4 Candida Aspergillus Rhizopus Cryptococcus Blastomyces Histoplasma CoccidioidesParacoccidioidesMorphology: Yeasts, mouldsMatch picture to name
5 Diagnosis of Fungal Infection Clinical: fever, pulmonary symptoms, skin lesions,sinus tenderness, pain, etc.Risk factors (host)Neutropenia, steroids, iron overload, SOTRadiologicalChest x-rayCT scans of chest, sinuses, abdomenMicrobiologicalHistological: biopsy of suspect lesionsSerological: Antibody (limited) and antigen tests (galactomannan and CRAG)Molecular: Nucleic acids (PCR)CultivationBlood cultures: low yield for most mouldsCulture of suspect lesions by biopsyBAL fluid culture in patients with pneumoniaGeneralSpecific
6 Case 1A 58 year old man s/p partial colectomy for colon cancer develops fever, tachycardia, and hypotension (85/60) and is transferred to the ICU. He is on broad spectrum antibiotics, has a central venous catheter (CVC), a foley catheter, and is receiving total parenteral nutrition. Creatinine is rising, now 2.5.The lab reports that a blood culture is growing yeasts.
7 Case 1: What is the best intervention? Remove the CVC and repeat blood cultureStart an amphotericin B product IV (e.g. ambisome)Start fluconazole IVStart an echinocandin IV (e.g. micafungin), and switch to fluconazole if yeast is susceptible
8 Debates Should you remove the central venous catheter with candidemia? IDSA guidelines say YES: studies show faster clearance of fungemia and improved survivalRecent study in Clinical Infectious Diseases showed that in a cohort of 842 patients with candidemia, line removal was associated with decreased mortality and improved treatment success, but not in multivariate analysis (CID 2010;51:295)This study has been criticized on grounds that authors over-adjusted in multivariate analysis.Should care teams obtain an ID consult?IDSA Abstract: Marwa Shoeb et al. Patients who received IDCs were 9 times more likely to survive at 30 days than patients without IDCs when controlling for Apache-II score (hazard 9.03, 95% CI , p=0.0004). Conclusion: Infectious diseases consultations for patients with candidemia were associated with improved adherence to standards of care and decreased mortality without increasing costs or hospital stays.
9 Candida speciesYeasts, pseudohyphae (elongated single cells with constricted ends), and true hyphae (septations)Candida species: C. albicans, C. dubliniensis, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. pseudotropicalis, C.lusitaniae, C. guilliermondiiPart of the normal human microbiota: opportunistsOral cavity, GI and genital tractsDisease Risk factors: AIDS, diabetes, surgery, catheters, antibiotics, neutropenia, burns, dialysis
10 Candida Diseases Superficial Thrush: white patches on oral mucosa Vaginal candidiasis: thick curdlike discharge, puritis & burningDermatitis: diaper rash, intertriginous assoc w/ moistureErythema, papules, fissures, itching, burningOnychomycosis and paronychia: nailsCMC: defect in TH17 signaling
11 Candida Diseases Deep and disseminated Esophagitis: odynophagia, ulcerationCandidemia: 4th most common organismGI tract: hematologic malignancyUrinary tract: bladder catheterizationVascular catheter infectionsDisseminated disease: hepatosplenic (Alk P), nephric, fungemicEndophthalmitis: expanding white cotton ball (retina/vitreous)Endocarditis: usually requires surgeryClinical pearl: Candida pneumonia is rare
12 Fluconazole vs. AmB for Candidemia Study population: 237 non-neutropenic, immunocompetant patients with candidemia206 evaluable subjects ( )AmB mg/kg/day vs. fluconazole 400 mg/day for 14 days after last + blood cultureSuccess: 79% AmB vs. 70% Fluconazole(95% CI –5%, 23%, not significant)41 deaths with AmB, 34 with Flu (p = 0.2)More toxicity with AmBRex JH et al. N Engl J Med. 1994;331:
13 Caspofungin versus Amphotericin B for Invasive Candidiasis Study population: 224 subjects with clinical evidence of infection and a culture positive for Candida from blood or other sterile site were stratified by APACHE II score and presence of neutropeniaRandomized, double-blind, multi-center study:IV caspofungin OR IV amphotericin BMinimum of 10 days of IV therapy required; antifungal therapy continued for 14 days after last positive Candida cultureLower toxicity in the caspofungin armNeutropenic and non-neutropenicMora-Duarte J et al. New Eng J Med 2002 Dec 19;347(25):2020-9
14 Caspofungin versus Amphotericin B for Invasive Candidiasis Analysis of all patients (non-stratified)CaspofunginAmphotericin B1008081%73%60Successful outcomes (%)62%65%40P<0.0520Modified ITTEvaluable patientsSuccessful outcome = symptom resolution and microbiological clearanceMora-Duarte J et al. New Eng J Med 2002 Dec 19;347(25):2020-9
15 Guidelines for Therapy of Candidemia Not neutropenic, no prior azoles, germ-tube positive (C. albicans)Fluconazole at mg/d (clinically stable)Echinocandins: Caspofungin, Micafungin, AnidulafunginAmB (0.7 mg/kg/d): increased toxicity (cost vs. toxicity)Lipid formulations of AmB 3-5 mg/kg (LFAB) in setting of renal toxicitiesNon-albicans Candida; neutropenic patients, prior azole RxEchinocandinsAmphotericin B 0.7 mg/kg/d; LFABSequential AmB Flu therapySusceptible organism & clinical responseConsider susceptibility testingVoriconazole approved for candidemia; C. glabrata still a problemCatheter should be pulled when feasibleSeveral studies suggest mortality benefit, but sicker patients tend to have catheter retainedWhen in doubt, echinocandinize and step down to fluconazole!
16 Candidemia: Take Home Messages Don’t blow off a positive blood culture!Remove central venous catheters with + blood culture30% mortality overall, but goes from 15% when Rx started on day 0 of culture, to 41% when started day 4Don’t delay!Echinocandins just as effective as other agents, but less toxic and greater spectrum of Candida coveredFluconazole is good choice for stable patient when not exposed to previous azoles, and not neutropenicTreat for at least 14 days
17 Case 2A 45-year-old woman from Boston with poorly controlled insulin-dependent diabetes had facial and periorbital swelling for four days. On the day of admission she was unable to open her right eye (Panel A). On admission she had a white-cell count of 22,000 per cubic millimeter, with 84% neutrophils and bands and a moderate degree of metabolic acidosis (blood pH, 7.22; plasma bicarbonate concentration, 8 mmol per liter). A CT scan of the head (Panel B) showed involvement of the paranasal sinuses (arrow) and periorbital soft tissues. Material from the periorbital tissue (Panel C), stained with periodic acid-Schiff stain (×560), demonstrated irregularly shaped broad hyphae with right-angle branching (arrow).
19 Case 2: The most likely diagnosis is: A. Invasive aspergillosis with sinusitisB. Sino-orbital mucormycosisC. BlastomycosisD. Invasive dermatophyte infectionE. Cryptococcosis
20 Case 2: The best treatment is: Sharpened steel: call the surgeonsTreat underlying DKA with insulin dripStart ambisome IV at 5 mg/kg per dayStart posaconazole at 200 mg PO QIDA, B, and C.
21 Treatment of Mucormycois Surgery: early consultation and interventionTreat underlying host factors; reverse immunosuppression, acidosis, hyperglycemiaAntifungal therapy:Lipid-AmB: high doses, empiric and directedPosaconazole: oral salvage, follow on RxUnproven approachesIron chelation therapy with deferasirox?Combination therapy?Ampho + Echinocandins?Ampho + Posaconazole?
22 Surgery for zygomycosis 255 cases of pulmonary zygomycosis30 Duke, 225 literatureOverall mortality = 80%Retrospective analysis of mortality by treatment group (in subset of treated pts)Surgical (n= 36): 11%Medical (n= 56): 68%Difference highly significant (p = )Limitations: retrospective, selection biasTedder M. et al. Ann Thorac Surg 1994;57:
23 Posaconazole for zygomycosis van Burik JA CID 2006;42:e61-65Salvage therapy in 91 patients who were refractory (81) or intolerant (10) of initial therapy; 800 mg/dayComplete and partial responses in 60%, with stable disease in another 21% at 12 weeksGreenberg RN et al AAC 2006;50:126-33Salvage therapy in 24 patients with zygomycosis who failed or were intolerant of conventional antifungal therapy (11 rhinocerebral, 4 disseminated) 800 mg /day orally dividedSurvival in 19/24 = 79% compared with historical survival rates of 50-70% using first line therapyThese were both salvage studies; there are no large published studies examining the efficacy of posaconazole for initial treatment of mucormycosis
24 Mucormycosis (a.k.a. zygomycosis) Rhinocerebral and sino-orbital diseaseRisks: Diabetes (DKA), iron chelation with deferoxamineInvasion of orbit and brain from sinusesRx: surgery and high dose lipid AmphoPulmonaryRisks: Stem cell tx, leukemia, lymphoma, Solid organ txMay disseminate to brainBehaves like Aspergillus infectionHalo, crescent signs; angioinvasionOther: GI, cutaneous,disseminated, isolated cerebralWhy do patients with DKA develop mucormycosis?
25 The Iron-pH Connection Deferoxamine: used by fungi as siderophore and therefore increased riskSerum from DKA: acidic = 69 ug/dl free iron vs. basic = 13 ug/dl better growth of Rhizopus in acidic serum due to increase iron
27 Case 3NeutrophilsA 39 year-old woman had relapse of her acute myeloid leukemia and was treated with cytarabine and mylotarg (Anti-CD33 Ab) resulting in prolonged neutropeniaShe developed unexplained fevers (“febrile neutropenia”) despite treatment with ceftazidime and fluconazoleRemote tobacco use. WA resident, no travelExam: fever without localizing signsLabs: ANC = 0, UA negative, Blood cx negCXR: Bibasilar opacities
29 Case 3: What is most likely diagnosis and best treatment? Candida pneumonia; micafunginAspergillosis; amphotericin BAspergillosis; voriconazolePulmonary mucormycosis; ambisomeCryptococcosis: ampho B + 5FCHow would you confirm the diagnosis?
30 Invasive Aspergillosis Aspergillus species: ubiquitous mouldsA. fumigatus, A. flavus, A. terreus, A. niger, A. ustusUbiquity means no geographic predispositionOpportunistic pathogens: it’s the host!Conidia are infectious unit inhaled, form hyphaePrimary respiratory infectionAngioinvasion leads to necrosis of tissuePneumonia, sinusitisDissemination associated with high mortalitySkin, brain, GI tract, pericardium, myocardium
32 Invasive Aspergillosis Labs: routine labs not helpful; neutropenia is riskDiagnosisSuspect when risk factors and radiological findings are present; may be clinically silentCT chest: nodules, halo, crescent, infiltrate, effusionHistology of tissue: hyphae proven fungal infectionSeptate hyphae with 45 0 angle dichotomous branchingCulture: sputum, BAL fluid, tissueBlood cultures negative even with disseminationGalactomannan antigen, PCR
33 Galactomannan antigen testing for diagnosis of invasive aspergillosis Sandwich ELISA detection limit = 0.5 ng/mlTissue: serum, BAL fluid, CSFApproved in the United States and Europe as aid to diagnosis of invasive aspergillosis in adults (0.5 OD cutoff)False negatives: antifungal therapy, limited disease, SOTSensitivities of % reportedFalse positive rate is quite variable, depending on patient population (kids), underlying disease (mucositis), and cutoffFalse + or True +? Definition: biological vs. clinical?Absorbed GM from food, cereal grains, Bifidobacterial antigenAntibiotics: Zosyn, AugmentinTHM: Think aspergillosis in an appropriate host with radiographic abnormalities. Dx: galactomannan, culture, histology.
34 Aspergillosis Treatment options What is the single best agent? Azoles: voriconazole, posaconazole, itraconazoleEchinocandins: caspofungin, micafungin, anidulafunginPolyenes: Ampho B, Ambisome (liposomal), Abelcet (lipid)CombinationRx, voriconazole + anidulafungin: RCT underwayWhat is the single best agent?Herbrecht R. et al. Voriconazole vs. amphotericin B for primary therapy of invasive aspergillosis NEJM 2002:347; Unblinded RCT.At 12 weeks, success in 53% on vori, 32% on AmphoBSurvival in 71% on vori, 58% on AmphoBMuch less toxicity in vori armFluconazole: no activity
38 Case 3: 12 days later… Treatment: voriconazole Prior CTNew CT
39 Day 0, 4, 10 CTsCaillot D et al. Increasing Volume and Changing Characteristics of Invasive Pulmonary Aspergillosis on Sequential Thoracic Computed Tomography Scans in Patients With Neutropenia Journal of Clinical Oncology, Vol 19, Issue 1 (January), 2001:
40 Combination Therapy: Aspergillosis Animal models of infection show combination therapy with an azole and echinocandin improves survival, reduces pathology, and reduces organism burdenPetraitis V et al. J Infect Dis. 2003:187:MacCallum DM et al. AAC :Results of randomized controlled trials of combo therapy?Non-randomized, uncontrolled study of 47 subjects who failed initial therapy with an AmphoB regimen, salvage31 vori, 16 vori + caspo (Marr K et al. CID 2004;39: )Small, retrospective, non-randomized, uncontrolled trialBottom line: we need a RCT!Combination salvage therapy was associated with reduced mortality relative to voriconazole alone (HR, 0.27; 95% CI, ; P = .008).
41 Case 458 y.o. woman s/p renal transplant in 12/2000 for polycystic kidney disease, on MMF, tacrolimus, and prednisone, was admitted for elective surgeryPost-op CXR showed a LLL lung mass that was new since 2001 when she had an episode of pneumoniaDenied any fevers or pulmonary complaints
43 Exposures and Social History Social History: Microbiologist.Remote exposure to parakeets and limited exposure to dogs (all healthy)Most recent travel to Orcas and San Juan Islands in 9/06. Lopez Island in 7/05. Traveled to Italy 1 ½ yrs ago.
46 Further EvaluationCT head with contrast - no masses or abnormalities other than old aneurysm clipLP performed with normal OPnormal protein and glucoseacellularCSF CrAg negativefungal stain and culture negativeSerum CrAg negativeBlood cultures negative
49 Cryptococcus neoformans Yeast with worldwide distributionHigh concentrations in pigeon droppings, soilThick polysaccharide capsuleSexual mould form detected: Filobasidiella neoformansVarieties of C. neoformansSerotype A : var. grubiiSerotypes B and C: C. gattiiOutbreak on Vancouver Is. = “B”Serotypes D: var. neoformans
50 CryptococcosisOpportunistic infection: AIDS, cancer, organ transplantation, steroids, diabetesPrimary pathogen in selected cases (10-40%)Pathophysiology: Pneumonia dissemination via blood to meninges, skinSelf limited pneumonia: well circumscribed lesions with surprisingly meager inflammatory response; commonly untreated in normal hostMeningitis: (or disseminated disease) / immunocompromised host: treat with antifungalsAIDS: crypto meningitis common opportunistic infectionComplication: Elevated intracranial pressure (measure opening pressure at time of LP!!)Rare lesions of bone, prostate
51 Cryptococcosis Labs: Routine labs not generally helpful Diagnosis India ink prep of CSF ( historical interest)Cryptococcal antigen: serum , CSFSensitivity >95% with high specificityCultivationHistology: narrow based budding yeast, capsuleMucicarmine stain for capsule: specific for cryptoTreatmentAmpho B + 5-FC Fluconazole: meningitisFluconazole alone, Lipid-Ampho aloneItraconazole for intolerance or refractory diseaseFalse + CRAG:Rheumatoid factor Cancer. Very low-titer false-positive reactions have been reported .Infection due to Trichosporon spp. This organism produces the same polysaccharide in its capsule as is produced by the cryptococcus [1375, 1478].Infection due to Stomatococcus mucilaginosis As with Trichosporon infections, this organism produces a polysaccharide that cross-reacts with that of the cryptococcus .Infection due to Capnocytophaga canimorsus (formerly known as DF-2) Reported only once , the cause of this cross-reaction is not known.Contamination during pipetting in the laboratory Soaps and disinfectants use for slide washing Hydroxyethyly starch (HES) for intravascular volume replacement (fluid resucitation)CSF shuntingInterferonTHM: Cryptococcus gattii outbreak in Pacific Northwest! Same Dx and Rx.
52 Antifungal Review Membrane Function Polyenes: Amphotericin B Lipid Formulation AmB (Abelcet, AmBisome)NystatinCell Wall SynthesisEchinocandins: glucanCaspofunginMicafunginAnidulafunginMicrotubulesGriseofulvinErgosterol SynthesisAzoles: FluconazoleKetoconazoleItraconazoleClotrimazole VoriconazolePosaconazoleSqualene epoxidase inhibitors:TerbinafineNucleic Acid SynthesisPyrimidine analog: 5-Fluorocytosine (5-FC)Antifungal Review
53 Spectrum of Antifungal Agents Drug / FungusAspergillus spp.Candida spp.EndemicZygosFluconazole-+VoriconazoleMicafunginItraconazoleAmphotericinPosaconazoleFluconazole has activity against Basidiobolus
54 References Doctor fungus: http://www.doctorfungus.org/ IDSA guidelines:Infections by Organism: Fungi AspergillusBlastomycosisCoccidioidomycosisCryptococcal Disease CandidiasisHistoplasmosisSporotrichosis
55 Case 530 year-old HIV+ man admitted complaining of fever, weight loss, and anorexia for 2 monthsSH: Born in Louisiana, resident of CaliforniaExam: 39.7oC, Pulse 105, BP 90/50 General: cachectic with umbilicated papules on skin. Lungs: clear. CV: tachycardic without murmur. Abd: No hepatosplenomegaly. Neuro: non-focalLabs: Pancytopenia Meds: TMP/SMXAdmission diagnosis: dehydration, feverNo hx OI
56 Case 5 Chest radiograph: No acute disease Treatment: IVF, Ceftriaxone + metronidazolePersistent fever despite antibioticsBlood, urine, sputum cultures: no growthNew skin lesions apparent in hospitalCD4 count 50Serum ferritin level 21, 240Serum cryptococcal antigen: negativeDifferential diagnosis?
57 What organism is this? What is the best treatment? Skin biopsy: Silver stainBlood cultures grew Histo at 4 weeks. He was treated with IV ampho B but expired.Giemsa blood smear
58 Histoplasmosis Agent: Histoplasma capsulatum Diagnosis Treatment Dimorphic, endemic mycosisHas no capsuleDiagnosisTreatmentEpidemiology: sporadic worldwide with hyperendemic region in U.S.Mississippi and Ohio river valleysAssociated with exposure tobird (not infected) and bat (infected) guanoCaves and spelunkingBuilding demolitionbanq-im/Images/cyto46.jpg
59 Other Regional Endemic Mycoses in the United States CoccidioidomycosisCoccidioides immitis & posadasiiDesert Southwest: CA, AZ and Mexican borderPneumonia, MeningitisDiagnosis: cx, histology, serology (good)Rx: Flucon, AmphoB, ItraBlastomycosisBlastomyces dermatitidisDistribution: shadows histo in mid-western and SE USPneumonia, skin, bone dzDiagnosis: cx, histology (BBBBY)Rx: Itra, AmphoB, FluconVori, caspoImmitis (CA)Posadasii (non-CA)
60 US Endemic Mycoses: Common Themes Fungus grows in the environment as mouldRelease spores into air inhaled, form yeasts in tissuePrimary pulmonary infectionNo person to person transmissionFrequently asymptomaticCell mediated immunity contains infectionExposure based on geographyImmunocompetent and immunocompromised hosts are both at riskMost disease is in the immunocompetent host: self limitedSevere, disseminated and reactivation disease more common in compromised hostsTHM: Take a travel history, match travel to mental map of endemic fungi, consider disease presentation, order appropriate diagnostic tests to exclude