DISSEMINATED FUNGAL INFECTIONS

SAMIR EL ANSARY

Disseminated fungal infection

Disseminated fungal infectionAs 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 infectionwhich mostly involves

the mucocutaneous structures, that is,

dermatitis, onychitis, stomatitis, esophagitis,

and keratitis,

Simple colonizationwhich is the isolation of a fungal pathogen from

a nonsterile site without any sign of infection

attributable to the specific pathogen.

lnvasive fungal infectionIs 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.

SuggestiveThree 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

micafunginare 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 ANSARYICU PROFESSOR

AIN SHAMSCAIRO

elansarysamir@yahoo.com