Transcript Candida
PHARMACOLOGIC MANAGEMENT OF VIRAL AND FUNGAL INFECTIONS IN THE IMMUNOCOMPROMISED HOST Ngoc-Yen Nguyen, PharmD February, 2014 Objectives Review risks for viral and fungal infections in the immunocompromised host Identify pharmacologic treatments for viral and fungal infections Apply appropriate therapeutic agents to specific patient scenarios ANTIFUNGALS Risk Factors for Invasive Fungal Infection Types of invasive fungal infections Yeasts Candida spp. Fourth most common nosocomial bloodstream infection in the U.S. Most common invasive fungal infection in critically-ill nonneutropenic patients Portals of entry Gastrointestinal tract Intravascular catheters Types of Candida spp. Candida albicans- most common Candida non-albicans Candida glabrata – most common non-albicans Candida spp. associated with bloodstream infection Candida krusei – more frequent cause of fungemia in patients with hematologic malignancy Cryptococcus neoformans Only pathogenic species in the genus Cryptococcus Source – contaminated soil with pigeon droppings Portal of entry – Inhalation of yeasts Types of invasive fungal infections Aspergillus spp. Ubiquitous environmental mold with airborne spores Most common cause of invasive mycotic infections in the severely immunocompromised population Common species: A. fumigatus, A. flavus, A. terreus Frequent sites of infection Lungs Central nervous system Sinuses Other difficult to treat organisms Fusarium spp. Second most frequent cause of invasive mycotic infections in the severely immunocompromised population Found in the soil known to cause localized skin infections in immunocompetent persons Common species: F. solani; F. oxysporum; F. moniliforme Mucor spp. Found in soil, plants, and decaying fruits Common species: M. amphibiorum; M. circinelloides; M. indicus Incidences of Invasive Fungal Infections Diagnosis Blood culture Biopsy Fungitell assay detects (1-3)--D-glucan in the diagnosis of invasive fungal infection, (1,3)- ß-Dglucan is sloughed from the cell walls during the life cycle of most pathogenic fungi assay detects the following pathogens: Candida spp., Aspergillus spp., Coccidioides immitis, Fusarium spp., Histoplasma capsulatum, Saccharomyces cerevisiae, and Pneumocystis jiroveci. does not detect Cryptococcus, Zygomycetes, such as Mucor, and Rhizopus, nor Blastomyces dermatitidis Aspergillus Galactomannan EIA assay uses EBA-2 monoclonal antibodies to detect Aspergillus galactomannan, in the diagnosis of invasive Aspergillosis concomitant use of mold-active, anti fungal therapy in some patients with invasive Aspergillosis may result in reduced sensitivity of this assay positive galactomannan test has result in patients receiving pip/tazo Antifungal classes Polyene Triazoles Echinocandins Flucytosine Polyenes MOA: binds to the ergosterol component of the fungal cell membrane and cause the fungus to leak electrolytes and die Mainstay of therapy for certain invasive systemic fungal infections Use is limited by the risks for nephrotoxicity and hypokalemia – but SE may be improved with newer dosage forms Agents Amphotericin B deoxycholate (conventional) Amphotericin B colloidal dispersion Amphotericin B lipid complex Amphotericin B liposomal Controlled comparative trials of original form to the newer formulations are lacking Note different dosing with different products Premedication may help prevent/decrease infusion related rxns with combination of acetaminophen, diphenhydramine, +/- hydrocortisone and +/- meperidine The Triazoles MOA: inhibition of cytochrome P-450-dependent ergosterol synthesis and inhibition of cell membrane formation. These agents are metabolized by the CyP450 system and may affect/may be affected by drugs that are dependent on this system Agents Fluconazole Itraconazole Voriconazole Posaconazole Fluconazole Place in therapy: Most often used as prophylaxis or treatment agent against C. albicans Most frequently seen adverse effect is elevation of LFTs (particularly hepatic transaminases) 80% of drug is renally eliminated – thus dosage adjustments may be needed in renal insufficiency Substrate and inhibitor of CYP450 - beware of drug interactions Dosage forms: oral and intravenous Itraconazole Has broad spectrum of activity including Aspergillus, Blastomyces, Candida, Coccidioides, Cryptococcus, Histoplasma capsulatum, and Sporotrichosis species Substrate and inhibitor of CPY3A4 – high risk for significant drug interactions Side effects Increased LFTs Case of new or exacerbation of heart failure has been reported Use with caution in renal impairment due to wide variations in plasma concentrations Available as oral capsule, tablet, and solution Capsule and oral solution formulations are not bioequivalent Capsule and tablet absorption is best if taken with food Solution should be taken on an empty stomach Voriconazole Place in therapy Dosing considerations Optimal doses in children is not well established – may require higher dosages than adults to achieve comparable serum levels; may need to monitor drug level Decrease dose by 50% in patients with mild to moderate hepatic dysfunction per ChildPugh Score For CrCl < 50 ml/minute, consider changing IV to oral, as the accumulation of IV formulation vehicle(SBECD) occurs Side effects Drug of choice for invasive aspergillosis Used in treatment of infections caused by Scedosporium apiospermum and Fusarium spp in patients intolerant of, or refractory to other therapy More active than fluconazole against Candida sp and has more activity than amphotericin B, except C. glabrata Visual changes reported in 30% of patients in clinical trials Increase in liver function enzymes (AST, ALT, Alk Phos) Substrate and inhibitor of CYP450 - beware of drug interactions Dosage forms: oral and intravenous Posaconazole Place in therapy Prophylaxis of invasive Aspergillus and Candida infections in severelyimmunocompromised patients Treatment of oropharyngeal candidiasis (including patients refractory to itraconazole and/or fluconazole) Excellent activity against both yeast and mould infections, specifically against zygomycosis in which voriconazole has no efficacy PK studies in pediatric is limited Inhibitor of CYP3A4 – beware of drug interaction Dosage forms: Available as an oral suspension only Bioavailability increased approximately 3-4 times when administered with a meal or an oral liquid nutritional supplement. Echinochandins MOA: block the synthesis of 1-3-D-glucan, a critical component of the fungal cell wall Available as intravenous preparations only Agents FDA indications PK considerations Drug interactions Caspofungin Invasive candidiasis; salvage therapy for aspergillosis; neutropenic fever; oroesophageal candidiasis • Undergo hepatic metabolism • May require dose adjustment in moderate to severe hepatic dysfunction •Dose adjustment not needed in renal impairment • Reduces tacrolimus AUC by 20% • Rifampin, phenytoin, nevirapine, etc. caspo trough by 30% Micafungin Invasive candidiasis; prophylaxis in HSCT; oroesophageal candidiasis • Undergo hepatic metabolism • Dose adjustment not needed in renal impairment • May blood concentration of drugs metabolized by CYP450 Anidulafungin Invasive candidiasis; oroesophageal candidiasis • Undergo slow nonhepatic, chemical degradation • Dose adjustment not needed in renal impairment Flucytosine Converted within the fungal cell to 5-fluorouracil, which inhibits thymidylate synthetase, thus inhibits DNA synthesis Adjunctive treatment IFI caused by susceptible strains of Candida or Cryptococcus, often synergistically with amphotericin B Widely distributed including to the CSF Adverse effects Nausea, vomiting , diarrhea, severe enterocolitis Neutropenia, thrombocytopenia, bone marrow aplasia– possibly irreversible Renal and hepatic toxicities Dosage form: capsule ANTIVIRALS What is a virus? Very small infectious agent Some are smaller than ribosome Approx 10x smaller than bacteria Consist of nucleic acid (DNA or RNA) Surrounded by a protein coat, which is often surrounded by another protective envelope Lack membranes, a cytoplasm, & any means to produce energy Rely on host cell to replicate, mutate and maintain genetic continuity Portal of entry Stages of virus replication Attachment and penetration Uncoating and releasing of viral genome into cell Transcription of the viral genome Assembly of virion particles Translation & modification of viral proteins Release of new viruses Pathogenesis of Selected Virus Infections Disease Common Site of Implantation Route of Spread Target Organ(s) Site of Shedding AIDS Injection, trauma, intestine Blood Immune system, brain Blood, semen Chickenpox Respiratory tract Blood, nerves (site of latency) Skin, lungs Repiratory tract, skin Hepatitis A Alimentary Tract Blood Liver Alimentary tract Hepatitis B Penetration of skin Blood Liver Blood Respiratory tract Nerves, leukocytes Many (brain, liver, skin) Respiratory tract, epithelial surfaces Ganglion Nerves (to site of latency) Skin, eye Skin, eyes HSV2 Genital tract Genital tract Genital tract Measles Respiratory tract Nerves (to site of latency) Blood Skin, lungs, brain Respiratory tract Poliomyelitis Alimentary Tract Blood CNS Alimentary tract Rabies Subcutaneously (bite) Nerves Brain Salivary glands Rubella Respiratory tract Blood Skin, lymph nodes, Respiratory tract, excreted fetus in newborn HSV1 Acute Recurrent Virus effect on cells Lytic Infection Causes destruction of host cell E.g. HSV, poxviruses Persistent Infection Virions are released continuously Host cell may not be lysed causes little adverse effect E.g. Lassa, retroviruses, rubella Latent Infection Delay between infection and appearance of symptoms E.g. fever blisters due to HSV-1 Cellular Transformation Changes normal cell into a tumor cell E.g. HPV, EBV Types of pathogenic viruses DNA viruses RNA viruses Type Associated Disease Type Associated Disease Poxviruses Smallpox Rubella German measles Pappilloviruses Warts, cervical cancer Rhabdoviruses Rabies Adenoviruses Conjunctivitis, sore throat Picornavirus Poliomyelitis, meningitis, colds Hepadnaviruses Hepatitis B Arenaviruses Meningitis, Lassa fever Herpesviruses Chickenpox, shingles, Arboviruses HSV, CMV, Karposi sarcoma, nonHodgkin’s lymphoma Orthomyxoviruses Epstein Barr virus Paramyxoviruses Retroviruses Yellow fever, arthropod-borne encephalitis Influenza Measles, mumps, RSV AIDS, T-cell leukemias Host factors Presence of target receptors on host cells Availability of enzymes essential for viral entry and replication Specific immunity against certain viral epitopes State of immunocompetence, i.e. ability of the immune system to control the viral replication effectively Defenses against infections Non-specific Anatomic barriers Nonspecific inhibitors Phagocytic cells Fever Inflammation Interferon Specific Humoral immunity Cellular immunity Diagnosis Clinical symptoms Blood tests and cultures Blood may be tested for antibodies to viruses or for antigens Polymerase chain reaction (PCR) Treatment Antivirals interfere with replication of viruses Target only limited cellular metabolic functions Cause many toxic side effects Development of resistance Strengthening the immune response of patients Interferons Immunoglobulins Vaccines Respiratory Syncytial Virus (RSV) Causes acute respiratory tract illness in all ages Most children are infected by 2nd year of age Seasonal outbreaks between October – May Highly contagious Previous infection does not protect against reinfection Transmission Direct contact with infected droplets RSV can survive for several hours outside the body Viral shedding ~ 3 – 8 days, up to 4 weeks Incubation ranges from 2 – 8 days RSV: High Risk Groups Infants (< 12 months) 1 -2 % require hospitalization Mean age of infants hospitalized: 3 months Duration of illness: up to 12 days 10% remain ill after 4 weeks Fatal in < 1% Immunocompromised patients Elderly Solid organ transplant Bone marrow transplant - Mortality of 70 to 100 % RSV: Clinical Presentation Usually self-limited process Infants and young children usually present with LRTI Bronchiolitis Bronchospasm Pneumonia Acute respiratory failure Wheezing Apnea - 20% of hospitalized infants RSV: Clinical Presentation Older children and adults usually have upper respiratory tract symptoms Cough Rhinorrhea Conjunctivitis High risk groups may develop LRTI RSV pneumonia can lead to respiratory failure RSV: Prevention exposure and the risk of acquiring RSV Avoidance of exposure to tobacco smoke Restricting participation in child care setting during RSV season for highrisk infants Handwashing in all settings Immunoprophylaxis with palivizumab Humanized monoclonal antibody against the RSV F glycoprotein Indicated for use in selected infants and children younger than 24 months with BPD preterm birth (≤35 weeks) hemodynamically significant congenital heart disease Dose scheduled monthly x 5 doses lower risk of hospitalization fewer hospital days requiring oxygen fewer total hospital days RSV: Treatment Supportive therapy Racemic epinephrine Bronchodilators Oxygen Ribavirin IH Routine use is not recommended Must be given within 48 hours of onset of symptoms Randomized controlled trials yielded mix results Uncontrolled studies on combination with IVIG improved survival, ventilator days, & incidence of bronchiolitis obliterans AAP recommends that use of ribavirin be based on clinical circumstances CHD Lung disease BMT (Early use resulted in morbidity and mortality) Need for mechanical ventilation Contraindication — pregnant women Adverse effects — headache , conjunctivitis , dizziness, pharyngitis, lacrimation, bronchospasm and/or chest pain Herpes Simplex Virus (HSV) Double stranded DNA virus with an envelope Infects > 40 million Americans between 15 and 75 yrs old Subtypes HSV-1: resides in trigeminal ganglion HSV-2: resides in sacral ganglia Life cycle Entry into the body replicates kills surface cells enters and remains dormant in the cell end-plates at skin surface (connected to internal nerve cells and eventually lead to a ganglion) HSV: Clinical presentation Primary Infection Recurrent Infection (occurs in 25 -30%) Transmitted from human-to-human contact Manifests as tiny, clear, fluid filled blisters Triggers: sunlight, fever, stress, immunosuppression Frequency of occurrence varies Lesions appear at same site Diseases caused by HSV Mucocutaneous Herpes keratitis CNS Neonatal herpes Disseminated infection Neonatal Herpes Occurs in 1/3000 to 1/20,000 births HSV-2 accounts for 80% of cases Usually transmitted during delivery 15% transmissionS from another neonate or family Symptoms & signs appears in 1st and 2nd week Local or disseminated disease Skin vesicles in 55% of cases CNS disease in those with no skin vesicles More serious forms of disease will follow within 10 days if localized disease is left untreated Neonatal Herpes: Prognosis Localized infection: Mortality: 50% 30% develop neurologic impairment, which may not manifest until 2 to 3 yr of age. Desseminated infection: Mortality: 85% Most survivors are neurologically impaired 92% if untreated 86% if treated Immunocompromised Host Incidence of reactivation 60 – 80% in solid organ tranplants > 80% after bone marrow transplant Can be local or disseminated Lesions at multiple sites Lesions may take 3 -5 weeks to heal Longer viral shedding period HSV: Treatment Acyclovir First line agent for HSV infection MOA Binds to HSV DNA polymerase, incorporated into viral DNA, and prevents further elongation of the chain Converted to the active monophosphate form by herpesvirus thymidine kinase Resistance is observed in virus strains that are deficient in thymidine kinase Adverse effects Nephrotoxicity - most significant Maintaining good hydration helps incidence HSV: Treatment (cont.) Acyclovir (cont.) Oral acyclovir - 10 – 20% bioavailable Valacyclovir - 50% bioavailable; pediatric dosing not well studied Ganciclovir Structurally similar to acyclovir active against HSV Cross-resistance occurs with acyclovir Foscarnet Second line agent, when acyclovir resistance is suspected Does not require thymidine kinase for drug activation Cytomegalovirus (CMV) Member of herpesvirus family Infects 50-80% of adults by 40 years old Primary infection Usually causes few symptoms Few long-term health consequences Some develop a mononucleosis-like syndrome with prolonged fever and a mild hepatitis Once infected, virus usually remain dormant for life Recurrence rarely occurs in a healthy person CMV (cont.) Transmission Person-to-person contact In households In day care centers Via saliva, urine, body fluid, breastmilk, transplanted organs, blood transfusions Prevention Handwashing Pregnant women to avoid direct contact with young children CMV: High-risk groups Unborn baby during pregnancy Highest risk occurs in women with primary infection during pregnancy 1/3 of infants will be infected 10 -15% of infected infants will have symptoms Symptoms range from enlargement of liver and spleen to fatal illness 80 to 90% will have hearing loss, vision impairment, and varying degrees of mental retardation 5 to 10% of asymptomatic infants will have varying degrees of hearing and mental or coordination problems CMV: High-risk groups (cont.) People who work with children CMV is commonly transmitted among young children and to child care providers Prevent transmission by practice handwashing and reduce personal contact Immunocompromised person Transplant patients, patients receiving immunosuppressive drugs, & HIV patients Pneumonia, retinitis, & GI illness are common presentations Avoid CMV+ blood products CMV: Treatment Ganciclovir Used primarily for CMV; active against herpes viruses MOA: An inhibitor and substrate for CMV DNA polymerase inhibits DNA synthesis and prevents DNA elongation Requires thymidine kinase in CMV-infected cell to phosphorylate drug to triphosphate (active) form ganciclovir phosphorylation indicator of CMV resistance Can be used in combination with foscarnet for synergistic activity dose when combining therapy to toxicity Adverse effects Myelosuppression Nephrotoxicity - much less than acyclovir or foscarnet Handling of this agent requires chemotherapy precautions CMV: Treatment Foscarnet Used for prophylaxis and treatment of CMV infection Second line agent for HSV refractory to acyclovir MOA: Inhibits viral RNA and DNA polymerases inhibits pyrophosphate exchange prevents elongation of DNA chain Does not require activation by thymidine kinase; active against HSV strains that are deficient in thymidine kinase Spectrum of activity HSV-1; HSV-2 Cytomegalovirus Varicella zoster virus Epstein-Barr virus Influenza virus (A Victoria and B Hong Kong strains) CMV: Treatment Foscarnet (cont.) Renally eliminated – adjust dose for impaired renal function Consider combination tx with ganciclovir to toxicities Adverse effects Nephrotoxicity Electrolyte abnormalities Hypokalemia Hypocalcemia Hyperphosphatemia OR hypophosphatemia Hypomagnesemia Neurotoxicity (seizures with rapid infusion) CMV: Treatment CMV-IVIG A preparation of IgG of pooled healthy blood donors with a high titer of CMV antibodies Provides a passive source of antibodies against CMV Prophylaxis in solid organ transplant Use in combination with antivirals for treatment of CMV pneumonia Dosing and length of therapy not well studied Adenovirus Non-enveloped, double-stranded DNA virus Consists of 51 distinct pathogenic types Some serotypes are endemic to specific parts of the world Some are usually acquired during childhood Some cause sporadic outbreaks Transmission Direct contact with respiratory droplet Fecal-oral Waterborne Adenovirus Clinical manifestations Respiratory illness (most common ) Gastroenteritis Conjunctivitis Hemorrhagic cystitis Hepatitis High risk groups Immunocompromised patients (viral reactivation) Occurs in 5 -29% of BMT patients • Deaths occur in 30 -50% Acute respiratory disease can be precipitated by overcrowding and stress • Adenovirus: Treatment Treat symptoms and complications of infection Cidofovir FDA-approved indication: CMV retinitis in AIDS patients MOA Inhibits viral DNA polymerase Does not depend on virus-specific thymidine kinase Spectrum of activity Herpesvirus (HSV-1, HSV-2) Cytomegalovirus BK virus Adenovirus Adenovirus: Treatment Cidofovir (conti.) Adverse effects Nephrotoxicity Renal tubular acidosis Granulocytopenia (not dose-related) Need appropriate hydration and probenecid Antivirals Drug Target Virus Adverse Effects Other considerations Acyclovir HSV Nephrotoxicity (require dosing adjustment in renal dysfunction) Ganciclovir HSV, CMV Myelosuppression, nephrotoxicty (< acyclovir & foscarnet) Foscarnet HSV,CMV Cidofovir HSV,CMV, adenovirus Renal toxicity (require dosing adjustment in renal dysfunction) Electrolyte abnormalities (K, Ca, P, Mag) Nephrotoxicity (SrCr, proteinuria, & renal tubular acidosis), granulocytopenia Ribavirin Broad coverage RSV, HSV, adenovirus 1st line agent for HSV. Must be well hydrated . Valacyclovir more bioavailable than oral acyclovir. 1st line agent for CMV. May use in combination with foscarnet for synergistic activity. Does not require thymidine kinase for activation; thus, can be used in cases of acyclovir and ganciclovir. Must be well hydrated. Is an option when ganciclovir and foscarnet fail. Must be administered with appropriate hydration and probenecid. IV preparation available via compassionate use protocol - requires prior FDA and IRB approval. FDA Pregnancy Category: Category X. IH form causes headaches & conjunctivitis. IV form causes hemolytic anemia, reticulocytosis, seizures and dizziness Conclusions A mature, intact immune system is the best defense against fungal viral infections Immunocompromised patients are most at risk for morbidity and mortality Premature neonates Elderly Immunosuppressed patients (HIV, SCID, transplant) Avoidance is perhaps the best prevention against infection Early recognition and implementation of appropriate therapy are vital to improved outcome References • Andes D. Optimizing antifungal choice and administration. Current Medical Research & Opinion 2013; 29 (S4): 13–18 • Boeckh M, Berrey M, et al . 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Diagnosis of invasive fungal infections in hematology and oncology. Guidelines of Infectious Diseases Working Party of the German Society of Hematology and Oncology. Ann Hematol 2003. 82 (S2): 141 – 148 • Steiner R. Treating Acute Bronchiolitis Associated with RSV. Am Fam Physician 2004; 69: 325-30 • Wade J. Viral Infections in Patients with Hematological Malignancies. Hematology 2006; 1: 368 – 374 • Zamora M, Davis RD, and Leonard L, for the CMV Advisory Board Expert Committee Management of Cytomegalovirus Infection in • Lung Transplant Recipients: Evidence-Based Recommendations. Transplantation 2005; 80: 157–163 • Accessed www.cdc.gov for RSV, CMV, and adenovirus. Jan 2009. • Accessed Micromedex for all drug agents discussed. Jan 2014. • Accessed LexiComp for all drug agents discussed. Jan 2014. Current Medical Research & Opinion 2013. 29 (S4): 3 – 11