Fungal Infections and Antifungals in ICU Dr. Ankit Jain

FUNGI IN CLINICAL PRACTICSE

Candidia spp Candida spp Candidiasis Spectrum of Disease Mucocutaneous disease and Asymptomatic funguria Invasive Fungal disease Candidemia ± Endopthalmitis Disseminated Hematological infection Single deep organ infection Meningitis Endocarditis IntraAbdominal infection

Candidia spp Candida species C. Glabrata C. Tropicalis C. Albicans Non Albicans C. Glabrata C. Tropicalis C. Parapsilosis C. Krusei C. Lusitanide C. guillermondii

Candidia spp C. albicans Commonest 40-60% of invasive candidiasis Source Endogenous e.g. GI flora or mucocutaneous Exogenous e.g. Healthcare worker, infusate

Candidia spp C. glabrata C. Tropicalis Increasing incidence 20-30% if invasive candidiasis Higher mortality than albicans Reduced sensitivity to azoles esp. Fluconazole C. Tropicalis Sensitive to most antifungals

Candidia spp C. parapsilosis C. krusei 10-20% in certain centers Associated with use of plastic derivatives e.g. IV catheter related infections, esp patients receiving TPN) Reduced sensitivity to Echinocandins C. krusei <15% Intrinsic resistance to Fluconazole

Candidia spp C. lusitanide C. guillermondi <15% Intrinsic resistance to Amphotericin B. C. guillermondi Sensitive only to AmphoB.

Moulds Invasive Aspergillosis Others A. fumigatus (commonest) A. flavus A. terreus Others Fusarium spp. Scedosporium spp. Zygomycetes spp.

Invasive Aspergillosis Spectrum of disease Lung and sinus disease Skin and CNS infection Rarely blood stream infection (Neutropenic) Lung transplant- Anastamosis Steroids- Cavitatory lesions Allergic reaction to spore inhalation.

Risk Factors for Invasive Fungal Infections

Mechanism of invasive candidiasis Proliferation of Candida in the gut Secondary to broad spectrum antibiotic exposure. Loss of GI mucosal integrity (Chemotherapy/inflammation) Candida enters blood stream from GIT. Failure of Immune system due to any cause T Cells (prevent colonization and superfi cial invasion) Epithelial cells (Barrier destroyed) Reduced phagocytosis by macrophages and neutrophils (prevent deep invasion and blood stream dissemination)

Patients at Risk Independent risk factors for candidaemia in ICU patients Internal (Patient Factors) External (Environmental Factors) Renal Failure Recent abdominal surgery Hematological malignancy Central venous catheters Neutropenia TPN Age <1month and >65 years Broad spectrum antibiotics Mucosal Candida colonization Corticosteroids Prolonged stay in ICU

Identifying the patient at risk Why?? Prevent invasive fungal infections. Reduce mortality of invasive fungal infections Therapy Prophylaxis Pre-emptive Empirical Avoid overuse of Antifungals thus preventing resistance.

Identifying the patient at risk How?? Scores Diagnostic Tests

Identifying the patient at risk (Scores)

Identifying the patient at risk (Scores) Many of the criteria are broad and encompass most ICU admissions. Sensitivity/Specificity?? Benefit/ positive outcome of using these scores lacking!

Challenges in Diagnosis of Invasive Fungal Infections Radiology Cannot id specific organism Difficult to differentiate from bacterial infection. Lack of immune response in immunocompromised – false negative Delay in symptoms

Challenges in Diagnosis of Invasive Fungal Infections Culture Reliable method for detecting fungemia. Replication time is longer for fungi than bacteria Unable to differentiate colonisation from true infection May require invasive specimen False negative Histopathology Definitive diagnosis! Invasive specimen Morphological differentiation might be difficult.

New Diagnostic Tests: Galactomannan Assay Identify Aspergillus with simple blood tests Approved for screening of IA in HSCT recepients. NOT a one time diagnostic tool. Serial sampling of patients at risk (2 / week) Increase in optical density in serial samples (Index value>) Predict disease upto 1 week before clinical symptoms develop.

New Diagnostic Tests: Galactomannan Assay Sensitivity 80%. Specificity 89% (In malignancy) Sensitivity and Specificity less in ICU patients and transplant patients Samples Used: Blood/Serum, BAL, CSF, Urine False Positive Patients on B Lactam (Piptaz) False Negative Prior antifungal exposure.

New Diagnostic Tests: Beta Glucan Test Non Specific Targets components of fungal cell wall. Diagnose Candida and Aspergillus Does NOT detect Cryptococcus or Zygomycetes. Serial Monitoring detects infection 1 week prior to clinical symptoms. A negative beta glucan test is associated with a negative predictive value >90% and can be used to rule out invasive fungal infection. False positive with dialysis filters, albumin, immunoglobulin

ANTIFUNGAL AGENTS

Site of action of Antifungals

Azoles MOA: Inhibit fungal cytochrome P450 → Reduce ergasterol production Classification Imidazoles, nonsystemic Ketoconazol, Miconazole Imidazoles, systemic Fluconazol, Voriconazole, Posaconazole, Ravuconazole Triazoles Itraconazole

Fluconazole Introduced in 1990 High Bioavailability – Oral and IV Highly active against many species of Candida. Fungistatic Low incidence of serious side effects. Conversion from IV to oral is simple. Non albicans species has limited its use.

Fluconazole Spectrum of Acticity Good Moderate Poor C. Albicans C. Glabrata Moulds C. Tropicalis Dimorphic fungi C. Parapsilosis C. Krusei C. Lusitaniae Cryptococcus neoformans Coccidiodes immites

Fluconazole Adverse Effects Generally well tolerated Hepatotoxicity and rash Lower intensity of drug interactions than other azoles. Does occur with drugs metabolised by cytochrome P450 pathway. QTc may be prolonged.

Fluconazole Dosing Fluconazole 200-400 mg IV/PO daily in 1-2 divided doses Renal dosing needed. Increase dose for C. glabrata (800 mg/day)

Fluconazole - Pearls Poorly active against all C. krusei and some C.glabrata. Check susceptibilities and give 800 mg per day of fluconazole. If lab does not do susceptibility testing - alternative agent such as an echinocandin. Often given as prophylaxis against Candida infections in high risk populations. In such patients try an echinocandin instead. High bioavailability of fluconazole makes it an excellent therapy to transition to as patients tolerate oral medications.

Voriconazole Broad spectrum antifungal. Active against candida and moulds. It is fungistatic for yeasts but fungicidal for some filamentous fungi Good bioavailability – Oral and IV Spectrum Good Moderate Poor C.Albicans C.Glabrata Zygomycetes C.Parapsilosis Flucon Resistent Albicans C.Tropicalis Fusarium spp C.Krusei Cryptococcus N Aspergillus spp

Voriconazole Side Effects Dosing Common to azoles Agent Specific Photo toxicity Visual disturbances. Dosing 6mg/kg IV q12h x 2 doses then 4mg/kg IV q 12h 200 mg PO q 2h

Voriconazole - Pearls The IV form contains a cyclodextrin vehicle that accumulates in renal dysfunction and may be nephrotoxic. It is contraindicated with a CrCl<50 ml/min. Oral preparation avoid this issue. Voriconazole is eliminated hepatically and is unlikely to be useful in the treatment of candiduria. Voriconazole is the drug of choice for invasive aspergillosis and is frequently used in the treatment of infections caused by other moulds. It can be used for candidiasis as well, but fluconazole and echinocandins are more frequently used for these infections. In the ICU setting drugs commonly given and interacting with voriconazole include omeprazole, phenytoin and warfarin.

Posaconazole Newest extended spectrum Azole. Only azole active against Zygomycetes. Prophylaxis of fungal infection in neutropenic patients and for oropharyngeal candidiasis. Only oral suspension available (IV formulation in development) To be administered with high fat diet. PEARL 200 mg q6h in fasting state achieves same concentrations as 400 mg q12h with high fat meal.

Echinocandins Latest class of antifungals introduced in clinical practice. Agents Caspofungin, Micafungin, Anidulafungin Mechanism of Action Site of action is fungal cell wall. (As against cell membrane by other antifungals) Inhibit synthesis of beta-1,3-glucan.

Echinocandins Virtually indistinguishable spectrum of activity. Fewer drug interactions than Azoles. Safer than Polyenes. Great activity against fluconazole resistant yeast. Lack of Oral form.

Echinocandins Spectrum Good Moderate Poor C. Albicans C. Parapsilosis Zygomycetes C. Glabrata Dimorphic fungi Non Aspergillus Molds C. Lusitaniae Cryptococcus N C. Tropicalis C. Krusei Aspergillus

Echinocandins Adverse Effects Excellent safety profile. Histamine mediated infusion related reactions (Red man syndrome of Vancomycin) Rarely Hepatotoxicity Clinically significant drug interactions rare.

Echinocandin Dosages Caspofungin 70 mg IV loading dose; then 50 mg IV OD Micafungin 100 mg IV OD Anidulafungin 200 mg IV loading dose; then 100 mg IV OD

Echinocandins - Pearls Caspofungin and micafungin are eliminated hepatically by non–cytochrome P450 metabolism. Anidulafungin degrades in the plasma and avoids hepatic metabolism. Despite this unique method of elimination, it is not completely devoid of hepatotoxicity. Excellent fungicidal activity against Candida. Against Aspergillus species they exhibit activity that is neither classically cidal nor static. Instead, they cause aberrant, nonfunctional hyphae to be formed by the actively growing mould. Although drug interactions are minor Be careful when you use them with the immunosuppressants cyclosporine (caspofungin) and sirolimus (micafungin).

Echinocandins Pearls Drug of choice for invasive candidiasis especially in hemodynamically unstable patients. Useful in treatment of invasive aspergillosis but dont have the level of supporting data like voriconazole and polyenes The level of echinocandins in special compartments such as cerebrospinal fluid and intraocular compartment remains low.

Polyenes Agents Amphotericin B deoxycholate Amphotericin B in lipid complex Amphotericin B colloidal dispersion Amphotericin B liposome Newer agents introduced to counter toxicities of AmphoB deoxycholate MOA Binding to ergosterol in the cell membrane of fungi, disrupting its function.

Polyenes Spectrum Good Moderate Poor Most Candida Zygomycetes C. Lusitaniae Aspergillus Asp. terreus Cryptococcus Dimorphic fungi Many moulds

Polyenes Side effects Nephrotoxicity Direct effect on distal tubules. Vasoconstriction of afferent arteriole. Nephrotoxicity leads to wasting of Mg and K which needs supplementation. Minimized with maintenance of appropriate hydration. (250-500 ml NS bolus immediately prior to dose) Administer drug by continuous infusion can prevent nephrotoxicity but does not optimize the concentration-dependent pharmacodynamics properties of AmpB.

Polyenes Infusion related reactions Fevers, chills and rigors Also with lipid based formulations Premedication with diphenhydramine and acetaminophen. Liposomal product associated with unique cardiopulmonary toxicity presenting as chest pain, hypoxia +/- flank pain. D/D ACS

Polyenes Dosages Amphotericin B deoxycholate - 0.5 to 1.5 mg/kg/day Lpid formulations - 3 to 6 mg/kg/day. Caution: Check your formulations. Fatal overdoses of amphotericin B deoxycholate have been given when dosed as the lipid forms. (5x)

Polyenes Pearls Amphotericin B formulations remain the drugs of choice for cryptococcal meningitis and serious forms of some other fungal infections, such as dimorphic fungi and some mould infections Because of their broad spectrum, they are also a reasonable choice if fungal infection is suspected but the infecting organism is not known, as in febrile neutropenia. Their use in candidiasis and aspergillosis has declined with the availability of newer, safer agents.

Antifungal Susceptibility Testing

Susceptibility/ Sensitivity Testing Method Broth Dilution and Disc Diffusion Commercially available kits. Advantages Guiding antifungal drug selection. De-escalation of therapy as in antibiotics.

Susceptibility/ Sensitivity Testing Breakpoints for Azole Susceptible (S) Susceptible dose dependent (S-DD) Resistant (R) Breakpoint for Echinocandins Susceptible i.e ≤ 2 mcg/ml No formal breakpoint for resistance MIC > 2 mcg/ml can be considered resistance.

Susceptibility/ Sensitivity Testing S-DD to Fluconazole Higher dose to reach therapeutic range. 400-800 mg/day dosing.

Treatment Stratergies

Treatment of Invasive Candidiasis Candida Blood Stream Infections When to start treatment?? Delaying treatment associated with higher mortality If candidaemia is suspected, blood cultures should be taken even in the absence of fever. Consequently treatment has to be started immediately after blood cultures grow yeasts without waiting for the results of identification of Candida species and susceptibility tests. How long?? 2 weeks after documented negative blood culture.

Treatment of Invasive Candidiasis Factors to consider while choosing empirical antifungal treatment Knowledge of local resistance patterns Co-morbidities of patient Risk factors favouring the presence of non - albicans species Prior treatment with fluconazole; Site of infection Spectrum of activity Known adverse effects Pharmacodynamics /pharmacokinetics. Cost of treatment Presence of haemodynamic instability

Treatment of Invasive Candidiasis Candida Blood Stream Infections First Line therapy : Echinocandins Especially if Hemodynamic instability Previous use of Azoles Isolation of C. glabrata, 3 agents interchangeable. No issue of resistance like Azoles C. parapsilosis resistance not translated to clinical practice

Treatment of Invasive Candidiasis Candida Blood Stream Infections Candida with Neutropenia Drug of choice : Caspofungin Can use fluconazole as empirical therapy if Low incidence of Non Albicans Low incidence of resistant albicans species. Fluconazole is preferred in haemodynamically stable patients with no fluconazole exposure during the last 30 days Known local epidemiology Step down to fluconazole once culture sensitivity made available.

Treatment of Invasive Candidiasis Candida Blood Stream Infections Candida BSI with ocular involvement Echinocandins have poor ocular penetration. Azoles are the drug of choice. Justifies dilated fundoscopy in all patients with suspected candida BSI.

Treatment of Invasive Candidiasis Candida Blood Stream Infections Clinical response to treatment in 48-72 hours. If no improvement after 72 hours of treatment Metastatic site of infection Drug resistance Suboptimal dose

Treatment of Invasive Candidiasis Urinary Tract Infections Do you treat every patient with candida in urine culture?? Colonization of urinary tract/catheter common especially in diabetics. Do not treat if Asymptomatic No Risk factors Remove urinary catheter if possible Treat if Sepsis of unknown origin Risk factors present Posted for urological procedure

Treatment of Invasive Candidiasis Urinary Tract Infections Drug of choice Fluconazole or Flucytosine All other antifungals – poor concentrations in urine. Duration of treatment 2 Weeks

Treatment of Invasive Candidiasis Lung Infection Contaminant?? Treat if : Candida in Sputum and Positive culture from another site (Blood, pleural fluid etc) s/o disseminated disease Risk factors for invasive fungal infection No other source of sepsis. Drug of Choice All anticandida antifungals have excellent lung penetration

Treatment of Invasive Candidiasis CNS infections cannot be treated with Echinocandins CVS infections LF AmpB High dose Echinocandins

Treatment of Invasive Candidiasis

INVASIVE MOULD INFECTIONS Unidentified mould infection: Amphotericin B Invasive Aspergillosis: Voriconazole Patients on antifungal prophylaxis: Use antifungal agent from another group. Caspofungin has shown favourable results in patients with IA refractory to first line antifungals Micafungin and anidulafungin are not approved for IA treatment despite their activity against Aspergillus spp. The duration of IPA treatment might last from several months to more than one year and should be tailored to patients’ response

Other Fungal Infections Cryptococcosis/Cryptococcal Meningitis Non HIV Amphoterecin B 4-6 weeks. Curative HIV infected Amphoterecin B (± 5 FU) x 2 weeks Fluconazole x life long prophylaxis. Treat IC HTN with LP/Shunts. Steroids / Immunomodulators(Animal studies, Clinical trials)

Other Fungal Infections Histoplasmosis AmpB (Severe) 3-12 months Itraconazole (Non Critical) HIV vs Non HIV