Christopher R. Fox MD
Merle A. Sande MD
Essentials of Diagnosis
General Considerations
Candida species cause a wide spectrum of clinical diseases that range from mild, superficial infection of the skin and mucous membranes to life-threatening, invasive, multisystem disease. Infection with Candida requires an alteration in the normal milieu that allows the fungus to proliferate and evade host responses.
Under correct conditions, Candida is able to infect any of the body's mucosal surfaces, as well as the skin. Three-quarters of women report vaginal candidiasis within their lifetime, and the incidence appears to have increased over the last 20 years. Risk factors include recent antibiotic use, pregnancy, oral contraceptive use, diabetes, and human immunodeficiency virus (HIV) infection.
Oral thrush is another frequent manifestation of mucosal candidiasis with similar risk factors to vaginal candidiasis. These risks include systemic disease such as HIV infection or diabetes, inhaled or oral corticosteroid use, and neutropenia induced by chemotherapy.
In addition to the local forms of disease described above, Candida species may cause invasive disease with systemic manifestations and multiple infected organs. Although once limited to the oncology ward and bone marrow transplant unit, candidemia is now more frequent in all areas of the hospital, with Candida the fourth most common organism reported from hospital blood cultures. Specific risk factors for invasive disease include previous isolation of Candida from another site, the use of antimicrobial agents, prolonged neutropenia, indwelling central catheters, and the use of parenteral nutrition.
Although the majority of Candida infections are caused by C albicans, several non-albicans species are emerging as important pathogens and deserve mention. C krusei appears to be less virulent than C albicans and rarely causes disease in the normal host. However, in those with depressed immune function, C krusei is able to cause significant infection. Candidemia, ocular infection, endocarditis, and renal disease all occur with some frequency. C krusei infection has important therapeutic implications as the organism is generally resistant to fluconazole. C glabrata, another Candida species with increasing recovery rates, usually has intermediate resistance to fluconazole.
Candida produces proteins expressed within the cell wall that promote binding and adherence to epithelial cells, endothelium, platelet and fibrin clots, and plastics. These proteins likely help the organism attach to and invade damaged mucosa and may play a role in Candida infection in hosts with indwelling bladder and central venous catheters. Candida species also produce proteases and phospholipases, which may aid the organism in evading host defenses and invading mucosal surfaces.
CLINICAL SYNDROMES
CANDIDA DERMATITIS
Clinical Findings
Chronic mucocutaneous candidiasis (CMC) is an abnormality of cell-mediated immunity that presents with recurrent infections of the skin and mucus membranes that may progress to disfiguring lesions (Candida granulomas) despite antifungal therapy. Symptoms usually begin in the first several years of life. CMC is associated with autoimmune endocrine failure, particularly hypoparathyroidism and adrenal insufficiency (polyglandular autoimmune syndrome type I), and endocrine disease often presents years to decades after the onset of CMC.
Cutaneous lesions may be superficial evidence of disseminated candidiasis and candidemia. Lesions are typically red or pink nodules 5–10 mm in diameter and may be single or widespread. Lesions resembling ecthyma gangrenosum or purpura fulminans have also been described.
Diagnosis
Diagnosis of Candida infection involving the skin or nails is generally made by recognition of the clinical pattern followed by demonstration of fungal elements on a KOH preparation of skin scrapings. Candida infection may also be diagnosed by microscopic examination of biopsy specimens. Culture of the skin should be interpreted with caution, as the presence of Candida spp. may represent colonization rather than infection.
Treatment
Treatment of Candida skin infections is generally straightforward. Intertrigo is managed by decreasing moisture in infected areas and by application of topical antifungal therapy. Nystatin cream, topical azoles (miconazole, clotrimazole), and amphotericin B cream are all effective when applied 2–3 times daily. Paronychia may be treated by keeping the area dry and with topical antifungal therapy. Onychomycosis requires several months of treatment with oral azoles, such as itraconazole, or terbenifine. Relapses may occur. Griseofulvin is not active against Candida..
CMC is treated with oral ketoconazole or fluconazole. Transfer factor, an immunomodulating factor composed of a cell-free leukocyte extract, was used in the past but has fallen out of favor because of lack of efficacy. Months to years of treatment are generally required.
ORAL CANDIDIASIS
Clinical Findings
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BOX 73-1 Dermatologic and Mucosal Candidiasis |
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Diagnosis
The diagnosis of oral Candida infection may be suspected when the characteristic appearance of the mucosa is present and, in the case of oral thrush, when scraping of the mucosa removes the white plaque and leaves an inflamed mucosa. Demonstration of dimorphic fungi on KOH-, Giemsa-, Gram-, or PAS-stained oral scrapings strongly supports the diagnosis. Culture of Candida species from oral scrapings is not generally required, and as Candida may be part of the normal flora of the oral cavity, positive cultures may not represent true infection.
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BOX 73-2 Deep-Tissue Candida Infection |
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Treatment
Generally, oral Candida infection should initially be treated with topical agents (Box 73-3). Nystatin suspension or clotrimazole troches are generally effective therapy. If infection occurs in a denture wearer, the dentures must be removed. Once the infection is cured, proper dental hygiene is important to prevent recurrence. Topical antifungal creams will treat angular cheilitis.
If topical therapy fails, or in those with severe infection, systemic therapy may be used. In patients with advanced HIV infection, itraconazole doses may require adjustment because of achlorhydria and impaired absorption. Treatment failure should prompt a search for other causes, such as bacterial infection or malignancy.
In those infected with HIV or with other immune deficits, frequent recurrences are common, and maintenance therapy may be necessary. Daily treatment with topical antifungal agents or fluconazole, 50–100 mg daily, every other day, or once weekly may prevent recurrence. Maintenance therapy with fluconazole should be avoided if possible because of concerns for the emergence of resistant fungal strains.
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BOX 73-3 Treatment of Oral Candidiasis |
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ESOPHAGEAL CANDIDIASIS
Clinical Findings
Diagnosis
Radiographic techniques using barium contrast (barium swallow) and endoscopy are useful for diagnosis of Candida esophagitis. The barium swallow has a characteristic appearance, with a shaggy-appearing mucosa and sometimes nodules and cobble stoning. This technique does not allow firm diagnosis, which requires histology or culture.
Endoscopy is the preferred method of diagnosis, as it allows direct visualization of the mucosa and biopsy of affected areas. The mucosa typically has adherent white plaques that may be removed with the endoscope to reveal an erythematous mucosa. Brushings of the mucosa may be prepared as for oral disease. Histologic specimens reveal fungal elements, which are more apparent on PAS-stained and silver-stained material than with hematoxylin-eosin staining.
Treatment
A subset of patients may be treated empirically. In those with HIV infection, oral thrush, and mild to moderate symptoms of esophagitis, treatment with topical agents or an azole may be warranted. If no oral thrush is present, or if treatment fails, endoscopy should be performed to exclude other causes of disease.
As with oral thrush, topical agents may be successful in treating esophagitis (Box 73-4). If patients fail topical treatment, have severe disease, or are considered to be at high risk for disseminated disease, systemic therapy should be used. Therapy for 10 days is generally adequate.
CANDIDA VULVOVAGINITIS
Clinical Findings
Examination may reveal discrete papular or pustular lesions of the vulva, with erythema and swelling of the vulva and labia. The discharge is present within the vaginal vault, and the vaginal mucosa is inflamed and may have adherent white plaques similar to oral thrush. The cervix appears normal.
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BOX 73-4 Treatment of Candida Esophagitis |
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Diagnosis
The diagnosis of vulvovaginitis is typically made by history, physical examination, and light microscopy. In women with appropriate symptoms and fungal elements on wet mount or KOH preparation, therapy is indicated without further testing. As up to 50% of symptomatic women with culture-proven infection have negative microscopy, vaginal culture is indicated in those patients with symptoms and no microscopic findings. A vaginal pH >4.5 or a large number of white cells on wet mount should prompt a search for a different or possibly coexistent process.
Treatment
Numerous agents are available for treatment of Candida vulvovaginitis in both topical and oral preparations (Box 73-5). Among topical agents, cure rates range from 75 to 90%, with the azole preparations (clotrimazole, miconazole, terconazole) having slightly better efficacy than nystatin. The formulation (cream versus suppository versus vaginal tablet) does not alter the success rate; therefore the choice of formulation is a matter of patient preference. Currently there is a trend toward higher doses of topical agents with shorter durations of therapy, with success reported with even high-dose, one-time therapy. Anecdotal failure rates are fairly high with one-dose therapy; thus this is best reserved for women with infrequent infections and mild or moderate symptoms.
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BOX 73-5 Treatment of Candida Vulvovaginitis1 |
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Oral azole agents are quite effective for vaginal infection and are more convenient than topical therapy but are more expensive. Fluconazole and itraconazole single-dose therapy are at least as effective as topical therapy.
Cure of Candida vulvovaginitis during pregnancy can be difficult, with relapses frequently occurring. If therapy is extended to 1–2 weeks, topical antifungal therapy is effective. Oral azoles should be avoided during pregnancy.
In women with frequent recurrent infections, therapy is often disappointing, with symptoms recurring within weeks of withdrawal of antifungal agents. In these women, predisposing factors such as diabetes or HIV infection should be considered. HIV testing is appropriate in women with risk factors for HIV infection. If fasting blood glucose values are normal, further testing for diabetes is not required. Oral contraceptives should be discontinued if possible, although continuation of low-dose estrogen preparations, as long as long-term antifungal therapy is used, may be considered. Vaginal douching and treatment of the sexual partner are not recommended. Frequently, no risk factors are identified, and prophylactic therapy is required. The best-studied regimen with proven efficacy for prophylaxis is ketoconazole, 100 mg daily. Toxicity, such as hepatitis, is infrequent but may occur. Other regimens with anecdotal support include fluconazole, 100–200 mg once weekly, and clotrimazole vaginal tablets, 500 mg once weekly.
CANDIDURIA, CANDIDA CYSTITIS & URINARY TRACT CANDIDIASIS
The presence of Candida spp. in the urine is common and does not necessarily represent infection. Candiduria is commonly associated with antibiotic use, indwelling urinary catheters, and diabetes mellitus and frequently resolves if predisposing factors can be corrected. Patients are generally asymptomatic, although some will have symptoms similar to bacterial cystitis, with dysuria, frequency, and urgency (Box 73-2). Urinalysis shows fungal elements and may reveal pyuria. At cystoscopy, the mucosa of the bladder typically has an inflamed appearance with adherent white plaques that may be removed with the scope.
Candida spp. may also cause urethritis, typically in male sexual partners of women with vaginal Candida infection, as well as higher urinary tract infection. The upper urinary tract and renal parenchyma may be infected from ascending infection or, more commonly, from hematogenous spread as part of a syndrome of disseminated candidiasis. With ascending infection, perinephric abscesses, papillary necrosis, fungus balls, and calyceal involvement have all been described. Risk factors are generally present and include diabetes mellitus, urinary tract obstruction, and renal stones. With hematogenous spread, the renal parenchyma becomes studded with multiple microabscesses.
Diagnosis
Candiduria is usually discovered when a urine culture reveals the presence of Candida spp. The presence of pyuria generally indicates true infection if other etiologies, such as bacterial infection, have been excluded. Infection may also be diagnosed by demonstrating the presence of a typical appearing fungus in biopsy specimens obtained during cystoscopy.
Of particular importance for treatment is whether candiduria represents colonization or true infection, and whether the upper urinary tract is involved, a distinction that can be troublesome. Those with risk factors for ascending infection (diabetes, stones) and those at risk for disseminated disease are more likely to have upper urinary tract infection. Computerized tomographic scans or ultrasound may reveal microabscesses or fungus balls.
Treatment
When treating Candida infection of the urinary tract, careful consideration must be given to whether candiduria represents colonization or true infection, and whether the upper urinary tract is involved. Asymptomatic candiduria usually does not require antifungal treatment, but indwelling catheters should be removed as soon as possible. (Treatment is summarized in Box 73-6.) In the presence of pyuria, diabetes mellitus, or renal transplantation, treatment is indicated. Oral fluconazole is recommended as the initial agent. Bladder irrigation with amphotericin B is also effective. Patients with candiduria should be treated prior to instrumentation of the urinary tract.
In patients with evidence of systemic toxicity, Candida infection at other sites, risk factors for ascending infection (structural or metabolic abnormality of the urinary tract such as stones or diabetes), or risk factors for disseminated candidiasis (burns, neutropenia, or GI surgery), consideration must be given to the possibility of upper urinary tract infection or disseminated candidiasis. Upper urinary tract involvement usually will respond to oral fluconazole, although intravenous amphotericin B is required for infections resistant to fluconazole or unresponsive to initial fluconazole treatment. Fungus balls and large perinephric abscesses may require surgical intervention. Treatment of disseminated candidiasis is discussed next.
CANDIDEMIA & DISSEMINATED CANDIDIASIS
Candidemia may present in a variety of fashions, ranging from asymptomatic to fulminant sepsis. The candidemic patient generally has risk factors for infection, such as malignancy, chemotherapy-induced neutropenia, organ transplantation, GI surgery, burns, indwelling catheters, or exposure to broad-spectrum antibiotics.
Disseminated candidiasis must be assumed to be present in those with positive blood cultures, although negative cultures do not preclude the possibility of disseminated disease. Dissemination usually manifests with many microabscesses involving multiple organs, especially the liver, spleen, and eye, but almost any organ may be involved (Box 73-2).
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BOX 73-6 Treatment of Urinary Tract Candidiasis |
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Diagnosis
Candidemia is diagnosed by recovering Candida species in blood culture. Candidemia may be isolated or may occur in the setting of disseminated candidiasis. The possibility of disseminated candidiasis should be considered in any patient with deep Candida infection, multiple sites of infection, or positive blood cultures. Disseminated candidiasis is diagnosed by tissue culture of biopsy material or demonstration of Candida in histologic specimens. At present, serology is available but has false-negative and false-positive rates too high to be of use clinically.
Treatment
The treatment of candidemia is the subject of much debate and controversy. Because isolation of Candida from the blood carries a high morbidity and because there is currently no method to predict which patients will not require treatment, there is agreement that all patients with candidemia should be treated. The standard treatment in the past has been amphotericin B, with or without 5-FC. Currently, fluconazole appears to be a reasonable alternative, although there are limited data comparing mortality of fluconazole-treated patients versus those treated with amphotericin. One randomized study of candidemic patients demonstrated fluconazole to be equally efficacious but associated with less toxicity when compared with amphotericin.
Fluconazole may be used as initial treatment of candidemia in a stable patient (Box 73-7). If patients had been treated with fluconazole for 2 days or greater at the time of candidemia, deteriorate on fluconazole therapy, or are unstable (hypotension, need for mechanical ventilation, multiple comorbid factors, etc.) at the time their candidemia is diagnosed, then treatment with amphotericin is warranted. Smaller doses may be used if amphotericin if chosen as the initial regimen for stable patients. Because of the potential bone marrow toxicity of 5-FC, particularly when combined with amphotericin, the dose of 5-FC is generally reduced when part of the treatment regimen. Treatment is generally continued until clinical improvement is seen and for 2 weeks after the last positive blood culture.
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BOX 73-7 Treatment of Candidemia and Disseminated Candidiasis1 |
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For all patients with candidemia, the possibility of disseminated infection must be considered. If infection with C krusei is suspected or documented, fluconazole should not be used as initial therapy because this species has a high level of resistance to fluconazole. C glabrata has an intermediate level of resistance, and fluconazole therapy may be used with caution. Clinical deterioration should prompt an early change of therapy to amphotericin. Treatment for disseminated disease should continue until there is definite resolution of parenchymal involvement and for 2 weeks after the last positive blood culture.
Intravenous catheters should be removed from candidemic patients if possible. In addition, all patients with candidemia should be followed clinically for at least 3 months, as deep infection caused by hematogenous spread may not manifest initially. Patients should be instructed to report any symptoms, which may represent late complications, such as fever, fatigue, jaundice, visual disturbances, abdominal pain, or bone pain.
CANDIDA ENDOCARDITIS
Endocarditis caused by Candida species has been reported with increasing frequency, particularly after valvular surgery. Other predisposing factors include underlying valvular disease, concomitant bacterial endocarditis, intravenous drug use, intravenous catheters, and chemotherapy. Aortic and mitral valves are commonly infected. The symptoms are similar to that of bacterial endocarditis with fever, malaise, weight loss, and signs and symptoms of embolic phenomena. Splinter hemorrhages, Osler's nodes, Janeway lesions, hepatosplenomegaly, hematuria, proteinuria, and pyuria may all occur. Candida has the ability to cause large vegetations and large emboli, which may be catastrophic, and valvular lesions may progress to cause perforation, congestive heart failure, and myocarditis (Box 73-2).
Diagnosis
Blood cultures are generally positive in Candida endocarditis, although negative cultures may occur in up to 25% of patients. Echocardiography reveals vegetations, which may become quite large. Transesophageal echocardiography is more sensitive for detection of vegetations than transthoracic echocardiography. The role of serologic tests (Candida antibodies) is uncertain, as both false positive and false negative results occur with some frequency.
Treatment
Treatment of Candida endocarditis generally requires combined surgical and medical therapy. Once the diagnosis is established, therapy with amphotericin B should be initiated and the valve replaced as soon as possible (Box 73-8). Antifungal therapy is generally required for a total of 6–10 weeks, and patients should be monitored for a minimum of 2 years after completion of therapy because of the high risk of relapse. For those in whom surgical treatment is not possible, such as those too ill to survive an operation, there exist case reports of treatment success with medical therapy alone (amphotericin B followed by fluconazole).
GI CANDIDIASIS (NONESOPHAGEAL)
Candida species may infect any mucosal surface of the GI tract. After esophageal candidiasis, infection of the stomach is most common. Typically, the organism is seen infecting benign ulcers, although a diffuse mucosal form of infection resembling thrush has been described. In the small and large bowel, ulceration and pseudomembrane formation are common. Mucosal GI involvement may cause deep ulcerations with resulting hemorrhage or perforation (Box 73-1).
Candida may also infect the peritoneum, liver, spleen, gallbladder, or pancreas. Peritoneal infection is associated with peritoneal dialysis, GI surgery, and GI perforation. Dissemination beyond the abdomen is uncommon. Involvement of the liver, spleen, and pancreas occurs most commonly in immunocompromised hosts, particularly with chemotherapy-induced neutropenia. Often, other manifestations of disseminated candidiasis are present. Fungus balls may form in the gallbladder and biliary tree and cause obstruction. Abscesses may involve the liver and spleen.
Diagnosis
Involvement of nonesophageal mucosal involvement of the GI tract is generally diagnosed by characteristic appearance during endoscopy and by demonstration of Candida by histology or culture of biopsy specimens. Involvement of the peritoneum, liver, spleen, gallbladder, and pancreas may be difficult to diagnose. Fluid returned after peritoneal dialysis may grow Candida in culture. Computer tomography or magnetic resonance imaging may reveal splenic or hepatic abscesses. Laparoscopy may be required for definitive diagnosis.
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BOX 73-8 Treatment of Candida Endocarditis |
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Treatment
Fluconazole is recommended for initial therapy of mucosal involvement in the stomach, small intestine, or colon (Box 73-9). Amphotericin B may also be used. Candida peritonitis may also be treated with fluconazole alone or amphotericin B followed by fluconazole. Peritoneal dialysis catheters should be removed if possible. For patients with a perforated viscus, prophylactic therapy is not indicated and should be reserved for those patients with intraoperative findings consistent with Candida infection and positive peritoneal cultures.
Involvement of the liver, spleen, gallbladder, or pancreas should be treated with fluconazole or amphotericin followed by fluconazole. Dosages and duration of therapy are the same as for candidemia and disseminated disease. Large abscesses and fungus balls may require drainage or surgical removal.
OTHER CANDIDA SYNDROMES
Candida species are capable of causing many other infectious syndromes, which will be mentioned briefly. Infection of the respiratory tract may result in bronchopneumonia or diffuse nodular infiltrates. Within the central nervous system (CNS), Candida spp. may cause meningitis and parenchymal abscesses, usually as part of a disseminated infection. Candida spp. have been described as the etiologic agents for osteomyelitis, septic arthritis, myositis, and chostochondritis. Ocular infection may involve any structure within the eye and is common following hematogenous dissemination.
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BOX 73-9 Treatment of Non-esophageal GI Candidiasis |
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Diagnosis
The diagnosis of Candida infection of the lung, CNS, musculoskeletal system, or eye generally requires demonstration of the organism by tissue culture or on histologic examination. However, visualization of the typical well-demarcated white retinal or vitreal lesion by funduscopic examination in the setting of positive blood cultures is adequate for the diagnosis of Candida endophthalmitis. It should be noted that sputum culture is generally not sufficient for diagnosis of respiratory involvement, particularly in an intubated patient, as the organism may only be colonizing the respiratory tract.
Treatment
Amphotericin B has been the standard treatment for Candida infection in the CNS, eye, lung, and musculoskeletal system. Prosthetic material or other foreign bodies should be removed, if possible. The role of 5-FC is not clear, but it may be added to amphotericin. There is growing support for the use of the azole class, particularly fluconazole, as treatment for deep Candida infection. While case reports of success with fluconazole exist, there are very limited data regarding fluconazole in these settings and virtually no data comparing fluconazole with amphotericin.
Prevention & Control of Candida Infections
Candida species are ubiquitous; thus prevention of disease is best accomplished by elimination of risk factors as opposed to elimination of the organism (Box 73-10). Antibiotic therapy should be focused to treat specific organisms whenever possible. Indwelling vascular and bladder catheters should be removed as early as possible. In the hospital environment, health care professionals should practice good hand washing to minimize introduction of Candida infection to patients at risk.
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BOX 73-10 Prevention & Control of Candidiasis |
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The role of prophylactic therapy is unclear but generally not supported. Prophylactic therapy has been shown to reduce mortality in bone marrow transplant patients but not in any other setting. Prophylactic therapy for candidemia may be warranted in patients' with negative blood cultures who have multiple risk factors for infection and have isolation of Candida from multiple sites but is generally discouraged because of concern for creating resistant organisms. Empiric therapy may also be employed in certain settings, such as neutropenic patients who remain persistently febrile for 7–14 days despite broad spectrum antibiotics and exclusion of other possible causes of infection or in patients with two or more risk factors for invasive Candida infection and isolation of Candida from sputum or urine. Fluconazole is the preferred agent in these settings.
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