Jack D. Sobel

Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases Society of America

Guidelines for the management of patients with invasive candidiasis and mucosal candidiasis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous guidelines published in the 15 January 2004 issue of Clinical Infectious Diseases and are intended for use by health care providers who care for patients who either have or are at risk of these infections. Since 2004, several new antifungal agents have become available, and several new studies have been published relating to the treatment of candidemia, other forms of invasive candidiasis, and mucosal disease, including oropharyngeal and esophageal candidiasis. There are also recent prospective data on the prevention of invasive candidiasis in high-risk neonates and adults and on the empiric treatment of suspected invasive candidiasis in adults. This new information is incorporated into this revised document.

Guidelines for Treatment of Candidiasis

Peter G. Pappas, John H. Rex, Jack D. Sobel, Scott G. Filler, William E. Dismukes, Thomas J. Walsh, and John E. Edwards Division of Infectious Diseases, University of Alabama at Birmingham, Alabama; AstraZeneca Pharmaceuticals, Manchester, Great Britain; Wayne State University School of Medicine, Detroit, Michigan; Harbor–University of California-Los Angeles Medical Center, Torrance, California; and Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland

Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America

Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)-infected individuals, (2) organ transplant recipients, and (3) non-HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.

Urinary Tract Infection

PURPOSE To estimate the annual incidence, cumulative probability of presumed urinary tract infection (UTI) by age, and the social costs. METHODS Analysis of a random digit dialing survey of 2000 women in the United States. RESULTS 10.8 percent (95% CI: 9.4, 12.1%) of women aged 18 and older reported at least one presumed UTI during the past 12 months, with the majority of the cases occurring among women with a history of two or more UTI episodes in their life. We estimate that by age 24, one-third of women will have at least one physician-diagnosed UTI that was treated with prescription medication. Overall, an estimated 11.3 million women in the United States had at least one presumed UTI treated with antibiotics in 1995. We estimate the annual cost of UTI cases with prescriptions to be

Practice Guidelines for the Treatment of Candidiasis

1.6 billion in 1995. If the costs occurring after 1995 are discounted at 5% annually, the total cost over 20 years has a present value of

Candida glabrata: Review of Epidemiology, Pathogenesis, and Clinical Disease with Comparison to C. albicans

25.5 billion. CONCLUSION If a vaccine were developed that would prevent either initial or recurrent UTI the net benefits to society would be substantial, even at a developmental cost of one billion dollars.

Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome

Infections due to Candida species are the most common of the fungal infections. Candida species produce a broad range of infections, ranging from nonlife-threatening mucocutaneous illnesses to invasive process that may involve virtually any organ. Such a broad range of infections requires an equally broad range of diagnostic and therapeutic strategies. This document summarizes current knowledge about treatment of multiple forms of candidiasis and is the guideline of the Infectious Diseases Society of America (IDSA) for the treatment of candidiasis. Throughout this document, treatment recommendations are scored according to the standard scoring scheme used in other IDSA guidelines to illustrate the strength of the underlying data. The document covers 4 major topical areas. The role of the microbiology laboratory. To a greater extent than for other fungi, treatment of candidiasis can now be guided by in vitro susceptibility testing. The guidelines review the available information supporting current testing procedures and interpretive breakpoints and place these data into clinical context. Susceptibility testing is most helpful in dealing with infection due to non-albicans species of Candida. In this setting, especially if the patient has been treated previously with an azole antifungal agent, the possibility of microbiological resistance must be considered. Treatment of invasive candidiasis. In addition to acute hematogenous candidiasis, the guidelines review strategies for treatment of 15 other forms of invasive candidiasis. Extensive data from randomized trials are really available only for therapy of acute hematogenous candidiasis in the nonneutropenic adult. Choice of therapy for other forms of candidiasis is based on case series and anecdotal reports. In general, both amphotericin B and the azoles have a role to play in treatment. Choice of therapy is guided by weighing the greater activity of amphotericin B for some non-albicans species (e.g., Candida krusei) against the lesser toxicity and ease of administration of the azole antifungal agents. Flucytosine has activity against many isolates of Candida but is not often used. Treatment of mucocutaneous candidiasis. Therapy for mucosal infections is dominated by the azole antifungal agents. These drugs may be used topically or systemically and have been proven safe and efficacious. A significant problem with mucosal disease is the propensity for a small proportion of patients to suffer repeated relapses. In some situations, the explanation for such a relapse is obvious (e.g., relapsing oropharyngeal candidiasis in an individual with advanced and uncontrolled HIV infection), but in other patients the cause is cryptic (e.g., relapsing vaginitis in a healthy woman). Rational strategies for these situations are discussed in the guidelines and must consider the possibility of induction of resistance over time. Prevention of invasive candidiasis. Prophylactic strategies are useful if the risk of a target disease is sharply elevated in a readily identified group of patients. Selected patient groups undergoing therapy that produces prolonged neutropenia (e.g., some bone-marrow transplant recipients) or who receive a solid-organ transplant (e.g., some liver transplant recipients) have a sufficient risk of invasive candidiasis to warrant prophylaxis.

Urinary tract infection: self-reported incidence and associated costs.

SUMMARY Until recently, Candida glabrata was considered a relatively nonpathogenic commensal fungal organism of human mucosal tissues. However, with the increased use of immunosuppressive agents, mucosal and systemic infections caused by C. glabrata have increased significantly, especially in the human immunodeficiency virus-infected population. A major obstacle in C. glabrata infections is their innate resistance to azole antimycotic therapy, which is very effective in treating infections caused by other Candida species. Candida glabrata, formerly known as Torulopsis glabrata, contrasts with other Candida species in its nondimorphic blastoconidial morphology and haploid genome. C. glabrata currently ranks second or third as the causative agent of superficial (oral, esophageal, vaginal, or urinary) or systemic candidal infections, which are often nosocomial. Currently, however, there are few recognized virulence factors of C. glabrata and little is known about the host defense mechanisms that protect against infection. Two established animal models (systemic and vaginal) have been established to study treatment, pathogenesis, and immunity. Treatment of C. glabrata infections can include azoles but often requires amphotericin B or flucytosine. This review summarizes all known clinical and experimental information about C. glabrata infections with comparisons to C. albicans as a means of contrasting the two species commonly observed and emphasizing the many recognized differences.

Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial.

BACKGROUND Treatment with low-dose amphotericin B (0.4 mg per kilogram of body weight per day) or oral azole therapy in patients with the acquired immunodeficiency syndrome (AIDS) and cryptococcal meningitis has been associated with high mortality and low rates of cerebrospinal fluid sterilization. METHODS In a double-blind multicenter trial we randomly assigned patients with a first episode of AIDS-associated cryptococcal meningitis to treatment with higher-dose amphotericin B (0.7 mg per kilogram per day) with or without flucytosine (100 mg per kilogram per day) for two weeks (step one), followed by eight weeks of treatment with itraconazole (400 mg per day) or fluconazole (400 mg per day) (step two). Treatment was considered successful if cerebrospinal fluid cultures were negative at 2 and 10 weeks or if the patient was clinically stable at 2 weeks and asymptomatic at 10 weeks. RESULTS At two weeks, the cerebrospinal fluid cultures were negative in 60 percent of the 202 patients receiving amphotericin B plus flucytosine and in 51 percent of the 179 receiving amphotericin B alone (P=0.06). Elevated intracranial pressure was associated with death in 13 of 14 patients during step one. The clinical outcome did not differ significantly between the two groups. Seventy-two percent of the 151 fluconazole recipients and 60 percent of the 155 itraconazole recipients had negative cultures at 10 weeks (95 percent confidence interval for the difference in percentages, -100 to 21). The proportion of patients who had clinical responses was similar with fluconazole (68 percent) and itraconazole (70 percent). Overall mortality was 5.5 percent in the first two weeks and 3.9 percent in the next eight weeks, with no significant difference between the groups. In a multivariate analysis, the addition of flucytosine during the initial two weeks and treatment with fluconazole for the next eight weeks were independently associated with cerebrospinal fluid sterilization. CONCLUSIONS For the initial treatment of AIDS-associated cryptococcal meningitis, the use of higher-dose amphotericin B plus flucytosine is associated with an increased rate of cerebrospinal fluid sterilization and decreased mortality at two weeks, as compared with regimens used in previous studies. Although consolidation therapy with fluconazole is associated with a higher rate of cerebrospinal fluid sterilization, itraconazole may be a suitable alternative for patients unable to take fluconazole.

VULVOVAGINAL CANDIDIASIS: EPIDEMIOLOGIC, DIAGNOSTIC, AND THERAPEUTIC CONSIDERATIONS

PURPOSE To estimate the annual incidence, cumulative probability of presumed urinary tract infection (UTI) by age, and the social costs. METHODS Analysis of a random digit dialing survey of 2000 women in the United States. RESULTS 10.8 percent (95% CI: 9.4, 12.1%) of women aged 18 and older reported at least one presumed UTI during the past 12 months, with the majority of the cases occurring among women with a history of two or more UTI episodes in their life. We estimate that by age 24, one-third of women will have at least one physician-diagnosed UTI that was treated with prescription medication. Overall, an estimated 11.3 million women in the United States had at least one presumed UTI treated with antibiotics in 1995. We estimate the annual cost of UTI cases with prescriptions to be