Fungal Infections and Antifungals

When to Empirically Treat

Persistent fever on broad spectrum
and Risk Factors
and Colonization at Multiple Non-Sterile Sites

Polyenes

Amphotericin B

produced from streptomyces nodosus

kills candida, cryptococcus, histoplasma, blastomyces, mucoraces, coccidiodes, paracoccidiodes, aspergillus spp, fusarium, sporothrix

resistant to aspergillus terreus, trichosporon, pseudallescheria, candida lusitaniae

hydrophobic, not removed by dialysis

release of inflammatory mediators can cause fever and hypotension

renal dysfunction, both acute and cumulative

also causes decreased erythropoietin

give 1 mg test dose prior to 1st dose and wait one hour

Volume load 500 cc-1000 cc if possible with administration

Lipid Associated Formulations have less nephrotoxicity

ABCD (AmphoB Colloidal Dispersion) has toxicities of its own

ABLC-Lipid complex

L-AMB-probably the best choice

Nystatin

No IV or PO form, topical only

Flucytosine (5-FC)

cryptococcus, candidiasis, chromomycosis

resistance develops quickly

causes rash, diarrhea, hepatic dysfunction; also in high levels thrombocytopenia and leukopenia

Renal dosing is necessary

The Azoles

adrenal insufficiency, drug interactions,

Miconazole

now almost exclusively a topical agent. use this one for ed skin infections

Ketoconazole

candida, histoplasma, blastomyces, coccidiodes, and sporothrix.

Modest activity against aspergillus

Oral formulation requires acidic environment for absorption

doesn’t penetrate CSF

side effects are n/v, hepatitis, and in high doses adrenal suppression

newer azoles are preferred

Fluconazole

triazole with activity mainly against yeast: candida and cryptococcus

Also histoplasma, blastomyces, coccidiodes.

Resistance has been seen against candida albicans, glabrata, and krusei

Oral and IV forms have equal bioavailability

Good CSF penetration

Needs renal dosing

Itraconazole

triazole with wider spectrum of action than fluconazole

candida, aspergillus, histoplasma, blastomyces, sporothrix, trichophyton, cryptococcus, coccidiodes, and paracoccidiodes

Originally available only in poorly absorbed capsule, but now two usable forms:

solution in cyclodextrin that enhances oral use and

IV form also in cyclodextrin

Poor CSF penetration

med interactions, gi, and hepatitis are side effects.

Candins

Candida and aspergillus

Capsofungin, Micafungin, and Anidulafungin

Candida

30-80% of us are colonized, higher with HIV

Majority of Fungal Health-Care Associated Infxn; 4th most common blood stream infection (never a contaminate in the blood)

disseminated disease can be treated with fluconazole or Ampho-B,

C. Glabrata and Krusei will often be resistant to fluconazole

Treat 14 days after the last positive culture for candidemia and 4 weeks for disseminated disease

remove all lines if possible

Consider empiric antifungal treatment in any ICU patient present for 4 days or more or who has received 4 days of broad spectrum antibiotics with unexplained fevers with the risk factors of immunocompromise, steroids, post gi surgery, urinary catheter, burns, or a low birth weight infant.

Esophageal needs 14-21 days of treatment

Asymptomatic candiduria should be treated if any of the risk factors above otherwise

CAUTI-change catheter and repeat cultures–and look for other source

Candida pneumonia requires biopsy to prove it and is extremely rare (case-reportable)

Candida Score (Crit Care Med 2006;34(3):730)

In patients with colonization of candida

Score > 2.5 (Sens 81%/Spec 74%)

TPN +0.908
Surgery +0.997
Multifocal Colonization +1.112 (even if diff species: orogastric, resp, urinary)
Severe Sepsis +2.038

How to Handle

Start an Echinocandin until speciation and sensitivities (Mycofungin)
In neutropenic pts-consider Ampho B
Fluconazole only if Albicans
Daily Blood Cx until negative
Treat 14 days from negative cultures
Remove central lines, Neutropenic patients will usually have a gi source though
Examine the eyes

Pneumocystis Jirovecii (Formerly PCP or Pneumocystis Carinii Pneumonia)

CD4<200 in adults, steroid use, immunosupressive drugs, cancer, cell-mediated immunity problems, severe malnutrition, Stem-cell transplant(see thrush-at risk for PCP)

non-productive cough, exertional dyspnea, weight loss. LDH>220. Give steroids if PO2 less than 70 or Aa>35 (Prednisone 40 mg PO BID).

3 Amps Bactrim Q 6 or Trimeth plus Dapsone or Pentamidine or Atovaquone or Clinda + Primaquine

Oral 2DS Tabs TID (Treatment: Bactrim (if allergic- Desensitize!) + 21 days of steroids)

Prone to pneumothorax

non-productive cough, exertional dyspnea, weight loss. LDH>220. Give steroids if PO2 less than 70 or Aa>35 (Prednisone 40 mg PO BID). 3 Amps Bactim Q 6.

Prone to pneumothorax

93 PCP cases: 63% had elevated LDH, hypoxemia in 57%, C-XR normal in 39%, interstitial 36%, and acinar infiltrates in 25%. (J Acquir Immune Defic Syndr 1994;7(1):39-45)

Cryptococcus Neoformans

not part of the normal flora

AIDS, immunocompromised, organ transplant patients, cirrhotics, and corticosteroid users

very little evidence to support a link to pigeons (only 1 reported case)

Transmitted by inhalation route

May cause lung disease such as pneumonia, mass lesions and nodules.

Neurological involvement via meningitis

Disseminated disease is also possible.

India Ink

Cultures take 3-7 days

Latex agglutination assay in serum CrAg Sens and Spec, detects antigen from capsule

CrAg may be negative if isolated lung disease

In HIV, 90% will have CNS disease as well. Uncommon until CD4<100.

Use Ampho B with or without flucytosine (toxicity with the latter)

Azoles are not indicated initially as they do not adequately cross the BBB.

Memory loss, confusion, and CN Palsies in addition to the normal signs of meningo-encephalitis. Do LP and they get more awake due to ICP decrease from the tap.

Aspergillosis

prolonged neutropenia is usually the cause or prolonged steroids

affects the pulmonary and sinonasal sources

lab tests usually negative, usually diagnosed by nodules on Xray or CT. Can also give hemoptysis. Cultures negative in 50%. Positive predictive value also low, especially in HIV.

AmpoB and possibly surgical treatment

LFABs are superior

Unless rapid recovery of immune function is achieved prognosis is poor

Histoplasmosis

AmphoB, noncritical cases can get itraconazole

Progressive Disseminated-liver disease, anemia, bone marrow effects. Hepatosplenomegaly

Zygomycosis

Ampho B and surgical resection

Coccidiomycosis

cactus=cocci; Arizona and California

50% of pts have reactivation
African and Filipino descent leaads to a greater risk of dissemination
Signs/Symptoms: similar to CAP
Treatment: Ampho B then fluconazole for long term therapy

What Does Isolation of a Fungus from a Culture Mean? How Are Fungal Infections Defined? Fungal pathogens can be isolated under a number of clinical conditions. Isolation of a fungal pathogen without any signs or symptoms of clinical infection is termed colonization. After colonization, Candida are believed to gain access to the bloodstream by three major routes: through the gastrointestinal tract mucosal barrier, from an intravascular catheter, and from a localized source of fungal infection. As many as 5080% of critically ill patients may become colonized at a single site with Candida species during prolonged ICU stay (25, 26, 31, 32). As noted previously, when multiple sites are tested and are negative, the absence of fungal colonization almost ensures that a fungal infection is not present (32). Nosocomial exogenous transmission of Candida and Aspergillus is considered a less frequent but possible mechanism for infection (4548). In a recent study of ICU patients and nurses, 6% of nurses hand cultures contained fungal pathogens, from which 2 of 57 patients with candidemia could be linked with DNA fingerprinting (48). Cross-infection of Candida by hand transmission has been described in several studies (15, 16). Nail contamination in the operating room has been linked to an outbreak of Candida tropicalisinfected sternal wounds (46). Parenteral nutrition has also been identified as a potential source of contamination with infections described with Candida parapsilosis (47). The isolation of Candida from the blood is now universally accepted as constituting a fungal infection (49, 50). The source of candidemia can be from hematogenous spread from a deep-seated infection, from a catheter-related infection, or from gastrointestinal translocation, to name a few. Thus, in a candidemic patient, the clinician must search carefully for potential sources. Common sources would include intravascular catheters, septic thrombophlebitis, and intraabdominal sites. In addition, patients may develop new sources that may have resulted from candidemia, such as endophthalmitis, infective endocarditis, hepatosplenic candidiasis, and arthritis. Although isolation of Candida from sputum is common, pneumonia secondary to Candida infection is rare (5052). The value of deep tracheal suction or even bronchoalveolar lavage in defining this disease should be questioned. Histopathologic confirmation is recommended (50). Laryngeal infection should be considered and can be rapidly progressive in some case reports. The importance and meaning of candiduria has been hotly debated (5355). Kauffman et al. (53) have suggested that candiduria in hospitalized patients is not an important clinical problem. Nassoura et al. (54), however, suggested that in ICU trauma patients, candiduria, when treated with bladder irrigation, was associated with a high rate of dissemination and death, whereas treatment with fluconazole in a small group of similar patients had an improved outcome. Candiduria is very common in hospitalized patients with urinary catheters for >14 days. In most cases, this represents colonization and not infection. However, most of these studies have not included ICU patients. In patients with a urinary catheter for >7 days, 389 of 1,765 patients had candiduria (55). Invasive Candida infections were seen in 105 of the 1,765 patients (5.9%), 48 of whom had candiduria (55). These authors also described a severity-of-illness adjusted increase in mortality in patients with candiduria (odds ratio, 1.58; 95% confidence interval, 1.252.0) (55). Invasion or infection is when a fungal pathogen is isolated from a patient with signs and symptoms of an infection. This definition is, however, too simple to be applied to fungal pathogens, and colonization would be frequently considered infection when it is not. However, no consensus opinion exists for what constitutes a fungal infection in a nonimmunocompromised host (25, 26, 49, 50, 56). However, in neutropenic patients, consensus definitions have been established (57). Fungal infections can be classified into definite and probable. In brief, definite fungal infections with deep-tissue invasion are present when tissue invasion via a biopsy or culture from a sterile site with clinical or radiologic abnormalities is demonstrated. A blood culture has traditionally been the gold standard for the diagnosis of candidemia. A positive blood culture is an indication to start antifungal therapy (49). However, systemic Candida infection may occur in the absence of positive blood cultures. A blood culture has a 50% false-negative rate and can take up to 4 days to yield results. The clinician, however, should not be led to believe that a fungal infection is not present in the absence of a positive blood culture, or tissue biopsy, because nearly 44% of patients with a negative blood culture at autopsy have evidence of disseminated fungal infection (28). No agreement exists as to what signs and symptoms constitute a probable or possible fungal infection in a nonneutropenic patient. At the present time, auxiliary serologic tests such as of fungal wall elements (mannan), D-arabinitol (cell membrane metabolite), enolase (cell cytoplasm), or polymerase chain reaction assays are of limited value (26). These tests have mixed sensitivities and specificities. However, recently, the results of the 1,3 beta glucan measurement for the diagnosis of invasive fungal infection was completed at six centers (58). At a cutoff of 60 pg/mL, the sensitivity and specificity of the assay were 69.9% and 87.1%, respectively, with a positive predictive value of 83.8% and a negative predictive value of 75.1%. At a cutoff value of 80 pg/mL, the sensitivity and specificity were 64.4% and 92.4%, respectively, with a positive predictive value of 89% and an negative predictive value of 73%. Of the 107 patients with proven candidiasis, 81.3% had positive results at a cutoff value of 60 pg/mL, and 77.6% had positive results at a cutoff value of 80 pg/mL. Of the ten patients with aspergillosis, 80% had positive results at cutoff values of 60 and 80 pg/mL. Patients with more unusual fungal pathogens have a similar reasonable positive predictive value and negative predictive value. Active investigation in this area is ongoing, but these early results are promising.

Fungal Infections and Antifungals