6/28/2012

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
1
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
2
6/28/2012

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
3
6/28/2012


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
4
6/28/2012

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
◦
◦
◦
◦
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
◦
◦
◦
◦
◦
◦
◦
◦
◦
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
5
6/28/2012


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

Transplant:
◦
◦
◦
◦

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




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
6
6/28/2012

Host
◦ Immune status
 Prolonged neutropenia
◦ Gastrointestinal absorption
◦ Renal function



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
7
6/28/2012


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
8
6/28/2012

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
















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
Allou N, Allyn J, Montravers P. When and how to cover for fungal infections in patients with severe sepsis
and septic shock. Curr Infect Dis Rep 2011; 13: 426-432
Azoulay et al. Systemic antifungal therapy in critically ill patients without invasive fungal infection. Crit
Care Med 2012; 40: 813-822
Bartlett JG, Auwaerter PG, Pham PA. Johns Hopkins Antibiotic Guide. Diagnosis and treatment of
Infectious Diseases. 2010
Bergman SJ, Tyagi I, Ronald K. Antifungal dosing in critically ill patients. Curr Fungal Infect Rep 2010; 4:
78-86
Drew RH & Townsend ML. Antifungal Drug Resistance: Clinical relevance and impact of antifungal drug
use. Curr Fungal Infect Rep 2010; 4: 129-136
Lai et al. Current challenges in the management of invasive fungal infections. J Infect Chemother 2008;
14: 77–85
Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 6th edition. 2004
Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of candida blood stream infection until
positive culture results are obtained: A potential risk factor for hospital mortality. Antimicrob Agents
Chemother 2005; 49: 3640-3645
Mokaddas et al. Value of (1-3)-b-D-glucan, Candida mannan, and Candida DNA detection in the
diagnosis of candidaemia. Clinical Microbiology and Infection 2011; 17: 1546–1553
Muskett H., et al. Risk factors for invasive fungal disease in critically ill adult patients: a systematic
review. Critical Care (2011) 15: R287
Nguyen et al. Performance of Candida Real-time Polymerase Chain Reaction, b-D-Glucan assay, and
blood cultures in the diagnosis of invasive candidiasis. Clinical Infectious Diseases 2012;54(9):1240
1248
Patel GP, et al. The effect of time to antifungal therapy on mortality in candidemia associated septic
shock. Am J. Ther. 2009; 16: 508-511
Perfect et al. Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by
the Infectious Diseases Society of America. Clinical Infectious Diseases 2010; 50:291–322
Perloth J, Choi B, Spellberg B. Nosocomial fungal infections: epidemiology, diagnosis, and treatment.
Medical Mycology (2007) 45: 321-346
Playford GE, Lipman J, Sorrell TC. Prophylaxis, empirical and preemptive treatment of invasive
candidiasis. Current Opinion in Critical Care 2010;16:470–474
Strasfeld L & Wienstock DM. Antifungal prophylaxis among allogeneic hematopoietic stem cell transplant
recipients: current issues and new agents. Expert Rev Anti Infect Ther . 2006; 4(3): 457-468
9