Fungal Infections - Part 1 PDF

Fungal infections – Part 1 ID2 module (PHAR 5338) Nicholas Beyda, PharmD Assistant Professor [email protected] 11/20/2023 Learning objectives • Identify clinical manifestations and risk factors for mucosal and invasive candidiasis • Recognize laboratory tests used for diagnosis and treatment of candi...

Fungal infections – Part 1 ID2 module (PHAR 5338) Nicholas Beyda, PharmD Assistant Professor [email protected] 11/20/2023 Learning objectives • Identify clinical manifestations and risk factors for mucosal and invasive candidiasis • Recognize laboratory tests used for diagnosis and treatment of candidiasis • Given a patient case, choose the most optimal treatment based on clinical symptoms, pathogen characteristics, laboratory test results, and host factors Medical mycology basics FOCUS POINTS • Recognize the most medically important yeasts, molds, and dimorphic fungi • Role of fungal cell wall in pathogenesis and diagnostics • Differences between opportunistic and primary fungal infections What are fungi? • Eukaryotes • Distinct from plants and animals - Saprophytes: nutrition through external ingestion and absorption - Key role in decomposing organic matter - Secrete hydrolytic enzymes Medically important fungi Fungal lecture 1 YEAST Unknown fungi Known species: 100,000 Human pathogens: 500 Candida Cryptococcus Pneumocystis Malassezia Microsporidia Immunocompetent host: 100 DIMORPHIC Coccidioides Histoplasma Blastomyces Paracoccidioides Sporothorix MOLD Aspergillus Mucor Rhizopus Fusarium Fungal morphology Yeasts Single-cell organism Spherical or oval Budding or hyphae / pseudohyphae Molds Multicellular organism Hyphae – septate or non-septate Conidia – spores for reproduction / spread Dimorphic fungi Yeast or hyphal forms (temperature dependent) Fungal cell structure • Fungal cell membrane - Ergosterol • Fungal cell wall - Chitin B-glucan Galactomannan Glycosylated proteins Medical problems caused by fungi • Mycoses: fungal infection! • Allergic disease (often pulmonary) • Intoxication (magic or poison?) Classifying mycoses Site of infection Route of acquisition Typical host immune status (virulence) Superficial Exogenous Opportunistic Subcutaneous Endogenous Primary / Pathogenic Deep / Systemic Deep mycosis Brain Superficial, cutaneous, subcutaneous mycoses Paranasal sinuses Immunocompromised Lungs Heart Liver Spleen Kidney Superficial (hair, nails, skin) Cutaneous (hair, nails, skin) Sub-cutaneous Blood vessels (e.g., intravascular catheter) Lungs Immunocompetent Esophagus Skin Stomach Intestine Opportunistic Primary Candidiasis (Candida spp.) FOCUS POINTS • Risk factors and clinical manifestations of different forms of candidiasis • Diagnostics methods used to diagnose candidiasis • Optimal treatment based on clinical risk factors, symptom severity, pathogen characteristics, and other host related factors Candida species •Yeasts, multiply by budding •Spherical or oval in shape •Can undergo morphologic changes •Opportunistic pathogen Candida spp. Distribution Pseudohyphae Yeast Hyphae Unique characteristics C. albicans 30-60% Considered most virulent; able to produce true hyphae (germ tubes) C. glabrata 30-60% Prevalent in elderly or prior antifungal use; ↓ fluconazole susceptibility C. parapsilosis 5-15% Prevalent in neonates; likes plastic; ↓ echinocandin susceptibility; least virulent C. tropicalis 5-30% Higher incidence in cancer patients C. krusei 1-5% Innately resistant to fluconazole Other species 1-2% ---- Candida specific pathogenesis • Morphologic switching - Yeast form = Dispersion and immune evasion - Hyphael form = Tissue and immune cell penetration - Pseudohyphae = non-albicans species • Biofilms • Complex structure of microrganisms • Form on mucosal surfaces or prosthetic devices • Mixed morphologic states • Extracellular matrix Candida species and identification methods Common Candida species C. albicans C. glabrata C. tropicalis C. parapsilosis C. krusei C. Lusitaniae ***C. auris*** Methods of speciation - Biochemical / physiological properties - Antifungal susceptibility patterns - Morphology (germ tube test) Hyphae Budding 13 Candida spp. antifungal susceptibility Polyene AmB Triazoles FLU ITR VRC Echinocandins POS ISA AND CAS Other MFG 5-FC C. albicans C. tropicalis C. parapsilosis C. krusei C. glabrata C. auris = Potent activity = Variable or species specific Reduced susceptible in-vitro Clinically shown to be effective Susceptible – dose dependent Use higher dose (12 mg/kg) Not indicated for treating Candida infections Types of candidiasis Oral candidiasis - Oropharyngeal - Esophogeal Mucosal candidiasis Invasive candidiasis Vulvovaginal candidiasis Candiduria - Cystitis - Pylenophritis Systemic candidiasis Mucosal candidiasis – Oral • Candida spp. part of oral flora in 30 – 60% of adults and 45 – 65% of infants • Can occur in immunocompetent & immunocompromised (more common) • > 90% of HIV patients will develop oral candidiasis at some point • Recurrence is common if underlying risk factors are not eliminated • C. albicans most common species (>80%), however non-albicans species can be prominent in infants and elderly Mucosal candidiasis – Oral (risk factors) • Risk factors for developing oropharyngeal / esophageal candiasis • • • • • • • • • Neonates and elderly Dentures Xerostomia Antibiotics Disruption of oral mucosa Diabetes HIV infection/AIDS Malignancies Immunosuppressing agents • The severity and extent of infection increase with the number and severity of predisposing risk factors Mucosal candidiasis – Oral Oropharyngeal Signs Symptoms Diagnostics Esophageal Diffuse erythema and white patches on buccal mucosa, throat, tongue, or gums White/beige plaques of variable size which can be hyperemic or edematous, ulcerations in severe cases Ranges from none to sore mouth, burning tongue, metallic taste, dysphagia, odynophagia Similar to OPC, although retrosternal chest pain may also be reported Usually diagnosed based on clinical presentation and risk factors Upper GI endoscopy Microscopic examination of scraped lesion can be done for confirmation Microscopic examination of scraped lesions done during endoscopy for confirmation Culturing to determine species and susceptibility not routinely performed, unless treatment refractory Cultures to determine species and susceptibility should be performed to tailor therapy Mucosal candidiasis – Oral (treatment) Oropharyngeal Esophageal Clotrimizole troches 10 mg PO 5 times daily x 7-14 days Mild Miconazole mucoadhesive tablet 50 mg PO QDAY x 7-14 days Fluconazole 400 mg PO/IV QDAY x 14-21 days Nystatin suspension PO QID x 7-14 days Moderate to Severe Fluconazole 200 mg PO QDAY x 7 – 14 days Echinocandin IV QDAY x 14 – 21 days - Anidulafungin 200 mg IV QDAY - Caspofungin 70 mg IV on day 1 then 50mg IV QDAY - Micafungin 150 mg IV QDAY Lipid formulation amphotericin B 3 mg/kg IV QDAY • For HIV infected patients, HAART strongly recommended to reduce incidence of recurrent infections • For denture related infections, nightly disinfection is highly recommended Mucosal candidiasis – Vulvovaginal (VVC) • Candida spp. are part of the normal vaginal flora in 25% of women • Second most common cause of vaginosis (1/3 of cases) - ~ 50% of women will experience ≥ 1 episode of VVC by age 25 - ~ 75% during lifetime • Recurrent infection common - ~10% report ≥ 4 infections within 12 months • C. albicans most common species (80-92%) - followed by C. glabrata and C. parapsilosis • VVC generally not considered opportunistic infection Mucosal candidiasis – Vulvovaginal (VVC) • Risk factors for VVC…. • • • • • • • Diabetes Antibiotic use Estrogen levels elevated Immunosuprresion Genetics (SIGLEC15, TLR2, mannose binding lectin polymorphisms) Combined oral contraceptives (?) Sexual behavior (?) Mucosal candidiasis – VVC Normal findings Signs Symptoms Diagnostics VVC Bacterial Vaginosis Normal discharge (1-4 mL/day) which is white/transparent, thin/thick, mostly odorless Vulvar erythema/edema, discharge Discharge can be off-white/gray, can be white and clumpy yellow, greenish, often thin None or mild, transient Pruritus, soreness, burning on urination, dyspareunia Malodorous discharge, burning on urination, no dyspareunia Vaginal pH = 4 – 4.5 Vaginal pH = 4 – 4.5 Vaginal pH = > 4.5 Amine test = negative Amine test = negative Amine test = positive (in > 70% cases) Saline/KOH microscopy = dominant rods, no pseudohyphae or blastospores Saline/KOH microscopy = rods dominate, pseudohyphae or blastospores present Saline/KOH microscopy = few rods, increased coccobacilli, no pseudohyphae or blastospores *VVC diagnosis requires presence of pseudohyphae/blastospores on microscopy PLUS positive signs / symptoms ** Cultures not recommended unless classic signs / symptoms/ diagnostics are inconclusive or recurrence Mucosal candidiasis – VVC (classification) Classification of VVC Uncomplicated VVC (must have all of these features) Complicated VVC (may have any of these features) Symptom severity Mild to moderate Severe Frequency Sporadic Recurrent (≥ 3 episodes within 1 year) Organism C. albicans Non-albicans species Host Normal Abnormal (uncontrolled diabetes, immunosuppressed, pregnant) Mucosal candidiasis – VVC (treatment) • Treatment indicated only in symptomatic patients!!! • Goal is complete resolution of symptoms, usually within 24 – 48 hours • Microbiologic cure often not obtained (25-40% have positive yeast cultures 6 weeks post-tx) Uncomplicated VVC TRADITIONAL TREATMENT OPTIONS Complicated VVC (non-recurrent) Clotrimazole cream QDAY x 3 – 7 days Topical Oral Miconazole cream QDAY x 3 – 7 days Miconazole vaginal suppository QDAY x 1 – 7 days Fluconazole 150 mg PO x 1 Topical azole x 10 – 14 days Fluconazole 150 mg PO Q72h x 2 – 3 doses • Pregnancy: Oral azoles should not be used due to teratogenicity • *Boric acid capsules reserved for drug-resistant cases Recurrent VVC -------------------------------------- Fluconazole 150 mg PO Q72h x 2 -3 doses then QWEEK x 6 months Mucosal candidiasis – VVC (treatment cont…) Uncomplicated VVC NEW AGE TREATMENT OPTIONS Complicated VVC (non-recurrent) Recurrent VVC Oteseconazole only Day 1: 600 mg PO x 1 Day 2: 450 mg PO x 1 Day 14: 150 mg PO weekly x 11 weeks Oral Ibrexafungerp 300 mg BID x 1 day Oteseconazole + fluconazole Day 1: Fluconazole 150 mg PO x 1 Day 4: Fluconazole 150 mg PO x 1 Day 7: Fluconazole 150 mg PO x 1 Day 14 - 20: Oteseconazole 150 mg PO QDAY Day 28: Oteseconazole 150 mg PO weekly x 11 weeks • Ibrexafungerp: Contraindicated in pregnant women. Advise females of reproductive potential to use effective contraception during treatment and minimum of 4 days following discontinuation. • Oteseconazole: Use of the drug is restricted to adult females who are not of reproductive potential; the drug is contraindicated in those who have the ability to become pregnant, are pregnant, or are lactating. Systemic candidiasis – Candiduria • Candiduria (funguria) refers to presence of candida in the urine - Positive urine culture with ≥103 yeast colonies/ml • Common in hospitalized patients - (3rd most common organism isolated in urine) • Patients often asymptomatic and merely colonized with yeast • C. albicans is most common • Types of Candiduria - Asymptomatic - Symptomatic (cystitis and pyelonephritis) Systemic candidiasis – Candiduria Risk factors • Urinary tract drainage devices • Older age • Female sex • Prior antibiotic therapy • Diabetes • Urinary tract pathology • Malignancy Systemic candidiasis – Candiduria Diagnosis and classification of candiduria • Asymptomatic candiduria - Positive urine culture with ≥103 yeast colonies/ml - Absence of dysuria, polyuria, flank pain, and/or fever (temperature of 37.8°C [100°F]) • Symptomatic Candiduria - Positive urine culture with ≥103 yeast colonies/ml - ≥ 1 documented symptom mentioned above without an alternative etiology Clinical signs and symptoms of cystitis vs. ascending pyelonephritis • Cystitis - Dysuria, urinary frequency, suprapubic pain, +/- hematuria • Pyelonephritis - Above symptoms + fever, chills, sepsis, flank pain, costovertebral angle tenderness, nausea, vomiting - Typically unilateral Systemic candidiasis – Candiduria Candiduria Treatment Asymptomatic candiduria Cystitis Pyelonephritis Primary Alternative ***Therapy only indicated for neutropenic, or undergoing urologic procedure*** FLU 400 mg PO x 3 days OR AmBD IV 0.3-0.6 mg/kg x 3 days Fluconazole susceptible isolates: FLU 200mg (3 mg/kg) PO x 14 days FLU 200 – 400 mg (3 – 6 mg/kg) x 14 days Comments Eliminate predisposing factors when possible Fluconazole resistant isolates: AmBD 0.3 – 0.6 mg/kg IV daily x 1-7 days OR 5-FC PO 25 mg/kg QID x 7-10 days Remove indwelling bladder catheter; AmBD 50 mg/L sterile water can be used AmBD 0.3 – 0.6 mg/kg IV daily x 1-7 days +/5-FC PO 25 mg/kg QID x 1 - 7 days OR 5-FC PO 25 mg/kg QID x 14 days Removal of obstruction, nephrostomy tubes, stents if feasible *Lipid AmB formulations not recommended for candiduria as they don’t penetrate kidney or concentrate well in urine Systemic candidiasis - Invasive candidiasis (IC) • Candida species are the most common cause of invasive fungal infections • Affects > 250,000 people per year globally • Causes > 50,000 deaths per year globally • Incidence of 2 – 14/100,000 persons (highest rates in wealthy countries) • 3rd – 4th most common cause of bloodstream infections in hospitalized patients • 93% are health-care associated infections, 80% occurring in-patient • Likely under diagnosed due to low sensitivity of current diagnostics (50%) Systemic candidiasis - Invasive candidiasis (IC) Systemic candidiasis - Invasive candidiasis (IC) • Risk factors for IC Host related factors Neutropenia Malignancy Immunosuppressive diseases Renal failure / hemodialysis Liver failure Diabetes mellitus High severity of illness Age Candida colonization Necrotizing pancreatitis Burns Treatment related factors Solid organ transplant Immunosuppressing therapy Corticosteroids Chemotherapy Hematopoietic stem cell transplant Broad-spectrum antibiotics Central venous or urinary catheter Major surgery (abdominal mainly) Total parenteral nutrition Di se as e Broad-spectrum antibiotic Catheters Neutropenia, corticosteroids Surgery, etc. bu rd en Systemic candidiasis - Invasive candidiasis (IC) No disease Colonization/ antigen Prophylaxis Pre-emptive Signs and symptoms Empiric Crude mortality 40% Cultures/ histopathology Definitive Sequelae Morbidity/ mortality • Symptoms range from mild fever to fulminant sepsis • Often suspected after persistent fever despite 48-72 hours of broad-spectrum antibiotics Systemic candidiasis - Invasive candidiasis (IC) • IC diagnostic timeline Day 0 Day 1-3 Signs of infection Initial blood sample We would like to start antifungals here Day 3-5 Broad Spectrum RX +/antifungal Yeast Gram Stain But we usually start them here Speciation Day 5-7 Targeted RX Antifungal susceptibility ….May not get it right until here Systemic candidiasis - Invasive candidiasis (IC) • Diagnosis of invasive candidiasis - Signs and symptoms are vague and overlap with bacterial infections - Recovery of Candida spp. in sputum, urine, peritoneal/central venous catheters may only indicate colonization rather than true infection - Blood culture (gold standard diagnostic) is slow and lacks sensitivity for deep-seeded infections Candidemia 100% detected by blood culture Candidemia + deep-seated candidiasis 50% detected by blood culture Deep-seated candidiasis 0% detected by blood culture Systemic candidiasis - Invasive candidiasis (IC) Non-culture based methods for diagnosis of IC β-D-glucan Mannan antigen/anti-mannan antibody PCR/T2Biosystems Method of detection Coagulation of fungal cell-wall component Antibody response to cell wall component Molecular detection of species specific genetic sequences Candida specific? No, also other fungi No, also other fungi Yes, certain species only Turnaround time < 24 hours < 24 hours 3 – 6 hours Performance Sensitivity=~60-90% Specificity=~60-90% Sensitivity=~60-80% Specificity=~80-90% Sensitivity=~90-95% Specificity=~99% Limitations False positives: glucancontaminated tubes, cellulosedialysis membranes, Gram + organisms, β-lactams), Optimal cutoff value not clear Positive results occur later in infection Species influences sensitivity Optimal cutoff value not clear Using test early may reduce sensitivity Only select species detected Pea et al. Expert Rev Anti Infect Ther 2013; 11:989-97 Pfaller et al. J Fungi 2015; 1:217-51 Systemic candidiasis - Invasive candidiasis (IC) • Important considerations in choosing empiric/initial antifungal therapy - History of recent antifungal exposure - History of intolerance to an antifungal agent - Hospital / unit specific data on Candida species distribution and susceptibility trends - Severity of illness - Relevant co-morbidities - Evidence of involvement of CNS, cardiac valves, organs Systemic candidiasis - Invasive candidiasis (IC) Empiric and initial treatment for IC Yes Is the patient… 1. Severely ill (ICU) 2. Had prior azole exposure 3. Likely to have FLU resistant Candia species? Echinocandin MFG 100 mg IV QDAY CAS 70 mg IV x 1 → 50 mg IV QDAY ANF 200 mg IV x 1 → 100 mg IV QDAY No Echinocandin or *FLU 800 mg IV (12 mg/kg) x 1 → 400mg IV (6 mg/kg) QDAY * FLU 12 mg/kg IV QDAY if C. glabrata Yes Has patient… 1. Had prior exposure to echinocandin 2. Suspected of azole and echinocandin resistant infection 3. Intolerant of azoles or echinocandins 4. Possible CNS involvement L-AmB (3-5 mg/kg) IV QDAY No Continue treatment selection as above Systemic candidiasis - Invasive candidiasis (IC) • Criteria for de-escalation from echinocandin or amphotericin to an azole - Clinically stable after 5 – 7 days - Isolates are susceptible to fluconazole or voriconazole - Have repeat negative blood cultures after treatment started • Species specific recommendations for de-escalation for de-escalation - C. albicans, C. tropicalis, C. parapsilosis • FLU 800 mg (12 mg/kg) PO/IV x 1  400 mg (6 mg/kg) PO/IV daily - For C. glabrata susceptible to fluconazole • High dose FLU 800 mg (12 mg/kg) PO/IV daily - For C. glabrata or C. krusei susceptible to VOR • VOR 400 mg (6 mg/kg) PO/IV BID X 2 doses  200 mg (3 mg/kg) PO/IV BID • Treatment duration - 2 weeks following first negative blood culture if no metastatic complications - Longer if disseminated infection Pappas et al. Clin Infect Dis 2016; 62:e1-50 Fungal infections – Part 1 ID2 module (PHAR 5338) Nicholas Beyda, PharmD Assistant Professor [email protected] 11/20/2023