Both these studies also demonstrated that, with appropriate monitoring, conventional amphotericin B is reasonably well tolerated, with drug discontinuations in 3% of patients in the first 2 weeks in the Mycoses Study Group trial . Saline and fluid loading equivalent to 1 litre normal saline daily should be given unless contraindicated, to minimize nephrotoxicity , and electrolytes replaced as required. Anaemia, secondary to suppression of erythropoietin transcription , is also a predictable side effect of amphotericin B [65–67]. This may be more clinically significant in populations with lower baseline haemoglobin levels, and where transfusion, when occasionally needed, is difficult.
Flucytosine, at the historically low daily dose of 100 mg/kg, was also well tolerated without real-time drug level monitoring in either trial. A substudy of the Thai trial comparing oral and intravenous flucytosine at the same daily dosage of 100 mg/kg has provided some insight into this observation. In contrast to earlier studies in other patient populations, oral bioavailability of flucytosine in these patients at a late stage of HIV infection was only around 50%, resulting in relatively low serum concentration, of an order not usually associated with toxicity. Nevertheless, despite the lower serum levels, patients on oral formulation had the same rate of clearance of infection as those on intravenous formulation , consistent with evidence for the dose-independent activity of flucytosine [69–71]. The data suggest that even 100 mg/kg daily, if given intravenously, may be in excess of that required for maximal additional fungicidal activity.
If renal impairment does develop, liposomal amphotericin B, at 3 mg/kg daily, provides a less nephrotoxic and equally effective alternative. A small study suggested liposomal amphotericin B, at 4 mg/kg daily, was more active than conventional amphotericin B , but a larger study found no difference in the proportion of patients with sterile CSF at 2 weeks in patients receiving daily liposomal amphotericn B at 3 or 6 mg/kg compared with conventional amphotericin B at 0.7 mg/kg daily .
Unfortunately, in many resource-poor settings, amphotericin B is not available or cannot be used safely because of lack of monitoring, and fluconazole, widely available, through a free access programme or in generic form, is the only treatment option. Outcomes with initial fluconazole monotherapy at 200–400 mg daily have not been good, either in early US-based studies [19,74], including a small randomized study in which 400 mg daily was clinically inferior to amphotericin B plus flucytosine , or in more recent series from Africa [57,75,76]. Although the earlier randomized study comparing amphotericin B with fluconazole found no significant difference in clinical outcomes, time to sterilization was very long for fluconazole (median 64 days), and outcomes for both drugs were poor . Furthermore, the dosages used for both drugs were lower than currently recommended, making interpretation difficult. The 10-week mortality of approximately 50% with initial fluconazole monotherapy reported by Schaars and colleagues  in South Africa represents a minimum estimate in this setting given the retrospective nature of the study with incomplete out-patient follow up. Recent work from Cape Town has demonstrated that 400 mg fluconazole daily is essentially fungistatic over the first 2 weeks of treatment . The resulting prolonged period with a high viable organism load may predispose to the development of fluconazole resistance. Such resistance is a significant problem when initial therapy is with fluconazole . A further concern is that prolonged active infection could also increase the risk of immune reconstitution reactions (see below) following introduction of ART, although data on this point are lacking.
Animal studies suggest a dose–response relationship with increasing fluconazole levels . There is a linear plasma concentration–dose relationship with fluconazole at up to 2 g daily , and doses up to 1600 mg daily have appeared safe in small numbers of patients [79,80]. In addition there is a suggestion of a dose–response relationship in terms of the time to sterilization of CSF: with a median time to CSF sterilization of 64 days with 200–400 mg daily , a mean time of 41 days with 400 mg daily , and 21  and 33 days  with 800 mg daily. On this basis, and given the unsatisfactory results of treatment at lower doses, a dose-escalation study of fluconazole therapy is currently underway in Uganda. In the meantime, in settings where amphotericin B cannot be used safely and fluconazole is the only option, the authors would suggest a starting dose of at least 800 mg daily (Table 1).
The combination of fluconazole plus flucytosine is additive or synergistic in murine models [83,84], although not in a study in rabbits . A clinical study in Uganda suggested benefit with addition of flucytosine to fluconazole, although the dose of fluconazole was low (200 mg daily) ; and in a small series from the United States, the combination of flucytosine and fluconazole at 400 mg daily resulted in a relatively short median time to sterilization of CSF of 23 days, although side effects with the combination appeared frequent . Further comparative trials to examine the fungicidal activity and toxicity of this combination with higher doses of fluconazole are warranted in settings where intravenous amphotericin B-based therapy is not possible.
In terms of management, few controlled trials have been carried out, so recommendations are based on small series and expert opinion. Current US guidelines suggest daily lumbar punctures for all patients with elevated baseline opening pressures (> 25 cmH2O), with the removal of sufficient CSF to reduce pressures by 50%, continued until pressure has been normal for several days . The maximum volume of CSF that is safe to remove at a single lumbar puncture is unclear but 20–30 ml is probably reasonable . If facilities allow, computed tomographic or magnetic resonance scanning of the head should be done prior to initial lumbar puncture or if suspected raised CSF pressure develops on therapy in order to exclude rare cases of true hydrocephalus and space-occupying lesions. In the rare cases in which hydrocephalus develops, a ventriculoperitoneal shunt should be inserted . When repeated lumbar punctures fail to control pressure and the patient's condition is deteriorating, CSF drainage can be achieved with a ventricular or, less invasive, lumbar drain [99,100]. It is unclear how long the defect in CSF reabsorption persists, but it may be that a significant proportion of patients will respond to relatively short-term drainage with a temporary system . These allow the continual, controlled drainage of high volumes of fluid (approximately 200 ml daily) to a set pressure level, are relatively straightforward to insert, and have a low risk of complications with adequate monitoring and nursing and medical staff who are familiar with their use [101,102].
The use of mannitol, acetazolamide, and corticosteroids for raised CSF pressure is not supported by available evidence . A randomized trial of acetazolamide was terminated early ; and high-dose steroids were associated with higher mortality in patients with elevated CSF pressures in a large, although uncontrolled, study .
The role of IRIS is less in doubt when cryptococcal cultures are negative, but it is likely that immune reconstitution also contributes to the presentation and re-presentation of some patients who are still culture positive .
The occurrence of cryptococcal IRIS has implications for the timing of ART. The apparent increase in the risk of cryptococcal IRIS with earlier initiation of ART has to be balanced against the risk of other HIV-related complications if initiation of ART is delayed. Optimal timing of ART may be earlier in developing countries where rates of death prior to initiation of ART are high [60,117]. Until trials currently underway report, most investigators would start ART from 4 weeks into antifungal therapy, although it is possible earlier ART may be safe if a rapidly fungicidal regimen is used for initial antifungal therapy. Treatment of cryptococcal IRIS is another area requiring further investigation. If clinical progression occurs, despite appropriate antifungal therapy and aggressive management of any raised CSF pressure, short-term steroids, which have been used successfully in case reports [108,118,119], can be considered.
The need for primary antifungal prophylaxis is reducing as access to ART expands, the best prophylaxis being rapid immune reconstitution with ART. However in the absence of ART, or in those who fail to respond to treatment, a strong case exists for primary prophylaxis with fluconazole in those with CD4 cell counts < 100 cells/μl in areas with a high incidence of cryptococcal disease [120,121]. Such a policy was introduced in Thailand prior to widespread availability of ART and is under investigation in east Africa. In areas of high incidence, in view of the significant proportion of patients now presenting after starting ART , a case can also be made for screening with serum cryptococal antigen  prior to ART in order to diagnose and treat subclinical infection before it is unmasked by immune reconstitution. However, studies are needed, and such a strategy is not justified and is not used in areas of lower incidence [18,123].
Regarding access to antifungal drugs, fluconazole is widely available through a free access programme and in generic form. In contrast, although generic amphotericin B is also available, the cost is variable and may be significant in very resource-limited settings . In addition, continuous supply has been an issue in some areas, including the United Kingdom, related perhaps to the reduced market for amphotericin B deoxycholate for treating other fungal infections in the developed world. Flucytosine is a simple and old molecule that nevertheless is not widely available either in Africa or Asia, where the burden of cryptococcal disease is so high. Only one manufacturer markets the drug to our knowledge. In countries where they are not marketed, flucytosine tablets can be obtained on a named patient basis from IDIS World Medicines (www.idispharma.com). If studies, currently underway, comparing high-dose fluconazole with flucytosine as a companion drug to give with amphotericin B show that flucytosine remains the second drug of choice, then advocacy is needed to expand access to flucytosine.
The rate of clearance of infection, or early fungicidal activity, from serial quantitative cultures of CSF provides a means by which the activity of new drugs or combinations for antifungal therapy can be accurately assessed in small numbers of patients; this would enable regimens for testing in phase III trials to be selected on a more rational basis . Such clearance studies are underway to examine whether 1 mg/kg amphotericin B daily is associated with a significant increase in fungicidal activity compared with 0.7 mg/kg daily, and to compare flucytosine and high-dose fluconazole as a second drug to give with amphotericin B. Comparative studies are also needed with new azoles with activity against C. neoformans, such as voriconazole , although interactions with antituberculous and antiretroviral medication are a problem. Minimal inhibitory concentrations, animal model data and penetration into the central nervous system for voriconazole and posaconazole are shown in Table 2. Of note, echinocandins have limited anticryptococcal activity because they target 1–3-β-D-glucan linkages, which are not important in the cryptococcal cell wall .
Given the limitations of current antifungal drugs, and uncertainty over further drug development, there is continuing interest in adjunctive immunotherapy. A monoclonal antibody directed against the capsular polysaccharide of C neoformans has reached phase I human studies ; and a monoclonal antibody fragment, Mycograb, directed against candidal heat shock protein 90, and reported to be beneficial when given with amphotericin B in invasive candidiasis , also has in-vitro activity against C. neoformans . Clinical trials in cryptococcal meningitis are planned.
An alternative approach is use of interferon-γ (IFN-γ). There is direct in-vivo evidence that IFN-γ is important for clearance of cryptococcal infection in HIV-infected patients . A placebo-controlled trial showed that adjuvant IFN-γ therapy was safe and well tolerated, with no detrimental effects on HIV viral load or CD4 cell counts. There was also a trend towards improved mycological outcomes, with 13% of placebo recipients achieving negative cultures at 2 weeks compared with 36% or 32% of those receiving IFN-γ . The trend in favour of IFN-γ was already seen after 2 weeks of treatment, and studies have shown that endogenous IFN-γ in the CSF peaks at day 3 and is virtually undetectable by day 14 , suggesting that short courses of adjuvant IFN-γ, which would be more feasible to implement, may be effective.
Finally, studies continue to identify suitable cryptococcal antigens for vaccine development  and to address the formidable challenges inherent in the vaccination of immunodeficient hosts, such as those with HIV infection .
1. Morgan J, McCarthy KM, Gould S, Fan K, Arthington-Skaggs B, Iqbal N, et al
. Cryptococcus gattii
infection: characteristics and epidemiology
of cases identified in a South African province with high HIV
seroprevalence, 2002–2004. Clin Infect Dis 2006; 43:1077–1080.
2. Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am 2006; 20:507–544, v-vi.
3. Lindberg J, Hagen F, Laursen A, Stenderup J, Boekhout T. Cryptococcus gattii
risk for tourists visiting Vancouver Island, Canada. Emerg Infect Dis 2007; 13:178–179.
4. Galanis E, MacDougall L, Li M, Kidd S, Lee M, Morshed M. Clinical and epidemiological aspects of locally acquired Cryptococcus gattii human infections, an emerging fungal pathogen in British Colombia, Canada. 17th European Congress of Clinical Microbiology and Infectious Diseases
. Munich, April 2007 [abstract O170].
5. Lazera MS, Salmito Cavalcanti MA, Londero AT, Trilles L, Nishikawa MM, Wanke B, et al
. Possible primary ecological niche of Cryptococcus neoformans
. Med Mycol 2000; 38:379–383.
6. Randhawa HS, Kowshik T, Preeti Sinha K, Chowdhary A, Khan ZU, Yan Z, et al
. Distribution of Cryptococcus gattii
and Cryptococcus neoformans
in decayed trunk wood of Syzygium cumini
trees in north-western India. Med Mycol 2006; 44:623–630.
7. Swinne D, Deppner M, Laroche R, Floch JJ, Kadende P. Isolation of Cryptococcus neoformans
from houses of AIDS-associated cryptococcosis patients in Bujumbura (Burundi). AIDS 1989; 3:389–390.
8. Swinne D, Taelman H, Batungwanayo J, Bigirankana A, Bogaerts J. Ecology of Cryptococcus neoformans
in central Africa. Med Trop (Mars) 1994; 54:53–55.
9. Goldman DL, Khine H, Abadi J, Lindenberg DJ, Pirofski L, Niang R, et al
. Serologic evidence for Cryptococcus neoformans
infection in early childhood. Pediatrics 2001; 107:E66.
10. Wickes BL, Mayorga ME, Edman U, Edman JC. Dimorphism and haploid fruiting in Cryptococcus neoformans
: association with the alpha-mating type. Proc Natl Acad Sci USA 1996; 93:7327–7331.
11. Hung JJ, Ou LS, Lee WI, Huang JL. Central nervous system infections in patients with systemic lupus erythematosus. J Rheumatol 2005; 32:40–43.
12. Ross JJ, Katz JD. Cryptococcal meningitis
and sarcoidosis. Scand J Infect Dis 2002; 34:937–939.
13. Goldman DL, Lee SC, Mednick AJ, Montella L, Casadevall A. Persistent Cryptococcus neoformans
pulmonary infection in the rat is associated with intracellular parasitism, decreased inducible nitric oxide synthase expression, and altered antibody responsiveness to cryptococcal polysaccharide. Infect Immun 2000; 68:832–838.
14. Salyer WR, Salyer DC, Baker RD. Primary complex of Cryptococcus
and pulmonary lymph nodes. J Infect Dis 1974; 130:74–77.
15. Garcia-Hermoso D, Janbon G, Dromer F. Epidemiological evidence for dormant Cryptococcus neoformans
infection. J Clin Microbiol 1999; 37:3204–3209.
16. Fessel WJ. Cryptococcal meningitis
after unusual exposures to birds. N Engl J Med 1993; 328:1354–1355.
17. MacDougall L, Fyfe M. Emergence of Cryptococcus gattii
in a novel environment provides clues to its incubation period. J Clin Microbiol 2006; 44:1851–1852.
18. Feldmesser M, Harris C, Reichberg S, Khan S, Casadevall A. Serum cryptococcal antigen in patients with AIDS. Clin Infect Dis 1996; 23:827–830.
19. Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK, et al
. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis
. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. N Engl J Med 1992; 326:83–89.
20. Brouwer AE, Rajanuwong A, Chierakul W, Griffin GE, Larsen RA, White NJ, et al
. Combination antifungal therapies for HIV
-associated cryptococcal meningitis
: a randomised trial. Lancet 2004; 363:1764–1767.
21. van der Horst CM, Saag MS, Cloud GA, Hamill RJ, Graybill JR, Sobel JD, et al
. Treatment of cryptococcal meningitis
associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med 1997; 337:15–21.
22. Graybill JR, Sobel J, Saag M, van Der Horst C, Powderly W, Cloud G, et al
. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis
. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis 2000; 30:47–54.
23. Lee SC, Casadevall A. Polysaccharide antigen in brain tissue of AIDS patients with cryptococcal meningitis
. Clin Infect Dis 1996; 23:194–195.
24. Lee SC, Casadevall A, Dickson DW. Immunohistochemical localization of capsular polysaccharide antigen in the central nervous system cells in cryptococcal meningoencephalitis. Am J Pathol 1996; 148:1267–1274.
25. Lee SC, Dickson DW, Casadevall A. Pathology of cryptococcal meningoencephalitis: analysis of 27 patients with pathogenetic implications. Hum Pathol 1996; 27:839–847.
26. Molez JF, Ginoux PY, Asselin P, Frezil JL. Demonstration of Cryptococcus neoformans
in a fatal meningeal disease in the Congo. Med Trop (Mars) 1982; 42:561–563.
27. Molez JF. The historical question of acquired immunodeficiency syndrome in the 1960s in the Congo River basin area in relation to cryptococcal meningitis
. Am J Trop Med Hyg 1998; 58:273–276.
28. Lamey B, Melameka N. Clinical and epidemiologic aspects of cryptococcosis in Kinshasa. Apropos of 15 personal cases. Med Trop (Mars) 1982; 42:507–511.
29. Swinne D, Kayembe K, Niyimi M. Isolation of saprophytic Cryptococcus neoformans
in Kinshasa, Zaire. Ann Soc Belg Med Trop 1986; 66:57–61.
30. Clumeck N, Mascart-Lemone F, de Maubeuge J, Brenez D, Marcelis L. Acquired immune deficiency syndrome in Black Africans. Lancet 1983; i:642.
31. Brunet JB, Bouvet E, Leibowitch J, Chaperon J, Mayaud C, Gluckman JC, et al
. Acquired immunodeficiency syndrome in France. Lancet 1983; i:700–701.
32. Offenstadt G, Pinta P, Hericord P, Jagueux M, Jean F, Amstutz P, et al
. Multiple opportunistic infection due to AIDS in a previously healthy black woman from Zaire. N Engl J Med 1983; 308:775.
33. Vandepitte J, Verwilghen R, Zachee P. AIDS and cryptococcosis (Zaire, 1977). Lancet 1983; i:925–926.
34. Selik RM, Karon JM, Ward JW. Effect of the human immunodeficiency virus epidemic on mortality from opportunistic infections in the United States in 1993. J Infect Dis 1997; 176:632–636.
35. Sorvillo F, Beall G, Turner PA, Beer VL, Kovacs AA, Kerndt PR. Incidence and factors associated with extrapulmonary cryptococcosis among persons with HIV
infection in Los Angeles County. AIDS 1997; 11:673–679.
36. Dore GJ, Hoy JF, Mallal SA, Li Y, Mijch AM, French MA, et al
. Trends in incidence of AIDS illnesses in Australia from 1983 to 1994: the Australian AIDS cohort. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 16:39–43.
37. Chuck SL, Sande MA. Infections with Cryptococcus neoformans
in the acquired immunodeficiency syndrome. N Engl J Med 1989; 321:794–799.
38. Hajjeh RA, Conn LA, Stephens DS, Baughman W, Hamill R, Graviss E, et al
. Cryptococcosis: population-based multistate active surveillance and risk factors in human immunodeficiency virus-infected persons. Cryptococcal Active Surveillance Group. J Infect Dis 1999; 179:449–454.
39. Chen S, Sorrell T, Nimmo G, Speed B, Currie B, Ellis D, et al
and host- and variety-dependent characteristics of infection due to Cryptococcus neoformans
in Australia and New Zealand. Australasian Cryptococcal Study Group. Clin Infect Dis 2000; 31:499–508.
40. Kaplan JE, Hanson D, Dworkin MS, Frederick T, Bertolli J, Lindegren ML, et al
of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy
. Clin Infect Dis 2000; 30(Suppl 1):S5–S14.
41. Mirza SA, Phelan M, Rimland D, Graviss E, Hamill R, Brandt ME, et al
. The changing epidemiology
of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992–2000. Clin Infect Dis 2003; 36:789–794.
42. Holmes CB, Losina E, Walensky RP, Yazdanpanah Y, Freedberg KA. Review of human immunodeficiency virus type 1-related opportunistic infections in sub-Saharan Africa. Clin Infect Dis 2003; 36:652–662.
43. Chariyalertsak S, Sirisanthana T, Saengwonloey O, Nelson KE. Clinical presentation
and risk behaviors of patients with acquired immunodeficiency syndrome in Thailand, 1994–1998: regional variation and temporal trends. Clin Infect Dis 2001; 32:955–962.
44. Gordon SB, Walsh AL, Chaponda M, Gordon MA, Soko D, Mbwvinji M, et al
. Bacterial meningitis in Malawian adults: pneumococcal disease is common, severe, and seasonal. Clin Infect Dis 2000; 31:53–57.
45. Bekondi C, Bernede C, Passone N, Minssart P, Kamalo C, Mbolidi D, et al
. Primary and opportunistic pathogens associated with meningitis in adults in Bangui, Central African Republic, in relation to human immunodeficiency virus serostatus. Int J Infect Dis 2006; 10:387–395.
46. Hakim JG, Gangaidzo IT, Heyderman RS, Mielke J, Mushangi E, Taziwa A, et al
. Impact of HIV
infection on meningitis in Harare, Zimbabwe: a prospective study of 406 predominantly adult patients. AIDS 2000; 14:1401–1407.
47. Okongo M, Morgan D, Mayanja B, Ross A, Whitworth J. Causes of death in a rural, population-based human immunodeficiency virus type 1 (HIV
-1) natural history cohort in Uganda. Int J Epidemiol 1998; 27:698–702.
48. French N, Gray K, Watera C, Nakiyingi J, Lugada E, Moore M, et al
. Cryptococcal infection in a cohort of HIV
-1-infected Ugandan adults. AIDS 2002; 16:1031–1038.
49. Corbett EL, Churchyard GJ, Charalambos S, Samb B, Moloi V, Clayton TC, et al
. Morbidity and mortality in South African gold miners: impact of untreated disease due to human immunodeficiency virus. Clin Infect Dis 2002; 34:1251–1258.
50. Suwanagool S, Ratanasuwan W. AIDS at Siriraj Hospital during 1985–1993. J Infect Dis Antimicrob Agents 1994; 11:117–124.
51. Kumarasamy N, Solomon S, Flanigan TP, Hemalatha R, Thyagarajan SP, Mayer KH. Natural history of human immunodeficiency virus disease in southern India. Clin Infect Dis 2003; 36:79–85.
52. Pappalardo MC, Melhem MS. Cryptococcosis: a review of the Brazilian experience for the disease. Rev Inst Med Trop Sao Paulo 2003; 45:299–305.
53. Lucas SB, Hounnou A, Peacock C, Beaumel A, Djomand G, N'Gbichi JM, et al
. The mortality and pathology of HIV
infection in a west African city. AIDS 1993; 7:1569–1579.
54. Lortholary O, Poizat G, Zeller V, Neuville S, Boibieux A, Alvarez M, et al
. Long-term outcome of AIDS-associated cryptococcosis in the era of combination antiretroviral therapy
. AIDS 2006; 20:2183–2191.
55. Robinson PA, Bauer M, Leal MA, Evans SG, Holtom PD, Diamond DA, et al
. Early mycological treatment failure in AIDS-associated cryptococcal meningitis
. Clin Infect Dis 1999; 28:82–92.
56. Imwidthaya P, Poungvarin N. Cryptococcosis in AIDS. Postgrad Med J 2000; 76:85–88.
57. Mwaba P, Mwansa J, Chintu C, Pobee J, Scarborough M, Portsmouth S, et al
. Clinical presentation
, natural history, and cumulative death rates of 230 adults with primary cryptococcal meningitis
in Zambian AIDS patients treated under local conditions. Postgrad Med J 2001; 77:769–773.
58. Maher D, Mwandumba H. Cryptococcal meningitis
in Lilongwe and Blantyre, Malawi. J Infect 1994; 28:59–64.
59. Heyderman RS, Gangaidzo IT, Hakim JG, Mielke J, Taziwa A, Musvaire P, et al
. Cryptococcal meningitis
in human immunodeficiency virus-infected patients in Harare, Zimbabwe. Clin Infect Dis 1998; 26:284–289.
60. Bicanic T, Meintjes G, Wood R, Hayes M, Rebe K, Bekker LG, et al
. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis
in antiretroviral-naive or -experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis 2007; 45:76–80.
61. Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, et al
. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 2000; 30:710–718.
62. Denning DW, Kibbler CC, Barnes RA. British Society for Medical Mycology proposed standards of care for patients with invasive fungal infections. Lancet Infect Dis 2003; 3:230–240.
63. Branch RA. Prevention of amphotericin B-induced renal impairment. A review on the use of sodium supplementation. Arch Intern Med 1988; 148:2389–2394.
64. Yeo EJ, Ryu JH, Cho YS, Chun YS, Huang LE, Kim MS, et al
. Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1. Blood 2006; 107:916–923.
65. Utz JP. Amphotericin B toxicity: general side effects. Ann Intern Med 1964; 61:340–343.
66. Brandiss MW. Amphotericin B toxicity: anemia. Ann Intern Med 1964; 61:343–344.
67. Brandriss MW, Wolff SM, Moores R, Stohlman F Jr. Anemia induced by Amphotericin B. JAMA 1964; 189:663–666.
68. Brouwer AE, van Kan HJ, Johnson E, Rajanuwong A, Teparrukkul P, Wuthiekanun V, et al
. Oral versus intravenous flucytosine in patients with human immunodeficiency virus-associated cryptococcal meningitis
. Antimicrob Agents Chemother 2007; 51:1038–1042.
69. Andes D, van Ogtrop M. In vivo characterization of the pharmacodynamics of flucytosine in a neutropenic murine disseminated candidiasis model. Antimicrob Agents Chemother 2000; 44:938–942.
70. Francis P, Walsh TJ. Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmacokinetics, and antifungal therapy
. Clin Infect Dis 1992; 15:1003–1018.
71. Lewis RE, Klepser ME, Pfaller MA. In vitro pharmacodynamic characteristics of flucytosine determined by time-kill methods. Diagn Microbiol Infect Dis 2000; 36:101–105.
72. Leenders AC, Reiss P, Portegies P, Clezy K, Hop WC, Hoy J, et al
. Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis
. AIDS 1997; 11:1463–1471.
73. Hamill RJ, Sobel J, el-Sadr W, et al. Randomized double blind trial of Ambisome (liposomal amphotericin B) and amphotericin B in acute cryptococcal meningitis in AIDS patients. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy.
San Francisco, September 1999 [abstract 1161].
74. Larsen RA, Leal MA, Chan LS. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis
in AIDS. A randomized trial. Ann Intern Med 1990; 113:183–187.
75. Schaars CF, Meintjes GA, Morroni C, Post FA, Maartens G. Outcome of AIDS-associated cryptococcal meningitis
initially treated with 200 mg/day or 400 mg/day of fluconazole. BMC Infect Dis 2006; 6:118.
76. Mayanja-Kizza H, Oishi K, Mitarai S, Yamashita H, Nalongo K, Watanabe K, et al
. Combination therapy
with fluconazole and flucytosine for cryptococcal meningitis
in Ugandan patients with AIDS. Clin Infect Dis 1998; 26:1362–1366.
77. Bicanic T, Harrison T, Niepieklo A, Dyakopu N, Meintjes G. Symptomatic relapse of HIV
-associated cryptococcal meningitis
after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clin Infect Dis 2006; 43:1069–1073.
78. Kartalija M, Kaye K, Tureen JH, Liu Q, Tauber MG, Elliott BR, et al
. Treatment of experimental cryptococcal meningitis
with fluconazole: impact of dose and addition of flucytosine on mycologic and pathophysiologic outcome. J Infect Dis 1996; 173:1216–1221.
79. Anaissie EJ, Kontoyiannis DP, Huls C, Vartivarian SE, Karl C, Prince RA, et al
. Safety, plasma concentrations, and efficacy of high-dose fluconazole in invasive mold infections. J Infect Dis 1995; 172:599–602.
80. Milefchik, E., Leal M, Haubrich R. A phase II dose escalation trial of high dose fluconazole with and without flucytosine for AIDS-associated cryptococcal meningitis. Fourth Conference on Retroviruses and Opportunistic Infections
. Washington DC, January1997 [abstract 5].
81. Haubrich RH, Haghighat D, Bozzette SA, Tilles J, McCutchan JA. High-dose fluconazole for treatment of cryptococcal disease in patients with human immunodeficiency virus infection. The California Collaborative Treatment Group. J Infect Dis 1994; 170:238–242.
82. Menichetti F, Fiorio M, Tosti A, Gatti G, Bruna Pasticci M, Miletich F, et al
. High-dose fluconazole therapy
for cryptococcal meningitis
in patients with AIDS. Clin Infect Dis 1996; 22:838–840.
83. Allendoerfer R, Marquis AJ, Rinaldi MG, Graybill JR. Combined therapy
with fluconazole and flucytosine in murine cryptococcal meningitis
. Antimicrob Agents Chemother 1991; 35:726–729.
84. Ding JC, Bauer M, Diamond DM, Leal MA, Johnson D, Williams BK, et al
. Effect of severity of meningitis on fungicidal activity of flucytosine combined with fluconazole in a murine model of cryptococcal meningitis
. Antimicrob Agents Chemother 1997; 41:1589–1593.
85. Larsen RA, Bozzette SA, Jones BE, Haghighat D, Leal MA, Forthal D, et al
. Fluconazole combined with flucytosine for treatment of cryptococcal meningitis
in patients with AIDS. Clin Infect Dis 1994; 19:741–745.
86. Bozzette SA, Larsen RA, Chiu J, Leal MA, Jacobsen J, Rothman P, et al
. A placebo-controlled trial of maintenance therapy
with fluconazole after treatment of cryptococcal meningitis
in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. N Engl J Med 1991; 324:580–584.
87. Powderly WG, Saag MS, Cloud GA, Robinson P, Meyer RD, Jacobson JM, et al
. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis
in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group. N Engl J Med 1992; 326:793–798.
88. Saag MS, Cloud GA, Graybill JR, Sobel JD, Tuazon CU, Johnson PC, et al
. A comparison of itraconazole versus fluconazole as maintenance therapy
for AIDS-associated cryptococcal meningitis
. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1999; 28:291–296.
89. Aberg JA, Price RW, Heeren DM, Bredt B. A pilot study of the discontinuation of antifungal therapy
for disseminated cryptococcal disease in patients with acquired immunodeficiency syndrome, following immunologic response to antiretroviral therapy
. J Infect Dis 2002; 185:1179–1182.
90. Vibhagool A, Sungkanuparph S, Mootsikapun P, Chetchotisakd P, Tansuphaswaswadikul S, Bowonwatanuwong C, et al
. Discontinuation of secondary prophylaxis for cryptococcal meningitis
in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy
: a prospective, multicenter, randomized study. Clin Infect Dis 2003; 36:1329–1331.
91. Mussini C, Pezzotti P, Miro JM, Martinez E, de Quiros JC, Cinque P, et al
. Discontinuation of maintenance therapy
for cryptococcal meningitis
in patients with AIDS treated with highly active antiretroviral therapy
: an international observational study. Clin Infect Dis 2004; 38:565–571.
92. Denning DW, Armstrong RW, Lewis BH, Stevens DA, et al
. Elevated cerebrospinal fluid pressures in patients with cryptococcal meningitis
and acquired immunodeficiency syndrome. Am J Med 1991; 91:267–272.
93. Rex JH, Larsen RA, Dismukes WE, Cloud GA, Bennett JE. Catastrophic visual loss due to Cryptococcus neoformans
meningitis. Medicine (Baltimore) 1993; 72:207–224.
94. Bach MC, Tally PW, Godofsky EW. Use of cerebrospinal fluid shunts in patients having acquired immunodeficiency syndrome with cryptococcal meningitis
and uncontrollable intracranial hypertension. Neurosurgery 1997; 41:1280–1282 [Discussion 1282–1283.].
95. Hoepelman AI, van der Flier M, Coenjaerts FE. Dexamethasone downregulates Cryptococcus neoformans
-induced vascular endothelial growth factor production: a role for corticosteroids in cryptococcal meningitis
? J Acquir Immune Defic Syndr 2004; 37:1431–1432.
96. Coenjaerts FE, van der Flier M, Mwinzi PN, Brouwer AE, Scharringa J, Chaka WS, et al
. Intrathecal production and secretion of vascular endothelial growth factor during cryptococcal meningitis
. J Infect Dis 2004; 190:1310–1317.
97. Sun HY, Hung CC, Chang SC. Management of cryptococcal meningitis
with extremely high intracranial pressure in HIV
-infected patients. Clin Infect Dis 2004; 38:1790–1792.
98. Park MK, Hospenthal DR, Bennett JE. Treatment of hydrocephalus secondary to cryptococcal meningitis
by use of shunting. Clin Infect Dis 1999; 28:629–633.
99. Macsween KF, Bicanic T, Brouwer AE, Marsh H, Macallan DC, Harrison TS. Lumbar drainage for control of raised cerebrospinal fluid pressure in cryptococcal meningitis
: case report and review. J Infect 2005; 51:e221–e224.
100. Fessler RD, Sobel J, Guyot L, Crane L, Vazquez J, Szuba MJ, et al
. Management of elevated intracranial pressure in patients with cryptococcal meningitis
. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17:137–142.
101. Coplin WM, Avellino AM, Kim DK, Winn HR, Grady MS. Bacterial meningitis associated with lumbar drains: a retrospective cohort study. J Neurol Neurosurg Psychiatry 1999; 67:468–473.
102. American Association of Neuroscience Nurses. Care of the Patient with a Lumbar Drain
. [AANN Reference Series for Clinical Practice
.] Glenview, IL: American Association of Neuroscience Nurses; 2007:1-15.
103. Newton PN, Thai le H, Tip NQ, Short JM, Chierakul W, Rajanuwong A, et al
. A randomized, double-blind, placebo-controlled trial of acetazolamide for the treatment of elevated intracranial pressure in cryptococcal meningitis
. Clin Infect Dis 2002; 35:769–772.
104. Robertson J, Meier M, Wall J, Ying J, Fichtenbaum CJ. Immune reconstitution syndrome in HIV
: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy
. Clin Infect Dis 2006; 42:1639–1646.
105. Ratnam I, Chiu C, Kandala NB, Easterbrook PJ. Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV
type 1-infected cohort. Clin Infect Dis 2006; 42:418–427.
106. Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV
-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005; 5:361–373.
107. Shelburne SA III, Darcourt J, White AC Jr, Greenberg SB, Hamill RJ, Atmar RL, et al
. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans
disease in the era of highly active antiretroviral therapy
. Clin Infect Dis 2005; 40:1049–1052.
108. Lortholary O, Fontanet A, Mémain N, Martin A, Sitbon K, Dromer F. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV
-associated cryptococcosis in France. AIDS 2005; 19:1043–1049.
109. Lawn SD, Bekker LG, Myer L, Orrell C, Wood R. Cryptococcocal immune reconstitution disease: a major cause of early mortality in a South African antiretroviral programme. AIDS 2005; 19:2050–2052.
110. Trevenzoli M, Cattelan AM, Rea F, Sasset L, Semisa M, Lanzafame M, et al
. Mediastinitis due to cryptococcal infection: a new clinical entity in the HAART era. J Infect 2002; 45:173–179.
111. Manfredi R, Pieri F, Pileri SA, Chiodo F. The changing face of AIDS-related opportunism: cryptococcosis in the highly active antiretroviral therapy
(HAART) era. Case reports and literature review. Mycopathologia 1999; 148:73–78.
112. Cattelan AM, Trevenzoli M, Sasset L, Lanzafame M, Marchioro U, Meneghetti F. Multiple cerebral cryptococcomas associated with immune reconstitution in HIV
-1 infection. AIDS 2004; 18:349–351.
113. Jenny-Avital ER, Abadi M. Immune reconstitution cryptococcosis after initiation of successful highly active antiretroviral therapy
. Clin Infect Dis 2002; 35:e128–e133.
114. Woods ML II, MacGinley R, Eisen DP, Allworth AM. HIV
: partial immune restitution unmasking latent cryptococcal infection. AIDS 1998; 12:1491–1494.
115. Shelburne SA III, Hamill RJ. The immune reconstitution inflammatory syndrome. AIDS Rev 2003; 5:67–79.
116. York J, Bodi I, Reeves I, Riordan-Eva P, Easterbrook PJ. Raised intracranial pressure complicating cryptococcal meningitis
: immune reconstitution inflammatory syndrome or recurrent cryptococcal disease? J Infect 2005; 51:165–171.
117. Lawn SD, Myer L, Orrell C, Bekker LG, Wood R. Early mortality among adults accessing a community-based antiretroviral service in South Africa: implications for programme design. AIDS 2005; 19:2141–2148.
118. Shelburne SA III, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, Atmar RL, Musher DW, et al
. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy
. Medicine (Baltimore) 2002; 81:213–227.
119. Boelaert JR, Goddeeris KH, Vanopdenbosch LJ, Casselman JW. Relapsing meningitis caused by persistent cryptococcal antigens and immune reconstitution after the initiation of highly active antiretroviral therapy
. AIDS 2004; 18:1223–1224.
120. Chetchotisakd P, Sungkanuparph S, Thinkhamrop B, Mootsikapun P, Boonyaprawit P. A multicentre, randomized, double-blind, placebo-controlled trial of primary cryptococcal meningitis
prophylaxis in HIV
-infected patients with severe immune deficiency. HIV
Med 2004; 5:140–143.
121. Chang LW, Phipps WT, Kennedy GE, Ruthefors GW. Antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV.
In The Cochrane Database of Systematic Reviews
, Issue 3. Chichester, UK: John Wiley; 2005:CD004773.
122. Tassie JM, Pepper L, Fogg C, Biraro S, Mayanja B, Andia I, et al
. Systematic screening of cryptococcal antigenemia in HIV
-positive adults in Uganda. J Acquir Immune Defic Syndr 2003; 33:411–412.
123. Hoffmann S, Stenderup J, Mathiesen LR. Low yield of screening for cryptococcal antigen by latex agglutination assay on serum and cerebrospinal fluid from Danish patients with AIDS or ARC. Scand J Infect Dis 1991; 23:697–702.
124. Bicanic T, Wood R, Bekker LG, Darder M, Meintjes G, Harrison TS. Antiretroviral roll-out, antifungal roll-back: access to treatment for cryptococcal meningitis
. Lancet Infect Dis 2005; 5:530–531.
125. Perfect JR, Marr KA, Walsh TJ, Greenberg RN, DuPont B, de la Torre-Cisneros J, et al
. Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis 2003; 36:1122–1131.
126. Roling EE, Klepser ME, Wasson A, Lewis RE, Ernst EJ, Pfaller MA, et al
. Antifungal activities of fluconazole, caspofungin (MK0991), and anidulafungin (LY 303366) alone and in combination against Candida
spp. and Cryptococcus neoformans
via time-kill methods. Diagn Microbiol Infect Dis 2002; 43:13–17.
127. Larsen RA, Pappas PG, Perfect J, Aberg JA, Casadevall A, Cloud GA, et al
. Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis
. Antimicrob Agents Chemother 2005; 49:952–958.
128. Matthews RC, Rigg G, Hodgetts S, Carter T, Chapman C, Gregory C, et al
. Preclinical assessment of the efficacy of mycograb, a human recombinant antibody against fungal HSP90. Antimicrob Agents Chemother 2003; 47:2208–2216.
129. Nooney L, Matthews RC, Burnie JP. Evaluation of Mycograb, amphotericin B, caspofungin, and fluconazole in combination against Cryptococcus neoformans
by checkerboard and time-kill methodologies. Diagn Microbiol Infect Dis 2005; 51:19–29.
130. Siddiqui AA, Brouwer AE, Wuthiekanun V, Jaffar S, Shattock R, Irving D, et al
. IFN-gamma at the site of infection determines rate of clearance of infection in cryptococcal meningitis
. J Immunol 2005; 174:1746–1750.
131. Pappas PG, Bustamante B, Ticona E, Hamill RJ, Johnson PC, Reboli A, et al
. Recombinant interferon-gamma 1b as adjunctive therapy
for AIDS-related acute cryptococcal meningitis
. J Infect Dis 2004; 189:2185–2191.
132. Datta K, Pirofski LA. Towards a vaccine for Cryptococcus neoformans
: principles and caveats. FEMS Yeast Res 2006; 6:525–536.
133. Wuthrich M, Filutowicz HI, Warner T, Deepe GS Jr, Klein BS, et al
. Vaccine immunity to pathogenic fungi overcomes the requirement for CD4 help in exogenous antigen presentation to CD8+ T cells: implications for vaccine development in immune-deficient hosts. J Exp Med 2003; 197:1405–1416.
134. Torres HA, Hachem RY, Chemaly RF, Kontoyiannis DP, Raad II, et al
. Posaconazole: a broad-spectrum triazole antifungal. Lancet Infect Dis 2005; 5:775–785.
135. Pfaller MA, Messer SA, Boyken L, Rice C, Tendolkar S, Hollis RJ, et al
. Global trends in the antifungal susceptibility of Cryptococcus neoformans
(1990 to 2004). J Clin Microbiol 2005; 43:2163–2167.
136. Barchiesi F, Arzeni D, Fothergill AW, Di Francesco LF, Caselli F, Rinaldi MG, et al
. In vitro activities of the new antifungal triazole SCH 56592 against common and emerging yeast pathogens. Antimicrob Agents Chemother 2000; 44:226–229.
137. Pfaller MA, Messer SA, Hollis RJ, Jones RN. In vitro activities of posaconazole (Sch 56592) compared with those of itraconazole and fluconazole against 3685 clinical isolates of Candida
spp. and Cryptococcus neoformans
. Antimicrob Agents Chemother 2001; 45:2862–2864.
138. Pfaller MA, Messer SA, Boyken L, Hollis RJ, Rice C, Tendolkar S, et al
. In vitro activities of voriconazole, posaconazole, and fluconazole against 4169 clinical isolates of Candida
spp. and Cryptococcus neoformans
collected during 2001 and 2002 in the ARTEMIS global antifungal surveillance program. Diagn Microbiol Infect Dis 2004; 48:201–205.
139. Espinel-Ingroff A. In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12 052 fungal isolates: review of the literature. Rev Iberoam Micol 2003; 20:121–136.
140. Perfect JR, Cox GM, Dodge RK, Schell WA, et al
. In vitro and in vivo efficacies of the azole SCH56592 against Cryptococcus neoformans
. Antimicrob Agents Chemother 1996; 40:1910–1913.
141. Pfaller MA, Zhang J, Messer SA, Brandt ME, Hajjeh RA, Jessup CJ, et al
. In vitro activities of voriconazole, fluconazole, and itraconazole against 566 clinical isolates of Cryptococcus neoformans
from the United States and Africa. Antimicrob Agents Chemother 1999; 43:169–171.
142. Klepser ME, Malone D, Lewis RE, Ernst EJ, Pfaller MA. Evaluation of voriconazole pharmacodynamics using time-kill methodology. Antimicrob Agents Chemother 2000; 44:1917–1920.
143. van Duin D, Cleare W, Zaragoza O, Casadevall A, Nosanchuk JD. Effects of voriconazole on Cryptococcus neoformans
. Antimicrob Agents Chemother 2004; 48:2014–2020.
144. Nguyen MH, Yu CY. In vitro comparative efficacy of voriconazole and itraconazole against fluconazole-susceptible and -resistant Cryptococcus neoformans
isolates. Antimicrob Agents Chemother 1998; 42:471–472.
145. Barchiesi F, Spreghini E, Schimizzi AM, Maracci M, Giannini D, Carle F, et al
. Posaconazole and amphotericin B combination therapy
against Cryptococcus neoformans
infection. Antimicrob Agents Chemother 2004; 48:3312–3316.
146. Mavrogiorgos N, Zaragoza O, Casadevall A, Nosanchuk JD. Efficacy of voriconazole in experimental Cryptococcus neoformans
infection. Mycopathologia 2006; 162:111–114.
147. Serena C, Mariné M, Marimon R, Pastor FJ, Guarro J. Efficacy of voriconazole in a murine model of cryptococcal central nervous system infection. J Antimicrob Chemother 2007; 60:162–165.
148. Lutsar I, Roffey S, Troke P. Voriconazole concentrations in the cerebrospinal fluid and brain tissue of guinea pigs and immunocompromised patients. Clin Infect Dis 2003; 37:728–732.
149. Al-Abdely HM, Alkhunaizi AM, Al-Tawfiq JA, Hassounah M, Rinaldi MG, Sutton DA. Successful therapy
of cerebral phaeohyphomycosis due to Ramichloridium mackenziei
with the new triazole posaconazole. Med Mycol 2005; 43:91–95.
150. Pitisuttithum P, Negroni R, Graybill JR, Bustamante B, Pappas P, Chapman S, et al
. Activity of posaconazole in the treatment of central nervous system fungal infections. J Antimicrob Chemother 2005; 56:745–755.
151. Schwartz S, Ruhnke M, Ribaud P, Corey L, Driscoll T, Cornely OA, et al
. Improved outcome in central nervous system aspergillosis, using voriconazole treatment. Blood 2005; 106:2641–2645.
152. Bakleh M, Aksamit AJ, Tleyjeh IM, Marshall WF. Successful treatment of cerebral blastomycosis with voriconazole. Clin Infect Dis 2005; 40:e69–e71.
153. Perfect JR, Durack DT. Comparison of amphotericin B and N
-D-ornithyl amphotericin B methyl ester in experimental cryptococcal meningitis
and Candida albicans
endocarditis with pyelonephritis. Antimicrob Agents Chemother 1985; 28:751–755.
154. Liu H, Davoudi H, Last T. Determination of amphotericin B in cerebrospinal fluid by solid-phase extraction and liquid chromatography. J Pharm Biomed Anal 1995; 13:1395–1400.