MYCOVIRO LEC 7 - Epidemiology and fungi of high priority

helps identify which populations are at highest risk and reveals emerging trends like the rise of resistant species.

Epidemiological knowledge

__ can develop targeted interventions, improve diagnostic strategies, and design effective treatment and prevention programs.

Public health officials and clinicians

It is slow, labor intensive, and has poor sensitivity

Traditional ‘Gold’ Standard

3 classes of antifungals

1. Azole

2. Echinocandins

3. Polyenes

These are non-competitive inhibitors of the fungal enzyme lanosterol 14-alpha-demethylase, rate-limiting enzyme in the fungal biosynthetic pathway

of ergosterol.

Azole

rate-limiting enzyme in the fungal biosynthetic pathway of ergosterol.

lanosterol 14-alpha-demethylase

destabilizes the fungal cell membrane, causing leakage of cellular contents, lysis, and eventual cell death.

Azole

What enzyme does azole inhibit?

lanosterol 14-alpha-demethylase

These inhibit the fungal enzyme 1,3-β-glucan synthase, which is responsible for synthesizing 1,3-β-glucan

Echinocandins

key component of the fungal cell wall

1,3-β-glucan

Loss of this cell wall component leads to osmotic instability and cell death.

1,3-β-glucan

What enzyme does echinocandins inhibit?

1,3-β-glucan synthase

Polyenes antifungals bind to ergosterol, which is a sterol unique to fungi.

Polyenes

sterol unique to fungi

ergosterol

creates pores in the fungal cell membrane, ultimately leading to electrolyte leakage, cell lysis, and cell death.

polyene-ergosterol complex

Mode of action of azole

inhibitor of lanosterol 14-alpha-demethylase → destabilizes the fungal cell → leakage, lysis, cell death

Mode of action of echinocandins

Inhibitor of 1,3-β-glucan synthase → osmotic instability → cell death.

Mode of action of polyenes

Binding to ergosterol → pores in the fungal cell membrane → leakage, lysis, cell death

almost always administered as combination therapy only or an adjunct to amphotericin B, which is a polyene

Flucytosine

an antimetabolite compound

flucytosine

Flucytosine characterized or classified as a ___

pyrimidine analog.

It is absorbed into fungal cells via cytosine permease.

flucytosine

Within the fungal cell, the flucytosine gets converted to

______, which interferes with fungal RNA biosynthesis.

5-FU (5-fluorouracil),

the number of identified that represent health threats because they cause severe invasive disease, and their emerging resistance to antifungal drugs

19 fungi

three priority groups:

1. Critical group

2. High group

3. Medium group

in making this pathogens priority list, WHO based it on criteria:

- Prioritization Criteria

- Corresponding Definition

- Levels

Critical group

1. Cryptococcus neoformans

2. Candida auris

3. Aspergillus fumigatus

4. Candida albicans

CCAC

High group

1. Nakaseomyces glabrata (Candida glabrata)

2. Histoplasma spp.

3. Eumycetoma causative agents

4. Mucorales

5. Fusarium

6. Candida tropicalis

7. Candida parapsilosis

NHEM FCC

Medium group

1. Scedosporium spp.

2. Lomentospora prolificans

3. Coccidiodes spp.

4. Pichia kudriavzeveii

5. Cryptococcus gattii

6. Talaromyces marnfeei

7. Pneumocystis jirovecii

8. Paracoccidiodes spp.

SLCP CTPP

most important criterion

Antifungal resistance (38.5%)

predominantly reported for HIV-positive patients.

Cryptococcus neoformans

T/F

Cryptococcus neoformans has vaccines

F

Cryptococcus neoformans median days

18 to 39 days

reduces the incidence o cryptococcal meningiti

prophylactic and preemptive therapy

Localized cryptococcosis treatment

Fluconazole

Severe and disseminated cases of Cryptococcus neoformans treatment

Amphotericin B in combination with flucytosine

followed by step-down to fluconazole

Cryptococcus neoformans intrinsically resistant to ___

Echinocandins

Cryptococcus neoformans acquired resistance to what drugs?

● Fluconazole

● Amphotericin B (Amp B)

● 5-flucytosine (5-FC)

Candida auris median length of hospital stay:

Adults →____

Pediatric → ___

Adults → 46-68 days

Pediatric → 70-140 days

Invasive candidiasis treatment

Echinocandins

Candida auris resistance rate to

Fluconazole =

amphotericin B =

Azoles =

Fluconazole = 87-100% (high)

amphotericin B = 8-35%

Azoles = 0-8%

used for following confirmation of in-vitro susceptibility of Candida auris

azoles

Candida auris:

_____ → Isolates resistant to at least one antifungal

____ → Isolates resistant to at least two antifungal

90%

30%

- emerging multidrug-resistant yeast

- first identified in 2009 in Asia

- Often multi-drug resistant, with some strains (types)

resistant to all three available classes of antifungals.

Candida auris

Reported cases of Candida auris increased by _____% in 2018 when compared to the average number of cases reported in 2015 to 2017

318%

Azole-resistant invasive aspergillosis is a life-threatening disease

Aspergillus fumigatus

____ for high-risk groups can prevent Invasive Aspergillosis

Antifungal prophylaxis

It is recommended even in azole-naive patients and especially in high-risk patients such as:

● Cancer patients,

● Patients with Cystic Fibrosis

● Those in ICU

Screening for azole resistance

overall mortality ranges from 20% to 50% despite the availability of active antifungal treatment.

Candida albicans, Invasive candidiasis

Invasive candidiasis length of stay

24 weeks and up to 2 months

Candida albicans, invasive candidiasis treatment

Echinocandins followed by a step down to azoles when appropriate.

a very serious disease with All-cause Mortality at 30 days up to 20-50%

Nakaseomyces glabrata (Candida glabrata)

shows High minimum inhibitory concentrations (HIGH MICs) to azoles.

Nakaseomyces glabrata (Candida glabrata)

Nakaseomyces glabrata (Candida glabrata), invasive candidiasis treatment

Echinocandins, although other antifungals such as azoles might be used following confirmation of in-vitro susceptibility.

Mortality rates in HIV/AIDS patients ranged from 21% to 53%.

9-11% (lower) in:

- Immunosuppressed Patients

- Solid Organ Transplant Patient

Histplasma spp.

Histplasma, severe cases treatment

Amphotericin B followed by Itraconazole is recommended

Affected low-income patients with many complications and sequelae

Eumycetoma causative agents

60-80% report a significant impact on their daily life and Amputation rates are as high as 39%.

Eumycetoma causative agents

Risk factors of Eumycetoma causative agents

farmer, male, and 11-30 years old

Eumycetoma causative agents treatment

Long-term Antifungals and Amputation is frequently required for full resolution of infection.

Mucorales mortality ranges:

Adults → ___

Pediatric px → ____

Adults → 23% to 80%

Pediatric px → 72.7%

Affects immunocompromised patients like cancer, and transplant patients. Also seen in poorly controlled diabetes mellitus and those with trauma injuries.

Mucorales

Risk factors of mucorales

Neutropenia

Diabetes mellitus

Trauma

risk factor for Subcutaneous Mucormycosis.

trauma

MICs for azoles are generally higher for ____ species compared with others.

Mucor

Mucorales are generally susceptible to ?

Amphotericin B

Mucorales are inherently resistant to ?

Fluconazole

Voriconazole

Echinocandins

Mucormycosis gained prominence due to infections in COVID-19 patients

COVID-19 Associated Mucormycosis (CAM)

known as BLACK FUNGUS, affects weakend immunity, diabetes or cancer.

Mucormycosis

Steroids in excess causes what?

1. weakened the patient's immune system,

2. raised their blood sugar levels, and

3. made them vulnerable to fungal invasion.

affects immunocompromised patients such as those with Hematological Malignancies or Post-hemopoietic stem cell transplantation (HSCT)

Invasive fusariosis (fusarium)

Scedosporium spp.

Invasive fusariosis (fusarium) risk factors

acute myeloid leukemia

allogeneic HSCT

cytomegalovirus reactivation,

Presence of skin lesions

Invasive fusariosis (fusarium) mortality rates

43% and 67% for invasive fusariosis.

Based on MICs, susceptibility to azoles is generally lower than to other antifungal medicines, such as amphotericin B.

Fusarium

showed reduced susceptibility to azoles compared with non-F. Solani species.

F. solani

Candida tropicalis mortality rate:

Adults =___

Pediatric patients = ___

Adults = 55-60%

Pediatric patients = 26% - 40%

- Critical illness

- Decreased Host Immunity

- NEONATAL ICUs

Candida tropicalis risk factors

Candida tropicalis is resistant to ?

Fluconazole,

Itraconazole,

Voriconazole

Posaconazole

Invasive Candida tropicalis is empirically treated with

Echinocandins

Candida parapsilosis mortality range

20-40%

Azole Resistance Rates: Excess of 10%

Candida parapsilosis

Candida parapsilosis is resistant to ?

Echinocandins,

Flucytosine

Amphotericin (rare)

overall shows intrinsically higher MICs to Echinocandins than other Candida species.

Candida parapsilosis

Studies assessing BIOFILM MASS are concerning for higher rates of resistance to all antifungal agents in biofilm situations (such as central lines, implants and prostheses).

Candida parapsilosis

Targets Mainly: RESPIRATORY SYSTEM

Others: Blood, Central Nervous System, Other Organs

Invasive Scedosporiosis (Scedosporium spp.)

Invasive Scedosporiosis ( Scedosporiosis (Scedosporium spp.)) risk factors

malignancy

HSCT

severe infection

Scedosporiosis (Scedosporium spp.) moratility rate

42-46% (adults and children)

Invasive scedosporiosis treatment

VORICONAZOLE, with other antifungal medicines

the most active antifungal against scedosporium spp.

Voriconazole

scedosporium spp. has reduced susceptibility to

Amphotericin B,

Itraconazole,

Isavuconazole

Echinocandins

AIIE

- A globally distributed, opportunistic pathogenic mold

- can produce invasive infection (INVASIVE LOMENTOSPORIOSIS)

Lomenstopora prolificans

Serious Nosocomial Infection that affects cancer patients

Lomenstopora prolificans

Lomenstopora prolificans mortality raets

Adults = ___

Immunocompromised children = ___

Adults = 55% - 71%

Immunocompromised children = 50%

INVASIVE LOMENTOSPORIOSIS treatment

Toriconazole and Terbinafine

current licensed antifungals have no in vitro activity against this fungus

Lomenstopora prolificans

is a very serious disease, with Mortality ranging from 2% to 13%

Coccidiodes

Coccidiodes spp. hospitaly stay length:

- Coccidiodes spp. Infection: ___

- Coccidiodal Meningitis: ___

- Coccidiodes spp. Infection: 3 to 7 Days (median)

- Coccidiodal Meningitis: 22.7 Days (median)

could resolve without antifungal treatment; however, treatment is recommended in risk groups

Primary Pulmonary Coccidioidomycosis

Disseminated coccidioidomycosis treatment

Fluconazole,

Itraconazole

Amphotericin B

Coccidiodes MICs ?

● HIGH MICs: Fluconazole

● VARIABLE MICs: Capsofungin

● LOW MICS: Anidulafungin and Micafungin