Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Diagnosis and treatment of invasive fungal infections Wouter Meersseman, University Hospital Leuven General Internal Medicine –Medical Intensive Care Ostersund, Sweden 26 05 2015 Global Action Fund for Fungal Infections (www.gaffi.org) Fungal infection Case fatality rate Estimated deaths Comments Cryptococcal meninigitis 15-20% USA > 50% developing world 600,000 CDC estimate Invasive aspergillosis 50% in developed world if treated > 100,000 Many missed diagnoses globally Chronic pulmonary aspergillosis 15% in developed world > 450,000 Underdiagnosed and mistaken for TB Candida bloodstream infection 40% if treated > 120,000 Pneumocystis pneumonia 15% in AIDS 50% in non-AIDS > 80,000 Most cases in Africa not diagnosed and 100% mortality Mucormycosis 10-25% cutaneous 95% disseminated 20,000 No exact figures Total > 1,350,000 Probably a significant underestimate Cryptococcal disease Cryptococcal disease • 67-year old man • Heart transplant recipient 6 yrs earlier • Presents with 3-month history of fever and fatigue • Was on mycophenolate and cyclosporin • Gradually apathetic and mild memory problems Lumbar puncture: 102 cells, 47% lymphocytes, protein 990 mg/lit and glucose 42 mg/dl, cryptococcal antigen negative, india ink staining negative Culture CSF after three days growth of Cryptococcus neoformans var. grubii Complete resolution of fever after 1 week of ampho B and 5flucytosine Cryptococcal disease: diagnosis • Symptoms begin indolently over a period of 1-2 weeks: fever, malaise, headache. Prolonged symptoms more frequent in HIV-negative patients (cancer, steroids, transplant recipients) • Mass lesions in the brain rarely occur in HIV-infected patients, and in 10% of HIV-negative patients • India ink staining positive > 75% of HIV-infected patients, in only 50% of HIV-negative patients • Cryptococcal antigen testing very sensitive in HIV-infected patients (95%) • Measure opening pressures in CSF !!! 42% of suspected cases had confirmed cryptococcal meningitis Amphotericin B + 5FC superior !! - Crypto-meningitis, 299 patients - Ampho B 1 mg/kg 5-FC 100 mg/kg/day Fluconazole 800 mg/day Treatment strategy - combo: 2 weeks→fluco 400 mg 8 wks - mono: 4 weeks→ fluco 400 mg 6 wks • Randomization after 7-11 days of combination therapy with amphotericin B 0,7-1,0 mg/kg and fluconazole 800 mg per day • Consolidation and maintenance phase with fluconazole • Therapeutic lumbar punctures on the day of diagnosis and day 7 and 14 of treatment • Primary end-point 26 week mortality Cryptococcal disease: still substantial mortality Cryptococcus gattii infections: this is another disease than neoformans infections !!! • • • • • • Originally most cases come from Papua New Guinea and other subtropical areas (Brazil, India,…) Linked to eucalyptus tree Animals serve as sentinels Can also cause meningo-encefalitis, but to a lesser extent Occurs nowadays also in more northern regions (climate change) Does occur more often in less immunocompromised patients (smokers, COPD, marihuana) Global Action Fund for Fungal Infections (www.gaffi.org) Fungal infection Cryptococcal meninigitis Invasive aspergillosis Chronic pulmonary aspergillosis Case fatality rate 15-20% USA 600,000 > 50% developing world Cryptococcal disease: 50% in developedIFI > 100,000 deaths/year world if treated Comments CDC estimate 40-50% of the 1,350,000 Many missed diagnoses globally 15% in developed > 450,000 and cost Underdiagnosed Drug availability challenges world and mistaken for TB Rapid bed-test available Candida bloodstream infection 40% if treated Pneumocystis pneumonia 15% in AIDS 50% in non-AIDS Mucormycosis 10-25% cutaneous 95% disseminated Total Estimated deaths > 120,000 Huge potential to save lifes > 80,000 Most cases in Africa not diagnosed and 100% mortality 20,000 No exact figures > 1,350,000 Probably a significant underestimate Global Action Fund for Fungal Infections (www.gaffi.org) Fungal infection Case fatality rate Estimated deaths Comments Cryptococcal meninigitis 15-20% USA > 50% developing world 600,000 CDC estimate Invasive aspergillosis 50% in developed world if treated > 100,000 Many missed diagnoses globally Chronic pulmonary aspergillosis 15% in developed world > 450,000 Underdiagnosed and mistaken for TB Candida bloodstream infection 40% if treated > 120,000 Pneumocystis pneumonia 15% in AIDS 50% in non-AIDS > 80,000 Most cases in Africa not diagnosed and 100% mortality Mucormycosis 10-25% cutaneous 95% disseminated 20,000 No exact figures Total > 1,350,000 Probably a significant underestimate Invasive aspergillosis Invasive aspergillosis • Is it a frequent disease? • In what kind of patients do we see invasive aspergillosis? • What is the significance of a positive culture result from a respiratory specimen? • How do you diagnose invasive aspergillosis? • What is the treatment for invasive aspergillosis? • Is there a problem of resistance? Invasive aspergillosis • Is it a frequent disease? • In what kind of patients do we see invasive aspergillosis? • What is the significance of a positive culture result from a respiratory specimen? • How do you diagnose invasive aspergillosis? • What is the treatment for invasive aspergillosis? • Is there a problem of resistance? Estimated number of cases of invasive fungal infection UK [2002] in several groups of immunocompromised patients Patient group Number of patients Invasive candidosis/ Expected number Invasive candidaemia risk invasive candidosis/ aspergillosis estimates** candidaemia risk estimates@ Allo HSCTx Expected number invasive aspergillosis 4% 32 10% 79 5% 148 1.9% 56 3% 488 6% 976 3% 869 2% 579 1% 1316 1.5%# 1975 1% 2101 0.2% 420 5.6% 21 1.9% 7 490 0.02% 5 1 4% 26 793 Solid organ Tx 2953 Leukaemia 16269 Solid tumour (neutropenic) Advanced cancer 28955 131678 ICU 210130 Burns 378 Renal dialysis 0.2% 24536 HIV/AIDS Probably underestimated 0.2% 661 Totals 5466 ** no estimate for surgical patients, but some are in ICU, or have advanced cancer @ no inclusion of most chronic chest, steroid-treated patients, an increasing group # the literature figure is 6%, but felt to be autopsy selection bias, so reduced by 75%. http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1196942156347 4120 Autopsy analysis of invasive fungal infections Data on 1200 autopsies over 20 years 31% had IFI Only 50% was diagnosed premortem Parameter Age, yrs, mean Sex, male, n Haematological patients, n Nonhematological patients, n COPD, n Solid organ transplants, n Systemic disease, n Cirrhosis, n Other, n SAPS II, mean Predicted mortality, % Observed mortality, % ICU length of stay, days Hemodialysis in ICU, n Mechanical ventilation, n Neutropenia (<500/mm3), n Autopsy, n All (n=1 27) 61 84 38 89 35 9 Proven (n=56) Probable (n=49) Possible (n=2) Colonization (n=20) 59 39 26 30 12 4 63 35 12 37 21 5 61 2 0 2 2 0 64 8 0 20 0 0 17 6 22 54 53% 86% 20 54 123 19 76 6 3 5 57 58% 98% 14 27 56 12 52 8 0 3 0 0 3 3 0 14 52 43 54 49% 31% 51% 90% 0% 50% 23 6.9% of 32 all admissions 28 20 0 7 Retrospective 47 2 18 A lot of 6 0 autopsy data 1 19 0 admissions 5 1850 Meersseman W. Invasive aspergillosis in critically ill patients without malignancy Am J Respir Crit Care Med 2004 40 critically ill patients with H1N1: 9 developed invasive aspergillosis (23%) Major risk factor: steroids for ARDS Clinical epidemiology (US data) Underlying disease (960 patients) (2004-2008) 1. 2. 3. 4. 5. 6. Haematological malignancy 464 Solid organ transplant 280 Stem cell transplant 268 HIV/AIDS 14 Immunodeficiency 4 Other 22 48.3 % 29.2 % 27.9 % 1.5 % 0.4 % 2.3 % Steinbach WJ et al. Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry. J Infect 2012, 65, 453-464 Increased time to onset of IA in SOT A positive airway sample is in line with colonisation in most cases 4 Danish hospitals (3 months) (Jan March 2007) 1. 11.368 airway samples 2. 151 patients 3. Proven (n=3), probable (n=11), ABPA (n=4), colonised (n=133) 4. 55% cystic fibrosis, 13% COPD, 7% hematological, 18% ICU 5. ? Incidence 0.9-1.1 per 100.000 inhabitants Mortensen KL et al. A prospective survey of Aspergillus spp, in respiratory tract samples. Eur J Clin Microb Infect Dis 2011, 30:1355 Risk of acquisition (and pace of progression) Examples of at-risk patients and pace of progression 25% 20% 15% 10% 5% True incidence invasive aspergillosis dependent on level of immunosuppression 0.1-15% PPV of culture depending on level of Degree of immunocompromise immunosuppression Invasive aspergillosis • Is it a frequent disease? • In what kind of patients do we see invasive aspergillosis? • What is the significance of a positive culture result from a respiratory specimen? • How do you diagnose invasive aspergillosis? • What is the treatment for invasive aspergillosis? • Is there a problem of resistance? EORTC-Strict Definitions for Invasive Fungal Infections – in hemato/onco patients 2002 criteria1 2008 criteria2 Proven Proven Positive culture from a tissue biopsy or a usually sterile fluid (excluding BAL) Positive culture from a tissue biopsy or a usually sterile fluid (excluding BAL) Probable Probable Mycology + 1 major (nodule with halo or air crescent) or 2 minor radio-clinical signs) Mycology + presence of dense, well-circumscribed lesion with/without halo, or an air-crescent sign, or a cavity Possible Either radioclinical signs or mycology 1 2 Ascioglu S, et al. Clin Infect Dis. 2002; 34:7–14. De Pauw B, et al. Clin Infect Dis. 2008; 46(12): 1813–1821. Possible Specific radiological signs (as defined above) ‘halo sign’ Patients presenting with a halo sign had significantly better responses to treatment and greater survival to 84 days than did patients who presented with other imaging findings. Halo sign almost exclusively seen in neutropenic patients (coagulation necrosis) Greene RE et al, Clin Infect Dis, 2007, 44: 373-9. 41-year old lady with acute myeloid leukemia Neutropenic for 15 days Fever for 4 days CT-scan: reversed halo sign DEVELOPMENT OF PULMONARY CAT-IMAGE Caillot et al. J Clin Oncol 2001; 19:253-9 Neutropenia Halo sign D 0-5 Air-space consolidation D 5-10 Air-crescent sign D 10 -20 Nodules in a patient with more than 10 days neutropenia and fever not responding to broadspectrum antibiotics A patient who is over 10 days neutropenic, develops pulmonary and brain lesions • Halo sign: only applicable to neutropenic patients • Radiology in ICU “clouded” by atelectasis, pleural effusions, ARDS • Necrotizing, cavitating lesions: not specific Direct examination and culture • Rapid • Useful to interpret culture results • PPV depends on the degree of immunodeficiency • Lacks sensitivity • Gram stain not optimal • Fluorescent dyes: Calcofluor White • No species identification – Yeast versus mold – Aspergillus-like hyphae versus Zygomycetes Sensitivity culture and microscopy No. (%) of patients Proven IA Probable IA Possible IA Total Result BAL (n = 4) (n = 43) (n = 20) (n = 67) Positive result of DE 1 (25%) 24 (56%) 5 (25%) 30 (45) Positive culture result 2 (50%) 32 (74%) 3 (15%) 37 (55) Positive result of DE and/or culture 2 (50%) 37 (86%) 7 (35%) 46 (69) DE, direct examination Cornillet A. Comparison of Epidemiological, Clinical and Biological Features of Invasive Aspergillosis. CID 2006; 43: 577 Non-culture based methods Mannan Galactomannan (1-3)β-D-glucan Hope WW, et al. Laboratory diagnosis of invasive aspergillosis. Lancet Infect Dis 2005; 5:609-22 Non-culture based methods in the diagnosis of mould and yeast infections A. fumigatus Non-fumigatus aspergillus Fusarium Zygomycetes Candida Cryptococcus Histoplasma Penicillium marneffei Trichosporon GM + + + + + + BetaG + + + + + + + Hope WW et al. Lancet Infect Dis 2005; 5: 609-22 PCR + + + + + + Sources of variability: patient population Corticosteroid-induced Chemotherapy-induced cytopenia immunosuppression Galactomannan: low Galactomannan: high Balloy et al. Infect Immun 2005; 73: 494 Chamilos et al. Haematologica 2006; 91: 986 In non-neutropenics galactomannan is cleared by circulating neutrophils Verweij. Failure to detect circulating Aspergillus markers. J Clin Microbiol 2000: 3900 Performance GM in serum and BAL OD index cut-off: 1,5 1,0 0,7 0,5 BAL serum BAL serum BAL serum BAL serum Sensitivity (%) 81 23 81 27 85 31 88 42 Specificity (%) 96 100 93 98 92 98 87 96 PPV (%) 81 100 79 88 73 89 72 85 NPV (%) 89 68 89 69 93 70 93 74 Meersseman et al., Am J Respir Crit Care Med 2008, 177: 27-34. Performance GM in serum and BAL Meersseman et al., Am J Respir Crit Care Med 2008, 177: 27-34. Important caveat: galactomannan less useful in patients on posa prophylaxis Performance GM in patients on posaconazole Conclusion: diagnosis of IA • Much easier nowadays • Combination of culture, biomarker and radiological signs • Blood GM and CT scan: applicable early in the diagnosis (in neutropenic patients) • BAL – GM: think of it in nonneutropenics (GVHD – ICU patients with risk factors) • 59-year old man • One year ago diagnosis of myelodysplastic syndrome with 5% circulating neutrophils • Now receiving ara-C and idarubicine for AML • Day 30 persistent fever and painful skin lesions • Negative galactomannan, negative blood cultures • Culture results of BAL negative According to protocol: look for another site and etiology Differential diagnosis - Aspergillosis Fusariosis Scedosporiosis (mucor) hyalohypho… Fungal culture of the skin biopsy: Fusarium solani Invasive aspergillosis • Is it a frequent disease? • In what kind of patients do we see invasive aspergillosis? • What is the significance of a positive culture result from a respiratory specimen? • How do you diagnose invasive aspergillosis? • What is the treatment for invasive aspergillosis? • Is there a problem of resistance? Amfotericin B Echinocandins Azoles Posaconazole: prophylaxis – Prophylaxis of invasive fungal infections in high-risk patients (SCTx – GvHD, AML-MDS) • Until March 2014 – only available as Noxafil oral suspension – Dosing: • Prophylaxis: 3 x 200 mg/day • Treatment: 2 x 400 mg/day or 4 x 200 mg/day Posaconazole oral suspension - PK • Absorption – 2.6-4-fold higher if taken with a meal – High-fat meal enhances absorption (Fresubin) – Ranitidine & PPI: gastric pH: 40% decrease in posaconazole AUC and Cmax • Avoid concomitant use of histamine 2blockers or PPIs! – Mucositis (HSCT recipients with GvHD?) Schiller D et al. Clin Ther 2007; 29: 1862-1886 Goodwin M et al. JAC 2007. NOXAFIL® (posaconazole) Gastro-resistant Tablets: Product Characteristics1 • Designed to help prevent immediate drug release in the stomach and delay the release of posaconazole until the tablets reach the small intestine1 • 100 mg posaconazole dispersed in hydroxypropylmethyl cellulose acetate succinate (4:1) • NOXAFIL gastro-resistant tablets are packaged in a blister in cartons of 24 (2x12) or 96 (8x12) tablets1 • No dose adjustments are required when used concomitantly with antacids, H2-receptor antagonists, and PPIs • No (significant) impact of food • Available & Reimbursed since March 2015 1. Krishna G et al. Antimicrob Agents Chemother. 2012;56;4196–4201. 2. SmPC NOXAFIL®(posaconazole), 09/2014. *Tablets not actual size NOXAFIL® Gastro-resistant Tablet* (100 mg) 53 NOXAFIL® (posaconazole) IV Solution: Composition and Nature1 • Each vial contains 300 mg of posaconazole. • Each mL contains 18 mg of posaconazole. • Posaconazole IV solution was developed to ensure adequate posaconazole exposure in patients unable to tolerate/absorb oral posaconazole formulations; a switch to oral administration is recommended as soon as the patient’s condition allows • The intravenous formulation of posaconazole is an aqueous solution containing the solubilizer sulfobutyl ether-beta-cyclodextrin (SBECD) • Available and reimbursed Q4 2015? . 1. SmPC NOXAFIL®(posaconazole), 09/2014. * Vial not actual size 54 Dosing posaconazole formulations Dosing Remarks Oral suspension Prophylaxis: 3 x 200 mg Treatment: 2 x 400 mg or 4 x 200 mg With a high-fat meal or Fresubin Without PPI or ranitidine, if not possible: add cola Dose fractionnation Gastro-resistent tablet LD day 1: 2 x 300 mg (= 2 x3 tablets) MD (day 2): 1 x 300 mg (= 1x3 tablets) No food effect No PPI effect Do not crush or chew tablet! IV formulation LD day 1: 2 x 300 mg MD (day 2): 1 x 300 mg Central line: 90 min Peripheral line (preferably only one administration): 30 min +16,7 mL WFI Dilute in 150 mL Glu 5% or NaCl 0,9% Targeted therapy for invasive aspergillosis 392 Amphotericin B Enrolled 3 8 Safety 196 185 Population 2 0 Voriconazole No Treatment Incorrect Randomization No Definite or Probable Aspergillosis per Blinded DRC Success at 12 wk Mortality 194 185 52 Intention to Treat 133 Population 50 144 53% 29% -21% -13% 32% 42% Herbrecht, N Engl J Med 2002 Isavuconazole or Cresemba Intravenous solution does not contain cyclodextrin, once-day regimen is possible, oral treatment is feasible, more predictable pharmacokinetics, some activity against mucormycosis Why TDM? Wide intra-and interindividual variability Correlation between efficacy/toxicity and drug levels Proposed reference interval trough levels at steady state: 2-5.5 µg/mL Pascual A et al. CID 2008; 46 (2): 201-11. Inter- en intrapatient variability in plasma exposure 1. Non linear kinetics – increasing the dose gives unproportional increase in exposure! 2. Extensive CYP450 metabolisation Drug-drug interactions – difficult to manage: in UZ Leuven: CPOE alerting module 3. Genetic polymorphism CYP2C19 – especially important in Asian population (up to 20% vs. Caucasians: 2%) 4. Influence of food (enteral feeding in ICU…) – should be given without meal! Interpatient variability (correlation dose - level) Intrapatient variability (consecutive levels within patient) Trifilio S. Cancer 2007; 8: 1532-5. Side effects • Cumulative dose – longterm treatment – Phototoxicity – Squamous cell carcinoma – Periosteal ossification (fluoride excess) • High levels – Hepatotoxicity – Visual disturbances – Neurotoxicity Luke DR. J Pharm Sci 2010; 99(8): 3291-301. Wermers RA et al. CID 2011; 52:604-611. Azole resistance frequency in A. fumigatus 1997–2009 Bueid A et al. J. Antimicrob. Chemother. 2010;65:2116-2118 SCARE study Overal resistance rate 3.2 % (pan-azole) Combination study voriconazole + anidulafungin or placebo • • Treatment with the combination of voriconazole and anidulafungin resulted in a lower all-cause mortality rate at six weeks compared to voriconazole alone This difference did not achieve the pre-specified threshold for statistical superiority KM Survival to Week 12 (MITT) • • • • Majority of MITT pts were diagnosed with probable IA based on positive GM (serum and/or BAL) (218/277 (78.7%)): In a post-hoc analysis superiority demonstrated in this subgroup. Mortality in the GM-based group at week 6 was 17/108 (15.7%) for combination and 30/110 (27.3%) for monotherapy; p-value was <0.05 (95% CI -22.69, -0.41) The safety and tolerability of the combination of voriconazole and anidulafungin in this study was similar to that of voriconazole monotherapy. Marr K et al. Ann Intern Med 2015;162: 81-89, P= 0.08 Global Action Fund for Fungal Infections (www.gaffi.org) Fungal infection Cryptococcal meninigitis Invasive aspergillosis Chronic pulmonary aspergillosis Candida bloodstream infection Pneumocystis pneumonia Case fatality rate 15-20% USA > 50% developing world Estimated deaths Comments 600,000 CDC estimate Invasive aspergillosis: 8-10% of the 1,350,000 50% in developed > 100,000 Many missed world if treated IFI deaths/year diagnoses globally 15% in developed > 450,000 Underdiagnosed world Substantial progress in early and diagnosis mistaken for TB (galactomannan, CT scan) 40% if treated > 120,000 Substantial progress in treatment (voriconazole TDM, posaconazole tablet and IV, 15% in AIDS isavuconazole) > 80,000 Most cases in Africa 50% in non-AIDS not diagnosed and Potential danger of azole resistance 100% mortality Mucormycosis Total 10-25% cutaneous No“things” exact figures No high20,000 potential for newer to improve 95% disseminated > 1,350,000 Probably a significant underestimate Global Action Fund for Fungal Infections (www.gaffi.org) Fungal infection Case fatality rate Estimated deaths Comments Cryptococcal meninigitis 15-20% USA > 50% developing world 600,000 CDC estimate Invasive aspergillosis 50% in developed world if treated > 100,000 Many missed diagnoses globally Chronic pulmonary aspergillosis 15% in developed world > 450,000 Underdiagnosed and mistaken for TB Candida bloodstream infection 40% if treated > 120,000 Pneumocystis pneumonia 15% in AIDS 50% in non-AIDS > 80,000 Most cases in Africa not diagnosed and 100% mortality Mucormycosis 10-25% cutaneous 95% disseminated 20,000 No exact figures Total > 1,350,000 Probably a significant underestimate Chronic aspergillosis Think of it in people with longstanding cough and low-grade fever, previous history of tuberculosis, COPD or sarcoidosis, No immunosuppression required. Important role for antibody testing (IgG against Aspergillus, precipitines) No role for antigen markers such as galactomannan in blood Role for long term treatment with voriconazole Global Action Fund for Fungal Infections (www.gaffi.org) Fungal infection Cryptococcal meninigitis Invasive aspergillosis Chronic pulmonary aspergillosis Candida bloodstream infection Pneumocystis pneumonia Mucormycosis Total Case fatality rate 15-20% USA > 50% developing world Estimated deaths Comments 600,000 CDC estimate Chronic aspergillosis: important entity under50% in developed > 100,000 Many missed diagnosed, especially of importance in “poor” world if treated diagnoses globally countries 15% in developed > 450,000 world Underdiagnosed and mistaken for TB Guidelines will be published in the near future 40% if treated > 120,000 Think of it in people with underlying lung diseases. Perform antibody testing 15% in AIDS > 80,000 Most cases in Africa 50% in non-AIDS notwith diagnosed and Role for longterm treatment voriconazole 100% mortality 10-25% cutaneous 95% disseminated 20,000 > 1,350,000 No exact figures Probably a significant underestimate Global Action Fund for Fungal Infections (www.gaffi.org) Fungal infection Case fatality rate Estimated deaths Comments Cryptococcal meninigitis 15-20% USA > 50% developing world 600,000 CDC estimate Invasive aspergillosis 50% in developed world if treated > 100,000 Many missed diagnoses globally Chronic pulmonary aspergillosis 15% in developed world > 450,000 Underdiagnosed and mistaken for TB Candida bloodstream infection 40% if treated > 120,000 Pneumocystis pneumonia 15% in AIDS 50% in non-AIDS > 80,000 Most cases in Africa not diagnosed and 100% mortality Mucormycosis 10-25% cutaneous 95% disseminated 20,000 No exact figures Total > 1,350,000 Probably a significant underestimate Candida bloodstream infections and invasive candidiasis: diagnostic issues Clinical scenario A 62-year old man was admitted to the intensive care unit with a severe pneumococcal pneumonia. On the sixth hospital day, he remained intubated and received broad-spectrum antibiotics for his pneumonia when new fever and hypotension developed, requiring volume resuscitation and administration of vasopressors. The patient has bilateral infiltrates, requires 55% oxygen and has a creatinine level of 3.4 mg/dl. Two days later, you get a phone call that yeasts grow from the blood cultures (taken on the day of new onset fever). A decision is made to start antifungal treatment. Relevant questions: - Should antifungal treatment have been started earlier? - Should your patient has been on prophylaxis? - What are the treatment options? Treatment of proven/probable invasive fungal infection Pre-emptive therapy in early diagnosis Empiric therapy in (persistent) fever Prophylaxis in high/medium risk patients Problems with the diagnosis of Candida infections • Three types of diseases Candidemia (CVC or bacterial translocation from the gut) Candidemia with deep-seated infection Deep-seated infection without candidemia • Gold standard of proven disease performs poorly Blood cultures require -at least 1 CFU/ml -equals 5.6 x 103 CFU in blood volume (0.2% of systemic circulation) •6-yr autopsy study •Autopsy rate 75% •41 of 803 autopsies (5.1%) disseminated candidiasis at autopsy •37 had blood cultures; 16 had fungaemia (43%) Berenguer et al,Diagn Microbiol Infect Dis 1993;17:103-109 If diagnosis performs bad, should we prophylaxe our ICU patients? Author Patients Setting Therapy Fungal infections fluconazole Pelz Mortality placebo fluconazole placebo 260 SICU FLU 800 load then 400mg po, od until ICU discharge 8.5 15.4 10.7 12.3 43 SICU FLU 400mg iv, od 8.7 35.0 30.4 50.0 Garbino 204 mixed FLU 100mg iv, od ( + other agents) 3.8 9.9 38.8 40.6 Ables 119 SICU FLU 800mg load then 400mg po/iv, od until ICU discharge 13.3 18.6 20.0 18.6 Eggimann FLU = fluconazole; po =oral; iv = intravenous; SICU=surgical intensive care unit Prophylactic Treatment with Fluconazole in ICU Patients → Decreases incidence of invasive candidiasis → Has no mortality benefit OR 0.44 (CI 0.27-0.72) OR 0.87 (CI 0.59-1.28) Comments • Widespread use of prophylaxis not warranted - emergence of resistance in previously susceptible strains - shift to less susceptible or resistant non-albicans spp. (e.g. C.glabrata) - may lead to more adverse drug reactions + potential for interactions • Should target only those patients at the highest risk - major abdominal surgery with recurrent perforation and/or anastomotic leaks - presumed risk of invasive candidiasis = 10-15% Can we predict more accurately and treat according to risk factors? • Prospective cohort study in 933 surgical ICU patients • 455 historical controls • 478 patients treated with fluconazole, 800mg iv load, then 400mg /day for 4 weeks, started when corrected colonization index (CCI)* > 0.4 CCI = highly positive samples total number of samples Candida infections 3.8% vs. 7.0%; p=0.03 %7 6 > 100 CFUs for rectal & oropharyngeal swabs > 105 CFUs/mL for urine, gastric & tracheal aspirate 5 Proven ICU-acquired candidiasis 0% vs. 2.2%; p< 0.001 4 3 2 1 0 Piarroux R, et al. Crit Care Med 2004; 32: 2443-9 fluconazole placebo Colonization from airway samples: no reason to treat 1587 admissions 301 died (19 %) 232 autopsies (autopsy rate 77%) 135 patients with evidence of pneumonia (58 %) 77 patients with respiratory sample positive for Candida spp (57 %) Candida pneumonia n=0 97 patiënts with no evidence of pneumonia (42 %) 58 patients without respiratory sample positive for Candida spp (43 %) Candida pneumonia n=0 Meersseman W et al. Intens Care Med 2009; 35: 1526-31 Pre-emptive Therapy: Candida score • Prospective cohort study in 1107 ICU patients • Patients had to be in the ICU for at least 7 days • Scoring system: - surgery 1 point - multifocal colonization 1 point - total parenteral nutrition 1 point - severe sepsis 2 points •Hypothesis: Candida score > 3 is associated with prevalence of Candidemia of 10-15% and as such the score could be used as a valuable pre-emptive tool •Drawback: diagnostic study, not a therapeutic study Leon C, et al. Crit Care Med 2009; 32: 2443-9 Pre-emptive Therapy: biomarkers (beta D-glucan) • Potential advantages - rapid turn-around time - not dependent on viable organisms - may be positive prior to cultures, and stay positive during treatment - may offer quantitative data with prognostic significance • Potential disadvantages - do not recover organisms - may not speciate Candida or distinguish between fungi - may need to be run in batch by clinical microbiology laboratory due limited number of samples - may have low treshold for contamination - financial costs Time to abandon prophylaxis and empiric therapy Select those patients in which you expect a 10-15% incidence of yeast infection - Candida score >3 - beta D-glucan or PCR In order to decrease the 50% “missed” diagnoses by picking up deep seated candidiasis Important caveat: false positive rate beta-Dglucan (high negative predictive value) Candida bloodstream infections and invasive candidiasis: therapeutic issues Candidemia treatment trials • “A is non-inferior to B” • Fungicidal anidulafungin (probably candins) clear Candida quicker than the fungistatic fluconazole (as does ampho B!) • Anidulafungin: only echinocandin that was compared to fluconazole What about increasing resistance to echinocandins? Problem is most relevant with Candida glabrata Increasing resistance of candida glabrata against echinocandins Echinocandin resistance against candida glabrata Clinical failure especially in patients with longstanding echinocandin use Global Action Fund for Fungal Infections (www.gaffi.org) Fungal infection Case fatality rate Estimated deaths Comments Cryptococcal meninigitis 15-20% USA 600,000 CDC estimate > 50% developing world Invasive candidiasis/candidemia Invasive aspergillosis 50% in developed world if treated Chronic pulmonary aspergillosis 15% in developed > 450,000 Underdiagnosed 100,000 deaths per year world and mistaken for TB Candida bloodstream infection Many missed diagnoses globally Emerging echinocandin resistance is a 40% if treated significant > 120,000 concern Pneumocystis pneumonia 15% in AIDS 50% in non-AIDS Mucormycosis 10-25% cutaneous 95% disseminated Total > 100,000 > 80,000 Most cases in Africa not diagnosed and 100% mortality 20,000 No exact figures > 1,350,000 Probably a significant underestimate Global Action Fund for Fungal Infections (www.gaffi.org) Fungal infection Case fatality rate Estimated deaths Comments Cryptococcal meninigitis 15-20% USA > 50% developing world 600,000 CDC estimate Invasive aspergillosis 50% in developed world if treated > 100,000 Many missed diagnoses globally Chronic pulmonary aspergillosis 15% in developed world > 450,000 Underdiagnosed and mistaken for TB Candida bloodstream infection 40% if treated > 120,000 Pneumocystis pneumonia 15% in AIDS 50% in non-AIDS > 80,000 Most cases in Africa not diagnosed and 100% mortality Mucormycosis 10-25% cutaneous 95% disseminated 20,000 No exact figures Total > 1,350,000 Probably a significant underestimate Pneumocystis jirovecii pneumonia • • • • • Cellullar immune deficiency (CD4) Most studies done in HIV High negative predictive value LDH Problems with PCR: “too sensitive”?? Immunofluorescence: “not sensitive enough”? Very high beta-D-glucan levels in PJP Global Action Fund for Fungal Infections (www.gaffi.org) Fungal infection Case fatality rate Estimated deaths Comments Cryptococcal meninigitis 15-20% USA > 50% developing world 600,000 CDC estimate Invasive aspergillosis 50% in developed world if treated > 100,000 Many missed diagnoses globally Chronic pulmonary aspergillosis 15% in developed world > 450,000 Underdiagnosed and mistaken for TB Candida bloodstream infection 40% if treated > 120,000 Pneumocystis pneumonia 15% in AIDS 50% in non-AIDS > 80,000 Most cases in Africa not diagnosed and 100% mortality Mucormycosis 10-25% cutaneous 95% disseminated 20,000 No exact figures Total > 1,350,000 Probably a significant underestimate Mucormycosis Incidences of mucormycosis over 6 decades (1940–1999), by host population, 929 cases Roden M et al., CID, 2005;41(5):634-53. Incidence of mucormycosis cases in a Belgian hospital from 2000 through 2009 • • • • • • 31 patients: 21 proven, 10 probable M/F: 16/15 Mean age: 54 years (12-79 years) 61% haematological patients 45% co-infections with Aspergillus (halo-sign!) Mortality rate = 65% (48%, directly related to infection) V. Saegeman et al., Emerg Infect Dis 2010, 16: 1456-1458. Big increasing mass in a neutropenic patients with BAL galactomannan negative: think of mucormycosis Galactomannan negative !! Mucormycosis Global Action Fund for Fungal Infections (www.gaffi.org) Fungal infection Case fatality rate Estimated deaths Comments Cryptococcal meninigitis 15-20% USA 600,000 > 50% developing world Mucormycosis CDC estimate Invasive aspergillosis 50% in developed world if treated Many missed diagnoses globally Chronic pulmonary aspergillosis 15% in developed > 450,000 recognized Underdiagnosed Increasingly in the voriconazole world and mistaken for TB era Candida bloodstream infection 40% if treated > 120,000 Does occur in immunocompetent patients Pneumocystis pneumonia Mucormycosis Total > 100,000 mainly as a necrotizing skin infection 15% in AIDS > 80,000 Most cases in Africa Liposomal ampho B preferred treatment 50% in non-AIDS not diagnosed and 100% mortality 10-25% cutaneous 95% disseminated 20,000 > 1,350,000 No exact figures Probably a significant underestimate Some new kids on the horizon… - In 2012 and 2013: 749 cases of infections with Exserophilum rostratum - Linked to epidural injections with methylprednisolone acetate - 61 deaths occurred Young lady in UZ Leuven, Belgium. Kidney transplant at the age of 34 Ethiopian origin. 6 months posttransplant: painful lesion left lower limb 4 months later Despite stopping immunosuppressants, transplantectomy Administration of lipo ampho B, isavuconazole, posaconazole Thick walled brown pigment on hematox eosin staining Cladophialophora bantiana Prospective study 2012005 TRANSNET - Skin Pulmonary Disseminated Brain (cladophialophora) In conclusion - High income countries Invasive infections: diagnostic issues (candida), emerging resistance (azole resistance in Aspergillus, echinocandin resistance in candida) - Resource limited countries Unacceptably high number of deaths in cryptococcal disease Increase in candida, aspergillus and mucormycosis in some countries No acces to drugs such as flucytosine