Clinical Considerations in the Management of Systemic Fungal Infections Conducted during the 41 st ASHP Midyear Clinical Meeting Anaheim, California
CONTINUING EDUCATION ACCREDITATION The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program provides 1 hour (0.1 CEU) of continuing education credit (program number 204-000-06-442-H01). After successful completion of the CE post test, participants can print the CE statement online at www.ashpadvantage.com.
Clinical Considerations in the Management of Systemic Fungal Infections PROGRAM AGENDA Introductory Remarks Peggy L. Carver, Pharm.D., Program Moderator Recent Trends and Practical Guidelines for Initiating and Managing Antifungal Therapy Peggy L. Carver, Pharm.D., FCCP Empiric and Combination Antifungal Therapy: Clinical Perspectives and Risks Melissa D. Johnson, Pharm.D. PROGRAM FACULTY Peggy L. Carver, Pharm.D., FCCP Associate Professor of Pharmacy Department of Clinical Sciences, College of Pharmacy Clinical Pharmacist, Infectious Diseases Department of Pharmacy Services University of Michigan Ann Arbor, Michigan Melissa D. Johnson, Pharm.D. Division of Infectious Diseases and International Health Duke University Medical Center Clinical Assistant Professor Department of Pharmacy Practice Campbell University School of Pharmacy Durham, North Carolina
Clinical Considerations in the Management of Systemic Fungal Infections PROGRAM DESCRIPTION Invasive fungal infections (e.g., candidemia, aspergillosis) cause substantial morbidity and mortality in the United States, despite the introduction of new antifungal agents. Candida species have become the fourth most common cause of nosocomial bloodstream infection. Azole antifungal agents have been a mainstay of systemic antifungal therapy, but the percentage of Candida isolates that are resistant to these agents has increased dramatically. The use of potent immunosuppressive agents and current hematopoietic stem cell and organ transplantation practices are among the factors that have increased the susceptibility of Americans to invasive fungal infections and the emergence of resistant pathogens in recent years. This program will describe recent trends in morbidity and mortality from invasive fungal infections and factors that increase susceptibility to such infections and the emergence of resistant pathogens. The efficacy, safety, and limitations of older and newer antifungal agents used to treat invasive fungal infections (e.g., conventional and lipid-based forms of amphotericin B, fluconazole and novel broad-spectrum azoles, echinocandins) will be compared and contrasted. The basis for choosing among these agents (e.g., the infecting species, the clinical status of the patient, and when available, institution-specific antifungal susceptibility test results) will be discussed. Pharmacoeconomic and patient-specific factors to consider in the selection of empiric antifungal therapy also will be addressed. Finally, the program will discuss the role of combination antifungal therapy in treating drug-resistant fungal infections. LEARNING OBJECTIVES At the conclusion of this presentation, participants should be able to: Describe recent trends in morbidity and mortality from invasive fungal infections in the United States, and identify a factor that increases susceptibility to such infections and the emergence of resistant pathogens. Compare and contrast the efficacy, safety, and limitations of conventional amphotericin B, fluconazole, and newer antifungal agents (i.e., lipid-based forms of amphotericin B, novel broad-spectrum azoles, and echinocandins). Identify a criterion for choosing among antifungal agents for the treatment of invasive fungal infections. Discuss three important factors to consider in the selection of empiric antifungal therapy. Explain the role of combination antifungal therapy in treating drug-resistant fungal infections.
Clinical Considerations in the Management of Systemic Fungal Infections PEGGY L. CARVER, PHARM.D., FCCP Associate Professor of Pharmacy Department of Clinical Sciences, College of Pharmacy Clinical Pharmacist, Infectious Diseases Department of Pharmacy Services University of Michigan Ann Arbor, Michigan Peggy Carver, Pharm.D., FCCP, is Associate Professor of Pharmacy in the Department of Clinical Sciences at the College of Pharmacy, University of Michigan, and Clinical Pharmacist in Infectious Diseases in Department of Pharmacy Services, University of Michigan Health Systems, Ann Arbor, Michigan. Dr. Carver earned her Doctor of Pharmacy degree and served a residency at the University of California School of Pharmacy in San Francisco, California. She also completed a fellowship at the Hartford Hospital in Hartford, Connecticut. Dr. Carver's research focuses on the pharmacokinetic and pharmacodynamic effects of drugs used in the treatment of fungal infections; the effects of gastrointestinal ph, transport proteins, and motility on drug absorption; drug interactions involving drugs used to treat fungal infections; and the cost/efficacy of antimicrobial agents. She is the author of a chapter on invasive fungal infections in the 2 nd thru 6 th editions of Pharmacotherapy: A Pathophysiologic Approach, a widely used and respected book. Dr. Carver has been an invited presenter at numerous national and international medical meetings and continuing education conferences. She was recently recognized as Fellow of the American College of Clinical Pharmacy.
Clinical Considerations in the Management of Systemic Fungal Infections 41st ASHP Midyear Clinical Meeting Anaheim ~ Orange County, California Recent Trends and Practical Guidelines for Initiating and Managing Antifungal Therapy Peggy L. Carver, Pharm.D., FCCP Associate Professor of Pharmacy University of Michigan Ann Arbor, Michigan Epidemiology of Fungal infetions
Mortality due to Invasive Mycoses Mortality rate per 100,000 population 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1980 1981 Candida Aspergillus Other Mycoses 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 The Fungal World 1997 McNeil MM et al. CID 2001:33:641-7. FUNGI YEASTS MOULDS Dimorphic Fungi Candida spp. Cryptococcus Trichosporon Zygomycetae Septate Fungi Rhizopus Mucor Fusarium Aspergillus spp. Absidia Paecilomyces Hyalohyphomycoses Fungal Infections are Deadly!! Crude and Attributable Mortality of Candida Infections 70% 60% 50% 40% 57% attributable crude 38% 61% crude attributable 49% 30% 20% 10% 0% 1988 2003 Wey SB, et al. Arch Intern Med. 1988; 148:2642-45. Gudlaugsson O, et al. Clin Infect Dis. 2003;37:1172-77.
Case Fatality Rate (%) 100 Mortality due to Invasive Aspergillosis Review of 1941 patients from 50 studies since 1995 90 80 70 60 50 40 30 20 10 0 Lin S-J et al. CID 2001;32:358-66. Type of Infection Dissem/CNS Overall BMT liver Leuk/Lymph Pulm # patients. 175 1941 285 288 1153 Epidemiology of Candidemia glabrata 16% krusei 2% tropicalis 10% Other 3% albicans 54% parapsilosis 12% Pfaller et al. J Clin Micro 2002;40:852-56. Antoniadou et al. Medicine 2003;82:309-21. Epidemiological Differences among Patients Surgical ICU C. albicans 48% C. glabrata 24% C. tropicalis 19% C. parapsilosis 7% Other species 2% Neonatal ICU C. albicans 63% C. parapsilosis 29% C. glabrata 6% Other species 3% Rangel-Frausto MS, et al. Clin Infect Dis. 1999;29(2):253-8.
The at risk Patient Patients at risk have expanded intravascular catheters antimicrobial therapy TPN corticosteroids chemotherapy immunosuppressives diabetes mellitus alemtuzumab (Campath) monoclonal antibodies (etanercept, infliximab, adalimumab) dialysis trauma, major surgery SOT & HSCT AIDS premature birth advanced age prolonged ICU stay Nucci M & Marr KA.CID 2005;41(4):521-6. SOT = solid organ transplant; HSCT = hematopoietic stem cell transplant Breakthrough Infections Fluconazole/Itraconazole Aspergillus spp. azole-resistant Candida spp. Voriconazole Zygomycosis C. glabrata others (Acremonium, Scedosporium, etc) Micafungin & Caspofungin Trichosporon Clinical trials: smattering of invasive aspergillosis, candidemia, fusariosis, zygomycosis Larch J, et al. CID. 2005;41 (9):1363. SLIDE adapted from Melissa Johnson, Pharm.D Chamilos G et al. CID 2005; 41:60-6. Imhoff A. et al. CID 2004; 39: 743-6. Alexander BD et al. Transplantation 2005; 80: 868-871. Myoken Y et al. CID 2003; 36: 1496-7. Matsue K et al. CID 2006;42:753-7. Goodman D. et al. CID 2002; 35:e35-6. Van Burik, JA et al. CID 39(10):1407-16, 2004. Walsh TJ et al. NEJM 351(14):1391-402, 2004. Marty FM, Cosimi LA. NEJM 2004; 350: 950-2. Siwek GT et al. CID 2004; 39: 584-587. Kontoyiannis et al. JID 2005;191:1350-60.. Selective Pressure of Antifungals Invasive Candidiasis Fluconazole Prophylaxis Invasive Aspergillosis Amphotericin Prophylaxis Non-fumigatus Aspergillosis 2nd Gen Azole Prophylaxis Zygomycosis Fusarium Scedosporium Slide courtesy of Nathan Wiederhold, Pharm.D.
So How Do I Choose an Antifungal Regimen? Selection of Antifungal Agents Clinical trials Not available for all bugs/infections Several agents may be deemed equivalent Spectrum of activity vs suspected or known pathogens Penetration of specific body sites? Drug side effects Drug interactions Other patient factors (renal or hepatic dysfunction, concomitant meds) Comparative Trials Candidemia in NonNeutropenic Patients Azoles vs AmB Flu vs AmB 1 Vori vs AmB Flu 2 Flu vs Flu + AmB 3 Echinocandins vs AmB Caspo vs AmB Flu 4 Mica vs Liposomal AmB 5 Echinocandins vs Azoles Anidula vs Fluconazole 6 Echinocandins vs Echinocandins Caspo vs Mica vs Mica 7 1 Rex JH et al. NEJM 1994;331:1325-30. 2 Kullberg BJ et al. Lancet 2005;366:1435-42. 3 Rex JH et al. CID 2003;36:1221-8. 4 Mora-Duarte et al. NEJM 2002;347:2020-9. Early studies established the role of azoles vs AmB (equal efficacy with lower toxicity) Echinocandins are also effective and less toxic than AmB; data for non-albicans species lacking Anidulafungin outcome SUPERIOR to fluconazole Efficacy of micafungin dose (150mg) = lower dose (100mg/d) = caspofungin 50mg/d 5 Ruhnke M et al. ICAAC 2005:abstract M-722c. 6 Reboli A et al. ICAAC 2005:abstract M-718. 7 Betts RF et al. ICAAC 2006:abstract M-1308a.
So How Do I Choose? Treatment of Invasive Candidiasis Consider alternatives to fluconazole when: Recent exposure to fluconazole or other azole Broader spectrum is desirable (e.g., persistently neutropenic patient) Non-albicans species isolated during or immediately following azole therapy (non-urine) Unstable or severely immunocompromised patient Biofilm-associated infection? In vitro Activity of Antifungals Mechanism of Action of Antifungals Fungal cell Cell membrane and cell wall Mannoproteins Echinocandins affect β-1,3 cross-linking b-(1,6)-glucan b-(1,3)-glucan Cell wall Chitin Cell Membrane (Phospholipid bilayer) Ergosterol b-(1,3)-glucan synthase Azoles inhibit enzymes involved in this pathway Ergosterol Synthesis Pathway AmB binds to ergosterol Squalene Slide adapted from R. Lewis, Pharm.D.; posted at www.doctorfungus.org.
Activity of Common Systemic Antifungal Agents against Candida Species Species albicans AmB Flu Itra Vori Posa Echino glabrata guilliermondii krusei 0 lusitaniae parapsilosis tropicalis reliable activity with occasional resistance moderate activity but resistance is noted + occasional activity 0 no meaningful activity Adapted from Arikan & Rex. Manual of Clinical Microbiology, eighth edition. 2003, p. 1859. Keto = ketoconazole; Flu = fluconazole; Itr = itraconazole; Vori = voriconazole; Echino = echinocandins (caspofungin, micafungin, anidulafungin) Activity of Common Systemic Antifungal Agents against non-candida Species Fungus AmB Flu Itra Vori Posa Echino Aspergillus spp. Fusarium (not A. terreus) occas R X X X (breakthrus) Conflicting data X Scedosporium occas R X +/-? X Zygomycetes X X X X Cryptococcus X X = no in vitro activity = in vitro activity; R = resistance Adapted from Arikan & Rex. Manual of Clinical Microbiology, eighth edition. 2003, p. 1859. Keto = ketoconazole; Flu = fluconazole; Itr = itraconazole; Vori = voriconazole; Echino = echinocandins (caspofungin, micafungin, anidulafungin) Susceptibility Testing and Resistance Antifungal susceptibility testing is not the standard of care not widely available results of testing may take days Breakpoints established for Candida spp. and azoles, flucytosine no breakpoints for AmB, echinocandins Outcome correlation mainly available for fluconazole AmB = amphotericin B
Correlation of MICs and Clinical Outcomes????? The 90-60 rule 90% of patients with a Sensitive isolate will respond to therapy 60% of patients with a Resistant isolate will respond to therapy In vitro susceptibility in vivo clinical success In vitro resistance treatment failure MIC = minimum inhibitory concentration Dosing & Monitoring Issues with Antifungal Agents Does Delaying Empiric Antifungal Therapy Make a Difference? 134 patients with Candida bloodstream infections over 4 years (2001-2004) Only 5.7% received antifungal treatment within 12 hours of 1 st blood sample Delayed empiric antifungal treatment 12 hours after a positive blood sample is associated with greater hospital mortality Percent Hospital Mortality 35 30 25 20 15 10 5 0 <12 12-24 24-48 >48 Delay in Start of Antifungal Treatment (hours) Morrell M, et. Antimicrob Agents Chemother. 2005;49:3640-5.
8000 Voriconazole Pharmacokinetics in Patients Plasma voriconazole concentrations (ng/ml) 7000 6000 5000 4000 3000 2000 1000 Individual pharmacokinetic profiles of voriconazole in patients receiving 200 mg q12h x 14 Days 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hours) Antifungal Prophylaxis of Invasive Candidiasis (IC) in Non-neutropenic Patients Evaluable IC Rate Inclusion Criteria Study Arm N % (N) P SICU > 48 hr No therapy 72 3 (2) NS Clotrim 10 mg PO Q8h 80 1 (1) Keto 200 mg PO QD 65 2 (1) Nys 2x10 6 U PO Q6h 75 7 (5) Recurrent GI Placebo 20 35 (7) 0.02 perf/leakage 1 FLU 400 IV QD 23 4 (1) SICU > 48h Placebo 59 19 (11) NS + risk factor for IC FLU 400 IV/PO QD 60 13 (8) SICU > 72h + Placebo 101 8.9 (9) 0.2 mechanical ventilation FLU 100 mg IV QD 103 3.9 (4) SICU > 72hr Placebo 130 15.3 (20) 0.07 + critically ill FLU 400 mg PO QD 130 8.5 (11) 1 Excluded hemo- and peritoneal dialysis Adapted from Rex JH & Sobel JD. Clin Infect Dis. 2001;32:1191-1200. Eggimann P, et al. Crit Care Med. 1999;27(6):1066-72. Nys = nystatin
Clinical Considerations in the Management of Systemic Fungal Infections MELISSA D. JOHNSON, PHARM.D. Division of Infectious Diseases and International Health Duke University Medical Center Clinical Assistant Professor Department of Pharmacy Practice Campbell University School of Pharmacy Durham, North Carolina Melissa Johnson, Pharm.D., is Clinical Pharmacist and Associate in Medicine in the Division of Infectious Diseases & International Health at Duke University Medical Center (DUMC) and Clinical Assistant Professor of Pharmacy Practice at Campbell University. After obtaining a Bachelor of Science in Biochemistry from the University of Georgia, she earned her Doctor of Pharmacy at Campbell University. Dr. Johnson completed a fellowship in Infectious Diseases Pharmacotherapy at DUMC and has continued her practice there for the past eight years. Dr. Johnson maintains a clinical practice in internal medicine and infectious diseases at Duke University Medical Center and in outpatient HIV care through the Infectious Diseases Clinic at the Durham Veterans Affairs Medical Center (VAMC). Her clinical research interests include invasive fungal infections in immunocompromised hosts with a special focus on immunogenetics, pharmacogenetics, and pharmacodynamics. Dr. Johnson is the recipient of a 5-year NIH/NIAID Mentored Career Award to pursue patientoriented research in invasive candidiasis, and is co-investigator on an NIH program grant to investigate microfluidic methods of detection for infectious pathogens including Candida spp. She has served as principal investigator or co-investigator in numerous clinical trials with antifungal, antiretroviral, and antibacterial agents. Dr. Johnson is studying to obtain a Masters of Health Science in Clinical Research at Duke University School of Medicine, concentrating on biostatistics and epidemiology. Dr. Johnson has been an active member of both the DUMC and Durham VAMC Antibiotic Evaluation Committees for the past 9 years. She has published in numerous peer-reviewed journals, and is a reviewer for Antimicrobial Agents and Chemotherapy, Clinical Infectious Diseases, Pharmacotherapy, Annals of Pharmacotherapy, and Journal of Antimicrobial Chemotherapy. She has been an invited speaker nationwide on topics such as antibiotic resistance, HIV, invasive fungal infections, and management of bacterial infections. She is an active member of American College of Clinical Pharmacy, American Society of Microbiology, and has served as President of the Triangle College of Clinical Pharmacy.
Empiric and Combination Antifungal Therapy: Clinical Perspectives and Risks Melissa D. Johnson, Pharm.D. Division of Infectious Diseases & International Health Duke University Medical Center Durham, North Carolina So How Do I Choose? Aspergillosis Prophylaxis Empirical Therapies Aspergillus Ubiquitous in our environment Spreads via spores (conidia) which are inhaled and reach alveoli in lungs Disease entities: allergic bronchopulmonary aspergillosis fungus ball aspergilloma aspergillus pneumonia and subsequent invasion other sites: CNS, valves
Treatment Options for Aspergillosis Voriconazole IV: loading 6 mg/kg q12 hours x 2 doses then 4 mg/kg q12 hours PO: 200 mg q12 hours Dose adjustments for pediatrics, drug interactions Amphotericin B AmB deoxycholate 1-1.5 mg/kg/day if neutropenic +/- flucytosine 50-150 mg/kg/day (divided q6h) Lipid formulations generally 5 mg/kg/day Caspofungin Approved for refractory/intolerant cases IV: loading 70 mg x1, then 50 mg q24 hours Children are dosed on BSA % Surviving 100 80 60 40 20 0 Time to Death: Vori vs. d-amb 22% relative survival benefit P = 0.02 Median voriconazole duration = 77 days Voriconazole AmB/OLAT* 0 14 28 42 56 70 84 # Days of Therapy OLAT (other licensed antifungal therapy) utilized: Lipid AmB 44%; itraconazole 36%; other or combo 21% Median d-amb duration = 10 days; (n=107) } 71% 58% Herbrecht R, et al. NEJM 2002;347(6):408-15. New Treatment Paradigms Combination antifungal therapy Induction/maintenance Prophylaxis/pre-emptive strategies in high-risk populations Broad empirical coverage with narrowing later New routes of administration
The Case For Simultaneous Combination Antifungal Therapy Mortality rates are HIGH Enables increased spectrum of activity More rapid killing Reduces chances of developing resistance No overlapping toxicities Combination Therapy for Invasive Aspergillosis Voriconazole + Caspofungin Animal models improved sterilization, may increase survival relative to caspofungin alone Human cohorts, only historical controls HSCT recipients: survival benefit Solid organ transplant recipients: trend towards improved survival (p=ns); may be beneficial in certain subgroups: those with renal failure, A. fumigatus Kirkpatrik WR, et al. Antimicrob Agents & Chemother 2002; 46: 2564-2568; MacCallum DM et al. Antimicrob Agents & Chemother 2005; 49(9): 3697-3701; Marr KA et al Clin Infect Dis 2004;39:797-802; Singh N et al. Transplantation 2006; 81(3): 320-6. Aspergillosis Voriconazole + Caspofungin Amphotericin B 1 mg/kg/day Prior to 2/2001 Voriconazole (n=31) Salvage therapy If no response in 7 days After 2/2001 Voriconazole + Caspofungin (n=16) Marr KA et al Clin Infect Dis 2004;39:797-802.
Combination Therapy- Voriconazole + Caspofungin Voriconazole (n) Voriconazole + Caspofungin (n) Marr KA et al. Clin Infect Dis 2004;39:797-802. Combination Therapy for IPA Transplant recipients, 2003-2005 Mostly lung, liver, & heart transplants Compared to historical controls (1999-2002) Proven (~53%) or probable invasive pulmonary aspergillosis (IPA) Primary endpoint: 90-day survival Singh N et al. Transplantation 2006; 81(3): 320-6. 90-Day Survival Combination: 67.5 % (27/40) vs. LFAB 51% (24/47) HR=0.58 (95% CI 0.30, 1.14 p=0.117) Singh N et al. Transplantation 2006; 81(3): 320-6.
Beneficial in Certain Subgroups? Variable HR 95% CI p Renal failure 0.32 (0.12-0.85) 0.02 A. fumigatus 0.37 (0.16-0.84) 0.019 Combination therapy vs. L-AmB was associated with reduced mortality in those with renal failure and A. fumigatus infection Singh N et al. Transplantation 2006; 81(3): 320-6. New Prophylaxis/Empiric Strategies Prophylaxis HSCT or High-Risk Leukemics Micafungin vs fluconazole Posaconazole vs fluconazole (GVHD) Posaconazole vs fluconazole or itraconazole On the way: inhaled amphotericin B lipid complex Empiric- Neutropenic Fever Caspofungin vs liposomal amphotericin B Voriconazole vs liposomal amphotericin B Van Burik, JA et al. Clin Infect Dis. 39(10):1407-16, 2004 Ullmann AJ, et al. 45 th ICAAC. M-716, 2005; Walsh TJ et al. N Engl J Med. 351(14):1391-402. 2004 Walsh TJ et al. N Engl J Med. 346(4):225-34, 2002. Populations in Which Antifungal Prophylaxis is Beneficial Clear indication for use. In selected High-risk patients Bone marrow transplant/hsct Liver transplant Fluconazole prevents Candida but not Aspergillus infxn Acute leukemia Allogeneic transplantation ICU But only in very high-risk patients
Newer Agents for Prophylaxis New agent Posaconazole Posaconazole Micafungin Comparator Fluconazole or itraconazole Fluconazole 400 mg qd Fluconazole 400 mg IV qd Population AML / MDS HSCT / GVHD HSCT Major Findings p/p IFI: 2% vs 8% 100 days 5% vs 11% p/p IFI: 2% vs 7% 16 wks 5% vs 9% p/p/s IFI: 19% vs 26% Dose 200 mg (5 ml) po TID, with fatty meal 50 mg daily IV Van Burik, JA et al. Clin Infect Dis. 39(10):1407-16, 2004 Ullmann AJ, et al. 45 th ICAAC. M-716, 2005. p/p = proven or probable IFI= invasive fungal infection p/p/s= proven, probable or suspected Newer Agents for Empiric Therapy New agent Comparator Population Major Findings Voriconazole Caspofungin Liposomal amphotericin B 3 mg/kg/day Liposomal amphotericin B 3 mg/kg/day Neutropenic Fever Neutropenic Fever Overall response: 26% vs 30.6% No Breakthrough: 98% vs 95% Overall response: 33.9% vs 33.7% Successful treatment of baseline IFI: 51.9% vs. 25.9% IFI= invasive fungal infection Walsh TJ et al. New England Journal of Medicine. 346(4):225-34, 2002 Jan 24; Walsh TJ et al. New England Journal of Medicine. 351(14):1391-402, 2004 Sep 30 Empirical Therapy- Outcomes Mortality benefit with caspofungin? Caspo 10.8% vs L-AmB 13.7% p=0.04 Walsh TJ et al. N Engl J Med. 351(14):1391-402, 2004 Sep 30.
Into the Future. Impact of prophylaxis/early empiric therapy Better diagnostics Role of susceptibility testing Defining the best doses and combinations (?) Individualized approached to care Microarrays, immunogenetics, pharmacogenomics Catheter salvage techniques Immunomodulators So How Do I Choose an Antifungal Regimen? Azoles Strengths Active vs wide range of fungal pathogens Vori- active vs Fusarium, Scedosporium, Aspergillus Posa- zygomycetes IV and PO formulations Well tolerated Weaknesses Drug interactions! Non linear PK (voriconazole) Azole cross resistance Side effect profiles: Vori: (conc related) ocular, LFTs, photosensitivity, hallucinations IV formulation (itra, vori) in renal failure Holes in spectrum Flu Aspergillus, C. krusei Vori zygomycetes C. glabrata? Need to monitor levels (itra, vori)
Amphotericin B Strengths Fungicidal against widest range of fungal pathogens Few drug interactions Synergistic nephrotoxicity No cross resistance with azoles Cost (deoxycholate) Weaknesses Nephrotoxicity limits dose Optimal dose? IV only NOT effective vs: A. terreus (rare) C. lusitaniae Cost (lipid products) Difficult to detect resistance Echinocandins Strengths Fungicidal against most Candida spp. Well tolerated Few drug interactions Cyclosporine Nifedipine, Sirolimus No cross resistance with azoles Drug resistance rare Weaknesses Penetration into CNS, urine? Optimal dose? IV only Limited spectrum (Candida, Aspergillus) NOT effective vs: C. parapsilosis? Endemic mycoses (Histoplasmosis, Coccidioidomycosis) Cryptococcus neoformans Trichosporon ZYGOMYCETES Cost Summary Know the pathogens in your hospital! unit- or patient population-specific epidemiology potential for resistant strains Yeast other than C. albicans and moulds other than Aspergillus fumigatus have emerged. Organisms have variable susceptibilities to antifungal drugs. Clinical mycology remains largely empiric and we have few evidence-based trials.
Summary More antifungal choices means more challenges. Several options exist for the treatment of febrile neutropenia; adverse effects, drug interactions, and the incidence of drug resistance should be used to guide the selection of optimal therapy. We have yet to discover the magic bullet. Questions and Discussion We welcome your questions. Staff will collect written question cards. Please approach a standing microphone in the aisle. Please complete the program evaluation and hand to staff as you exit. Thank you for your attention. Join us again for CE in the Mornings.
Clinical Considerations in the Management of Systemic Fungal Infections FACULTY DISCLOSURE STATEMENTS ASHP Advantage requires that faculty members disclose any relationships (e.g., shareholder, recipient of research grant, consultant or member of an advisory committee) that the faculty may have with commercial companies whose products or services may be mentioned in their presentations. The existence of these relationships is provided for the information of attendees and should not be assumed to have an adverse impact on faculty presentations. The faculty reports the following relationships: Peggy L. Carver, Pharm.D., FCCP Dr. Carver reports that she has no relationships to disclose. Melissa D. Johnson, Pharm.D. Dr. Johnson reports that she has received research grant support from Astellas Pharma and Merck. She has been a consultant for Enzon and Schering-Plough and serves as a speaker for Enzon and Pfizer.