Richard J. Hamill

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.

A Prospective Observational Study of Candidemia: Epidemiology, Therapy, and Influences on Mortality in Hospitalized Adult and Pediatric Patients

We conducted a prospective, multicenter observational study of adults (n=1447) and children (n=144) with candidemia at tertiary care centers in the United States in parallel with a candidemia treatment trial that included nonneutropenic adults. Candida albicans was the most common bloodstream isolate recovered from adults and children (45% vs. 49%) and was associated with high mortality (47% among adults vs. 29% among children). Three-month survival was better among children than among adults (76% vs. 54%; P<.001). Most children received amphotericin B as initial therapy, whereas most adults received fluconazole. In adults, Candida parapsilosis fungemia was associated with lower mortality than was non-parapsilosis candidemia (24% vs. 46%; P<.001). Mortality was similar among subjects with Candida glabrata or non-glabrata candidemia; mortality was also similar among subjects with C. glabrata candidemia who received fluconazole rather than other antifungal therapy. Subjects in the observational cohort had higher Acute Physiology and Chronic Health Evaluation II scores than did participants in the clinical trial (18.6 vs. 16.1), which suggests that the former subjects are more often excluded from therapeutic trials.

Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome

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.

Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy.

Background:There is little systematic information regarding the immune reconstitution inflammatory syndrome (IRIS). Objective:To determine the incidence, risk factors, and long-term outcome of IRIS in HIV-infected patients receiving highly active antiretroviral therapy (HAART) who were coinfected with one of three common opportunistic pathogens. Design:A retrospective cohort identified through a city-wide prospective surveillance program. Methods:A retrospective chart review was performed for 180 HIV-infected patients who received HAART and were coinfected with Mycobacterium tuberculosis, Mycobacterium avium complex, or Cryptococcus neoformans between 1997 and 2000. Medical records were reviewed for baseline demographics, receipt and type of HAART, response to antiretroviral therapy, development of IRIS, and long-term outcome. Results:In this cohort, 31.7% of patients who received HAART developed IRIS. Patients with IRIS were more likely to have initiated HAART nearer to the time of diagnosis of their opportunistic infection (P < 0.001), to have been antiretroviral naive at time of diagnosis of their opportunistic infection (P < 0.001), and to have a more rapid initial fall in HIV-1 RNA level in response to HAART (P < 0.001). Conclusions:IRIS is common among HIV-infected persons coinfected with M. tuberculosis, M. avium complex, or C. neoformans. Antiretroviral drug-naive patients who start HAART in close proximity to the diagnosis of an opportunistic infection and have a rapid decline in HIV-1 RNA level should be monitored for development of this disorder.

Antifungal Susceptibility Survey of 2,000 Bloodstream Candida Isolates in the United States

ABSTRACT Candida bloodstream isolates (n = 2,000) from two multicenter clinical trials carried out by the National Institute of Allergy and Infectious Diseases Mycoses Study Group between 1995 and 1999 were tested against amphotericin B (AMB), flucytosine (5FC), fluconazole (FLU), itraconazole (ITR), voriconazole (VOR), posaconazole (POS), caspofungin (CFG), micafungin (MFG), and anidulafungin (AFG) using the NCCLS M27-A2 microdilution method. All drugs were tested in the NCCLS-specified RPMI 1640 medium except for AMB, which was tested in antibiotic medium 3. A sample of isolates was also tested in RPMI 1640 supplemented to 2% glucose and by using the diluent polyethylene glycol (PEG) in lieu of dimethyl sulfoxide for those drugs insoluble in water. Glucose supplementation tended to elevate the MIC, whereas using PEG tended to decrease the MIC. Trailing growth occurred frequently with azoles. Isolates were generally susceptible to AMB, 5FC, and FLU. Rates of resistance to ITR approached 20%. Although no established interpretative breakpoints are available for the candins (CFG, MFG, and AFG) and the new azoles (VOR and POS), they all exhibited excellent antifungal activity, even for those strains resistant to the other aforementioned agents.

Relatively Poor Outcome after Treatment of Clostridium difficile Colitis with Metronidazole

BACKGROUND Clostridium difficile is a frequent cause of serious nosocomial infection. Earlier reports have suggested that treatment with metronidazole cured nearly 90% of patients, with only a modest rate of recurrence of infection. In recent years, the rate of response to treatment with this drug has appeared to be much lower. METHODS We undertook a prospective, observational study of 207 patients who were treated with metronidazole for C. difficile colitis. RESULTS A total of 103 patients (50%) were cured by the initial course of therapy and had no recurrence of disease. Forty-six patients (22%) continued to have symptoms of colitis for > or = 10 days despite treatment, and 58 (28%) responded initially but had a recurrence within the ensuing 90 days. The mortality rate among patients who developed C. difficile colitis was 27%, and it was higher among patients who did not respond fully to an initial course of therapy, compared with those who did (33% vs. 21%; P < .05). CONCLUSIONS Because of the relatively poor response to therapy, additional approaches to prevention and/or treatment of C. difficile colitis appear to be warranted.

Immune reconstitution inflammatory syndrome. Emergence of a unique syndrome during highly active antiretroviral therapy

The discovery of effective therapy for human immunodeficiency virus (HIV) infection has improved the outlook for patients with the acquired immunodeficiency syndrome (AIDS) (75, 88, 115, 121, 134). Since the introduction of highly active antiretroviral therapy (HAART), there has been a decrease in the incidence of opportunistic infections among HIVinfected patients along with a corresponding reduction in the mortality rate (7, 30, 45, 102, 117). The basis for these improvements appears to be a result of partial recovery of the host’s immune system. Suppression of viral replication by antiretroviral therapy allows for the reappearance of immune effector cells, that in turn, provide vital protection against opportunistic pathogens (15, 32, 92, 95, 132). However beneficial HAART has been, experience during the past several years has disclosed the emergence, in a small proportion of cases, of a unique set of complications. Soon after treatment is begun, some patients experience clinical deterioration due to restoration of their capacity to mount an inflammatory immune response against both infectious and noninfectious antigens. This phenomenon which carries such labels as the immune reconstitution syndrome (IRS) and immune restoration disease (IRD), has been described for a wide variety of infectious pathogens (26, 36, 46). The manifestations of this syndrome are diverse and depend on the particular infectious agent involved. Given that an increased inflammatory response underlies its presentation, we propose the name immune reconstitution inflammatory syndrome (IRIS). Autoimmune diseases that occur following institution of HAART may also be considered as part of the same process. For the purpose of this review, IRIS is defined as a paradoxical deterioration in clinical status attributable to the recovery of the immune system during HAART. Recognition of this entity is crucial, for successful treatment relies on alleviation of the patient’s symptoms without compromising antiretroviral or antimicrobial therapy. In this article, we review the present understanding of the basic science underlying IRIS, with illustrative examples from our case series, and review the existing clinical literature.

Cryptococcosis in Human Immunodeficiency Virus-Negative Patients in the Era of Effective Azole Therapy

We conducted a case study of human immunodeficiency virus (HIV)-negative patients with cryptococcosis at 15 United States medical centers from 1990 through 1996 to understand the demographics, therapeutic approach, and factors associated with poor prognosis in this population. Of 306 patients with cryptococcosis, there were 109 with pulmonary involvement, 157 with central nervous system (CNS) involvement, and 40 with involvement at other sites. Seventy-nine percent had a significant underlying condition. Patients with pulmonary disease were usually treated initially with fluconazole (63%); patients with CNS disease generally received amphotericin B (92%). Fluconazole was administered to approximately two-thirds of patients with CNS disease for consolidation therapy. Therapy was successful for 74% of patients. Significant predictors of mortality in multivariate analysis included age > or =60 years, hematologic malignancy, and organ failure. Overall mortality was 30%, and mortality attributable to cryptococcosis was 12%. Cryptococcosis continues to be an important infection in HIV-negative patients and is associated with substantial overall and cause-specific mortality.

The Changing Epidemiology of Cryptococcosis: An Update from Population-Based Active Surveillance in 2 Large Metropolitan Areas, 1992–2000

To examine trends in the incidence and epidemiology of cryptococcosis, active, population-based surveillance was conducted during 1992-2000 in 2 areas of the United States (the Atlanta, Georgia, and Houston, Texas, metropolitan areas; combined population, 7.4 million). A total of 1491 incident cases were detected, of which 1322 (89%) occurred in HIV-infected persons. The annual incidence of cryptococcosis per 1000 persons with AIDS decreased significantly during the study period, from 66 in 1992 to 7 in 2000 in the Atlanta area, and from 24 in 1993 to 2 in 1994 in the Houston area. Poisson regression analysis revealed that African American persons with AIDS were more likely than white persons with AIDS to develop disease. Less than one-third of all HIV-infected persons with cryptococcosis were receiving antiretroviral therapy before diagnosis. Our findings suggest that HIV-infected persons who continue to develop cryptococcosis in the era of highly active antiretroviral therapy (HAART) in the United States are those with limited access to health care. More efforts are needed to expand the availability of HAART and routine HIV care services to these persons.

Practice Guidelines for the Management of Patients with Histoplasmosis

OBJECTIVE The objective of this guideline is to provide recommendations for treating patients with the more common forms of histoplasmosis. PARTICIPANTS AND CONSENSUS PROCESS: A working group of 8 experts in this field was convened to develop this guideline. The working group developed and refined the guideline through a series of conference calls. OUTCOMES The goal of treatment is to eradicate the infection when possible, although chronic suppression may be adequate for patients with AIDS and other serious immunosuppressive disorders. Other important outcomes are resolution of clinical abnormalities and prevention of relapse. EVIDENCE The published literature on the management of histoplasmosis was reviewed. Controlled trials have been conducted that address the treatment of chronic pulmonary and disseminated histoplasmosis, but clinical experience and descriptive studies provide the basis for recommendations for other forms of histoplasmosis. VALUE: Value was assigned on the basis of the strength of the evidence supporting treatment recommendations, with the highest value assigned to controlled trials, according to conventions established for developing practice guidelines. BENEFITS AND COSTS: Certain forms of histoplasmosis cause life-threatening illnesses and result in considerable morbidity, whereas other manifestations cause no symptoms or minor self-limited illnesses. The nonprogressive forms of histoplasmosis, however, may reduce functional capacity, affecting work capacity and quality of life for several months. Treatment is clearly beneficial and cost-effective for patients with progressive forms of histoplasmosis, such as chronic pulmonary or disseminated infection. It remains unknown whether treatment improves the outcome for patients with the self-limited manifestations, since this patient population has not been studied. Other chronic progressive forms of histoplasmosis are not responsive to pharmacologic treatment. TREATMENT OPTIONS Options for therapy for histoplasmosis include ketoconazole, itraconazole, fluconazole, amphotericin B (Fungizone; Bristol-Meyer Squibb, Princeton, NJ), liposomal amphotericin B (AmBisome; Fujisawa, Deerfield, IL), amphotericin B colloidal suspension (ABCD, or Amphotec; Seques, Menlo Park, CA), and amphotericin B lipid complex (ABLC, or Abelcet; Liposome, Princeton, NJ).