 |
|
|
|
|
新生隐球菌（隐球菌病）
Updated August, 2008
M. Hong Nguyen, M.D. Associate Professor of Medicine Department of Medicine, Division of Infectious Diseases University of Florida College of Medicine and Chief, Infectious Disease Section VA Medical Center Gainesville, Florida Address: University of Florida College of Medicine Department of Medicine P.O. Box 100277, JHMHC Gainesville, FL 32610 Phone: (352) 379-4027; Fax: (352) 379-4015 E-mail: nguyemt@medicine.ufl.edu
Cornelius J Clancy, M.D. Assistant Professor Department of Medicine, Division of Infectious Diseases Address: University of Florida College of Medicine, Department of Medicine P.O. Box 100277, JHMHC Gainesville, FL 32610 Phone: (352) 379-4027; Fax: (352) 379-4015 E-mail: clancyn@medicine.ufl.edu
Ismail Zafer Ecevit, M.D. Post-doctoral Associate Department of Medicine Address: University of Florida College of Medicine, Department of Molecular Genetics and Microbiology, Box 100266 JHMHC, Gainesville, FL 32610 Phone: (352) 379-4027; Fax: (352) 379-4015
From the Department of Medicine, University of Florida College of Medicine, and the VA Medical Center, Gainesville, Florida.
译者：张雪晗 住院医师 北京协和医院 内科
审阅者：范洪伟 副教授 北京协和医院 感染科
GENERAL DESCRIPTION 概况 Microbiology Guided Medline Search 微生物学 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). 新型隐球菌是一种普遍存在的酵母菌。可造成人类患病的有两型：新生型（血清型A和D）和刚地型（血清型B和C）。这两种型别主要通过不同的地理分布，宿主选择和感染后临床表现来鉴别（表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. 由于在美国出现的隐球菌感染绝大部分为新生型，此篇主要介绍此型隐球菌感染。故除非特别注明，此章中提到到隐球菌均指此型。 Epidemiology Guided Medline Search 流行病学 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. 因艾滋病的廣泛流行，新型隐球菌在医学上的重要性已明顯的加增。目前也是全世界真菌性脑膜炎的主要致病源。在美国，5-10%艾滋病患者最终会患有隐球菌脑膜炎。由于氟康唑的广泛应用和高效抗逆转录病毒治疗（HAART）的出现，过去几年内，在发达国家隐球菌病的发病率显著下降。但是，在发展中国家中，隐球菌脑膜炎仍是艾滋病病人常见的机会感染。 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. T细胞免疫缺陷患者（例如HIV感染或特发性CD4淋巴细胞减少症患者）是隐球菌感染的高危人群。实体器官或骨髓移植患者、长期接受大剂量糖皮质激素治疗患者、淋巴网状内皮系统恶性肿瘤、肉状瘤病、糖尿病和肝硬化患者也易感染隐球菌。在未知或沒有「免疫抑制」的人群中，仍会发生不寻常的隐球菌感染。 Review Article: Singh, N., Perfect, J. Immune Reconstitution Syndrome Associated with Opportunistic Mycoses. The LANCET Infectious Diseases 2007; Vol.7, Issue 6, 395-401. 临床表现 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). 虽然肺是隐球菌进入的门户，但肺隐球菌病不是主要的临床问题。肺隐球菌病的患者，大多是无症状的或有类似一般病毒感染的非特异症状。肺隐球菌病的诊断常常是在行常规检查时胸部影像上看到肺结节和肺门淋巴结肿大而偶然发现的。有呼吸系统症状的患者，胸部影像上表现为肺叶或段的间质浸润，弥漫结节或网格影，肺空洞和胸腔积液（35，91）。由于宿主的免疫状态和/或吸入真菌数量的不同，隐球菌可局限于肺或弥散到任何的器官（包括中枢神经系统（CNS）、皮肤，骨骼、关节、肌肉、乳腺、眼、消化系统、泌尿系统、甲状腺和肾上腺）。 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). 中枢神经系统是最容易受播撒累及的器官。临床主要表现为脑膜炎，然而脑脓肿或隐球菌瘤則是較罕见的。免疫抑制宿主也可表现为真菌血症，可伴有各种皮肤表现。皮肤表现包括斑丘疹、囊泡、丘疹或脐状的丘疹，其表現无法与传染性软疣鉴别（40）。新型隐球菌经常累及泌尿生殖道，特别是前列腺，尽管给予长期抗真菌治疗，隐球菌仍持续存在。前列腺是HIV感染患者停止抗真菌治疗后隐球菌脑膜炎复发的根源（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. 免疫缺陷宿主隐球菌感染后也可以出现蜂窝织炎、局部皮肤溃疡、脓肿、化脓性关节炎和骨髓炎，這特别发生於实体器官移植和接受糖皮质激素治疗的患者。 Laboratory Diagnosis Guided Medline Search 实验室诊断 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. 隐球菌感染的诊断依据包括：1)在感染体液或组织中直接找到病原体；2)在体液中检测到隐球菌多聚糖抗原；3)培养。 Direct Microscopic Examination: India ink examination is a useful and rapid diagnostic test that relies upon direct visualization of the distinctive cryptococcal capsule within body fluids, especially CSF. India ink examination can also be performed on urine, sputum and abscess fluid. The sensitivity of india ink examination of CSF from HIV-infected patients with cryptococcal meningitis is approximately 80% (14,40). The sensitivity is less in patients who are not HIV-infected due to lower fungal burdens. India ink performed on a sediment of a large CSF volume can increase the sensitivity. Leukocytes, fat droplets and tissue cells might lead to false positive results. 直接镜检：墨汁染色是一项有效快捷的诊断方法，其診断依赖于在体液中直接看到隐球菌特异的荚膜，特别是在脑脊液的檢测。墨汁染色同样可用于尿液、痰液和脓液的检测。在HIV感染患者并发隐球菌脑膜炎时，墨汁染色的敏感度大约在80%（14，40）。在非HIV感染的隐球菌脑膜炎患者中，因为其病原体数量相对較少，其墨汁染色的敏感性較低。较多的脑脊液离心后可提高墨汁染色的敏感性。然而脑脊液中的白细胞、脂肪滴和组织细胞可导致假阳性结果。 In tissue, yeasts are easily identified as cells of approximately 5-20 um in size, globose in shape and with narrow budding. These organisms can be identified using non-specific histologic stains (hematoxylin and eosin, Gram stain or Papanicolaou), and specific fungal stains (Gomori methenamine silver and calcouor stains) (14,40). Stains that specifically target the polysaccharide capsule include mucicarmine, periodic acid-Schiff and alcian blue stains. 在组织中隐球菌为球形，有窄的出芽，直径在5-20um，较易辨认。通过非特异组织染色（苏木精和伊红、革兰氏染色或巴氏染色）和特异性真菌染色（六胺银和钙荧光白染色）可以识别隐球菌（14，40）。针对多聚糖荚膜的特异性的染色包括粘卡、PAS、甲苯胺兰染色。 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). 体液中隐球菌多聚糖抗原：检测体液中隐球菌多聚糖荚膜抗原，对于诊断和判断预后和治疗反应有其臨床用處。目前已经有几种商业化的隐球菌抗原乳胶试验和酶联免疫法试验盒（14，40）。这些实验的敏感性（90%）和特异性（大约100%）都很高。血清或体液标本检测隐球菌抗原可快速得到诊断。然而也有报道存在假阳性（由于存在干扰物，脱水剂污染，与毛滴虫抗原交叉反应）和假阴性（由于前带现象，隐球菌抗原含量低）结果（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. 培养：培养阳性是诊断隐球菌病的標準。新型隐球菌可以在大部分用于分离细菌和真菌的培养基上生长。萨布罗右旋糖琼脂是大多数临床微生物实验室应用的标准真菌培养基。尽管大多数菌株在48-72小时内在人工培养基中长出，但有时需延长培养时间（例如，当病人正在接受抗隐球菌治疗）（40）。因而，高度怀疑隐球菌感染时，临床医生需告诉实验室延长培养时间至少三到四周。 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). Niger seed琼脂是新型隐球菌的一种选择性培养基。两种亚型的新型隐球菌都含有苯基氧化酶，其可以氧化种子提取物中的咖啡酸，产生黑色素。在这种培养基上新型隐球菌为棕色菌落。Niger seed培养基（添加抗生素和联苯）用于污染或含菌量高的标本的初级培养，如痰液或尿液。Niger seed培养基筛选出新型隐球菌，因此提高了检测的敏感性（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). 在HIV感染患者出现播散性隐球菌病时，血培养阳性率为35-68%（14，40）。尽管如此，大部分临床微生物实验室血培养采用放射法，例如BACTEC系统，在菌量低时（<1CFU/ml）检测不够敏感。若怀疑存在新型隐球菌血症时，临床医生应通知实验人员，在培养结束后，进行传代培养。此外，当中含菌量低时，裂解离心法可增加其測試的敏感度（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). 两种亚型新型隐球菌的鉴别：刀豆氨酸-氨基乙酸-溴麝香草酚蓝（CGB）可以用来区分两种亚型的新型隐球菌。培养5天，刚地型可将CGB培养基变蓝，但新生型不能。D-脯氨酸培养基也可用于区分两者。只有刚地型可以利用脯氨酸作为唯一氮来源。两种亚型新型隐球菌也可以通过血清型加以区分。根据新型隐球菌荚膜结果的不同，目前已有用于鉴别四种血清亚型的商业试剂盒（14）。
Pathogenesis Guided Medline Search 发病机理 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. 鸟类粪便是最常见的新型隐球菌传染貯源。由于厚厚的多聚糖荚膜可以抵抗干燥环境，在鸟类粪便中的新型隐球菌，数年后仍具有其传染性。有证据表明吸入粪便中的病原体可使人类感染隐球菌。在呼吸道内，新型隐球菌发育为出芽酵母菌，获取水分，形成特有的多聚糖荚膜（12）。早期感染通常没有症状或引起自限的症状。当宿主免疫系统受损或吸入大量真菌时，病原体可以压倒宿主免疫系统，经血液播散到身体任何器官。新型隐球菌是嗜神经组织的，正如上文所述，中枢神经系统是最常累及的器官。 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). 多聚糖荚膜是由葡糖苷酸木甘露聚糖构成，是新型隐球菌毒力的必需成分，也是其最主要的毒性因素（12，14，40）。荚膜可以通过几种途径保证病原体逃脱宿主防御机制：保护病原体不被多形核白细胞、单核细胞和巨噬细胞吞噬；减少向T细胞的抗原呈递；诱导产生调节T细胞，减弱对新型隐球菌的体液和细胞免疫反应（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). 新型隐球菌的另一个毒力因素是产生黑色素。黑色素保护新型隐球菌不被宿主细胞氧化破坏，同时也避免抗体介导的巨噬细胞吞噬作用。黑色素密集地沉积在细胞壁，因而维持了细胞壁的完整性，同时使隐球菌可以抵抗作用于细胞壁的药物，如两性霉素B（12，14，40）。生物化学分析显示，黑色素是由苯酚氧化酶（或虫漆酶）以二羟基苯酚为底物，如二羟苯丙氨酸（DOPA），转化成多巴醌而生成的。由于新型隐球菌不能合成DOPA，它需要从周围环境中摄取底物以合成黑色素。大脑内多巴胺含量高，为合成黑色素提供了充足的底物，此可部分解释为何病原体易侵犯中枢神经系统的原因（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). 新型隐球菌必须在37°C或略高的温度下才能够生长，才能感染人体。病原体在宿主37°C的环境存活，必须具有完整的编码神经钙蛋白A催化亚单位的基因（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). 其它因素，例如α-交配型、甘露醇、过氧化物岐化酶、蛋白酶和磷脂酶的产量，某些蛋白质的肉豆蔻酰化，均增加了新型隐球菌的致病性。目前正在研究辅助酶系统在新型隐球菌感染宿主中的作用（14，37）。 SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo 体内和体外易感性 In Vitro Susceptibility Data 体外易感性数据 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). 三唑类：目前还没有三唑类药物对新型隐球菌的折点值。为了讨论的方便，我们将采用NCCLS的念珠菌属的折点值：敏感（氟康唑 MICs<16ug/ml；伊曲康唑 MICs≤0.125ug/ml），剂量依赖性敏感（氟康唑 MICs 16-32 ug/ml，伊曲康唑MICs 0.25- 0.5 ug/ml和耐药（氟康唑 MICs>32ug/ml；伊曲康唑 MICs>0.5ug/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). 总体来说，新型隐球菌在体外对氟康唑敏感（表2）。一项研究包括1999年以前来自美国和非洲566株新型隐球菌，80%来自美国的分离株和94%来自非洲的分离株对氟康唑敏感（MICs< 16 ug/ml)，剂量依赖性敏感株分别为19%和6%(MICs 16-32 ug/ml)，耐药株分别为0.7%和0% (MICs > 32 ug/ ml)（63）。但是，由于广泛的抗真菌预防治疗，耐药率可能会有升高的傾向。例如，对柬埔寨的隐球菌分离株的分析显示，在2000-2001年3.7%的分离株对氟康唑MICs≥ 32 ug/ml ，而到2001-2002年，增长到20.5%（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. 尽管伊曲康唑和伏立康唑在体外对新型隐球菌分离株敏感，但伊曲康唑和伏立康唑与氟康唑存在交叉耐药性。Nguyen et al等的研究显示，伊曲康唑和伏立康唑对新型隐球菌的MIC值与氟康唑相平行，即当氟康唑MIC值高时，伊曲康唑和伏立康唑的MIC值也相应高（54）。但有一点需要指出，相当一部分氟康唑耐药或S-DD新型隐球菌分离株对伊曲康唑和伏立康唑敏感。例如，一项研究显示对氟康唑S-DD的新型隐球菌分离株中，43%对伊曲康唑敏感(MIC < 0.125 ug/ml)，57% 为S-DD (MIC = 0.125-0.25 ug/ml)。同样，28%的菌株对伏立康唑的MICs为< 0.125 ug/ml，72%的菌株MICs为0.125-0.25 ug/ml（54）。抑制体外对氟康唑不敏感(MIC > 16 ug/ml)的新型隐球菌，通常需要高剂量的伊曲康唑和伏立康唑（伊曲康唑和伏立康唑MICs≥ 0.5 ug/ml)（54，63）。总的说来，要抑制对氟康唑S-DD和耐药的新型隐球菌分离株的生长，伏立康唑的MICs比伊曲康唑要低，提示伏立康唑可能比伊曲康唑杀菌效果更好。 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). 两性霉素B和氟胞嘧啶（5-FC）：在体外对两性霉素B耐药的新型隐球菌分离株很少（66）。在一项732株分离株耐药性的试验中，只有0.3%对两性霉素B的MICs>1 ug/ml。另外，只有2%对氟胞嘧啶的MICs > 16 ug/ml（10）。 Correlation of In Vitro Susceptibility Results and Response to Therapy 体外敏感试验与疗效的关系 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. 念珠菌属的敏感和耐药的折点已经确定，对于新型隐球菌，氟康唑的体外敏感性与治疗反应的关系尚未广泛研究。Nguyen等采用鼠隐球菌脑膜炎模型，证实氟康唑MICs（按照标准NCCLS方法）与体内疗效相关（53）。氟康唑MICs和对药物的反应呈现剂量依赖性关系：MICs为2ug/ml的分离株对氟康唑治疗反应良好，MICs为16ug/ml的分离株反应中等，而MICs为32ug/ml的分离株则无效。这些结果显示，体外敏感试验对于评价氟康唑治疗隐球菌脑膜炎的疗效是可行的。 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. 到目前为止，对于人类隐球菌脑膜炎，有关氟康唑体外敏感性与疗效的关系的资料很少（3，93）。一项研究采用了改良的敏感性测定方法（Yeast Nitrogen Base培养基微量滴定，分光光度测定法为终点），结果显示MICs ≥ 16 ug/mL预示着治疗失败（3）。但是，在其应用到临床前，为了使測試方法标准化，保证其可重复性及结果的准确性，仍有大量工作要做。 ANTIMICROBIAL THERAPY Guided Medline Search Smart search 抗微生物治疗 Currently Available Anticryptococcal Agents (Table 2). 现有的抗隐球菌药物（表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. 氟胞嘧啶：氟胞嘧啶（5-FC）在体外对新生隐球菌有很好的抗菌活性，并且对脑脊液渗透性好。应用此药的最大限制是其毒性和用此药单药治疗时氟胞嘧啶耐药真菌分离株的产生。氟胞嘧啶作为两性霉素B或氟康唑的辅助用药时可以提高抗隐球菌治疗的疗效。 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. 酮康唑：酮康唑体外抗新型隐球菌的活性差异较大，目前只有少数治疗皮肤和肺隐球菌感染的经验（26）。酮康唑只有口服制剂，需要胃的酸性环境方可吸收。由于大部分AIDS患者胃酸缺乏，故在这类患者中的应用有限。此外，酮康唑不能渗透到脑脊液中；若治疗球孢子菌脑膜炎，剂量需≥ 1,200 mg/天，此剂量很难耐受。已有报道，酮康唑单药治疗隐球菌脑膜炎失败（62）。现在已经有了更有效的，耐受性更好的唑类药物，酮康唑不推荐作为新型隐球菌病的首选治疗。 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. 咪康唑：咪康唑体外抗新型隐球菌的活性有差异。仅有数例报道咪康唑治疗严重隐球菌病，有成功的病例和也有失败的病例（83，92）。由于缺少治疗隐球菌病的临床资料，该药半衰期短，溶媒有毒性，目前已有更多更有效的唑类药物，限制了咪康唑在临床的应用。 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. 氟康唑：氟康唑有口服和静脉剂型。氟康唑口服生物利用度高。不同于酮康唑和伊曲康唑，其在胃肠道的吸收不依赖胃的pH。氟康唑在体内广泛分布，包括脑脊液，其在血清和体液中浓度高。氟康唑半衰期长，可以保证每日用药一次。此药已成功用于HIV感染者隐球菌脑膜炎的急性期和维持期治疗。在隐球菌属中已经有氟康唑耐药（3），但远较念珠菌属低。 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. 伊曲康唑：伊曲康唑目前仅有口服剂型，静脉剂型正在評驗中 (靜脈剂型已经獲得美国FDA批準使用)，然而大部分临床观察使用在治疗隐球菌脑膜炎的是伊曲康唑胶囊，其吸收依赖胃液的pH值。像酮康唑一样，此点使伊曲康唑不适于AIDS患者。伊曲康唑口服液比胶囊剂型易于吸收；但仍不明确其是否改善了疗效。伊曲康唑的另一缺点是其脑脊液穿透性不佳。目前已有几个伊曲康唑治疗隐球菌脑膜炎成功的报道（22，23，90）。伊曲康唑有疏水性，同时可在宿主细胞中聚集，使药物可集中到达感染部位（61）。据我们所知，目前还没有隐球菌属体外对伊曲康唑耐药的报道。 Therapy of specific types of cryptococcosis. 特殊类型隐球菌病的治疗。 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). 国际过敏和感染性疾病协会（NIAID）霉菌病研究组已经发布了隐球菌病的治疗指南（74）。本章节的目的是：1）综述主要的支持或否定NIAID推荐意见的重要文章；2）综述NIAID指南形成后的最新的文章，重点介绍脂质体两性霉素B和新出现唑类在治疗上的应用。总的来说，隐球菌病的治疗主要取决于宿主的免疫状态，疾病的严重程度和感染的解剖部位。以下介绍的治疗方法主要依据患者类型和隐球菌感染的部位进行分类（表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) CRYPTOCOCCOSIS IN NON-AIDS PATIENTS 非AIDS患者隐球菌病 Meningeal Infection 脑膜感染 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. 标准治疗：目前非AIDS患者隐球菌脑膜炎标准治疗方案是两性霉素B联合氟胞嘧啶。一项随机研究比较两组隐球菌脑膜炎患者，一组单用两性霉素B 0.4 mg/ kg/ 天，另一组用两性霉素B(0.3 mg/kg/d)联合氟胞嘧啶(150 mg/kg/d)，两性霉素B单药治疗的死亡率显著的較联合治疗高(分别为47% (15/32)和24% (8/34); p<0.05)（5）。此外，治疗10天后，两性霉素B单药治疗(64%, 7/11)组脑脊液的培养阴性率显著低于联合治疗患者(100% , 16/16; p< 0.001)。有一点需要注意，两性霉素B单药治疗组的药物剂量相对较低(0.4 mg/kg/d)；如果增加两性霉素B的剂量(≥ 0.7 mg/kg/d)，单药的疗效是否与两性霉素B联合氟胞嘧啶的疗效相当，仍不明确。 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. 药物的毒性是接受氟胞嘧啶辅助治疗患者遇到的主要问题（5，27）。30-40%患者出现不良反应，18%(6/34)的患者因毒性而停药。氟胞嘧啶最常见的毒性是骨髓抑制造成的贫血和白细胞减少症。56%的毒性反应出现在治疗的前2周，87%出现于治疗的前4周。此项研究中使用的氟胞嘧啶剂量大(150 mg/kg/d)，因此观察到的毒性反应比率高。最新研究结果显示，氟胞嘧啶100 mg/kg/d可以获得一定的血液浓度，同时减少药物毒性（87）。如果氟胞嘧啶使用较长时间(> 2 周)，特别是在肾功能不全患者，需监测药物峰浓度，使其维持在30～80 ug/ml。氟胞嘧啶血浓度持续高于100ug/ml与骨髓毒性相关。 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). 隐球菌脑膜炎的疗程需由宿主的免疫状态、基础疾病和感染的严重程度决定。非免疫抑制和非复杂感染的患者需治疗4周。但是，以下患者至少需治疗6周：1）免疫抑制患者，如淋巴网状系统肿瘤或移植患者，或每日服用糖皮质激素剂量大于20mg强的松；2）有预后不佳因素的患者，如有神经系统异常，神经系统外隐球菌培养阳性，治疗前脑脊液WBC< 20/mm3或隐球菌抗原≥ 1:32，治疗4周后脑脊液墨汁染色阳性，治疗4周后血清或脑脊液隐球菌抗原≥ 1:8（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). 移植患者隐球菌脑膜炎的死亡率接近50%（82，94），大部分发生于抗真菌治疗的前40天。另外，治疗起效需较长的时间。因此在此阶段有指征采用两性霉素B单药或联合氟胞嘧啶治疗（58）。此后序贯为大剂量氟康唑(≥ 400 mg/天)治疗8-10周，或直到获得临床或影像学好转。一篇综述推荐氟康唑剂量高达400mg，一天四次（81）。 Alternative Therapy Guided Medline Search 替代治疗 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). 短疗程两性霉素B单药或联合氟胞嘧啶，氟康唑序贯治疗：由于两性霉素B和氟胞嘧啶显著的副作用，两性霉素B治疗期间需要长时间的血管通路和严密监测实验室检查，因此要考虑替代治疗方法。目前常用的方法是起始阶段用两性霉素B单药或联合氟胞嘧啶（诱导治疗），随后长期氟康唑治疗（巩固和/或抑制治疗）。此方案由AIDS并发隐球菌脑膜炎患者的治疗方案衍生而来（87），其显示出比传统的两性霉素B治疗更好的疗效和较少的副作用。但是，一项随机对照研究（两性霉素B联合氟胞嘧啶治疗2周，序贯氟康唑治疗8周，对照氟康唑联合氟胞嘧啶治疗6周，序贯氟康唑治疗4周）显示，以氟康唑为基础的方案死亡率为80%（4/5），而以两性霉素B为基础的方案死亡率为0%（0/9）。由于研究者不愿意将严重患者分到以氟康唑为基础的治疗组，这项研究被迫提前结束（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. 在一项非艾滋病患者并发隐球菌脑膜炎治疗反应观察中， 两性霉素B单药治疗组治疗成功率为79%，两性霉素B联合氟胞嘧啶治疗组为84%（57）。在接受两性霉素B治疗的患者中，平均治疗总剂量和疗程分别是805mg和27天。在154名患者中有99名后来接受了氟康唑序贯治疗（平均剂量400mg/天，平均疗程70天），有16名患者接受了更长的氟康唑序贯治疗（平均剂量400mg/天，平均疗程681天）。此项观察的一个显著结果是复发率只有4%，明显低于之前报道的研究结果。这可能是长期应用氟康唑巩固治疗的结果。 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. 氟康唑：一项法国的非艾滋病患者隐球菌脑膜炎的研究显示，氟康唑与两性霉素B疗效相当（29）。两性霉素B的总治愈率是74%（26/35），而氟康唑的治愈率是68%（17/25）。但考虑到此项研究的几个重大缺陷，此结果值得商榷。首先，此研究不是随机对照研究，由于患者基础疾病和病情严重程度，选择治疗方案时可能存在偏差。例如，患有淋巴系统疾病、严重感染或出现提示预后不佳的临床体征和症状时，更倾向选择用两性霉素B治疗。其次，两组的病例数少（两性霉素B35名，氟康唑25名），因此，在比较两组差别时，没有统计学意义。第三，也是最重要的一点，每组患者的治疗结果没有按照已知的独立影响因素进行分层，例如播散感染、恶性肿瘤和意识障碍。由于这些原因，这项研究不能确切的说明氟康唑在治疗非艾滋病患者的隐球菌脑膜炎中的角色。 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. 其他抗真菌药物：伊曲康唑和各种脂质体两性霉素B治疗非艾滋病患者隐球菌脑膜炎的经验非常有限，目前没有关于适当的剂量、治疗疗程和疗效的结论。 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). 其它治疗：作为静脉注射两性霉素B的辅助治疗，鞘内注射两性霉素B的疗效尚不明确。成功或失败的案例均有报道。鉴于鞘内注射的并发症和尚缺乏治疗隐球菌脑膜炎有效的确凿证据，此治疗方法不推荐常规应用。一般可用于难治性隐球菌脑膜炎，或由于明显的副作用，难以全身抗真菌治疗的患者（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. 非艾滋病患者并发隐球菌脑膜炎治疗的摘要：总得来说，非艾滋病患者隐球菌脑膜炎的推荐治疗方案是，两性霉素B 0.5-1mg/kg/天，联合氟胞嘧啶100mg/kg/天，疗程至少四周。对于免疫抑制状态或存在预后不佳因素的患者，推荐至少治疗六周。急性期治疗结束后，若患者临床好转和脑脊液培养阴性，可序贯口服氟康唑(≥ 400 mg/天)8-10周。若存在残余感染，特别是当患者仍处于严重免疫抑制状态时，推荐氟康唑巩固治疗（200mg）。 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). 减少或停止免疫抑制药物是抗真菌治疗的重要辅助措施，以提高治疗效果。对于需长期服用糖皮质激素治疗的患者，泼尼松减量至10mg/天，可能会改善其预后（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. 鉴于对非艾滋病患者隐球菌脑膜炎治疗，单用氟康唑或氟康唑联合氟胞嘧啶的效果不佳（28，58），不推荐氟康唑作为首选治疗，实际上氟康唑也不应作为首选治疗。 [Review Article: IDSA Practice Guidelines for the Management of Cryptococcal Disease. Clin Infect Dis 2000;30:710-8.] Pulmonary Cryptococcosis 肺隐球菌病 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. 肺是隐球菌病的第二常见部位。免疫功能正常的宿主无需特殊治疗，免疫抑制的宿主需积极抗真菌治疗。对免疫功能正常的宿主，肺隐球菌感染通常为自限性，不需治疗即可好转（38，39）。但是，由于新型隐球菌有播散和侵犯中枢神经系统的倾向，肺隐球菌病患者均需进行血清和脑脊液隐球菌抗原测定。血清或脑脊液隐球菌抗原阳性提示已经出现肺外播散，这些患者需接受一个疗程的抗真菌治疗。Aberg等对这个常规方案提出质疑。在一项42例肺隐球菌病的回顾分析中，18例免疫功能正常的患者没有发生播散性感染，但是25%（6/24）存在免疫抑制的非艾滋病患者出现播散性感染。鉴于此结果，作者认为并非所有患者均需除外播散性感染，仅限于免疫抑制患者。但需要指出的是，此研究为回顾性队列研究，没有进行系统的检查，确凿地令人信服地排除中枢神经系统或播散性感染（76）。鉴于隐球菌的嗜神经性，而且播散性感染和脑膜感染的死亡率高，当在身体任何部位分离出新型隐球菌时，我们仍强烈建议行腰穿检查。若证实存在中枢神经体统或播散性感染，需按照上述隐球菌脑膜炎治疗方案进行治疗。 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. 孤立的肺隐球菌病的最佳治疗方案仍不明确，有用两性霉素B（联合和不联合氟胞嘧啶）、酮康唑和氟康唑治疗成功的经验（1，26，29，55，77，89，90，95）。所有免疫抑制患者均需治疗。由于两性霉毒B的毒性，而唑类药物的疗效好，因此两性霉素B的应用在减少。在一项109例肺隐球菌病的研究中，使用氟康唑或起始应用两性霉素B，序贯氟康唑治疗，总计有84%的患者获得临床治疗成功（57）。疗程仍不清楚，用唑类抗真菌治疗3月或直到症状消失是合理的。氟康唑或伊曲康唑400mg/天比同剂量的酮康唑疗效好，耐受性佳。 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). 对于非免疫抑制宿主，尽管缺乏强有力的证据，NIAID霉菌病研究组制订的指南推荐，有症状的肺隐球菌病患者需接受抗真菌治疗（74）。一项36例非免疫抑制患者肺隐球菌病（67%有症状）的回顾性分析显示，无论是否接受治疗，患者的预后都好（50）。因此，这些患者可能不需要抗真菌治疗，但此决定需个体化（50）。密切观察和仔细随访非常重要。症状重或症状持续，或胸部影像学上病变范围大的患者可能会从抗真菌治疗中获益（50）。 Non-Pulmonary, Extra-Neural Cryptococcosis 肺外、神经系统外隐球菌病 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. 实际上所有器官均可感染新型隐球菌。肺是神经系统外最易受累的器官，其次是膀胱、前列腺、皮肤、眼睛和肝脏（61）。这些部位隐球菌感染治疗的经验有限，主要基于病例研究（1，57）。总的来说，需根据疾病的严重程度，患者的基础疾病和感染部位确定治疗方案。 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. 此外，最佳治疗方案仍不清楚。若可排除中枢神经系统或播散性隐球菌感染，所有患者需接受氟康唑200-400mg/天，至少3-6月，或伊曲康唑200-400mg/天，至少6-12月（若患者不能耐受氟康唑）。对于严重感染病例，可以起始用两性霉素B 0.4-0.7mg/kg/天，临床症状缓解后换用氟康唑或伊曲康唑长期治疗。 CRYPTOCOCCAL INFECTION IN PATIENTS WITH AIDS 艾滋病患者隐球菌感染 Meningeal Infection 脑膜感染 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. 两性霉素B和氟康唑联合或不联合氟胞嘧啶是目前艾滋病患者隐球菌脑膜炎的治疗方案。与非艾滋病患者相比，艾滋病患者体内隐球菌很难根除。实事上，艾滋病患者隐球菌脑膜炎急性期成功后，复发率至少为50%（9，18）。复发率高，导致死亡率也高，因此艾滋病患者隐球菌脑膜炎需接受长期巩固治疗（见二级预防治疗）（9，18）。因此，艾滋病患者隐球菌脑膜炎时最佳治疗方案包括急性期积极治疗阶段和慢性长期巩固治疗阶段。 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). 急性期标准治疗：目前推荐方案是单用两性霉素B0.7-0.8mg/kg/天，或联合氟胞嘧啶（100mg/kg/天），治疗2周（诱导治疗），随后用氟康唑或伊曲康唑（400mg/天）治疗8周（巩固治疗）（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). 两性霉素B作为诱导治疗非常有效，两周内死亡率为5.5%（87）。在治疗前2周采用氟胞嘧啶联合两性霉素B，可以起到更快杀菌（87）和降低复发率的作用（73）。氟胞嘧啶100mg/kg/天耐受良好。此外，两周治疗不需监测血药浓度。一项随机试验比较艾滋病患者隐球菌脑膜炎接受两性霉素B（0.7mg/kg）单药治疗，两性霉素B联合氟胞嘧啶（100mg/kg/天），两性霉素B联合氟康唑（400mg/天），两性霉素B联合氟康唑和氟胞嘧啶三种药物共四种方案治疗时脑脊液内的杀菌活性（测定新型隐球菌菌落计数的下降速度）。Brower等发现两性霉素B联合氟胞嘧啶的杀菌活性强于两性霉素B联合氟康唑（11）。在隐球菌脑膜炎治疗中，联合治疗的杀菌活性均强于两性霉素B单药治疗。值得注意的是，两性霉素B、氟胞嘧啶和氟康唑三药联合治疗的杀菌活性不如两性霉素B联合氟胞嘧啶（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. 2周诱导治疗后，给予氟康唑或伊曲康唑400mg/天（87）。尽管在治疗10周时，氟康唑治疗组（1%）和伊曲康唑治疗组的死亡率（3%）无显著差别。但氟康唑可能比伊曲康唑略好，因为在治疗10时，氟康唑组脑脊液培养阴性率高（氟康唑组为70%，伊曲康唑组为60%；p<0.05）。伊曲康唑组效果不佳可能与其脑脊液穿透性差和患者胃酸缺乏导致吸收不佳有关。在一项前瞻性研究中，患者随机分为氟康唑组（19名患者）或伊曲康唑组（16名患者，剂量均为600mg/天），在治疗10周时氟康唑组的脑脊液培养阴性率为100%，而伊曲康唑组为94%（47）。因而，氟康唑或伊曲康唑600mg/天的疗效优于氟康唑400mg/天。 Acute Alternative Therapy 急性期次选治疗 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). 氟康唑：目前已进行了两个前瞻性随机试验比较氟康唑与两性霉素B（0.3mg/kg/天）治疗艾滋病患者隐球菌脑膜炎的效果（42，71）。在两个试验中，达到脑脊液培养阴性所需时间，氟康唑长于两性霉素B。在一项试验中，接受氟康唑400mg/天治疗的14名患者的死亡率和失败率（分别为14%和60%）显著高于接受两性霉素B 0.7mg/kg/天联合氟胞嘧啶150mg/kg/天治疗的6例患者（0%）（42）。在一项包括194名患者的大规模随机研究中，两组患者分别接受氟康唑（200mg/天）或两性霉素B（治疗成功者平均剂量为0.4mg/kg，治疗失败者为0.5mg/kg），总的死亡率和治疗失败率在两组间没有显著差别（氟康唑组分别为18%和66%，两性霉素B组分别为14%和60%）。在治疗2周时，氟康唑组较两性霉素B组死亡率有增高的趋势(15% 对8%; p=0.25)，同时氟康唑组脑脊液培养阴性所需时间长(64天对42 天; p=0.25)（71）。该试验的整体疗效较差，可能是与使用较低的药物剂量有关（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. 一些无对照的研究报道中，大剂量氟康唑治疗艾滋病患者隐球菌脑膜炎有效且耐受好。在一篇报告中，对于HIV患者接受抗真菌感染治疗失败者，氟康唑每天800mg作为补救治疗的有效率是62%（5/8）（7）。在另一篇报告中，6例患者接受负荷剂量的氟康唑静脉注射（1600mg），继而口服氟康唑（800mg/天）作为初始治疗。83%（5/6）患者获得临床改善，所有6例患者在治疗82天（中位数：21天）时达到脑脊液培养阴性（36）。这个剂量的氟康唑耐受良好，呕吐2例，轻度肝酶升高5例。 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. 一项前瞻性随机试验增加氟康唑剂量（每天800mg，1200mg，1600mg和2000mg），单独应用或与氟胞嘧啶（150mg/kg/天）（43）联合使用，初步数据显示增加剂量后疗效没有显著差别（800mg对2000mg）。另一方面，氟康唑联合氟胞嘧啶的疗效明显好于单用氟康唑（43）。尽管氟胞嘧啶的毒性反应明显，大多数患者至少可以耐受2周的治疗。这些数据提示，氟康唑联和氟胞嘧啶可以作为艾滋病患者隐球菌脑膜炎时有效的口服替代方案。 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). 伊曲康唑：一项前瞻性对照试验比较伊曲康唑（200mg，每天2次）和两性霉素B（0.3mg/kg/天）联合氟胞嘧啶（150mg/kg/天）的效果，结果显示联合治疗疗效更好。经6周治疗后，两性霉素B联合氟胞嘧啶治疗组脑脊液菌培养阳性率为0%(0/9)，伊曲康唑治疗组50%(6/12)（21）。长期随访同样显示两性霉素B联合氟胞嘧啶优于伊曲康唑。尽管给予伊曲康唑（200mg每天）维持治疗，联合治疗组和伊曲康唑组的复发率分别为22%(2/9)和58%(7/12)。 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. 在一项类似的试验中，观察29例艾滋病并发隐球菌脑膜炎患者，经伊曲康唑（200mg每天2次）治疗的效果（22，23）。64%患者疗效好，22%患者获得部分疗效（症状好转但脑脊液培养持续阳性），14%患者治疗失败。获得脑脊液培养阴性平均所需治疗时间大约为30天。42%的治疗有效的患者复发；复发时测定了血清伊曲康唑浓度。值得注意的是，菌株在体外仍保持对伊曲康唑的敏感性。 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. 脂质体两性霉素B：在一项前瞻性随机对照试验中，比较两性霉素B脂质复合物（ABLC）和两性霉素B治疗艾滋病患者隐球菌感染的治效，ABLC耐受性更好。总体临床和真菌学有效率分别为69%和38%，在两性霉素B组（0.7mg/kg/天）和ABLC组（1.5-5mg/kg）之间没有显著差别（78）。但是，值得注意的是，在治疗4周末，ABLC组脑脊液培养持续阳性率为42%，而两性霉素B组为14%。尽管此结果提示ABLC疗效可能不如两性霉素B，或不能很好通过血脑屏障，但需要指出的是，随机分到ABLC组的患者较两性霉素B组患者重。因此，两组之间无法进行公平的比较。 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). 脂质体两性霉素B治疗19例艾滋病患者隐球菌脑膜炎的结果令人鼓舞（20）。死亡率是16%，临床治疗成功率为63%。真菌学治疗成功率为67%，脑脊液中清除真菌所需的中位治疗时间为11天（范围7-36天）。这些数据可以与两性霉素B联合氟胞嘧啶相媲美（71）。比较脂质体两性霉素B和常规两性霉素B的大规模前瞻性、随机、对照研究正在进行。一项已完成的随机对照试验比较脂质体（4mg/kg/天）和常规两性霉素B（0.7mg/kg/天）治疗3周，随后氟康唑400mg/天治疗7周的效果，脂质体组表现的毒性更小（44）。而且尽管两组的临床疗效相同，脂质体两性霉素B组获得脑脊液培养阴性所需时间（在7-14天）显著短于两性霉素B组（>21天）。 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. 持续的巩固治疗：若不给予维持治疗，超过50%的艾滋病患者，隐球菌脑膜炎急性期治疗好转后，仍有很高的复发风险（9）。复发意味初始治疗未能完全清除隐球菌，而不是新发感染。事实上，初始治疗结束后，有19%的患者持续脑脊液真菌培养阳性，而没有脑膜炎的临床表现（64）。前列腺和中枢神经系统是隐球菌感染持续存在的潜在来源（41）。鉴于复发后病死率高，目前已有几套巩固治疗方案。艾滋病患者急性隐球菌脑膜炎经初始治疗，脑脊液培养阴性后，目前推荐氟康唑200mg/天进行巩固治疗（64）。在一项研究中，接受氟康唑巩固治疗的患者的复发率为2%。 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. 次选的持续巩固治疗：艾滋病患者隐球菌脑膜炎的巩固治疗可选用两性霉素B 1mg/kg/周（64）。但此方法的效果不如氟康唑巩固治疗。在一项随机对照试验中比较每周用两性霉素B和每天用氟康唑两种巩固方法的疗效，两性霉素B组的复发率为18%（14/78），氟康唑组仅为2%（2/111）。此外，两性霉素B组（36%）细菌感染较氟康唑组（17%）多见。两性霉素B组细菌感染率高可能与长期建立血管通路相关。 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. 用伊曲康唑200mg/天巩固治疗，疗效不如氟康唑（73）。在一项研究中，伊曲康唑组的复发率（23%；13/57）高于氟康唑组（4%；2/51）。复发的患者没有死亡。在两组之间总体死亡率无差别，氟康唑组为16%（8/51），伊曲康唑组为10%（6/57）。伊曲康唑疗效差的原因包括血药物浓度持续低于氟康唑，以及脑脊液穿透率低。 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. 总之，由于隐球菌脑膜炎的高复发率，美国公共健康和美国感染疾病协会推荐，艾滋病患者感染新型隐球菌时，应该同其它机会性感染（卡式肺孢子菌、鸟型分支杆菌和巨细胞病毒）一样，需要终生持续巩固治疗。已经证明氟康唑是巩固治疗最好的药物。 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). HAART免疫重建后长期巩固治疗：自从应用HAART以来，所有的机会感染明显下降。临床观察和随机研究均显示，经过有效的抗病毒治疗，免疫功能改善， CD4T细胞计数增加，因此感染明显减少。HAART有可能会使艾滋病患者清除机会性感染。实际上，当CD4T细胞数量增加后，可以停用卡氏肺孢子菌、弓型虫、鸟型分支杆菌和巨细胞病毒的长期巩固治疗。目前已有多个研究报道，隐球菌脑膜炎患者经HAART免疫重建后，可停止长期巩固性抗真菌治疗（2，56，70，48，80）。最大的一宗多中心回顾性研究包括了100例隐球菌脑膜炎患者，当患者CD4细胞数量大于100个/ul时，停止巩固治疗。中位随访26.5月（从12.7-76.8月）（48），隐球菌脑膜炎的复发率为4%，与应用HAART前有显著差别。由于复发率低，因此该研究不能评估预示复发的危险因素。已经证实，停止抗真菌巩固治疗之前的HAART的疗程，CD4T细胞计数和病毒载量，以及隐球菌抗原阳性都对预测复发帮助有限。在四例复发患者中，有三例患者复发时出现新部位的隐球菌感染（分别为肺，脾和淋巴结）。综上，这些实验结果提示经HAART治疗后，当CD4 T细胞 ≥ 100 个/µl时，停止长期巩固治疗可能是安全的。目前在HAART失败时重新开始氟康唑预防治疗的标准还不确定。目前推荐密切监测CD4 T细胞计数，当CD4 T细胞突然下降时需重新开始预防性抗真菌治疗。监测血清隐球菌抗原的作用仍不明确，但有研究建议当抗原阳转时需考虑开始预防性抗真菌治疗（48）。 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. 辅助治疗 颅内高压：至少75%隐球菌脑膜炎患者会出现颅内高压，即颅内压力≥ 200 mmH2O（34）。尽管患者通常会表现神经系统症状，如头痛、视乳头水肿、听力丧失、视野改变和惊厥，但也可能没有症状。另外，大部分患者CT扫描或MRI无脑积水的表现（34）。因而，无症状或头颅扫描正常不能除外存在颅内高压。 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). 颅内高压能引起严重的神经系统后遗症，包括死亡（34）。在一项研究中，93%（13/14）有颅内高压的患者在2周内死亡，其余患者40％在随后的3周内死亡，因此需要积极降低颅内高压（30，34，49）。最近的研究显示，26例隐球菌脑膜炎患者中，仅有50%行开放性颅内压力监测，并且54%（14/26）的患者高颅压没有得到有效控制。总之，50%的患者由于颅内高压没有得到有效治疗而出现新的神经系统并发症（新的神经损害、视力和听力改变）（79）。因而，临床医生必需理解隐球菌脑膜炎患者颅内高压的重要性，作为起始评估的一部分，所有患者需测定颅内压力。如果存在颅内高压必需积极治疗（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. 隐球菌脑膜炎颅内高压有几种治疗方法。其中，最好的方法是脑室机械减压。美国感染病学会指南推荐有颅内高压患者需连续腰椎穿刺，每次腰椎穿刺放出足够的脑脊液，使压力降低到约200mm H2O或起始压力的50%（74）。为维持压力在正常范围内，有时需要每天腰穿放脑脊液。如果连续腰穿还不足以控制升高的压力，放置临时脑室外引流可以快速降低压力（13，34）。一小部分患者可能最终需要永久性分流装置。脑室外引流装置和脑室腹腔引流最重要的并发症是其他病原体的感染，脑室腹腔引流并发症，池包括脑脊液引流过度和装置堵塞，但其发生率很低。 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. 颅内高压也可以用药物治疗。糖皮质激素的降颅压效果被质疑，不常规用于颅高压患者。乙酰唑胺，一种碳酸酐酶抑制剂，能减少脉络膜丛脑脊液的生成。个例报告显示其可以降低颅内压力。但是，一项乙酰唑胺治疗隐球菌脑膜炎患者高颅压的前瞻性研究中，乙酰唑胺有许多并发症（电解质失衡和严重的酸中毒）和死亡（52）。此外，两性霉素B联合乙酰唑胺会加重肾小管并发症。 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. 脑积水：脑积水也是隐球菌脑膜炎的并发症，发生率为9-63%。脑积水会压迫脑血管，导致脑缺血和神经系统状况恶化。只有在意识状态恶化前，早期放置脑室腹腔引流（VPS）才能改善预后（60，84）。当患者出现严重意识障碍48小时以上，即使放置VPS装置也不会改善预后。 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). 免疫调节治疗：尽管HAART和积极抗真菌治疗可以改善艾滋病患者隐球菌脑膜炎的预后，该病的发病率和死亡率仍很高。干扰素α是一种内源性细胞因子，可以提高巨噬细胞、单核细胞、NK细胞和中性粒细胞的功能，在宿主防御病原菌(包括真菌)上起重要的作用（8）。 FDA批准重组干扰素α1b用于治疗慢性肉芽肿性疾病。在体外试验和隐球菌脑膜炎动物模型上，该药联合传统抗真菌治疗取得了令人鼓舞的结果（19）。一项双盲、安慰剂对照的 = 2 \* ROMAN II期临床试验，艾滋病患者隐球菌脑膜炎单独使用两性霉素B或联合氟胞嘧啶时，重组干扰素α1b耐受好，不影响CD4 T细胞计数和HIV病毒载量。在75例患者中，23例接受安慰剂，47例接受每周3次干扰素α 1b。接受干扰素α 1b的患者2周脑脊液培养阴性率明显提高（34%对安慰剂的13%；p=0.06）。此外，治疗2周和10周时，重组干扰素α 1b有改善真菌学疗效和临床疗效的趋势。因此，重组干扰素α 1b辅助治疗急性隐球菌脑膜炎有希望，值得进一步研究（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. 何时开始HAART HARRT通过降低HIV病毒载量和提高CD4 T细胞计数可以显著降低机会感染（OIs）的发生率，减慢AIDS进展和HIV感染患者的总体死亡率。由于这些原因，临床医生常急于为正在治疗机会感染的AIDS患者开始HAART。近年来在这些患者中出现了免疫重建综合症，使大家开始考虑在治疗急性机会性感染时，抗病毒治疗的位置。 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. 免疫重建综合征（IRS），也称免疫重建炎症综合征（IRIS），是针对既往已治疗的感染或亚临床感染的病理性炎症反应。已有报道25-35%HIV感染患者在接受HAART时出现IRS（31，51）。造成预后不良的IRS与分支杆菌、巨细胞病毒和新型隐球菌感染相关。 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). 目前尚未发现新型隐球菌导致IRS的诱发因素。有两种不同的临床综合征。第一种临床综合征表现为，在HAART治疗前几周内发生的急性炎症反应，患者处于亚临床感染或有既往脑膜炎治疗史。通常CD4 T细胞<50，HAART治疗后出现免疫学和病毒学应答，典型表现是脑脊液中大量炎症细胞。脑脊液和/或血中常能分离到隐球菌。第二个综合征是慢性炎症反应，发生在免疫重建的后期。常表现为淋巴结炎，伴有颅高压的无菌性脑膜炎、脊髓及脑内局灶性炎症损害。这些损害在组织病理学上通常表现为肉芽肿性炎症、坏死或化脓；尽管在组织病理标本中可能存在病原体，但是培养无菌生长。目前认为这种炎症是隐球菌抗原刺激T淋巴细胞反应的结果（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. 隐球菌IRS的最佳治疗方法仍不明确。抗炎症治疗有效，继续HAART和抗真菌治疗，IRS可自发缓解。另外，在开始抗隐球菌治疗后，开始HAART的最佳时机仍不清楚。 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. 监控治疗的终点 移植患者的前6周治疗是至关重要的，有时疗效出现的比较晚。这些患者最初4-6周应该采用两性霉素B联合氟胞嘧啶治疗。在一项研究中，81%HIV阴性的中枢神经系统隐球菌病患者，经两性霉素B治疗成功，疗程的中位数为4-6周（57）。此后，患者使用氟康唑（400mg，每天四次）治疗8-10周或直到临床和影像学改善。血清隐球菌抗原（在86-88%移植患者在感染起始时可检测到）转阴，可用来指导巩固治疗的疗程。移植患者一般不需接受终生的维持治疗。 [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. 隐球菌抗原滴度有帮助于预测患者预后。在非艾滋病患者，治疗前血清和脑脊液中抗原滴度高（基础滴度）预示死亡率高，治疗反应欠佳，和易于复发（5，10，27）。在艾滋病患者，一些研究显示基线脑脊液抗原滴度高，预示死亡率高（71，96），但也有研究无此结果（18）。这些研究之间的偏差可能与使用多种不同的抗原试剂盒相关。实际上，使用不同厂家生产的测试盒，检测抗原滴度一致性最多只有60%（85）。因而，需谨慎看待抗原滴度对预后的预测价值。 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). 隐球菌抗原滴度有助于监测急性期治疗反应和预测复发。在非艾滋病患者，脑脊液隐球菌抗原滴度升高预示复发；因而，这些病例需延长治疗时间（25，26）。在艾滋病患者，在急性期治疗期间，脑脊液中隐球菌抗原滴度不变或升高，预示临床或微生物学治疗失败，和巩固治疗期间复发的可能性较大（34，66，68）。移植患者通过治疗，血清隐球菌抗原可以转阴（急性感染患者阳性率为86-88%），也可以用来确定疗程（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. 尽管脑脊液隐球菌抗原滴度对AIDS患者有其预测预后的价值，我们认为不必在急性治疗时常规监测脑脊液隐球菌抗原。首先，由于非常高的复发率，所有AIDS患者都需接受长期巩固治疗。其次，复发可发生在抗原滴度下降时，在一项研究中，29%（4/14）患者复发，尽管其脑脊液隐球菌抗原滴度下降四倍以上（66）。第三，复发患者常有症状（69）。由于这些原因，在AIDS患者隐球菌脑膜炎巩固治疗期间，常规腰穿检查的价值值得怀疑。密切监测其症状和体征可能更加合理（66，69）；当症状和体征提示疾病复发时，需要行腰穿检查。 VACCINES Guided Medline Search 疫苗 There are no vaccines for Cryptococcus. 没有隐球菌的疫苗。
PREVENTION Guided Medline Search Smart search 预防 Fluconazole Prophylaxis 氟康唑预防 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). 是否需要进行一级预防机会性感染由几个因素决定：1）疾病的流行情况，2）发病率和死亡率，3）预防治疗的效果和对预后的影响，4）预防治疗的代价（费用、副作用和出现耐药菌）。 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. 根据这些标准，用甲氧苄啶-磺胺甲噁唑有效预防卡氏肺孢子菌肺炎（PCP）是预防治疗的成功例子。PCP在CD4 < 200/ mm3人群中发生率至少为30%，有很高的死亡率。此外，甲氧苄啶-磺胺甲噁唑非常有效地减少了PCP的发病率（发病率<6%），改善患者预后，费用低，到目前没有出现耐药现象。此药还可以预防弓形虫病，也是导致AIDS患者死亡的常见疾病。 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). 隐球菌预防治疗的效果不如肺孢子菌预防治疗显著。在美国和欧洲，AIDS患者隐球菌感染的发病率在5-10%，较卡式肺孢子菌、MAI和巨细胞病毒感染低。在一项关于CD4 <200/mm3人群预防真菌感染的随机研究中，与安慰剂（发病率7%，15/211）相比，氟康唑200mg/天明显减少隐球菌感染（发病率为0.9%，2/217）（67）。由于大部分感染经治疗可以控制，故预防治疗对生存率没有影响。CD4 ≤ 100/mm3患者采用小剂量氟康唑（200mg每周三次）作为一级预防有效且费用低（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). 目前顾虑长期使用氟康唑会出现耐药（4）。尽管在Singh等的研究中没有发现氟康唑耐药株，但其12.1月的随访时间短（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). 事实上，已经有报道当隐球菌菌株对氟康唑的MICs高时，氟康唑预防治疗失败；这些报道中的患者CD4 T细胞数量很低(< 25/mm3)，接受氟康唑预防治疗时间长（> 12月）（6）。尽管在接受氟康唑一级预防的患者中，耐氟康唑隐球菌的流行率很低，将来可能会出现氟康唑耐药株。此外，氟康唑预防治疗的费用高，为预防一例侵袭性真菌感染，估计需要用7800剂量的氟康唑（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. 在美国及其他发达国家，由于费用高，有耐药的风险，和对生存率没有影响，限制了氟康唑一级预防的应用。这使得美国公共卫生服务/感染疾病协会决定不推荐HIV感染者常规行抗真菌预防治疗。值得注意的是在1992-1994年期间，即蛋白酶抑制剂应用以前，HIV感染者隐球菌脑膜炎发生率下降；最可能的原因是使用氟康唑治疗鹅口疮和念珠菌食管炎。 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). 在资源缺乏的国家，隐球菌感染很常见，由于缺乏理想的治疗，死亡率很高（32）。例如，在泰国的HIV住院患者中，隐球菌脑膜炎占AIDS相关疾病中的38%（86）。同安慰剂比较，每周400mg氟康唑预防治疗可将死亡率由11.7/10000人日减少到2.7/10000人日（rate difference=9; 95% CI: 0.4 17.5; P=0.046)。氟康唑预防组隐球菌脑膜炎的发病率明显低于安慰剂组（危险比率=2.23；95%可信区间（CI）：0.58 8.63；P=0.245）。在这些国家中，还需要进一步评估预防治疗的费用和收益（17）。 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. 伊曲康唑预防治疗：在一项前瞻性双盲试验中，63名CD4 <200/mm3的HIV患者随机分配到伊曲康唑200mg/天治疗组，而66名患者在安慰剂组（15）。伊曲康唑组中一例患者（1.6%）发生系统性真菌感染(P. marneffei)，在安慰剂组为17%（新型隐球菌7例,P. marneffei4例, p= 0.003)（14）。伊曲康唑耐受好性、安全、有效。但是死亡率在两组之间无显著差别。
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]
REFERENCES 1. Aberg JA, Mundy LM, Powderly WG. Pulmonary cryptococcosis in patients without HIV infection. Chest. 1999;115:734-40. [PubMed] 2. 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 [PubMed] 3. Aller AI, Martin-Mazuelos E, Lozano F, Gomez-Mateos J, Steele-Moore L, Holloway WJ, Gutierrez MJ, Recio FJ, Espinel-Ingroff A. Correlation of fluconazole MICs with clinical outcome in cryptococcal infection. Antimicrob Agents Chemother. 2000;44:1544-8. [PubMed] 4. Amengou A, Porcar C, Mascaro J, Garcia-Bragado F. Possible development of resistance of fluconazole during suppressive therapy for AIDS-associated cryptococcal meningitis. Clin Infect Dis. 1996;23:1337-1338. [PubMed] 5. Bennett JE, Dismukes WE, Duma RJ, Medoff G, Sande MA, Gallis H, Leonard J, Fields BT, Bradshaw M, Haywood H, McGee ZA, Cate TR, Cobbs CG, Warner JF, Alling DW. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med. 1979;301:126-131. [PubMed] 6. Berg J, Clancy CJ, Nguyen MH. The hidden danger of primary fluconazole prophylaxis in patients with Acquired Immunodeficiency Syndrome. Clin Inf Dis 1997; Clin Infect Dis. 1998;26:186-7. [PubMed] 7. Berry AJ, Rinaldi MG, Graybill JR. Use of high-dose fluconazole as salvage therapy for cryptococcal meningitis in patients with AIDS. Antimicrob Agents Chemother. 1992;36: 690-692. [PubMed] 8. Bogdan C, Mattner J, Schleicher U. The role of type I interferons in non-viral infections. Immunol Rev. 2004;202:33-48. [PubMed] 9. Bozzette SA, Larsen RA, Chiu J, Leal MA, Jacobsen J, Rothman P, Robinson P, Gilbert G, McCutchan JA, Tilles J, Leedom JM, Richman DD, and the California Collaborative Treatment Group. A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the Acquired Immunodeficiency Syndrome. N Engl J Med. 1991; 324: 580-584. [PubMed] 10. Brandt ME, Pfaller MA, Hajjeh RA, Hamill RJ, Pappas PG, Reingold AL, Rimland D, Warnock DW. Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998. Antimicrob Agents Chemother. 2001;45:3065-9. [PubMed] 11. Brouwer AE, Rajanuwong A, Chierakul W, Griffin GE, Larsen RA, White NJ, Harrison TS. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet. 2004;363:1764-7. [PubMed] 12. Buchanan KL, Murphy JW. What makes Cryptococcus neoformans a pathogen? Emerg Infect Dis. 1998;4:71-83. [PubMed] 13.Calvo A, Hernandez P, Spagnuolo E, Johnston E. Surgical treatment of intracranial hypertension in encephalic cryptococcosis. Br J Neurosurg. 2003;17:450-5. [PubMed] 14. Casadevall A, Perfect JR. 1998. Cryptococcus neoformans. In Casadevall A, Perfect JR (ed) Cryptococcus neoformans. ASM Press, Washington, DC. [PubMed] 15. Chariyalertsak S, Supparatpinyo K, Sirisanthana T, Nelson KE. A controlled trial of itraconazole as primary prophylaxis for systemic fungal infections in patients with advanced human immunodeficiency virus infection in Thailand. Clin Infect Dis. 2002;34:277-84. [PubMed] 16. Chen S, Sorrell T, Nimmo G, Speed B, Currie B, Ellis D, Marriott D, Pfeiffer T, Parr D, Byth K. Epidemiology 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. [PubMed] 17. 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;5:140-3. [PubMed] 18. Chuck SL, Sande MA. Infections with Cryptococcus neoformans in the Acquired Immunodeficiency Syndrome. N. Engl J Med. 1989;321:794-799. [PubMed] 19. Clemons KV, Lutz JE, Stevens DA. Efficacy of recombinant gamma interferon for treatment of systemic cryptococcosis in SCID mice. Antimicrob Agents Chemother. 2001;45:686-9. [PubMed] 20. Coker RJ, Viviani M, Gazzard BG, DuPont B, Pohle HD, Murphy SM, Atouguia J, Champalimaud JL, Harris JR. Treatment of cryptococcosis with liposomal amphotericin B (AmBisome) in 23 patients with AIDS. AIDS. 1993;7:829-835. [PubMed] 21. De Gans J, Portegies P, Tiessens G, Eeftinck Schattenkerk JK, van Boxtel CJ, van Ketel RJ, Stam J. Itraconazole compared with amphotericin B plus flucytosine in AIDS patients with cryptococcal meningitis. AIDS. 1992;6:185-190.[PubMed] 22. Denning DW, Tucker RM, Hanson LH, Hamilton JR, Stevens DA. Itraconazole therapy for cryptococcal meningitis and cryptococcosis. Arch Intern Med. 1989;149:2301-2308. [PubMed] 23. Denning DW, Tucker RM, Hostetler JS, Gill S, Stevens DA. Oral itraconazole therapy of cryptococcal meningitis and cryptococcosis in patients with AIDS. Mycoses in AIDS Patients. H. Vanden Bossche, Editor. Plemem Press, New York, 1990:305-324. [PubMed] 24. Denning DW, Armstrong RW, Lewis BH, Stevens DA. Elevated cerebrospinal fluid pressures in patients with cryptococcal meningitis and Acquired Immunodeficiency Syndrome. Am J Med. 1991;91:267-272. [PubMed] 25. Diamond RD, Bennett JE. Prognostic factors in cryptococcal meningitis. Ann Int Med. 1974;80:176-181. [PubMed] 26. Dismukes WE, Stamm AM, Graybill JR, Craven PC, Stevens DA, Stiller RL, Sarosi GA, Medoff G, Gregg CR, Gallis HA, Fields BT, Marier RL, Kerkering TA, Kaplowitz LG, Cloud G, Bowles C, Shadomy S. Treatment of systemic mycoses with ketoconazole: Emphasis on toxicity and clinical response in 52 Patients. Ann Int Med. 1983;98:13-20. [PubMed] 27. Dismukes WE, Cloud G, Gallis HA, Kerkering TM, Medoff G, Craven PC, Kaplowitz LG, Fisher JF, Gregg CR, bowles CA, Shadomy S, Stamm AM, Diasio RB, Kaufman L, Soong SJ, Blackwelder WC, and the National Institute of Allergy and Infectious Diseases Mycoses Study Group. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. N Engl J Med. 1987;317:334-341. [PubMed] 28. Dismukes WE. Current recommendations for the treatment of cryptococcosis in non-AIDS patients. 3rd International Conference on Cryptococcus and Cryptococcosis, 1996. Paris, France. [PubMed] 29. Dromer F, Mathoulin S, Dupont B, Brugiere O, Letenneur L. Comparison of the efficacy of amphotericin B and fluconazole in the treatment of cryptococcosis in Human Immunodeficiency Virus-negative patients: Retrospective analysis of 83 cases. Clin Inf Dis. 1996;22:S154-160. [PubMed] 30. Fessler RD, Sobel J, Guyot L, Crane L, Vazquez J, Szuba MJ, Diaz FG. Management of elevated intracranial pressure in patients with cryptococcal meningitis. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17:137 42. [PubMed] 31. French MA, Lenzo N, John M, Mallal SA, McKinnon EJ, James IR, Price P, Flexman JP, Yay-Kearney M-L. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Med 2000; 1:107-115. [PubMed] 32. French N, Gray K, Watera C, Nakiyingi J, Lugada E, Moore M, Lalloo D, Whitworth JA, Gilks CF. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS. 2002;16:1031-8. [PubMed] 33. French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS. 2004;18:1615-27. [PubMed] 34. Graybill JR, Sobel J, Saag M, van Der Horst C, Powderly W, Cloud G, Riser L, Hamill R, Dismukes W. 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. [PubMed] 35. Hammerman KJ, Powell KE, Christianson CS, Huggin PM, Larsh HW, Vivas JR, Tosh FE. Pulmonary cryptococcosis: clinical forms and treatment. Am. Resp. Dis. 1973;108:1116-1123. [PubMed] 36. 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. J Inf Dis. 1994;170:238-242. [PubMed] 37. Hogan LH, Klein BS, Levitz SM. Virulence factors of medically important fungi. Clin Microbiol Rev. 1996;9(4):469-88. [PubMed] 38. Houk VN, Moser KM. Pulmonary cryptococcosis. Must all receive amphotericin B? Ann Int Med. 1965;63:583-596. [PubMed] 39. Kerkering TM, Duma RJ, Shadomy S. The evolution of pulmonary cryptococcosis. Ann Int Med. 1981;94:611-616. [PubMed] 40. Kwon-Chung K.J and Bennett JE. 1992. Cryptococcosis, p. In K.J. Kwon-Chung and J.E. Bennett. (ed.), medical Mycology. Lea & Febiger, Philadelphia. [PubMed] 41. Larsen RA, Bozzette S, McCutchan JA, Chiu J, Leal, MA, Richman DD, and California Collaborative Treatment Group. Persistent Cryptococcus neoformans infection of the prostate after successful treatment of meningitis. Ann Int Med. 1989;111:125-128. [PubMed] 42. Larsen RA, Leal MA, Chan LS. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. Ann Int Med. 1990;113: 183-187. [PubMed] 43. Larsen RA. Combination therapy for cryptococcosis and speculations for future. 3rd International Conference on Cryptococcus and Cryptococcosis, 1996. Paris, France. [PubMed] 44. Leenders AC, Reiss P, Portegies P, Clezy K, Hop WC, Hoy J, Borleffs JC, Allworth T, Kauffmann RH, Jones P, Kroon FP, Verbrugh HA, de Marie S. Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS. 1997;11(12):1463-71. [PubMed] 45. Mitchell DH, Sorrell TC, Allworth AM, Heath CH, McGregor AR, Papanaoum K, Richards MJ, Gottlieb T. Cryptococcal disease of the CNS in immunocompetent hosts: influence of cryptococcal variety on clinical manifestations and outcome. Clin Infect Dis. 1995;20:611-6. [PubMed] 7756484 46. Mitchell TG, Perfect JR. Cryptococcosis in the era of AIDS--100 years after the discovery of Cryptococcus neoformans. Clin Microbiol Rev. 1995;8:515-48. [PubMed] 47. Mootsikapun P, Chetchotisakd P, Anunnatsiri S, Choksawadphinyo K. The efficacy of fluconazole 600 mg/day versus itraconazole 600 mg/day as consolidation therapy of cryptococcal meningitis in AIDS patients. J Med Assoc Thai. 2003 Apr;86:293-8. [PubMed] 48. Mussini C, Pezzotti P, Miro JM, Martinez E, de Quiros JC, Cinque P, Borghi V, Bedini A, Domingo P, Cahn P, Bossi P, de Luca A, d'Arminio Monforte A, Nelson M, Nwokolo N, Helou S, Negroni R, Jacchetti G, Antinori S, Lazzarin A, Cossarizza A, Esposito R, Antinori A, Aberg JA; International Working Group on Cryptococcosis. 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;38:565-71.[PubMed] 49. Mylonakis E, Merriman NA, Rich JD, Flanigan TP, Walters BC, Tashima KT, Mileno MD, van der Horst CM. Use of cerebrospinal fluid shunt for the management of elevated intracranial pressure in a patient with active AIDS-related cryptococcal meningitis. Diagn Microbiol Infect Dis 1999; 34:111 4. [PubMed] 50. Nadrous HF, Antonios VS, Terrell CL, Ryu JH. Pulmonary cryptococcosis in nonimmunocompromised patients. Chest. 2003;124:2143-7. [PubMed] 51. Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998; 158:157-161. [PubMed] 52. Newton PN, Thai le H, Tip NQ, Short JM, Chierakul W, Rajanuwong A, Pitisuttithum P, Chasombat S, Phonrat B, Maek-A-Nantawat W, Teaunadi R, Lalloo DG, White NJ. A randomized, double-blind, placebo-controlled trial of acetazolamide for the treatment of elevated intracranial pressure in cryptococcal meningitis. Clin Infect Dis. 2002;35:769-72. [PubMed] 53. Nguyen MH, Najvar LK, Yu CY, Graybill JR. Combination therapy with fluconazole and flucytosine in the murine model of cryptococcal meningitis. Antimicrob Agents and Chemo. 1997;41:1120-1123. [PubMed] 54. Nguyen MH, Yu CY. In vitro comparative efficacy of voriconazole and itraconazole against fluconazole-susceptible and -resistant Cryptococcus neoformans isolates. Antimicrob Agents Chemother. 1998;42:471-2. [PubMed] 55. Nunez M, Peacock JE Jr, Chin R Jr. Pulmonary cryptococcosis in the immunocompetent host. Therapy with oral fluconazole: a report of four cases and a review of the literature. Chest. 2000 Aug;118:527-34. [PubMed] 56. Nwokolo NC, Fisher M, Gazzard BG, Nelson MR. Cessation of secondary prophylaxis in patients with cryptococcosis. AIDS. 2001;15:1438-9. [PubMed] 57. Pappas PG, Perfect JR, Cloud GA, Larsen RA, Pankey GA, Lancaster DJ, Henderson H, Kauffman CA, Haas DW, Saccente M, Hamill RJ, Holloway MS, Warren RM, Dismukes WE. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis. 2001;33:690-9. [PubMed] 58. Pappas PG. Therapy of cryptococcal meningitis in non-HIV-infected patients. Curr Infect Dis Rep. 2001 Aug;3:365-370.[PubMed] 59. Pappas PG, Bustamante B, Ticona E, Hamill RJ, Johnson PC, Reboli A, Aberg J, Hasbun R, Hsu HH. Recombinant interferon-gamma 1b as adjunctive therapy for AIDS-related acute cryptococcal meningitis. J Infect Dis. 2004;189:2185-91. [PubMed] 60. Park MK, Hospental DR, Bennett JE. Treatment of hydrocephalus secondary to cryptococcal meningitis by use of shunting. Clin Infect Dis 1999:28:629-33.[PubMed] 61. Perfect JR, Durack DT, Gallis HA. Cryptococcemia. Medicine. 1983;62:98-109. [PubMed] 62. Perfect JR, Durack DT, Hamilton JD, Gallis HA. Failure of ketoconazole in cryptococcal meningitis. JAMA 1982;247.3349. [PubMed] 63. Pfaller MA, Zhang J, Messer SA, Brandt ME, Hajjeh RA, Jessup CJ, Tumberland M, Mbidde EK, Ghannoum MA. 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;43:169-71. [PubMed] 64. Powderly WG, Saag MS, Cloud GA, Robinson P, Meyer RD, Jackbson JM, Graybill JR, Sugar AM, McAuliffe VJ, Follansbee SE, Tuazon CU, Stern JJ, Feinberg J, Hafner R, Dismukes WE, NIAID AIDS Clinical Trials Group, and the NIAID Mycoses Study Group. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the Acquired Immunodeficiency Syndrome. N Engl J Med. 1992;326:793-798. [PubMed] 65. Powderly WG, Keath EJ, Sokol-Anderson M, Robinson K, Kitz D, Little JR, Kobayashi G. Amphotericin B-resistant Cryptococcus neoformans in a patient with AIDS. Infect Dis Clin Pract 1994;1:314-316. [PubMed] 66. Powderly WG, Cloud GA, Dismukes WE, Saag MS. Measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of AIDS-associated cryptococcal meningitis. Clin Infect Dis 1994;18:789-792. [PubMed] 67. Powderly WG, Finkelstein D, Feinberg J, Frame P, He W, vanderHorst C, Koletar SL, Eyster ME, Carey J, Waskin H. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced Human Immunodeficiency Virus infection. N Engl J Med. 1995;332:700-705. [PubMed] 68. Powderly WG. Use of cryptococcal antigen testing in management of cryptococcosis. 3rd International Conference on Cryptococcus and Cryptococcosis, 1996. Paris, France. [PubMed] 69. Powderly WG. Cryptococcosis: Current status of diagnosis and treatment. Clinic guide to Fungal Infections. 1997;8:1-15. [PubMed] 70. Rollot F, Bossi P, Tubiana R, Caumes E, Zeller V, Katlama C, Bricaire F. Discontinuation of secondary prophylaxis against cryptococcosis in patients with AIDS receiving highly active antiretroviral therapy. AIDS. 2001;15(11):1448-9. [PubMed] 71. Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK, Thompson SE, Sugar AM, Tuazon CU, Fisher JF, Hyslop N, Jacobson JM, Hafner R, Dismukes, WE, and the NIAID Mycoses Study Group and the AIDS Clinical Trials Group. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. N Engl J Med. 1992; 326: 83-89. [PubMed] 72. Saag MS. The treatment of cryptococcal disease in AIDS patients. 3rd International Conference on Cryptococcus and Cryptococcosis, 1996. Paris, France. [PubMed] 73. Saag MS, Cloud GA, Graybill JR, Sobel JD, Tuazon CU, Johnson PC, Fessel WJ, Moskovitz BL, Wiesinger B, Cosmatos D, Riser L, Thomas C, Hafner R, Dismukes WE. 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(2):291-6. [PubMed] 74. Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, Sobel JD, Dismukes WE. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis. 2000;30(4):710-8. [PubMed] 75. Sar B, Monchy D, Vann M, Keo C, Sarthou JL, Buisson Y. Increasing in vitro resistance to fluconazole in Cryptococcus neoformans Cambodian isolates: April 2000 to March 2002. J Antimicrob Chemother. 2004; 54(2): 563-5. [PubMed] 76. Sarosi GA. Cryptococcal lung disease in patients without HIV infection. Chest. 1999;115:610-611. [PubMed] 77. Sarosi GA. Cryptococcal pneumonia. Semin Respir Infect. 1997;12:50-53. [PubMed] 78. Sharkey PK, Graybill JR, Johnson ES, Hausrath SG, Pollard RB, Kolokathis A, Mildvan D, Fan-Havard P, Eng RHK, Patterson TF, Pottage JC, Simberkoff MS, Wolf J, Meyer RD, Gupta R, Lee LW, Gordon DS. Amphotericin B lipid complex compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis. 1996;22:315-321. [PubMed] 79. Shoham S, Cover C, Donegan N, Fulnecky E, Kumar P. Cryptococcus neoformans meningitis at 2 hospitals in Washington, D.C.: adherence of health care providers to published practice guidelines for the management of cryptococcal disease. Clin Infect Dis. 2005;40(3):477-9.[PubMed] 80. Singh N, Barnish MJ, Berman S, Bender B, Wagener MM, Rinaldi GM, Yu VL. Low-dose fluconazole as primary prophylaxis for cryptococcal infection in AIDS-patients with CD4 cell counts of < 100/mm3. Clin Inf Dis 1996;23:1282-1286. [PubMed] 81. Singh N. Treatment of opportunistic mycoses: how long is long enough? Lancet Infect Dis 2003:703-708. 82. Singh N, Alexander B, Gupta KL. And the Cryptococcus Collaborative Transplant Group. Characteristics and outcome of Cryptococcus neoformans infection of the central nervous system in organ transplant recipients: a prospective, multicenter study. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego, CA; Septembe, 2002. Abstract M-885.[PubMed] 83. Sung JP, Campbell GD, Grendahl JG. Miconazole therapy for fungal meningitis. Arch Neurol. 1978;35:443-447. [PubMed] 84. Tang LM. Ventriculoperitoneal shunt in cryptococcal meningitis with hydrocephalus. Surg Neurol 1990:33(5):314-9. [PubMed] 85. Tanner DC, Weinstein MP, Fedorciw B, Joho KL,Thorpe JJ, Reller LB. Comparison of commercial kits for detectionof cryptococcal antigen. J Cllin Microbiol. 1994;32:1680-1684. [PubMed] 86. Tansuphasawadikul S, Amornkul PN, Tanchanpong C, Limpakarnjanarat K, Kaewkungwal J, Likanonsakul S, Eampokalap B, Naiwatanakul T, Kitayaporn D, Young NL, Hu DJ, Mastro TD. Clinical presentation of hospitalized adult patients with HIV infection and AIDS in Bangkok, Thailand. J Acquir Immune Defic Syndr. 1999 Aug 1;21(4):326-32. [PubMed] 87. Van der Horst CM, Saag MS, Cloud GA, Hamill RJ, Graybill JR, Sobel JD, Hohnson PC, Tuazon CU, Kerkering T, Moskovitz BL, Powderly WG, Dismukes WE. Treatment of cryptococcal meningitis associated with the Acquired Immunodeficiency Syndrome. N Engl J Med. 1997;337:15-21. [PubMed] 88. Vibhagool A, Sungkanuparph S, Mootsikapun P, Chetchotisakd P, Tansuphaswaswadikul S, Bowonwatanuwong C, Ingsathit A. 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 (10):1329-31. [PubMed] 89. Vilchez RA, Irish W, Lacomis J, Costello P, Fung J, Kusne S. The clinical epidemiology of pulmonary cryptococcosis in non-AIDS patients at a tertiary care medical center. Medicine (Baltimore). 2001;80(5):308-12. [PubMed] 90. Viviani MA, Tortorano AM, Giani PC, Arici C, Goglio A, Crocchiolo P, Almaviva M. Itraconazole for cryptococcal infection in the Acquired Immunodeficiency Syndrome. Ann Int Med. 1987;106:166. [PubMed] 91. Warr W, Bates JH, Stone A. The spectrum of pulmonary cryptococcosis. Ann Int Med. 1968;69:1109-1116. [PubMed] 92. Weinstein L, Jacoby I. Successful treatment of cerebral cryptococcoma and meningitis with miconazole. Ann Int Med. 1980;93:569-571. [PubMed] 93. Witt MD, Lewis RJ, Larsen RA, Milefchik EN, Leal ME, Haubrich RH, Richie JA, Edwards Jr JE, Ghannoum MA. Identification of patients with acute AIDS-associated cryptococcal meningitis who can be effectively treated with fluconazole: The role of antifungal susceptibility testing. Clin Inf Dis. 1996;22:322-328. [PubMed] 94. Wu G, Vilchez RA, Eidelman B, Fung J, Kormos R, Kusne S. Cryptococcal meningitis: an analysis among 5,521 consecutive organ transplant recipients. Transpl Infect Dis. 2002;4(4):183-8. [PubMed] 95. Yamaguchi H, Ikemoto H, Watanabe K, Ito A, Hara K, Kohno S. Fluconazole monotherapy for cryptococcosis in non-AIDS patients. Eur J Clin Microbiol Infect Dis. 1996;15:787-792. [PubMed] 96. Zuger A, Louie E, Holzman RS, Simberkoff MS, Rahal JJ. Cryptococcal disease in patients with the Acquired Immunodeficiency Syndrome. Ann Int Med. 1986;104:234-240. [PubMed] |
|