DISSEMINATED FUNGAL
INFECTIONS
SAMIR EL ANSARY

Disseminated fungal infection
Disseminated fungal infection
As the presence of a fungal pathogen in the
blood (fungemia) and/or any other sterile deep-
seated structure because of hematogenous
seeding.
This distinguishes disseminated infection from
superficial infection
which mostly involves
the mucocutaneous structures, that is,
dermatitis, onychitis, stomatitis, esophagitis,
and keratitis,

Simple colonization
which is the isolation of a fungal pathogen from
a nonsterile site without any sign of infection
attributable to the specific pathogen.
lnvasive fungal infection
Is a more general term and refers to
fungemia and other fungal
infections such as disseminated
candidiasis, endocarditis, meningitis,
and hepatosplenic infection.

Most clinically important fungal
pathogens
Candida spp., Aspergillus spp., and
Cryptococcus spp. are by far the most
common fungal pathogens encountered in the
hospital setting, with Candida being the
leading fungal pathogen.
Of note is that Aspergillus spp. have been
steadily increasing in the intensive care unit
(ICU) setting.

Epidemiology of fungal
infections in hospitalized
patients
In the last 25 years the total number of fungal
infections in hospitalized patients has
increased from 6% in 1980 to 10.4% in 1990
and currently may be as high as 25%.
Candida species
are the fourth most commonly
recovered blood culture isolates
in the United States.

Why has the incidence of fungal
infection increased so dramatically?
Fungi generally do not cause invasive infection in
healthy individuals.
Robust cellular and antibody-mediated
immunity and intact mucosal barriers
play a major role in shielding the human body from
opportunists such as Candida spp., which seek a
way of passing through tissues and entering the
bloodstream and other deep-seated organs.

Why has the incidence of fungal
infection increased so
dramatically?
With the numbers of immunosuppressed
patients increasing through cancer and
chemotherapy, transplantation, and HIV
infection, as well as with the increased use of
vascular and urinary catheters and
broadspectrum antibacterial agents, an
alarming increase of deep-seated fungal
infections has been seen in clinical practice.

Responsible fungi for invasive
infection in humans
•C. albicans accounts for the majority (mostly
>50%-60%) of all Candida infections, but this
percentage is declining to 45%.
•C. tropicalis, C. glabrata, and C. krusei
account for most of the remainder.
•This is particularly important because certain
Candida spp. such as C. krusei can be
resistant to fluconazole.

Responsible fungi for invasive
infection in humans
•On the other hand,Aspergillus spp. account
for at least 15% to 20% of all fungal infections;
however, the rate can be higher in patients after
lung transplantation.
•Other less-common but increasing mycoses
include
•Blastomycoses, Coccidioidomycoses,
Cryptococcosis, Histoplasmosis, and
Sporotrichosis.

The most important risk factors
for disseminated Candida
infection
•ICU stay immunosuppression (hematologic
malignancy, hematopoietic stem cell
transplantation, immunosuppressive therapy
such as steroids and chemotherapeutic
regimens, neutropenia,and HIV infection)
•Total parenteral nutrition
•Comorbidities and a high APACHE (Acute
Physiology, Age, and Chronic Health Evaluation) score

The most important risk factors
for disseminated Candida
infection
•Broad-spectrum antimicrobial agents
•Candida colonization in multiple sites
•Acute renal failure especially requiring
hemodialysis
•Foreign bodies (central venous, arterial, or
urinary catheters)
•General and especially abdominal surgery

The diagnostic criteria for
disseminated fungal infection.
Definitive
•Single positive blood culture (never mistake a
positive fungal blood culture as a contaminant)
•Fungus cultured from biopsy specimen
•Burn wound invasion
•Endophthalmitis
•Fungus cultured from peritoneal or
cerebrospinal fluid

The diagnostic criteria for
disseminated fungal infection.
Suggestive
Three confirmed colonized sites
(should be regarded as a risk factor rather than a
definite sign of infection)
How reliable are these diagnostic criteria?
The preceding criteria are positive in only 30%
to 50% of patients with disseminated fungal
infection.
Therefore a high index of suspicion must be
maintained.

Should asymptomatic candiduria
be treated?
•Among low-risk individuals no treatment is
recommended.
•Amphotericin bladder irrigation is no longer
recommended.
•Usually a change of urinary catheter should
suffice.
•Among high-risk patients
(patients with neutropenia or with urologic
manipulations, low-birth-weight infants)
treatment is similar to the one used for
invasive candidiasis.

Should a central venous catheter be
removed once candidemia is
confirmed?
Practice guidelines indicate that all central venous
catheters should be removed once candidemia is
confirmed .
Of note is that a recent randomized controlled trial
and other studies
question the benefit of early removal of central
venous catheters in the onset of candidemia for
some selected patients.

Should a central venous catheter
be removed once candidemia is
confirmed?
We recommend following the standard practice
guidelines.
RECOMMENDATION ON CVC REMOVAL IN
PATIENTS WITH
CANDlDEMlA
VENOUS ACCESS RECOMMENDATION
Normal venous access  Remove CVC {
Central venous catheter } and send tip for
culture.

Should a central venous catheter
be removed once candidemia is
confirmed?
Limited venous access (impossible to
remove ) .  Exchange CVC over a
guidewire, and perform catheter tip cultures 
If catheter is colonized with the same
Candida sp. that is found in the blood, then
it is prudent to remove catheter.

When should you suspect
disseminated candidiasis?
•Unfortunately, disseminated
candidiasis has a wide spectrum of
manifestations from a mild fever to a
sepsis syndrome with multiorgan
failure.

When should you suspect
disseminated candidiasis?
•On certain occasions the hematogenous spread
of Candida produces visible changes throughout
the body including muscle, skin, and eyes,
making a bloodstream process clinically
apparent.
•However, this is not always the case, and that is
why there must be a low threshold for the
disease especially in patients with multiple risk
factors for candidiasis.

If disseminated candidiasis is
suspected, where should you look
for it?
•The first consideration is to perform
blood cultures.
•Then examine the retina for
endophthalmitis. However, recent reports
show that rate of hematogenous
endophthalmitis is considerably lower
(2%-3%) compared with older studies that
reported a 30% rate of such complication.

•Keep in mind that patients with neutropenia
may have no symptoms until they regain
their normal counts.
•You can also search for Candida in the heart
valves for endocarditis; the bone for
osteomyelitis; and the liver, spleen, and
kidneys for renal abscesses and candiduria.
•Also make sure to perform a biopsy of skin
lesions to add extra yield to the diagnosis
along with blood cultures.
•This is important because blood cultures are
only 50% to 60% sensitive.

•The overall mortality associated with
candidemia is 40% to 68%, with an
attributable mortality of 25% to
40%.
•However, the earlier the initiation of
antifungal agents, the better the
prognosis.

•Early targeted antifungal therapy is difficult to
accomplish because cultures take 24 to 48 hours
to yield the species and antifungal resistance
profiles.
•That is why empirical therapy should take into
account risk factors for antifungal resistance, that
is, prolonged exposure to antifungal agents or
long length of hospital stays, and also risk factors
for non-albicans species intrinsically resistant to
fluconazole.

Should antifungal therapy be
delayed until blood cultures are
positive for fungus?
Absolutely not ! Early therapy
means lower mortality.
Blood cultures have been found to
be only 40% to 70% sensitive.

Systemic antifungal therapy should be
strongly considered, especially in a patient
who is at high risk for disseminated fungal
infection, if:
•Fever persists despite antibacterial agents and
negative blood cultures
•High-grade funguria occurs in the absence of
a bladder catheter
•Funguria persists after removal of a bladder
catheter
•Fungus is cultured from at least two body sites
•Visceral fungal lesions are confirmed

The major classes of antifungal drugs
Antifungal drugs in clinical use today fall
into three broad categories
•Polyene antifungals (amphotericin B)
•Antifungal azoles .
•Echinocandins.

According to recent guidelines, physicians
should choose among an
echinocandin, fluconazole, an amphotericin B
preparation, or combination of amphotericin B
with flucytosine.
The therapeutic strategy should take into
account any previous use of antifungal agents
(because it can select resistant species), the
epidemiology of fluconazole-resistant or non-
albicans strains in the community, and any
comorbid conditions
(which could influence drug pharmacokinetics or
worsen coexisting conditions such as renal
failure).

An echinocandin { CASPOFUNGIN 50 MG / 12
Hrs } , or amphotericin B should be preferred
over fluconazole among patients with
neutropenia and critically ill patients, as well as
those known to be exposed to fluconazole-
resistant strains.
Of course the physician can always switch to
fluconazole whenever an antifungal resistance
profile becomes available.

Amphotericin B, a polyene, is
fungicidal.
It binds irreversibly to ergosterol (but
not to cholesterol, the major sterol in
mammalian cell membranes),
creating a membrane channel that
allows leakage of cytosol leading to
cell death.

Flucytosine is sometimes used in
conjunction with amphotericin B and
is synergistic
Flucytosine acts directly on fungal
organisms by competitive inhibition
of purine and pyrimidine uptake.

What antifungal azoles are
available, and how do they
work?
Fluconazole, itraconazole, voriconazole,
and posaconazole, which are triazoles, are
fungistatic against Candida spp.
They inhibit C-14 a-demethylase, a
cytochrome P-450-dependent fungal
enzyme required for synthesis of
ergosterol, the major sterol in the fungal
cell membrane.

What antifungal azoles are
available, and how do they
work?
This alters cell membrane fluidity,
decreasing nutrient transport, increasing
membrane permeability, and inhibiting cell
growth and proliferation.

How do echinocandins work, and are
they being used?
The target for echinocandins is the complex
of proteins responsible for synthesis of cell wall
polysaccharides.
Caspofungin, anidulafungin, and
micafungin
are used in the treatment of
candidemia and other forms of disseminated
Candida infections.

What advantages does fluconazole offer
over amphotericin B in the treatment or
prevention of disseminated fungal
infections?
Fluconazole is available in both intravenous
(IV) and oral (PO) forms; patients have been
successfully treated with 7 days of IV
fluconazole followed by PO if the patient is
able.
Administration by mouth is both easier and
less costly than IV administration.

Fluconazole
Is not nephrotoxic and has
fewer overall adverse effects
than
amphotericin B, which can
cause hypokalemia, fever,
and chills.

Limitations to the use of
fluconazole
•Yes. Fluconazole is not active against Aspergillus
spp. or C. krusei and other resistant Candida spp.
•Fluconazole may inhibit the P-450 detoxification
system and cause hepatotoxicity, increasing
phenytoin and cyclosporin levels and potentiating
warfarin's anticoagulant effects.
•Fluconazole has fewer overall
adverse effects than amphotericin B .

What should be done when a
Candida infection fails to respond to
fluconazole?
An echinocandin agent or an amphotericin B
preparation should be considered.
Make sure that the diagnosis is confirmed,
the dosage is appropriate, and drug-drug
interactions are ruled out
(for example, rifampin decreases fluconazole
levels).

What should be done when a
Candida infection fails to respond to
fluconazole?
Keep in mind that resistance can happen
to all antifungal agents.
•For example :
•C. krusei and C. glabrata can be resistant to
azoles.
•C. lusitaniae can be resistant to
amphotericin B .
•C. parapsilosis can have higher minimum
inhibitory concentration to echinocandins.

Less toxic forms of amphotericin
B available
To reduce the toxicity associated with
amphotericin B, lipid formulations have been
produced.
The earliest and most widely studied of these
is AmBisome, which in randomized trials has
been shown to be safer than amphotericin B
with many fewer side effects.

Less toxic forms of amphotericin
B available
Other lipid-associated, nonliposomal products
are amphotericin B lipid complex (Abelcet)
and amphotericin B colloidal dispersion
(Amphocil).
The disadvantage of these alternative forms of
amphotericin B is their currently high cost.

Can health care providers help
prevent the spread of fungal
colonization in the ICU?
Easily. Wash hands and wear gloves when
working directly with patients.
Candida species were found on the hands of
33% to 75% of ICU staff in one study.

Can health care providers help
prevent the spread of fungal
colonization in the ICU?
CONTROVERSY
Does the strategy of presumptive or
preemptive treatment of high-risk patients
prevent severe candidiasis in critically ill
surgical patients?

The effectiveness of fluconazole in
treating overt candidiasis has
unfortunately provoked its widespread,
unjustified use in patients without
neutropenia in the ICU setting.
This practice has likely led to an
increase in non-albicans species,
which are resistant to fluconazole.

Several studies have shown decreased
incidence of colonization and the risk of
candidiasis with such empirical treatment but
have failed to show decreased mortality in any
group other than high-risk patients who have
received a transplant.
Recent reviews have suggested that targeted
preemptive strategy may be of benefit in
preventing candidiasis in the ICU.

Of note is that fluconazole should be
given as secondary prophylaxis in
patients with HIV with CD4 < 200
cells/mm3 who survived
cryptococcosis.

•Fungal infections are an
increasing source of morbidity
and mortality in ICUs.
•Simple colonization does not
require treatment.

•Candida species and Aspergillus
account for more than 90% of
disseminated fungal infections.
•Fluconazole is comparable to
amphotericin B for most forms of
disseminated candidiasis without the
toxicity caused by amphotericin.

•Do not wait for confirmation by
culture to treat, because up to 50%
of lethal infections may be culture
negative before death.
•Presumptive or preemptive therapy
may be useful in selected high-risk
groups.

•The earlier the
administration of
antifungal treatment the
lower the mortality.

An echinocandin
•CASPOFUNGIN 50 MG / 12 Hrs
•MICAFUNGIN { MYCAMINE } 100
MG DAILY FOR 10-45 DAYS
{ MEAN 15 DAYS }

GOOD LUCK
SAMIR EL ANSARY
ICU PROFESSOR
AIN SHAMS
CAIRO
elansarysamir@yahoo.com