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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 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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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. 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