Candidiasis

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Practice Essentials

Candidiasis is a fungal infection caused by yeasts from the genus Candida. Candida albicans is the predominant cause of the disease.

Essential update: FDA issues warning for antifungal medication ketoconazole

The FDA announced that clinicians should no longer prescribe ketoconazole (Nizoral, Janssen Pharmaceuticals) tablets as a first-line therapy for any fungal infection, including Candida and dermatophyte infections, because of the risk for severe liver injury, adrenal insufficiency, and adverse drug interactions. The FDA also cautioned that ketoconazole tablets should not be prescribed for any patient with underlying liver disease. The labeling changes do not apply to topical formulations of ketoconazole in creams, shampoos, foams, and gels. Oral ketoconazole is now indicated only for endemic mycoses in patients who fail to respond to or cannot tolerate other treatments.

Ketoconazole tablets were also withdrawn from the market in the European Union in July.[1, 2]

Signs and symptoms

Chronic mucocutaneous candidiasis

Findings reveal disfiguring lesions of the face, scalp, hands, and nails. Chronic mucocutaneous candidiasis is occasionally associated with oral thrush and vitiligo.

Oropharyngeal candidiasis

Individuals with oropharyngeal candidiasis (OPC) usually have a history of HIV infection, wear dentures, have diabetes mellitus, or have been exposed to broad-spectrum antibiotics or inhaled steroids. Although patients are frequently asymptomatic, when symptoms do occur, they can include the following:

Physical examination reveals a diffuse erythema and white patches that appear on the surfaces of the buccal mucosa, throat, tongue, and gums.

The following are the 5 types of OPC:

Esophageal candidiasis

Patients with esophageal candidiasis may be asymptomatic or may have 1 or more of the following symptoms:

Physical examination almost always reveals oral candidiasis.

Nonesophageal gastrointestinal candidiasis

The following symptoms may be present:

Genitourinary tract candidiasis

The types of genitourinary tract candidiasis are as follows:

See Clinical Presentation for more detail.

Diagnosis

Diagnostic tests for candidiasis include the following:

See Workup for more detail.

Management

See Treatment and Medication for more detail.

Image library


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A moist, erosive, pruritic patch of perianal skin and perineum (with satellite pustule formation) is demonstrated in this woman with extensive candidi....

Background

Candidiasis is caused by infection with species of the genus Candida, predominantly with Candida albicans.Candida species are ubiquitous fungi that represent the most common fungal pathogens that affect humans. The growing problem of mucosal and systemic candidiasis reflects the enormous increase in the number of patients at risk and the increased opportunity that exists for Candida species to invade tissues normally resistant to invasion. Candida species are true opportunistic pathogens that exploit recent technological advances to gain access to the circulation and deep tissues.

The increased prevalence of local and systemic disease caused by Candida species has resulted in numerous new clinical syndromes, the expression of which depends primarily on the immune status of the host. Candida species produce a wide spectrum of diseases, ranging from superficial mucocutaneous disease to invasive illnesses, such as hepatosplenic candidiasis, Candida peritonitis, and systemic candidiasis. The management of serious and life-threatening invasive candidiasis remains severely hampered by delays in diagnosis and the lack of reliable diagnostic methods that allow detection of both fungemia and tissue invasion by Candida species.

Advances in medical technology, chemotherapeutics, cancer therapy, and organ transplantation have greatly reduced the morbidity and mortality of life-threatening disease. Patients who are critically ill and in medical and surgical ICUs have been the prime targets for opportunistic nosocomial fungal infections, primarily due to Candida species. Studies suggest that the problem is not under control and, in fact, show it is worsening. On a daily basis, virtually all physicians are confronted with a positive Candida isolate obtained from one or more various anatomical sites. High-risk areas for Candida infection include neonatal, pediatric, and adult ICUs, both medical and surgical.[5] Candida infections can involve any anatomical structure.

Pathophysiology

Candida species are yeastlike fungi that can form true hyphae and pseudohyphae. For the most part, Candida species are confined to human and animal reservoirs; however, they are frequently recovered from the hospital environment, including on foods, countertops, air-conditioning vents, floors, respirators, and medical personnel. They are also normal commensals of diseased skin and mucosal membranes of the gastrointestinal, genitourinary, and respiratory tracts.

Candida species also contain their own set of well-recognized but not well-characterized virulence factors that may contribute to their ability to cause infection.[6] The main virulence factors include the following:

As with most fungal infections, host defects also play a significant role in the development of candidal infections. Host defense mechanisms against Candida infection and their associated defects that allow infection are as follows:

Risk factors associated with invasive or systemic candidiasis include the following:[7]

The first step in the development of a candidal infection is colonization of the mucocutaneous surfaces. All of the factors outlined above are associated with increased colonization rates. The routes of candidal invasion include (1) disruption of a colonized surface (skin or mucosa), allowing the organisms access to the bloodstream, and (2) persorption via the gastrointestinal wall, which may occur following massive colonization with large numbers of organisms that pass directly into the bloodstream.

Frequency

United States

Candida species are the most common cause of fungal infection in immunocompromised persons. Oropharyngeal colonization is found in 30-55% of healthy young adults, and Candida species may be detected in 40-65% of normal fecal flora.

Three of every 4 women experience at least one bout of vulvovaginal candidiasis (VVC) during their lifetime.

More than 90% of persons infected with HIV who are not receiving highly active antiretroviral therapy (HAART) eventually develop oropharyngeal candidiasis (OPC), and 10% eventually develop at least one episode of esophageal candidiasis.[8]

In persons with systemic infections, Candida species are now the fourth most commonly isolated pathogens from blood cultures.[9]

Clinical and autopsy studies have confirmed the marked increase in the incidence of disseminated candidiasis, reflecting a parallel increase in the frequency of candidemia. This increase is multifactorial in origin and reflects increased recognition of the fungus, a growing population of patients at risk (eg, patients undergoing complex surgical procedures, patients with indwelling vascular devices), and the improved survival rates among patients with underlying neoplasms or collagen-vascular disease and patients who are immunosuppressed.

International

Similar rates of mucocutaneous and systemic candidiasis/candidemia have been observed worldwide.[10, 11] In fact, throughout the world, Candida species have replaced Cryptococcus species as the most common fungal pathogens affecting immunocompromised hosts.

Mortality/Morbidity

Mucocutaneous candidiasis: Most candidal infections are mucocutaneous and, as such, do not cause mortality. However, in patients with advanced immunodeficiency due to HIV infection, these mucosal infections can become refractory to antifungal therapy and may lead to severe oropharyngeal and esophageal candidiasis that initiates a vicious cycle of poor oral intake, malnutrition, wasting, and early death.

Candidemia and disseminated candidiasis: Mortality rates associated with these infections have not improved markedly over the past few years and remain in the range of 30-40%. Systemic candidiasis causes more case fatalities than any other systemic mycosis. More than a decade ago, investigators reported the enormous economic impact of systemic candidiasis in hospitalized patients. Candidemia is associated with considerable prolongation in hospital stays (70 d vs 40 d in comparable patients without fungemia). Although mucocutaneous fungal infections, such as oral thrush and Candida esophagitis, are extremely common in patients with AIDS, candidemia and disseminated candidiasis are uncommon.

Sex

Neither sex is predisposed to candidal colonization; however, VVC is the second most common cause of vaginitis in women.

Age

Persons at the extremes of age (neonates and adults >65 y) are most susceptible to candidal colonization. Mucocutaneous candidiasis is also more prevalent in neonates and older adults. Very-low-birth-weight and extremely-low-birth-weight infants are at high risk for blood culture–proven late-onset candidiasis (defined as sepsis that develops after age 72 h).[12]

History

Candidiasis can cause a wide spectrum of clinical syndromes, as described below. The clinical presentation can vary depending on the type of infection and the degree of immunosuppression.

Cutaneous candidiasis syndromes

Generalized cutaneous candidiasis: This is an unusual form of cutaneous candidiasis that manifests as a diffuse eruption over the trunk, thorax, and extremities. The patient has a history of generalized pruritus, with increased severity in the genitocrural folds, anal region, axillae, hands, and feet. Physical examination reveals a widespread rash that begins as individual vesicles that spread into large confluent areas.

Intertrigo: The patient has a history of intertrigo affecting any site in which skin surfaces are in close proximity, providing a warm and moist environment. A pruritic red rash develops. Physical examination reveals a rash that begins with vesiculopustules that enlarge and rupture, causing maceration and fissuring. The area involved has a scalloped border with a white rim consisting of necrotic epidermis that surrounds the erythematous macerated base. Satellite lesions are commonly found and may coalesce and extend into larger lesions (see image below).


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Erythema, maceration, and satellite pustules in the axilla, accompanied by soreness and pruritus, result in a form of intertrigo. Courtesy of Matthew ....

Metastatic skin lesions: Characteristic skin lesions occur in approximately 10% of patients with disseminated candidiasis and candidemia. The lesions may be numerous or few and are generally described as erythematous, firm, nontender macronodular lesions with discrete borders. Biopsy specimens of these lesions demonstrate yeast cells, hyphae, or pseudohyphae, and cultures are positive for Candida species in approximately 50% of cases.

Candida folliculitis: The infection is found predominantly in the hair follicles and, rarely, can become extensive.

Paronychia and onychomycosis: Paronychia and onychomycosis are frequently associated with immersion of the hands in water and with diabetes mellitus. The patient has a history of a painful and erythematous area around and underneath the nail and nail bed. Physical examination reveals an area of inflammation that becomes warm, glistening, tense, and erythematous and may extend extensively under the nail. It is associated with secondary nail thickening, ridging, discoloration, and occasional nail loss.

Chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis describes a group of Candida infections of the skin, hair, nails, and mucous membranes that tends to have a protracted and persistent course.

Gastrointestinal tract candidiasis

Respiratory tract candidiasis

The respiratory tract is frequently colonized with Candida species, especially in hospitalized patients. Approximately 20-25% of ambulatory patients are colonized with Candida species.

Laryngeal candidiasis: This is an uncommon form of invasive candidiasis that sometimes results in disseminated infection. It is primarily seen in patients with underlying hematologic or oncologic malignancies. The patient may present with a sore throat and hoarseness. The physical examination findings are generally unremarkable, and the diagnosis is frequently made with direct or indirect laryngoscopy.

Candida tracheobronchitis: This is also an uncommon form of invasive candidiasis. Most patients with Candida tracheobronchitis are HIV-positive or are severely immunocompromised. Most patients with Candida tracheobronchitis report fever, productive cough, and shortness of breath. Physical examination reveals dyspnea and scattered rhonchi. The diagnosis is generally made with bronchoscopy.

Candida pneumonia: This rarely develops alone and is associated with disseminated candidiasis in rare cases. The most common form of infection is multiple lung abscesses due to the hematogenous dissemination of Candida species. The high degree of Candida colonization in the respiratory tract greatly complicates the diagnosis of Candida pneumonia. The history reveals risk factors similar to those of disseminated candidiasis, along with reports of shortness of breath, cough, and respiratory distress. Physical examination reveals fever, dyspnea, and variable breath sounds, ranging from clear to rhonchi or scattered rales.

Genitourinary tract candidiasis

Vulvovaginal candidiasis (VVC): This is the second most common cause of vaginitis. The patient's history includes vulvar pruritus, vaginal discharge, dysuria, and dyspareunia. Approximately 10% of women experience repeated attacks of VVC without precipitating risk factors. Physical examination findings include a vagina and labia that are usually erythematous, a thick curdlike discharge, and a normal cervix upon speculum examination.[3]

Candida balanitis: Patients report penile pruritus along with whitish patches on the penis. Candida balanitis is acquired through direct sexual contact with a partner who has VVC. Physical examination initially reveals vesicles on the penis that later develop into patches of whitish exudate. The rash occasionally spreads to the thighs, gluteal folds, buttocks, and scrotum (see image below).


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

Candida cystitis: Many patients are asymptomatic. However, bladder invasion may result in frequency, urgency, dysuria, hematuria, and suprapubic pain. Candida cystitis may or may not be associated with the use of a Foley catheter. Physical examination may reveal suprapubic pain; other findings are unremarkable.

Asymptomatic candiduria: Most catheterized patients with persistent candiduria are asymptomatic, similar to noncatheterized patients. Most patients with candiduria have easily identifiable risk factors for Candida colonization. Thus, invasive disease is difficult to differentiate from colonization based solely on culture results because approximately 5-10% of all urine cultures are positive for Candida.[13]

Ascending pyelonephritis: The use of stents and indwelling devices, along with the presence of diabetes, is the major predisposing risk factor in ascending infection. Most patient report flank pain, abdominal cramps, nausea, vomiting, fever, chills and hematuria. Physical examination reveals abdominal pain, costovertebral-angle tenderness, and fever.

Fungal balls: This is due to the accumulation of fungal material in the renal pelvis. The condition may produce intermittent urinary tract obstruction with subsequent anuria and ensuing renal insufficiency.

Hepatosplenic candidiasis (chronic systemic candidiasis)

Hepatosplenic candidiasis is a form of systemic candidiasis in patients with an underlying hematologic malignancy and neutropenia and develops during the recovery phase of a neutropenic episode. The patient's history includes the following:

Physical examination findings include right upper quadrant tenderness and hepatosplenomegaly (< 40%).

Systemic candidiasis

Systemic candidiasis can be divided into 2 primary syndromes: candidemia and disseminated candidiasis (organ infection by Candida species). Deep organ infections due to Candida species are generally observed as part of the disseminated candidiasis syndromes and may involve one or more organs.

Physical

See History for physical examination findings paired with clinical syndromes.

Causes

Over 200 species of Candida exist in nature; thus far, only a few species have been associated with disease in humans.

Laboratory Studies

Unfortunately, results from the routine laboratory studies are often nonspecific and not very helpful. Clinicians are required to act definitively and early based on a high index of suspicion. In the past, many patients with life-threatening candidiasis died without receiving antifungal therapy. Systemic candidiasis should be suspected in patients with persistent leukocytosis and either persistent neutropenia or other risk factors and who remain febrile despite broad-spectrum antibiotic therapy. To be effective, antifungal therapy should be provided early and empirically in such high-risk patients. Cultures of nonsterile sites, although not useful for establishing a diagnosis, may demonstrate high degrees of candidal colonization. Always consider positive culture results from sterile sites to be significant and evidence of infection.

A new, rapid test for Candida infections of the bloodstream may cut patient mortality from 40% to 11% by diagnosing candidemia 25 times faster than blood culture can and quickly identifying the Candida species that is causing the infection. The new test, T2Candida, uses polymerase chain reaction (PCR) assay to amplify Candida DNA in blood, with the genetic material hybridizing to superparamagnetic nanoparticles coated with complementary DNA. The nanoparticles aggregate into "microclusters," which greatly alter a T2 magnetic resonance (T2MR) signal.[24, 25]

Imaging Studies

Imaging studies are not required or useful in the diagnosis of cutaneous candidiasis, oropharyngeal candidiasis (OPC), or vulvovaginal candidiasis (VVC).

Chest radiography may be useful in differentiating a bacterial pneumonia as the cause of fever in patients who are hospitalized. Patients with bronchopneumonia due to hematogenous candidiasis usually have multilobar involvement.

Esophagography/upper gastrointestinal studies may be useful for detecting abnormalities in the esophagus and stomach. Unfortunately, these studies are not helpful in determining the microbiologic etiology of the infection.

Ultrasonography may be useful for diagnosing hepatosplenic abscess. The classic bull's eye or target lesions are observed in the liver and spleen.

CT scanning with contrast enhancement may be useful for diagnosing the following:

Echocardiography may be useful for excluding or including Candida endocarditis as a possible diagnosis. It is extremely useful because fungal endocarditis is frequently associated with large vegetations that are easily observed on standard echocardiograms.

Procedures

In patients with candidemia or disseminated candidiasis, obtaining a tissue biopsy of the involved areas is frequently helpful in establishing the presence of Candida infection and invasion.

Bronchoscopy with bronchoalveolar lavage and transbronchial biopsy provide adequate tissue for diagnosis of pulmonary candidiasis.

Endoscopy provides direct examination of the esophagus and stomach, one of the organ systems most commonly infected with Candida species. It is also necessary for excluding other causes of esophagitis.

Echocardiography may be useful for excluding or including Candida species as a cause of endocarditis. It is extremely useful because fungal endocarditis is frequently associated with large vegetations that are easily observed using standard echocardiography.

Histologic Findings

Fixed tissues can be stained with hematoxylin and eosin. In addition, fungal hyphae may be demonstrated with Grocott silver-methenamine, methylene blue, or periodic acid-Schiff staining. The classic appearance demonstrates the Candida species as either round or ovoid yeast cells, hyphae, or pseudohyphae.

Medical Care

The treatments used to manage Candida infections vary substantially and are based on the anatomic location of the infection, the patients' underlying disease and immune status, the patients' risk factors for infection, the specific species of Candida responsible for infection, and, in some cases, the susceptibility of the Candida species to specific antifungal drugs.

There have been significant changes in the management of candidiasis in the last few years, particularly related to the appropriate use of echinocandins and expanded-spectrum azoles for candidemia, other forms of invasive candidiasis, and mucosal candidiasis. Newer updated guidelines were published in March 2009 by the Infectious Disease Society of America (IDSA),[26] replacing a previous version from 2004.[27] These latest recommendations include the echinocandins caspofungin, micafungin, and anidulafungin, along with voriconazole and posaconazole, as well as lipid formulations of amphotericin B in various situations.

Fluconazole is still considered a first-line agent in nonneutropenic patients with candidemia or suspected invasive candidiasis. However, a post-hoc analysis of clinical trial data comparing anidulafungin with fluconazole for treatment of invasive candidiasis found that anidulafungin was more effective in treating severely ill patients.[28] A revision of data outcomes on treatment of invasive candidiasis in clinical trials appears to favor use of echinocandins in terms of increased rate of survival. This type of finding may have an impact on future treatment recommendations and strategies of drug use for invasive candidiasis in different groups of patients.[29, 30]

The therapeutic options available for the management of invasive candidiasis and candidemia have continued to increase with the addition of newer echinocandins[31, 32] and triazoles.

Surgical Care

Major organ infections associated with candidal abscess formation may require surgical drainage procedures along with the appropriate antifungal therapy.

Prosthetic joint infection with Candida species requires the removal of the prosthesis.

Surgical debridement is generally necessary for sternal infections and frequently for vertebral osteomyelitis.

Splenic abscesses occasionally require splenectomy.

Valve replacement surgery is always indicated to treat endocarditis.

In addition to medical management, vitrectomy is a therapeutic option in fungal endophthalmitis.[41]

Consultations

In some forms of candidiasis, involving physicians of different specialties for some of the specific infections may be necessary. Some examples of these situations include endocarditis, endophthalmitis, peritonitis, osteomyelitis, and other forms of invasive candidiasis that may require surgical drainage and debridement.

Medication Summary

Successful therapy for serious systemic Candida infections requires initiation of antifungal therapy as early as possible, as soon as adequate culture results are obtained.

Different classes of antifungals are now available to manage any type of candidal infection. Azoles, fluconazole in particular,[33] have become the mainstay of therapy over the past few years. These include topical and systemic agents. Posaconazole is the most recent addition to this group of antifungals. Polyenes include amphotericin B, liposomal amphotericin B formulations, and topical nystatin. Allylamines include terbinafine, which is formulated in a topical preparation and an oral tablet. The newest group of antifungals is echinocandins, including caspofungin, micafungin, and anidulafungin. These drugs have shown excellent clinical efficacy, a low incidence of adverse events, a good safety profile, and ease of use.[42, 43]

Fluconazole (Diflucan)

Clinical Context:  Triazole with less effect on human sterol metabolism. Does not decrease cortisol and testosterone levels, as occurs with ketoconazole. Has fewer adverse effects and better tissue distribution than older systemic imidazoles. Available PO/IV and has demonstrated efficacy in topical and invasive forms of candidiasis. Available in 50-, 100-, 150-, and 200-mg tabs.

Daily dose varies with indication.

Itraconazole (Sporanox)

Clinical Context:  Has fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P450-dependent synthesis of ergosterol, a vital component of fungal cell membranes. Effective against broad range of fungi, including Candida species, and is indicated for treatment of cutaneous, oral, esophageal, and disseminated candidiasis.

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

Caps 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 caps can be used in onychomycosis and dermatophyte infections.

Voriconazole (Vfend)

Clinical Context:  Available as tablet, suspension and parenteral preparations. Effective as fluconazole against esophageal candidiasis, and as effective as amphotericin B deoxycholate in treatment of candidemia and invasive candidiasis. In Europe, it has been approved for "treatment of fluconazole-resistant serious invasive Candida infections (including C krusei)." Additionally, associated with fewer breakthrough fungal infections when used as empiric therapy in febrile neutropenic patients. FDA approved for esophageal candidiasis and candidemia.

Posaconazole (Noxafil)

Clinical Context:  Novel triazole antifungal agent. Blocks ergosterol synthesis of cell membrane by inhibiting enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. Action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Approved for treatment of OPC, including OPC refractory to itraconazole and/or fluconazole and for prophylaxis of infections due to Candida and Aspergillus in patients who are at high risk, such as those undergoing stem cell transplants with graft versus host disease or with prolonged neutropenia due to a hematologic malignancy or its treatment.

Class Summary

These agents are synthetic compounds that include 2 groups, imidazoles and triazoles. Triazoles have 3 atoms of nitrogen in the azole ring. Imidazoles have only two. The primary mechanism of action is inhibition of lanosterol 14-alpha-demethylase, an enzyme required for the synthesis of ergosterol, the main component of fungal cell membranes. Imidazole agents include miconazole, ketoconazole, and clotrimazole. Triazole agents, which are now the most commonly used azoles, include fluconazole, itraconazole, econazole, terconazole, butoconazole, and tioconazole. Newer triazoles (ie, voriconazole, posaconazole, ravuconazole) are active against fluconazole-resistant strains of Candida. Voriconazole and posaconazole have shown high efficacy against candidiasis in recent clinical trials.[44, 37, 45]

Topical agents are frequently used as front-line agents to manage localized or superficial forms of candidiasis such as cutaneous candidiasis, oropharyngeal candidiasis (OPC), and vulvovaginal candidiasis (VVC). These preparations are available as a cream for topical use, as troches for OPC, and as a vaginal suppositories or tablets for vaginitis.

Caspofungin (Cancidas)

Clinical Context:  FDA approved to treat candidemia, invasive candidiasis, and esophageal candidiasis. Initially approved to treat refractory invasive aspergillosis. Also approved as empiric therapy for presumed fungal infections in febrile neutropenic patients. First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of (1,3) β -D-glucan, an essential component of fungal cell wall. This component is not found in mammalian cell walls.

Micafungin (Mycamine)

Clinical Context:  A member of a new class of antifungal agents, echinocandins, that inhibit cell wall synthesis. Echinocandins inhibit the synthesis of (1,3)-β -D-glucan, an essential component of the fungal cell wall, not present in mammalian cells. Indications include prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation, treatment of esophageal candidiasis, candidemia, and invasive candidiasis.

Anidulafungin (Eraxis)

Clinical Context:  One of the newer antifungal agents belonging to the echinocandin class. Also inhibits synthesis of (1,3)-β -D-glucan, an essential component of fungal cell walls. Indicated for treatment of esophageal candidiasis, candidemia, and other forms of candidal infections (eg, intra-abdominal abscesses, peritonitis).

Class Summary

These agents inhibit the formation of fungal cell wall. The antifungal class has expanded with the approvals of caspofungin, micafungin, and anidulafungin. Indications are evolving but have been approved for complicated forms of invasive candidiasis, candidemia, disease refractory to other systemic antifungals, and intolerance to amphotericin B. They are broad spectrum and fungicidal against most Candida species, except C parapsilosis and C guilliermondii.

Amphotericin B (Fungizone, Amphocin)

Clinical Context:  One of the oldest antifungals, in use for more than 40 y, and the criterion standard of antifungal therapy.

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

Amphotericin B, lipid formulations (Amphotec, Abelcet, AmBisome)

Clinical Context:  Novel lipid formulations of amphotericin B that deliver higher concentrations of drug with a theoretical increase in therapeutic potential and decreased nephrotoxicity.

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 intolerant of conventional amphotericin B or with fungal infections refractory to conventional amphotericin B. L-AMB is approved for aspergillosis, candidiasis, cryptococcosis, and neutropenic patients with persistent fever on broad-spectrum antibiotics.

Nystatin (Mycostatin)

Clinical Context:  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. Membrane channel activity is increased at lower doses, and pores are formed at higher concentrations.

Class Summary

These are broad-spectrum fungicidal agents. Mechanism of action is by insertion into fungal cytoplasmic membrane, causing increases in permeability. Membrane channel activity is increased at lower doses, and pores are formed at higher concentrations.

Flucytosine (Ancobon)

Clinical Context:  It is deaminated to 5-fluorouracil in the fungal cell by an enzyme not present in mammalian cells, and inhibits RNA and protein synthesis. Active against Candida and Cryptococcus species and generally used in combination with amphotericin B. It has been used in studies in invasive candidiasis. Avoid use as single agent because of ability to quickly develop resistance in vivo.

Class Summary

Flucytosine is an antimetabolite originally developed for the treatment of leukemia.

Clotrimazole (Mycelex, Femizole-7)

Clinical Context:  Broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing death of fungal cells.

Butoconazole (Femstat-3, Gynazole-1)

Clinical Context:  Broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing death of fungal cells.

Use 2% vaginal cream. Available OTC.

Miconazole vaginal (Monistat, Micatin)

Clinical Context:  Damages fungal cell wall membrane by inhibiting biosynthesis of ergosterol. Membrane permeability is increased, causing nutrients to leak out, resulting in fungal cell death. Lotion preferred in intertriginous areas. If cream is used, apply sparingly to avoid maceration effects.

Tioconazole (Vagistat-1)

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

Terconazole vaginal (Terazol-7, Terazol-3)

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

Class Summary

These agents are used extensively to treat common mucocutaneous uncomplicated forms of candidiasis.

Terbinafine (Daskil, Lamisil)

Clinical Context:  For treatment of paronychia; allylamine antifungal, which inhibits squalene epoxidase and decreases ergosterol synthesis, causing fungal-cell death.

Use medication until symptoms significantly improve.

Duration of treatment should be >1 wk but not >4 wk. May not be as effective for candidal infections as azole antifungals.

Class Summary

These agents cause a deficiency of ergosterol within the fungal cell wall, causing fungal cell death.

Further Inpatient Care

Inpatient care is frequently prolonged because of the severe nature of the disseminated infections. Antifungal therapy may be necessary for a prolonged period, either parenterally or orally.

(1,3)β-D-glucan assay is a useful nonculture method for diagnosis of invasive candidiasis. A decrease in levels during therapy has been associated with treatment success in patients on echinocandin therapy with proven invasive candidiasis. Consecutive serum measurements may be useful as prognostic markers of response.[46]

Further Outpatient Care

Mucocutaneous candidiasis

Patients treated in the outpatient area may be discharged home with medications. Instruct patients to follow up if the symptoms persist or worsen.

If the infections are recurrent, perform an HIV antibody test and rule out conditions that produce immune suppression, such as hematologic malignancies, solid organ malignancy, and diabetes mellitus. If no etiology is established, refer the patients for consultation with an infectious disease specialist to rule out an underlying immune deficiency.

Candidemia and disseminated candidiasis

Because of the severity of the infections, some patients may remain hospitalized for a prolonged period.

Patients on outpatient amphotericin B must be monitored 2-3 times weekly because of its high incidence of adverse effects. The parameters that need to be monitored include CBC count with differentials; electrolyte evaluations; and serum magnesium, BUN, and serum creatinine levels.

Inpatient & Outpatient Medications

With newer treatment modalities that have been recently instituted, de-escalation of antifungal therapy or the rapid switch from intravenous to oral administration is encouraged. Recent clinical studies suggest that patients who are clinically stable and have a functional gastrointestinal tract on day 4-5 of parenteral intravenous antifungal administration should be switched from intravenous to oral therapy with either fluconazole or voriconazole.

Although relatively uncommon, patients may be discharged home on parenteral antifungal therapy or oral azole therapy with close monitoring for toxicity.

Transfer

Transfer patients to the service that can care for the specific candidal infections (eg, general surgery, ICU).

Transfer patients with sepsis or altered mental status to an appropriate critical care unit.

Deterrence/Prevention

Antifungal prophylaxis of invasive candidiasis in high-risk patients is currently recommended for the following:[26, 47]

Currently, no strong indications exist for primary or secondary prevention of oropharyngeal candidiasis (OPC) or vaginal candidiasis in patients infected with HIV. However, concern does exist about the potential development of resistance or colonization by resistant species or strains of Candida. Prophylaxis may be indicated in a select group of patients with recurrent symptomatic candidiasis.

Control the blood glucose level in patients with diabetes mellitus.

Eliminate or decrease risk factors such as steroids, cyclosporin, and tacrolimus.

Nosocomial candidemia prevention should be based on hand hygiene, optimal catheter care, and prudent antimicrobial use.[51]

Complications

If left untreated, candidemia can lead to metastatic foci of infection in the eyes, vertebral column, liver, spleen, CNS, and kidneys. Initiate prompt treatment to prevent foci of infection, abscess formation, and death.

Prognosis

Prognosis depends on several factors, such as the site of infection, the degree and type of immunosuppression, and the rapidity of diagnosis and treatment.

Mucocutaneous candidiasis carries an excellent prognosis, with no mortality and only minimal morbidity.

Systemic candidiasis carries a mortality rate of 30-40% and is generally correlated with the degree of immunosuppression and the underlying disease. In certain groups of patients, the presentation of Candida infection increases the likelihood of death, lengthens hospital stays, and increases hospitalization costs.[52, 53]

The longer the delay to initiate antifungal therapy, the higher the morbidity and mortality associated with candidemia and disseminated candidiasis.

Author

Jose A Hidalgo, MD, Assistant Professor, Universidad Nacional Mayor de San Marcos; Attending Physician, Department of Internal Medicine, Division of Infectious Diseases, Guillermo Almenara Hospital, Peru

Disclosure: Nothing to disclose.

Coauthor(s)

Jose A Vazquez, MD, FACP, FIDSA, Professor of Medicine, Section Chief, Division of Infectious Diseases, Department of Medicine, Georgia Regents University

Disclosure: pfizer Grant/research funds Independent contractor; Merck Grant/research funds Independent contractor; Pfizer Honoraria Speaking and teaching; Forest Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching

Specialty Editors

David Hall Shepp, MD, Program Director, Fellowship in Infectious Diseases, Department of Medicine, North Shore University Hospital; Associate Professor, New York University School of Medicine

Disclosure: Gilead Sciences Salary Management position

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Ronald A Greenfield, MD, Professor, Department of Internal Medicine, University of Oklahoma College of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center

Disclosure: Nothing to disclose.

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

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

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. Courtesy of Matthew C. Lambiase, DO.

Soreness and cracks at the lateral angles of the mouth (angular cheilitis) are a frequent expression of candidiasis in elderly individuals. Courtesy of Matthew C. Lambiase, DO.

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

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

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. Courtesy of Matthew C. Lambiase, DO.

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

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. Courtesy of Matthew C. Lambiase, DO.

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

A nailfold with candidal infection becomes erythematous, swollen, and tender with occasional discharge. Courtesy of Matthew C. Lambiase, DO.

Soreness and cracks at the lateral angles of the mouth (angular cheilitis) are a frequent expression of candidiasis in elderly individuals. Courtesy of Matthew C. Lambiase, DO.

Fine, superficial pustules on an erythematous patchy base are suggestive of candidiasis. Courtesy of Matthew C. Lambiase, DO.

Candidal infection should be in the differential diagnosis when one or more nails become discolored, have subungual discoloration, have nailplate separation from the nailbed, and lack evidence of a dermatophyte. Courtesy of Matthew C. Lambiase, DO.

Candida dermatitis in the diaper area. Courtesy of Hon Pak, MD.