Candidiasis

INTRODUCTION

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Background: Candida species are ubiquitous fungi and the most common fungal pathogens affecting humans. The growing problem of mucosal and systemic candidiasis reflects the enormous increase in the pool 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 primarily is dependent upon 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. Management of serious and life-threatening invasive candidiasis remains severely hampered by delay 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 had a major impact in reducing the morbidity and mortality of life-threatening disease. Patients who are critically ill and in medical and surgical intensive care units 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 of various anatomical sites. High-risk areas for Candida infection include neonatal, pediatric, and adult intensive care units (ICUs), both medical and surgical. Candida infections may 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 the human and animal reservoirs; however, they frequently are recovered from the hospital environment, including on foods, counter tops, air-conditioning vents, floors, respirators, and medical personnel. They also are 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 virulence factors. Although not well characterized, several virulence factors may contribute to their ability to cause infection. The main virulence factors are surface molecules that permit adherence of the organism to other structures (human cells, extracellular matrix, prosthetic devices), acid proteases, and the ability to convert to a hyphal form.

As with most fungal infections, host defects also play a significant role in the development of candidal infections. Numerous host defects are associated with candidal infections.

Table 1. Host Defense Mechanisms Against Candida Infection

• Granulocytopenia
• Bone-marrow transplantation
• Solid-organ transplantation (liver, kidney)
• Parenteral hyperalimentation
• Hematologic malignancies
• Foley catheters
• Solid neoplasms
• Recent chemotherapy or radiation therapy
• Corticosteroids
• Broad-spectrum antibiotics
• Burns
• Prolonged hospitalization
• Severe trauma
• Recent bacterial infection
• Recent surgery
• Gastrointestinal tract surgery
• Central intravascular access devices
• Premature birth
• Hemodialysis

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

Frequency:

• In the US: Candida species are the most common cause of fungal infection affecting patients who are immunocompromised. 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 have at least one bout of vulvovaginal candidiasis (VVC) during their lifetime.

  In the population positive for HIV, more than 90% of patients experience oropharyngeal candidiasis (OPC), and 10% have at least one episode of esophageal candidiasis.

  In systemic infections, Candida species are now the fourth most commonly isolated pathogens from blood cultures.

  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 (ie, patients undergoing complex surgical procedures, patients with indwelling vascular devices), and the improved survival of patients with underlying neoplasms or collagen-vascular disease and patients who are immunosuppressed.

• Internationally: Similar rates of mucocutaneous and systemic candidiasis have been observed worldwide. In fact, Candida species have replaced Cryptococcus species as the most common fungal disease affecting hosts who are immunocompromised throughout the world.

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 for these infections have not improved markedly over the past few years and remain in the range of 30-40%. Systemic candidiasis is the cause of more case fatalities than any other systemic mycoses. More than a decade ago, investigators reported the enormous economic impact of systemic candidiasis in patients who are hospitalized. Candidemia is associated with considerable prolongation of length of stay in the hospital (70 vs 40 d in patients who are comparable, matched, and nonfungemic). 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: Colonization with Candida species occurs in equal numbers of males and females; however, in women, VVC is the second most common cause of vaginitis.

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Genitourinary tract candidiasis

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• Vulvovaginal candidiasis: 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 includes a vagina and labia that usually are erythematous, a thick curdlike discharge, and a normal cervix on speculum examination.

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• Candida balanitis: Patients complain of itchiness of the penis. Lesions and whitish patches are present. Candida balanitis is acquired through sexual intercourse with a partner who has VVC. Physical examination reveals vesicles on the penis that develop later into patches resembling thrush. The rash may spread to the thighs, gluteal folds, buttocks, and scrotum.

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• Candida cystitis: Many patients frequently 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; otherwise, the examination may be unremarkable.

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• Asymptomatic candiduria: Most catheterized patients with persistent candiduria are asymptomatic, as noncatheterized patients may be. The majority of patients with candiduria have easily identifiable risk factors for candida colonization. Thus, the distinction between invasive disease and colonization cannot be made solely on culture results because approximately 5-10% of all urine cultures may be positive for Candida.

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• Ascending pyelonephritis: The use of stents and indwelling devices, along with the presence of diabetes, is the major risk factor predisposing patients to ascending infection. The patient frequently has a history associated with flank pain, abdominal cramps, nausea, vomiting, fever, chills, and hematuria, Physical examination reveals abdominal pain, costovertebral-angle tenderness, and fever.

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• 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.

WORKUP

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Lab Studies:
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• Unfortunately, findings from the laboratory studies often are nonspecific. 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. Patients who remain febrile despite broad-spectrum antibiotic therapy, with either persistent neutropenia or other risk factors and persistent leukocytosis, should be suspected of having systemic candidiasis. To be effective, provide therapy early and empirically in such patients.

• Cultures of nonsterile sites, though not useful in establishing a diagnosis, may demonstrate high degrees of candidal colonization. This may be useful in initiating antifungal therapy in patients with fever unresponsive to broad-spectrum antimicrobials. Therefore, appropriate interpretation is required. In contrast, positive blood cultures and cultures from any other sterile sites imply that invasive disease is present. Always consider positive culture results from sterile sites to be significant and evidence of infection.

• Nonculture Candida detection assays: Unfortunately, nonculture detection assays currently are not available in the United States; however, several are used in Europe and Asia.

• Candida Mannan assay - Sensitivity of 31-90% (less for non-albicans Candida species)
• Candida heat labile antigen - Sensitivity of 10-71%
• D-arabinatol - Sensitivity of 50% (not useful for infection with C krusei or C glabrata)
• Enolase assay - Sensitivity of 55-75% (improved with serial testing)
• 1-3 D-glucan assay - Amebocyte lysis assay with a sensitivity of 75-100% and a specificity of 88-100% (broad-spectrum assay that detects Aspergillus, Candida, Fusarium, Acremonium, and Saccharomyces)
• Molecular assays - Polymerase chain reaction (PCR) tests and DNA probes still are under development and in the early investigational phases, but they appear promising.

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

TREATMENT

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Medical Care: Treatment of Candida infections varies substantially and is 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 strain to antifungal drugs. In April of 2000, practice guidelines for the treatment of candidiasis were published by the Infectious Disease Society of America.

• Genitourinary tract candidiasis

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  • VVC can be managed with either topical antifungal agents or single-dose oral fluconazole. Recently, single-dose oral fluconazole has been approved by the Food and Drug Administration (FDA) for acute episodes of VVC and has been shown to have clinical and microbiological efficacy as good as or better than topical antifungal agents. A small percentage of women (<5%) experience chronic recurrent vulvovaginal candidiasis (RVVC) infections, which often require chronic or prophylactic oral azole therapy for control. In women who experience recurrent attacks, the standard recommended regimen includes fluconazole at a dose of 150 mg every other day for 3 doses, followed by weekly fluconazole at a dose of 150-200 mg for 6 months. Using this regimen, more than 80% of women do not experience RVVC infections.

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  • Asymptomatic candiduria: Therapy generally depends on the presence or absence of an indwelling Foley catheter. The candiduria frequently will resolve with change of the Foley catheter (20-25% of patients). Thus, when candiduria is associated with a Foley catheter, most clinicians believe that it should not be treated most of the time. However, eradicating candiduria prior to any form of instrumentation or urological manipulation is prudent.

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  • Candida cystitis: In noncatheterized patients should be treated with fluconazole 200 mg/d orally for at least 10-14 days. In catheterized patients, the first step is always to remove the nidus of infection. Thus, the Foley catheter should be discontinued or replaced prior to initiating antifungal therapy. If the candiduria persists after the catheter change, then patients can be treated with 200 mg/d of fluconazole orally for 14 days. Alternative therapy includes amphotericin B bladder irrigation. Using this technique, 50 mg of amphotericin B is diluted in 1 L of sterile water and infused by slow continuous flow (40 mL/h) via a 3-way indwelling catheter. Administering IV amphotericin B to treat candiduria rarely is necessary.

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• Renal candidiasis: Regardless of the route of infection, whether it involves hematogenous dissemination to the kidney or ascending infection (pyelonephritis), systemic antifungal therapy is required. The most recent comparative studies indicate that fluconazole (Diflucan) 400-800 mg/d IV or orally is as effective as amphotericin B without the toxicities normally associated with amphotericin B. For amphotericin B, the daily dose is 0.5-0.7 mg/kg/d IV for a total dose of 1 to 2 g administered over a 4- to 6-week period.

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• Candidemia requires treatment in all patient populations. For most situations, fluconazole has become the drug of choice in the management of candidemia and disseminated candidiasis. Studies conducted by the Mycosis Study Group have demonstrated that fluconazole at a dose of 400 mg/d is as efficacious as amphotericin B. In addition, fluconazole has several advantages, which are lower nephrotoxicity (<2%) and ease of use because of the high degree of bioavailability and the long half-life of the drug. Thus, once the GI tract is functional, the parenteral dose may be switched to the oral formulation with the same efficacy.

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  • The standard recommended dose for most Candida infections is fluconazole at 800 mg as the loading dose, followed by fluconazole at a dose of 400 mg/d for at least 2 weeks of therapy after a demonstrated negative blood culture or clinical signs of improvement. This treatment regimen can be utilized for infections due to C albicans, C tropicalis, C parapsilosis, C kefyr, C dubliniensis, C lusitaniae, and C guilliermondi.

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  • A critical component in the management of candidemia and disseminated candidiasis is the removal of the focus of infection, such as intravenous and Foley catheters.

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  • Alternative options for candidemia include the following:

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    • Amphotericin B 0.7 mg/kg/d IV for a total dose of 1-2 g, over a 4- to 6-week period

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    • Liposomal preparations of amphotericin B also may be options if (1) a patient is refractory to fluconazole or at least 500 mg of standard amphotericin B, (2) a patient has severe infusion-related toxicity, (3) a patient develops renal insufficiency while on amphotericin B (generally with an increase in creatinine >2.5 mg/dL).

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    • Caspofungin acetate (Cancidas) as a 70-mg loading dose is followed by 50 mg/d IV for a minimum of 2 weeks after improvement or after blood cultures have cleared. Caspofungin is a new semisynthetic echinocandin recently developed and approved for aspergillus infections. Although not yet FDA approved for candidal infections, early studies seem to indicate it will be an effective alternative for severe mucosal infections and systemic infections due to Candida, especially those due to non-albicans Candida species.

• Special situations involving several of the Candida species require special mention because of their known intrinsic resistance to antifungals.

• Infections due to C glabrata because of its lower susceptibility to antifungals require higher daily doses of fluconazole at 800 mg/d or amphotericin B at 1 mg/kg/d.

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• Infections due to C krusei necessitate the use of amphotericin B at 1 mg/kg/d because this organism is intrinsically resistant to fluconazole and less susceptible to itraconazole, ketoconazole, and amphotericin B.

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• Infections due to C lusitaniae or C guilliermondi necessitate the use of fluconazole because these isolates frequently are intrinsically resistant to amphotericin B or develop resistance to amphotericin B while the patient is on therapy.

• The optimum dosage and duration of therapy for various types of deep candidal infection has not been definitively determined.

• Alternative antifungal regimens may be considered if the patients are either intolerant to the treatment regimens or are refractory to the antifungal regimen. The combination of amphotericin B and flucytosine has been recommended in several special situations. For instance, this combination has been used for patients who are immunocompromised with Candida endophthalmitis and Candida meningitis. Flucytosine appears to interact synergistically with amphotericin B in animal models.

Complications:
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• 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 from occurring.

Prognosis:
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• Prognosis depends on several factors, such as the site of infection, the degree and type of immunosuppression, and the rapidity of diagnosis and treatment. The longer it takes to initiate antifungal therapy, the higher the morbidity and mortality associated with candidemia and disseminated candidiasis.

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

• Systemic candidiasis carries a mortality rate of 30-40% and generally is associated with the degree of immunosuppression.

Patient Education:
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• Inform patients and their families about the risk factors associated with mucosal and systemic candidiasis. In addition, inform both that the systemic form of the disease is extremely serious and has a high morbidity and mortality unless aggressive action is undertaken.