Maschmeyer Georg, Haas Antje
Department of Hematology and Oncology, Klinikum Ernst von Bergmann, Charlottenstrasse 72, D-14467, Potsdam, Germany.
Med Mycol. 2006 Sep 1;44(Supplement_1):S315-S318. doi: 10.1080/13693780600835690.
In patients with invasive aspergillosis (IA), there are numerous clinical settings where stable disease or progression of findings or deterioration of the patient's condition does not indicate failure, and subsequent response to a 'salvage' antifungal is not necessarily attributable to this drug. Many patients, in whom pulmonary aspergillosis emerges during profound neutropenia, show enlargement of their lesions on computer tomography (CT) scans, eventually accompanied by clinical deterioration, during hematopoietic recovery. This may in fact represent the recruitment of neutrophils and monocytes to the pulmonary 'battlefield', resulting in a favorable clinical outcome also without changing antifungal treatment. Infarcted tissue may contain vital filamentous fungi, because it is poorly penetrated by the antifungal, not indicating a lack of efficacy of this drug against the respective fungal pathogen. In patients treated with an echinocandin, serum galactomannan levels may increase despite successful treatment. Piperacillin-tazobactam or other semi-synthetic beta-lactam antibiotics may cause false positive serum Aspergillus galactomannan levels. Patients primarily treated with a lipid formulation of AmB (LF-AmB), who are switched to a 'salvage' antifungal, will unequivocally receive a combination therapy due to the persistence of high LF-AmB concentrations in tissue. Criteria to define 'clinical refractoriness', 'resistance', 'non-response' or 'failure' respectively should be re-defined. One option to establish a more valid definition would be to use a composite score including clinical as well as radiological and microbiological or mycological criteria. The latter may include non-culture based methods such as serum galactomannan. Assessment should not be made earlier than after seven days of full-dose systemic antifungal treatment. However, in individual cases, e.g. a patient with hematopoietic recovery, who shows an increasing volume of pulmonary aspergillosis and clinical deterioration, it may be recommended to refrain from switching the patient to another regimen and continue the current antifungal treatment for another seven days before failure is stated. Clinical studies on second-line antifungal treatment for IA should be randomized and blinded, patients should be evaluated separately with respect to their reason for 'failure' of primary antifungal treatment, and stratified according to their previous antifungal treatment. Ideally, the first-line regimen would be standardized. Host criteria such as neutropenia or graft-versus-host disease (GVHD) should be clearly defined and documented with respect to their course over time, and patients should be stratified according to these criteria. A three-arm study (continuation of primary antifungal vs. combination of primary antifungal with a 'salvage' drug vs. the 'salvage' drug alone) would be ideal.
在侵袭性曲霉病（IA）患者中，存在许多临床情况，即病情稳定、检查结果进展或患者病情恶化并不意味着治疗失败，随后对“挽救性”抗真菌药物的反应也不一定归因于该药物。许多在严重中性粒细胞减少期间出现肺部曲霉病的患者，在造血恢复过程中，其计算机断层扫描（CT）显示病灶增大，最终伴有临床恶化。这实际上可能代表中性粒细胞和单核细胞被募集到肺部“战场”，即使不改变抗真菌治疗也会带来良好的临床结果。梗死组织可能含有存活的丝状真菌，因为抗真菌药物难以渗透进去，这并不表明该药物对相应真菌病原体缺乏疗效。在接受棘白菌素治疗的患者中，尽管治疗成功，血清半乳甘露聚糖水平仍可能升高。哌拉西林 - 他唑巴坦或其他半合成β - 内酰胺类抗生素可能导致血清曲霉半乳甘露聚糖水平出现假阳性。主要接受两性霉素B脂质体（LF - AmB）治疗的患者，在改用“挽救性”抗真菌药物时，由于组织中LF - AmB浓度持续较高，将明确接受联合治疗。应重新定义分别用于界定“临床难治性”“耐药性”“无反应”或“治疗失败”的标准。建立更有效定义的一个选择是使用包括临床、放射学以及微生物学或真菌学标准的综合评分。后者可能包括基于非培养的方法，如血清半乳甘露聚糖。评估不应在全剂量全身抗真菌治疗7天之前进行。然而，在个别情况下，例如造血恢复的患者，其肺部曲霉病病灶增大且临床恶化，可能建议在宣布治疗失败前，不要将患者换用其他治疗方案，而是继续当前抗真菌治疗7天。关于IA二线抗真菌治疗的临床研究应采用随机和盲法，应根据患者一线抗真菌治疗“失败”的原因分别对患者进行评估，并根据其先前的抗真菌治疗进行分层。理想情况下，一线治疗方案应标准化。应明确界定并记录诸如中性粒细胞减少或移植物抗宿主病（GVHD）等宿主标准及其随时间的变化过程，并根据这些标准对患者进行分层。三项研究（继续一线抗真菌治疗与一线抗真菌治疗联合“挽救性”药物与单独使用“挽救性”药物）将是理想的。
