PHARMACOLOGIC MANAGEMENT OF VIRAL AND FUNGAL INFECTIONS IN THE IMMUNOCOMPROMISED HOST Ngoc-Yen...
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Transcript of PHARMACOLOGIC MANAGEMENT OF VIRAL AND FUNGAL INFECTIONS IN THE IMMUNOCOMPROMISED HOST Ngoc-Yen...
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-D-glucan 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 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 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 Child-Pugh Score
For CrCl < 50 ml/minute, consider changing IV to oral, as the accumulation of IV formulation vehicle(SBECD) occurs
Side effects 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
severely-immunocompromised 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
Transcription of the viral genome
Translation & modification of viral proteins
Assembly of virion particles
Release of new viruses
Uncoating and releasing of viral genome into cell
Pathogenesis of Selected Virus InfectionsDisease Common Site of
ImplantationRoute 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
HSV1Acute Respiratory tract Nerves, leukocytes Many
(brain, liver, skin)Respiratory tract, epithelial surfaces
Recurrent Ganglion Nerves (to site of latency)
Skin, eye Skin, eyes
HSV2 Genital tract Nerves (to site of latency)
Genital tract Genital tract
Measles Respiratory tract 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, fetus
Respiratory tract, excreted in newborn
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
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, HSV, CMV, Karposi sarcoma, non-Hodgkin’s lymphoma Epstein Barr virus
Arboviruses Yellow fever, arthropod-borne encephalitis
Orthomyxoviruses Influenza
Paramyxoviruses Measles, mumps, RSV
Retroviruses AIDS, T-cell leukemias
Types of pathogenic viruses
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
Anatomic barriers Nonspecific inhibitors Phagocytic cells Fever Inflammation Interferon
Humoral immunity Cellular immunity
Non-specific Specific
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 high-risk 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 cycleEntry 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
Transmitted from human-to-human contact Manifests as tiny, clear, fluid filled blisters
Recurrent Infection (occurs in 25 -30%) 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
Drug Target Virus Adverse Effects Other considerationsAcyclovir HSV Nephrotoxicity (require dosing
adjustment in renal dysfunction)1st line agent for HSV.Must be well hydrated . Valacyclovir more bioavailable than oral acyclovir.
Ganciclovir HSV, CMV Myelosuppression, nephrotoxicty (< acyclovir & foscarnet)
1st line agent for CMV.May use in combination with foscarnet for synergistic activity.
Foscarnet HSV,CMV Renal toxicity (require dosing adjustment in renal dysfunction)Electrolyte abnormalities (K, Ca, P, Mag)
Does not require thymidine kinase for activation; thus, can be used in cases of acyclovir and ganciclovir. Must be well hydrated.
Cidofovir HSV,CMV, adenovirus
Nephrotoxicity (SrCr, proteinuria, & renal tubular acidosis), granulocytopenia
Is an option when ganciclovir and foscarnet fail.Must be administered with appropriate hydration and probenecid.
Ribavirin Broad coverageRSV, HSV, adenovirus
FDA Pregnancy Category: Category X. IH form causes headaches & conjunctivitis. IV form causes hemolytic anemia, reticulocytosis, seizures and dizziness
IV preparation available via compassionate use protocol - requires prior FDA and IRB approval.
Antivirals
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
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