Fungal Infection

how is mold classified/grow?

grow in multicellular filament called hyphae - these tubular branches have multiple genetically identical nuclei, yet form a single organism, known as a colony

how are yeasts classified/grow?

grow as a single cell and form a colony

examples of opportunistic yeasts

candida, cryptococcus, rhodotorula

examples of opportunistic molds

aspergillus, zygomycetes, scedosporidium, cladosporidium, ulocladium, fusarium, paecilomyces

examples of true pathogens (dimorphic)

coccidioides, histoplasma, blastomycosis, paracoccidioides, sporothrix

which species are in the critical group?

cryptococcus neoformans, candida auris, aspergillus fumigatus, and candida albicans

what are the 5 groups of fungal infections?

invasive fungal infections, chronic lung or deep tissue infections, allergic fungal disease, mucosal infection, and skin/hair/nail infections

which type of fungal infections are often fatal?

invasive - cryptococcal meningitis, invasive aspergillosis, candida bloodstream infection, and pneumocystis pneumonia

what typically causes chronic lung or deep tissue infections

chronic pulmonary aspergillosis

examples of allergic fungal diseases

allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS)

examples of mucosal infections

oral and esophageal candidiasis (thrush) and candida vaginitis

examples of skin, hair, and nail infections

ringworm, tinea capitis, athlete’s foot, onychomycosis

what are the most common invasive fungal infections?

candidemia and invasive candidiasis, intra-abdominal candidiasis (candida peritonitis), cryptococcal meningitis, histoplasmosis acute pulmonary and disseminated, invasive aspergillosis, invasive rhinosinusitis, mucormycosis, pneumocystis pneumonia

which fungal infections cause the biggest burden globally

invasive aspergillosis in COPD, invasive aspergillosis in ICU, invasive aspergillosis in leukemia, invasive aspergillosis (lung cancer), candida bloodstream infection, and invasive candidiasis without positive blood

T/F: all invasive fungal infections require therapy

true

are fungi prokaryotes or eukaryotes?

eukaryotes

how are fungi different from their host's cells

have a rigid cell wall that contains complexed glucans (rigidity and support), mannan, chitin, and other polysaccharides, and a cytoplasmic membrane that contains ergosterol

what are the four antifungal options?

echinocandins, -azoles, polyenes, and nucleoside inhibitors

which antifungals are used as monotherapy?

echinocandins, -azoles, and polyenes

which antifungals are typically first line

echinocandins and -azoles

MOA of -azoles

disruption of cell membrane via ergosterol synthesis inhibition

MOA of polyenes

direct membrane damage

MOA of echinocandins

disruption of cell wall via inhibition of glucan synthesis

MOA of nucleoside inhibitors (flucytosin)

inhibition of nucleic acid synthesis

spectrum of triazoles

broad

triazole impact on yeast

fungistatic

triazole impact on molds

fungicidal

how are triazoles available?

IV and oral

which diseases use triazoles for first line treatment?

superficial candida infections (fluconazole), aspergillosis (voriconazole, posaconazole, isavuconazole), cryptococcosis (fluconazole), and prophylaxis (vori, fluc, posa)

limitations of triazoles

fluconazole has no mold activity, drug resistance, voriconazole ADRs of CNS and photosensitivity, posaconazole needs TDM

examples of echinocandins

caspofungin, micafungin, anidulafungin, rezafungin

echinocandin impact on yeasts

fungicidal

echinocandin impact on molds

fungistatic

what are the drugs of choice for nearly all candidiasis and candidemia?

echinocandins

how are echinocandins available?

IV only

which class of antifungals are safe and have few DDIs?

echinocandins

which medication class is active on azole resistant yeasts?

echinocandins

T/F: echinocandins have low levels of drug resistance for most species

true

spectrum of activity for polyenes

broad - active on yeasts and molds

which antifungal class is fungicidal

polyenes

how are polyenes available?

IV - require detergent or lipids for solubility

examples of polyenes

amphotericin B, nystatin

T/F: polyenes have low levels of resistance

true

limitations of polyene use

highly nephrotoxic (lipid formulations are better), infusion related adverse events, and nystatin is used topically only

examples of infection due to candida species (candidiasis)

keratitis, oral thrush

risk factors for fungal infections include:

acute renal failure, parenteral nutrition, prior surgery specially GI, indwelling catheters, broad spectrum antibiotics, diabetes, burns, mechanical ventilation, steroids, bone marrow transplant, solid organ transplant, underlying malignancy

which species of candida is most common?

C. albicans

which fungi c ause intra-abdominal candidiasis?

candida spp., particularly C.albicans, C.glabrata

what are intra-abdominal candidiasis infections?

Patients either develop intra-abdominal candidiasis after abdominal surgery pancreatitis or other intra-abdominal sepsis or as a complication of peritoneal dialysis. The symptoms are indistinguishable from those of bacterial peritonitis, and bacterial and intra-abdominal candidiasis may occur together

when does vulvovaginal candidiasis often occur?

with recent antibiotic use, pregnancy, uncontrolled diabetes mellitus, AIDS, corticosteroid use, other immunosuppression.

what is recurrent vulvovaginal candidiasis (RVVC)?

involves multiple episodes of vulvovaginal
candidiasis (VVC; vaginal yeast infection) within a 12-month period, adversely affects quality of life, mental health, and sexual activity

which oral antifungal is used for VVC?

fluconazole (Diflucan)

examples of new agents used to treat VVC?

Oteseconazole (VIVJOA) and Ibrexafungerp (BREXAFEMME)

how are fungal infections diagnosed?

blood culture (gold standard), PCR testing is more sensitive than blood cultures for invasive candidiasis, tissue biopsy, and detailed examination of the retina

primary antifungal treatments:

echinocandins

secondary antifungal treatment:

-azoles

tertiary antfungals:

polyenes

diagnostic testing for aspergillus

The key tests are CT scans, biopsy for histology, Aspergillus antigen
and/or PCR on blood or sputum or bronchoalveolar lavage. Microscopy for hyphae and culture are insensitive and slow. No one test can confirm the diagnosis of invasive aspergillosis and different tests perform differentially in different patient groups.

treatments for aspergillus infections:

Voriconazole is the most effective agent for IA, with alternatives including
amphotericin B (liposomal or lipid formulations), micafungin, caspofungin, posaconazole or itraconazole. Triazoles (itraconazole, voriconazole, posaconazole) are first-line therapies for CPA.

hpw to detect acquired antifungal resistance?

gold standard is the antifungal susceptibility test (MIC); another option is molecular Dx Mechanism dependent (triazole resistance in A.fumigatus, echinocandin resistance in candidsa spp.)

therapy optiosn for patients with azole resistant aspergillus infections:

polyene (lipid form of ampB to reduce nephrotoxicity), echinocandin (micafungin or caspofungin) and new therapeutic options (rezafungin, olorofim, fosmanogepix, and ibrexafungerp)

mechanism of azole resistance in A.fumigatus

Point mutations in Cyp51A (drug target). TR34/L98H and TR46/Y121F/T289A are most common

MOA of echinocandin resistance

involves amino acid substitutions in
two hot spot regions (HS1 and HS2) of the Fks subunit(s) of glucan synthase (echinocandin target)

why is candida auris a problem?

it is often resistant to medicines - some infections have been resistant to all three types of antifungal medicines in the US, different to identify, it can spread in hospitals and nursing homes

which fungus is the staph aureus of the fungal world?

candida auris