Candidiasis in Emergency Medicine

The Candida fungus is both normal flora and an invasive pathogen. The range of infection with Candida species varies from a benign local mucosal membrane infection to disseminated disease. Severe disease is typically associated with an immunocompromised state, which includes patients who are vulnerable to iatrogenic pathogens in the intensive care unit (ICU) or those with predisposing immunologic conditions such as malignancy, organ dysfunction, or immunosuppressive therapy.

Rash due to candidiasis is shown in the images below.

Candidiasis. Image courtesy of Hon Pak, MD.

Candidiasis. Erythema, maceration, and satellite pustules in the axilla, accompanied by soreness and pruritus, result in a form of intertrigo. Image courtesy of Matthew C Lambiase, DO.

Candida is a unicellular yeast whose cells reproduce by budding. This organism can flourish in most environments. It frequently colonizes the oropharynx, skin, mucous membranes, lower respiratory tract, gastrointestinal tract, and genitourinary tract. Pathogenesis occurs with increased fungal burden and colonization, such as in the setting of broad-spectrum antimicrobial therapy; breakdown of normal mucosal and skin barriers, which can occur with indwelling intravascular devices or with recent surgery/trauma or tissue damage secondary to chemotherapy or radiation; or immune dysfunction secondary to disease states or iatrogenic conditions.

Candidiasis is the most common opportunistic fungal infection. Disease manifestations of candidal infection can vary by type of host immunodeficiency. Lymphocytes and cell-mediated immunity are important in the prevention of mucosal candidiasis. Therefore, patients with T-cell deficiency, such as those with human immunodeficiency virus (HIV), have a propensity to develop recurrent and/or persistent mucocutaneous candidiasis. Patients with neutropenia are at risk for invasive candidiasis and candidemia, as functioning monocytes and polymorphonuclear cells are responsible for killing pseudohyphae and blastospores. Complement and immunoglobulins are necessary for intracellular killing of the organisms, and patients with these deficiencies can have a more prolonged and complicated course of candidal infection.

Frequency

United States

Candida is the third or fourth most common cause of nosocomial bloodstream infection in the United States, accounting for 8%-10% of all bloodstream infections.[1]

Invasive candidiasis is the most common invasive fungal infection in the United States, accounting for 70%-90% of all invasive fungal infections.[1] There is an increasing shift toward infections caused by non-albicans Candida species, which now cause 40%-60% of reported cases.

International

In Europe, Candida species are the sixth to tenth most common cause of bloodstream infections.[1]

Candida species distribution varies from country to country in Europe; however, Candida glabrata and Candida parapsilosis tend to be the most common isolates after Candida albicans in invasive candidiasis.[2]

Invasive candidiasis is still most commonly due to C albicans in Latin American countries; however, unlike in North America, C parapsilosis is the second most common Candida species in many Latin American countries. Furthermore, Candida tropicalis infection has also increased in frequency.[3]

In one study, non-albicans Candida accounted for 70% of candidemia cases in a northern Indian pediatric ICU. Isolated Candida species included C tropicalis (48.4%), C albicans (29.7%), Candida guilliermondii (14.1%), C krusei (6.3%), and C glabrata (1.6%).

C glabrata and C krusei have been identified as common causes of candidemia in patients with hematologic malignancies.[4]

C parapsilosis has been identified as the leading cause of candidemia secondary to medical instrumentation such as with central venous catheters, prosthetic devices, and nosocomial spread.[5]

C dubliniensis has been identified in an immunocompromised patient with multifocal osteomyelitis in Germany[6] and in a patient with meningitis in Australia.[7]

Fungal keratitis is more prevalent in the tropics; therefore, Candida accounts for proportionately more fungal corneal isolates at temperate latitudes.

Mortality/Morbidity

Invasive candidiasis has a mortality rate of 40%-50% and is associated with prolonged hospitalization.

Outcomes of candidemia in neonates and children demonstrate significant morbidity and mortality, with one study reviewing over 1000 hospitalized pediatric patients showing a 10% higher rate of mortality when compared to matched controls without candidemia.[8]

Risk factors for invasive candidiasis include colonization of body sites with Candida, prolonged ICU stay, broad-spectrum antibiotic use, intravascular access devices, diabetes mellitus, parenteral nutrition, mechanical ventilation, renal insufficiency, surgery, acute necrotizing pancreatitis, and treatment with corticosteroids.[1]

Risk factors for death or poor prognosis include advanced age, failure to remove central lines, malnutrition, and non-albicans fungemia.

Race

Candida infection has no racial predilection.

Sex

Three quarters of all women experience at least one episode of vulvovaginal candidiasis in their lifetime, and about one half of these women experience a recurrence.

Age

Populations at high risk for candidal infection include elderly persons with high Acute Physiology and Chronic Health Evaluation (APACHE) II scores and neonates with low gestational age, low APGAR scores, and congenital malformations.

The incidence of invasive candidiasis is higher among infants (< 1 year) and adults older than 70 years.[2]

Candidal infection has a wide range of clinical manifestations, from self-limited local mucocutaneous disease to severe sepsis with multiorgan system failure.

Local mucous membrane infections

Oral candidiasis, also referred to as thrush, is characterized by creamy-white curd-like patches on the tongue and oral mucosa. These patches are a pseudomembrane of Candida, desquamated epithelial cells, leukocytes, bacteria, keratin, necrotic tissue, and food debris. Chronic atrophic candidiasis, or denture sore mouth, is a chronic inflammatory reaction with epithelial thinning under dental plates. Saliva usually protects oral mucosa against Candida, while dry mouth increases yeast counts. Dentures also create a reservoir for Candida to incorporate into the biofilm covering the material and increase the risk of invasive candidiasis, especially in immunocompromised persons.

Candidal leukoplakia consists of firm white plaques on the cheeks, lips, and tongue that frequently have a protracted course and can be precancerous. Angular cheilitis is characterized as erythema and fissuring at the corners of the mouth.

Risk factors for oral infection include antibiotic use, immunodeficiency (up to 90% of untreated HIV-positive persons have a symptomatic episode of oropharyngeal candidiasis sometime during progression to AIDS), xerostomia, inhaled corticosteroids, and denture use. Symptoms include dry mouth, loss of taste, and, occasionally, pain with eating.

Candidiasis. White plaques are present on the buccal mucosa and the undersurface of the tongue and represent thrush. When wiped off, the plaques leave red erosive areas. Image courtesy of Matthew C Lambiase, DO.

Candida epiglottitis is another entity that can develop in immunocompromised persons. It may exist as a co-infection with bacterial organisms or on its own. A KOH preparation and fungal cultures may be helpful in identifying candidal epiglottitis that would not be expected to improve with antibiotics alone.[9]

Candida esophagitis is most commonly associated with treatment of hematopoietic or lymphatic malignancies. It is also an AIDS-defining illness, although cases of Candida esophagitis without underlying illness have been reported. Symptoms include dysphagia, sensation of obstruction upon swallowing, retrosternal chest pain, nausea, and vomiting. Definitive diagnosis is made with endoscopic biopsy. On endoscopy, white plaques similar to thrush may be present; ulcerations, pseudomembrane formation, and diverticula may also be seen. Candidal esophagitis can occur concomitantly with herpes simplex virus (HSV) and cytomegalovirus (CMV) infection in severely immunocompromised persons.

Other locations of the gastrointestinal tract are often infected with Candida. Lesions may be found in the stomach and small and large intestines, most commonly in patients with neoplastic disease. Candidal cholecystitis is also a possible location of infection and has been reported in a patient without any history of underlying malignancy.[10]

Candidal vaginitis is the most common form of mucosal candidiasis. Vulvovaginal candidiasis is usually secondary to overgrowth of normal flora Candida species in the vagina. Bacteria such as Lactobacillus acidophilus balance Candida and prevent yeast overgrowth and pathogenic infection. Conditions that disrupt the balance of normal vaginal flora include antibiotic use, oral contraceptives, contraceptive devices, high estrogen levels, and immunocompromised states such as in diabetes mellitus and HIV infection. Another risk factor for vulvovaginal candidiasis may be intrauterine contraceptive devices.[11]

Of vulvovaginal candidiasis cases, 70%-90% are caused by C albicans, while the remainder of infections are caused by C glabrata and C tropicalis. Symptoms are typically described as pruritus, vaginal irritation, and dysuria. Thick curd-like discharge is often present, but scant discharge may also characterize infection. Vaginal edema and erythema are also often present on examination.

Epidemiologically, vaginal Candida infections are important, as they may increase viral shedding in HIV-infected women.

Cutaneous candidiasis syndromes include the following:

• Generalized cutaneous candidiasis: This infection affects persons of any age and is characterized by widespread eruptions with increased severity in the genitocrural folds, anal region, axillae, and hands and feet.

• Erosio interdigitalis blastomycetica: This is an infection of the web spaces between digits, which is predisposed to maceration.

• Candida folliculitis: This is most frequently seen in immunocompromised hosts and among intravenous drug users.

• Candida balanitis: Rash typically begins as vesicles on the penis that develop into patches similar in appearance to thrush (shown in the image below). Extension may occur to the scrotum and buttocks. Symptoms include burning and pruritus. C glabrata has been implicated as the cause of Fournier gangrene in an immunocompromised patient.[12]

  Candidiasis. Dry, red, superficially scaly, pruritic macules and patches on the penis represent candidal balanitis. Image courtesy of Matthew C Lambiase, DO.

• Mammary candidiasis: This is a condition that can affect breastfeeding women, with both cutaneous and local ductal inflammatory manifestations.[13]

• Intertriginous infections: These develop in sites where skin surfaces are close in proximity, such as the axilla or anogenital region. Lesions begin as vesicopustules that enlarge, rupture, and develop maceration and fissuring. Satellite lesions may also be present. A variant form of cutaneous candidiasis in the intertriginous region has a miliary appearance.

• Candidal paronychia: This is associated with frequent hand immersion in water and diabetes mellitus.

• Diaper rash: Skin irritation is exacerbated by wet diapers (shown in the image below).

  Candidiasis. A moist, erosive, pruritic patch of the perianal skin and perineum (with satellite pustule formation) is demonstrated in this woman with extensive candidosis. Image courtesy of Matthew C Lambiase, DO.

• Perianal candidiasis: Skin maceration and pruritus are common, with frequent extension to the perineum.

• Onychomycosis: Candida species are the most common fungal cause of this nail disease.[14] An example of this infection is shown in the image below.

  Candidiasis. A nailfold with candidal infection becomes erythematous, swollen, and tender with an occasional discharge. Image courtesy of Matthew C Lambiase, DO.

Chronic mucocutaneous candidiasis is a term used to describe a heterogeneous group of Candida infections of the skin, mucous membranes, hair, and nails, which has a protracted course despite typical therapy. It is associated with T-cell lymphocyte dysfunction. A specific subset of individuals with this phenomenon have autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED) syndrome with associated endocrine disorders.

Invasive candidal infections

Invasive candidiasis is a term used to describe severe and invasive disorders that include candidemia, disseminated candidiasis, deep organ involvement, endocarditis, endophthalmitis, and meningitis. Invasive infection is also described as the isolation of Candida from a normally sterile body site, including blood, peritoneal fluid, pleural fluid, intra-articular fluid, or cerebrospinal fluid (CSF).

Risk factors for invasive candidiasis include prolonged ICU stay (incidence peaks around day 10), presence of a central venous catheter, acute renal failure, treatment with broad-spectrum antibiotics, parenteral nutrition, high APACHE II scores, diabetes, immunosuppressive therapy, surgery (especially upper gastrointestinal tract), hemodialysis, pancreatitis, malignancy, transplantation, and organ dysfunction.[15]

Skin manifestations of disseminated candidiasis include clusters of painless pustules on an erythematous base on any area of the body. These lesions may be macular or pustular or may have central necrosis.

Acute disseminated candidiasis, or hepatosplenic candidiasis, is most commonly seen in patients with hematologic malignancy who recently had an episode of neutropenia. Symptoms include fever, right upper quadrant pain, and tender hepatosplenomegaly. Multiple organs are frequently involved, and discrete persistent microabscesses occur in the liver, spleen, and kidneys. A palpable erythematous rash may be present, indicating evidence of small-vessel vasculitis. The presumed etiology is a prior episode of candidemia, although invasion through portal vasculature has been theorized.

Central nervous system (CNS) candidiasis usually occurs as a complication of hematogenously disseminated candidiasis. Candida typically forms multiple microabscesses and small macroabscesses scattered throughout the brain.[16] Patients with Candida meningitis usually have meningeal irritation and CSF pleocytosis. Untreated, the mortality rate is high. Intraventricular drains increase risk of CNS candidal infection.

Candidal pneumonia occurs rarely as bronchopneumonia originating from endobronchial inoculation, its etiology is more commonly from hematogenous seeding and presents as nodular and diffuse infiltrates. This presentation may be difficult to distinguish from congestive heart failure, acute respiratory distress syndrome (ARDS), or Pneumocystis pneumonia. Diagnosis is also complicated by the inability to confirm that positive cultures are not an oropharyngeal contaminant or colonization. Candida empyema cases have also been documented.[17]

Candida can infect both the pericardium and myocardium, and these infections are usually associated with disseminated disease. Candidal pericarditis is rare but fatal without treatment and has been known to cause tamponade. Infective endocarditis with Candida is usually seen in patients with a chronic indwelling intravenous catheter or large-caliber hemodialysis catheter. Other risk factors include congenital cardiac abnormalities, prosthetic valves, and intravenous illicit drug use. Fungal vegetations are often large and more frequently associated with embolic events. The mortality rate is approximately 45% with combined medical and surgical therapy.

Urethral candidiasis can occur in both men and women. In women, it is commonly secondary to an extension of Candida vaginitis. In men, it is usually secondary to sexual contact with women with vaginitis. Invasive infections of the bladder and kidneys can occur, typically in immunocompromised patients secondary to hematogenous spread. This hematogenous spread can also lead to acute renal infarction secondary to the infiltration of the renal parenchyma and occlusion of the hilar vessels.[18]

Ocular candidiasis can occur in the form of endophthalmitis. Endophthalmitis may result from exogenous spread, such as trauma or surgery, or endogenous spread due to hematologic seeding.

Untreated candidemia has been associated with retinal lesions in up to 37% of patients. Candida ophthalmitis begins as a choroidal lesion that progresses to an area of retinal necrosis followed by vitreitis and endophthalmitis. Endophthalmitis is characterized by retinal infiltrates and vitreous abnormalities. Chorioretinal involvement appears as focal, white, infiltrative lesions on the retina. Vitreal haze is present with vitreous extension of the infection. Symptoms include pain and decreased visual acuity. Untreated, ophthalmitis will lead to blindness. Typically, involvement is unilateral, but bilateral cases have been reported. C albicans is the most frequent culprit.

Osseous or intra-articular infections may result from either hematogenous spread or exogenous inoculation during trauma or joint injection. Osteomyelitis occurs most commonly in vertebrae in adults and in long bones in children.[19, 20] Spinal infection can progress to a diskitis. Arthritis can be acute and suppurative, and the knee is most commonly affected.[21] Diagnosis of osteoarticular infections may be delayed, as symptoms are frequently more subtle than bacterial infections in the same location and patients often present several weeks to months after an episode of candidemia. Fever is typically absent.

Candidal peritonitis is most frequently secondary to peritoneal dialysis catheter seeding or gastrointestinal surgery.

Mediastinitis secondary to candidal infection may occur after thoracic surgery.

Neonatal invasive candidiasis occurs with an incidence inversely proportional to birth weight. Candida colonization is found in approximately 30% of infants weighing less than 1500 g at birth weight. Sources of invasive infection in one study included blood (70%), urine (15%), CSF (10%), and peritoneal fluid (5%). C albicans and C parapsilosis are the most common species found in neonates.

Candida amnionitis may occur after prolonged rupture of the membranes in mothers given parenteral antibiotics. A neonate's skin may have pustules, vesicles, or diffuse erythema (shown in the image below). Neonates can also develop candidemia even after cesarean delivery due to premature rupture of amniotic membranes.[22]

Candidiasis. Discrete superficial pustules developed within hours of birth on the hand of an otherwise healthy newborn. A potassium hydroxide preparation revealed spores and pseudomycelium, and culture demonstrated the presence of Candida albicans. Image courtesy of Matthew C Lambiase, DO.

See History.

Currently, there are more than 150 known species of Candida; however, only 15 of these species have been isolated from patients as infectious agents.[2]

Ninety-five percent candidal infections can be attributed to C albicans, Cglabrata, C parapsilosis, C tropicalis, and Ckrusei, among which C albicans continues to be the most common despite its decreasing share.[2]

The isolation rates of non-albicans species vary according to features of the infected hosts (eg, age, comorbid conditions, location and length of hospitalization). Examples are as follows[2] :

• C parapsilosis causes 30% of the candidemia cases among newborns; however, it is isolated in only 10%-15% of adults with bloodstream infections.

• C glabrata infection is more common in elderly and neoplastic patients.

• C parapsilosis commonly colonizes the skin and is therefore a common pathogen found in indwelling catheter–related infections.

• C tropicalis is more common in patients with leukemia and those who are neutropenic.

• C krusei is more common is stem cell recipients and in those with leukemia who have received fluconazole prophylaxis.

Denture use, immunosuppressant use, antibiotic therapy, and aging are risk factors for oral colonization with C glabrata. C glabrata exhibits lower oral keratinocyte-adherence capacity but higher denture surface–adherence ability.

New antifungal resistant species:

• Candida auris is a new nosocomial fungal pathogen belonging to the candida genus, first described in Japan in 2009, but has since been reported in 33 countries and over 4000 cases.  Most cases were reported in South African and the United States.  Candidiasis caused by C. auris is concerning because recent systematic reviews and meta-analysis showed an overall crude mortality rate of 39%, and C. auris candidemia (blood stream infection) to have a mortality rate of 45%.  Additionally, C. auris has shown to be highly resistant to certain antifungals, 91% resistant to fluconazole, 12% resistant to amphotericin B, 12.1% resistant to caspofungin, and 0.8% resistant to micafungin. ^[23]

The criterion standard diagnostic tool for mucocutaneous candidiasis is culture. Cutaneous or mucosal scrapings can be used for a potassium hydroxide smear or Gram stain, which show hyphae, pseudohyphae, and budding yeast forms. The sensitivity of wet mount is as low as 39.6%.

Savyon Diagnostics has developed a rapid yeast detection kit for diagnosis of vulvovaginal candidiasis at home or at the physician’s office. Preliminary data indicate better sensitivity than wet mount, and it costs less than culture.

Invasive Candida infections are typically difficult to diagnose because the clinical presentation is frequently similar to other disease states or bacterial infections (eg, of the blood, urine, CSF), and cultures are unreliable. In one report, blood cultures were positive in only 50%-70% of disseminated candidiasis cases when the disease was proven by autopsy. Thus, nonculture diagnostic techniques are frequently used to aid in diagnosis. The 1,3 beta-glucan assay, which measures the fungal cell was component, has a sensitivity of 70% and specificity of 87%.

In September 2014, the US Food and Drug Administration (FDA) approved the marketing of a direct blood test used to detect the five most common Candida species that cause bloodstream infections: C albicans, C tropicalis, C parapsilosis, Cglabrata, and Ckrusei. The test, T2Candida, utilizes amplified DNA technology with magnetic resonance to allow for rapid identification of potentially fatal candidemia to facilitate timely parenteral treatment.[27]

Imaging studies are not necessary for routine mucocutaneous candidiasis.

Radiographic evaluations for systemic candidiasis are often nonspecific; thus, differentiation of candidiasis from other disease processes may be difficult.

Chest radiography may be helpful in diagnosing pulmonary candidiasis. Disease spreads via the airway system. Chest radiographic findings are characterized by bilateral, diffuse, and poorly marginated areas; pulmonary parenchymal densities are common. Other nonspecific findings include air bronchogram and obscure cardiac and hemidiaphragm borders. Hematogenous infection may produce a miliary nodular pattern.

Esophagography with contrast is an option to aid in diagnosis of esophagitis caused by Candida species; however, this should not prevent empirical treatment, as it is a clinical and visual diagnosis (ie, with esophagogastroduodenoscopy (EGD) or pathology). Peristaltic abnormalities caused by small plaques appear as superficial filling defects. A nodular or cobblestone pattern may be seen. Findings may be similar to those seen with esophagitis caused by CMV or HSV. Stricture may occur in severe esophageal candidiasis.

Ultrasonography is useful for diagnosis of microabscesses in the liver, spleen, or kidneys. "Wheel-within-a-wheel" hypoechoic zones surrounded by hyperechoic zones are early findings. Typical "bull's-eye" lesion may evolve from the initial lesion. A uniformly hyperechoic lesion may be observed. Echogenic foci with variable degrees of acoustic shadowing are late findings.

CT scan allows diagnosis of microabscesses, represented by low-attenuation foci, in the liver, spleen, or kidneys.

Intravenous pyelography (IVP) may be helpful in the diagnosis of urinary tract candidiasis. Renal edema due to multiple microabscesses may be present. Deformity of renal outline may also be present. In addition, diminished renal excretion, papillary necrosis, and candidal fungal balls in the bladder or collecting system may be seen. Hydronephrosis is a common late finding.

CT scan/MRI is indicated for evaluation of CNS lesions and prior to lumbar puncture in immunocompromised patients, especially those who present with altered mental status.

Endoscopy, tissue biopsy, and percutaneous needle aspiration of a body site suspected of Candida infection are recommended to aid in diagnosis if clinically indicated. Positive candidal cultures in a normally sterile site should not be disregarded as a contaminant.

Mucocutaneous candidiasis is often encountered and treatment initiated in the emergency department. Systemic infections in patients with risk factors for Candida infection should be admitted to the hospital and cultures taken prior to initiating antimicrobial therapy.[28, 25]

Other treatment of candidiasis

Generally, the echinocandin class of antifungals should be used as the first-line treatment of candidemia (ie, critically ill patients or patients with prior azole treatment). Unfortunately, there are already reports of echinocandin resistance after long-term therapy for candidemia.[29]

Polyenes should not be used to treat patients who have renal failure, and echinocandins and azoles should not be used in patients with severe liver disease because of their respective side effect profiles and pharmacokinetic properties.[30]

Mucocutaneous infection of the oropharynx typically responds to topical therapy. Nystatin is the least expensive option for oral thrush, but patients frequently complain of its bitter taste. Clotrimazole troches are as effective and less bitter. Proper denture cleansing and care are important measures against oral candidiasis. Systemic therapy is first line for esophageal candidiasis, with fluconazole as the preferred first-line agent.

Intertrigo and diaper rash respond to decreased moisture around the skin. Nystatin powder or cream is used with the addition of a topical steroid for diaper rash.

Uncomplicated vulvovaginal candidiasis treatment includes many options of topical or oral therapy. Recurrent candidal vaginitis requires a prolonged course of oral medication; probiotic Lactobacillus may help in facilitating treatment of this disease.[31]

A 2020 Cochrane Library systematic review and meta-analysis showed, with a moderate certainty, that oral treatment probably improves both short term and long-term cure of vulvovaginal candidiasis when compared to intravaginal therapy. The benefit is significant, but potentially marginal. The data suggested that if short term intravaginal therapy cure rates are 80%, then oral therapy would have a cure rate of 80-85%. If long term intravaginal therapy cure rates are 66%, then oral therapy would have a cure rate of 67-76%. Thus, given the marginal benefit, the authors of this review suggest that medication availability, side effects, cost, and use preference all be considered when deciding on method of therapy.[32]

Invasive candidiasis typically requires parenterally administered antifungal therapy.

Candida endocarditis frequently requires both medical and surgical therapy. Valve replacement and vegetation removal are often necessary. Antifungal therapy is typically continued for 6 to 10 weeks parenterally.

CNS candidal infection can often successfully be treated without intrathecal instillation.

Peritoneal candidal infection secondary to peritoneal dialysis may respond to peritoneal infusion of antifungal agents in dialysate fluid.

Candida keratitis may require corneal grafting if not responsive to treatment.

Full-term infants with Candida amnionitis typically respond to topical therapy. Premature infants frequently require systemic antifungal agents and have a poorer prognosis.

Endophthalmitis may require vitrectomy and direct intravitreal antifungal instillation.

Infectious disease specialists are typically involved in cases of invasive candidiasis.

Gastroenterologists typically perform diagnostic endoscopy.

Surgical drainage may be required with organ involvement and abscess formation.

Orthopedic surgeons are involved in the management of osteomyelitis and intra-articular infections.

Cardiothoracic surgeons are frequently necessary in the treatment of endocarditis.

Ophthalmologic consultation should be obtained for all patients with candidemia to exclude evidence of ocular involvement.

Dermatologist consulation can be considered in treatment resistant cutaneous/mucocutaneous candidiasis.

Guidelines on the treatment of Candida infections by the Infectious Diseases Society of America are as follows[33] :

• The IDSA recommends an echinocandin as first-line treatment for candidemia (caspofungin: loading dose 70 mg, then 50 mg daily; micafungin: 100 mg daily; anidulafungin: loading dose 200 mg, then 100 mg daily), rather than fluconazole, as echinocandins kill, rather than inhibit, these pathogens.
• Fluconazole, intravenous or oral, 800 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily is an acceptable alternative to an echinocandin as initial therapy in selected patients, including those who are not critically ill and who are considered unlikely to have a fluconazole-resistant Candida species.
• In neutropenic patients, lipid formulation amphotericin B, 3-5 mg/kg daily, is an effective but less attractive alternative because of the potential for toxicity.
• Fluconazole could be used in high-risk patients in adult ICUs with a high rate (>5%) of invasive candidiasis.
• Daily bathing of ICU patients with chlorhexidine, which has been shown to decrease the incidence of bloodstream infections including candidemia, could be considered.
• The updated guidelines also advocate consultation with infectious disease specialists for the early identification of different Candida strains, optimal antifungal treatment, and better patient outcomes.
• The guidelines advocate testing for azole susceptibility in clinically relevant Candida isolates. Testing for echinocandin susceptibility should be considered in patients who have undergone prior treatment with an echinocandin and in those with C glabrata or C parapsilosis infection.
• Candidiasis should be considered in patients who deteriorate with no obvious cause, have unexplained fever, have an elevated white blood cell count, have recently undergone abdominal surgery, or have a central venous catheter.
• Remove a catheter as early as possible in patients with candidemia if the catheter is the presumed source and can be safely removed. Other intravascular devices should also be removed.
• For neonatal candidiasis, amphotericin B deoxycholate 1 mg/kg daily is recommended for neonates with disseminated candidiasis.
• Lumbar puncture and dilated retinal examination are recommended in neonates with serum or urine cultures that are positive for Candida species .
• Empiric antifungal therapy should be considered in patients with clinical evidence of intra-abdominal infection and significant risk factors for candidiasis, including recent abdominal surgery, anastomotic leaks, or necrotizing pancreatitis.

Guidelines on the consideration and treatment of candidiasis as a cause of sepsis by the 2016 Surviving Sepsis Campaign International Guidelines are as follows[25] : 

• Invasive candidiasis should be considered in selected patients. For example, neutropenic patients are at risk for an especially wide range of potential pathogens, including Candida species.
• Risk factors for invasive Candida infections include immunocompromised status (neutropenia, chemotherapy, transplant, diabetes mellitus, chronic liver failure, chronic renal failure), prolonged invasive vascular devices (hemodialysis catheters, central venous catheters), total parenteral nutrition, necrotizing pancreatitis, recent major surgery (particularly abdominal), prolonged administration of broad-spectrum antibiotics, prolonged hospital/ICU admission, recent fungal infection, and multisite colonization. ^{[34, 35]}
• If the risk of Candida sepsis is sufficient to justify empiric antifungal therapy, the selection of the specific agent should be tailored to the severity of illness, the local pattern of the most prevalent Candida species, and any recent exposure to antifungal drugs.
• Empiric use of an echinocandin (anidulafungin, micafungin, or caspofungin) is preferred in most patients with severe illness, especially in those patients with septic shock, who have recently been treated with other antifungal agents, or if Candida glabrata or Candida krusei infection is suspected from earlier culture data. ^{[33, 36]}
• Triazoles are acceptable in hemodynamically stable, less ill patients who have not had previous triazole exposure and are not known to be colonized with azole-resistant species.
• Liposomal formulations of amphotericin B are a reasonable alternative to echinocandins in patients with echinocandin intolerance or toxicity. ^{[33, 36]}
• Knowledge of local resistance patterns to antifungal agents should guide drug selection until fungal susceptibility test results, if available, are received.
• Rapid diagnostic testing using β-D-glucan or rapid polymerase chain reaction assays to minimize inappropriate anti-Candida therapy may have an evolving supportive role. However, the negative predictive value of such tests is not high enough to justify dependence on these tests for primary decision-making.

Antifungal therapy should be started immediately after necessary cultures have been obtained from all suspected sites of infection.

Significant advances have been made in the treatment of Candida with the development of newer azoles, echinocandins, and lipid formulations of amphotericin B.

Class Summary

Azoles are fungicidal only at very high concentrations. Azoles function by selectively inhibiting the synthesis of an essential component of fungal cell membrane, ergosterol.

In August 2013, the FDA announced that clinicians should no longer prescribe ketoconazole because of the risk of severe liver injury, adrenal insufficiency, and adverse drug reactions. Topical formulations of the medication can continue to be prescribed. The only indication for the oral medication is now in patients with endemic mycoses who fail to respond to other treatments or cannot tolerate other treatments.[37]

A 2020 meta-analysis found that Posaconazole was both equally safe and significantly superior to fluconazole in prevention of invasive fungal infection, including candidiasis, in immunocompromised patients.  The meta-analysis specifically supported the use of Posaconazole for invasive fungal infections in immunocompromised patients, hematologic malignancies, and stem-cell transplant recipients with conclusive and high-quality evidence.[38]

Fluconazole (Diflucan)

Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. Has little affinity for mammalian cytochromes, which is believed to explain its low toxicity. Available as tablets for oral administration, as a powder for oral suspension, and as a sterile solution for IV use. Has fewer adverse effects and better tissue distribution than older systemic imidazoles.

Daily dose varies with indication.

Fluconazole penetrates the cerebrospinal fluid, kidneys, and liver well. It is concentrated and excreted by the kidneys in its active form so is effective against urinary tract infections.

Terconazole vaginal (Terazol-3, Terazol-7, Zazole)

Damages fungal cell wall membrane by inhibiting biosynthesis of ergosterol. Membrane permeability is increased, causing nutrients to leak out, resulting in fungal cell death.

Butoconazole (Gynazole-1)

Broad-spectrum antifungal agent that inhibit yeast growth by altering cell membrane permeability, which causes fungal cell death.

Use 2% vaginal cream. Available over the counter.

Voriconazole (VFEND)

Available in oral and parenteral forms. FDA approved for esophageal candidiasis and candidemia. Used clinically for serious candidal infections refractory to amphotericin B. Voriconazole has been found to be active against C glabrata and C krusei as well as isolates that have developed resistance to fluconazole.

Ketoconazole (Nizoral, Extina, Xolegel)

Imidazole broad-spectrum antifungal agent. Nizoral impairs synthesis of ergosterol (the main sterol of fungal cell membranes), allowing increased permeability and leakage of cellular components, causing cell death. Used in treatment of chronic mucocutaneous candidiasis and cutaneous infections.

Itraconazole (Sporanox, Onmel)

Has fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes. Effective against broad range of fungi, including Candida species and is indicated for the treatment of cutaneous, oral, esophageal, and disseminated candidiasis.

Available in IV, 100-mg capsules, and oral solution at 10 mg/mL.

Capsules require gastric acidity for absorption and should be taken with food to increase absorption. Liquid formulation increases bioavailability and decreases need for acidity for proper absorption.

Use of solution has been recommended in mucosal and invasive candidiasis, while capsules can be used in onychomycosis and dermatophyte infections.

Miconazole topical (Desenex, Micatin, Micaderm)

Inhibits biosynthesis of ergosterol, damaging fungal cell wall membrane, which results in fungal cell death.

Lotion preferred in intertriginous areas; cream must be applied sparingly to avoid maceration effects.

Effective in treating vaginitis and cutaneous infections.

Clotrimazole (Mycelex, Lotrimin, Alevazol)

Nonabsorbable imidazole. Broad-spectrum synthetic antifungal agent that inhibits growth of yeasts and fungal growth by altering cell membrane permeability, which causes fungal cell death.

Therapy is directed at the underlying condition, with the goal of minimizing symptoms and preventing complications.

Tioconazole (Vagistat-1)

Damages fungal cell wall membrane by inhibiting biosynthesis of ergosterol. Membrane permeability is increased, causing nutrients to leak out, resulting in fungal cell death.

Posaconazole (Noxafil)

Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.

Econazole (Ecoza)

Antifungal agent that is a water-miscible base consisting of pegoxol 7 stearate, peglicol 5 oleate, mineral oil, benzoic acid, butylated hydroxyanisole, and purified water. The color of the soft cream is white to off white, and it is for topical use only. Interferes with RNA and protein synthesis and metabolism. Disrupts fungal cell wall permeability, causing fungal cell death. Exhibits broad-spectrum antifungal activity against many gram-negative organisms. Effective in cutaneous infections.

Class Summary

Polyenes (nystatin and amphotericin B) bind to ergosterol on the fungal cell membrane and create pores in the membrane resulting in leakage of intracellular proteins thereby destroying the fungal cell.

Amphotericin B, conventional

Produced from a strain of Streptomyces nodosus. Antifungal activity of amphotericin B results from its ability to insert itself into fungal cytoplasmic membrane at sites containing ergosterol or other sterols. Aggregates of amphotericin B accumulate at sterol sites, resulting in an increase in cytoplasmic membrane permeability to monovalent ions (eg, potassium, sodium). At low concentrations, the main effect is increased intracellular loss of potassium, resulting in reversible fungistatic activity; however, at higher concentrations, pores of 40-105 nm in cytoplasmic membrane are produced, leading to large losses of ions and other molecules. A second effect of amphotericin B is its ability to cause auto-oxidation of the cytoplasmic membrane and release of lethal free radicals. Main fungicidal activity of amphotericin B may reside in ability to cause auto-oxidation of cell membranes.

In recent years, lipid formulations have been developed. Total dose needs to be adjusted depending on type of candidal infection being treated. Most patients receive a total dose of 0.5-1.5 g.

Amphotericin B, liposomal (AmBisome)

Novel lipid formulations of amphotericin B that deliver higher concentrations of the drug, with a theoretical increase in therapeutic potential and decreased nephrotoxicity. Produced from a strain of S nodosus. Antifungal activity of amphotericin B results from its ability to insert itself into fungal cytoplasmic membrane at sites containing ergosterol or other sterols. Aggregates of amphotericin B accumulate at sterol sites, resulting in an increase in cytoplasmic membrane permeability to monovalent ions (eg, potassium, sodium). At low concentrations, the main effect is increased intracellular loss of potassium, resulting in reversible fungistatic activity; however, at higher concentrations, pores of 40-105 nm in cytoplasmic membrane are produced, leading to large losses of ions and other molecules. A second effect of amphotericin B is its ability to cause auto-oxidation of the cytoplasmic membrane and release of lethal free radicals. Main fungicidal activity of amphotericin B may reside in ability to cause auto-oxidation of cell membranes.

Formulation types include amphotericin B lipid complex (ABLC, Abelcet), amphotericin B colloidal dispersion (ABCD, Amphotec), and liposomal amphotericin B (L-AMB, AmBisome).

ABLC and ABCD approved for treating adults and children with fungal infections refractory to or intolerant of conventional amphotericin B. L-AMB is approved for aspergillosis, candidiasis, and cryptococcosis, and also for patients with neutropenia who have persistent fever on broad-spectrum antibiotics.

Nystatin (Nyamyc, Bio-Statin)

Fungicidal and fungistatic antibiotic obtained from Streptomyces noursei; effective against various yeasts and yeastlike fungi. Changes permeability of fungal cell membrane after binding to cell membrane sterols, causing cellular contents to leak.

Treatment should continue until 48 h after disappearance of symptoms. Used for treatment of oral thrush (although not in patients with AIDS) and cutaneous infections.

Class Summary

Flucytosine is given occasionally in combination with amphotericin B for CNS infections.

Flucytosine (Ancobon)

Although the exact mode of action is unknown, it is proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism where it is converted to 5-fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against Candida and Cryptococcus species and generally used in combination with amphotericin B.

Use in combination with another agent because acquired resistance develops frequently when flucytosine is administered alone.

Well absorbed orally but should be administered IV to critically ill patients.

Class Summary

Echinocandins have potent fungicidal activity against Candida species and have successfully treated Candida resistant to azoles. These drugs are not metabolized through the CYP450 system. They act by inhibiting the synthesis of an essential cell wall component that is not present in mammalian cells.

A 2021 Japanese systematic review and meta-analysis compared mortality between echinocandins and polyenes for initial treatment of candidemia and found that there was a higher association between initial echinocandin therapy and reduced mortality.  This agrees with current American guideline recommendations.[39]

In 2019, a meta-analysis showed that echinocandins were non-inferior and led to fewer pediatric patients having anti-fungal therapy discontinuations when compared to amphotericin B.[40]

Caspofungin (Cancidas)

FDA approved to treat candidemia, invasive candidiasis, and esophageal candidiasis. A glucan synthesis inhibitor that inhibits synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall. Caspofungin has demonstrated activity against C albicans, C glabrata, C guilliermondii, C krusei, C parapsilosis, and C tropicalis. Activity against C parapsilosis may only be fungistatic. Response rate has been demonstrated to be 73% for caspofungin as compared to 62% for amphotericin B.

Micafungin (Mycamine)

Member of new class of antifungal agents, echinocandins, that inhibit cell wall synthesis. Inhibits synthesis of 1,3-beta-D-glucan, an essential fungal cell wall component not present in mammalian cells.

Indications include (1) prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation and (2) treatment of esophageal candidiasis.

Anidulafungin (Eraxis)

Antifungal agent of the echinocandin class. Inhibits synthesis of 1,3-beta-D-glucan, an essential component of fungal cell walls. Indicated to treat esophageal candidiasis, candidemia, and other forms of candidal infections (eg, intraabdominal abscesses, peritonitis).

Class Summary

These are fungicidal agents.

Terbinafine (Terbinex, Lamisil)

Inhibits squalene epoxidase, which decreases ergosterol synthesis, causing fungal-cell death.

Use medication until symptoms significantly improve.

Uncomplicated vaginal and cutaneous candidiasis: When treated in the ED and discharged with medication, patients should be instructed to see their primary physician if symptoms persist or worsen. For recurrent vulvovaginitis, patients should be screened for HIV infection, diabetes mellitus, leukemia, or other immunologic dysfunction.

Severe candidiasis: If an underlying disorder is suspected, patients should be referred for workup of possible primary causes leading to the immunocompromised state.

Patients with invasive candidiasis often have a prolonged inpatient course and may require several weeks of parenteral antifungal therapy.

Removal of invasive catheters with positive fungal culture results is an essential step in management.[41]

Localized mucocutaneous infections are treated with outpatient topical and oral medication. Patients with invasive infections that have stabilized may be discharged with parenteral medications administered at home.

Patients with invasive candidiasis may require transfer to a facility where intensive care and specialty consultations are available.

Multiple studies have been performed evaluating fluconazole prophylaxis in the ICU; however, the studies had either limited numbers or were performed in only one center, thereby limiting the ability to apply the evidence to the general population.[42]

Candida prevention in the neonatal ICU is also controversial. Fluconazole prophylaxis can lead to the emergence of Candida species that are not susceptible to fluconazole. This is a concern, as mortality varies substantially by Candida species. C glabrata is associated with the highest mortality rate in neonates. Studies have demonstrated that less frequent dosing may delay the emergence of antifungal resistance, but more evidence-based data are required.

Screening pregnant women for vaginal infection and subsequently treating the infection, including vaginal candidiasis, reduces preterm delivery rates by 50%.

Oral candidiasis can be prevented in patients who wear dentures (ie, immunocompromised population) by various methods of disinfections, which include microwave irradiation and sodium hypochlorite soaks.[43, 44]

Untreated candidemia can lead to disseminated invasive candidiasis and organ failure of vitually any organ system with high mortality.

The prognosis of candidal infection varies based on location of infection. Local mucocutaneous infections typically respond well to medical therapy. Response to invasive infection is determined by how quickly infection with Candida is recognized and treatment is initiated, as well as underlying host immune response and comorbidities.

If left untreated, candidemia has over a 60% mortality rate.[45] With appropriate antifungal treatment, the mortality improves to between 25 to 40 percent.[46, 47, 48]

Patients should be informed that immunocompromising agents and widespread administration of antibiotics may increase the likelihood of developing candidal infections.

Patients should be educated to follow diets low in refined sugars and to avoid clothing that is tight and/or synthetic. Cotton underclothing may be beneficial.

For patient education resources, see the Yeast and Fungal Infections Center; Children's Health Center; and Skin, Hair, and Nails Center, as well as Candidiasis (Yeast Infection), Understanding Vaginal Yeast Infection Medications, Yeast Infection Diaper Rash, and Yeast Infection Skin Rash.