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Dr. Ilan Schwartz MD PhD (@GermHunterMD) teaches us that we should always at least consider fungi in the differential diagnosis of unexplained sepsis, especially in patients with impaired immune systems or complex medical or surgical histories, and walks us through an approach to antifungals. Be sure to check out the Mycoses Study Group Education & Research Consortium (@MSG_ERC), an organization of clinicians who are dedicated to advancing diagnostics and treatment of fungal disease (where Dr. Schwartz serves on the board of directors!) Claim CME for this episode at curbsiders.vcuhealth.org!
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).
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?
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.
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).
Basics of Candidemia
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.
Fungal endocarditis only makes up a small portion of infective endocarditis cases (3-5%) but they are very hard to manage without cardiovascular surgery (Thompson 2023). The medical treatment is usually a very long course of antifungals, such as echinocandin (which gets decent biofilm penetration) with eventual transition to an azole drug such as fluconazole (Thompson 2023). Treatment duration for fungal endocarditis is usually at least 6 weeks after surgery, and treatment might need to be indefinite if surgery is not performed, especially if a prosthetic valve is involved (IDSA 2016; Thompson 2023).
Candida albicans is the species most likely to cause invasive candidiasis. But it is usually susceptible to fluconazole. Candida krusei is one which can be challenging to treat because it is resistant to fluconazole (Pfaller 2008). C. glabrata is also one with increasing resistance: it is less susceptible to fluconazole (requiring higher dosing) and can be resistant to echinocandins up to 10% of the time (Kumar 2019). Candida auris is a different beast altogether, says Dr. Schwartz. It is spreading around the globe but is not yet everywhere. While C. albicans, krusei, glabrata are commensals of the human GI tract, C. auris colonizes the skin (Ahmad 2021). As such, C. auris is more associated with contact-related spread. It can also form biofilms in the environment which can be challenging to remove with standard disinfectants (Ahmad 2021). On top of all this, it is highly resistant to antifungal agents, including our most potent antifungals medicines. Check out this NEJM article about a Candida auris outbreak.
Pneumocystis jiroveci pneumonia
Features of Pneumocystis jiroveci pneumonia (PJP) include dry cough and hypoxia (Thomas 2004). PJP was initially described in patients with advanced HIV but we can also see PJP in patients who have T-cell immunosuppressive therapies, including patients with organ transplantation, hematopoietic stem cell transplantation (Thomas 2004). Generally, patients considered high-risk are advised to receive prophylaxis and this is highly effective at reducing rates of PJP (Stern 2014). Daily prednisone equivalent of 20mg for at least a month is considered the general threshold for immunosuppression where we might be concerned about PJP, per Dr. Schwartz but generally, those patients should be receiving TMP-SMX prophylaxis (Zhou 2023). Cyclophosphamide use is also a red flag for concern for PJP, as those patients are not always receiving prophylaxis (Schmajuk 2018). Dr. Schwartz reports breakthrough infections do occur but they are rare and they tend to occur in patients who are not on the first-line agent for PJP prophylaxis (ie: drug sensitivity to TMP-SMX).
Per Dr. Schwartz, HIV-associated PJP is typically a more protracted illness, with a subacute to chronic presentation (over months). In patients with non HIV-associated PJP, the presentation tends to be more acute (over weeks), with more tendency towards rapid progression. Expert pearl from Dr. Schwartz: If an immunocompromised patient has chest imaging changes, the absence of hypoxia dramatically reduces your pre-test probability for PJP.
First line treatment is high-dose TMP-SMX, with approx. 15 mg/kg of TMP. Side effects include hyperkalemia and bone marrow suppression. Also of note, TMP-SMX predictably causes creatinine to rise because it blocks tubular creatinine secretion but does not reduce GFR.
Hungry for More Mycoses?
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.
Listeners will gain an understanding of fungal disease and its manifestations as well as an appropriate work-up and management.
After listening to this episode listeners will…
Dr. Schwartz reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.
Garbitelli BC, Schwartz IS, Williams PN, Watto MF. “#416 Antifungals, Candida, Mucorales, Aspergillus, Pneumocystis: The Fungus Among Us with Dr. Ilan Schwartz MD”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast November 20, 2023.
Producer, Writer, Show Notes, Infographic/Cover Art: Beth Garbitelli MD
Hosts: Matthew Watto MD, FACP; Paul Williams MD, FACP, Beth Garbitelli MD
Reviewer: Emi Okamoto MD
Showrunners: Matthew Watto MD, FACP; Paul Williams MD, FACP
Technical Production: PodPaste
Guest: Ilan Schwartz MD, PhD
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