Ngoc-Yen Nguyen, PharmD February, 2014

Ngoc-Yen Nguyen, PharmD February, 2014
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 ABLC - As a modification of dimyristoyl phosphatidylcholine:dimyristoyl phosphatidylglycerol 7:3 (DMPC:DMPG) liposome, amphotericin B lipid-complex has a higher drug to lipid ratio and the concentration of amphotericin B is 33 M. ABLC is a ribbon-like structure, not a liposome. Ambisome - Amphotericin B (liposomal) is a true single bilayer liposomal drug delivery system. Liposomes are closed, spherical vesicles created by mixing specific proportions of amphophilic substances such as phospholipids and cholesterol so that they arrange themselves into multiple concentric bilayer membranes when hydrated in aqueous solutions. Single bilayer liposomes are then formed by microemulsification of multilamellar vesicles using a homogenizer. Amphotericin B (liposomal) consists of these unilamellar bilayer liposomes with amphotericin B intercalated within the membrane. Due to the nature and quantity of amphophilic substances used, and the lipophilic moiety in the amphotericin B molecule, the drug is an integral part of the overall structure of the amphotericin B liposomal liposomes. Amphotericin B (liposomal) contains true liposomes that are <100 nm in diameter. Controlled comparative trials of original form to the newer formulations are lacking Thus, comparative data discussing differences among the formulations should be interpreted cautiously

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 Inhibits CYP1A2 (weak), CYP2C19 (strong), CYP2C9 (moderate), CYP3A4 (moderate)

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 Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP3A4 (strong), P-glycoprotein Has negative inotropic properties The benefit:risk for therapy in the treatment of other types of fungal infections should be carefully considered in each patient, particularly those with HF and in heart transplant recipients. If indicated after cardiac, renal, or liver transplantation, itraconazole can increase cyclosporine levels by up to 50% at high doses. It also increases serum levels of lovastatin and simvastatin by up to 20-fold, as well as other HMG-CoA reductase inhibitors (except fluvastatin and rosuvastatin), by inhibiting CYP3A4. This is important since many post-transplantation patients are also hyperlipidemic and on HMG-CoA reductase inhibitors. Itraconazole may also increase levels of digoxin, disopyramide, dofetilide, and quinidine. The simultaneous administration of these medications may increase the risk of cardiotoxicity. Edema has been reported in patients concurrently receiving itraconazole and calcium channel blockers (CCBs). CCBs may cause additive negative inotropic effects when used concurrently with itraconazole. Use caution with concurrent use of itraconazole and CCBs due to an increased risk of HF. Concurrent use of itraconazole and dofetilide, nisoldipine and quinidine is contraindicated.

Voriconazole Place in therapy Dosing considerations 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 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 Visual changes such as blurred vision, photophobia, changes in visual acuity and color have been reported in 30% of patients in clinical trials. sulfobutylether-β-cyclodextrin Substrate of CYP2C19 (major), CYP2C9 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C19 (moderate), CYP2C9 (moderate), CYP3A4 (strong

Posaconazole Place in therapy PK studies in pediatric is limited
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. Prophylaxis of invasive Aspergillus and Candida infections in severely-immunocompromised patients [eg, hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with prolonged neutropenia secondary to chemotherapy for hematologic malignancies]

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 May  blood concentration of drugs metabolized by CYP450 Anidulafungin Invasive candidiasis; oroesophageal candidiasis Undergo slow nonhepatic, chemical degradation

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 Flucytosine appeared on the market in the early 1970s, followed by the systemic azoles ketoconazole in 1980 and fluconazole and itraconazole in the early 1990s. Antimetabolite - cytotoxic drug Systemic fungistatic Flucytosine is metabolized to fluorouracil which may cause adverse events if administered during pregnancy; refer to the fluorouracil monograph for additional information.

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 Viruses are quite different from cells. They contain only one type of nucleic acid, DNA or RNA, never both. They lack membranes and a cytoplasm, as well as ribosomes and any means to produce energy. Although viruses can replicate, mutate and maintain genetic continuity, they depend entirely upon a host cell to supply a habitat, energy and raw materials (precursors) for viral replication. Thus, viruses must exist as obligate intracellular parasites of cellsA.

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 Stages of virus replication and possible targets for antiviral activity 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 Liver Alimentary tract Hepatitis B Penetration of skin HSV1 Acute Nerves, leukocytes Many (brain, liver, skin) Respiratory tract, epithelial surfaces Recurrent Ganglion Nerves (to site of latency) Skin, eye Skin, eyes HSV2 Genital tract Measles Skin, lungs, brain Poliomyelitis CNS Rabies Subcutaneously (bite) Nerves Brain Salivary glands Rubella Skin, lymph nodes, fetus Respiratory tract, excreted in newborn This table list some viruses the sites of implantation, how they are spread, the organs they attack, and site of shedding

Virus effect on cells Lytic Infection Persistent 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 There are several possible consequences to a cell that is infected by a virus, and ultimately this may determine the pathology of a disease caused by the virus. Lytic infections result in the destruction of the host cell. Lytic infections are caused by virulent viruses, which inherently bring about the death of the cells that they infect. Acute cytolytic infection, the most common form of virus-host cell interaction results in destruction of the infected cell. (e.g., herpesviruses, poxviruses, and paramyxoviruses) When enveloped viruses are formed by budding, the release of the viral particles may be slow and the host cell may not be lysed. Such infections may occur over relatively long periods of time and are thus referred to as persistent infections. Viruses may also cause latent infections. The effect of a latent infection is that there is a delay between the infection by the virus and the appearance of symptoms. Fever blisters (cold sores) caused by herpes simplex type 1 result from a latent infection; they appear sporadically as the virus emerges from latency, usually triggered by some sort of stress in the host. Some animal viruses have the potential to change a cell from a normal cell into a tumor cell, the hallmark of which is to grow without restraint. This process is called transformation. Viruses that are able to transform normal cells into tumor cells are referred to as oncogenic viruses .

Types of pathogenic viruses
DNA viruses RNA viruses 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

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 Presence of target receptors on host cells Availability of enzymes in host cells which are essential for viral entry and replication State of immunocompetence of the individual host Specific immunity against certain viral epitopes in the individual host and target population Ability of the immune system to control the viral replication effectively without causing serious collateral damage to the host by its inflammatory response

Defenses against infections
Non-specific Specific Anatomic barriers Nonspecific inhibitors Phagocytic cells Fever Inflammation Interferon Humoral immunity Cellular immunity Most viral infections are limited by defenses that are antigen nonspecific and/or specific. Nonspecific defenses act sooner than specific defenses. Some are always in place (anatomic barriers, nonspecific inhibitors, and phagocytic cells); others are evoked by the infection (fever, inflammation, and interferon). Specific defenses include humoral and cellular immunity

Diagnosis Clinical symptoms Blood tests and cultures
Blood may be tested for antibodies to viruses or for antigens Polymerase chain reaction (PCR) Diagnosis Common viral infections may be diagnosed based on symptoms. For infections that occur in epidemics (such as influenza), the presence of other similar cases may help doctors identify a particular infection. For other infections, blood tests and cultures may be done. Blood may be tested for antibodies to viruses or for antigens (proteins on or in viruses that trigger the body's defenses). Polymerase chain reaction (PCR) techniques may be used to make many copies of the viral genetic material.

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 Compared to viruses, bacteria are relatively large organisms, commonly reproduce by independently outside of cells, and have many metabolic functions that antibacterial drugs (antibiotics) can target. In contrast, viruses are small and replicate inside host cells using the cells' own metabolic functions, there are only a limited number of metabolic functions that antiviral drugs can target. Therefore, antiviral drugs are much more difficult to develop than antibacterial agents. Many antiviral drugs work by interfering with replication of viruses. Other challenges in the treatment of viral infection include: toxic side effects of antivirals and the development of viral resistance to antiviral drugs. Another strategy used is strengthening the immune response to the viral infection. Agents used include several types of interferons, immunoglobulins, and vaccines. Interferon drugs are replicas of naturally occurring substances that slow or stop viral replication. Immune globulin is a sterilized solution of antibodies (also called immunoglobulins) collected from a human donors. Vaccines are materials that help prevent infection by stimulating the body's natural defense mechanisms. Many immune globulins and vaccines are given before exposure to a virus to prevent infection. Some immune globulins and some vaccines, such as those for rabies and hepatitis B, are also used after exposure to the virus to help prevent infection from developing or reduce the severity of infection. Immune globulins may also help treat some established infections and also prevent infection after exposures to the virus.

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 % For most people, RSV produces only mild symptom, often very similar to the common cold. However, according to the CDC, it is the “most common cause of bronchiolitis and pneumonia among infants and children under 1 year of age. In these patients who develop brionchiolitis, leading to severe respiratory illness requiring hospitalization and rarely, causing death. This is more likely to occur in patients that are immunocompromised or infants born prematurely. It is associated with up to 120,000 pediatric hospitalizations each year, and is increasing in frequency. Data compiled by the Centers for Disease Control, RSV pneumonia has been blamed or an average of 2700 adult and pediatric deaths each year.

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 The clinical manifestations vary depending upon the patient's age, health status, and whether the infection is primary or secondary. Infants and young children with primary infections usually present with LRTI Apnea may be the presenting symptom in approximately 20 percent of infants hospitalized with RSV, and may be the cause of sudden unexpected death.

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 Older children and adults typically have primarily upper respiratory tract symptoms, but may develop LRTI, particularly if they are elderly or immunocompromised. RSV pneumonia leading to respiratory failure can be a significant cause of acute morbidity and mortality in the immunocompromised host, with mortality rates of 70 to 100 percent being described in bone marrow transplant patients Long-term pulmonary sequelae in these patients have not been adequately studied. However, chronic pulmonary dysfunction as a result of RSV infection does not appear to be a problem in lung or renal transplant patients, as indicated by the following observations: Lung transplant patients showed a return to baseline spirometry five months after RSV infection. Pediatric renal transplant patients showed a return to baseline pulmonary function three months after RSV infection.

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 The virus is spread through droplets when a person coughs or sneezes (breathing in the droplets.) The virus can also live on surfaces such as contertops or doorknobs, and on hands and clothing. It can be easily spread when a person touches a contaminated object or surface. (Hand to mouth.) Because RSV is highly contagious and can cause serious infections , preventive measure should be practice to minimize the impact, especially in high risk patients. Prevention is most important for infants with congenital heart or lung disease, bone marrow and lung transplant recipients, and the frail elderly with multiple underlying conditions. Patients/Families should be advised to avoid tobacco smoke, …. Immunoprophylaxis also should continue even if the infant experiences breakthrough infection . This is because high-risk infants may be hospitalized more than once during an RSV season and more than one strain of RSV may cocirculate in a community. Efficacy and effectiveness — The efficacy of palivizumab for preventing severe RSV infection in infants and children with prematurity, BPD, and congenital heart disease has been demonstrated in randomized controlled trials: In the IMpact-RSV Trial, 1502 patients with BPD and/or prematurity (<35 weeks) were randomly assigned to monthly treatment with palivizumab or placebo . Palivizumab was associated with significantly fewer RSV-associated hospitalizations (4.8 versus 10.6 percent with placebo, a 55 percent reduction). In another trial, 1287 children with hemodynamically significant congenital heart disease were randomly assigned to monthly treatment with palivizumab or placebo. Palivizumab was associated with fewer RSV-associated hospitalizations (5.3 versus 9.3 percent, a 45 percent reduction), fewer hospital days requiring oxygen (178 versus 658, a 73 percent reduction) and fewer total hospital days (367 versus 876, a 56 percent reduction). The mortality rates were similar in both groups (3.3 versus 4.3 percent). No deaths or adverse events were attributed to palivizumab.

RSV: Treatment Supportive therapy Ribavirin IH 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 The routine use of nebulized ribavirin in infants and children with RSV LRTI is not recommended. efficacy of ribavirin in this population has not been clearly proven ribavirin is expensive must be given early in the course to be effective concerns regarding occupational exposure Randomized controlled trials comparing ribavirin to placebo in children with RSV LRTI have yielded mixed results. Some studies have demonstrated decreased severity of illness, decreased duration of mechanical ventilation, oxygen therapy and hospital stay, and decreased viral shedding Other studies have not demonstrated these benefits studies of children with RSV infection and LRTI found that trials of ribavirin lack sufficient power The efficacy of ribavirin for patients with solid-organ transplants is unknown. Contraindications — contraindicated in pregnant women. Ribavirin is a known teratogen in rodent species. However, it has not been shown to be teratogenic in primates, and no adverse effects have been found in the human fetus. Adverse effects — Adverse effects related to occupational exposure to ribavirin have not been reported. However, the National Institute of Occupational Safety and Health has published recommendations to reduce the ambient air concentrations of ribavirin and limit occupational exposure to hospital personnel.

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) is a double-stranded DNA virus with an enveloped, icosahedral capsid. a common cause of infections of the skin and mucous membranes, manifesting itself as tiny, clear, fluid-filled blisters usually around the mouth or genitals. The virus infects more than 40 million Americans between the ages of 15 and 75, and in extreme cases, can appear in and about the eyes, esophagus, trachea, brain, and arms and legs Both types of herpes simplex virus (HSV), HSV-1 and HSV-2, can cause oral or genital infection. Most often, HSV-1 causes gingivostomatitis, herpes labialis, and herpes keratitis. HSV-2 usually causes genital lesions. Transmission of HSV occurs from close contact with an individual who is actively shedding virus. Viral shedding generally occurs from lesions but can occur even when lesions are not apparent. After the initial infection, HSV remains dormant in nerve ganglia from which it can periodically emerge, causing symptoms. Recurrent herpetic eruptions are precipitated by overexposure to sunlight, febrile illnesses, physical or emotional stress, immunosuppression, or unknown stimuli. Recurrent eruptions are generally less severe, and generally occur less frequently over time.

HSV: Clinical presentation
Primary Infection Transmitted from human-to-human contact Manifests as tiny, clear, fluid filled blisters Recurrent Infection (occurs in %) 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 Primary infection refers to the first time an individual is infected with any type of HSV. This primary event may or may not be accompanied by clinical symptoms and the individual may be unaware of the infection. The primary infection can be accompanied by blisters, ulcers, or red inflamed areas (lesions), which may occur at a variety of body sites including the eye and the internal and external areas of the mouth or genitals. Recurrent infection occur as often as every few weeks or as seldom as once a year, and they usually appear at the same site. Many factors can initiate a recurrence, such as sunlight, menstruation, wind, fever, suppression of immune system, emotional stress, and intense dental work. Importantly, the immune system can never fully eliminate the virus; however, people with immunocompetent systems can have less severe and less frequent outbreaks. Mucocutaneous infection is most common. Ocular infection (herpes keratitis), CNS infection, and neonatal herpes are unusual but more serious manifestations. HSV rarely causes fulminant hepatitis in the absence of cutaneous lesions. In patients with HIV infection, herpetic infections can be particularly severe. Progressive and persistent esophagitis, colitis, perianal ulcers, pneumonia, encephalitis, and meningitis may occur. HSV outbreaks may be followed by erythema multiforme possibly from an immune reaction to the virus. Eczema herpeticum is a complication of HSV infection in which patients have severe disease in skin regions with eczema.

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 simplex virus (HSV) infection has high mortality and significant morbidity. Incidence estimates range from 1/3,000 to 1/20,000 births. HSV type 2 causes about 80% of cases; 20% are caused by HSV type 1. HSV is usually transmitted during delivery through an infected maternal genital tract. Transplacental transmission of virus and hospital-acquired spread from one neonate to another by hospital personnel or family may account for about 15% of cases. Mothers of neonates with HSV infection tend to have no history or symptoms of genital infection at the time of delivery. Symptoms and Signs Manifestations generally occur between the 1st and 2nd wk of life but may not appear until as late as the 4th wk. Patients may present with local or disseminated disease. Skin vesicles are common in either form, occurring in about 55% overall. Those with no skin vesicles usually present with localized CNS disease. In patients with isolated skin or mucosal disease, progressive or more serious forms of disease frequently follow within 7 to 10 days if left untreated. Prognosis The mortality rate of untreated disseminated disease is 85%; among those with untreated local disease and encephalitis, it is about 50%. At least 95% of survivors have severe neurologic sequelae. Death is uncommon in those with local disease but without CNS or organ disease, except as the result of concomitant medical problems, but about 30% develop neurologic impairment, which may not manifest until 2 to 3 yr of age.

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 Prognosis The mortality rate of untreated disseminated disease is 85%; among those with untreated local disease and encephalitis, it is about 50%. At least 95% of survivors have severe neurologic sequelae. Death is uncommon in those with local disease but without CNS or organ disease, except as the result of concomitant medical problems, but about 30% develop neurologic impairment, which may not manifest until 2 to 3 yr of age. Mortality without treatment is >80%, with treatment 57% (9), all but a few survivors impaired (abnormal neurologic status at one year 92% in untreated patients and 86% in treated patients with disseminated disease).

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 Patients whose immune responses are suppressed, immunocompromised, frequently suffer from recurrent HSV infections that are much more painful than infections in immunocompetent patients. The recurrences are mostly caused by reactivation of a latent infection that was acquired prior to the period of immunosuppression. The reactivated infections usually have lesions that may take 3-5 weeks to heal, a longer period of viral shedding, and are more likely to cause lesions at multiple sites compared to lesions in an immunocompetent host (Pielop et al., 2000). In addition, recurrent infections can result in local or systemic infection, dehydration, and nutritional deficiencies secondary to oral and esophageal lesions. If left untreated, HSV infections can cause severe morbidity and mortality because it is an opportunistic infection in immunocompromised patients. The reactivation rate of HSV among seropositive transplant patients is between 60 and 80% for patients with solid organ transplants and over 80% after bone marrow transplants.

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.) Ganciclovir Foscarnet
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 Cytomegalovirus, or CMV, is found throughout all geographic locations and socioeconomic groups and infects between 50% and 80% of adults in the United States by 40 years of age. In the United States, CMV is also the virus most frequently transmitted to a developing child before birth. For most healthy persons who acquire CMV after birth, there are few symptoms and no long-term health consequences. Some persons with symptoms experience a mononucleosis-like syndrome with prolonged fever and a mild hepatitis. Once a person becomes infected, the virus remains alive, but usually dormant, within that person's body for life. Recurrent disease rarely occurs unless the person's immune system is suppressed due to therapeutic drugs or disease. Therefore, for the vast majority of people, CMV infection is not a serious problem.

CMV (cont.) Transmission Prevention 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 Transmission and Prevention Transmission of CMV occurs from person to person. Infection requires close contact with a person excreting the virus in their saliva, urine, or other body fluids. CMV can be sexually transmitted and can also be transmitted via breast milk, transplanted organs, and occasionally from blood transfusions. Although the virus is not highly contagious, it has been shown to spread in households and among young children in day care centers. Transmission of the virus is often preventable because it is often transmitted through infected body fluids that come in contact with hands and then are absorbed through the nose or mouth of a susceptible person. Therefore, care should be taken when interacting with children and handling items like diapers. Simple hand washing with soap and water is effective in removing the virus from the hands. Pregnant women should also be counseled to avoid direct contact with the saliva of young children through behaviors such as kissing on the lips. CMV infection without symptoms is common in infants and young children; therefore, it is unjustified and unnecessary to exclude from school or an institution a child known to be infected. Similarly, hospitalized patients do not need separate or elaborate isolation precautions. General screening of children and patients for CMV is of questionable value. The cost and management of such procedures are impractical. Children known to have CMV infection should not be singled out for exclusion, isolation, or special handling. Instead, staff education and effective hygiene practices are advised in caring for all 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 However, CMV infection is important to certain high-risk groups. Major areas of concern are (1) the risk of infection to the unborn baby during pregnancy, (2) the risk of infection to people who work with children, and (3) the risk of infection to the immunocompromised person, such as organ and bone marrow transplant recipients and persons infected with human immunodeficiency virus (HIV). Pregnancy The incidence of primary (or first) CMV infection in pregnant women in the United States varies from 1% to 4%. Healthy pregnant women are not at special risk for disease from CMV infection. When infected with CMV, most women have no symptoms and very few have a disease resembling mononucleosis. It is their developing unborn babies that may be at risk for congenital CMV disease. CMV remains the most important cause of congenital viral infection in the United States. For infants who are infected by their mothers before birth, two potential problems exist: Generalized infection may occur in the infant, and symptoms may range from moderate enlargement of the liver and spleen (with jaundice) to fatal illness. With supportive treatment most infants with symptomatic CMV disease usually survive. However, from 80% to 90% will have complications within the first few years of life that may include hearing loss, vision impairment, and varying degrees of mental retardation. Another 5% to 10% of infants who are infected but without symptoms at birth will subsequently have varying degrees of hearing and mental or coordination problems. These risks are highest among women who previously have not been infected with CMV and who are having their first infection with the virus during pregnancy. Even in this case, two-thirds of the infants will not become infected, and only 10% to 15% of the remaining third will have symptoms at the time of birth. Recs for pregnant women: practice good personal hygiene, especially handwashing with soap and water, after contact with diapers or oral secretions (particularly with a child who is in day care). Avoid direct contact with the saliva of young children through behaviors such as kissing on the lips, sharing food, drinks, or utensils. Women who develop a mononucleosis-like illness during pregnancy should be evaluated for CMV infection and counseled about the possible risks to the unborn child.

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 People Who Work with Infants and Children Most healthy people working with infants and children face no special risk from CMV infection. However, for women of child-bearing age who previously have not been infected with CMV, there is a potential risk to the developing unborn child (the risk is described above in the Pregnancy section). Contact with children who are in day care, where CMV infection is commonly transmitted among young children (particularly toddlers), may be a source of exposure to CMV. Since CMV is transmitted through contact with infected body fluids, including urine and saliva, child care providers(meaning day care workers, special education teachers, therapists, as well as mothers) should be educated aboutthe risks of CMV infection and the precautions they can take. Day care workers appear to be at a greater risk than hospital and other health care providers, and this may be due in part to the increased emphasis on personal hygiene and the lower amount of personal contact in the health care setting. Recommendations for individuals providing care for infants and children include the following: Female employees should be educated concerning CMV, its transmission, and hygienic practices, such as hand washing, which minimize the risk of infection. Immunocompromised Patients Primary CMV infection in the immunocompromised patient can cause serious disease. However, the more common problem is the reactivation of the dormant virus. Infection with CMV is a major cause of disease and death in immunocompromised patients, including organ transplant recipients, patients undergoing hemodialysis, patients with cancer, patients receiving immunosuppressive drugs, and HIV-infected patients. Pneumonia, retinitis (an infection of the eyes), and gastrointestinal disease are the common manifestations of disease. Because of this risk, exposing immunosuppressed patients to outside sources of CMV should be minimized. Whenever possible, patients without CMV infection should be given organs and/or blood products that are free of the virus.

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 MOA: An inhibitor and substrate for CMV DNA polymerase  inhibits DNA synthesis and end DNA elongation Requires thymidine kinase in CMV-infected cell to phosphorylate the drug to triphosphate form (active)  ganciclovir phosphorylation  CMV resistance

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) MOA: Foscarnet is a pyrophosphate analogue which acts as a noncompetitive inhibitor of many viral RNA and DNA polymerases as well as HIV reverse transcriptase. Inhibitory effects occur at concentrations which do not affect host cellular DNA polymerases; however, some human cell growth suppression has been observed with high concentrations in vitro. Inhibition of DNA polymerase results in inhibition of pyrophosphate exchange which prevents elongation of the DNA chain. Because foscarnet does not require activation by thymidine kinase, it is active in vitro against herpes simplex virus mutant strains that are deficient in thymidine kinase

CMV: Treatment Foscarnet (cont.) Adverse effects
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 Prophylaxis for organ transplant: maximum total dosage for infusion is 150 mg/kg; administer according to the following schedule: Within 72 hours of transplant: 150 mg/kg 2, 4, 6, and 8 weeks post-transplant: mg/kg 12 and 16 weeks post-transplant: mg/kg Severe CMV pneumonia: Various regimens have been used, including 400 mg/kg CMV-IGIV in combination with ganciclovir on days 1, 2, 7, or 8, followed by 200 mg/kg CMV-IGIV on days 14 and 21. improved total survival, reduced CMV disease, and CMV-associated deaths

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 High risk groups
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 % 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) 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 coverage RSV, 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.

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: 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: 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): 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 (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 (S2): 141 – 148 Steiner R. Treating Acute Bronchiolitis Associated with RSV. Am Fam Physician 2004; 69: 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 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.

Ngoc-Yen Nguyen, PharmD February, 2014

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