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. 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