Candidiasis

Candida albicans is the most common cause of human candidal infections,¹ but other pathogenic species include Candida glabrata, Candida parapsilosis, Candida tropicalis, Candida krusei, Candida lusitaniae, and Candida stellatoidea.

Pathophysiology

Infections caused by Candida may affect numerous organ systems, such as the eyes, lungs, kidneys, heart, and CNS.

Skin

The most common manifestation of candidal infection is diaper dermatitis in infants. Candida organisms can also cause intertrigo in older individuals. Intertrigo has a predilection for dark moist areas, such as the groin or fat folds. Predisposing conditions include diabetes mellitus, obesity, and hyperhidrosis.

Nails

A chronic paronychia may be caused by one of several Candida species. Candida organisms can also cause onychomycosis, including total nail dystrophy due to chronic mucocutaneous candidiasis (CMCC), a rare T-cell disorder.

Mucous membranes

Thrush, or oral candidiasis, is also common in infants. Oral candidiasis may also be an adverse effect from using inhaled corticosteroids for asthma due to oral deposition. Patients who are immunocompromised may suffer from candidal esophagitis as well as thrush.

Genitals

Vaginal yeast infections affect nearly 75% of women. Male partners may develop balanitis or balanoposthitis. Individuals with chronic indwelling catheters are also predisposed to recurrent candidal infections.

Systemic

Candida organisms can cause severe systemic infections in immunocompromised patients, compared with benign cutaneous or localized infections in immunocompetent patients. Reports of systemic candidiasis are common in children with acquired immunodeficiency syndrome (AIDS) and other immune deficiencies, as well as in very low birth weight premature infants. Risk factors for candidemia in critically ill children have been identified.⁴⁷ Manifestations include fungemia, endophthalmitis, meningitis, renal or bladder bezoars, and arthritis.

Virulence factors

Numerous factors can contribute to the likelihood of candidal infections. An intact skin barrier is protective. Candidal infections are promoted in the face of lymphocyte dysfunction, as is observed in persons with AIDS and those with CMCC. Adherence of Candida organisms to oral and vaginal epithelium is believed to be promoted by biologic factors (eg, fibronectin in thromboses) and by iatrogenic factors (eg, presence of plastic catheters, disruption of normal bacterial flora). In neonates, risk factors include indwelling catheters, prolonged antibiotic use, necrotizing enterocolitis, previous bloodstream infections, total parenteral nutrition, and low birth weight.

Chronic mucocutaneous candidiasis

CMCC is a heterogeneous group of disorders characterized by chronic candidal infections of the nails, skin, and mucous membranes. Most CMCC disorders are autosomal recessive and related to a mutation in the AIRE gene. Lymphocyte numbers are normal; however, response to in vitro exposure to candidal antigen is absent.

Thrush occurs in approximately 2-5% of healthy newborns and a slightly higher percentage of infants in the first year of life. Vaginal candidal infections occur in approximately 75% of women, and 40-50% of women experience recurrence. Approximately 2-5% of premature infants weighing less than 1500 g develop disseminated disease.

History

Thrush
 
Infants with thrush may experience pain, poor feeding, or fussiness.

Cutaneous candidiasis

Patients with cutaneous candidiasis experience itching, burning, and soreness.

Most commonly affected areas are the diaper area in infants and toddlers and abdominal fat folds and groin in older individuals.

Paronychia and onychomycosis

Candidal paronychia and nail disease has a predilection for the fingernails.

Paronychia is usually painful.

Vulvovaginitis

Most women with vulvovaginitis complain of a creamy vaginal discharge with soreness and burning.

Dyspareunia is often present.

Otitis externa

Otitis externa is found most commonly in tropical and subtropical climates.

Malnutrition and immunosuppression are risk factors.

Candidiasis is clinically difficult to distinguish from other causes of otitis externa.

GI candidiasis

GI candidiasis is primarily observed in individuals who are immunocompromised, especially in persons with human immunodeficiency virus (HIV) infection and/or primary immunodeficiency.

This may be a cause of chronic diarrhea.

Common in infants, glossitis may occur in older children following use of broad-spectrum antibiotics or may signal immunodeficiency.

Esophagitis should be suspected in individuals who are immunocompromised when oral candidiasis is present. Symptoms include dysphagia and odynophagia. Risk of esophagitis is elevated in children taking H2 blockers.

Pneumonia
 
This is extremely rare and usually results from disseminated disease.

Cystitis

Risk factors for cystitis include indwelling urinary catheters, immunosuppression, diabetes mellitus, and use of broad-spectrum antibiotics.

Endophthalmitis

Endophthalmitis is the most common intraocular infection in newborns.

Risk factors include low birth weight and prolonged hospitalization.

CNS infections

CNS infections usually present as subacute meningitis.

Risk factors include indwelling catheters (especially shunts), prematurity, malnutrition, immunodeficiency, and organ transplantation.

Endocarditis

Risk factors for endocarditis include immunosuppression, HIV infection, intravenous catheters, corticosteroid use, prolonged hospitalization, and use of broad-spectrum antibiotics.

Hepatic (hepatosplenic) candidiasis

Risk factors include neutropenia.

Hepatic candidiasis may present with fever of unknown origin. It is usually a manifestation of disseminated candidiasis.

Hepatic candidiasis commonly occurs in oncology patients after a prolonged course of neutropenia. Symptoms develop with return of neutrophils.

Physical

Thrush

White plaques are observed in the mouth and may affect the lips, tongue, gums, and palate

Scraping of the lesions may reveal erythema and bleeding at the base (see following image). The plaques do not scrape off easily.

Cutaneous candidiasis

Lesions consist of beefy-red plaques, often with scalloped borders.

Satellite papules and pustules may be observed surrounding the plaques.

Maceration is often present, especially in intertriginous areas

Candidal diaper dermatitis  is generally confluent in intertriginous areas, whereas generic diaper dermatitis may demonstrate sparing in the folds.

Paronychia and onychomycosis

Paronychia typically involves the cuticular fold of fingernails, causing redness, swelling, and pain.

Pus may be present.

Nail involvement usually stems from long-standing paronychia and causes a yellow discoloration of the nail, often with separation of the nail from the nail bed.

Genital candidiasis

With vulvovaginitis, a creamy white discharge is usually present. White plaques may be observed on an erythematous base of the vaginal mucosa or vulvar skin. Papules and pustules may be present.

With balanitis, lesions are usually observed on the glans penis and consist of erythematous plaques, pustules, or erosions.

GI disease

Glossitis is characterized by creamy or curdlike white plaques, which may be painful and bleed beneath when scraped.

With esophagitis, oral candidiasis may or may not be present. Weight loss is common.

Otitis externa

Tenderness of the pinna, aural discharge, and erythema characterize otitis externa.

Lymphadenopathy of postauricular or preauricular nodes may be present.

A grayish membrane may be present in the canal.

Hepatic candidiasis

This infection usually presents as abscesses in the liver and/or spleen.

Endocarditis

Endocarditis is characterized by fever and a new or changing heart murmur.

Symptoms relating to embolization to other organs (eg, CNS, kidneys, lungs, retina and choroid, skin) may be present.

Endophthalmitis

White well-circumscribed lesions of the retina and choroid in the posterior pole characterize endophthalmitis.

Isolation of candida from blood, urine, or other sources supports the diagnosis of endophthalmitis.

CNS infections

Signs consistent with meningitis are often present with CNS infections.

Evidence of candidal infection of other organ systems may be present.

Causes

Candidal infections have differing presentations in patients who are immunocompetent versus persons who are immunocompromised.

Patient who is immunocompetent

Although candidal diaper rash is common in healthy infants, predisposing factors causing candidal infections in older individuals are often present.

The most common factor is the disruption of normal flora following a course of antibiotic therapy, which is most commonly observed as cutaneous candidiasis or vulvovaginitis.

Other risk factors for candidal infection relate to impaired immune function, including individuals with diabetes mellitus, premature infants, hosts who are immunocompromised, and persons using systemic or topical corticosteroids.

Other risk factors include obesity, heat, and excessive sweating.

Patient who is immunocompromised

Individuals who are immunocompromised are more susceptible to oral and cutaneous candidiasis and often have a more severe course.

Oral candidiasis may appear as acute or chronic atrophic candidiasis, which causes painful red erosions of the tongue and mucous membranes.

Candida species are frequent causes of central venous catheter infections.

Immunosuppression may also cause systemic candidiasis, which may present as fungemia or funguria. Candida species may cause fungal bezoars in the kidney or bladder, or candidiasis may cause abscesses in the liver or spleen. Candidal meningitis, arthritis, and endophthalmitis all have been reported.

Neonates

Neonates with very low birth weight are at a higher risk of developing candidemia.

Risk factors include low birth weight, broad spectrum antibiotic use, total parental nutrition, previous bloodstream infections, or necrotizing enterocolitis.

Chronic mucocutaneous candidiasis (CMCC)
 
CMCC is a cluster of disorders of cell-mediated immunity that presents as chronic severe candidal infections of the skin and mucous membranes.

 

Treatment of candidal infections is primarily accomplished with appropriate antifungal drugs.² Today, neonatal intensive care units in some centers are routinely starting fluconazole prophylaxis to very low birth weight neonates and those with other risk factors to prevent invasive candidiasis

Medication

Candidal infections are sensitive to a broad range of antifungal agents. Nystatin and one of the imidazoles are the most commonly used agents for oral or cutaneous candidiasis. Noting the resistance pattern in your area is important; fluconazole-resistant Candida has been reported. New antifungals include the echinocandins (eg, caspofungin, micafungin, anidulafungin). The mechanism of action of this group is to interfere with the cell wall integrity inhibiting 1,3 beta-D-glucan synthase. Caspofungin has recently been approved by the US Food and Drug Administration (FDA) for use in the pediatric population.

Topical antifungals (oral preparations)

These agents are used for the treatment of oral candidiasis (thrush).

Nystatin oral suspension (Nilstat)

Drug of choice (DOC) for PO candidiasis. Fungicidal and fungistatic antibiotic obtained from Streptomyces noursei.

Gentian violet

Effective as second-line agent for PO candidiasis resistant to nystatin.

Topical antifungals (dermatologic)

These agents are used to treat cutaneous candidiasis.

Nystatin cream (Mycostatin, Nilstat)

DOC in cutaneous candidiasis. Each gram of cream contains 100,000 U.

Clotrimazole 1% cream (Lotrimin, Mycelex)

Second-line agent in treatment of cutaneous candidiasis.

Miconazole 2% cream (Absorbine, Micatin)

Alternate topical antifungal. Lotion is preferred in intertriginous areas. If cream is used, apply sparingly to avoid maceration effects.

Systemic antifungals (oral)

These agents are used for treatment of cutaneous infections refractory to treatment by topical agents or as adjunctive therapy for systemic candidal infection.

Fluconazole oral (Diflucan)

Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal CYP450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes.

Itraconazole (Sporanox)

Effective PO systemic antifungal. Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP450-dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Ketoconazole (Nizoral)

Well absorbed PO. Administer with food to reduce nausea and vomiting. Imidazole broad-spectrum antifungal agent. Inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death.

Flucytosine (Ancobon)

Also known as 5-FC. Converted to fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against Candida and Cryptococcus species and generally used in combination with amphotericin B.

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 due to severe immunosuppression.

Voriconazole oral (Vfend)

Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.

Systemic antifungals (intravenous)

The mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Fluconazole IV (Diflucan)

Second-line agent for treatment of systemic candidal infection.

Amphotericin B, liposome (AmBisome)

Amphotericin B in a 10% lipid emulsion appears to have less nephrotoxicity than standard preparation of amphotericin. Lipid emulsion does not appear to decrease antifungal properties of amphotericin B.

Amphotericin B desoxycholate (Amphocin, Fungizone)

DOC for treatment of systemic fungal infections. Polyene antibiotic produced by strain of Streptomyces nodosus; can be fungistatic or fungicidal. Binds to sterols (eg, ergosterol) in fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death.
Premedication with acetaminophen may help reduce rigors, chills, and fever associated with infusion. Hydrocortisone directly added to infusate also may reduce febrile reactions.

Caspofungin (Cancidas)

First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall.

Voriconazole IV (Vfend)

Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis. May be used as combination therapy in Candidemia