Systemic Fungal Infections

Question 1

Antibiotics Are For PATHOGENS
This general process is the same for all infectious diseases and is worth committing to memory.

Answer 1

Kill the
PATHOGEN that is
CAUSING the
disease! This
means we always
need to be
thinking: “what
pathogens are at
play in my
specific patient?”

What is the
diagnosis?
Is this really an
infection? What
pathogens could
cause this?

Microbiologic
testing orders
If feasible, useful,
and if possible –
prior to antibiotics

Empiric
Antimicrobials
Based on most
common
pathogens for this
diagnosis and site
Culture-Directed
Therapy
Based on receipt
of microbiologic
testing

Question 2

Yeast Molds Dimorphic

Answer 2

Yeast
Unicellular, colorless,
oval-shaped fungi,
reproduce by budding
Some are human
commensals
Candida spp (many)
Cryptococcus spp
Pneumocystis
Malassezia
Others

Molds
Multicellular, colorful,
branching-shaped fungi
with hyphae/septa
reproductive elements
Often environmental
Aspergillus spp (many)
Mucorales/Rhizopus
Penicillium spp
Fusarium
Dermatophytes

Dimorphic
Yeast in the heat
(appear as yeast in
human specimens)
Mold in the cold;
depends on environment

Histoplasma spp
Blastomyces
Coccidioides
Paracoccidioides
Sporothrix

Question 3

Primary versus Opportunistic Pathogens

Answer 3

PRIMARY PATHOGENS
Can cause disease in
otherwise healthy
individuals if exposed to
the infectious
microorganism
E.g.
* Dimorphic fungi
* (like Histoplasma,
Blastomyces, others)

Both, depending
Many molds
(depending on
the host)
Aspergillus,
others

OPPORTUNISTS
Can cause disease typically
in patients who cannot
defend themselves
against fungus
(specifically
immunocompromised)
E.g.,
* Yeasts (i.e., Candida,
Cryptococcus,
Pneumocystis)

Question 4

Host Immunity & Systemic Fungal Infections

Answer 4

Invasive Pulmonary
Aspergillosis

Chronic Cavitating
Pulmonary
Aspergillosis

Allergic
Bronchopulmonary
Aspergillosis (ABPA)

Molds can cause DIFFERENT diseases depending on the strength of the hosts immunity!

Question 5

Remembering Your Antibiotics: Place Into A Schema!

Answer 5

Azole Antifungals
Early Generations:
* Topicals (miconazole,
ketoconazole, etc.)
* Fluconazole
* Itraconazole
Late Generations:
* Voriconazole
* Posaconazole
* Isavuconazole

Echinocandins
* Micafungin
* Caspofungin
* Anidulafungin

Polyenes
Amphotericin B
* Nystatin

Miscellaneous
Flucytosine
* Terbinafine,
tolnaftate, other
topicals
* Griseofulvin
(discontinued)

Question 6

Common Antifungals Used in Systemic Fungal Infections
Polyene Antifungals
Echinocandins
Azole Antifungals

Answer 6

Polyene Antifungals
(amphotericin B)
Directly inserts pores in ergosterol cell wall.
Used for: endemic mycoses, resistant fungi

Echinocandins
(micafungin, caspofungin ) – IV ONLY
Inhibits beta-1,3-glucan synthase – no homology
Used for: invasive candidiasis

Azole Antifungals
(fluconazole, itraconazole, voriconazole, etc )
Inhibits lanosterol 14-a demethylase (CYP enzyme)!
Used for: Candida, invasive mold infections (later
generation azoles, voriconazole and posaconazole)

Question 7

Memorizing Spectra of Activity: Antifungals

Answer 7

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Question 8

Memorizing The Microbiome: Critically Important!

Answer 8

Skin / Cutaneous
* Staphylococcus aureus (MSSA or MRSA)
* Coagulase –ve Staphylococcus
* Streptococci (beta-hemolytic > oral)
* Candida spp

Mouth / Oropharynx
* Streptococci (VGS, S. anginosus > betahemolytic, but GAS present)
* Oral anaerobes
* Candida spp

Stomach / Small-Intestine / Biliary Tree
* Stomach (mostly H. pylori, Streptococci)
* SI / Biliary Tree: Enterobacteriales (E.
coli, Klebsiella, Proteus), Enterococcus,
Streptococcus (GI > beta-hemolytic)
* Candida spp

Large Intestine / Colon
* Enterobacteriales, Enterococcus
* Enteric Anaerobes
* The peritoneum (cavity surround intraabdominal organisms) should be
STERILE (no bacteria)
* Candida spp

Question 9

Local Candidiasis vs. Systemic/Invasive Candidiasis

Answer 9

Oro/esophageal Candidiasis (aka. “Oral Thrush”):
* Opportunistic yeast infection of the
mouth/esophagus common in patients with
mucositis from chemotherapy but ANY patient who
is even partially immunodeficient (i.e., newborns!)

Vaginal Candidiasis (aka. “vaginal thrush”; and yes,
candidal balanitis in men)
* Opportunistic yeasts infection – locally
immunocompromised (i.e., normal barrier defenses
disrupted, pH imbalance/antibiotic treatment,
bacterial flora disruption, etc.)

Question 10

Invasive Candidiasis & Candidemia

Answer 10

DEFINITIONS:
* Candidemia = Candida spp isolated in the blood
* Invasive candidiasis = generic term for systemic
fungal infection w/ Candida spp (since can involve
distant organs)
Yeast in the blood represents a MAJOR breakdown
in normal host immune capability!
* Normally our immune system is extremely
effective at clearing yeast in the blood
* In hospital mortality = ~30% with candidemia!

Yeast found in the blood is never a contaminant and requires urgent assessment and treatment!

Question 11

Invasive Candidiasis: Risk Factors

Answer 11

Loss of Host Immune
Defense
Exposure to broadspectrum antibiotics,
uncontrolled diabetes
mellitus, neutropenia

Loss of Host Barrier
Defenses
(Portal of Entry)
Intravenous catheters
(++ central lines), total
parenteral nutrition
(TPN), intra-abdo
surgery

Just being admitted to the ICU has been identified as a risk factor for candidemia. Can you tell why?

Question 12

Invasive Candidiasis: Revisiting Our Patient Case
55-year-old male with crushing abdominal trauma after
being pinned in a motor vehicle collision. Required ICU
admission and prolonged broad-spectrum antibiotics
for secondary bacterial peritonitis with multiple surgical
revisions for bowel injury. Started on total parenteral
nutrition (TPN) because of prolonged lack of access to
enteral route.
Day 47 of admission, becomes febrile, hypotensive
(responsive to fluids), and peripheral and central blood
cultures are drawn. Antibiotics are escalated from
piperacillin-tazobactam to meropenem.
35 hours after blood culture collected, specimen flags as
positive with note: yeast seen.
But why is the mortality rate so high? How do people die from candidiasis?

Is 35 hours a long time? Do you need a special type of culture for detecting fungus?

Answer 12

Candidemia can itself cause a non-specific febrile
illness (fevers, chills, rigors) OR septic shock from
fungemia – which in itself can be life-threatening.
* Elevated WBC count – Q: with what cell line?
However: Candida also has the behavior to cause
METASTATIC INFECTION (similar to which bacteria
most commonly?) – and cause “seeding” from initial
source – causing distant organ disease via the blood.
Sites of possible seeding include:
o Candida endophthalmitis (eyes)
o Infective endocarditis
o Osteoarticular infections
o Hepatic/splenic abscess formation
Candidemia should prompt evaluation for potential “seeding sites” for metastatic infection!

Question 13

Metastatic Infection & Invasive Candidiasis

Answer 13

Metastatic sites of infection can serve as NEW “sources” or “niduses” of persistent infection.

Question 14

Microbiologic Testing: The Progression of Reporting

Answer 14

First: GRAM-STAIN REPORT
(~12-24 hours depending on lab/specimen)
Will demonstrate if anything grew in gross amounts visible via
microscopy (e.g., Gram-positive cocci in clusters)
Also, can report if WBCs are seen – which can be a hint there is
active inflammation, a piece of the puzzle to tell if there is a real
infection

Molds are NOT detectable via regular bacterial blood cultures
(require special FUNGAL blood cultures)
YEAST however CAN be found in regular bacterial blood
culture – will flag as “YEAST” seen in the gram-stain! – but
instead of 12-24 hours, can be AS LATE AS 4-5 DAYS!

Second: IDENTITY REPORT
(~24-48 hours depending on organism)
Will tell us if anything grew out in final culture (specimen taken
for separate culture for growth) – and the NAME of the bacteria
The identity report usually follows ~24 hours after yeast is
isolated – and may be reported as “Candida species” before
it is identified as a SPECIFIC Candida

Third: SUSCEPTIBILITY REPORT
(~24-48 hours after ID depending on organism)
Will give us a report of the bacteria’s antibiotic susceptibility,
agents are tested based on lab standards (i.e., CLSI / EUCAST
standards)
Susceptibility report follows sometimes 3-4 DAYS after
receipt of pathogen identity – which highlights need to
KNOW EMPIRIC ANTIFUNGAL SUSCEPTIBILITIES BEFOREHAND!

Question 15

Detecting yeast in the blood IS ALWAYS ABNORMAL and should
always be taken seriously with follow-up blood cultures (until
clearance).
However….
Q: What is the significance of yeast grown from the following
sites?
o Biliary tree-drainage?
o Bronchoscopy specimen? Sputum culture?
o The urine?
REMINDER: Yeast grown in non-sterile sites is NOT always pathogenic!

Answer 15

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Question 16

Candida Species & Antifungal Susceptibility

Answer 16

In different parts of the world – different
Candida species dominate as the most
common species isolated from the blood. In
Alberta and most of North America:
* Candida albicans (majority; >85%)
* Candida glabrata (~5-10%)
* Candida parapsilosis
* Candida tropicalis
* Candida dubliniensis
* Candida lusitaniae
* Candida krusei
* Candida auris (global superbug, only < 50
cases in Canada since 2012)

Not all Candida species are managed effectively with empirical azole antifungals!

Question 17

Antifungal Susceptibility: Difficulty with Interpretation

Answer 17

Consult your ID expert colleagues when dealing with strange and unfamiliar susceptibility reporting. Don’t guess!

Question 18

Antifungal Drug Resistance: Different Than Bacterial Resistance

Answer 18

Antifungal drug resistance is certainly a clinical
problem but does not emerge in the same way
clinically we see with bacteria.
Fungi generally do NOT make antifungalhydrolysing enzymes (like ESBLs), and generally
take YEARS of exposure and circulation to
develop resistance, and RARELY pass resistance
mechanisms to eachother.
* Instead – antifungal pressure can SELECT for
specific drug-resistant species!
* E.g., patient given fluconazole, but risk factors
persist, may develop C. krusei candidemia

Antifungal resistance often involves drug-efflux pumps or target-enzyme modification mechanisms!

Question 19

Empiric Therapy for Candidemia
55-year-old male with crushing abdominal trauma after
being pinned in a motor vehicle collision. Required ICU
admission and prolonged broad-spectrum antibiotics for
secondary bacterial peritonitis with multiple surgical
revisions for bowel injury.
Day 47 of admission, becomes febrile, hypotensive
(responsive to fluids), and peripheral and central blood
cultures are drawn.
35 hours after blood culture collected, specimen flags as
positive with note: yeast seen.
Q: What empiric antifungal therapy would you select?
Consider LOCAL frequencies of drug-resistant Candida species when making recommendations!

Answer 19

• And so for empiric therapy for academia. You only know at this point, as you will likely in practice, that you have a patient with you seen, and it stays that way for a long time. What would be the empiric anti fungal therapy that you’d select and so, of course, we think about the local frequencies of drug resistant Canada when we’re picking our empiric therapy.
• But in general we think about it kind of echinocandins first, and the reason is because, of course, we know about Canada Glibrata
• So when we have 10 to the Glibrata in the blood we’re worried that normal doses of flu con is all will be insufficient to clear from the blood

Question 20

Empiric Antifungal Therapy for Invasive Candidiasis

Answer 20

Yeast seen in the blood
Gram-stain

Start micafungin 100 mg IV Q24H
Effective empiric option for ALL
candidemia in-case of C. glabrata
fungemia which has higher MICs to
azole antifungals

C. albicans isolated
Identified

Change to fluconazole 400 mg PO Q24H
Fluconazole and all azoles reliable for C.
albicans and most other common species – so
before susceptibility returns – can stepdown
immediately to fluconazole

Antibiotics should be assessed on day of prescription but again on day 3 for appropriateness!

Question 21

FOLLOW-UP: Monitoring Therapy for Treatment Success

Answer 21

Antifungal therapy is effective when chosen correctly
based on pathogen species and known antifungal
susceptibilities.
However: patients STILL have an increased mortality
rate despite adequate antifungal treatment. Why?
* Antifungal therapy is ONE component of
treatment
* MOST importantly – effective SOURCE CONTROL
is needed for the INDEX SOURCE as well as
hematogenous METASTATIC SITES in order to
control infection and prevent death
* Ongoing immunodeficiency may make clearance
extremely difficult

Treatment failure DOES NOT INFER drug failure – CONSIDER IT, but AFTER the above are ruled out.

Question 22

Causes of Apparent Clinical Failure

Answer 22

Lack of Source Control (e.g., endocarditis – despite
antibiotics persistently positive BCx, may require
surgery to remove infected valve vegetation)

Immunodeficiency (e.g., even if optimal antibiotics
given, patients without an immune system may not
improve at all, or very slowly)

Wrong Diagnosis (e.g., never was infectious – and not
improving on antibiotics. Can be proof that antibiotics
are not indicated – e.g., in UTI/ASB)

Other Diseases/Infx (e.g., if clinically stable, may be
persistently sick from other issues (surgery, etc))

Delayed improvement (e.g., cellulitis – takes few days
for redness/swelling to improve; or pneumonia –
where CXR can take weeks to resolve)

Question 23

Cryptococcosis

Answer 23

PATHOGEN: Cryptococcus neoformans (encapsulated yeast; extremely rare C.
gatii associated endemically with Vancouver Island); opportunist
GEOGRAPHY: worldwide distribution, environmental certain trees/bird excreta
(maybe with Eucalyptus trees?; pigeons’ excreta?); most patients have been
exposed at some point (70% seropositivity in New York City in pediatrics)
ACQUISITION: inhalation of airborne yeast; typically, only in
immunocompromised patients (uncontrolled HIV CD4 <50; AIDS)
CLINICAL PRESENTATION:
* Entry into lung > uncommonly causes pulmonary disease, usually
sequestered in granulomas in the lung and dies
* Can cause subacute meningitis (fatal if untreated; headache, stiff neck,
FNDs) or disseminated disease, can have umbilicated skin lesions (looking
like molluscum contagiosum)

Question 24

Cryptococcosis
diagnosis
tx

Answer 24

DIAGNOSIS: CrAg (cryptococcal antigen for polysaccharide capsule), sensitive
TREATMENT:
* Initially Amphotericin B IV daily + Flucytosine PO x 2/52 (induction phase)
followed by fluconazole (maintenance) for prolonged course, immune
reconstitution (beware of IRIS!)

Question 25

Histoplasmosis

Answer 25

PATHOGEN: Histoplasma capsulatum (var. capsulatum OR duboisii; in Africa)
GEOGRAPHY: worldwide distribution, Ohio/Mississippi River Valley, in Canada
in Alberta and Northwest Territories as well as BC and Central
ACQUISITION: inhalation of airborne microconidia (thought to be from
bird/bat droppings into soil/spelunking/caves, chicken coops, construction);
rare primary from graft in organ transplant
CLINICAL PRESENTATION:
* Asymptomatic in majority of patients (90+%)
* Passes as community-acquired pneumonia in most cases!
* Some may develop pulmonary nodules/cavitation (like TB/cancer),
mediastinal fibrosis > and disseminate if immunocompromised (CNS,
bone marrow, spleen; higher risk if on TNF-a inhibitors)

Question 26

Histoplasmosis
diagnosis
tx

Answer 26

DIAGNOSIS: serology testing first, urinary Histoplasma Ag, culture
TREATMENT:
* Initially amphotericin B 3 mg/kg IV daily, with usually 2-4/52 before
stepdown to itraconazole to finish 1-2 weeks (4/52 total pulmonary,
longer if immunocompromised, 1-2 years if disseminated

Question 27

Blastomycosis

Answer 27

PATHOGEN: Blastomyces dermatitidis (or gilchristii), a dimorphic fungi
(with characteristic “broad-based budding” yeast phenotype)
GEOGRAPHY: Midwest/SE USA; In Canada >Southern Ontario/Manitoba,
(Great Lakes Region) Quebec, reported in Alberta but worldwide
ACQUISITION: inhalation of airborne conidia (from soil/decaying matter
woods/leaves); traumatic inoculation rare; can infect dogs!
CLINICAL PRESENTATION:
* Asymptomatic in 50% of patients, sometimes constitutional illness
* Pulmonary blastomycosis; but often combination with cutaneous
* Recurrent; extrapulmonary, cutaneous, joint, genitourinary/prostate
and CNS disease (manifesting as chronic meningitis)

Question 28

Blastomycosis
diagnosis
tx

Answer 28

DIAGNOSIS: serology testing first, EIA from urine/serum, culture
TREATMENT:
* Initially amphotericin B 3 mg/kg IV daily, with usually 2-4/52 before
stepdown to itraconazole to finish course usually 6-12 months

Question 29

Mucormycosis

Answer 29

PATHOGEN: Mucorales group molds (either Mucor spp or Rhizopus spp; also called
Zygomycetes molds, Rhizomucor or Cunninghamella spp), which are rapidly
growing hyphal molds (“lid-lifters”) relatively aseptate
GEOGRAPHY: worldwide distribution, environmental (bread molds)
ACQUISITION: inhalation of airborne conidia; classically associated with DKA and
uncontrolled diabetes, prolonged neutropenia >14-days, heme malignancy, iron
overload syndromes? (hemochromatosis)
CLINICAL PRESENTATION:
* Rhinocerebral mucormycosis – destructive soft-palate eschar/nasal/sinuses
disease which can extend into the CNS/skull
* Pulmonary mucormycosis – rapidly progressive lung-necrotizing disease in
neutropenic patients, tough to parse from aspergillosis; can disseminate; is
angioinvasive and has HIGH mortality rate
* Cutaneous mucormycosis – involving necrotic skin lesions

Question 30

Mucormycosis
diagnosis
tx

Answer 30

DIAGNOSIS: difficult to culture, histopathology, can be contaminant, clinical Dx
TREATMENT:
* SURGERY/DEBRIDEMENT MOST IMPORTANT. Initially Amphotericin B but
possibly isavuconazole as first-line with salvage options, prolonged treatment

Question 31

Systemic Fungal Infections: Selected Interventions for Antifungal Stewardship

Answer 31

DE-ESCALATION
With receipt of final culture reports, de-prescribing empiric
antifungal agents may be possible once fungal involvement has
been excluded.

IV -> PO STEPDOWN
Many antifungal agents are highly bioavailable and excellent
candidates for switch from intravenous > oral routes of
administration (e.g., fluconazole, voriconazole).

DURATION OF THERAPY
With source of infection managed and immune system
reconstitution, duration of therapy can be considered to limit
unnecessary long-term exposure to antifungal agents.

Question 32

Practice Case Example – Antifungal Stewardship
34M with new diagnosis of HIV severely uncontrolled (CD4 =
4 cells/mm3
) presents to the emergency department with
headache, photophobia and neck stiffness x 2 weeks. The
patients GCS falls to 8/15 and the patient is intubated and
admitted to the neuro-ICU. Blood cultures and CSF cultures
are negative for bacteria, but the patient has a serum CrAg
that returns as positive.
Patient is started on amphotericin B and flucytosine and
improves to baseline over the next two weeks. On day 14, the
patient is de-escalated to fluconazole 400 mg IV Q24H.
Q: What could you suggest at this point from an
antifungal stewardship perspective?
Consider high-impact, easy to do interventions to improve patient care with systemic fungal infections

Answer 32

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Question 33

Antifungal Clinical Pharmacology: Azole Antifungals

Answer 33

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