Fungal Infections and Antifungals
Treatment of Invasive Candida
How to Select an Anti-Fungal Agent
Best Review of Dx and Treatment of Candida
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.
from Curbsiders
- Risk factors for invasive fungal infections include surgeries that transect the gut wall, presence of central venous catheters, receiving broad spectrum antibiotics, total parenteral nutrition, mucositis, neutropenia, transplant recipient, or otherwise being immunocompromised (Poissy 2020; Li 2017).
- Regular aerobic blood cultures will detect candida in most cases (Nawrot 2015) . However, in suspected intra-abdominal candidiasis, however, we might miss 50% of cases or more with blood culture alone(Lamoth 2020).
- While Candida albicans, krusei, glabrata are commensals of the human GI tract, Candida auris is actually found as part of skin flora (Ahmad 2021). As such, C auris is more associated with contact-related spread and extensive resistance.
- Per Dr. Schwartz, HIV-associated PJP is typically a protracted illness, with a subacute to chronic presentation. In patients with non HIV-associated PJP, the presentation tends to be more acute, with more tendency towards rapid progression.
- Expert pearl from Dr. Schwartz: If a patient is immunocompromised and feels breathless, but they are not hypoxic, that dramatically reduces your pre-test probability for PJP.
Adding antifungal coverage is often discussed when patients sicken without clear cause as physicians delve into ‘spiraling empiricism.’ Dr. Schwartz reports the most common invasive fungal infection we encounter is invasive candidiasis (Perlroth 2007; Wen 2022). Generally, fungal infections occur in medically and surgically complex patients. Risk factors for invasive fungal infections include surgeries that transect the gut wall, presence of central venous catheters, receiving broad spectrum antibiotics, total parenteral nutrition, mucositis, neutropenia, transplant recipient, or being immunocompromised (Poissy 2020; Li 2017). In Dr. Schwartz’s expert opinion, you may consider empiric antifungal treatment if a patient is decompensating, while already being on broad spectrum antibiotics, with at least one of the aforementioned risk factors. He also recommends a low threshold to consult your Infectious Disease team in these cases.
Starting Empiric Treatment
If you’re worried about invasive fungal infections, Dr. Schwartz recommends obtaining blood cultures and considering a CT chest if you’re concerned about a mold infection. The first line treatment for invasive candidiasis is an echinocandin such as caspofungin or micafungin (IDSA 2016). For a suspected mold infection, the first line treatment would be liposomal amphotericin B (Cornely 2007) until you can exclude mucormycosis. In aspergillosis (the most common cause of invasive mold infections), a mold-active azole, such as voriconazole or posaconazole, is preferred (Smith 2022).
Uh Oh, Mucormycosis!
Another concerning clinical scenario to be aware of on overnight call is mucormycosis. There are two main types: 1) Rhino-orbito-cerebral mucormycosis is seen in patients with poorly controlled diabetes, usually in the setting of hyperglycemia or DKA (Prakash 2019, Husain 2017). Symptoms include facial edema with pain, dusky skin on the sinus region/periorbital, severe rhinorrhea, dental pain, tooth loosening, and altered mental status refractory to insulin treatment. Eschars can also be noted on the skin or in the mouth or nares. This is a surgical emergency as well and would require ENT consultation and potentially Neurosurgery involvement (Cornely 2019). 2) Pulmonary and disseminated mucormycosis is seen in immunocompromised patients, typically with hematological malignancies like acute myelogenous leukemia (AML) or after allo-stem cell transplantation (Prakash 2019). It can be more difficult to diagnose, requiring bronchoscopy samples for fungal cultures, or biopsy of affected tissue like skin lesions. In addition to surgery to resect infected and necrotic tissue, the mainstay of antifungal treatment is liposomal amphotericin B (Cornely 2019).
Testing Basics And…What’s The Deal with Fungal Blood Cultures?
Direct Testing
With regards to testing, Dr. Schwartz differentiates direct (detecting organisms via culture, PCR) versus indirect (biomarkers) testing. Regular aerobic blood cultures will detect Candida in most cases (Nawrot 2015). However, in suspected intra-abdominal candidiasis, we might miss upwards of 50% of cases with blood culture alone (Lamoth 2020). Fungal blood cultures use centrifugation and lysis to break down the macrophages to improve recovery of intracellular organisms (Kosmin 2008). Theoretically, this methodology could have better yield for cases when you’re concerned with an intracellular organism like Histoplasma (or the non-fungal bad actor tuberculosis.) But most fungal organisms are extracellular as well as intracellular so they will come positive from just regular blood cultures, per Dr. Schwartz. PCR for different fungi can be done on tissue samples or BAL, but availability is variable.
Indirect Testing
Beta-D-glucan is an indirect test that assesses for a polysaccharide present on the cell wall of many fungi and may detect fungi such as as pneumocystis, candidiasis, and aspergillosis (Morjaria 2019, Lamoth 2021). But not all fungi have beta-D-glucan – mucorales, cryptococcus, and blastomycosis do not have detectable levels (Theel, 2013). False positives can occur from ECMO circuits, dialysis, even severe sepsis (Kanda 2001, Albert 2001, Fekkar 2021). Per Dr. Schwartz, anything that causes transient translocation of fungus across the gut can cause a positive result that might not be clinically significant (Mikulska 2021). Antibiotics have also been associated with false positives (Liss 2016).
Aspergillus galactomannan is another indirect test, which measures a sugar also found on cell walls. It is not just found on Aspergillus but also other fungi including Fusarium and Histoplasma (Min 2012, Tortorano 2012). It can be detected in serum for patients with invasive aspergillosis (Hites 2016) and is particularly useful in patients with profound immunodeficiencies (such as AML, other hematologic malignancies) (Cordonnier 2008). Per Dr. Schwartz, serum galactomannan is less sensitive in patients with solid organ transplants and other immunosuppression (e.g., chronic steroid use in COPD) (Miceli 2016).
Certain types of candidiasis are increasing in prevalence (Ricotta 2021). Risk factors include presence of central venous catheters, receiving broad spectrum antibiotics, total parenteral nutrition, mucositis, neutropenia, and surgeries that transect the gut wall (Pappas 2018). It is typical for blood cultures to take several days to return positive for yeast. If you have candidiasis, it is important to assess the persistence of infection, so blood cultures need to be collected everyday to every other day. It is common for people to remain candidemic for days, especially if a central venous catheter remains in place. Catheter removal is mandatory and should occur as soon as feasible (IDSA 2016).
Echocardiography should be obtained in all patients with persistent candidemia to rule out fungal endocarditis (Fernández-Cruz 2015). Ophthalmologic examination is an important component too. IDSA recommends obtaining an ophthalmologic exam within 7 days in all non-neutropenic patients with candidemia, and within 7 days of neutrophil recovery in neutropenic patients with candidemia (IDSA 2016). If endophthalmitis is present, the treatment is longer (usually 21 days minimum), usually with fluconazole (which penetrates the eyes better than echinocandins) and patients require intravitreal administration of voriconazole. If missed, fungal endophthalmitis can cause blindness.
Hungry for More Mycoses?
Dr. Schwartz recommends checking out https://funguseducationhub.org/ and https://drfungus.org/ for more insight into the weird and wonderful world of fungal infections.
Another excellent resource is the European Confederation of Medical Mycology (ECMM) which has a lot of additional information, including guidelines and score cards for many common fungal diseases, that allows you to ensure compliance according to best practices.