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Invasive FungalInfections Management Updates Ahmed Saad MD. FACP. Ass Prof .Cairo university
Review• Different types of Invasive fungi• Changing local epidemiology• Risk factors• Clinical picture• Diagnosis• Treatment & prophylaxis
Incidence of Systemic Infections: Bacterial vs Fungal 225,000No. of Cases of Sepsis 150,000 Gram-positive bacteria Gram-negative bacteria Fungi 75,000 25,000 15,000 10,000 5000 0 1991 1993 1995 1997 1999 2001 YearMartin GS, et al. N Engl J Med. 2003;348(16):1546-1554.
Nosocomial Bloodstream Infections in US Hospitals: 1995-2002CoNS, coagulase-negative staphylococci; BSI, blood stream infection.Surveillance and Control of Pathogens of Epidemiological Importance (SCOPE) study.Wisplinghoff H, et al. Clin Infect Dis. 2004;39:309-317.
Invasive Candidiasis Mortality Associated with Candidemia 45 40 35 40% Percent of Patients 30 25 20 25% 15 10 5 0 Patients with Patients with bacterial candidal bloodstream (non-candidal) infections bloodstream infectionsAdapted from Edmond MB et al Clin Infect Dis 1999;29:239–244. 9
Impact of delayed treatment on mortalityMorrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of Candida bloodstream infection until positive bloodculture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005;49: 3640–5.
Review• Different types of Invasive fungi• Changing epidemiology• Clinical picture• Risk factors• Diagnosis• Treatment & prophylaxis
Infections Caused by Non-albicans Candida Are Increasing100 90 80 C. krusei 70 C. parapsilosis 60 C. tropicalis 50 C. glabrata 40 C. albicans 30 Other 20 10 0 1997-1998 1999 2000 2001 2002 2003Neither C. glabrata nor C. krusei showed a consistent increase or decrease in isolation rates overallIncreased rates of isolation of C. tropicalis (4.2% to 7.5% increase) and C. parapsilosis (4.6% to 7.3% increase)over 134,000 consecutive isolates of Candida from cases of invasive candidiasis at 127 medical centersPfaller MA, et al. Clin Microbiol Rev. 2007;20(1):133-163.
Candida Species: Incidence vs MortalityIncidence of Candida albicans, 45.6%; incidence of non-albicans Candida, 54.4%*% Candida Species *This study is based on data for the 2019 patients (pediatric and adult) enrolled from July 1, 2004 through March 5, 2008 from 23 North American centers who received a diagnosis of proven candidemia, including 2.1% other non-albicans Candida [C. lusitaniae, C. dubliniensis, C. guilliermondii, other (not specified), and unknown]. Horn DL, et al. Clin Infect Dis. 2009;48(12):1695-1703.
Incidence of Fungal Infections after SOT Invasive Fungal Aspergillus Candida Infections Kidney & liver 1.4–14% 0–10% 90–100% Heart 5–20% 77–91% 8–23% Lungs/Heart- Lungs 15–35% 25–50% 43–72% Small Intestine 40–59% 0–3.6% 80–100%bardi S. et al. Transplant Int 2007;20:993–1015, Singh N. Clin Infect Dis 2000:31;545–53.
No of Candidal isolates (115) in 18 monthes Candida albicans 63.5% Candida dublinensis 4.3% Candida krusei 1.7% Candida parapsilosis 4.3% Candida glabrata 6.1% Candida tropicalis 20.0%
Am 0 20 40 60 80 100 120 ph o te ric in B Fl uc yt o si ne Fl uc on a zo le Vo r ic on az ol e C as po fu ng Candida Albicans in
0Am 20 40 60 80 100 120 ph ot er ic i n B Fl uc yt os in e Fl u co na zo le Vo ric on az ol e Ca sp of u ng in Candida tropicalis
Am 0 20 40 60 80 100 120 ph o te ric in B Fl uc yt os in e Fl uc on az ol e Vo ric on az ol e C as po fu ng in Candida Glabrata
Am 0 20 40 60 80 100 120 ph ot er ic in B Fl uc yt o si ne Fl uc on az ol e Vo ric on az ol e C as po fu ng in Candida parapsislosis
Am 20 40 60 80 0 100 120 ph ot er ici n B Fl uc yt os in e Fl uc on az ol e Vo ric on az ol e Ca sp of un gi n Candida Krusei
Am 0 20 40 60 80 100 120 ph o te ri c in B Fl uc yt os in e Fl uc on az o le Vo ric on az o le C as po fu ng in Candida Dubliniensis
Review• Different types of Invasive fungi• Epidemiology• Risk factors• Clinical picture• Diagnosis• Treatment & prophylaxis
Risk Factors for Invasive Candidiasis In ICU ∀ ≥3 antibiotics • Neutropenia • Antibiotics ≥4 d • Immunosuppression • Time ≥4 d in ICU • Concomitant infection • Mechanical vent >48 • Diabetes mellitus • Major Abd surgery • Candida coloniz ≥2 sites • Candiduria (>100,000 • CVP colonies) • TPNPappas PG et al. Clin Infect Dis 2004;38:161-189;Ostrosky-Zeichner L et al. Crit Care Med 2006;34:857-63
Invasive Aspergillosis: Risk factors Post liver transplant Early IA < 3 months p OR (95% CI) 4.9 Renal failure after SOT < 0.0001 (2.4 -9.8) Hemodialysis after SOT 3.2 0.014 (1.3 - 8.1) > 1 episode of bacterial 3.2 < 0.006 infection (3.2 - 17.4) CMV disease 2.3 < 0.029 (1.1 - 4.9) Reintervention is also risk factorGavaldà J et al, Clin Inf Dis 2005; 41:52-9
Risk factors of IA after Renal transplantation• High doses or prolonged duration of corticosteroids• Graft failure requiring Hemodialysis• Potent immunosuppressive therapy for rejectionSingh N et al, Am J Transplant 2009, 9, S180-S191 .
Risk factors of IA after Heart transplantation• Isolation of Aspergillus from respiratory tract cultures• Reintervention• CMV disease• HemodialysisMunoz P et al, Curr Opin Infect Dis 2006; 19: 365-370Singh N et al, Am J Transplant 2009, 9, S180-S191 .
Fungal Infection Post Biologics• Till 2007 ,281 reports of invasive fungal infections (IFIs) associated with the 3 anti-TNF- alpha agents, ie, infliximab, etanercept, and adalimumab• 226 (80%) were associated with infliximab, 44 (16%) with etanercept, and 11 (4%) with adalimumab• Histoplasmosis (n=84 [30%]), candidiasis (n=64 [23%]), and aspergillosis (n equals 64 [23%]).• Inﬂ iximab induces apoptosis memory T cells, whereas etanercept is antiapoptotic
Review• Different types of Invasive fungi• Epidemiology• Clinical picture• Risk factors• Diagnosis• Treatment & prophylaxis
SPECTRUM OF INVASIVE CANDIDA INFECTIONS organ infectioncandidemia acute ‘hepato-candidemia disseminated splenic’ candidiasis candidiasis
Candida: Infection sites C. parapsilosis C. parapsilosis C. tropicalis C. tropicalisC. albicansC. albicans C. krusei C. krusei C. glabrata C. glabrata
Interaction of Aspergillus with the host A unique microbial-host interaction Frequency of aspergillosisFrequency of aspergillosis Acute IA ABPA Allergic sinusitis Subacute IA Aspergilloma Chronic cavitary Chronic fibrosing Immune dysfunction Immune hyperactivity . www.aspergillus.man.ac.uk www.aspergillus.man.ac.uk
Serology• 1,3-,D-glucan is a component of fungal cell walls that can be detected by serology• One way to effectively use the 1,3-,D-glucan or galactomannan assays may be to serially screen patients who are at high risk for IFIs and/or use them to monitor response to therapy .
Review• Different types of Invasive fungi• Epidemiology• Clinical picture• Risk factors• Diagnosis• Treatment & prophylaxis
Cell Wall Active Antifungals Cell membrane • Polyene antibiotics • Azole antifungals DNA/RNA synthesis • Pyrimidine analogues - Flucytosine Cell wall • Echinocandins -Caspofungin acetate - micafunginAtlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001
Amphotericin B (Fungizone™)• Binds ergosterols in fungal cell membrane forming pores in the membrane & interferes with permeability and transport functions.• Broad spectrum antifungal• Lipid formulations facilitate drug insertion within the fungal cytoplasmic membrane while reducing uptake in human cells, so limiting toxicity.
Amphotericin B - Nephrotoxicity• Renovascular and tubular mechanisms – Vascular-(decrease in renal blood flow) leading to drop in GFR, azotemia – Tubular-distal tubular ischemia, wasting of potassium, sodium, and magnesium• Sodium loading-> blunt the vasoconstriction and tubular-glomerular feedback – Administration of 500 ml of NaCl before and after amphotericin B infusion
Azoles - Mechanism• Azoles bind to (fungal P450 enzymes) lanosterol 14α-demethylase inhibiting the production of ergosterol – Some cross-reactivity is seen with mammalian cytochrome p450 enzymes • Drug Interactions • Impairment of steroidneogenesis (ketoconazole, itraconazole)
Fluconazole Advantages Disadvantages• Well tolerated • Fungistatic• IV/PO formulations • Resistance is• Favorable increasing pharmacokinetics • Narrow spectrum• Good activity against • (Drug interactions) C. albicans and • Not in biofilm Cryptococcus
Key Biopharmaceutical Characteristics of the Triazole Antifungals Fluconazole Voriconazole Spectrum vs. C. albicans, C. tropicalis +/- Broad, includes most Candida and Candida spp., Aspergillus No Aspergillus Aspergillus, Fusarium sp. Not Zygomycoses Oral formulation Tablet (>90%) Tablet (>90%) (% bioavailibility) Intravenous Available, no solubilizer Available, cyclodextrin formulationR.E. Lewis 2002. Exp Opin Pharmacother 3:1039-57.
Voriconazole –Dose & Side Effects• Dose 6mg/kg 1st day 6mg/kg bid then 4mg/kg bid• Visual disturbances (~ 30%) – Decreased vision, photophobia, altered color perception and ocular discomfort – IV > oral – No evidence of structural damage to retina
The Fungal Cell Wall mannoproteinsEchinocandins inhibitionof ß-(1,3)glucan synthaseosmotic fragility β1,3 β1,6 glucans Cell β1,3 glucan chitin membrane synthase ergosterolAtlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001
Echinocandins - spectrumHighly active Very activeCandida albicans, Candida parapsilosis Candida gulliermondiiCandida glabrata, Aspergillus fumigatusCandida tropicalis, Aspergillus flavusCandida krusei Low MIC ,with Low MIC, but without fungicidal fungicidal activity and activity in most instances. good in-vivo
Echinocandins Caspofungin Micafungin AnidulafunginAbsorption Not orally absorbed. IV onlyMetabolism spontaneous degradation, Chemical degradated hydrolysis and N-acetylation Not hepatically metabolizedElimination Limited urinary excretion. Not dialyzable Half-life 9-23 hours 11-21 hours 26.5 hours Dose 70 mg IV on day 100 mg IV 200 mg IV on day 1, 1, then 50 mg IV once daily then 100 mg IV daily thereafter daily thereafter Dose Child-Pugh B None NoneAdjustment 70 mg IV on day 1, then 35 mg IV daily thereafter
Review• Different types of Invasive fungi• Changing epidemiology• Risk factors• Clinical picture• Diagnosis• Treatment &prophylaxis• Updated guidelines
Candidemia • If species is unknown, either fluconazole (800mg loading dose, 400 mg daily) or an echinocandin is appropriate initial therapy for most adult patients (AI) • An echinocandin is favored if – Moderately severe to severe illness. – Recent azole use for treatment or prophylaxis (AIII), or – Isolate is known to be C. glabrata or C. krusei (BIII) • Fluconazole for patients who are – less critically ill and – who have no recent azole exposure (AIII). • Remove or exchange intravenous catheters • Treat for two weeks after clearance of bloodstreamIDSA Guidelines 2010.
Treatment options of blood candidal infections in adultsTreatment options of invasive fungal infections in adults 2010
Candidemia: catheter removal • Removal of central venous line – is a consensus recommendation for the non-hematological patients II A - in hematology patients the quality of evidence is lower IIIB - removal is always recommended when C parapsilosis is isolated II AIDSA Guidelines 2010.
Duration of antifungal therapy in candidemia : recommendations Non-neutropenic adults: at least 14 days after the last +ve blood culture and resolution of signs and symptoms : III B Neutropenic patients: at least 14 days after the last +ve blood culture and resolution of signs and symptoms and resolved neutropenia: III CIDSA Guidilines 2010.
Invasive pulmonary aspergillosis :1st line Agent Grade Comments Voriconazole IA 2 x 6 mg/kg D1 then 4 mg/kg BID Ambisome IB 3 – 5 mg/kg Caspofungin IC Amphotericin B IDIDSA Guidelines 2010.
Treatment options of aspergillus infectionsTreatment options of invasive fungal infections in adults 2010
Aspergillosis• Surgery (CIII) in case of – Lesion near to a large vessel – Hemoptysis from a single lesion (embolization is an alternative) – Localized extrapulmonary lesion including central nervous system lesion – Fungal sinusitis
Timing of Intervention Directedinfection Empiricspecific symptom Pre-emptiverefractory fever Prophylacticnonspecific symptom ± early markerssuppressive Rxbasic disease Progression
Different antifungal strategies for treatment in invasive fungal infections based on diagnostic stage. Prophylactic treatment preventive administration of an antifungal agent to patients at risk of IFI without attributable signs and symptoms. Empiric treatment is defined as the initiation of antifungal treatment in patients at high risk of IFIs and established clinical signs and symptoms, but without microbiological documentation. Preemptive therapy aims to treat a suspected early IFI but uses radiologic studies, laboratory markers, applied when the decision of treatment is based on early diagnostic test. (Radiographic imaging,( Halo sign, air crescent) Serology: Galactomannan B-D-Glucan, histopathology Targeted therapy needs a pathogen identification to be defined.1.Zaragoza R et al. Therapeutics and Clinical Risk Management 2008:4(6) 1261–1280.
Treatment of Suspected Invasive Candidiasis (Definitions)• Prophylactic therapy: given to everyone in a given class (ex. BMT patients who are at very high risk for IC).• Preemptive therapy: patients at risk are monitored closely and therapy is initiated with early evidence suggesting infection (ex. positive Candida cultures at non-sterile sites, clinical suspicion) to prevent disease.• Empirical therapy: (ex. therapy is started because a cancer patient has remained febrile after 4days of broad-spectrum antibiotics).• Directed therapy: is based on a clinical or laboratory finding indicating that an infection is present (ex. positive blood culture for Candida species).
Empirical antifungal treatment in ICU Clinical Prediction Rule (CPR) • All of – [(day 1–3 of ICU stay): mechanical ventilation, – broad spectrum antibiotics – And central venous catheter CVC • And ONE of – TPN (total parentral neutrition) (d1-3) – Dialysis (d1-3) – Major surgery (d-7-0), – Pancreatitis (d-7-0), – Steroids (d-7-3), – Other immunosuppressive agents (d-7-0)]. sensitivity of 90%, a specificity of 48%Ostrosky-Zeichner L, et al. 2007. Eur J Clin Microbiol Infect Dis, 26:271–6.Ostrosky-Zeichner L, et al. Mycoses. 2011 Jan;54
Empirical antifungal treatment in ICU The Candida Score• Parenteral nutrition ................................................. (+1)• Prior surgery ............................................................ (+1)• Multifocal Candida colonization *........................... (+1)• Severe sepsis ........................................................... (+2)The authors concluded that a “Candida score” of 2.5 could accurately select patients who would benefit from early antifungal treatment Leon C, et al. 2006. Crit Care Med, 34:730–7. Leon C, et al. 2009 Crit Care Med 37:1624–1633.
Prophylaxis of high-risk patients after Liver transplantation(Recommendations of the AST Infectious disease Community of Practice)• Lipid formulation of AmB (II 2) – 3-5 mg/kg/day• Or an Echinocandin (II 3)• Duration 3-4 weeks or until resolution of risk factorsSingh N et al, Am J Transplant 2009, 9, S180-S191 .
Prophylaxis for high-risk patients after Lung transplantation (recommendations of the AST Infectious disease Community of Practice)• Inhaled lipid formulations of amphotericin B – Nebulized L-AmB • 25 mg three times per week x 2 months• In high-risk patients – Voriconazole* : 400 mg/day x 4 monthsSingh N et al, Am J Transplant 2009, 9, S180-S191 .
Prophylaxis for high-risk patients after Heart transplantation(Recommendations of the AST Infectious disease Community of Practice)• Voriconazole – 200mg BID for 50-150 daysSingh N et al, Am J Transplant 2009, 9, S180-S191 .
Fluconazole Prophylaxis: ? Pre Emptive ApproachHCT & AML Monitor with Serum galactomannan Thrice wkly Antifungal use if Asp GM x consecutive 2 positive • CT abnorm & BAL (+) Aspergillus • antifungal use reduced by 78% Survival with IFI, 64% Maertens J et al, Clin Infect Dis 2005;41:1242
Antifungal prophylaxis in haematology patients CLINICAL MICROBIOLOGY AND INFECTION April 20123rd European Conference on Infections in Leukaemia (ECIL-3)
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