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Cryptococcus neoformans (Cryptococcosis)
Updated January, 2010
M. Hong Nguyen, M.D., Cornelius J Clancy, M.D., Ismail Zafer Ecevit, M.D.
From the Department of Medicine, University of Florida College of Medicine, and the VA Medical Center, Gainesville, Florida.
MICROBIOLOGY Guided Medline Search Cryptococcus neoformans is an encapsulated yeast that can be found ubiquitously. There are two varieties of C. neoformans that are pathogenic in humans: C. neoformans variety neoformans (serogroups A and D) and C. neoformans variety gattii (serogroups B and C). These variants are characterized by distinct geographic distribution, host preference and clinical manifestations of infection (Table 1) (16,45,46). Since the vast majority of the infections in the U. S. are caused by C. neoformans var. neoformans, the remainder of this chapter will be focus on this variety. For this reason, the use of the name C. neoformans will refer to var. neoformans unless stated otherwise. Datta K, Bartlett KH, et al. Spread of Cryptococcus gattii into Pacific Northwest region of the United States. Emerg Infect Dis. 2009 Aug;15:1185-91. Baron EJ. Yeast
EPIDEMIOLOGY Guided Medline Search C. neoformans gained increased medical importance as a consequence of the AIDS epidemic. It is currently the most common cause of fungal meningitis worldwide. In the U.S., 5 to 10% of patients with AIDS ultimately develop cryptococcal meningitis. Due to the widespread use of fluconazole and the introduction of highly active antiretroviral therapy (HAART), the rate of cryptococcosis has declined significantly in the developed world over the past few years. Cryptococcal meningitis, however, remains a common opportunistic infection in AIDS patients in developing countries. Patients with T-cell mediated immunodeficiency (such as those infected with HIV or those with idiopathic CD4 lymphopenia) are at greatest risk for cryptococcal infections. Solid organ or bone marrow transplant recipients, patients receiving long-course and high dose corticosteroids, and patients with lymphoreticular malignancies, sarcoidosis, diabetes mellitus and hepatic cirrhosis are also at risk for cryptococcal infections. Patients with no known immunosuppression can uncommonly acquire cryptococcal infection. Review Article: Singh, N., Perfect, J. Immune Reconstitution Syndrome Associated with Opportunistic Mycoses. The LANCET Infectious Diseases 2007; Vol.7, Issue 6, 395-401. Review Article: Singh, N., Novel immune regulatory pathways and their role in immune reconstitution syndrome in organ transplant recipients with invasive mycoses. Eur J Clin Microbiol Infect Dis 2008;27(6):403-408. Datta K, Bartlett KH, et al. Spread of Cryptococcus gattii into Pacific Northwest region of the United States. Emerg Infect Dis. 2009 Aug;15:1185-91. Springer DJ, Chaturvedi V. Projecting Global Occurrence of Cryptococcus gattii. Emerg Infect Dis. 2010 Jan;16:14-20.
CLINICAL MANIFESTATIONS Guided Medline Search
Although the lungs are the portal of entry for C. neoformans, pulmonary
cryptococcosis is not a major clinical problem. Most patients with pulmonary
cryptococcosis are either asymptomatic or experience non-specific symptoms
consistent with a viral illness. The diagnosis of pulmonary cryptococcosis is
generally made during routine work-up of incidental pulmonary nodules or hilar
adenopathy noted on chest radiograph. In patients who present with pulmonary
symptoms, chest radiographs show lobar or segmental interstitial infiltrates,
diffuse nodular or reticular infiltrates, cavitary lung lesions and pleural
effusions (35,91). Depending on the host immune status and/or the inhaled fungal
burden, the organism can either remain localized in the lung or disseminate to
virtually any organ system (including central nervous system (CNS), skin, bone,
joints, muscle, breast, eyes, gastrointestinal and genitourinary tracts, thyroid
and adrenal glands)
The CNS is the most common site of dissemination. Meningitis is the predominant manifestation, whereas brain abscesses or cryptococcoma are more rarely encountered. Immunocompromised hosts can also present with fungemia with or without diffuse skin manifestations. Skin manifestations include maculopapules, vesicles, plaques or umbilicated papules that are indistinguishable from molluscum contagiosum (40). C. neoformans frequently affects the genitourinary tract, especially the prostate where the organism can persist despite prolonged courses of antifungal therapy. This site is a source of relapse of cryptococcal meningitis in HIV-infected patients after the discontinuation of antifungal therapy (43). Cellulitis, localized infected skin ulcers, abscesses, septic arthritis and osteomyelitis have also been described in immunocompromised hosts, especially those having undergone solid organ transplant and those receiving corticosteroids. Deresinski, S. Immune Reconstitution Inflammatory Syndrome (IRIS) in HIV-Infected Patients with Cryptococcal Meningitis. Clin Infect Dis 2009;49: iii-iv. Sun HY, Wagener MM, et al. Cryptococcosis in Solid-Organ, Hematopoietic Stem Cell, and Tissue Transplant Recipients: Evidence-Based Evolving Trends. Clin Infect Dis. 2009 Jun 1;48:1566-76.
LABORATORY DIAGNOSIS Guided Medline Search The diagnosis of cryptococcal infection can be made by several means: 1) direct microscopic examination of infected body fluids or tissues; 2) detection of cryptococcal polysaccharide antigen in body fluids; and 3) culture. Direct
Microscopic Examination: India ink
In tissue, yeasts are easily identified as cells of approximately 5-20 um in
size, globose in shape and with narrow budding
Cryptococcal Polysaccharide Antigen in Body Fluids: Detection of cryptococcal polysaccharide capsular antigen is useful in both the diagnosis of infection and the prediction of prognosis and response to therapy. There are several commercially available latex cryptococcal antigen tests as well as enzyme-linked immunoassays (14,40). These tests are both sensitive (90%), and specific (approaching 100%). When performed on serum or body fluids, cryptococcal antigen detection provides rapid diagnosis. Both false positive (due to interfering substances, contamination of syneresis fluids, cross-reaction with Trichosporon beigelii antigen), and false negative tests (due to prozone phenomenon, low cryptococcal antigen concentrations) have been reported (40). Culture: Culture is the gold standard for diagnosing cryptoccocosis. C. neoformans can grow on most standard media used for isolating bacteria and fungi. Sabouraud dextrose agar is the standard fungal medium used in most clinical microbiology laboratories. Although most C. neoformans can grow well in artificial medium within 48 to 72 hours, the organism will rarely require a longer period to become visible (for example, when the patients are receiving anti-cryptococcal therapy) (40). Thus, when the suspicion of cryptococcosis is high, physicians should notify the clinical laboratory to retain the culture for at least three to four weeks before discarding. Niger seed agar is a selective medium for C. neoformans. Both varieties of C. neoformans possess phenyloxidase that oxidizes caffeic acid in the niger seed extract to produce melanin. C. neoformans are visualized as brownish colonies on this medium. Niger seed agar (supplemented with antibiotics and biphenyl) is used for primary culture for C. neoformans from contaminated or heavily colonized specimens such as sputum or urine. Niger seed agar selects for C. neoformans thus increasing the sensitivity of detection (40). C. neoformans is detected in the blood cultures of 35 to 68% of HIV-infected patients with disseminated cryptococcosis (14,40). Despite this yield, there is still concern that the radiometric methods for blood culture used in most clinical microbiology laboratories, such as the BACTEC system, are not sensitive enough to detect low fungal inocula (< 1 CFU/ ml of specimen). If C. neoformans fungemia is suspected, physicians should alert the laboratory personnel to blindly subculture the blood culture bottles at the end of the incubation period. Furthermore, the lysis-centrifugation method may be more sensitive in detecting low fungal inocula in blood (14,40). Distinction Between Varieties of C. neoformans: Canavanine-glycine-bromothymol blue (CGB) can be used to distinguish the two varieties of C. neoformans. Within five days of incubation, C. neoformans variety gattii turns CGB medium blue, whereas the variety neoformans does not. D-proline medium is also effective in differentiating the two varieties. Only the gattii variety can utilize proline as the sole source of nitrogen. The two varieties of C. neoformans can also be distinguished by serotyping. There are commercial serological typing kits that differentiate the four serotypes based on capsular structure of C. neoformans (14).
PATHOGENESIS Guided Medline Search The most common reservoir of C. neoformans is bird droppings. C. neoformans remains infectious for several years in droppings, where it is protected from drying by its thick polysaccharide capsule. Evidence suggests that infection in the human host begins by the inhalation of organisms from within droppings. In the respiratory tract, C. neoformans germinates into budding yeast, gets hydrated and acquires the characteristic polysaccharide capsule (12). The initial infection is usually asymptomatic or causes self-limited symptoms. When host immunity is impaired or when the inhaled fungal inoculum is high, the organism can overwhelm the host immune system and disseminate to virtually any organ of the body via the bloodstream. C. neoformans is neurotropic, and, as mentioned, the most common organ involved in cryptococcal disease is the CNS. The yeast polysaccharide capsule, which is made up of glucuronoxylomannan, is an essential virulence factor for C. neoformans (12,14,40). The capsule enables the organism to escape host defense mechanisms by several means: protecting the organism from phagocytosis and killing by polymorphonuclear cells, monocytes and macrophages; diminishing antigen presentation to T-cells; and inducing regulatory T-cells that dampen the humoral as well as cell-mediated immune response to C. neoformans (12,14,40). Another virulence factor of C. neoformans is melanin production. Melanin protects C. neoformans from oxidative damage by host cells, as well as antibody-mediated phagocytosis and killing by macrophages. Melanin is densely deposited in the cell wall, thereby contributing to the cell wall integrity and making the organism more resistant to cell wall active drugs such as amphotericin B (12,14,40). Biochemical analyses suggest that melanin is formed by conversion of the dihydroxyphenol substrates such as DOPA to dopaquinone by the enzyme phenoloxidase (or laccase). Since C. neoformans cannot form DOPA, it must acquire the substrate from its surrounding environment in order to synthesize melanin. Areas of high dopaminergic concentration within the brain provide ample substrate for melanin production, partially accounting for the organism’s predilection for the CNS (12). To cause infection in humans, C. neoformans must be able to grow at the human body temperature of 37°C or slightly higher. An intact gene that encodes calcineurin A catalytic subunit is a basic requirement for the organism to survive in the host at 37°C (40). Other factors, such as α-mating type, mannitol, superoxide dismutase, protease and phospholipase production, and myristoylation of certain proteins may enhance the pathogenicity of C. neoformans. Housekeeping enzyme systems are being investigated for their possible contributions to the maintenence of C. neoformans infections in the host (14,37). Review Article: Singh, N., Perfect, J. Immune Reconstitution Syndrome Associated with Opportunistic Mycoses. The LANCET Infectious Diseases 2007; Vol.7, Issue 6, 395-401.
SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo In Vitro Susceptibility Data Triazole Agents: Interpretive breakpoint values have not been proposed for the triazole agents against C. neoformans. For simplicity of discussion in this chapter, we will adopt the breakpoint values proposed by the NCCLS for Candida spp.: susceptibility (fluconazole MICs < 16 ug/ml; itraconazole MICs ≤ 0.125 ug/ml), susceptibility dose-dependent (fluconazole MICs 16-32 ug/ml, itraconazole MICs 0.25-0.5 ug/ml), and resistance (fluconazole MICs > 32 ug/ml, itraconazole MICs > 0.5 ug/ml). In general, C. neoformans isolates are susceptible to fluconazole in vitro (Table 2). In a study of 566 C. neoformans isolates recovered from the U. S. and Africa before 1999, 80% of the isolates from the U. S. and 94% from Africa were susceptible to fluconazole (MICs < 16 ug/ml), 19% and 6%, respectively, were S-DD (MICs 16-32 ug/ml), and 0.7% and 0%, respectively, were resistant (MICs > 32 ug/ ml) (63). Nevertheless, there is concern that the emergence of resistance might be increasingly recognized in the setting of widespread use of antifungal prophylaxis. In a study of isolates recovered from patients in Cambodia in the years of 2000, for example, fluconazole MICs ≥ 32 ug/ml were noted for 20.5% of isolates recovered in 2001-2002, compared to 3.7% of isolates recovered in 2000-2001 (75). Although itraconazole and voriconazole are potent in vitro against C. neoformans isolates, cross-resistance between fluconazole and these agents does exist. Nguyen et al. showed that the MICs of itraconazole and voriconazole against C. neoformans parallel those of fluconazole, as higher fluconazole MICs are associated with higher voriconazole and itraconazole MICs (54). It is important to point out, however, that a significant number of C. neoformans isolates that are either S-DD or resistant in vitro to fluconazole retain susceptibility to itraconazole and voriconazole. Among fluconazole S-DD C. neoformans isolates in one study, for example, 43% were susceptible (itraconazole MIC < 0.125 ug/ml) and 57% S-DD to itraconazole (MIC = 0.125-0.25 ug/ml). Similarly, 28% and 72% of these fluconazole S-DD C. neoformans isolates exhibited voriconazole MICs < 0.125 ug/ml and 0.125-0.25 ug/ml, respectively (54). C. neoformans isolates that are less susceptible to fluconazole in vitro (MIC > 16 ug/ml) generally require higher concentrations of itraconazole and voriconazole for inhibition (itraconazole and voriconazole MICs ≥ 0.5 ug/ml) (54,63). Overall, the MICs required to inhibit growth of C. neoformans isolates that are either S-DD or resistant to fluconazole are lower for voriconazole than itraconazole, suggesting that voriconazole might be more potent than itraconazole. Amphotericin B and Flucytosine (5-FC): C. neoformans isolates that are resistant in vitro to amphotericin B are very rare (66). In one study where the susceptibility of 732 isolates was determined, only 0.3% exhibited amphotericin B MICs >1 ug/ml. Furthermore, only 2% exhibited flucytosine MICs > 16 ug/ml (10). Kontoyiannis DP, Lewis RE, et al. Calcineurin Inhibitor Agents Interact Synergistically with Antifungal Agents In Vitro against Cryptococcus neoformans isolates: Correlation with Outcome in Solid Organ Transplant Recipients with Cryptococcosis. Antimicrob Agents Chemother 2008;52:735-738.
Correlation of In Vitro Susceptibility Results and Response to Therapy Unlike the experience with Candida spp. where breakpoints for susceptibility and resistance have been proposed, the correlation between in vitro susceptibility to fluconazole and response to therapy has not been extensively studied for C. neoformans. Using a murine model of cryptococcal meningitis, Nguyen et al. demonstrated a correlation between fluconazole MICs (determined using the standardized NCCLS method) and the in vivo outcome (53). A dose response was demonstrated between fluconazole MICs and the degree of response to the drug: an isolate exhibiting an MIC of 2 ug/ml responded well to fluconazole, an isolate with an MIC of 16 ug/ml responded moderately, and an isolate with an MIC of 32 ug/ml did not respond. These results suggest that in vitro susceptibility testing may be useful in the evaluation of fluconazole therapy for cryptococcal meningitis. To date, there is limited data for the correlation between in vitro fluconazole susceptibility results and the response to fluconazole therapy among humans with cryptococcal meningitis (3,93). In one study using a modified susceptibility method (microtiter with Yeast Nitrogen Base as medium, and endpoint determined spectrophotometrically), MICs ≥ 16 ug/mL predicted clinical failure (3). Further work is needed, however, to standardize the methods, assure reproducibility, and validate the results of testing before it can be routinely advocated in the clinical setting.
ANTIMICROBIAL THERAPY Guided Medline Search Smart search Drug of Choice Currently Available Anticryptococcal Agents (Table 2). Amphotericin B:
Flucytosine: Flucytosine (5-FC) has good in vitro activity against C. neoformans and penetrates well into the CSF. The major limitations of this drug are its toxicity and the development of flucytosine-resistant fungal isolates when the drug is used as monotherapy. Flucytosine has enhanced anti-cryptococcal effects when given as adjunctive therapy to either amphotericin B or fluconazole. Ketoconazole: Ketoconazole has variable in vitro activity against C. neoformans, and experience with cryptococcosis has been limited to a few cases with skin and lung involvement (26). Ketoconazole is available only in oral formulation, and requires acidic gastric pH for absorption. This property makes it less attractive for the treatment in AIDS patients, since most of these patients have achlorhydria. Furthermore, ketoconazole does not penetrate well into the CSF; dosages of ≥ 1,200 mg/day, which are poorly tolerated, are required to treat coccidioidal meningitis. Furthermore, failure of this drug has been reported in the treatment of cryptococcal meningitis when it was used as monotherapy (62). This agent is no longer recommended as primary therapy for C. neoformans given the existence of more potent and better tolerated triazole agents. Miconazole: Miconazole has variable in vitro activity against C. neoformans. Miconazole has been used seldomly in the treatment of severe cases of cryptococcosis; both successes and failures have been reported with this drug (83,92). The lack of clinical information of against cryptococcosis, the drug’s short half-life, toxicity of the vehicle, and the availability of more potent new generation azoles have negated the use of this agent in the clinical setting. Fluconazole: Fluconazole is available for both oral and intravenous administrations. Fluconazole has high bioavailability after oral administration. Unlike ketoconazole and itraconazole, its absorption through the gastrointestinal tract is independent of gastric pH. Fluconazole is widely distributed in the body, reaching high concentrations in serum and tissues, including the CSF. Its long half-life enables once daily dosing. This drug has been used with success for both acute and suppressive therapy for cryptococcal meningitis in HIV-infected patients. Fluconazole-resistance has also been recognized among Cryptococcus spp. (3), but less commonly than among Candida spp. Itraconazole: Itraconazole is currently available for oral use only, although an intravenous formulation is being evaluated. Most clinical experience with itraconazole has been with the capsulated form, which depends on acidic pH in the stomach for absorption. As for ketoconazole, this property makes it less attractive for the treatment of AIDS patients. The oral suspension of itraconazole is better absorbed than the capsulated formulation; whether this formulation provides better efficacy against cryptococcosis is yet to be determined. Another weakness of itraconazole is its poor penetration into the CSF. Several reports of success of this drug in cryptococcal meningitis have been reported, however (22,23,90); its hydrophobicity and accumulation in host cells may target the drug to the site of infection (61). To our knowledge, in vitro itraconazole resistance has not been reported for Cryptococcus spp. Therapy of specific types of cryptococcosis. Practice guidelines for the management of cryptococcal diseases have been published by an 8-person subcommittee of the National Institute of Allergy and Infectious Diseases (NIAID) Mycoses Study Group (74). The purpose of this chapter is to 1) review major landmark articles that support or disclaim the NIAID recommendations; and 2) review updated studies published after the formulation of the NIAID recommendations, with special emphasis on alternative therapy with liposomal formluations of amphotericin B and the newer triazole agents. Overall, the management of cryptococcosis is determined by the immune status and the severity of illness of the affected patients and the anatomical site of infection. The therapeutic approaches outlined below are stratified by the types of patients and the sites of cryptococcal infections (Table 3). [Review Article: IDSA Practice Guidelines for the Management of Cryptococcal Disease. Clin Infect Dis 2000;30:710-8.]
(Printable Version of Antimicrobial Therapy for Cryptococcus neoformans) Sun HY, Wagener MM, et al. Cryptococcosis in Solid-Organ, Hematopoietic Stem Cell, and Tissue Transplant Recipients: Evidence-Based Evolving Trends. Clin Infect Dis. 2009 Jun 1;48:1566-76. CRYPTOCOCCOSIS IN NON-AIDS PATIENTS Meningeal Infection Standard Therapy: Combined amphotericin B and flucytosine is currently the standard therapy for cryptococcal meningitis in non-AIDS patients. In a randomized study of patients with cryptococcal meningitis where amphotericin B at 0.4 mg/ kg/ day was compared with combined amphotericin B (0.3 mg/kg/d) and flucytosine (150 mg/kg/d), the mortality was significantly higher for patients treated with amphotericin B alone (47% (15/32) versus 24% (8/34); p<0.05) (5). Furthermore, sterilization of the CSF after 10 days of therapy was achieved in significantly fewer patients treated with amphotericin B alone (64%, 7/11) than those treated with combination therapy (100% , 16/16; p< 0.001). It is worthwhile to note that the dosage used in the amphotericin B alone group was relatively low (0.4 mg/kg/d); whether higher dosages of amphotericin B given alone (≥ 0.7 mg/kg/d) would be as effective as the combination of amphotericin B and flucytosine in the eradication of Cryptococcus is not known. Toxicity was the major problem among the patients receiving adjunctive flucytosine therapy (5,27): side effects occurred in 30 to 40% of patients, and in 18% (6/34) of these patients, flucytosine had to be discontinued due to toxicity. The most common toxicity associated with flucytosine was anemia and leukopenia due to bone marrow suppression. Fifty-six percent of toxicity appeared during the first two weeks of therapy, and 87% during the first four weeks. The flucytosine dosage used in the study was high (150 mg/kg/d), which might have explained the high rate of toxicity observed. More recent data showed that a dosage of 100 mg/kg/d provides adequate blood levels, and reduces toxicity (87). If flucytosine is to be used for long-term therapy (> 2 weeks), especially in patients with renal insufficiency, peak levels should be monitored, and maintained between 30 to 80 ug/ml. Sustained flucytosine levels of >100 ug/ml are associated with bone marrow toxicity. The duration of therapy for cryptococcal meningitis is dictated by the immune status and underlying disease of the patients and severity of the infection. Four weeks of therapy is adequate for non-immunosuppressed patients with uncomplicated infections. However, at least six weeks of therapy is indicated for the following patients: 1) those with immunosuppression, such as lymphoreticular cancer or transplant, or those receiving daily corticosteroid dosages equivalent to >20 mg of prednisone; 2) those with associated poor prognostic factors such as the presence of a neurological abnormality, positive cultures for Cryptococcus at extra-neural sites, a pre-treatment CSF WBC of < 20/mm3 or a pre-treatment CSF cryptococcal antigen ≥ 1:32, a positive CSF India ink after four weeks of therapy, and serum or CSF cryptococcal Ag ≥ 1:8 after four weeks of therapy (25,27). In transplant recipient patients with cryptococcal meningitis, the mortality rate approaches 50% (82,94), and most deaths occur 40 days after the initiation of antifungal therapy. In addition, the response to therapy might be protracted. For these reasons, aggressive therapy with amphotericin B with or without flucytosine during this stage is indicated (58). After this stage, patients can be switched to high dose fluconazole (≥ 400 mg/day) for an additional 8-10 weeks or until clinical or radiological findings have resolved. Indeed, one review recommended fluconazole dosages as high as 400 mg four times a day (81). Sun HY, et al. Lipid Formulations of Amphotericin B Significantly Improve Outcome In Solid Organ Transplant Recipients with Central Nervous System Cryptococcosis. Clin Infect Dis 2009;49:1721-1728. Alternative Therapy Guided Medline Search Short-Term Amphotericin B With or Without Flucytosine, Followed by Fluconazole: Due to the significant side effects associated with amphotericin B and flucytosine, as well as the need for long-term vascular access and close monitoring of laboratory values during amphotericin B therapy, alternative treatment strategies have been sought. A popular approach is to initially treat patients with a course of amphotericin B with or without flucytosine (induction therapy) followed by a longer course of fluconazole (consolidation and/or suppressive therapy). This approach is extrapolated from the experience of cryptococcal meningitis in AIDS patients (87) (see below), which shows better outcome and fewer side-effects than with conventional amphotericin B therapy. Unfortunately, a randomized comparative study to address this alternative approach (combined amphotericin B and flucytosine for 2 weeks, followed by fluconazole for 8 weeks versus combined fluconazole and flucytosine for 6 weeks, followed by fluconazole for 4 weeks) showed that the mortality rates were 80% (4/5) for the fluconazole-based regimen, and 0% (0/9) for the amphotericin B-based regimen. This study was stopped prematurely, due to the reluctance of investigators to enroll severely ill patients to the fluconazole arm (28). In a pilot study of cryptococcal meningitis in non-AIDS patients, overall success was documented in 79% of patients treated with amphotericin B alone and 84% of patients treated with amphotericin B and 5-FC (57). Among patients receiving amphotericin B, the median total dose and duration of therapy were 805 mg and 27 days. Overall, 99 of these 154 patients subsequently received consolidation therapy with fluconazole (median dosage 400 mg/day, median duration 70 days), and 16 received a more prolonged suppressive fluconazole therapy (median dosage 400 mg/day, and median duration 681 days). A notable finding from this study was that the relapse rate was only 4%, which is significantly lower than the rate reported in previous studies. This finding is most likely the result of the extensive use of fluconazole for consolidation. Fluconazole: In a pilot study of cryptococcosis in France, fluconazole was as efficacious as amphotericin B for non-AIDS patients with cryptococcal meningitis (29): the overall cure rate was 74% (26/35) for patients treated with amphotericin B and 68% (17/25) for those treated with fluconazole. These results should be interpreted with caution, however, given several major limitations of this study. First, the study was a non-randomized comparative trial, and the allocation of therapy might have been biased by patients’ underlying diseases and severity of illness at the onset of cryptococcal infection. For example, patients with lymphoid disorders, those with more severe infections, and those with clinical signs and symptoms associated with poor outcome were more likely to receive amphotericin B. Second, the number of patients assigned to each therapeutic group was small (35 for amphotericin B, and 25 for fluconazole), and therefore the study might not have the statistical power to detect significant differences in outcome between the two groups. Third and most importantly, the outcome of patients in each group was not stratified by factors that are known to independently affect outcome such as presence of dissemination, malignancy, and abnormal mental status. For these reasons, this study was not able to definitively address whether fluconazole has any role in the treatment of cryptococcal meningitis in non-AIDS patients. Other Antifungal Agents: The experience with itraconazole and various liposomal formulations of amphotericin B in the treatment of cryptoccocal meningitis in non-AIDS patients is very limited, and no conclusions about appropriate dosage, duration of therapy and efficacy can be drawn. Miscellaneous Therapy: The role of intraventricular administration of amphotericin B as an adjunct to intravenous amphotericin B in the therapy of cryptococcal meningitis is unclear. Success as well as failure has been reported with this route of administration. Given the complications associated with intraventricular therapy and the lack of conclusive evidence for its efficacy in cryptococcal meningitis, this therapeutic modality cannot be routinely advocated. Rather, it should be reserved for those patients with refractory infection, or in whom systemic antifungal therapy cannot be administered due to significant side effects (25). Summary of treatment recommendations for meningeal infections in non-AIDS patients: In summary, a minimum of four weeks of combined amphotericin B at 0.5-1 mg/kg/day and flucytosine at 100 mg/kg/day is recommended for the treatment of cryptococcal meningitis in non-AIDS patients. For patients who are immunosuppressed or have poor prognostic factors, at least six weeks of therapy is indicated. After this acute therapy, the regimen can be switched to oral fluconazole (≥ 400 mg/day) for 8-10 weeks if the patient is clinically well and culture from CSF weeks yields no growth. Further fluconazole suppressive therapy (at a dosage of 200 mg) is recommended for any residual infection, especially when patient is still profoundly immunosuppressed. An important adjunct to antifungal therapy is the minimization or discontinuation of immunosuppressive drugs in order to optimize the chance of response to therapy. For those patients who require long-term steroid therapy, reduction of the dosage to an equivalent of 10 mg/day of prednisone might result in improved outcome (74). Given the unsatisfactory outcome of fluconazole therapy given either alone or in combination with fluctyosine in cryptococcal meningitis in non-AIDS patients (28,58), initial therapy with fluconazole cannot be recommended and, in fact, should be discouraged. [Review Article: IDSA Practice Guidelines for the Management of Cryptococcal Disease. Clin Infect Dis 2000;30:710-8.] Pulmonary Cryptococcosis The lung is the second most common site of cryptococcal disease. The therapeutic approach ranges from no specific therapy for immunocompetent hosts, to aggressive antifungal therapy for immunocompromised hosts. For immunocompetent hosts, the pulmonary process is often self-limited and can resolve spontaneously without antifungal therapy (38,39). Nevertheless, due to the propensity of C. neoformans to disseminate and to affect the CNS, all patients with pulmonary cryptococcosis should have a cryptococcal antigen determined in both serum and CSF; a positive antigen titer in either serum or CSF suggests that extrapulmonary dissemination has occurred, and these patients should be treated with a course of antifungal therapy. This routine recommendation has recently been challenged by Aberg et al (1). In a retrospective review of 42 cases of pulmonary cryptoccocosis, none of the 18 immunocompetent patients developed disseminated infections, whereas 25% (6/24) of the non-AIDS patients who were immunosuppressed did. Based on this finding, the authors suggested that the routine work-up to rule out disseminated disease is not necessary for all patients and should be limited to those patients with immunosuppression. It should be pointed out, however, that this study was a retrospective chart review, and systematic testing was not performed to consistently or convincingly rule out CNS or disseminated disease (76). Given the neurotropic nature of the organism and the high mortality of disseminated or meningeal infection, we still strongly recommend a lumbar puncture when C. neoformans is isolated from any body site. If CNS or disseminated infection is documented, treatment should be pursued as described above for cryptococcal meningitis. The optimal therapy for patients with isolated pulmonary cryptococcosis is unclear, but amphotericin B (with or without flucytosine), ketoconazole, or fluconazole have been used with success (1,26,29,55,77,89,90,95). All immunosuppressed patients should be treated. The toxicity of amphotericin B and the availability of effective yet benign azole agents mitigate against its use in these patients. In a pilot study of 109 patients with pulmonary cryptococcosis, an overall clinical success rate of 84% was achieved in patients treated with either fluconazole or a short induction course with amphotericin B followed by fluconazole (57). The duration of therapy is unclear, but it is reasonable to treat patients with at least 3 months of azole antifungals or until all symptoms resolve, whichever is longer. Fluconazole or itraconazole at 400 mg/day are superior to and better tolerated than ketoconazole at the same dosage. For non-immunosuppressed hosts, the practice guidelines issued by the NIAID Mycosis Study Group recommend that antifungal therapy should be given to patients with pulmonary cryptococcosis who are symptomatic (74), although hard evidence for such an approach is acknowledged to be lacking. A retrospective study of 36 non-immunosuppressed patients with pulmonary cryptococcosis (67% of whom were symptomatic) demonstrated that these patients generally experience an excellent outcome regardless of whether therapy was instituted (50). For this reason, antifungal therapy in these patients may not be needed, although this decision should be individualized (50). Close observation and careful follow-up are very important. Those patients with severe or persistent symptoms, or extensive disease seen on chest radiographs may benefit from antifungal therapy (50). Non-Pulmonary, Extra-Neural Cryptococcosis Virtually all organs can be affected by C. neoformans. Lungs are the most common extra neural sites of involvement, followed by bladder, prostate, skin, eye, and liver (61). Experience with the therapy of cryptococcal infection at these sites is limited, and is based mainly on case studies (1,57). In general, the therapeutic decision should be guided by the severity of illness and the underlying disease of patients as well as the site of infection. Again, optimal therapy is unclear. Once concomitant CNS or disseminated infection is ruled out, all patients should be treated with either fluconazole 200-400 mg/day for at least 3-6 months, or itraconazole 200-400 mg/day for at least 6-12 months (if the patients cannot tolerate fluconazole). For severe cases of infection, therapy can be started with amphotericin B at 0.4-0.7 mg/kg/day until clinical improvement, then switched to fluconazole or itraconazole for a more prolonged course of therapy.
CRYPTOCOCCAL INFECTION IN PATIENTS WITH AIDS Meningeal Infection Amphotericin B and fluconazole with or without flucytosine are the currently acceptable therapies for cryptococcal meningitis in AIDS patients. In contrast to the experience in non-AIDS patients, Cryptococcus can be rarely eradicated in AIDS patients. Indeed, the relapse rate for AIDS patients after a successful course of therapy for acute cryptococcal meningitis (acute therapy) is at least 50% (9,18). This high relapse rate along with its associated mortality rate mandate chronic suppressive therapy (also known as secondary prophylaxis) for AIDS patients with cryptoccocal meningitis (9,18). Therefore, the optimal treatment in AIDS patients includes an aggressive course of acute therapy followed by a prolonged course of chronic suppressive therapy. Jarvis JN et al. Screening for Cryptococcal Antigenemia in Patients Accessing an Antiretroviral Treatment Program in South Africa.Clin Infect Dis. 2009 Apr 1;48(7):856-62. Acute Standard Therapy: Amphotericin B at 0.7 to 0.8 mg/kg/d either alone or in combination with flucytosine (100 mg/kg/d) for the first 2 weeks of therapy (induction therapy), followed by either fluconazole or itraconazole (400 mg/day) for the following 8 weeks (consolidation therapy) is the current recommended therapy (87). Amphotericin B as an induction therapy is very effective with a two week mortality rate of 5.5% (87). Flucytosine in combination with amphotericin B during the first 2 weeks of therapy leads to more rapid sterilization of the CSF at two weeks (87) and decreases in relapses over time (73). Flucytosine at 100 mg/kg/day is well tolerated. Furthermore, the two weeks course precludes the need for drug level monitoring. A randomized trial of amphotericin B (at 0.7 mg/kg), amphotericin B plus flucytosine (100 mg/kg daily), amphotericin B plus fluconazole (400 mg daily), and triple therapy with amphotericin B, flucytosine and fluconazole in AIDS patients with cryptococcal meningitis was performed to assess the fungicidal activity in the CSF (measured by the rate of reduction of C. neoformans colony forming units). Browner et al. demonstrated that the fungicidal activity is greater for amphotericin B and flucytosine than amphotericin and fluconazole (11). These combinations have greater fungicidal activity than amphotericin B alone in cryptococcal meningitis. Notably, the triple therapy of amphotericin B, flucytosine and fluconazole was inferior to the combination of amphotericin B and flucytosine (11). After the initial two weeks of induction therapy, patients should be treated with either fluconazole or itraconazole at 400 mg/ day (87). Although the mortality rates at 10 weeks were not different for patients treated with fluconazole (1%) or itraconazole (3%), fluconazole might be slightly better than itraconazole because it leads to a higher rate of CSF sterilization at 10 weeks (70% for fluconazole group and 60% for itraconazole group; p< 0.05). The lower response observed for itraconazole might be attributed to the poor CSF penetration and the poor absorption of this drug due to achlorhydria. In a prospective study where patients were randomized to fluconazole (19 patients) or itraconazole (16 patients; both drugs at 600 mg daily), the CSF sterilization rate at 10 weeks were 100% for fluconazole and 94% for itraconazole (47). Thus, fluconazole or itraconazole at 600 mg daily might be superior to fluconazole at 400 mg. Bicanic T, et al. High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. Clin Infect Dis. 2008 Jul 1;47(1):123-30. Acute Alternative Therapy Fluconazole: Two prospective, randomized studies have been performed to evaluate the role of fluconazole compared with amphotericin B (0.3 mg/kg/d) in the treatment of cryptococcal meningitis in AIDS patients (42,71). In both studies, the time required to attain sterilization of the CSF was longer for fluconazole than for amphotericin B. In one study, the mortality and failure rates were significantly higher for the 14 patients treated with fluconazole at 400 mg/d (14 and 60%, respectively) than for the 6 patients treated with a combination of amphotericin B at 0.7 mg/kg/d and flucytosine at 150 mg/kg/d (0%) (42). In a larger study in which 194 patients were randomized to receive fluconazole (200 mg/d) or amphotericin B (mean daily dosages of 0.4 mg/kg for treatment success and 0.5 mg/kg for treatment failure), the overall mortality and failure rates were not significantly different between the groups (18% and 66%, respectively, for fluconazole, versus 14% and 60%, respectively, for amphotericin B). There was a trend, however, toward a higher mortality at 2 weeks among the fluconazole group (15% versus 8%; p=0.25), as well as a trend toward a longer time to sterilize the CSF (64 days versus 42 days; p=0.25) (71). The suboptimal outcomes in this trial might reflect the suboptimal dosages of the medications used (87). Several anecdotal reports have documented that high dosages of fluconazole are efficacious and well tolerated in AIDS patients with cryptococcal meningitis. In one report, fluconazole at 800 mg/day was effective as salvage therapy for cryptococcal meningitis for 62% (5/8) HIV patients who had failed a variety of antifungal therapies (7). In another report, six patients were treated with an intravenous fluconazole loading dose (1,600 mg) followed by oral fluconazole (800 mg/day) as primary therapy. Overall, 83% (5/6) had clinical improvement, and all 6 patients attained sterilization of CSF by day 82 (median: 21 days) (36). This dosage of fluconazole was well tolerated: nausea occurred in 2 patients, and mild elevation in liver enzyme tests in 5 patients. Preliminary data from a prospective, randomized study of escalating dosages of fluconazole (800 mg, 1200 mg, 1600 mg, and 2000 mg/day) alone or in combination with flucytosine (150 mg/kg/day) (43) demonstrated that there was no significant difference in the response rate among patients treated with the escalating dosages (800 mg versus 2,000 mg). On the other hand, there was a significant improvement in the response rate for patients treated with combined fluconazole and flucytosine compared to those treated with fluconazole alone (43). Although there were significant toxicities associated with flucytosine, most patients tolerated this drug for at least 2 weeks. These data suggest that fluconazole and flucytosine may emerge as a useful oral alternative to amphotericin B in the treatment of cryptococcal meningitis in AIDS patients. Pappas PG, Chetchotisakd P, et al. A Phase II Randomized Trial of Amphotericin B Alone or Combined with Fluconazole in the Treatment of HIV-Associated Cryptococcal Meningitis. Clin Infect Dis 2009; 48:1775-83. Itraconazole: A prospective, comparative study of itraconazole (200 mg twice daily) versus amphotericin B (0.3 mg/kg/day) combined with flucytosine (150 mg/kg/day) demonstrated that the combination regimen was significantly more effective in the therapy for cryptococcal meningitis: 0% (0/9) of patients in the combined amphotericin B and flucytosine group, and 50% (6/12) of patients in the itraconazole group had persistent positive culture in the CSF despite 6 weeks of therapy (21). Long-term follow-up also demonstrated the superiority of combined amphotericin B and flucytosine over itraconazole: 22% (2/9) of the combination group, and 58% (7/12) of the itraconazole group relapsed despite itraconazole maintenance therapy (200 mg daily). A similar experience was observed in a pilot study of 29 patients with AIDS-associated cryptococcal meningitis treated with itraconazole (200 mg twice daily) (22,23). Complete response was achieved in 64%, and partial response (improvement of symptoms but with persistent positive CSF cultures) in 22%. Failure was documented in 14%. The median time to sterilization of the CSF was approximately 30 days. Among the responders, recrudescence occurred in 42%; therapeutic serum itraconazole levels were documented at the time of recrudescence. Of note, the breakthrough cryptococcal isolates retained their initial in vitro susceptibility to itraconazole. Liposomal Formulations of Amphotericin B: In a prospective, randomized, comparative study of Amphotericin B lipid complex (ABLC) versus amphotericin B for cryptococcal infection in patients with AIDS, ABLC was significantly better tolerated. The overall clinical and mycologic responses were approximately 69% and 38%, respectively, and were not significantly different between the amphotericin B (at 0.7 mg/kg/day) and ABLC groups (at 1.5 to 5 mg/kg) (78). It was noted, however, that rates of persistent positive CSF cultures at the end of 4 weeks of therapy were 42% for ABLC, and 14% for amphotericin B. Although this finding raises the concern that ABLC might not be as potent as amphotericin B or might not readily cross the blood brain barrier, it should be pointed out that patients randomized to ABLC arm were more severely ill than those randomized to the amphotericin B arm. For this reason, a fair comparison between these two groups cannot be made. Experience with liposomal amphotericin B (Ambisome) in 19 AIDS patients with cryptococcal meningitis was encouraging (20). The mortality rate was 16%, and the clinical cure rate was 63%. The mycologic cure rate was 67%, and the median time to CSF sterilization was 11 days (range: 7 to 36 days). These rates are comparable to those reported for the combination of amphotericin B and flucytosine (71). A large prospective randomized comparative study of ambisome and amphotericin B is in progress. In a randomized comparative study of ambisome (4 mg/kg/day) versus amphotericin B (0.7 mg/kg/day) for three weeks followed by fluconazole 400 mg/day for 7 weeks, ambisome was less nephrotoxic (44). Although the clinical response was the same for both arms, the median time to CSF sterilization was significantly shorter (between 7-14 days) for ambisome than amphotericin B (> 21 days). Chronic Suppressive Therapy: Upward of 50% of AIDS patients who have completed a course of acute therapy for cryptoccocal meningitis are at risk for relapse if chronic suppressive therapy is not administered (9). These relapses represent a failure of the initial therapy to completely eradicate the infection, rather than the acquisition of a new infection. Indeed, clinically silent infection with persistently positive cultures at the end of primary therapy occurred in 19% (16/ 84) of patients in one study (64). The prostate and the CNS represent potential reservoirs for persistent cryptococcal infection (41). Given the high fatality rate associated with relapse, several regimens have been evaluated for chronic suppressive therapy. Daily fluconazole at 200 mg is the current therapy of choice as maintenance therapy for AIDS patients who have achieved culture negative status after primary treatment for acute cryptococcal meningitis (64). In one study, only 2% (2/ 111) of patients maintained on fluconazole relapsed. Alternative Chronic Suppressive Therapy: Weekly Amphotericin B at 1 mg/ kg can be used as maintenance therapy for AIDS patients with cryptococcal meningitis (64). The efficacy of this regimen however, inferior to daily fluconazole. In a randomized comparative study of weekly amphotericin B versus fluconazole, 18% (14/78) of patients receiving amphotericin B relapsed compared to only 2% (2/111) of those receiving fluconazole. Furthermore, bacterial infections were significantly more frequent in the amphotericin B group (36%) than in the fluconazole group (17%). The higher incidence of bacterial infections in the amphotericin B group was most likely related to vascular catheters required for chronic amphotericin B administration. Itraconazole at 200 mg/day is also inferior to fluconazole as maintenance therapy for cryptococcal meningitis (73). In one study, the relapse rate was higher for patients treated with itraconazole (23%; 13/57) than for those treated with fluconazole (4%; 2/51). None of the patients who relapsed died. The overall mortality rates were the same in both arms: 16% (8/51) for fluconazole and 10% (6/57) for itraconazole. Reasons for worse outcome with itraconazole include drug concentrations that are consistently lower in plasma than fluconazole, and low penetration of itraconazole into the CSF. In summary, given the high relapse rate of cryptococcal meningitis, the United States of Public Health in conjunction with the Infectious Diseases Society of America recommended that AIDS patients infected with C. neoformans should be managed as those infected with other opportunistic pathogens (Pneumocystis carinii, Mycobacterium avium Intracellulare and Cytomegalovirus), with maintenance of lifelong suppressive therapy. Fluconazole has proven to be the best regimen for this purpose. Chronic Suppressive Therapy Following Immune Reconstitution with HAART: Since the introduction of HAART, the rates of all opportunistic infections have significantly decreased. Both observational and randomized studies have suggested that the immunologic improvements seen with potent antiretroviral therapy, as measured by increased CD4 counts, are accompanied by a reduction in clinical infections. HAART might therefore enable AIDS patients to eradicate their opportunistic infections. Indeed, chronic suppressive therapy against Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium intracellulare and cytomegalovirus infections has been successfully discontinued following improvement in the CD4 counts. To date, there are several reports on the safety of discontinuation of chronic suppressive antifungal therapy once the patients with cryptococcal meningitis have immune reconstitution from HAART (2,56,70,48,88). The largest is a multicenter retrospective study involving 100 patients with cryptococcal meningitis in whom such therapy was discontinued after the CD4 rose to > 100 cells/µl. The relapse rate was 4% over a median follow-up time of 26.5 months (range 12.7-76.8 months) (48), a sharp contrast with the rate in the pre-HAART era. The risk factors predicting relapse in these studies cannot be evaluated because of the low relapse rates. It has been demonstrated, however, that the duration of HAART therapy before the discontinuation of antifungal maintenance therapy, the median CD4 count and viral load at the time of discontinuation, and the presence of cryptococcal antigen did not predict relapse. Interestingly, among the four relapsing patients, three had a different site of cryptococcal infection at relapse than at initial infection (lungs, spleen and lymph node, respectively). Taken together, these studies suggest that it is likely to be safe to discontinue chronic suppressive antifungal therapy after patients achieve CD4 counts ≥ 100 cells/µl with HAART. The criteria for re-institution of fluconazole prophylaxis with the failure of HAART are unclear at this time. It is recommended, however, that CD4 counts should be monitored closely for a sudden drop so that antifungal prophylaxis can be re-started. The role of following serum cryptococcal antigen is unclear, but some reports suggest that restarting antifungal prophylaxis should be considered if antigen reverts from negative to positive (48). Review Article: Singh, N., Perfect, J. Immune Reconstitution Syndrome Associated with Opportunistic Mycoses. The LANCET Infectious Diseases 2007; Vol.7, Issue 6, 395-401. ADJUNCTIVE THERAPY Guided Medline Search Intracranial Hypertension: Intracranial hypertension, defined as intracranial pressure of ≥ 200 mmH2O), occurs in at least 75% of patients with cryptococcal meningitis (34). Although these patients often manifest neurological symptoms such as headache, papilledema, hearing loss, visual changes and seizure, they can also be asymptomatic. In addition, CT scan or MRI of the majority of these patients shows no evidence of hydrocephalus (34). Thus, the absence of symptoms or a normal head scan does not exclude the presence of intracranial hypertension. Intracranial hypertension is associated with serious neurological sequelae, including death (34). In one study, 93% of patients (13/14) with intracranial hypertension died within the first 2 weeks of diagnosis, and an additional 40% died within the ensuing three weeks. Aggressive management to decrease ICP improves (30,34,49). It was recently shown, however, that only 50% of 26 patients with cryptococcal meningitis had opening pressures (OP) measured, and 54% (14/26) of patients did not receive optimal management of intracranial hypertension. Overall, 50% of patients in whom intracranial hypertension was suboptimally managed developed new neurological complications (new neurological deficits, visual and auditory changes) during therapy (79). Therefore, the significance of intracranial hypertension should be appreciated by clinicians caring for patients with cryptococcal meningitis, and all such patients should have their OP measured as part of the initial evaluation. If documented, intracranial hypertension should be treated (74). Several treatment modalities have been described for intracranial hypertension during cryptococcal meningitis. Among these, the best described is mechanical decompression of the ventricles. IDSA guidelines recommend that patients with intracranial hypertension should have serial lumbar punctures, with removal of enough CSF with each puncture to reduce the pressure to approximately 200 mm H2O or 50% of the initial pressure (74). Lumbar puncture with fluid withdrawal should be performed every day if necessary to maintain the pressure within the normal range. If serial lumbar punctures are not sufficient to control the increased pressure, placement of a temporary external ventricular draining device can provide acute relief (13,34). A small percentage of these patients will eventually require a permanent shunt placement. The most important complications of external ventricular devices and ventricular peritoneal shunts are superinfections by other organisms. Ventricular peritoneal shunt complications also include overdraining of CSF fluid and mechanical obstruction, although these are of low incidence. Medical means have also been recommended for the treatment of elevated ICP. Corticosteroids have questionable effects in controlling pressure, and should not be routinely administered to patients. Acetazolamide, a carbonic anhydrase inhibitor, reduces the rate of CSF production by the choroid plexus. Anecdotal reports suggest that this is efficacious in reducing elevated pressures. However, in a prospective trial of acetazolamide for the treatment of patients with cryptococcal meningitis with elevated intracranial pressure, acetazolamide was associated with excess complications (electrolyte imbalances and severe acidemia) and death (52). Furthermore, it is believed that the combination of amphotericin B and acetazolamide potentiate complications in the renal tubules. Hydrocephalus: Hydrocephalus is also a complication of cryptococcal meningitis, with an incidence of 9-63%. Hydrocephalus can compromise brain vessels and lead to brain ischemia and deterioration of neurological status. Placement of a VPS improves outcome only if placed early, before deterioration of consciousness occurs (60,84). VPS placement in patients with poor level of consciousness for greater than 48 hours does not appear to improve outcome. Immunomodulatory Therapy: Although HAART and aggressive antifungal therapy improves the outcome of AIDS patients with cryptococcal meningitis, this disease still has significant morbidity and mortality. Interferon (IFN)- α is an endogenous cytokine that enhances responses of macrophages, monocytes, NK cells and neutrophils, and plays an important role in host defenses against pathogenic organisms including fungi (8). Recombinant IFN-α 1b is approved by the FDA for use in patients with chronic granulomatous disease. This agent in combination with conventional antifungal therapy has yielded promising results in vitro and in animal models of cryptococcosis (19). A phase 2, double-blind, placebo-controlled study of cryptococcal meningitis in AIDS patients receiving amphtoericin B with or without flucytosine demonstrated that rIFN- α 1b is well tolerated, and does not affect CD4 cell counts or HIV viral load. Among 75 patients, 23 received placebo and 47 received thrice weekly IFN-α1b. The 2-week CSF sterilization rate was higher in patients receiving IFN-α 1b (34% vs. 13% for placebo; p=0.06). In addition, there was a trend toward improved combined mycologic and clinical success in rIFN-α 1b recipients at both week 2 and week 10. Thus, adjunctive therapy with rIFN-α 1b holds promise for patients with acute cryptococcal meningitis and warrants further study (59). When to start HAART HAART, inducing both a decrease in HIV viral load and an increase in CD4 cell counts, has led to a dramatic decrease in incidence of opportunistic infections (OIs), the progression to AIDS, and the overall mortality for HIV-infected patients. For these reasons, clinicians are often eager to start HAART in AIDS patients being treated for OIs. Recent evidence of immune reconstitution syndromes in these patients, however, raises concerns about the proper place of antiretrovirals in the setting of acute OIs. Immune reconstitution syndrome (IRS), also known as immune reconstitution inflammatory syndrome (IRIS), is a pathological inflammatory response to either previously treated infections or subclinical infections. It has been reported to occur in 25-35% of HIV-infected patients receiving HAART (31,51). IRS, which can result in poor clinical outcomes, has been associated with infections due to Mycobacterium spp., Cytomegalovirus, and C. neoformans. To date, there are no known predisposing factors to IRS in response to C. neoformans. There appears to be two distinct clinical syndromes. The first syndrome is an acute inflammatory reaction to subclinical or previously treated meningeal infections during the first few weeks of HAART. This typically occurs in patients with CD4 cells <50 who have an immunological and virological response to HAART, and is characterized by a prominent inflammatory cell reaction in the CSF. Cryptococcus is frequently recovered from the CNS and/or blood. The second syndrome is a chronic inflammatory reaction that occurs later in the course of immune reconstitution. The common manifestations of this syndrome are lymphadenitis, aseptic meninigitis associated with elevated intracranial pressure, and localized inflammatory lesions in the spinal cord or brain. The histopathology of these lesions typically shows granulomatous inflammation, necrosis or suppuration; the culture of these lesions yield no growth although organisms might be present in histopathologic samples. This type of inflammatory response is thought to be initiated by a T-cell response to the antigens of non-viable cryptococci (33). The optimal management of cryptococcal IRS is not clear. Anti-inflammatory therapy has been used successfully, but spontaneous resolution with maintenance of HAART and antifungal therapy has also been documented. In addition, the optimal time to start HAART after the initiation of antifungal therapy against C. neoformans infection is not known.
ENDPOINTS FOR MONITORING THERAPY Guided Medline Search The first 6 weeks of therapy are crucial in transplant recipients, and the response to therapy may be protracted. The use of amphotericin B combined with flucytosine as indication therapy for 4-6 weeks is rational in these patients. This period was also the median duration of amphotericin B treatment in a study in HIV-negative patients in which 81% of those with CNS cryptococcosis were successfully treated (57). After this stage, the patient can continue on fluconazole (400 mg four times daily) for 8-10 weeks or until clinical and radiographic findings have resolved. Serum cryptococcal antigen (detected in 86-88% of transplant recipients at the onset of infection) ultimately becomes undetectable and can be used to guide the duration of consolidation therapy. Life-long suppressive therapy is generally not necessary in transplant recipients. [Review Article: Singh N, Treatment of opportunistic mycoses: how long is long enough ? .Lancet Infect Dis 2003;3:703-08] The titered cryptococcal antigen can assist in the prediction of patients’ outcomes. In non-AIDS patients, high antigen titers in both serum and CSF before therapy (baseline titers) predict higher mortality, suboptimal response to therapy, and relapse (5,10,27). In AIDS patients, high baseline CSF antigen titers predict mortality in some studies (71,96) but not in others (18). The discrepancies between these studies might be attributed to the use of a wide variety of uncontrolled antigen test kits between different centers. Indeed, the agreement in titer results between the test kits from different manufacturers was, at best, only 60% (85). Therefore, the prognostic significance assigned to a specific titer value should be interpreted with caution. The titered cryptococcal antigen can also assist in monitoring response during acute therapy and the prediction of relapse. In non-AIDS patients, rising CSF titers after therapy are associated with relapse; therefore, a more prolonged course of therapy should be contemplated in these cases (25,26). In AIDS patients, an unchanged or rising cryptococcal antigen in the CSF during acute therapy is also associated with a higher likelihood of clinical and microbiologic failure, as well as relapse during maintenance therapy (34,66,68). In transplant recipients, the serum cryptococcal antigen (detected in 86-88% of patients with acute infection) ultimately becomes undetectable with therapy, and therefore can be used to guide the duration of therapy (81). Despite the prognostic value of CSF cryptococcal antigen in patients with AIDS, we do not believe that routine determination of CSF cryptococcal antigen following acute therapy is warranted. First, due to the extremely high relapse rate, all AIDS patients will undergo chronic suppressive (maintenance) therapy. Second, relapse can occur in the setting of improving antigen titers from baseline: in one study, 29% (4/14) of patients relapsed despite a reduction of CSF cryptococcal antigen titer by four-fold or more (66). Third, subjective symptoms are universally present among patients presenting with relapse (69). For these reasons, routine lumbar puncture is of doubtful value in the management of AIDS patients during maintenance therapy for cryptococcal meningitis. Close monitoring of signs and symptoms of infection is a more rational approach to these patients (66,69); lumbar puncture should be reserved for situations where clinical symptoms or signs suggest recurrence of disease.
VACCINES Guided Medline Search There are no vaccines for Cryptococcus.
PREVENTION Guided Medline Search Smart search Fluconazole Prophylaxis Several factors influence the decision of whether to implement primary prophylaxis against opportunistic infections: 1) the prevalence of disease, 2) the associated morbidity and mortality, 3) the efficacy of the prophylactic regimen and its impact on outcome, and 4) the cost of the prophylactic regimen (monetary cost, side effects, and emergence of resistant organisms). By these criteria, the prototype for effective prophylaxis is the use of trimethoprim-sulfamethoxazole against pneumocystis pneumonia (PCP). PCP occurs in at least 30% of patients with CD4 < 200/cu mm, and carries a high mortality rate. Furthermore, trimethoprim-sulfamethoxazole is very effective in reducing the incidence of PCP (breakthrough infection occurs in < 6% of patients), improves the outcome of patients, is inexpensive, and has not been associated with the emergence of resistance. Furthermore, the agent is also protective against toxoplasmosis, a significant cause of mortality in AIDS patients. The indication for cryptococcal prophylaxis is not as apparent as for pneumocystis prophylaxis. The prevalence of cryptococcal infection among AIDS patients is between 5 to 10% in the US and Europe, less than that of pneumocystis, MAI, and cytomegaloviral infections. In a randomized trial of the prevention of fungal infections in patients with CD4 <200/mm3, fluconazole at 200 mg daily significantly reduced cryptococcal infections (breakthrough rate of 0.9%, 2/217) compared to placebo (breakthrough rate 7%, 15/ 211) (67). A survival benefit could not be demonstrated, however, as most infections resolved once therapy was instituted. Primary prophylaxis with a lower dosage of fluconazole (200 mg thrice weekly) given only to patients with CD4 ≤ 100/mm3 was as efficacious, and much less costly (80). An area of concern is the emergence of fluconazole-resistance with prolonged use of fluconazole (4). Although fluconazole-resistance was not documented in the breakthrough cryptococcal isolate in the study by Singh et al., the follow-up time of 12.1 months was short (80). Indeed, there have been anecdotal reports linking failure of primary fluconazole prophylaxis to cryptococcal strains exhibiting high fluconazole MICs; these reports involved patients with very low CD4 counts (< 25/mm3) who had received primary fluconazole prophylaxis for a prolonged period of time (> 12 months) (6). Although the prevalence of fluconazole-resistant Cryptococcus among patients receiving primary fluconazole prophylaxis is low, the experience with fluconazole resistance might be a harbinger for the emergence of fluconazole resistance among isolates in the future. Furthermore, the cost of fluconazole prophylaxis is significant: it is estimated that 7,800 doses of fluconazole would have to be used to prevent a case of invasive fungal infection (80). The cost, the risk of emergence of fluconazole resistance, and the lack of impact on survival argue against primary fluconazole prophylaxis in the U.S. and other developed countries. These issues have led U. S. Public Health Service/Infectious Diseases Society of America task force to decide that routine antifungal prophylaxis for patients with HIV infection should not be recommended. It is worthwhile to note that the incidence of cryptococcal meningitis in HIV-infected patients decreased in 1992-1994, before the era of protease inhibitors; the most likely cause was the rising use of fluconazole for chronic treatment of thrush and Candida esophagitis. In resource-poor countries where cryptococcal infections are common, the mortality rate is high due to the lack of optimal therapy (32). For example, in Thailand, cryptococcal meningitis accounts for 38% of AIDS-defining illnesses among HIV hospital admissions (86). In Thailand, weekly fluconazole prophylaxis at a dosage of 400 mg reduces the number of deaths per 10,000 person-days to 2.7 compare with 11.7 for the placebo group (rate difference=9; 95% CI: 0.4 17.5; P=0.046). Patients in the fluconazole group were also less likely to develop cryptococcal meningitis than those in the placebo group [hazard ratio=2.23; 95% confidence interval (CI): 0.58 8.63; P=0.245]. The cost and benefit of this prophylaxis should be assessed further in these countries (17). Jarvis JN et al. Screening for Cryptococcal Antigenemia in Patients Accessing an Antiretroviral Treatment Program in South Africa.Clin Infect Dis. 2009 Apr 1;48(7):856-62. Itraconazole Prophylaxis: In a prospective double-blind trial, 63 patients with HIV and CD4 <200 were randomized to itraconazole at 200 mg/day and 66 patients to placebo (15). Systemic fungal infection occurred in one patient (1.6%) in the itraconazole group (P. marneffei) and in 17% (14) in the placebo group (C. neoformans in 7 patients, and P. marneffei in 4 patients, p= 0.003). Itraconazole was well tolerated, safe and effective. Mortality was, however, not significantly different within these 2 groups.
Table 1. Geographic Distribution and Clinical Characteristics of the Two Varieties of C. neoformans. Table 2. Currently Available Antifungal Agents Against Cryptococcus Neoformans, and Their Characteristics. Table 3. Recommended treatment for cryptococcosis. [Download PDF]
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