Significant mortality
 Delayed therapy = risk factor for mortality
◦ Diagnosis may be difficult
 Empiric therapy often necessary
 What to use & when to initiate remain challenging questions

Candidal infection of a sterile tissue or fluid
+/- positive blood culture


Candida spp. = 4th most common cause
nosocomial bloodstream infection (BSI) in US
◦ 3rd most common in ICU setting
◦ Annual incidence of candidemia in US

◦ 30-50% autopsy proven disseminated candidiasis had
negative blood cx
 Estimated 60-70K cases/year in US
Disease severity
Known or suspected species of Candida
◦ Local susceptibility patterns


 10 cases/100,000 population
Host immune status
Infection site
Prior antifungal drug exposure
◦ Cross-resistance between azoles
◦ Emergence of resistant organisms during treatment
 Pts receiving fluconazole who develop candidemia:
 OR 11.6 (95% CI, 2.28-68.6) infxn due to non-albicans Candida
 15-20 fold increase in last 2 decades
 Attributable mortality 40 - 50%

◦ Prior allergy or intolerance to an antifungal
Kett et al 2011
Perloth et al 2007
Allou et al 2011
Drew & Townsend, 2010
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6/28/2012



Reported frequency varies

C. albicans
◦ Severe sepsis: 30%
◦ Septic shock: 10-38%

C. glabrata

C. tropicalis

C. parapsilosis
◦ Most common: > 50% of invasive candidal infections
◦ < 5% have 1º resistance to fluconazole (in US)
Time to onset does not distinguish candidal vs.
bacterial source of sepsis
Time to initiation of therapy important
◦ Delay in antifungal therapy > 12 h s/p positive blood cx
assoc. with increased mortality
 AOR 2.09, 95% CI 1.53-2.84
◦ 2nd most common: 15-25% cases
◦ 0-23% fluconazole resistance
 20%-75% if include dose/delivery dependent resistance
◦ ≈15% cases
◦ 91-100% susceptible to fluconazole
◦ 10-20% cases
◦ Increased in vitro MICs to echinocandins
◦ In 120 pts. with septic shock due to Candida
 Association b/w time to initiation of antifungal tx after onset
of hypotension & mortality

C. krusei
◦ <3% in general
 Up to 15% in centers with significant fluconazole prophylaxis
 AOR 1.119 per hour delay, 95% CI 1.103 -1.136
◦ Intrinsic fluconazole resistance
Allou et al. 2011
Morrell et al. 2005
Patel et al. 2009

Perloth et al. 2007
Initial empiric therapy:
◦ Fluconazole




Nonneutropenic, and
No recent azole exposure, and
Hemodynamically stable, and
Not at high risk for C. glabrata or C. krusei




Neutropenic, or
Recent azole exposure, or
Hemodynamically unstable, or
High risk for C. glabrata or C. krusei

C. albicans & C. tropicalis

C. glabrata
◦ Transition to fluconazole if clinically stable
◦ Echinocandin
 Unless:
◦ Echinocandin

 Azole susceptibility confirmed, or
 Exhibiting clinical improvement on empiric azole

C. krusei

C. parapsilosis
◦ Echinocandin
Duration:
 Minimum:
◦ Fluconazole
 2 weeks s/p documented clearance from blood
 Resolution of signs & symptoms attributable to candidemia
 Unless clinically improving & negative blood cx on echinocandin
 Extend in cases with metastatic foci
Pappas et al. CID, 2009


Pregnancy
◦
◦
◦
◦
Pappas et al. CID, 2009
Amphotericin B is drug of choice for IC in pregnancy
Fluconazole & posaconazole = Category C
Echinocandins = Category C
Voriconazole and flucytosine = Category D
Remove of all central venous catheters
◦ Associated with reduced mortality & shorter duration of
candidemia
 Generally applied to arterial catheters as well
◦ Less data in neutropenic patients

Dilated fundoscopic exam during first week tx
◦ Most important in pts unable to report visual disturbances
◦ After recovery of neutrophils in neutropenic pts

Routine f/u blood cultures to document clearance
◦ Daily or every other day
◦ If persistent positive cultures, search for source
 Echo to r/o endocarditis
 Consider suppurative thrombophlebitis
Pappas et al. CID, 2009
Pappas et al. CID, 2009
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
Candida endophthalmitis
◦ Amphotericin B-deoxycholate (AmB-d) + flucytosine for lesions
threatening macula
◦ Fluconazole 6-12 mg/kg daily for less severe


High index of suspicion required
In absence of + culture from sterile site:
◦ Clinical and laboratory signs of infection
 Treatment duration dependent on response
 Not responding to appropriate empiric anti-bacterial
treatment
 Minimum 4-6 wks
 Surgical intervention for severe endopthalmitis or vitreitis
◦ Risk factors for disseminated candidiasis
◦ Clinical response with empiric antifungal therapy
 Partial vitrectomy & intravitreal antifungal therapy

Candida endocarditis
◦ Valve replacement plus antifungal therapy for ≥ 6 wks post
surgery
 LFAmB +/- flucytosine, or
 AmB-d +/- flucytosine, or
 Echinocandin
Pappas et al. CID, 2009

Candida Colonization

ICU stay
Broad spectrum Abx
Disruption mucocutaneous
barrier

◦ Central venous catheter
◦ TPN

Prolonged hospitalization
Mechanical Ventilation
Neutropenia
DM
Corticosteroids
Transplantation
◦ Higher burden = higher risk


 Mucosal atrophy
◦ Surgery:
 GI or cardiac
◦ Burns
◦ Gastrointestinal perforation



◦ APACHE II score





◦
◦
◦
◦
◦
◦
◦
◦
◦ Hematologic
◦ Liver
◦ Pancreas
Renal Replacement Tx
Controversial in non-neutropenic, non-transplant pts
Poorly defined criteria for starting
Muskett et al. 2011

◦ Examples:
 Multifocal colonization (1.112)
 Surgery (0.997)
 TPN (0.908)
 Severe sepsis (2.038)
 “Candida score” > 2.5 predictive of candidal infection
 SN 81%, SP 74%
 Re-evaluated score ≥ 3
 SN 78%, SP 66%, PPV 14%, NPV 98%
Potential Benefits:
◦ Early initiation antifungal therapy may:
 Reduce morbidity
 Reduce mortality
 Not shown in RCT of prophylaxis in ICU pts
 Ostrosky-Zeichner et al. (2007): prediction rule for clinical trials
 Reduce length of stay
 Systemic abx. and CVC + 2 of the following:
 TPN, RRT, surgery, pancreatitis, & steroids/immunosuppressants
 SN 30%, SP 90%, PPV 0.09, NPV 0.97
Potential Risks
 Toxicity
 Emergence of resistance
Several clinical prediction models have been developed
 Pittett et al.(1994) : rule based on intensity of Candida colonization
 Leon et al. (2006) : bedside prediction score
 Prophylaxis in high-risk pts (>10%) in ICUs with high rates of ICI
 Empiric tx in critically ill pts w/ risk factors for ICI & signs of infxn

Surgery
TPN
Fungal Colonization
RRT
Infection & Sepsis
Mechanical Ventilation
DM
APACHE II or APACHE III score
Perloth et al. 2007
Allou et al. 2011
Muskett et al. 2011
◦ Consider:

Significant risk factors identified in multiple studies:

No clear consensus on which is best
◦ New studies underway to develop/validate risk model
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

Proposed as adjunctive methods to accelerate IC diagnosis
1,3--D-glucan

Nonneutropenic
◦ Treat as with documented candidemia
 Fluconazole:
 Varying reports re: SN & SP
 Not validated in ICU patients
 Hemodynamically stable
 No risk factors for azole resistance
 Factors known to cause false positives common in ICU pts
◦ Mannan/anti-mannan antibodies




 Echinocandin:
Mannan = Candida specific cell wall component
Used primarily in Europe
Poor sensitivity
Investigational
 Hemodynamicaly unstable
 Increased risk of azole resistance

◦ Real time PCR
Neutropenic
◦ Empiric antifungal therapy for persistent fever not responding
to empiric antibiotics
 One assay recently validated
 Encouraging results for deep seated candidemia
 Not yet readily available
 Lipid formulation amphotericin B, or
 Caspofungin (other echinocandins not studied), or
 Voriconazole
 Standardization needed
 Clinical utility remains to be established
Mokaddas et al. 2011
Nguyen et al. 2012
Pappas et al. CID, 2009


Ubiquitous environmental mold
Most common pathogenic species:
◦ A. fumigatus
◦ A. flavus
◦ A. terreus
 Resistant to polyenes
◦ A. niger
 2nd
most common cause of nosocomial IFI
◦ 5/100,000 population in US
 Crude mortality rates: 45-80%

Primary infection generally via respiratory tract

Immunocompromised:
◦ Pulmonary infection
◦ Sinus infection
◦ Hematogenously disseminate or extend to adjacent tissues
Walsh et al. 2008

Traditional risk
factors
◦ Prolonged neutropenia
◦ Lung transplantation
◦ Hematopoietic stem cell
transplant
◦ Immunosuppression
 High dose corticosteroids
 Cytotoxic chemotherapy

ICU patients without
traditional risk factors


increasingly encountered
Associated with
 COPD
 Cirrhosis
 Ethanol Abuse
 Post surgical
 Post-influenza
◦ Advanced AIDS
◦ Innate Immunodeficiency

Challenging
◦ Blood cultures rarely positive
◦ Cx from respiratory tract must be interpreted in clinical context
 Potential laboratory contaminant or colonizer

Diagnosis:
◦ Positive culture in appropriate clinical setting
 Culture on fungal media improves yield
◦ Histopathology:
 Dichotomously branching, septate hyphae
◦ Imaging
 Classic CT finding: Halo sign or air-crescent sign in neutropenic
 CGD
Limper et al. 2010
Walsh et al. 2008
Perloth et al. 2007
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
Galactomannan
◦ Constituent of Aspergillus cell wall

 Released during fungal growth; requires angioinvasion to be
released in blood

◦ Surrogate marker for IA
Voriconazole = 1st line therapy
Alternative:
◦
◦
◦
◦
 Galactomannan EIA
 Serum
 BAL for pulmonary IA
 Sensitivity demonstrated in pts with hematologic malignancy
 May be lower in non-neutropenic pts
Lipid formulation AmB
Caspofungin
Micafungin
Posaconazole
 False positives: including in pts receiving piperacillin/tazobactam
◦ Investigation ongoing re: serial assessment
 Therapeutic monitoring & pre-emptive therapy

1,3--D-glucan

PCR testing promising but not yet standardized
◦ Found in Aspergillus spp, Candida, and Fusarium spp
Lai et al. 2008
Walsh et al. 2008
Walsh et al. 2008

Encapsulated fungus
◦ 19 species within genus
 Cryptococcus neoformans = primary human pathogen
 Cryptococcus gatii recently reclassified as own species
 Immunocopetent
 Outbreak in Pacific NW

Cryptococcal meningitis first described in 1914
◦ Prior to 1980s, rare human pathogen
◦ Now a common worldwide opportunistic infection
 Incidence in US
 Pre-AIDS era: 0.8 case/million/year
 1992: 5 cases /100,000/year in cities
 Incidence remains high in areas with uncontrolled HIV & limited
health care access
Mandell et al. 2004
Perfect et al. 2010

CNS
◦ Meningitis

 Acute, subacute, chronic
◦ Cryptococcomas of brain

Pulmonary
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Nodules
Infiltrates
Cavities
Endobronchial masses

Eye

Cardiovascular
◦ Keratitis
◦ Endophtalmitis
◦ Choreoretinitis
◦ Cryptococcemia
◦ Endocarditis,
◦ Myocarditis,/pericarditis
Skin
◦ Abscesses
◦ Ulcers
◦ Molluscum contagiosum-like
lesions

GU tract

Musculoskeletal

GI tract

Endocrine
◦ Prostatitis
◦ genital lesions
◦ Arthritis
◦ Myositis
◦ Hepatitis
◦ Peritonitis

Predisposing conditions
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AIDS
Prolonged treatment with corticosteroids
TNF-inhibitors
Monoclonal antibodies
Organ transplantation
Advanced malignancy
Diabetes mellitus
Sarcoidosis
Approx. 20% have no apparent underlying disease
◦ Thyroiditis
◦ Adrenal insufficiency
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Positive culture
◦ Most common

 CSF
 Blood

◦ Induction:
 AmB-d + flucytosine x > 14 d
 LFAmB alternative to AmB-d in pt predisposed to renal failure
Crytptococcal Antigen
 High dose (800mg-1200mg) fluconazole an alternative
◦ CSF
◦ Serum
◦ Maintenance:
 Fluconazole 400 mg po daily x 8 wks, then
 Fluconazole 200 mg daily for minimum 12 months & until immune
recovery
 Sensitivity 95%

2010 IDSA guideline specifically addresses
complications, non-HIV populations, C. gatii infection
Cryptococcal Meningoencephalitis: HIV-infected
LP necessary if serum crypto Ag positive or if
cryptococcus isolated from any non-CSF site
 CD4 > 100 x 3 months and virologic supression on HAART
◦ Asymtomatic antigenemia with negative LP and blood cx
 Fluconazole 400 mg daily until immune reconstitution
Perfect et al. 2010
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Transplant:
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AmB-d generally avoided due to increased risk of toxicity
Maintenance phase 6-12 months
Specific guidelines for non-CNS disease based on severity
Reduction of immunosuppression as much as possible

◦ More neurological complications
◦ Delayed response to therapy

◦ Longer induction phase
 AmB-d + flucytosine x > 4 weeks
 Re-image
 Consider surgical management if compression of vital
structures or medical tx failure
 Extend to 6 weeks with neurologic complications or if flucytosine not
given
 LFAmB may be substituted in
Treatment:
◦ CNS & disseminated disease tx same as C. neoformans
◦ Heightened awareness for hydrocephalus &
cryptococcomas
Non-transplant
2nd
Intracranial infection in HIV-negative host
2 weeks
 Consider shortening to 2 weeks only in pts at low risk of tx failure
◦ Similar consolidation and maintenance phases
Perfect et al. 2010

Management of intracranial pressure key

Immune Reconstitution Inflammatory Syndrome (IRIS)
= potential complication
Antifungal Resistance
◦ CSF drainage if CSF pressure ≥ 25 cm


◦ Treatment failure may occur despite in vitro susceptibility
◦ Secondary resistance to fluconazole rare, may be increasing
 Series of 36 cases:
 76% cx + relapse due to isolates with fluconazole MICs ≥ 64 μg/mL
 Associated with receiving fluconazole as initial therapy
 Consider susceptibility testing for breakthrough infxn

Fusarium spp
Zygomycetes
◦ Rhizopus
◦ Mucormycosis

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Scedosporium apiospermum
Dematiaceous fungi
Blastomycosis
Histoplasmosis
 Especially in pts who received prior azole therapy
 Some C. gatii have high azole MICs
◦ Echinocandins have no activity against Cryptococcus
Perfect et al. 2010
Drew & Townsend 2010
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Host
◦ Immune status
 Prolonged neutropenia
◦ Gastrointestinal absorption
◦ Renal function
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Severity of fungal infection
Virulence of the pathogen
PK/PD of antifungal
◦ Bioavailablity, metabolism


Presence of biofilm
Presence of antifungal resistance
Drew & Townsend , 2010

Mechanism:
 Interferes w/ ergosterol sythesis   fungal cell membrane
permeability


Several drug-drug interactions

Standard dosing in invasive candidiasis:
 Cytochrome P3A4 & P2C9
Spectrum (FDA approved):
 Candida
 Cryptococcus

Excellent oral bioavailablility

Widely distributed in body tissues and fluids
◦ 800 mg loading dose x 1, then 400 mg daily
 Dose adjustment for renal insufficiency required
 Use with caution in severe hepatic disease
 Not affected by gastric pH or food consumption
 CSF and vitreous body: 50 - 90% of serum concentrations
 Urine: 10-20x serum concentration

Adverse effects:
 Generally well tolerated
 GI intolerance, transaminase elevations most common
 Severe hepatitis rare
Bartlett et al. 2010

Mechanism

3 currently available echinocandins
 Inhibit  (1,3) -D-glucan synthase affecting fungal cell wall formation

Fewer drug-drug interactions than azoles

Caspofungin
 Caspofungin affected by co-admin with CYP enzyme inducers
 Caspofungin
 Anidulafungin
 Micafungin

 Decrease dose for Child-Pugh score 7-9: 35 mg/day
 Use with caution for Child-Pugh score > 9
 Increase to 70 mg daily in obese patients or CYP inducers
 No renal dose adjustment
Spectrum of activity similar for all 3
 Candida
 Aspergillus (only caspofungin has FDA approval)



◦ 70 mg x 1, then 50 mg daily

Anidulafungin

Micafungin
◦ 200 mg IV x one, then 100 mg daily
 No renal or hepatic dose adjustment
IV only
Poor penetration into urinary tract, CSF
Adverse effects:
◦ 100 mg daily in IC
◦ 150 mg daily in IA or empiric treatment fever & neutropenia
 No loading dose
 Generally well tolerated
 Histamine mediated infusion reaction reported with rates > 1.1 mg/min
 Caspofungin associated w/ transaminase, bilirubin, & alk phos elevation
Bartlett et al. 2010
◦ No renal dose adjustment
◦ Some experts recommend dose adjustment for moderate to severe
hepatic dysfunction
Bartlett et al. 2010
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
2nd generation triazole
 Oral bio-availability >90%

 6 mg/kg IV q 12 hr x 2, then 4 mg/kg q 12 hr, infused over 1-2 hrs
Activity against:

◦ Aspergillus
 Pts failing therapy or at high risk AEs
◦ Fusarium spp
◦ Scedosporium apiospermum , not Scedosporium prolificans
◦ No activity against Zygomycetes
◦ Target trough concentrations in critically ill: 2-5 mg/L

Additional considerations
◦ Oral bio-availability decreased by high fat foods
More toxicities than echinocandins
 Give 1 hr before or 3 hr after meal
◦ Visual disturbances common (20%)
◦ Elevated transaminases (13%)

Inter & intra-patient variability in drug concentrations
◦ Therapeutic drug monitoring
 1st line therapy for IA
◦ Candida including fluconazole-resistant spp.

Dose depends on indication
◦ Invasive Fungal Infection
◦ IV and PO formulations
 Interrupt continuous enteral supplementation
◦ IV formulation contraindicated if GFR <50
Significant drug-drug interactions
 Toxicity of sulfobutylether -cyclodextrin vehicle
◦ Metabolized by CYP2C19, CYP2C9, & CYP3A4
◦ Dosage adjustments required with hepatic impairment
Bartlett et al. 2010
Strasfeld & Weinstock 2006

PO formulation only

Activity:

Indications:
◦ Must be administered with full meal or liquid nutrition
◦ H2 blockers and PPIs may decrease levels
Bergman et al 2010

◦ Attaches to erogosterols in cytoplasmic cell membrane
 increased permeability
◦ Concentration-dependent pharmacodynamics
◦ Aspergillus, Zygomycosis, Candida, Fusarium spp & endemic fungi
◦ Prophylaxis IA & disseminated candidiasis in severely
immunocompromised
◦ Oropharyngeal candidiasis
 Long post-antifungal effect
◦ Broad spectrum of antifungal activity
 Off label use: Treatment of IFIs

Adverse effects:

Drug-drug interactions:

Dosing:
Amphotericin B




Cryptococcus
Aspergillus
Zygomycosis
Endemic mycoses: blastomycosis, histoplasmosis,
coccidiodomycosis, Coccidioides
 Candidiasis
◦ Generally well tolerated, similar to fluconazole
◦ Inhibitor of CYP3A4
◦ Prophylaxis: 200 mg q 8 hr
◦ Treatment IFI: 200 mg q 6 hr or 400 mg q 12 hr
Bartlett et al 2010
Bergman et al 2010

Conventional formulation = Amphotericin B
deoxycholate (AmBd)
Bartlett et al 2010
Bergman et al 2010

◦ Examples:
 Amphotericin: C. lusitaniae, Aspergillus terreus
 Fluconazole: C. krusei
 Echinocandins: Cryptococcus, Fusarium, Zygomycetes
◦ Increased toxicity compared to newer agents
 Nephrotoxicity
 Electrolyte abnormalities

3 lipid formulations
 Amphotericin B colloidal dispersion (ABCD)
 High rates of infusion reactions
 Amphotericin B lipid comlex (ABLC)
 Liposomal amphotericin B (L-AmB)
◦ Similar efficacy to AmBd
◦ Standard dosing of lipid formulations: 3-5 mg/kg/day IV
Intrinsic (primary)

Acquired (secondary)
◦ Pathogen mutates or acquires new genetic material after drug
exposure
 Example:
 Fluconazole: C. glabrata
◦ May confer cross resistance within & between classes
 High level fluconazole resistance associated with up to 50%
voriconazole cross resistance
 No cross-resistance between echinocandins & other antifungals
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
Standards only established for select pathogens &
antifungals

◦ Case reports
◦ Small studies
◦ Difficulty in establishing breakpoints for amphotericin
 Lack of correlation between MICs and treatment
failure/success
 Narrow ranges for MICs

 AmB + flucytosine in Cryptococcus meningitis
◦ Refractory mold infections
 Echinocandin + liposomal ampho B or voriconazole
 More likely to help with predicting resistance than response
 Especially helpful in cases failing to respond to therapy
Minimize immunosuppression

Remove catheters/lines & prosthetic material if feasible
Optimal timing and dosing of antifungals
◦ Neutrophil recovery main predictor of survival
◦ gCSF and granulocyte transfusions
 Consider in select cases

◦ Early treatment

IFIs are associated with high mortality in critically ill
patients
Incidence of IFI expected to continue to rise

Epidemiology of IFI varies by geography & host

◦ Increasing numbers of susceptible patients
◦ Knowledge of local IFI patterns useful
◦ Consideration of host risk factors important
 Fungal biomarkers may help promote early diagnosis
◦ Serum levels
 Voriconazole, posaconazole, itraconazole

Early surgical intervention
◦ Invasive mold infections
 Zygomycetes
 IA in certain settings
◦ Candidal endovascular infections

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Settings where used:
◦ Established practice:
◦ Increasing confidence in MIC breakpoints for azoles &
echinocandins in Candida

Limited data to support


Heightened clinical suspicion necessary for timely dx
Future directions
◦ Improvement in clinical prediction rules & strategies for
empiric/pre-emptive/prophylactic therapy
◦ Increased standardization & availability of adjunctive
diagnostic methods
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