invasive candidisis.pptx

fungal infections
candidal infections

1. Invasive CANDIDIASIS : Updated Diagnosis & Management

2. Invasive fungal infections (IFIs) are among the leading causes of morbidity and mortality in immunocompromised individuals and a large proportion of critically ill non-neutropenic patients. Ref: Epidemiology and Antifungal Susceptibility Patterns of Invasive Fungal Infections (IFIs) in India: A Prospective Observational Study Andrea Cortegiani et al. What Is the Most Recent Evidence on the Prevention and Early Treatment of Invasive Fungal Infections in Nonneutropenic Critically Ill Patients? Arch Clin Infect Dis. 2017 October; 12(4):e12414. Flückiger U, Marchetti O, Bille J, et al. Swiss Med Wkly. 2006;136(29-30):447-63. Invasive Fungal Infection Opportunistic pathogens of IFIs Most Common IFIs Invasive mycoses in Non - neutropenic Candidiasis Aspergillosis 70–90% 10–20% Most common causative agents of IFIs are- Candida spp. Aspergillus spp. Cryptococcus spp. and Mucorales

3. Ref: Mathur P, Prince Varghese VT, Gunjiyal J, Lalwani S, Kumar S, Misra MC. Epidemiology of blood stream infections at a level-1 trauma care center of India. Journal of laboratory physicians. 2014 Jan;6(1):22. Total number of organisms isolated from sources: None- 128 Respiratory tract - 119 Wound - 23 Urine - 19 CVP - 22 Multiple - 5 Candida: 4th Most Common Cause of BSI

4. INVASIVE CANDIDIASIS Blood stream infection ( Candidemia) or its complications (deep seated tissue/organ infections) including endophthalmitis, endocarditis, septic thrombophlebitis, renal candidiasis, hepatosplenic (chronic disseminated) candidiasis and meningitis. Most infections are due to Candida albicans but other non albicans species include C glabrata, C parapsilos , C tropicalis and C krusei . The frequency of Non-albicans are increasing worldwide. Important to know because of reduced susceptibility to fluconazole in C glabrata and C parapsilosis and intrinsic resistance to fluconazole in C krusei . Acquired resistance to fluconazole is uncommon.

5. Risk Factors for IFIs Ref: Distribution of invasive fungal infections: Molecular epidemiology, etiology, clinical conditions, diagnosis and risk factors: A 3-year experience with 490 patients under intensive care Luzzati et al. Mycoses 2013; 56: 664; Muskett et al. Crit Care 2011; 15: R287 Prolonged hospital/ICU stay Neutropenia Broad-spectrum antibiotics Urinary/Intravenous catheters Immuno -suppressive & antineoplastic agents Surgery/ Trauma Malignancy AIDS Steroid Therapy Total Parenteral Nutrition Burns >50% Renal replacement therapy Severe acute pancreatitis Diabetes mellitus Kidney failure Hemodialysis Extremes of age

6. Diagnosis of IC: Suspect+risk factor+unexplained fever+unresponsive to antibiotics Gold std - Blood culture or tissue culture from suspected site of infection Early diagnosis and decision to treat may be made preemptively/empirically due to low yield from cultures and slow culture ( candida spp multiply slowly than bacteria) turnaround time. A 1-2 day delay in initiation of effective antifungal therapy–associated with doubling of mortality Perform f/u blood cultures in all patients to establish time of clearance of Candidemia

7. Adjunctive blood tests –Aid in diagnosis Beta d glucan assay (pan fungal marker) Cell wall component of many fungi including Candida, Aspergi llus, and Fusarium species False positives common – cotton use during surgery, the administration of plasma protein or coagulation factors, Ivig hemolysis HD with cellulose membranes G+ bacteremia, and in patients receiving β-lactam antibiotics Sensitivity and specificity vary in pt population

8. Mannan antigen and antimannan antibody test Adjunct to culture Rising titre of anti mannan antibody is important Not approved by US FDA, available in Europe Detection of mannan and/or anti-mannan antibodies was effective in some studies, with sensitivity and specificity rates of 80–90% when these two tests were combined

9. Molecular Diagnostics-DNA based techniques Various commercially available PCR based test assays available T2Candida Panel test (T2 Biosystems) is FDA approved test for diagnosis of Candidemia It detects five most common Candida spp. 1.Candida albicans or C tropicalis 2.C glabrata 3. C krusei 4. S Cerevisie or C bracarensis or C parapsilosis 5. C metapsilosis or C orthopsilosis so test can not identify a specific species The pooled sensitivity and and specificity were 91.1% and 99.4% respectively

10. Mortality Mortality is high with reported rates ranging from 5% to 71% Depending on organ involvement and treatment (early/late diagnosis, inadequate treatment due to late diagnosis)

11. Anidulafungin Caspofungin Micafungin Echinocandins Amphotericin B Lipid formulation of amphotericin Polyenes Fluconazole Voriconazole Itraconazole Posaconazole isavuconazole Azoles Antifungal agents for IFIs Ref: Pre-Existing Liver Disease and Toxicity of Antifungals

12. Patient in hospital ≥ 7 days Antibiotic in last 7 days or Central venous catheter for 7 days Candida colonization or β - glucan &/or Very low procalcitonin Start Antifungal therapy Criteria to Start Early Antifungal Therapy Two of the following: TPN (days 1-3) Any dialysis (days 1-3) Major surgery (days -7-0) Pancreatitis (days -7-0) Steroid (days -7-3) Immunosuppressives (days -7-0 ) Bassetti M, Peghin M and Timsit JF. J Antimicrob Chemother. 2016;71(suppl 2):ii13-ii22.

13. Garey KW, Rege M, Pai MP, et al. Clin Infect Dis. 2006;43(1):25-31. Morrell M, Fraser VJ and Kollef MH. Antimicrob Agents Chemother . 2005;49(9):3640-5. Delaying Therapy- What is the Impact?

14. Elisabeth Paramythiotou et al. Invasive Fungal Infections in the ICU: How to Approach, How to Treat. Molecules 2014, 19, 1085-1119 How to manage our patient?

15. Drug susceptibility testing Intrinsic resistance identified by correct spp identification Acquired resistance require correct susceptibility testing CLSI and EUCAST have developed reference std. for antifungal susceptibility testing with associated clinical breakpoints for most common species- compound combinations Both uses microbroth dilution test- excellent methodology to identify resistant isolates A range of other commercial susceptibility test are available

16. Management Early Diagnosis, Source Control and early initiation of treatment The recommended first line agent for most proven or suspected patients is an ECHINOCANDIN for minimal 2 weeks – micafungin 100 mg iv daily ,anidulafungin 200 mg iv loading dose then 100 iv daily , caspofungin 70mg iv as loading then 50 mg iv daily Consider step down therapy/switching to fluconazole ( azole susceptible spp.) later once pt is stable and culture sterile/ or on susceptible testing results / or Candida species identification results available for unaffordable patients. C. glabrata, C. krusei C guilliermondi and C. auris are resistant to fluconazole but here VORICONAZOLE is acceptable. Posaconazole and isavuconazole (in vitro) – C krusei , C guilliermondi,and C glabrata

17. Alternative treatments Fluconazole 800mg (12mg/kg) orally or IV loading dose then 400mg (6mg/kg) orally and iv once daily for those who are not critically ill and are unlikely to have an azole resistant strain. Lipid formulaton of amphotericin b 3-5mg / kg daily if intolerant to other antifungals or known resistance AMPHOTERICIN is an alternative for pregnant women and for severly ill patients in whom the infecting species is not known For Candidemia without known complications treat for 14 days after a negative blood culture and resolution of symptoms .

18. IV to ORAL Transition from initial therapy to either higher dose fluconazole 800mg (12mg/kg) daily or Voriconazole 200-300mg (3-4mg/kg) twice daily for infection with fluconazole – susceptible or voriconazole susceptible C glabrata infection

19. Duration Osteomyelitis – 6 to 12 months septic arthritis – 6 weeks Endophthalmitis and chorioretinitis -4-6 weeks Pacemaker,ICD , VA device – 6weeks after device removal Native valve Endocarditis-at least 6 weeks following valve replacement Suppurative thrombophlebitis-at least 2 weeks after clearance of Candidemia .

20. Guidelines

21. Guideline Recommendations Ref: 1. Pappas PG, Kaurtman CA, Andes DR, et al. Executive summary: Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):409−17. 2. Antibiotic Guidelines 2015−2016. Treatment Recommendations for Adult Inpatients. Available at: https://www.medbox.org/document/antibioticguidelines- 2015-2016#GO Accessed on: 22 Feb 2021. 3. Bassett, M Marchetti M, Chakrabarti A. et al. A research agenda on the management of intra-abdominal candidiasis. Results from a consensus of multinational experts. Intensive Care Med. 2013;39(12):2092–106. 4. Cornely OA, Bassetti M, Calandra T, et al. ESCMID guideline for the diagnosis and management of Candida diseases 2012: non- neutropenic adult patients. Clin Microbiol Infect. 2012:18(7):19–37 Echinocandins :First-line choice for candidemia and invasive candidiasis in neutropenic and non-neutropenic cases Anidulafungin favored in susceptible strains over amphotericin B products due to better tolerability Consensus on managing intra-abdominal candidiasis recommends Anidulafungin due to superiority data over fluconazole and also rising azole resistance Anidulafungin: The only echinocandin superior to fluconazole

22. Caspofungin Micafungin Anidulafungin Hepatic metabolism? Yes ( N-acetylation) Yes ( Arylsulfatase and catechol-O-methyltransferase; some CYP3A hydroxylation) No CYP3A4 inhibitor? No Weak No Drug Interactions? Cyclosporine; Tacrolimus Rifampin; Efavirenz; Nevirapine; Phenytoin; Dexamethasone; Carbamazepine Sirolimus Nifedipine No known interactions Dose adjustments? Yes Moderate hepatic insufficiency and/or With CYP inducers Inadequate data in pts. With severe hepatic insufficiency No No data in patients with severe hepatic insufficiency No Anidulafungin has least complex metabolism and interaction profile of the available echinocandins Cancidas ( caspofungin ). EMA summary of product characteristics. Hoddesdon , Hertfordshire, UK: Merck Sharp & Dohme Ltd. 2006 Sept. [Accessed on 20 September 2019] available from: www.ema.europa.eu/docs/ en_GB /document...Product.../WC500021033.pdf Astellas Pharma , Inc. Mycamine ( micafungin sodium) for injection. Tokyo, Japan; January 2008. [Accessed on 1 st Feb 2020] available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021506s004lbl.pdf Ecalta [Summary of Product Characteristics]. Sandwich, Kent; UK: Pfizer Limited; June 2007. DRAFT. [Accessed on 1 st Feb 2020] Available from www.ema.europa.eu/docs/ en_GB /document...Product.../WC500020673.pdf

23. Ref: Systemic fungal infections in renal diseases   Fungal Infections in various Renal-related Conditions AKI : Patients with AKI have a higher incidence of fungal infections than normal hosts. These infections remain a major cause of death among patients with AKI CKD : independent risk factor for fungal infections Hemodialysis: Dialysis patients are at increased risk of fungal infection mortality compared to the general population.USRDS reported candidiasis (79%) as the dominant etiology of fungal infection in chronic dialysis patients. Chronic ambulatory peritoneal dialysis (CAPD): Fungal Peritonitis (FP) is a rare complication of peritoneal dialysis . Incidence of FP comprises 2-15% of total peritonitis episodes as reported in the literature. In CAPD fungal infections; Candida species such as C. albicans, C. tropicalis , and C. parapsilosis are common etiological agents. The FP carries a high morbidity and mortality than BP (bacterial peritonitis).

24. Ref: Systemic fungal infections in renal diseases   Fungal infections after Renal Transplantation Systemic fungal infection is a significant and often a lethal problem in renal transplant population through out the world; but is much more so in developing countries because of more intense immunosuppression, delay in diagnosis and management, and overcrowded environment. From USRDS registry, fungal infections in post-renal transplant patients were most commonly associated with secondary diagnoses of- oesophagitis (23.9%) pneumonia (19.8%) meningitis (7.6%), and urinary tract infection (10.3%). Prevalence of IFI in Solid organ transplant recipients in western countries: 1.4-9.4% But in the Indian subcontinent, Incidence: 6-10% Mortality: 70-100%

25. Ref: Pappas PG, Alexander BD, Andes DR, et al. Invasive Fungal Infections among Organ Transplant Recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50:1101–1111 Allizond V, Banche G, Giacchino F, et al. Candida albicans infections in renal transplant recipients: Effect of caspofungin on polymorphonuclear cells. Antimicrob Agents Chemother . 2011;55(12):5936–5938. Patel MH, patel RD, Vanikar AV, et al. Invasive fungal infections in renal transplant patients: a single center study. Ren Fail. 2017;39(1):294–298. Dis Transpl . 2019;30:1137–1143. Predominant Etiology of IFI in Patients With Renal Impairment In post-transplant patients, 53% of IFI occurs due to Candida species. Candida species causes 60% mortality among IFI patients post-transplantation Candida is the predominant species accountable for IFI in patients with any form of renal impairment Many of the non-albicans Candida are resistant/less susceptible to azole. Rapid diagnosis and appropriate therapy are imperative to improve the prognosis.

26. Anidulafungin in Patients With Renal Impairment Ref: Echinocandins for management of invasive candidiasis in patients with liver disease and liver transplantation Anidulafungin possesses potent antifungal activity against Candida spp. including azole-resistant strains. Anidulafungin is indicated as a first line treatment for invasive candidiasis in critically ill patients. Anidulafungin can be easily administered to patients with any degree of renal impairment without dosage adjustment. 01 02 03

27. Safety of Anidulafungin in Solid Organ Transplant Recipients Ref: Aguado JM, Varo E, Usetti P, et al. Safety of anidulafungin in solid organ transplant recipients. Liver Transpl . 2012;18:680–685. 32.6% of the patients had serum creatinine level >1.5 mg/ dL at the time of Anidulafungin therapy initiation No significant changes in SrCr levels were observed during therapy period Anidulafungin is a well-tolerated drug in solid organ transplant recipients including kidney transplant patients. From the study of Aguado et al. where 86 SOT patients were evaluated (8 kidney transplant recipients) it was found that-

28. Summary IC : One of the most dangerous infection. Immunocompromised /neutropenic patients (Malignancy, Transplant recipient, HIV, Steroid, MMF, newer biologicals …) with sepsis : suspect fungal infection – do fungal blood culture assay and smear from body fluids/ pus and newer fungal assays. In Suspected candidiasis start fluconazole, if proven invasive Candidiasis use echinocandins Once stable can switch to oral fluconazole or voriconazole in susceptible spp. long term therapy needed

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