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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




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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



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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

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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 . 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?
•
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.
Current Medical Research & Opinion 2013. 29 (S4): 3 – 11