Systemic Fungal Infections Flashcards
Antibiotics Are For PATHOGENS
This general process is the same for all infectious diseases and is worth committing to memory.
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
Yeast Molds Dimorphic
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
Primary versus Opportunistic Pathogens
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)
Host Immunity & Systemic Fungal Infections
Invasive Pulmonary
Aspergillosis
Chronic Cavitating
Pulmonary
Aspergillosis
Allergic
Bronchopulmonary
Aspergillosis (ABPA)
Molds can cause DIFFERENT diseases depending on the strength of the hosts immunity!
Remembering Your Antibiotics: Place Into A Schema!
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)
Common Antifungals Used in Systemic Fungal Infections
Polyene Antifungals
Echinocandins
Azole Antifungals
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)
Memorizing Spectra of Activity: Antifungals
q
Memorizing The Microbiome: Critically Important!
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
Local Candidiasis vs. Systemic/Invasive Candidiasis
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.)
Invasive Candidiasis & Candidemia
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!
Invasive Candidiasis: Risk Factors
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?
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?
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!
Metastatic Infection & Invasive Candidiasis
Metastatic sites of infection can serve as NEW “sources” or “niduses” of persistent infection.
Microbiologic Testing: The Progression of Reporting
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!
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!
q
Candida Species & Antifungal Susceptibility
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!
Antifungal Susceptibility: Difficulty with Interpretation
Consult your ID expert colleagues when dealing with strange and unfamiliar susceptibility reporting. Don’t guess!
Antifungal Drug Resistance: Different Than Bacterial Resistance
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!
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!
• 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
Empiric Antifungal Therapy for Invasive Candidiasis
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!
FOLLOW-UP: Monitoring Therapy for Treatment Success
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.
Causes of Apparent Clinical Failure
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)
Cryptococcosis
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)
Cryptococcosis
diagnosis
tx
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!)