1. Antifungal Therapy in Immunocompromised Patient

2. Immunocompromised  An Immunocompromised host is a patient who does not have the ability to respond normally to an infection due to an impaired or weekend immune system.  This inability to fight infection can be caused by a number of conditions including:  Primary immune Deficiency  AIDS (HIV)  Trauma  Diabetes mellitus  Malnutrition  Secondary to medical treatment such as chemotherapy or following organ transplantation or HCT Therapeutic Advances in Respiratory Disease 5 (5)

3. Risk factor for Infection in Immunocompromised Patients NeutropeniaDecreased cellular ImmunityMuco-cutenaous barriers alterationIndwelling central venous catheter and parenteral nutritionProphylactic antibioticsTherapeutics Antibiotics Therapeutic Advances in Respiratory Disease 5 (5)

4. Incidence  People living with HIV worldwide continued to grow in 2008, reaching an estimated 33.4 million.  The total number of people living with the virus in 2008 was more than 20% higher than the number in 2000, and the prevalence was roughly threefold higher than in 1990 (AIDS epidemic updates, 2009, UNAIDS).  HIV-infection severely compromises cell-mediated immunity and, as a consequence, individuals are at increased risk for a specific set of mycoses.  The increasing use of aggressive immunosuppressive treatment regimens in organ transplant recipients has resulted in profound levels of immunosuppression lasting for longer periods, thus increasing the high-risk population for invasive mycoses.  There is growing evidence to suggest that critically ill patients are also immunocompromised and, therefore, at high risk of invasive mycoses Therapeutic Advances in Respiratory Disease 5 (5)

5. Incidence Trend’s  First trend observed in:  Hematopoietic stem cell transplant (HSCT) recipients and in neutropenic patients with acute leukemia.  An increased incidence of invasive mold infections—in particular, invasive aspergillosis—has occurred.  This has necessitated changes in the first choice for antifungal therapy from less broad-spectrum agents covering Candida spp.  Predominantly to ones that are active against Aspergillus and other molds. Medicine Reports 2011, 3:14 (doi:10.3410/M3-14)

6. Second trend observed:  Increasing incidence of non-albicans Candida spp.the utility of fluconazole as first line initial therapy for invasive candidiasis has waned due to reduced susceptibility of the yeasts to this drug.  Unfortunately, resistance to even the newer echinocandinclass of antifungals is now also being observed.  Finally, similar to the pattern of resistance arising because of antibiotic pressure, antimicrobial pressure exerted by the use of broad-spectrum antifungal agents such as voriconazole has precipitated the emergence of invasive mold infections caused by the Zygomycetes class of fungi.

7. Third trend observed: Emergence of zygomycosis

8. Incidence of Invasive Fungal Infections  The Transplant-Associated Infection Surveillance Network conducted a 5-year prospective study among 1,063 organ transplant recipients.  One thousand two hundred eight were diagnosed with IFI.  The most common IFIs were:  Invasive candidiasis (53%),  Invasive aspergillosis (IA) (19%),  Cryptococcosis (8%),  Non-Aspergillus molds (8%),  Endemic fungi (5%), and  Zygomycosis (2%)  IA is a life-threatening complication in patients who undergo solid organ transplantation, having an incidence between  0.5% and 2.2% with a mortality rate of > 70% and a high case-fatality rate of up to 88%

9. Aspergillosis in SOT Recipients Transplant type, n (%) Incidence* Mortality † Heart3 (0.8)2 (66.7) Kidney3 (0.1)2 (66.7) Liver3 (0.3)1 (33.3) Lung10 (3.5)2 (20.0) Other1 (0.4)0 Analysis of interim data from 4110 SOT procedures from 19 centers in the United States from March 2001 to December 2002 *Weighted aggregate incidence after 12 months. † Three months after diagnosis of aspergillosis. SOT indicates solid organ transplant. Morgan J, et al. Med Mycol. 2005;43(suppl 1):S49-S58.

10. Indian Prospective  Recipients of solid organ transplants have 6–10% incidence of opportunistic fungal infections with a very high mortality of 70– 100% in the Indian subcontinent.

11. Common Invasive Pulmonary Mycoses Affecting HIV-infected Patients  Cryptococcosis,  Pneumocystis  Pneumonia, histoplasmosis,  Blastomycosis,  Coccidioidomycosis  Aspergillosis A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5 (5)

12. Fungal Diagnostic Techniques MethodPathogen(s) detected Comments Culture AllReplication time is longer for fungi than for bacteria: may take a long time to complete; may be negative for certain fungal pathogens in blood; unable to differentiate colonization form true infection may require invasive specimen. Histopathology AllCannot identify specific pathogens and may be difficult to distinguish from bacterial or other causes; lack of immune response in immunosuppressed patients results ; delay in symptoms related to infection. Radiology All Traditional Methods “Fungal Infection in the intensive care unit”

13. Fungal Diagnostic Techniques Rapid Diagnostic Tools MethodPathogen(s) detectedComments Galactomannan Aspergillus onlyFalse positive with B lactum antibiotics: low sensitivity in solid organ transplant recipients; Controversy regarding positive test cut-off. Beta-Glucan Candida Spp.and Aspergillus only False positive with dialysis filters gauze sponges, albumins, immune globulin; controversy regarding positive test cut-off. Fungal PCR All; test is specific to organism Not Commercially available. PNA FISH Candida albicans and candida glabrata PCR= polymerase chain reaction,PNA FISH= peptide nucleic acid fluorescence in situ hybridization. “Fungal Infection in the intensive care unit”

14. Galactomannan Test  Component of the cell wall of Aspergillus spp.is released during early stages of growth thereby allowing the tests for its presence to be fairly sensitive (71%) and specific (89%).  It can be detected in serum and also bronchoalveolar lavage fluid thus providing a surrogate marker for the diagnosis of invasive aspergillosis.

15. Other Diagnostic Techniques  Chest X –Ray  In case of Aspergillus ling Disease the Presence of aspergillomas or “air crescent” formation on chest CT cab be diagnostic if present.  Funsoscopy may revels cotton-wool ball changes within the retina if candida chrorodorentitis is present. “Fungal Infection in the intensive care unit”

16. Diagnosis Traditional microbiological culture-based testing for fungi produces low yields and creates time delays: it is inexpensive and provides valuable material on which to perform drug- sensitivity testing, which has become increasingly relevant due to the changing patterns of resistance New methods to detect invasive fungal infections early and with high sensitivity and specificity are needed.

17. The Treatment for Candidemia in Neutropenic Patients

18. Strong recommendation; moderate-quality evidence Strong recommendation; low-quality evidence Weak recommendation; low-quality evidence An echinocandin as initial therapy Caspofungin: loading dose 70 mg, then 50 mg daily; Micafungin: 100 mg daily; Anidulafungin: loading dose 200 mg, then 100 mg daily For infections due to C. krusei An echinocandin, lipid formulation AmB, or voriconazole is recommended Fluconazole, 800-mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily is An alternative for patients who are not critically ill and have had no prior azole exposure Lipid formulation AmB 3–5 mg/kg daily, is an effective but less attractive alternative because of the potential for toxicity. Recommended minimum duration of therapy for candidemia without metastatic complications is 2 weeks after documented clearance of Candida from the bloodstream, provided neutropenia and symptoms attributable to candidemia have resolved Fluconazole, 400 mg (6 mg/kg) daily Can be used for stepdown therapy during persistent neutropenia in clinically stable patients who have susceptible isolates and documented bloodstream clearance Ophthalmological findings of choroidal and vitreal infection are minimal until recovery from neutropenia; therefore, dilated funduscopic examinations should be performed within the first week after recovery from neutropenia Voriconazole, 400 mg (6 mg/kg) twice daily for 2 doses, then 200–300 mg (3–4 mg/kg) twice daily, Can be used in situations in which additional mold coverage is desired The 2016 Revised Recommendations for the Management of Candidiasis Clin Infect Dis. (2015) doi: 10.1093/cid/civ933

19. The Treatment for Candidemia in Neutropenic Patients Strong recommendation; moderate-quality evidence Strong recommendation; low-quality evidence Weak recommendation; low-quality evidence In the neutropenic patient, sources of candidiasis other than a CVC (eg, gastrointestinal tract) predominate. Catheter removal should be considered on an individual basis Voriconazole Can also be used as step-down therapy during neutropenia in clinically stable patients who have had documented bloodstream clearance and isolates that are susceptible to voriconazole Granulocyte colony-stimulating factor (G-CSF)–mobilized granulocyte transfusions Can be considered in cases of persistent candidemia with anticipated protracted neutropenia Clin Infect Dis. (2015) doi: 10.1093/cid/civ933

20. Aspergillosis

21.  Aspergillosis is the most common invasive filamentous fungal (mold) infection observed in the immunocompromised population.  Infection is usually acquired through inhalation of the conidia of the ubiquitous soil dwelling fungus, Aspergillus spp.  Other Common: Aspergillus fumigatus, A. flavus and A. terreu, A. nigers.  Depending on the immune status of the host and the presence of underlying lung disease including:  Invasive pulmonary aspergillosis (IPA),  Chronic necrotizing pulmonary aspergillosis (semi-invasive aspergillosis)  Allergic bronchopulmonary  Aspergillosis and aspergilloma. A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5

22. Invasive pulmonary aspergillosis  Over the last two decades, the incidence of IPA has increased due to the increase in the number of immunocompromised patients. Risk Factor: Immunocompromised patients with prolonged and severe neutropenia, Recipients of hematopoietic stem cell transplants (HSCT) or solid organ transplants Patients with haematological malignancy Chronic granulomatous disease or advanced acquired immunodeficiency syndrome are at high risk for invasive aspergillosis A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5 IDSA Guidelines for Aspergillosis CID 2008:46

23. Antifungal therapy for pulmonary aspergillosis in immunocompromised hosts Disease CategoryTreatment Invasive pulmonary aspergillosisPrimary therapy Intravenous voriconazole (preferred) 6 mg/kg IV every 12 h for two doses as a loading dose, followed by 4 mg/kg IV every 12 h until clinical improvement, then oral Itraconzole or voriconazole for continuation. Oral voriconazole (400mg every 12 h for two doses as a loading dose, followed by 200mg every 12 h). Alternative therapy Liposomal amphotericin B (35 mg/kg/day IV) or amphotericin B lipid complex (5 mg/kg/day IV) until clinical improvement, then oral itraconazole or voriconazole for continuation Salvage therapy Caspofungin voriconazole Posaconazole A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5 IDSA Guidelines for Aspergillosis CID 2008:46

24. Chronic Necrotizing Pulmonary Aspergillosis  Chronic necrotizing pulmonary aspergillosis is a subacute infection most commonly seen in patients with impaired local defence from pre-existing pulmonary disease or in patients with more mild immunosuppression. Chronic necrotizing pulmonary aspergillosis is an indolent, destructive process due to invasion by Aspergillus and has cavalry, necrotizing and/or fibrosing components. A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5 IDSA Guidelines for Aspergillosis CID 2008:46

25. Management of Chronic necrotizing pulmonary Aspergillosis Disease Category Treatment Chronic necrotizing pulmonary aspergillosis Primary therapy: Itraconazole 200400 mg/day (oral therapy is preferred due to the requirement of longer duration of treatment). Alternative therapy: Oral voriconazole (400mg every 12 h for two doses as a loading Dose, followed by 200mg every 12 h) If antifungal therapy fails, consider surgical resection. A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5 IDSA Guidelines for Aspergillosis CID 2008:46

26. Cryptococcosis

27.  Cryptococcosis is one of the leading causes of mortality and morbidity in immunocompromised hosts, particularly those infected with HIV.  The majority of cases of cryptococcosis in immunocompromised hosts are caused by the encapsulated yeast, Cryptococcus neoformans (serotype A and D). A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5 Guidelines for Management of Cryptococcosis CID 2010:50

28. Treatment of pulmonary cryptococcosis in immunocompromised hosts Diseases categoryTreatment Cryptococcosis limited to lungs Pulmonary with positive culture, asymptomatic or pneumonia with mild-to-moderate symptoms: Fluconazole 400mg daily for a minimum of 612 months, followed by prophylaxis with fluconazole 200 mg/day. Alternatives: Itraconazole 200400 mg/day for 6-12 months, followed by prophylaxis with fluconazole 200 mg/day. Severe, progressive disease including ARDS Amphotericin B deoxycholate (0.7-1.0 mg/kg per day) or lipid preparations of amphotericin B (35 mg/kg/day) if possible with Flucytosine (100 mg/kg per day) for 2 weeks, then fluconazole 400 mg/ day for 8 weeks, followed by prophylaxis with fluconazole 200 mg/ day. Amphotericin B deoxycholate (0.7-1.0 mg/kg per day) or lipid preparations of amphotericin B (35 mg/kg/day), if possible with flucytosine (100 mg/kg per day) for 610 weeks, followed by prophylaxis with fluconazole 200 mg/day Alternatives: Itraconazole may be substituted for fluconazole A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5

29. Management Of Pulmonary Cryptococcosis With CNS Or Disseminated Disease Disease CategoryTreatment Pulmonary cryptococcosis with CNS or disseminated disease Amphotericin B deoxycholate (0.7-1.0 mg/kg/day) or lipid preparations of amphotericin B (3-5 mg/kg/day), if possible with flucytosine (100 mg/kg/day) for 2 weeksb, then fluconazole 400 mg/day for 8weeks, followed by prophylaxis with fluconazole 200 mg/ day Amphotericin B deoxycholate (0.71.0 mg/kg/day) or lipid preparations of amphotericin B (3-5 mg/kg/day) with or without flucytosine (100 mg/kg per day) for 6-10 weeks, followed by prophylaxis with fluconazole 200 mg/day. Alternatives: Itraconazole may be substituted for fluconazole A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5 Guidelines for Management of Cryptococcosis CID 2010:50

30. Pneumocystis pneumonia

31.  Pneumocystis pneumonia is one of the most prevalent and potentially fatal fungal lung infections in HIV-infected patients.  Pneumocystis pneumonia is caused by Pneumocystis species.  In immunocompromised patients, all forms of Pneumocystis pneumonia should receive treatment regardless of severity. A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5

32. Treatment of Pneumocystis pneumonia in immunocompromised patients. DrugDoseRoute First choice Trimethoprim plus sulfamethoxazole 1.15-20 mg/kg/day Trimethoprim plus 2.Oral or intravenous 75-100 mg/kg/day sulfamethoxazole in four daily divided doses. Oral or intravenous IV is preferable for severe cases, IV can be switched to oral form after clinical improvement Plus corticosteroids if hypoxemic Alternative options Primaquine plus clindamycin 30mg of primaquine/day plus 600mg of clindamycin three times a day Oral Atovaquone Pentamidine 750mg two times daily. Intravenous or intramuscular Aerosol is rarely used Oral Intravenous or intramuscular Aerosol is rarely used A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5

33. Histoplasmosis

34.  Histoplasmosis, the most common endemic mycosis reported in immunocompromised patients, is caused by the dimorphic fungus Histoplasma capsulatum.  Immunocompromised patients including patients with haematological malignancies, and those treated with tumour necrosis factor (TNF) antagonists or corticosteroids are at risk for histoplasmosis.  Progression to more extensive pneumonia with marked hypoxemia and acute respiratory distress syndrome (ARDS) can occur quickly in immunosuppressed patients. A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5

35. Antifungal Treatment For Pulmonary Histoplasmosis Disease CategoryTreatment Progressive disseminated Histoplasmosis Mild to moderate pulmonary histoplasmosis Liposomal amphotericin B, 3 mg/kg/day for 12 weeks, then oral itraconazole. 200mg twice daily for 12 months. Amphotericin B lipid complex (5 mg/kg/day) or amphotericin B deoxycholate (0.71.0 mg/kg/day) may be used as an alternative to liposomal amphotericin B, but is less preferred. Chronic maintenance therapy with itraconazole may be necessary if immunosuppression cannot be reduced. Itraconazole 200mg three times daily for the first 3 days followed by 200mg twice daily for 12 months (monitor liver enzymes) Monitoring serum itraconazole level may be helpful A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5 IDSA Guidelines for Management of Histoplasmosis CID 2007:45 (

36. Blastomycosis

37.  Blastomycosis is an uncommon but potentially fatal fungal disease that is caused by the thermally morphic fungus Blastomyces dermatitis's.  Blastomycosis is relatively uncommon in immunocompromised patients compared with other endemic mycoses such as:  Cryptococcosis  Histoplasmosis  Coccidioidomycosis A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5

38. Treatment options for Blastomycosis. Types of blastomycosisDrugs and Doses Moderately severe to severe pulmonary blastomycosis with or without nonmeningeal dissemination Lipid formulation of amphotericin B (35 mg/kg/day) or amphotericin B deoxycholate (0.71 mg/kg/day) for 12 weeks or until clinical improvement, followed by oral itraconazole 200mg twice daily for at least 12 months Mild localized pulmonary blastomycosisItraconazole, 200mg two or three times per day for at least 12 months CNS blastomycosisLipid formulation of amphotericin B, 5 mg/kg/day for 46 weeks, followed by an oral azole for at least 12 months A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5

39. Coccidioidomycosis

40.  Most common clinical presentation of coccidioidomycosis is a self-limiting acute or subacute community acquired pneumonia.  Approximately 5% of infections result in residual pulmonary sequelae, usually nodules or thin-walled cavities and less than 1% develop extrapulmonary diseases.  In immunocompromised patients, all forms of coccidioidomycosis require therapy due to the high risk of dissemination. A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5

41. Treatment options for coccidioidomycosis Disease manifestationDrugs and doses Acute coccidioidal pneumonia without any complication Fluconazole (preferred) or itraconazole, 200400 mg/day for 36 months Chronic pulmonary Coccidioidomycosis associated with a pulmonary nodule or Cavity Fluconazole (preferred) or itraconazole, 200400 mg/day for at least 18 months Diffuse pneumoniaAmphotericin B dexoycholate, 0.51.5 mg/kg per day or alternate day, or lipid formulations of amphotericin B, 2.05.0 mg/kg or greater per day intravenously until the clinical improvement, followed by fluconazole or itraconazole for lifelong unless the immune reconstitution occurs. Coccidioidal meningitisFluconazole 400 mg/day is the treatment of choice, lifelong Alternative: Intrathecal amphotericin B, 0.11.5 mg/dose at intervals ranging from daily to weekly A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5

42. Zygomycosis

43.  The term zygomycosis describes a group of fungal infections caused by the pathogenic moulds belonging to the class Zygomycetes.  This fungus usually causes infections in lungs, sinuses, skin, and gastrointestinal tract.  Pulmonary zygomycosis is often fatal and one study reported 76% mortality among patients with pulmonary zygomycosis in the immunocompromised population A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5

44. Treatment options for pulmonary zygomycosis. DiseaseTreatment Pulmonary zygomycosis First choice: Lipid formulations of amphotericin B (liposomal amphotericin B and amphotericin B lipid complex) at 5 mg/kg/day Alternative Posaconazole (400mg twice a day, orally). Adjunctive therapy: Surgery A Islam and CH Mody Therapeutic Advances in Respiratory Disease 5

45. Highlights  Epidemiologic changes in the occurrence of invasive fungal infections (IFIs) in a rapidly expanding population of immunocompromised patients present a real challenge to physicians managing them.  Persistently high morbidity and mortality associated with these infections continues despite the increasing spectrum of antifungal pharmacotherapy.  The recent development of Aspergillus polymerase chain reaction (PCR) for the rapid diagnosis of infections holds promise for increasing the sensitivity and specificity.  Early initiation of antifungal therapy is a major contributor to enhanced survival.  Reducing immunosuppression whenever possible with prompt initiation of appropriate antifungal therapy (monotherapy or combination).

46. Highlights  Development of an effective vaccine will be the next important solution to this major problem among immunocompromised patients.

47. Thank you