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

References• Andes D. Optimizing antifungal choice and administration. Current Medical Research & Opinion 2013; 29 (S4): 13–18

• Boeckh M, Berrey M, et al . Phase 1 Evaluation of the Respiratory Syncytial Virus–Specific Monoclonal Antibody Palivizumab in

Recipients of Hematopoietic Stem Cell Transplants. JID 2001;184:350–4

• Katragkou A and Roilides E. Current Opinion in Infectious Diseases 2011; 24: 225-229

• Klimpel GR. Immune defenses. gsbs.utmb.edu/microbook/ch050.htm.

• K riengkauykiat J, Ito J, Dadwal S. Epidemiology and treatment approaches in management of invasive fungal infections. Clinical Epidemiology 2011; 3: 175-191

• Lujan-Zilbermann J, Benaim E, et al. Respiratory Virus Infections in Pediatric HSCT • Clinical Infectious Diseases 2001; 33:962–8

• Naesens L and Clercq E. Recent Developments in Herpesvirus Therapy. Herpes 2001; 8 (1): 12 -16

• Razonable RR and Emery VC. Management of CMV Infection and Disease in Transplant Patients-A Consensus Article. Herpes 2004; 11 (3): 77 – 86.

• Perfect J. Fungal diagnosis: how do we do it and can we do better?   Current Medical Research & Opinion 2013. 29 (S4): 3 – 11

• Ruhnke M, et al. 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.