Pharmacologic management of viral and fungal infections in the immunocompromised host

1. Pharmacologic management of viral and fungal infections in the immunocompromised host Ngoc-Yen Nguyen, PharmD February, 2014

2. 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

3. ANTIFUNGALS

4. Risk Factors for Invasive Fungal Infection

5. 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-albicansCandida 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

6. Types of invasive fungal infections • Aspergillusspp. • 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 • Fusariumspp. • 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 • Mucorspp. • Found in soil, plants, and decaying fruits • Common species: M. amphibiorum; M. circinelloides; M. indicus

7. Incidences of Invasive Fungal Infections

8. 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., Coccidioidesimmitis, Fusarium spp., Histoplasmacapsulatum, Saccharomycescerevisiae, and Pneumocystisjiroveci. • does not detect Cryptococcus, Zygomycetes, such asMucor, and Rhizopus, nor Blastomycesdermatitidis • AspergillusGalactomannan EIA • assay uses EBA-2 monoclonal antibodies to detect Aspergillusgalactomannan, 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

10. Antifungal classes • Polyene • Triazoles • Echinocandins • Flucytosine

11. 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

12. 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

13. 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

14. Itraconazole • Has broad spectrum of activity including Aspergillus, Blastomyces, Candida, Coccidioides, Cryptococcus, Histoplasmacapsulatum, 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

15. Voriconazole • Place in therapy • Drug of choice for invasive aspergillosis • Used in treatment of infections caused by Scedosporiumapiospermum and Fusariumspp 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, AlkPhos) • Substrate and inhibitor of CYP450 - beware of drug interactions • Dosage forms: oral and intravenous

16. Posaconazole • Place in therapy • Prophylaxis of invasive Aspergillus and Candida infections in severely-immunocompromised patients • Treatment of oropharyngealcandidiasis (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.

17. Echinochandins • MOA: block the synthesis of 1-3-D-glucan, a critical component of the fungal cell wall • Available as intravenous preparations only

18. Flucytosine • Converted within the fungal cell to 5-fluorouracil, which inhibits thymidylatesynthetase, 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

21. ANTIVIRALS

22. 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

23. Portal of entry

24. 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

26. 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

27. Types of pathogenic viruses

28. 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

29. Defenses against infections Non-specific Specific • Anatomic barriers • Nonspecific inhibitors • Phagocytic cells • Fever • Inflammation • Interferon • Humoral immunity • Cellular immunity

30. Diagnosis • Clinical symptoms • Blood tests and cultures • Blood may be tested for antibodies to viruses or for antigens • Polymerase chain reaction (PCR)

31. 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

32. 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

33. 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 %

34. 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

35. 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

36. 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

37. 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 bronchiolitisobliterans • 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

38. 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)

39. 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

40. 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

41. 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

42. 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

43. 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 herpesvirusthymidinekinase • Resistance is observed in virus strains that are deficient in thymidinekinase • Adverse effects • Nephrotoxicity - most significant • Maintaining good hydration helps  incidence

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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

50. 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)