1. “Current Status of Diagnosis & Management of Invasive Fungal Infection”

2. Outline of the Presentation
Invasive Fungal Infection
Fungal Pathogens
Fungal infections
Fungal ICU infection
Incidence of ICU acquired candidemia in India
Underlying disease and risk factors
Risk factors for Invasive Fungal Infections in the ICU
Fungal Diagnostic Techniques
Management of Invasive Fungal Infection
Summary of IDSA Guideline for treating Invasive Candidiasis and Aspergilliosis

3. Invasive Fungal Infection
Invasive fungal infections (IFIs) have emerged as a major cause of morbidity and mortality amongst critically ill patients.
Cancer patients admitted to the Intensive Care Unit (ICU) have multiple risk factors for IFIs.
The vast majority of IFIs in the ICU are due to Candida spp.
The incidence of invasive candidiasis (IC) has increased over recent decades, especially in the ICU.
Continuing Education in Anaesthesia, Critical Care & Pain j 2013

4. Fungal Pathogens Candida sp Aspergillus sp Cryptococcus Fusarium
Pneumocystis

5. Invasive Fungal infections
Candidiasis: Mucocutaneous, disseminated, UTI,
Cryptococcosis: Central nervous system (CNS), pulmonary, dematologic, skeletal, and organ-specific disease.
Aspergillosis: Pneumonia, genitourinary, CNS, rhinocerebral, gastrointestinal, and skin.
Zycomocoses: Rhizopus and Mucor species Pneumocystis Pneumonia
Histoplasmosis: Pneumonia or disseminated disease

6. Fungal ICU infection
High mortality rate 35-75%, so early antifungal is essential for survival
ICU acquired fungal infection patients characteristically have several underlying medical and surgical risk factors and frequently exposed to high-risk medications.
Mainly Candidemia in ICU and rarely mold infections.
Rising trend of non-albicans Candida species.
Few multicentric studies on Candidemia from Asian countries.
Chakrabarti et al, Intensive Care Medicine 2015

7. “Incidence of ICU acquired candidemia in India” s
Study: 215,112 patients admitted
27 intensive care units
North -11, East -3, West-3 Central- 4, South – 6
11 public sector and 16 private/corporate hospitals
Adult ICU > 18 years
ICU acquired Candidemia after 48 hrs ICU admission
Chakrabarti et al, Intensive Care Medicine 2015

8. ICU acquired candidemia in India
Incidence of candidemia = 6.51/1000 ICU admission •
Highest burden in north India (8.95/1,000) and lowest from west (3.61/1000 admissions)
65.2% were adults with median age of 50 years
Median duration of onset of candidemia in ICU – 8 days
Majority were non- neutropenic (98.7%)
Median APACHE II score of 17.0 at admission
Chakrabarti et al, Intensive Care Medicine 2015

9. Underlying disease and risk factors
Underlying respiratory illness (25.0%):
Pneumonia (32.9%)
ARDS (17.9%)
COPD (15.4%)
Underlying renal disease (22.9%)
Acute (61.2%) or chronic renal failure (30.1%)
Malignancy (12.8%)
Solid organ (82.9%) and haematological (17.1%)
47.9% gastrointestinal, 60.7% were intraperitoneal
Surgical procedure (37.3%) within 30 days
Gastrointestinal, hepatobiliary and pancreatic surgeries (48.4%)
Chakrabarti et al, Intensive Care Medicine 2015

10. Risk factors for Invasive Fungal Infections in the ICU
Adult Patients
Solid Organ Transplant Recipients
Patients with Malignancy
Candida Colonization
All Transplant recipient
All patients with Malignancy
Diabetes Mellitus
Immunocomsupresnats medications
Neutropenia: duration and severity
Kidney Failure
Corticosteroids
Mucosal Damage
Hemodialysis
Recipients of more than one organ
Concomitant viral infection
Severe Acute Pancreatitis
Acute or Chronic rejection
Recent Chemotherapy
High APACHE II Score
Advance donor age
Prolonged Stay in Mechanical Ventilation
CMV Infection
“Fungal Infection in the intensive care unit”

11. Risk factors for Invasive Fungal Infections in the ICU
Adult Patients
Solid Organ Transplant Recipients
Patients with Malignancy
Central venous or urinary catheter
Liver Transplant recipient
HSCT recipients
Prolonged stay in ICU
Intraoperative blood requirement > 40 Units
Graft vs Host Disease
Broad Spectrum Antibacterial
Choledochojejunostomay
Prior Invasive Fungal Infection
Parenteral Nutrition
Retransplantation
Delayed engraftment
Major Surgery
Reexploreation
Underlying malignancy
Burns
Length of Transplant operation
Induction with Cytarbine
Fluminat hepatic Failure
“Fungal Infection in the intensive care unit”

12. Risk factors for Invasive Fungal Infections in the ICU
Adult Patients
Solid Organ Transplant Recipients
Patients with Malignancy
Lung transplant recipients
Delayed chest closure
Bronchiolitis obliterans
Heart transplant recipients
“Fungal Infection in the intensive care unit”
APACHE II= Acute Physiological and Chronic health Evaluation II scale, CMV Cytomegalovirus,HSCT= hematopoietic stem cell transplantation, ICU = Intensive care unit

13. Fungal Diagnostic Techniques
Traditional Methods
Method
Pathogen(s) detected
Comments
Culture
All
Replication 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
Cannot 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
“Fungal Infection in the intensive care unit”

14. Fungal Diagnostic Techniques
Rapid Diagnostic Tools
Method
Pathogen(s) detected
Comments
Galactomannan
Aspergillus only
False 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
“Fungal Infection in the intensive care unit”
PCR= polymerase chain reaction,PNA FISH= peptide nucleic acid fluorescence in situ hybridization.

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. Management of Invasive Fungal Infection

17. Spectrum of action of systemic antifungal agents
Mayo Clin Proc. • August 2011;86(8):

18. Treatment Strategies
Prophylactic
Pre-emptive
Empiric Strategies

19. Clin Infect Dis. (2015) doi: 10.1093/cid/civ933
Prophylactic Therapy
Prophylaxis therapy provides antifungal agents to a broad populations of patients to prevent disease.
Fluconazole (Azoles) as Prophylaxis in various ICU patients.
If Azole resistant candida spp. or the emergence of disease with pathogens inherently resistant to fluconazole
Prophylaxis Be Used to Prevent Invasive Candidiasis in the Intensive Care Unit Setting as per IDSA 2015
Fluconazole, 800-mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily, could be used in high-risk patients in adult ICUs with a high rate (>5%) of invasive candidiasis
An alternative is to give an echinocandin
“Fungal Infection in the intensive care unit”
Clin Infect Dis. (2015) doi: /cid/civ933

20. Pre Emptive Antifungal therapy
Early Intervention in the course of Disease.
Empiric antifungal therapy should be started as soon as possible in patients who have the risk factors and who have clinical signs Fungal Infection.
Echinocandin:
(caspofungin: loading dose of 70 mg, then 50 mg daily; micafungin: 100 mg daily; anidulafungin: loading dose of 200 mg, then 100 mg daily)
Lipid formulation AmB, 3–5 mg/kg daily, is an alternative if there is intolerance to other antifungal agent
Fluconazole, 800-mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily,

21. Treatment for fungal Infection
Category
Drug
Formulation
Main Indication
Azoles (Trizoles)
Fluconazole
PO/IV
Candida albicans
Itraconzole
Balstomycosis, histoplasmosis, aspergillosis, candidiasis, cryptococcal meningitis
Posaconzole PO
Aspergillus (alternative treatment), zygomycosis, fluconazole-resistant Candida spp.
Voriconzole
Invasive aspergillosis, non-albicans candidaemia, coccidioidomycosis, fluconazole-resistant Candida spp.
“Fungal Infection in the intensive care unit”

22. Treatment for fungal Infection
Category
Drug
Formulations
Main Indication
Echinocandins
Anidulofungin IV
Candida Species
Caspofungin
Most Candida Infections, Potential salvage treatment for Aspergillus.
Micafungin
Polyenes
Amphotericin B
Active against most systemic fungal infection including aspergillosis.
Liposomal amphotericin

23. Treatment for fungal Infection
Category
Drug
Formulation
Main Indication
Other
Flucytosine IV
Cryptococcal meningitis (Used in combination with Amphotericin)
Other topical antifungal agents
Amorolfine
Benzoic acid
Griseofulvein
Nystatin
Terbinafine
Undecantoes
“Fungal Infection in the intensive care unit”

24. Treatment of Fungal Infection
Candidiasis: Fluconazole; or if a resistant Candida species is likely: an Echinocandin or an Amphotericin. Aspergillosis: Voriconazole, an Amphotericin, or both. Zygomycosis: an Amphotericin+posaconazole. Cryptococcosis: An amphotericin with flucytosine, followed by fluconazole. Blastomycosis: Itraconzole, fluconazole, or an amphotericin (depending on the site and severity of the disease).
Continuing Education in Anaesthesia, Critical Care & Pain j 2013

25. Treatment of Fungal Infection
Histoplasmosis: itraconazole or an amphotericin (possibly with steroids in acute pulmonary disease). Coccidioidosis: Fluconazole or an Amphotericin. Paracoccidioidosis: Co-trimoxazole (fluconazole or an amphotericin if co- trimoxazole not tolerated). Pneumocystis pneumonia: co-trimoxazole (with steroids); alternatively, if co- trimoxazole is not tolerated: pentamidine or primaquine/atovaquone with clindamycin.
Continuing Education in Anaesthesia, Critical Care & Pain j 2013

26. Alternative Regimen(s)
Summary of IDSA (2008) Guideline for treating Invasive Candidiasis and Aspergilliosis
Disease State
First line Treatment
Alternative Regimen(s)
Invasive Aspergillosis
Voriconazole 6 mg/kg Iv q 12 h for 2 doses then 4 mg/kg IV q 12 h or 200 mg PO q 12 h
Lipid Amphotericin B 3-5 mg/kg IV q 24 h
Caspofungin 70 mg IV loading dose then 50 mg/kg/day IV
Micafungin mg/day/IV
Posaconazole 800 mg/day PO 2-4 divided doses
Itraconzole dose depends on formulation
Candidemia
(Non-Neutropenic patient moderate-severe illness)
Caspofungin 70 mg IV loading dose then 50 mg/day IV
Micafungin 100 mg/day IV
Anidulafungin 200 mg IV loading dose the 100mg/day IV
Fluconazole 800 mg IV loading dose then 400 mg/day IV or PO
Candidemia (Neutropenic)
Micafungin 100 mg IV daily
Anidulafungin 200 mg IV loading dose then 100 mg /day IV
Fluconazole 800mg IV loading dose then 400 mg/day IV or PO
Voriconazole if mold coverage desired
Voriconazole 6 mg/kg IV q 12 h for doses then 4 mg kg IV q 12 h or 200 mg PO q 12 h
Continuing Education in Anaesthesia, Critical Care & Pain j 2013

27. Clin Infect Dis. (2015) doi: 10.1093/cid/civ933
Summary of IDSA Guideline for treating Invasive Candidiasis and Aspergilliosis
Candida glabrata
Echinocandin
Fluconazole or Voriconazole with susceptibility testing
Candida Parpsilos
Solid organ transplant
Recipient (prophylaxis )
Fluconazole
Fluconazole mg/day IV or PO for 7-14 days
Echinocandin if already responding to therapy
Liposomal amphotericin B 1-2 mg/kg/day IV for 7-14 days
ICU Prophylaxis (High Risk Patient only )
Fluconazole 400 mg/day IV or PO
Clin Infect Dis. (2015) doi: /cid/civ933

28. The Treatment for Candidemia in Neutropenic Patients
The 2016 Revised Recommendations for the Management of Candidiasis
The Treatment for Candidemia in Neutropenic Patients
Strong recommendation;
moderate-quality evidence
low-quality evidence
Weak recommendation;
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
Clin Infect Dis. (2015) doi: /cid/civ933

29. The Treatment for Candidemia in Neutropenic Patients
Strong recommendation;
moderate-quality evidence
low-quality evidence
Weak recommendation;
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: /cid/civ933

30. Thank you