# Invasive Fungal Infections - Candida and Aspergillus

## Invasive Candidiasis

### Epidemiology

Candida species represent the fourth most common cause of healthcare-associated bloodstream infections in the United States. Candidemia carries a mortality rate of 30 to 50 percent, with an attributable mortality of approximately 15 to 25 percent. The epidemiology of invasive candidiasis has been shifting, with Candida albicans declining from its historically dominant position though it remains the most common species at approximately 45 to 50 percent of isolates. Non-albicans species are increasing in relative importance, and the current species distribution is approximately C. albicans at 45 percent, C. glabrata at 25 percent, C. parapsilosis at 15 percent, C. tropicalis at 8 percent, C. krusei at 3 percent, and C. auris as a rapidly emerging pathogen.

### Risk Factors for Invasive Candidiasis

The risk factors for invasive candidiasis include central venous catheters, total parenteral nutrition, broad-spectrum antibiotic exposure, prolonged ICU stay, abdominal surgery, necrotizing pancreatitis, immunosuppression, neutropenia, solid organ transplant, and renal replacement therapy. These factors converge in hospitalized patients to create a milieu conducive to both Candida colonization and subsequent invasive disease.

### Candida auris -- Emerging Threat

Candida auris, first identified in 2009 in Japan, has achieved global dissemination and has been designated as an urgent threat by the CDC. The organism demonstrates multidrug resistance, with approximately 90 percent of isolates resistant to fluconazole, 30 percent resistant to amphotericin B, and fewer than 5 percent resistant to echinocandins, though echinocandin resistance is emerging. C. auris demonstrates persistent environmental contamination, surviving on hospital surfaces for weeks and requiring specific disinfection protocols to eradicate. Identification poses a significant challenge, as C. auris is frequently misidentified as C. haemulonii by conventional laboratory methods and requires MALDI-TOF mass spectrometry or molecular identification for accurate speciation. Treatment consists of echinocandins as the first-line agents, with antifungal susceptibility testing guiding therapy, and contact precautions combined with enhanced environmental cleaning are essential for containment.

### Diagnosis

Blood cultures remain the single most common diagnostic method for candidemia but achieve a sensitivity of only 50 to 75 percent. 1,3-beta-D-glucan is a pan-fungal cell wall component with a sensitivity of 65 to 80 percent and a specificity of approximately 80 percent, though it also becomes positive in PCP and aspergillosis and is subject to false-positive results with intravenous immunoglobulin, albumin, surgical gauze, and hemodialysis with cellulose membranes. The T2Candida panel utilizes magnetic resonance-based technology to identify the five most common Candida species directly from whole blood in three to five hours without the need for culture, achieving a sensitivity of 91 percent and specificity of 98 percent. Mannan antigen and anti-mannan antibody testing, used more commonly in Europe, achieves a combined sensitivity of approximately 80 percent. Recovery of Candida from a sterile site such as peritoneal fluid or tissue is considered diagnostic.

<image>A species identification and antifungal susceptibility quick-reference chart for Candida. Create a grid with columns for each major species: C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, and C. auris. Rows should show: typical morphology on CHROMagar (each species has a distinct colony color), fluconazole susceptibility (green for susceptible, yellow for dose-dependent/intermediate, red for resistant), echinocandin susceptibility, amphotericin B susceptibility, and key clinical associations (e.g., C. parapsilosis with CVC, C. krusei with prior fluconazole, C. auris with environmental persistence). Include a note about C. glabrata being dose-dependent susceptible to fluconazole and the need for MIC testing. Use a clean medical reference table with color-coded susceptibility patterns.</image>

### Treatment of Candidemia

| Candida Species | Fluconazole | Echinocandins | Amphotericin B | Preferred Treatment | Key Notes |
|---|---|---|---|---|---|
| C. albicans (~45%) | Susceptible | Susceptible | Susceptible | Echinocandin → step-down fluconazole | Most common species |
| C. glabrata (~25%) | Dose-dependent | Susceptible | Susceptible | Echinocandin (continue unless FLU MIC ≤8) | Do not assume fluconazole susceptibility |
| C. parapsilosis (~15%) | Susceptible | Higher MICs | Susceptible | Fluconazole preferred if susceptible | Associated with CVCs |
| C. tropicalis (~8%) | Susceptible | Susceptible | Susceptible | Echinocandin → step-down fluconazole | Virulent; common in neutropenia |
| C. krusei (~3%) | Intrinsically resistant | Susceptible | Susceptible | Echinocandin or voriconazole | Selected by prior fluconazole use |
| C. auris (emerging) | ~90% resistant | Susceptible (resistance emerging) | ~30% resistant | Echinocandin; check susceptibilities; CDC consult | MDR; environmentally persistent; MALDI-TOF needed |

The IDSA 2016 guidelines establish echinocandins as the first-line treatment for candidemia. Caspofungin is dosed with a 70 milligram intravenous loading dose followed by 50 milligrams intravenously daily. Micafungin is administered at 100 milligrams intravenously daily without a loading dose. Anidulafungin is given as a 200 milligram intravenous loading dose followed by 100 milligrams intravenously daily.

Step-down to fluconazole at 400 milligrams (6 milligrams per kilogram) intravenously or orally daily is appropriate for susceptible species, particularly C. albicans and C. parapsilosis, after clinical improvement has been achieved, species identification and susceptibility have been confirmed, and repeat blood cultures are negative. C. glabrata is intrinsically dose-dependent susceptible to fluconazole, and echinocandin therapy should be continued unless the fluconazole MIC is confirmed at 8 or below and the patient is stable. C. krusei is intrinsically fluconazole-resistant, and treatment should consist of an echinocandin or voriconazole. C. parapsilosis may have higher echinocandin MICs, and fluconazole is often preferred if the organism is susceptible, a nuance acknowledged in the IDSA guidelines. C. auris should be treated with an echinocandin as first-line therapy, with susceptibilities checked and CDC consultation recommended.

### Duration and Management Principles

The duration of treatment for candidemia is 14 days from the first negative blood culture, not from the first positive culture. Blood cultures should be repeated every 24 to 48 hours until clearance is documented. Central venous catheters should be removed whenever feasible, especially non-tunneled CVCs, as removal reduces both treatment failure and time to clearance. An ophthalmologic examination with dilated fundoscopy is mandatory for all patients with candidemia, as endophthalmitis occurs in 2 to 16 percent of cases and may be more common in neutropenic patients after neutrophil recovery. Echocardiography should be considered, as although the yield of TTE is low, Candida endocarditis carries extremely high mortality if missed. Metastatic complications including endophthalmitis, endocarditis, osteomyelitis, and hepatosplenic candidiasis in recovering neutropenic patients must be actively evaluated.

## Invasive Aspergillosis

### Epidemiology and Risk Factors

Aspergillus fumigatus is the most common species responsible for invasive aspergillosis, accounting for approximately 70 percent of cases, followed by A. flavus, A. niger, and A. terreus. The classic risk groups include patients with prolonged neutropenia such as those undergoing AML induction chemotherapy, allogeneic HSCT recipients particularly those with graft-versus-host disease, solid organ transplant recipients with lung transplant carrying the highest risk, patients receiving high-dose corticosteroids, and those with chronic granulomatous disease. An emerging and increasingly recognized risk group consists of ICU patients with influenza or COVID-19, with COVID-associated pulmonary aspergillosis reported at an incidence of 5 to 30 percent among severe COVID ICU patients. Mortality from invasive aspergillosis ranges from 30 to 50 percent with treatment and exceeds 90 percent without treatment, with worse outcomes seen in disseminated disease or CNS involvement.

### Clinical Syndromes

Invasive pulmonary aspergillosis is the most common form of invasive disease, presenting as persistent fever despite broad-spectrum antibiotics in a neutropenic patient, accompanied by cough, pleuritic chest pain, and hemoptysis. Tracheobronchial aspergillosis represents invasive airway disease and is particularly common in lung transplant recipients. CNS aspergillosis results from hematogenous dissemination, produces ring-enhancing lesions on imaging, and carries a very high mortality exceeding 80 percent. Invasive fungal sinusitis occurs in neutropenic and immunosuppressed patients and manifests with tissue necrosis of the nasal turbinates and palate.

### Diagnosis

High-resolution CT of the chest is the cornerstone of imaging diagnosis. The halo sign, consisting of ground-glass opacity surrounding a pulmonary nodule, represents hemorrhage surrounding infarcted tissue and is an early finding seen in neutropenic patients. The air crescent sign, a crescent of air within a cavitating nodule, is a later finding observed during neutrophil recovery. Nodules and wedge-shaped infarcts are additional CT features. Serum galactomannan, an Aspergillus cell wall component, achieves a sensitivity of 70 to 80 percent in patients with hematologic malignancy or HSCT but a lower sensitivity of approximately 30 percent in solid organ transplant recipients, with a specificity of 85 to 95 percent. Serial monitoring is useful for tracking treatment response. False-positive results have been reported with piperacillin-tazobactam in older formulations and with amoxicillin-clavulanate. BAL galactomannan achieves higher sensitivity at 80 to 90 percent, with an optical density index cutoff of 1.0 or above. 1,3-beta-D-glucan is positive in aspergillosis but is nonspecific. Aspergillus PCR from blood or BAL has an increasing role in diagnosis, with standardized assays now available that are used in combination with galactomannan testing. Tissue biopsy and culture provide the definitive diagnosis, revealing septate hyphae with 45-degree angle dichotomous branching, which must be distinguished from the ribbon-like, pauciseptate, 90-degree branching pattern of Mucorales. Culture produces growth in three to seven days, and species identification is important because A. terreus is intrinsically resistant to amphotericin B.

<image>A diagnostic imaging and pathology comparison for invasive aspergillosis. Panel 1: "CT chest - Halo sign" showing a pulmonary nodule surrounded by ground-glass opacity (ground-glass halo) with labels explaining this represents hemorrhage around the infarcted tissue, seen early in neutropenic patients. Panel 2: "CT chest - Air crescent sign" showing a cavitating nodule with an air crescent visible between the necrotic fungal ball and the cavity wall, seen during neutrophil recovery. Panel 3: "Histopathology (GMS stain)" showing septate hyphae with 45-degree angle dichotomous branching invading tissue, compared to a smaller inset showing Mucorales (ribbon-like, pauciseptate, 90-degree branching) for contrast. Panel 4: "Sinus CT" showing opacification with bony erosion of a paranasal sinus in invasive fungal sinusitis. Use medical imaging and histopathology conventions with appropriate staining colors.</image>

### Treatment of Invasive Aspergillosis

Voriconazole is the first-line agent for invasive aspergillosis per the IDSA 2016 guidelines. Intravenous loading consists of 6 milligrams per kilogram every 12 hours for two doses, followed by 4 milligrams per kilogram intravenously every 12 hours. Oral dosing is 200 to 300 milligrams orally every 12 hours with therapeutic drug monitoring. TDM is mandatory with voriconazole, targeting a trough of 1.0 to 5.5 micrograms per milliliter, as levels below 1.0 are associated with treatment failure while levels above 5.5 are associated with neurotoxicity and hepatotoxicity. CYP2C19 polymorphisms affect voriconazole metabolism, with poor metabolizers accumulating high trough levels and ultrarapid metabolizers potentially achieving subtherapeutic concentrations.

Isavuconazole, administered as isavuconazonium sulfate, represents an alternative first-line agent. Loading consists of 200 milligrams intravenously or orally every eight hours for six doses, followed by 200 milligrams daily. Isavuconazole offers several advantages over voriconazole including the absence of visual disturbances, no phototoxicity, no QTc prolongation (it actually shortens the QTc), fewer drug interactions, and no concerns regarding the intravenous cyclodextrin vehicle in renal impairment. The SECURE trial demonstrated non-inferiority of isavuconazole compared to voriconazole for invasive aspergillosis. TDM for isavuconazole is less well established but a trough above 1 microgram per milliliter is recommended.

Liposomal amphotericin B at 3 to 5 milligrams per kilogram per day serves as second-line therapy for azole-refractory disease or azole intolerance, but it is not effective against A. terreus due to intrinsic resistance.

Echinocandins are not recommended as monotherapy for aspergillosis because they are fungistatic rather than fungicidal against Aspergillus. Their role as salvage combination therapy with voriconazole remains controversial, and routine combination therapy is not recommended following the negative results of the Marr 2015 trial.

### Duration

Treatment should continue for a minimum of 6 to 12 weeks, extending until resolution of immunosuppression and radiographic improvement. Transition to oral voriconazole or isavuconazole should occur when the patient is clinically stable and tolerating oral intake.

### Antifungal Prophylaxis

Posaconazole at 300 milligrams intravenously or orally daily, with a loading dose of 300 milligrams twice on day one, is the standard prophylactic agent for patients undergoing AML induction chemotherapy and allogeneic HSCT recipients with GVHD, as demonstrated by the Cornely 2007 trial in AML and the Ullmann 2007 trial in GVHD. Posaconazole TDM targets a trough above 0.7 micrograms per milliliter for prophylaxis and above 1.25 micrograms per milliliter for treatment. In solid organ transplant, particularly lung transplant, voriconazole or itraconazole is used according to institution-specific protocols. Micafungin serves as an alternative for prophylaxis in HSCT recipients who cannot tolerate azole therapy.

## Azole Resistance in Aspergillus

### Environmental Resistance

Azole resistance in Aspergillus is mediated primarily by mutations in the cyp51A gene, which encodes the target of ergosterol synthesis. The two most important resistance-conferring mutations are TR34/L98H and TR46/Y121F/T289A, which are driven by environmental exposure to agricultural triazole fungicides belonging to the same drug class as medical azoles. The prevalence of environmental azole resistance reaches 5 to 25 percent in parts of Europe, particularly the Netherlands, and is emerging globally. The clinical impact of these mutations includes resistance to voriconazole and itraconazole, leading to treatment failure. Antifungal susceptibility testing on all clinical Aspergillus isolates is recommended in regions with high rates of azole resistance.

<image>A comprehensive treatment algorithm for invasive aspergillosis. Start with "Suspected invasive aspergillosis (neutropenic fever unresponsive to antibiotics, high-risk host)." Diagnostic workup: "CT chest (HRCT), serum galactomannan, BAL galactomannan and culture (if feasible), beta-D-glucan." Confirmed or probable IA: "Start voriconazole (6 mg/kg IV q12h x2 then 4 mg/kg q12h) with TDM target trough 1-5.5 mcg/mL." Alternative pathway: "Isavuconazole if voriconazole contraindicated or not tolerated (QTc, visual, hepatic)." Assessment at 1-2 weeks: "Clinical and radiographic response?" If yes: "Continue voriconazole, switch to oral when stable, minimum 6-12 weeks, continue until immunosuppression resolves." If no: "Consider: check voriconazole levels, evaluate for resistant Aspergillus, switch to liposomal amphotericin B (3-5 mg/kg/day), consider surgical debridement." Sidebar: "A. terreus: avoid amphotericin B (intrinsic resistance)." Use a clinical decision tree format.</image>

## Key Clinical Pearls

- Echinocandins are first-line for candidemia -- always start with an echinocandin before susceptibilities are known (broadest reliable Candida coverage)
- Remove central venous catheters in ALL candidemia patients when feasible -- delays in removal increase mortality
- Every candidemia patient needs a dilated ophthalmologic exam to rule out endophthalmitis
- Voriconazole requires therapeutic drug monitoring (trough 1-5.5 mcg/mL) -- subtherapeutic levels cause treatment failure, supratherapeutic levels cause toxicity
- Isavuconazole is non-inferior to voriconazole for invasive aspergillosis with a more favorable side effect profile (no visual disturbances, no phototoxicity)
- C. auris is an emerging global threat: multidrug-resistant, environmentally persistent, and difficult to identify without MALDI-TOF
- The halo sign on CT is an EARLY finding in invasive pulmonary aspergillosis (within first week in neutropenic patients) -- do not wait for cavitation to make the diagnosis
- Posaconazole prophylaxis reduces invasive aspergillosis and mortality in high-risk patients (AML induction, GVHD)

## References
1. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the IDSA. *Clin Infect Dis*. 2016;62(4):e1-e50.
2. Patterson TF, Thompson GR III, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the IDSA. *Clin Infect Dis*. 2016;63(4):e1-e60.
3. Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease (SECURE). *Lancet*. 2016;387(10020):760-769.
4. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. *N Engl J Med*. 2007;356(4):348-359.
5. Satoh K, Makimura K, Hasumi Y, et al. Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal. *Microbiol Immunol*. 2009;53(1):41-44.