Candida albicans is the most common cause of mucosal candidiasis and is responsible for about half of all cases of candidemia in hospitalized patients
John E. Bennett
Candida albicans is the most common cause of mucosal candidiasis and is responsible for about half of all cases of candidemia in hospitalized patients. A small proportion of C. albicans isolates have been transferred to a new species, C. dubliniensis. C. tropicalis, C. parapsilosis, C. guilliermondii, C. glabrata (formerly Torulopsis glabrata), C. krusei, and a few other Candida species also cause potentially fatal bloodstream infection. Many of these non-albicans species can enter the bloodstream through an intravascular catheter. Candida species, taken together, are the fifth most common cause of nosocomial bloodstream infections in the United States.
All Candida species pathogenic for humans are also encountered as commensals of humans, particularly in the mouth, stool, and vagina. These species grow rapidly at 25° to 37°C on simple media as oval, budding cells. In special culture media and in tissue, hyphae or elongated branching structures called pseudohyphae are formed. C. glabrata differs from other members of the genus in that it forms no true hyphae or pseudohyphae in vitro or in infected tissue. C. albicans and C. dubliniensis can be identified presumptively by their ability to form germ tubes in serum or by the formation of thick-walled large spores called chlamydospores. Final identification of all Candida species requires biochemical tests.
Candidiasis is often preceded by increased colonization of the mouth, vagina, and stool with Candida due to broad-spectrum antibiotic therapy. Additional local and systemic factors favor infection. Oropharyngeal thrush is particularly likely to occur in neonates and in patients with diabetes mellitus, HIV infection, or dentures. Vulvovaginal candidiasis (Chap. 132) is especially common in the third trimester of pregnancy. Candida from the perineum can enter the urinary tract via an indwelling bladder catheter. Cutaneous candidiasis most often involves macerated skin, such as that in the diapered area of infants, under pendulous breasts, or on hands constantly in water or covered by occlusive gloves. Candida can pass from the colonized surface into deep tissue when the integrity of the mucosa or skin is violated, as, for example, by perforation of the gastrointestinal tract through trauma, surgery, or peptic ulceration or by mucosal damage due to cytotoxic agents used for cancer chemotherapy. Although Candida is not normally a resident of the skin, secretions from the mouth, rectum, or vagina as well as drainage from surgical wounds or tracheostomy sites can contaminate the hub or skin site of a catheter in an umbilical or central vein. Intravenous drug abuse or third-degree burns can also provide a skin portal for Candida that can lead to deep candidiasis. Once Candida has passed the integumentary barrier, very low birth weight (in neonates) and neutropenia or glucocorticoid therapy (in any patient) markedly compromise host defense. Hematogenous seeding is particularly evident in the retina, kidney, spleen, and liver.
Oral thrush (Figs. 205-CD1 and 205-CD2) presents as discrete and confluent adherent white plaques on the oral and pharyngeal mucosa, particularly in the mouth and on the tongue. These lesions are usually painless, but fissuring at the corners of the mouth can be painful. Unexplained oropharyngeal thrush raises the possibility of HIV infection. Oral thrush is common in acute HIV infection and becomes increasingly common as the CD4+ cell count falls. At CD4+ counts <50/uL, esophageal thrush also becomes common. HIV infection appears not to be an independent risk factor for vulvovaginal thrush.
Cutaneous candidiasis (Figs. 205-CD3, 205-CD4, and 205-CD5) presents as red macerated intertriginous areas, paronychia, balanitis (Fig. 205-CD6), or pruritus ani. Candidiasis of the perineal and scrotal skin may be accompanied by discrete pustular lesions on the inner aspects of the thighs. Chronic mucocutaneous candidiasis or candidal granuloma typically presents as circumscribed hyperkeratotic skin lesions, crumbling dystrophic nails, partial alopecia in areas of scalp lesions, and both oral and vaginal thrush. Systemic infection is very rare, but disfigurement of the face and hands can be severe. Other findings may include chronic epidermophytosis, dental dysplasia, and hypofunction of the parathyroid, adrenal, or thyroid gland. A variety of defects in T cell function have been described in these patients. Vulvovaginal thrush (Chap. 132, Fig 205-CD7) causes pruritus, discharge, and sometimes pain on intercourse or urination. Speculum examination reveals an inflamed mucosa and a thin exudate, often with white curds.
Esophageal candidiasis is often asymptomatic but can cause substernal pain or a sense of obstruction on swallowing. Most lesions are in the distal third of the esophagus and appear on endoscopy as areas of redness and edema, focal white patches, or ulcers. Biopsy or brushing is required for diagnosis and for detection of concomitant infections, particularly herpes simplex in patients with hematologic malignancies and cytomegalovirus infection in AIDS patients. Esophagography (barium swallow) is diagnostically insensitive but may reveal spasm or mucosal irregularities. Candida esophagitis can cause bleeding and impaired alimentation. Hematogenous dissemination from the esophagus probably occurs in some neutropenic patients but is rarely reported in HIV-infected patients.
Candida can cause cystitis, pyelitis, or renal papillary necrosis in an obstructed urinary tract. When a colonized urinary tract is operated on or instrumented, candidemia may result. However, most patients with Candida cultured from the urine simply have bladder colonization from a Foley catheter or a sizable volume of residual urine. Contamination of a voided midstream specimen by vaginal Candida is also common.
Candidemia originating from an intravascular catheter may clear in the immunocompetent patient when the catheter is removed. Focal seeding of the retina can take place even if candidemia clears and the patient becomes afebrile. Unilateral or bilateral small white retinal exudates appear within 2 weeks of the onset of candidemia. Lesions may regress spontaneously or enlarge slowly. The vitreous humor becomes cloudy, and the patient notices blurring, ocular pain, or a scotoma. Retinal detachment, vitreous abscess, and extension to the anterior chamber can occur over the ensuing weeks. These retinal lesions, present in ~10% of nonneutropenic patients with candidemia, are the principal reason that systemic antifungal therapy is recommended for all patients with candidemia. Funduscopy should be performed to be certain that retinal lesions, if present, resolve completely. Most cases with ocular involvement have occurred in nonneutropenic patients. In contrast, so-called hepatosplenic candidiasis is usually recognized in patients with acute leukemia who are recovering from profound neutropenia. This entity, better called chronic disseminated candidiasis, originates from intestinal seeding of the portal and venous circulation. Fever, modestly elevated serum concentrations of alkaline phosphatase, and multiple small abscesses evident on ultrasonography, magnetic resonance imaging, or computed tomography of the liver, spleen, or kidney suggest the diagnosis. During acute candidemia in neutropenic patients, small erythematous papules may appear anywhere on the skin (Plate IID-57D, Fig. 205-CD8). If the patient does not expire promptly from disseminated candidiasis, the lesions will develop a necrotic center. Painful muscle lesions may also be found. Punch biopsy of a skin lesion helps distinguish this extremely grave condition from Malassezia folliculitis, a similar-appearing but benign condition that can involve the cape area of the chest or the extremities of a sweaty febrile patient.
Hematogenous seeding in the neutropenic patient is occasionally visible radiologically as tiny pulmonary nodules. Candida pneumonia, apart from hematogenous candidiasis, is very rare. Organisms seeding a native or prosthetic cardiac valve originate principally from central venous catheters; occasionally, valvular seeding is encountered in intravenous drug abusers. Emboli to large arteries, such as the iliac or femoral artery, are characteristic. Intravenous injection of impure brown heroin has caused a clinical syndrome consisting of Candida endophthalmitis and purulent folliculitis, sometimes accompanied by vertebral osteomyelitis. This diffuse folliculitis favors hairy areas, including the scalp and bearded facial skin.
Candida can cause indolent arthritis, most commonly of the knee, in patients who have received glucocorticoid injections into the joint, in patients who are immunosuppressed, and in low-birth-weight neonates. Prosthetic joints may become infected during implantation. Scanty growth of Candida from joint fluid can cause the laboratory to incorrectly dismiss the organism as a contaminant.
Hematogenous dissemination can lead to brain abscess or chronic meningitis. Diagnosis of infections of ventriculoperitoneal shunts is difficult because symptoms are indolent and cultures of lumbar fluid are usually sterile.
Demonstration of pseudohyphae on wet smear with confirmation by culture is the procedure of choice for diagnosing superficial candidiasis (Fig. 205-CD9). Scrapings for the smear may be obtained from skin, nails, and oral and vaginal mucosa. Culture alone is not diagnostic; however, recovery of Candida species from multiple superficial sites in immunosuppressed patients may portend visceral invasion.
Deeper lesions due to Candida may be diagnosed by histologic section of biopsy specimens or by culture of cerebrospinal fluid, blood, joint fluid, or surgical specimens. Blood cultures are useful in the diagnosis of Candida endocarditis and intravenous catheter-induced sepsis but are positive less often in other forms of disseminated disease. Serologic tests for antibody or antigen are not useful.
Cutaneous candidiasis of macerated areas responds to measures that reduce moisture and chafing plus topical application of an antifungal agent in a nonocclusive base. Nystatin powder or a cream containing ciclopirox or an azole is useful. Clotrimazole, miconazole, econazole, ketoconazole, sulconazole, and oxiconazole are available as creams or lotions. Candida vulvovaginitis responds better to an azole than to nystatin suppositories. There is little difference in efficacy among miconazole, clotrimazole, tioconazole, butoconazole, and terconazole vaginal formulations. Systemic treatment of Candida vulvovaginitis with a single 150-mg capsule of fluconazole is more convenient than topical treatment but also poses a higher risk of adverse effects. Clotrimazole troches, used five times a day, are more effective in oral and esophageal candidiasis than nystatin suspension. Oral fluconazole (100 to 200 mg once daily) is more convenient and more effective in esophagitis than clotrimazole troches. Esophagitis not responding to fluconazole may warrant repeat endoscopy to exclude other conditions. Itraconazole suspension (100 to 200 mg/d) alleviates Candida esophagitis in some patients in whom fluconazole treatment fails. Amphotericin B suspension has limited use but can be tried in patients whose oropharyngeal candidiasis does not respond to azoles.
Management of recurrent oropharyngeal candidiasis in the HIV-infected patient presents special problems. Patients with CD4+ cell counts <100/uL who have received prolonged fluconazole therapy are at risk of developing azole resistance, requiring an increased dose to mount a response, relapsing early, and eventually failing to respond well to any dose of fluconazole. The increasing azole resistance in this population suggests that HIV-infected patients with oropharyngeal candidiasis should be treated for each individual episode and that only when episodes become intolerably frequent should weekly or daily preventive therapy be given and even then at the lowest dose required to maintain remission. In contrast, AIDS patients with Candida esophagitis are so prone to relapse that preventive therapy with fluconazole is recommended for all proven cases. Most HIV-infected patients with azole-resistant oropharyngeal candidiasis also have esophagitis. Nearly all patients with azole-resistant oropharyngeal or esophageal candidiasis respond to intravenous amphotericin B (0.3 to 0.5 mg/kg daily) but relapse promptly after the completion of therapy.
Bladder thrush responds to bladder irrigations with amphotericin B (50 ug/mL for 5 days). If no bladder catheter is in place, oral fluconazole can be used to control candiduria. In all forms of superficial candidiasis, relapse after successful treatment is common unless the underlying factor can be eliminated.
Intravenous amphotericin B is the drug of choice in disseminated candidiasis. The deoxycholate formulation is usually given at a dosage of 0.5 to 0.7 mg/kg daily. Open, noncomparative studies of the lipid formulations of amphotericin B have suggested that they may be useful in disseminated candidiasis, but the optimal dose and formulation remain unknown. Fluconazole in an adult dose of 100 mg/d is probably the drug of choice for chronic mucocutaneous candidiasis.
In immunocompetent patients with intravenous catheter-acquired C. albicans fungemia, the catheter should be removed in conjunction with the administration of either fluconazole (400 mg/d) or amphotericin B (0.5 mg/kg daily). Patients with suppurative phlebitis of a peripheral vein should have the infected portion of the vein excised. Therapy for candidemia is continued for 2 weeks after the patient becomes afebrile. The Candida species involved should be considered in choosing between fluconazole and amphotericin B. C. krusei and C. inconspicua are rare causes of candidemia but are resistant to fluconazole in vitro. C. glabrata exhibits intermediate susceptibility to fluconazole, but too few cases have been studied to determine whether candidemia involving that species will respond as well to fluconazole as to amphotericin B. Strains of C. lusitaniae resistant to amphotericin B but susceptible to azoles have been encountered. Intravenous amphotericin B, with or without flucytosine, is the preferred treatment for Candida endophthalmitis, although cures have been reported with fluconazole. Pars plana vitrectomy may facilitate diagnosis and cure when a Candida vitreous abscess is present. Injection of amphotericin B into the vitreous humor can also be helpful.
Injection of amphotericin B into an infected joint, pleural cavity, or peritoneum is rarely indicated. Removal of prostheses, including prosthetic joints, cardiac valves, peritoneal dialysis catheters, and central venous catheters, is usually essential. Collections of pus, such as those in the postoperative abdomen, need to be drained surgically or by percutaneous, computed tomography-guided catheterization; an exception relates to the numerous small abscesses in liver, spleen, or kidney in chronic disseminated candidiasis, which cannot be drained effectively and require prolonged antifungal therapy. In general, treatment should continue until the patient with chronic disseminated candidiasis has been afebrile and nonneutropenic for at least 2 weeks. Defects may persist on imaging studies long after cure. Relapse during another episode of neutropenia is common unless the patient is receiving amphotericin B. Repeat cytotoxic therapy or even bone marrow transplantation can be undertaken in patients with prior chronic disseminated candidiasis, but amphotericin B should be given prophylactically during neutropenia.
Fluconazole can decrease the incidence of deep candidiasis in recipients of allogeneic bone marrow transplants when 400 mg is given daily until engraftment. Although the incidence of superficial candidiasis is also decreased by fluconazole prophylaxis, superficial infection can be readily detected and treated. Aspergillosis is not prevented by prophylactic fluconazole. Studies of leukemic and other neutropenic patients have found no beneficial effect of prophylactic fluconazole.^
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