4Rank order of nosocomial bloodstream pathogens and their associated mortality 1Coagulase negative-staphylococci30.9212Staphylococcus aureus15.7253Enterococci11.1324Candida species9385Escherichia coli5.7246Klebsiella species5.4277Enterobacter species4.5288Pseudomonas species4.433Serratia species1.42610Viridans streptococci23
9Incidence of Invasive Fungal Infections Solid Organ Transplant %Kidney – 14%Heart – 32%Heart-Lung/Lung 15 – 36%Pancreas 18 – 38%Liver – 42 %Bone Marrow Transplant %Intensive Care Unit 17%Singh, N. CID 2000; 31:545-53Vincent JL. Intensive Care Med 1998; 24:
10Mortality Rates Candidemia has a mortality rate of ~40%. Invasive aspergillosis continues to be a highly lethal opportunistic infection:375% increase in mortality due to Aspergillus species from 1980 to 1997.Overall mortality rate in patients with invasive aspergillosis is reported to be 58%.Mortality continues to be high regardless of the antifungal therapy used.Edmond MB et al. CID 1999;29:National Center for Health Statistics ( )Lin S et al. CID 2001;32:
11ChallengesDelaying antifungal therapy until blood cultures are positive is associated with increased mortalityDiagnostic limitations
13Clinical approaches to assess risk Fungal colonizing index: the greater the number of positive sites, the greater the increased risk for invasive infectionCombine colonization with other risk factors: surgery on admission, TPN, and sepsisNo colonisation index but include variables: ≥ 4 days in ICU, CVC, DM, new hemodialysis, TPN, and broad-spectrum antibioticsPittet D. Ann Surg. 1994;220:Paphitou NI. Med Mycol. 2005;43:
14Colonization in ICU patients Prevalence of colonization in ICU is high (50% to 70% or more) compared with relatively low rate of infection, so predictive value of colonization is poorHowever colonisation with unexplained fever, leukocytosis, and hypotension may indicate invasive candidiasisOstrosky-Zeichner L. Crit Care Med. 2006;34:Eggimann P. Lancet Infect Dis. 2003;3:
15CI is ratio of # of sites positive to total number of sites tested. CCI is CI times the ratio of # of sites with heavy growth to the total # of positive sites.
16Which antifungal to choose? Candida speciation may take up to 5 daysand fluconazole susceptibility testing may take an additional 5 days In patients who are critically ill, hypotensive with multi-organ failure, most authorities would favour the initial use of IV amphotericin. This recommendation was based on efficacy trends that favoured IV amphotericin over Iv fluconazole (but were not statistically different) and that candidemia was cleared faster with IV amphotericin compared to fluconazole
17Targeted anti-fungal therapy The “challenging” wisdom Withhold Antifungal therapy unless positive diagnostic testAdvantagesDirected therapy, ?less cost, less anti-fungal toxicityDisadvantagesVariable sensitivity and specificity diagnostic testsUnproven benefit in reducing mortality, ?costs17
19Treatment options of invasive fungal infections in adults Treatment options of invasive fungal infections in adults. Swiss Med Wkly Jul 22;136(29-30):447-63
20Spellberg BJ et al. Clin Infect Dis. 2006 Jan 15;42(2):244-51
21Diagnostic Dilemma Clinical Setting: with other risk factors Radiology: applicable more for AspergillusCultures: Low yield and longer timeStaining: GMS and Calcofluor whitePCR Assay: not widely available1-3 Beta Glucan Assay:Galactomannan Assay: For AspergillusPNA FISH:
23PNA FISH: Clinical Benefits Summary Rapid and accurate identification of bloodstream pathogens direct from positive blood culturesSimple to implement and easy to useMaintains species morphologyActionable PNA FISH results for 95% of BC+Development of new therapeutic guidelinesImproved patient safetyEarly appropriate and effective antibiotic therapyReduction in mortalityReduction in unnecessary antimicrobial and antifungal useReduction in hospital length of stay (LOS)Significant cost savings25 March 201723
24Antifungal choice Organism (proven, suspected) Site of disease Host factors (eg age, neutropenia, mucositis)History of antifungal therapy and/or prophylaxisTolerability/ side effectsDrug-Drug interactionsCosts24
26Antifungal Drug Development 1950s1960s1970s1980s1990s2000sGriseofulvinKetaconazoleFluconazoleItraconazoleTerbinafineAMB lipidFormulationsEconazole,miconazole(IV)Itra (IV)CaspofungVoriconMicafungAnidulofungPosaconRavuconAMBd5FCmiconazole (top)clotrimazole (top)
28Biochemical Targets for Antifungal Chemotherapy Arrangement of the biomolecular components of the cell wall accounts for the individual identity of the organism. Although, each organism has a different biochemical composition, their gross cell wall structure is similar.Antifungal agents targeted towards:Inhibition of fungal cell wall synthesis – caspofungin is a -glucan synthesis inhibitor; several more compounds are under investigationInhibition of fungal cell membrane synthesis – ergosterol is the target (cell membranes of fungi and mammals contain different sterols): polyenes, azoles, triazoles, alkylaminesInhibition of cell division – microtubule effects: griseofulvin; DNA: flucytosine.