Candidiasis

• ANATOMY OR SYSTEM AFFECTED: Abdomen, bladder, blood, gastrointestinal system, genitals, immune system, mouth, reproductive system, skin, urinary system
• CAUSES: Fungal infection
• SYMPTOMS: Dependent on region; may include white patches on tongue, difficult or painful swallowing, endocarditis, vaginal discharge, intense itching, diaper rash, urinary tract infection
• DURATION: Temporary or chronic
• TREATMENTS: Antifungal drugs, removal of foreign material or infected tissue

DEFINITION: An acute or chronic fungal infection of humans and animals that can be superficial or deep-seated, caused by a species of the fungus Candida.

Causes and Symptoms

Candida is a genus of dimorphic fungi found widely in nature. This fungus may be found in soil, inanimate objects, or plants, or as a harmless parasite of humans and other mammals. It can exist in two forms: as a yeast and as a mold. In the yeast phase, this fungus exists as a normal inhabitant in and on human bodies. Nearly all infections are of such endogenous origin, but human-to-human transmission may occasionally occur from mother to newborn or between sexual partners. The yeasts reproduce asexually by budding, and a sexual stage has been recognized only in a few species. Pseudohyphae develop when yeasts and their progeny adhere to one another, forming chains. Hyphae, the branching tubular structures of molds, are formed in tissue invaded by the fungus.

Identification of Candida as the causative agent in clinical infections depends largely on the microscopic examination of infected tissue or secretions and on a culture of Candida prepared from infected material. Histopathological examination may reveal yeast forms and/or hyphal or pseudohyphal forms. The microscopic appearance of these organisms is similar to that of some other fungi, and a culture is necessary to confirm this fungus as the responsible pathogen. Candida will grow on many types of artificial microbiologic media and can usually be grown on the same media used to grow bacteria. With some types of infection, however, the use of special media or techniques may lead to a higher yield from cultures.

After a yeast strain is grown on artificial media, tests must be performed to determine its identity. Most laboratories initially use the germ tube test, in which yeast is introduced into rabbit or human plasma at 35 degrees Celsius for one to two hours. In this test, a structure called a germ tube is observed if the yeast is Candida albicans or rare strains of Candida tropicalis. If this test is positive (a germ tube is produced), then most laboratories assume that the microorganism is C. albicans—by far the most common species to cause disease—and conduct no further, and usually expensive, tests. Simple cultural tests can be used to identify C. albicans, including the formation of spiderlike colonies on eosin methylene blue agar or the production of chlamydoconidia on cornmeal agar. The identification of Candida antigens in the serum of patients with widespread or disseminated infection is used to assist in the diagnosis of candidiasis, but this test is neither sensitive nor specific.

The bodies of humans and other mammals possess multiple defense mechanisms against candidiasis. The skin and mucous membranes provide a protective wall, but breaks in the mucocutaneous barrier may occur in many ways, including trauma, surgery, and disease. A balanced microbial flora in the gastrointestinal tract prevents the overgrowth of Candida organisms; if overgrowth is not prevented, this can lead to penetration of this fungus into the lining of the gastrointestinal tract and its entrance into the bloodstream. When invasion occurs, phagocytic cells (including monocytes, neutrophils, and eosinophils) further protect the body by ingesting and killing Candida organisms. Phagocytosis is assisted by serum proteins called opsonins. Lymphocytes are also important defenders against this fungus and are part of the cell-mediated immune system. Candidiasis may result when cell-mediated immunity is defective, as is the case with the hereditary condition of chronic mucocutaneous candidiasis or with acquired immunodeficiency syndrome (AIDS).

Candidiasis may be divided into superficial mucocutaneous and deep-seated, tissue-invasive types. There are more than 150 species of this fungus, but only around twenty are recognized as human pathogens. C. albicans is considered the most important, although C. auris, first identified in 2009, raised serious health concerns due to its atypical behavior and multidrug resistance. Oral candidiasis, or thrush, is a common infection characterized by white patches on the tongue and oral mucosal surfaces (oropharyngeal infection). Scrapings taken from these patches contain masses of yeasts, pseudohyphae, and hyphae. Culturing is not as useful as clinical appearance and microscopic examination, since Candida organisms can be grown from normal mouths. Thrush is particularly common when the immune system is impaired, as in patients with cancer, AIDS, or asthma treated with inhaled steroids. Infection of other parts of the gastrointestinal tract, especially the esophagus, may occur in patients with various underlying conditions, including an impaired immune system, gastrointestinal surgery, and antibiotic treatment. Esophageal involvement often results in difficult or painful swallowing. Many patients with esophageal candidiasis may also have an oropharyngeal infection. Some patients with gastrointestinal candidiasis will develop systemic infection, which encompasses both candidemia (the presence of the fungus in the bloodstream) and invasive or disseminated candidiasis (infection of the organs).

Vaginal candidiasis, the most common type of vaginitis, is a common form of the infection associated with an overgrowth of Candida organisms in the vagina, followed by mucocutaneous invasion. The patient will have a thick, curdlike vaginal discharge and itching of the surrounding skin areas. Antibiotic therapy, pregnancy, birth control pills, diabetes, and AIDS all predispose women to this form of infection. Recurrent or chronic infection can occur and may be associated with tissue invasion or impaired response of lymphocytes to the infection in some patients.

Cutaneous infection is common with candidiasis. This fungus is often the cause of diaper rash in infants; the condition often results from infection of the skin under wet diapers by Candida organisms from the gastrointestinal tract. Intertrigo is another skin condition produced by candidiasis in the warm, moist area of skin folds, and similar environments result in perianal or scrotal infections that cause intense itching (pruritus). A widespread eruption of infection involving the trunk, thorax, and extremities is occasionally seen in both children and adults. Invasive or disseminated candidiasis, typically in association with persistent candidemia, may be characterized by widely distributed nodular skin lesions. Candidiasis of the skin, mucous membranes, hair, and nails beginning early in life and associated with defective cell-mediated immunity has been called chronic mucocutaneous candidiasis. This disease is often associated with a variety of endocrine diseases, including diabetes mellitus and decreased function of the parathyroid, thyroid, and adrenal glands.

Deep-organ involvement with candidiasis is serious and often life-threatening. The placement in the body of foreign material used for medical therapy may provide the initial breeding ground for the infection. Examples of these devices include vascular catheters, artificial heart valves, artificial vascular grafts, and artificial joints and other orthopedic implants. The environment created by these foreign materials makes it impossible for the normal defense mechanisms of the body to function.

Urinary tract infection with Candida organisms is seen in association with urinary catheters, especially when usage is chronic. Colonization of the urine with Candida organisms may also occur following a course of antibiotics or in patients with diabetes. Infection of the kidney can result if the candida spreads upward from the bladder through the ureter or via the bloodstream. Renal involvement has been reported in 80 to 90 percent of patients with disseminated candidiasis. In these cases, infection is spread to the kidney through the bloodstream, with the formation of renal abscesses. Primary renal infection occurs when the kidney is invaded directly without concomitant invasion through the blood. Such direct infection may occur in association with urinary catheters or following surgical procedures involving the genital and urinary tracts. A particularly severe form of ascending renal infection, more frequent in patients with diabetes, causes necrosis of the renal papillae and renal failure.

Ocular candidiasis (endophthalmitis) may occur when the eye is infected with Candida organisms either by direct invasion or through the bloodstream. Virtually any portion or structure of the eye may be involved. Examination of the retina using an ophthalmoscope can reveal white spots that resemble cotton balls, indicating Candida organisms in the blood vessels of the eye. This finding may also be a clue to infection elsewhere in the body that has spread through the bloodstream to the eye.

Endocarditis (inflammation of the lining of the heart) occurs when a native or artificial heart valve becomes infected. Candida is a cause of endocarditis of the native valves of individuals who use intravenous drugs and artificial valves of all varieties. Such endocarditis is presumptively diagnosed when the organism is grown from blood specimens in the presence of a heart murmur. Abnormal growth on the heart valves, called vegetation, can usually be demonstrated using echocardiography. Fragments of vegetation may break off and circulate in the bloodstream, leading to the obstruction of vessels in many organs of the body, including the brain, eyes, lungs, spleen, and kidneys. Without treatment, this disease is uniformly fatal.

Disseminated candidiasis is seen in the most susceptible patients, including those with cancer, prolonged postoperative illness, and extensive burns. In these patients, further risk is associated with the use of central venous or arterial catheters, broad-spectrum antibiotic therapy, artificial feeding, or abdominal surgery. Dysfunction of neutrophils, or neutropenia, may increase the susceptibility of the patient to widespread infection with Candida organisms and can also be seen with AIDS. The kidney, brain, heart, and eye are the most common organs to be involved. Despite severe and extensive disease, specific diagnosis of disseminated candidiasis is difficult during life, as blood cultures produce negative results in approximately half of these cases.

Treatment and Therapy

Candidiasis may be prevented by avoiding or ameliorating the underlying predisposing factor or disease state and by decreasing or halting the growth of the fungi. Dry or cracked skin can be treated with dermatologic lubricants. Invasive devices used for medical treatment should be placed in the body under the most sterile conditions and only employed when absolutely necessary. Care of these devices, including urinary catheters, intravascular lines, and peritoneal renal dialysis catheters, must be performed by skilled personnel using the most sterile approach possible. If antibacterial therapy is used excessively, fungal overgrowth may occur; Candida organisms can grow with ease in the gastrointestinal tract and vagina when bacteria are inhibited or killed by antibiotics, and overgrowth can lead not only to local infection but also to bloodstream invasion and secondary infection elsewhere in the body. Moreover, the treatment of underlying disease states such as diabetes mellitus, neoplasia, and AIDS will lessen the detrimental effects of candidiasis on the immune system.

Growth of Candida organisms can be decreased by altering the local conditions that favor their proliferation. For example, changing a baby’s diaper frequently and applying a drying powder can help prevent the wet and warm conditions that can lead to diaper rash. Patients who are obese can lose weight, which will minimize skin fold infections. Wearing nonocclusive clothing, especially cotton fabrics, is often helpful in discouraging candidiasis.

Antifungal agents are often used to prevent candidiasis. Patients in the hospital recovering from surgery who have received antibacterial agents are given nystatin, an oral, nonabsorbed antifungal, to prevent Candida overgrowth in the gastrointestinal tract. For patients with cancer receiving chemotherapy, systemic antifungal drugs are often employed during the period when the chemotherapy has had the most deleterious effects on the immune system.

Antifungals are administered topically, orally, parenterally (through a blood vessel or muscle), or by irrigation for the treatment of candidiasis. Among the many antifungal agents, azoles (fluconazole, voriconazole, and posaconazole) and echinocandins (caspofungin, micafungin, and anidulafungin) are commonly used. Other antifungals include nystatin, flucytosine, amphotericin B, and various imidazole agents. Topical clotrimazole and miconazole may be used to treat superficial infections. Antifungals utilize several mechanisms that impede the metabolic activities of the organism or disrupt the integrity of the cell membrane on the outer surface of the fungus. Fluconazole is usually used in cases of mild to moderate infection. However, many fluconazole-resistant strains emerged in the 2010s and 2020s, making it less effective. Voriconazole, ibrexafungerp, opesconazole, and posaconazole have been used in many of these cases, but in more severe infections, more powerful drugs may be needed.

Echinocandins are useful in the treatment of systemic or deep-organ disease. For serious or life-threatening infection or when a Candida species has been demonstrated by laboratory testing to be resistant to other antifungal agents, amphotericin B may be administered intravenously for systemic and deep-organ disease and by bladder irrigation for lower urinary tract infection (cystitis). However, it has serious side effects.

In addition to antifungals, removal of foreign material or infected tissue is often necessary to treat severe candidiasis. Catheters, vascular grafts, artificial heart valves, artificial joints, and other devices must be removed and then replaced, if necessary, while the patient is receiving antifungal therapy or after the infection is cured. In some cases, such as with endocarditis, the infected tissue must be surgically removed to ensure a cure.

As with prevention, treatment of the underlying disease greatly assists other measures directed against candidiasis. Gaining control of hyperglycemia in patients with diabetes mellitus, viral infection in patients with AIDS, and bone-marrow suppression in patients with cancer will aid in the treatment of candidiasis when it is present.

Perspective and Prospects

More than two thousand years ago, the Greek physicians Hippocrates and Galen described oral lesions that were probably thrush, but it was not until 1839 that fungi were found in such lesions. Deep-seated infection was first described in 1861, and endocarditis was identified in 1940. Candidiasis was recognized as an indicator disease in the 1987 surveillance definition for AIDS by the Centers for Disease Control and Prevention (CDC) in the United States. Candida ranks among the most common pathogens in hospital-acquired infections.

The incidence of Candida infections rose in the late twentieth and early twenty-first centuries, largely due to increasingly sophisticated medical therapies, as well as the growing prevalence of organ transplantation, resulting in a rise in immunocompromised individuals. C. glabrata showed increased resistance to treatment with drugs in the azole class, and C. auris became resistant to multiple antifungal classes. As candidiasis cases and antifungal resistance increased, more effective preventive and therapeutic measures became necessary to combat candidiasis, including the development of new antifungal agents. Early identification of resistant organisms benefits patients by providing more effective antifungal therapy at an earlier stage of treatment.

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