Dismukes W E, Cloud G, Gallis H A, Kerkering T M, Medoff G, Craven P C, Kaplowitz L G, Fisher J F, Gregg C R, Bowles C A, Shadomy S, Stamm A M, Diasio R B, Kaufman L, Soong S, Blackwelder W C
N Engl J Med. 1987 Aug 6;317(6):334-41. doi: 10.1056/NEJM198708063170602.
One hundred ninety-four patients with cryptococcal meningitis were enrolled in a multicenter, prospective, randomized clinical trial to compare the efficacy and toxicity of four as compared with six weeks of combination amphotericin B and flucytosine therapy. Among 91 patients who met preestablished criteria for randomization, cure or improvement was noted in 75 percent of those treated for four weeks and in 85 percent of those treated for six weeks. The estimated relapse rate for the four-week regimen was higher--27 as compared with 16 percent--whereas the incidence of toxic effects for the two regimens was similar--44 as compared with 43 percent. Among 23 transplant recipients, 4 of 5 treated for four weeks relapsed, leading to the decision to treat the rest of the group for six weeks. Only 3 of the 18 treated for six weeks relapsed. In a third group of 80 patients, the protocol was not followed during the initial four weeks, and these patients were not randomized. Thirty-eight died or relapsed. Multifactorial analysis of pretreatment factors for all 194 patients identified three significant predictors (P less than 0.05) of a favorable response: headache as a symptom, normal mental status, and a cerebrospinal fluid white-cell count above 20 per cubic millimeter. These and other findings in this study are consistent with the view that the four-week regimen should be reserved for patients who have meningitis without neurologic complications, underlying disease, or immunosuppressive therapy; a pretreatment cerebrospinal fluid white-cell count above 20 per cubic millimeter and a serum cryptococcal antigen titer below 1:32; and at four weeks of therapy, a negative cerebrospinal fluid India ink preparation and serum and cerebrospinal fluid cryptococcal-antigen titers below 1:8. Patients who do not meet these criteria should receive at least six weeks of therapy.
194例隐球菌性脑膜炎患者参与了一项多中心、前瞻性、随机临床试验，以比较两性霉素B与氟胞嘧啶联合治疗四周和六周的疗效及毒性。在91例符合预设随机标准的患者中，接受四周治疗的患者有75%治愈或改善，接受六周治疗的患者有85%治愈或改善。四周治疗方案的估计复发率更高——27%，而六周治疗方案为16%；两种治疗方案的毒性发生率相似——分别为44%和43%。在23例移植受者中，接受四周治疗的5例中有4例复发，因此决定对该组其余患者进行六周治疗。接受六周治疗的18例中只有3例复发。在第三组80例患者中，最初四周未遵循方案，这些患者未被随机分组。38例死亡或复发。对所有194例患者的预处理因素进行多因素分析，确定了三个对良好反应有显著预测作用的因素（P<0.05）：头痛症状、精神状态正常以及脑脊液白细胞计数高于每立方毫米20个。本研究中的这些及其他发现与以下观点一致，即四周治疗方案应仅用于无神经系统并发症、基础疾病或免疫抑制治疗的脑膜炎患者；预处理时脑脊液白细胞计数高于每立方毫米20个且血清隐球菌抗原滴度低于1:32；治疗四周时，脑脊液墨汁负染色及血清和脑脊液隐球菌抗原滴度低于1:8。不符合这些标准的患者应接受至少六周的治疗。
