鸟胞内分枝杆菌复合体

Updated October, 2008

 

Michelle S. Cespedes, M.D.

New York University AIDS Clinical Trials Unit

550 First Avenue

C & D Building, Room 558

New York, NY 10016

Email: michelle.cespedes@med.nyu.edu

Tel: 212.263.6565

Fax:  212.263.8264

 

Judith A. Aberg, M.D.

New York University AIDS Clinical Trials

Unit 550 First Avenue

C & D Building, Room 558

New York, NY 10016

Email: judith.aberg@med.nyu.edu

Tel:  212.263.6565

Fax:  212.263.8264 

 

译者：刘媛 博士

           中国协和医科大学

           Email：asydarka@gmail.com  

 

审阅者：吴婵媛 博士

               北京协和医院 内科

               Email：wuchanyuan@sina.com

 

 

GENERAL DESCRIPTION

概述

               Mycobacterium avium complex (MAC) includes the organisms Mycobacterium avium and Mycobacterium intracellulare and are ubiquitous in the environment. The spectrum of disease is predominately limited to pulmonary manifestations and lymphadenitis in normal hosts and disseminated disease in severely immunocompromised hosts, namely AIDS patients. Disease due to MAC has increased in incidence since the early 1980’s coinciding with the advent of the AIDS epidemic and improved diagnostic methods. The introduction of newer macrolides has improved treatment outcomes and their prophylactic use for patients with advanced AIDS continues to decrease the incidence of disseminated disease in patients with access to care (33).

　　鸟胞内分枝杆菌复合体（英文缩写MAC）含有鸟分枝杆菌和胞内分枝杆菌两种细菌成分，在环境中广泛存在。其在正常免疫力的宿主中导致肺病和淋巴结炎，但在免疫抑制的宿主，主要是艾滋病患者中，则引起播散性感染。MAC病的发病率从20世纪80年代早期开始逐渐增加，这和艾滋病流行的加剧和诊断手段的进步均有关。新型大环内酯类药物的出现提高了MAC病的治疗效果，其在早期艾滋病患者中的预防性应用降低了该人群中MAC播散性感染的几率(33)。

 

Microbiology Guided Medline Search

微生物学

               MAC are facultative intracellular organisms that are aerobic, slow growing (10 – 21 days on solid media) acid fast bacilli. They form translucent or dome-shaped tan to yellow colonies. Colonies can be of the smooth transparent type or domed-opaque type. MAC has a trilaminar cell wall with a lipophilic outer layer and basal peptidoglycan layer. The relative resistance of these organisms to traditional antimycobacterial chemotherapy is attributed to poor penetration of the hydrophilic medications through the lipophilic outer layer.

　　MAC是一种需氧的兼性胞内生长微生物,,生长缓慢（固体培养基需10～21天），抗酸染色阳性。它们形成半透明或圆顶状，黄棕色的菌落。菌落可以是透明的光滑型或不透明的圆顶型。MAC具有一种三层的细胞壁，包括一层亲脂性外膜，以及一层基底肽聚糖层。这种微生物对传统抗分枝杆菌药物的相对不敏感，即是由其亲脂性外膜对亲水性药物的通透性较差造成的。

               MAC is divided into 28 serovars via glycopeptide typing, with serovars 1 through 6, 8 through 11, and 21 classified as M. avium, the remainder classified as M. intercellulare. Serovars 1, 4, and 8 are the most commonly isolated strains in AIDS patients with disseminated disease. MAC clinical isolates in disseminated disease are always of the smooth-translucent type.

　　MAC通过糖肽分型分为28个血清型：其中血清型1～6、8～11和21为鸟分枝杆菌，其余血清型为胞内分枝杆菌。1、4和8型是发生播散性感染的艾滋病患者中最常分离到的血清型。播散感染病例中MAC的临床分离株多为光滑半透明型菌落。

 

Epidemiology Guided Medline Search

流行病学

               Mycobacterium avium complex disease has been increasingly recognized as an important pathogen in both pulmonary disease and as an opportunistic infection in severely immunocompromised AIDS patients.

　　人们逐渐认识到，MAC是一种会导致肺部疾病，以及重度免疫缺陷的艾滋病患者机会感染的重要病原体。

               MAC organisms can be found throughout the environment in soil, water, and animals. In addition to natural water sources, MAC has been cultured from recirculating hot water systems including hospital water systems, hot tubs and swimming pools (67). Investigators have theorized that the increased use of showers which create aerosolized droplets may be a vehicle for respiratory transmission. Humans are thought to acquire the organisms via inhalation or via the gastrointestinal tract through ingestion. Person-to-person transmission has not been documented and not thought to be a route of transmission.

　　MAC在环境中分布广泛，包括土壤、水体和动物体内。除自然水源外，循环热水系统，如医院用水系统、热水浴缸和游泳池中也曾分离到MAC(67)。研究者们认为，淋浴可制造气溶胶，其使用的增加可能成为MAC经由呼吸道传播的载体。人们通过呼吸道吸入或胃肠道食入获得该病原体。人对人的传播尚未被证实，遂不被认为是MAC的传播方式。

Pulmonary Disease: Pulmonary MAC disease is more common in HIV negative subjects, usually in patients with predisposing pulmonary conditions including COPD, bronchiectasis, or fibrotic lung disease (29). MAC has been recovered from the sputum of patients with cystic fibrosis (68). People with a history of prior pulmonary tuberculosis or heavy smoking may be at increased risk for pulmonary MAC. In developed countries, the average age of a patient presenting with pulmonary MAC is greater than 55 years and there is a predilection for men.

MAC肺病：MAC肺病多见于HIV阴性的个体，他們多是伴有慢性阻塞性肺病（COPD）、支气管扩张症或肺纤维化等易感因素疾病的患者(29)。MAC曾在囊性纤维化病人的痰液中分离出來(68)。既往肺结核病史或大量吸烟史也是MAC肺病的易感因素。在发达国家，MAC肺病患者的平均年龄大于55岁，以男性居多。

Lymphadenitis: Since the 1980’s MAC has surpassed Mycobacterium scrofulaceum as the etiology for nontuberculous lymphadenitis in the US. MAC cervical lymphadenitis in the US is mostly a disease of children, most cases occurring before the age of three years (43). Infection of the submandibular, submaxillary, cervical, or preauricular lymph nodes in children between 1 and 5 years old is the most common presentation of MAC lymphadenitis. Investigators have speculated that there is a correlation to the ability to culture MAC from pasteurized milk and the cervical adenitis seen in young children (23). It is proposed that ingestion of the organisms via milk leads to dissemination via the lymphatics.

MAC淋巴结炎：在美国，MAC自上世纪80年代以来逐渐取代了瘰疬分支杆菌，成为非结核淋巴结炎的首要病因。在美国，MAC颈淋巴结炎主要为一种儿童疾病，多在3岁以前发病(43)。其最常见表现为1～5岁儿童颌下、颏下、颈部或耳前淋巴结的感染。研究者推测，巴氏消毒奶中MAC的检出率与儿童颈淋巴结炎之间存在着一定相关性(23)。普遍认为食入牛奶中的病原体导致了MAC沿淋巴管的播散。

               In HIV positive patients, focal lymphadenitis with MAC has also been reported as part of the immune reconstitution syndrome after the initiation of antiretroviral therapy (59).

　　有报道发现，在HIV阳性患者中的MAC局部淋巴结炎是抗逆转录病毒治疗（ART）后免疫重建炎症综合征（IRIS）的一个表现(59)。

Disseminated Disease: Prior to the advent of the AIDS epidemic, cases of documented disseminated MAC were extremely rare. MAC is the most common bacterial opportunistic infection in advanced AIDS in the developed world. Disseminated MAC is uncommon in the developing world, possibly due to the high mortality associated with tuberculosis. A retrospective review of PPD positive HIV patients with CD4 less than 200 cells/mm3 suggests that prior infection with tuberculosis may provide protection against MAC infection (35). Prior to the advent of potent antiretroviral therapy, estimates of the prevalence of disseminated MAC in AIDS patients ranged from 20 – 40% (53). Early in the epidemic, more than 50% of patients had evidence of disseminated disease at post-mortem examination (71). The rate of MAC infection in this population has improved substantially. A Johns Hopkins cohort estimated a rate of less than 1% per year in patients with advanced disease (39). Disseminated MAC is rarely seen in patients with CD4 greater than 100 cells/mm3, and is almost exclusively seen in patients with a CD4 of less than 50 cells/mm3. Prior opportunistic infections, particularly PCP or CMV disease, predispose advanced AIDS patients to disseminated MAC. It is thought that the opportunistic infections serve as a marker for the level of immunosuppression rather than any causal relationship (44).

播散性MAC病：在艾滋病流行加剧之前，播散性MAC病例的报道极为罕见。MAC是发达国家中末期艾滋病患者最常见的机会性细菌感染。播散性MAC病在发展中国家较少见，也许与结核感染导致高死亡率相关。一项针对PPD阳性且CD4细胞低于200/mm3的HIV患者的回顾性综述指出，既往结核感染可能对MAC感染具有保护效应(35)。在有效的ART出现之前，艾滋病患者中播散性MAC的流行率估计可达20～40％(53)。而至艾滋病流行初期，在尸检中发现半数以上患者有播散性MAC的証据(71)。该人群中MAC的感染率已有显著增加。约翰·霍普金斯大学（JHU）的研究者们估计，其在早期艾滋病患者中的年增长率接近1％(39)。播散性MAC病在CD4细胞高于100/ mm3的患者中少见，而在CD4低于50/ mm3的患者中几乎均有感染。既往的机会感染，尤其是PCP（卡氏肺孢子菌肺炎）和CMV（巨细胞病毒）感染，使早期艾滋病患者对播散性MAC更加易感。人们推测，这是由于任何机会性感染均是与免疫抑制水平直接相关的，而并非（各种感染间）存在某种因果联系所致(44)。

MAC Immune Reconstitution Inflammatory Syndrome: A more recently recognized phenomenon associated with the initiation of antiretrovirals for HIV positive patients is the immune reconstitution inflammatory syndrome (25, 58, 65). Tending to occur in patients with pretreatment CD4 counts < 100 cells/mm, the syndrome is defined as a recrudescence of previously treated opportunistic infections or a pathological robust immune response to subclinical disease after starting antiretroviral therapy (31). The most common opportunistic infections associated with this paradoxical clinical worsening are ophthalmic cytomegalovirus disease, CNS Cryptococcal disease, tuberculosis, and disseminated MAC.

MAC免疫重建炎症综合征（IRIS）：近期引起注意的一个现象是伴随HIV阳性者ART出现的免疫重建炎症综合征（IRIS）(25,58,65)。IRIS多发生于治疗前CD4细胞低于100/ mm3的患者，這被认为是ART后其机会性感染的复发，或一种对亚急性感染的免疫增强病理性反应(31)。和这个反常的临床现象的最常见机会性感染則是CMV眼炎、隐球菌脑膜炎、结核及播散性MAC。

 

Clinical Manifestations Guided Medline Search

临床表现

               There are three common clinical syndromes due to MAC: (a) Lymphadenitis, (b) disseminated MAC in HIV positive individuals, (c) pulmonary MAC disease. Therapeutics for HIV-positive individuals includes either prophylaxis or treatment depending on the stage of the underlying disease. In general, prophylaxis with monotherapy is the standard, while treatment of infection requires combination therapy including a newer macrolide.

　　常见的MAC所致临床综合征包括以下三种：（1）淋巴结炎；（2）HIV阳性者的MAC播散性感染；（3）MAC肺病。对HIV阳性者的处理包括，按不同MAC感染状态采取预防或治疗措施。通常，预防采取单药疗法，而治疗则要求包含新大环内酯类的联合用药。

Pulmonary Disease: Pulmonary disease usually presents with chronic productive cough in the absence of hemoptysis. Diagnosis can be delayed due to underlying lung disease. In HIV negative patients, MAC presents as bilateral upper lobe fibrocavitary disease radiographically (15). Pulmonary MAC tends to cavitate more often than pulmonary TB. MAC can also cause hypersensitivity pneumonitis.

MAC肺病：MAC肺病的临床表现通常为慢性咳痰而不伴咯血，常常被既往肺病史掩盖而延误诊断。HIV阴性患者在影像上表现为双上肺的纤维空洞样改变(15)。MAC肺病比肺结核更易形成空洞。MAC还可导致过敏性肺泡炎。

               Recently pulmonary MAC has been recognized with increasing frequency in elderly women, usually thin, with no history of underlying pulmonary disease. Thoracic lymphadenopathy is uncommon. The syndrome, referred to as Lady Windermere syndrome, is characterized by chronic cough with minimal constitutional symptoms, and atypical chest x-ray findings usually limited to the lingual and right middle lobe. The x-rays tend to demonstrate fibronodular disease with bronchiectasis.

　　最近人们发现，MAC肺病在老年女性中发病率日趋增高，患者通常是体型偏瘦且无基础肺病者。其中伴胸腔淋巴结肿大者少见。有一症候群被称为Lady Windermere综合症，特征是慢性咳嗽；轻微的非特异性全身症状；以及局限在舌叶或右肺中叶的非典型胸片表现，常包括纤维结节样变和支气管扩张。

Lymphadenitis: MAC lymphadenitis is generally a disease of young children. It usually manifests as cervical or submandibular involvement identical to that of tuberculosis, except the involvement is usually unilateral. Bilateral disease occurs in fewer than 10% of documented cases. It is rare for more than a single node to be enlarged in MAC lymphadenitis. The presentation is generally painless node enlargement and fever is usually absent.

MAC淋巴结炎：MAC淋巴结炎多见于儿童，通常表现为与结核相似的颈部或颌下淋巴结肿大，不同的是往往为单侧受累。文献报道只有少于10％病例为双侧受累。MAC淋巴结炎中，多数淋巴结肿大的情况较少见。通常淋巴结肿大是无痛性的，且不伴发热。

Disseminated Disease: The presenting signs and symptoms of AIDS related disseminated MAC infection are nonspecific and can mimic other infections. These include tuberculosis, systemic fungal disease, disseminated bartonella, and malignancies such as lymphoma or may be incorrectly attributed to progression of HIV disease itself (38). Patients most commonly report persistent fever, night sweats, fatigue, weight loss, and anorexia. Abdominal pain or chronic diarrhea may result from involvement of retroperitoneal lymph nodes or gut mucosa, respectively. Hepatosplenomegaly, lymphadenopathy, and (rarely) jaundice also may be present. Hematologic dissemination of organisms seed lymph nodes and organs of the reticuloendothelial system, usually the liver, spleen and bone marrow. Anemia, which can be severe, is the most common laboratory abnormality. Leukopenia and elevated alkaline phosphatase levels are common. Rare manifestations of disseminated disease include cutaneous lesions, joint involvement, and osteomyelitis.

播散性MAC：艾滋病相关MAC播散感染的临床症状缺乏特异性。其表现与其他一些感染相似，如结核、全身真菌感染、播散性巴通体病或淋巴瘤等恶性肿瘤；亦常常被误诊为HIV本身感染的加重(38)。最常见主诉包括持续发热、盗汗、疲劳、体重减轻和食欲减退。腹痛和慢性腹泻亦可分别由腹膜后淋巴结和胃肠道粘膜受累所致。肝脾大、淋巴结大和黄疸（少见）也可出现。血行播散造成病原体在淋巴结和其他网状内皮系统，如肝、脾和骨髓中的种植。实验室检查最常见为贫血，可以非常严重；白细胞减少和碱性磷酸酶升高也较常见。播散性MAC病其他少见的表现还包括皮损、关节症状和骨髓炎。

MAC Immune Reconstitution Inflammatory Syndrome

               MAC immune reconstitution syndrome generally presents as localized peripheral lymphadenitis, but cases of MAC associated intra-abdominal disease, MAC osteomyelitis, joint, and soft tissue disease have been reported (1). The majority of cases are accompanied with fever, but bacteremia is absent.

MAC免疫重建炎症反应综合症（IRIS）：MAC免疫重建综合症一般表现为局部外周淋巴结炎，也曾发现腹腔内MAC感染、MAC骨髓炎及关节软组织病等(1)。大多数病例伴有发热，但不发生菌血症。

Laboratory Diagnosis Guided Medline Search

实验室诊断

               MAC can be cultured on solid or liquid media, although liquid media yields results in fewer days (7 – 10 days) and is more sensitive. DNA or RNA hybridization probes can be used to confirm the presence of MAC. Direct detection by PCR is not commercially available outside of specific research laboratories. 　　

　　MAC可在固体或液体培养基中生长，后者得到结果更快（约需7～10天）且更敏感。DNA或RNA杂交探针可用于证实MAC的存在。PCR法直接检测仅在专门实验室研究中使用，至今尚无商业试剂供临床推广应用。

               Diagnosis of MAC lymphadenitis is made by culture of the organism from the node. Excision of the entire node is recommended for diagnosis since biopsy or aspiration of a suspected node frequently results in fistula formation.

　　MAC淋巴结炎的诊断方法是淋巴结组织培养获得病原体。由于活检或穿刺常致窦道形成，建议在诊断过程中切除整个淋巴结。

               Sputum isolation of MAC can be misleading since patients can be asymptomatically colonized. The American Thoracic Society has formal guidelines for the diagnosis of active MAC pulmonary disease that include multiple positive cultures with smear evidence in the presence of symptoms and radiological evidence of disease (4). [Table 1]

　　痰标本MAC培养可产生假阳性，因为患者可能为无症状的MAC定植。美国胸科协会（ATS）为活动性MAC肺病的诊断标准制定了正式指南，包括多次培养阳性、痰涂片镜检阳性、相应症状和胸片表现(4)[表1]。

               Confirmation of disseminated MAC is achieved by isolation of the organism from an otherwise sterile site. These include culture from blood, bone marrow aspirate, liver, or spleen. The vast majority of cases can be confirmed with isolation in a single blood culture, with recovery form two blood cultures increasing the yield to greater than 99%. The number of MAC organisms obtained in quantitative bone marrow cultures can be more than thirty times higher than those obtained in blood cultures (32). Low colony counts seen early in disseminated disease can promote false negative blood culture results, therefore repeat cultures are recommended if there is a high clinical suspicion of MAC. Growth in liquid media will usually become positive in 14 days, but must be held for at least six weeks before they can be called negative. Isolation of MAC from non sterile sites including bronchial washings, gastrointestinal biopsy specimens, or stool may represent only colonization and a full treatment course should not be initiated on recovery of organisms from these sites alone.

　　播散性MAC的确诊依靠从无菌部位，包括血液、骨髓穿刺、肝脏或脾脏等分离获得病原体。绝大多数病例仅通过一次血培养即能确诊，两次血培养可将检出率提高至99％以上。从定量的骨髓培养中获得的病原体量是血培养获得量的30倍(30)。播散感染早期培养的菌落数较少可导致血培养结果出现假阴性，因此当临床高度怀疑MAC感染时应重复培养。MAC在液体培养基中往往需要生长14天才能达到阳性水平，但需要至少6周未生长才能判断阴性。而在非无菌部位，如支气管灌洗液、胃肠道活检标本或粪便中MAC培养阳性可能只代表定植，因此不可仅凭该结果就开始MAC的完整疗程。

 

Pathogenesis Guided Medline Search

发病机制

               The serovars that infect AIDS patients with disseminated disease have shown to be more aggressive in animal models suggesting associated virulence factors. Investigated virulence factors include enhanced adhesion to gastrointestinal epithelium, interference of lysosomal acidification promoting intracellular persistence, and catalase production (16). Increased pathogenicity has been associated with antibiotic susceptibility, the presence of plasmid, and certain RFLP patterns. Smooth-translucent isolates have decreased antimicrobial susceptibility in vitro and more likely to induce TNF-α and interlukin-1 production.

　　在动物试验中，可致艾滋病患者播散性感染的MAC血清型的侵袭性更强，提示相关毒力因子的存在。已研究的毒力因子作用包括：增强胃肠道上皮黏附力，影响溶酶体酸化从而在胞内存活，以及产生过氧化氢酶(16)。致病性的增强与抗生素敏感性、质粒的存在及特定RFLP形式具有相关性。光滑半透明分离株的体外抗菌药敏感性较低，且更易诱导TNF-α和IL-1产生。

               MAC organisms are phagocytosed by local macrophages where they persist intracellularly. In pulmonary disease after inhalation of the organisms, macrophages organize into granulomas and form nodules which can be visualized on gross pathology.

　　MAC菌体被感染局部的巨噬细胞吞噬，并在其胞内生存。在病原体吸入所致的肺病中，巨噬细胞聚集为肉芽肿，并在大体标本上形成肉眼可见的结节。

               Disseminated disease can occur after ingestion or inhalation. When acquired through the gastrointestinal tract, phagocytosed organisms that have penetrated the gut wall appear as foamy macrophages in the intestinal lamina propria resulting in gut wall thickening (34, 45). This thickened bowel wall can lead to the rare complications of gastrointestinal hemorrhage, intussusception, or obstruction. Hematologic dissemination occurs after macrophages are transported to abdominal nodes via lymphatic drainage. The spleen, liver, and bone marrow are the organs most commonly seeded after hematologic dissemination.

　　播散感染可因吸入或食入所致。进入胃肠道后，被吞噬的病原体穿过肠壁，表现为固有层中的泡沫巨噬细胞，使肠壁增厚(34,35)。增厚的肠壁可导致一些少见并发症，如胃肠道出血、肠套叠或肠梗阻。血行播散发生于巨噬细胞随淋巴管汇入腹腔淋巴结时。脾脏、肝脏和骨髓是血行播散时最易受累的器官。

               The predominate symptoms of disseminated MAC disease are fever, night sweats, and cachexia, similar to the presenting signs of tuberculosis. The symptoms are attributed to elevated levels of TNF-α and other cytokines, namely interlukin-6, induced by the presence of MAC in the host’s blood stream. A marked elevation of serum alkaline phosphatase in the absence of other abnormal markers of hepatic function is seen in approximately 5% of patients with disseminated disease.

　　播散性MAC的主要症状是发热、盗汗和体力消耗，类似结核的表现。这些症状被归因于血液中MAC菌体诱发的TNF-α和其他细胞因子如IL-6水平的升高。约5％播散感染的患者ALP显著升高，而其他肝功指标正常。

 

SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo

体外和体内的药物敏感性

               MAC is resistant to most of the standard agents used for the treatment of tuberculosis. Susceptibility testing for MAC is not standardized to date and is only available in research institutions. The precise MIC (Minimum Inhibitory Concentration) breakpoint for resistance has not been standardized and is being evaluated by the National Committee for Clinical Laboratory Standards (NCCLS). In addition, clinical correlation with in vitro sensitivity testing has not been established. Susceptibility testing is not recommended for initial selection of therapeutic agents.

　　MAC对多数经典抗结核药物耐药。针对MAC的药敏试验至今尚未标准化，仅在研究领域使用。判断耐药性的精确MIC（最小抑菌浓度）界值尚无统一标准，正处于美国国家临床实验标准委员会（NCCLS）的评估进程中。此外，体外药物敏感性与临床疗效的相关性尚未被确立。目前，初次治疗用药选择并不需依照药敏试验。

               In vitro testing is dramatically influenced by the pH at which the test is performed and the medium used (30a). Tween-containing broth enhances antimicrobial activity. While in vitro testing has not been standardized, there is consensus among researchers regarding certain features. A broth medium may be more reliable than agar. When using radiometric broth dilution methods, inoculum preparation is critical. An inoculum size of 104 and 105 colony-forming units (CFU)/mL has been recommended. In the absence of well-established correlations with clinical efficacy and outcome, especially in infections in AIDS patients, use of the MIC to determine resistance or susceptibility is problematic (36).

　　体外试验受pH条件和培养基类型的影响较大(30a)。含非离子活性剂的肉汤培养基可以提高抗菌药的活性。尽管体外检测方法尚未标准化，研究者们在某些问题上已达成共识，例如：肉汤比琼脂培养基更加可靠；而采用肉汤放射稀释测量法时，接种物的准备非常关键，通常推荐的接种量为104～105CFU（菌落形成单位）/mL。在实验室结果与临床疗效的相关性无法确立的前提下，使用MIC确定敏感或耐药性，尤其在艾滋病患者中，是存在问题的(26)。

               Molecular mechanisms of antimicrobial resistance are not well described for MAC. (48) There is no evidence that MAC produces aminoglycoside- and peptide-inactivating enzymes; however, there is evidence for low-level, β-lactamase production (49). Macrolide resistance has been linked to base pair substitution within the V domain of the 23S ribosomal RNA (47). This mutation appears to confer cross-resistance among the currently available macrolides.

　　MAC抗菌药耐药的分子机制尚未被阐明(48)。尚无证据表明MAC产生氨基糖甙和肽类的灭活酶；但低水平的β-内酰胺酶合成曾被报道(49)。大环内酯类耐药与MAC 23SrRNA V区一碱基对的替换突变有关(47)。并且，该突变似乎介导了对目前所有大环内酯类的交叉耐药性。

               M. avium is an intracellular pathogen, therefore, the intracellular concentration of a therapeutic agent is an important consideration when evaluating the MIC. For example, azithromycin, which has a lower Cmax in the serum than clarithromycin, has a longer half-life and reaches much higher concentrations in the macrophage than clarithromycin (28,37). Intracellular activity is often studied in the human macrophage model. With the aid of the beige-mouse animal model, agents with in vitro activity are selected for human study.

　　鸟分枝杆菌是一种胞内菌，因此抗菌药的细胞内浓度是评价MIC时的一个重要方面。例如，阿奇霉素虽然血清Cmax（最大浓度）低于克拉霉素，却有更长的半衰期，且能获得更高的巨噬细胞内浓度(28,37)。胞内活性常常在人体巨噬细胞模型中进行研究。利用Beige鼠动物模型，可从具有体外活性的药物中筛选出适合人体研究的品种。

               Susceptibility testing with rifabutin and the antituberculosis drugs is not recommended. Routine testing against clarithromycin should not be performed. Susceptibility testing for clarithromycin should only be performed on isolates from patients who have failed prior macrolide therapy or prophylaxis. Minimal inhibitory concentration (MIC) of > 32 µg/ml is the recommended clarithromycin resistance breakpoint.

　　利福布丁和其他抗结核药物的药敏试验不推荐使用；也不推荐常规的克拉霉素药敏试验，只有既往大环内酯类治疗或预防失败的患者才需进行。MIC > 32ug/mL是目前推荐的克拉霉素耐药性界值。

               Due to increased intrinsic resistance, especially in a population with previous exposure to macrolides, in vitro susceptibility is increasingly useful in treatment failures. Treatment failure is defined as poor clinical response and ability to culture organisms 4 - 6 weeks after initiation of first line combination therapy. Recent data suggests that in the era of potent antiretroviral therapy, there is an increasing incidence of macrolide resistance that may warrant consideration of routine susceptibility testing (26).

　　尤其是在曾使用过大环内酯类的患者中，由于其耐药性的增强，体外敏感试验在治疗失败病例中显得愈加重要。治疗失败被定义为：临床反应不佳，或一线联合治疗开始4～6周后培养仍阳性。最近的数据表明，在有效ART出现后，大环内酯类耐药的增加可能将促使其药敏试验成为常规(26)。

               The quinolones have known anti-M. tuberculosis activity and there is a growing body of work investigating their use as first line agents against MAC (77). The use of quinolones is an attractive prospect because of their proven efficacy in other mycobacterial species and favorable side effect profile. Investigations of several early quinolones against MAC were disappointing (70). In general, MAC has reduced susceptibility to ciprofloxacin and levofloxacin in vitro, and neither have proven to be of clear clinical benefit in the mouse model (9). Moxifloxacin has significant in vitro activity against MAC (27, 61). Moxifloxacin is bacteriostatic and reaches higher intracellular levels in macrophages than levofloxacin. In vitro testing suggests that the addition of moxifloxacin to an azithromycin based regimen may further prevent resistance (8).

　　喹诺酮类的抗结核活性已被认可，对于其作为MAC一线用药的研究也与日俱增(77)。喹诺酮类的使用前景值得期待，不仅由于它对其他分枝杆菌的确凿疗效，也因为其副作用相对较小。对几种早期喹诺酮类的研究发现其对MAC的疗效欠佳(70)。总的来说，MAC对环丙沙星和左氧氟沙星的体外敏感性较差，在小鼠模型中也未获得明确的临床疗效(9)。然而莫西沙星对MAC的体外敏感性却较好(27,61)。它是一种抑菌药物，在巨噬细胞中的浓度高于左氧氟沙星。体外试验表明，以阿奇霉素为主的治疗方案中加入莫西沙星，可进一步预防耐药性的产生(8)。

 

ANTIMICROBIAL THERAPY Guided Medline Search Smart search  

抗菌治疗

               Combination therapy for MAC that includes a macrolide and the use of potent antiretroviral therapy in HIV patients promoting immune restoration has dramatically improved morbidity and mortality rates. Eradication of disease requires prolonged therapy and careful monitoring is recommended to prevent drug related toxicities.

　　在发生免疫重建的HIV患者中，同时进行抗MAC大环内酯类治疗和有效的ART，会显著改善发病率和死亡率。彻底清除感染需要长时间的治疗和细心监测，以防药物毒性作用的发生。

Guideline:  An Official ATS/IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculosis Mycobacterial Diseases. Am J Respir Crit Care Med 2007:175;367-416.

Pulmonary Disease

MAC肺病

               The American Thoracic Society recommends a regimen of daily clarithromycin or azithromycin, rifampin or rifabutin, and ethambutol initially at higher doses (25 mg/kg/d for two months, then 15 mg/kg/d) for adults with isolated pulmonary MAC not infected with HIV (4) [Table 3]. The society recommends that a trial of streptomycin two to three times per week should be considered for the first eight weeks as tolerated. Patients should be treated until culture-negative on therapy for one year. The majority of patients with pulmonary MAC disease receive therapy for about 18 – 24 months on average.

　　美国胸科协会（ATS）对非HIV成人MAC肺病患者推荐的一种治疗方案包括：每天服用克拉霉素或阿奇霉素，利福平或利福布丁，和乙胺丁醇（以大剂量起始25mg/kg/d，两个月后减为15mg/kg/d）(4)[表3]。协会推荐，在最初8周里，应依据耐受情况试验性地加入每周2～3次的链霉素治疗。治疗应持续直到治疗后培养转阴后1年。大多MAC肺病患者的治疗时程平均为18～24个月。

MAC Lymphadenitis

MAC淋巴结炎

               For MAC lymphadenitis in children, excisional surgery without concomitant antibiotics is the mainstay of treatment (62, 75). Incisional biopsy often leads to sinus tract formation and drainage and is therefore not recommended. Recurrence is rare after resection in immunocompetent children, and to date there have been no prospective studies on the use of adjunctive antimycobacterials for treatment of recurrent disease.

　　儿童MAC淋巴结炎的治疗方案是手术切除受累淋巴结，而无需抗菌药治疗(62,75)。切开活检往往导致窦道形成和内容物排出，遂不推荐采用。切除后复发在免疫正常的患儿中少见，目前尚无抗分枝杆菌药物辅助治疗MAC淋巴结炎复发的前瞻性研究。

Disseminated MAC

MAC播散感染

               Mycobacterial infections are notoriously difficult to treat. MAC is intrinsically resistant to most of the standard antimycobacterial agents used to treat tuberculosis. To prevent the emergence of resistance, the use at least two antimycobacterial agents is recommended for the treatment of MAC (21, 38, 46). Clinical trials conducted prior to the availability of potent antiretroviral therapy concluded that the addition of rifabutin further prevented the emergence of resistance and provided some survival benefit. Initial therapy with three agents is recommended for patients in whom antiretroviral therapy has not been initiated. Multiple studies have shown improved treatment success and survival benefit from macrolide containing regimens in disseminated MAC in AIDS patients (13, 14). Clarithromycin is the preferred first agent in the treatment of disseminated MAC and appears to promote more rapid clearance of MAC from blood cultures as compared to azithromycin (22).

　　分枝杆菌感染的难治性是众所周知的，MAC更是对许多治疗结核的抗分枝杆菌药物还具有内在耐药性。为了避免耐药性的产生，MAC治疗推荐联合使用至少两种药物(21,38,46)。一项在有效ART出现之前进行的临床试验发现，加入利福布丁进一步避免了耐药性的产生，并可带来一定的存活收益。对于未进行ART的患者，起始治疗推荐三种药物的联合。多项研究证明了包含大环内酯类的治疗方案能提高艾滋病患者播散性MAC的治疗成功率和存活收益 (13,14)。克拉霉素是播散性MAC的首选药物，它比阿奇霉素更快地从血液中清除MAC(22)。

               Agents that have activity against MAC include macrolides and azalides, ethambutol, rifampin, ciprofloxacin, levofloxacin, streptomycin and amikacin. Antimicrobials that were previously used but limited by adverse effects and poor response to therapy include clofazimine, cycloserine, and ethionamide. Prior to the introduction of macrolides, treatment for MAC usually required at least 36 months of therapy and there was increased risk of toxicity due to available regimens. Macrolides have decreased the occurrence of treatment failures. First line treatment for disseminated MAC is now clarithromycin in combination with ethambutol plus or minus rifabutin  (6, 7) [Table 2]. Clarithromycin has a number of significant drug – drug interactions. Azithromycin, which minimally inhibits the hepatic cytochrome P 450 metabolism system, can be substituted for clarithromycin (74).

　　具有抗MAC活性的药物包括大环内酯类、氮杂内酯类、乙胺丁醇、利福平、环丙沙星、左氧氟沙星、链霉素和阿米卡星。曾被使用但副作用大或药效不佳的抗菌药包括氯法齐明/氯苯吩嗪、环丝氨酸和乙硫异烟胺。在大环内酯类被引入前，MAC治疗至少需持续36个月，因此药物相关副反应也相应增加。大环内酯类降低了治疗的失败率。目前，播散性MAC的一线治疗是克拉霉素联合乙胺丁醇，可选择性加用利福布丁(6,7)[表2]。克拉霉素与许多药物间存在相互作用。在这种情况下，对肝细胞色素P450代谢系统的抑制作用较小的阿奇霉素可作为替代(74)。

               The use of rifampin in HIV positive patients is avoided whenever possible due to interference with the hepatic metabolism of protease inhibitors. Use of rifampin with protease inhibitors can promote subtherapeutic protease inhibitor levels (5). Rifabutin is preferred over rifampin because it has more activity against MAC in vivo, but it may also increase the risk of certain adverse events, including leukopenia. Higher doses of rifabutin in combination with clarithromycin have lead to an increase risk of uveitis. In individual cases where rifabutin cannot be tolerated due either to side effects or medication pharmacokinetic interactions, the addition of a third line agent (either a fluoroquinolone or parenteral amikacin) is recommended. While the current treatment guidelines recommend the use of ciprofloxacin or levofloxacin as a fourth agent in disseminated disease, moxifloxacin has more potent activity in vivo.

　　对HIV阳性患者应避免使用利福平，因为它影响肝脏对蛋白酶抑制剂（PI）的代谢。利福平与PI共用可使后者达不到所需治疗浓度(5)。利福布丁比利福平更受欢迎，它对MAC有更强的体内活性，但也存在副作用，如白细胞减少。较大剂量的利福布丁与克拉霉素共用，会增加葡萄膜炎的风险。对个别利福布丁不耐受的病例（因副作用或药代动力学相互作用），推荐改用一种三线药物（氟喹诺酮或胃肠外应用阿米卡星）。目前的治疗指南推荐环丙沙星或左氧氟沙星为播散感染的四线药物，但莫西沙星的体内活性更强。

               A multicenter prospective study was conducted to determine whether antimycobacterial therapy for disseminated MAC could be discontinued in HIV positive patients once their immune systems recovered after the addition of antiretroviral therapy (2). Pill burden, potential drug interactions, and the emergence of macrolide resistant respiratory flora all supported discontinuation if it was found to be safe (3). All subjects had completed a least 12 months of macrolide based therapy. After a median duration of follow up of 77 weeks, only one patient had a recurrence of MAC disease (MAC osteomyelitis) giving an estimated recurrence rate of 1.44 / 100 person-years of follow up. A French retrospective study found similar results (78). One subject was extremely immunosuppressed with a CD4 T-cell count of <50 cells/cu mm at the time of relapse highlighting the importance of re-initiating prophylaxis in the presence of immunologic failure. Hence, the joint guidelines of the CDC and the HIV Medicine Association of the Infectious Disease Society of America now recommend that HIV positive patients with disseminated MAC should continue on chronic maintenance therapy until they have completed at least 12 months of therapy, remain asymptomatic, and their CD4 count is consistently greater than 100 cells/mm3 for at least six months after the initiation of antiretroviral therapy (6).

　　一项多中心前瞻性研究旨在回答这样的问题：HIV阳性患者在ART使其免疫系统恢复后，其针对MAC播散感染的抗分枝杆菌治疗是否可以就此停止(2)。若停药被证明是安全的，其对避免过多药物共用可能出现的相互作用，和避免呼吸道出现大环内酯类耐药的菌群均有好处(3)。所有被试都完成了至少12个月的大环内酯为主的治疗。在约77周的随访期中，只有一名患者的MAC感染复发（MAC骨髓炎），据此估计复发率约为1.44/100人-随访年。一项法国的回顾性研究得到相似的结果(78)。一名处于严重免疫抑制状态被试者，复发时CD4细胞计数不足50/uL，强调了在免疫缺陷时重新开始预防用药的必要性。因此，CDC和美国感染性疾病协会HIV医学分会的联合指南中推荐，HIV阳性患者的MAC播散感染应当持续给予长期维持治疗直至达到12个月，持续无症状状态，并且在ART开始后CD4细胞计数连续至少6个月保持在100/uL以上(6)。

MAC Immune Reconstitution Inflammatory Syndrome:

MAC免疫重建炎症反应综合症

               Systemic anti-inflammatory therapy can be added to relieve symptomatic complaints in severe cases. In cases of immune reconstitution inflammatory syndrome with recrudescence of MAC disease, patients should be maintained on chronic maintenance therapy as recommended for HIV treatment guidelines. It is not recommended that the antiretroviral regimen to be discontinued or interrupted.

　　对严重IRIS者，可结合全身抗炎治疗以缓解主诉症状。对伴有MAC复发的IRIS者，患者应按HIV治疗指南的进行长期维持治疗，而不推荐暂停或终止ART。

 

Novel Agents

新药

               Management of treatment failures or cases with documented macrolide resistance is challenging. Novel therapies have been implemented for cases of disseminated MAC unresponsive to standard therapy.

　　治疗失败或既往大环内酯耐药史的处理均是棘手难题。新的治疗方案已开始被用于标准疗法反应不佳的MAC播散感染。

               Linezolid, used mainly in clinical practice for the treatment of methicillin resistant Staphylococcus aureus, has in vitro activity against MAC (57, 73). While linezolid has been shown to be bactericidal, to date there have been no animal studies conducted to document its usefulness in the treatment in MAC in vivo (76). The antimalarial agent mefloquine also has in vitro activity against clarithromycin resistant MAC strains and a promising activity profile in the mouse model, but there is limited clinical experience (10, 11). Nannini et al report a case of refractory disseminated cutaneous MAC in a patient with cell-mediated immunodeficiency secondary to CLL (50). In this case, the patient’s disseminated MAC infection responded to the addition of moxifloxacin, mefloquine, and linezolid. Further trials using these agents in clinically refractory disease are warranted.

　　利奈唑胺，一种主要被用于MRSA（耐甲氧西林的金黄色葡萄球菌）感染的抗菌药，对MAC具有体外活性(57,73)。尽管它是杀菌型药物，目前尚无动物试验证明其在体内对MAC有效(76)。抗疟疾药物甲氟喹宁也对耐克拉霉素的MAC具有体外活性，它在小鼠模型中的效果也令人满意，但临床使用经验仍有限(10,11)。Nannini等人报道了一例继发于CLL（慢性淋巴细胞白血病）的细胞免疫缺陷患者顽固的皮肤MAC播散感染(50)。在该病例中，莫西沙星、甲氟喹宁和利奈唑烷的联合使用起到了效果。但以上药物对顽固感染的临床疗效尚需进一步临床试验来证明。

(Printable Version of Antimicrobial Therapy for Mycobacterium avium Complex)

Review Article: Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, et al.  An Official ATS/IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases.  Am J Respir Crit Car Med 2007;175:367-416.

ADJUNCTIVE THERAPY Guided Medline Search

辅助治疗

Surgical Resection

手术切除

               Adjunctive surgical resection of involved lung tissue was of limited survival benefit prior to the availability of macrolides and is not routinely recommended. Surgical intervention should be limited to areas of severe disease where antibiotic penetration of the tissue is poor.

        在大环内酯类出现之前，手术切除受累肺组织的辅助治疗仅能带来有限的存活收益，因此不推荐常规采用。只有对受累严重且抗菌药穿透性差的组织，才需行手术干预。

Corticosteroid Therapy

糖皮质激素治疗

               Persons who have symptoms of moderate-to-severe intensity because of an immune reconstitution inflammatory syndrome (IRIS) in the setting of ART should receive treatment initially with nonsteroidal, anti-inflammatory agents. If symptoms fail to improve, short-term (4–8 weeks) systemic corticosteroid therapy, in doses equivalent to 20–40 mg of oral prednisone QD, has been successful (6). To date, there have been no randomized, control trials designed to investigate the long term safety and efficacy of adjuvant corticosteroid use the treatment of disseminated MAC or its use in IRIS.

　　接受ART的IRIS症状较重者应接受抗炎治疗。开始先用非甾体抗炎药物；若症状不好转，则可开始短期（4～8周）全身糖皮质激素治疗，相当于每日口服强的松20～40mg的剂量往往能够有效地控制炎症(6)。目前尚无随机对照试验来检测长期辅助糖皮质激素治疗对MAC播散感染或IRIS的安全性和有效性。

Immunomodulatory Therapy

免疫调节治疗

               The use of immunomodulatory cytokines and GM-CSF, are currently being investigated as adjunctive therapy for use in refractory cases with extensive disease (69). Immunomodulatory cytokines inhibit the growth of MAC in macrophages (65). Both granulocyte-macrophage colony-stimulating factor (GM-CSF ) and TNF-α significantly reduced numbers of organisms in macrophages. In a small randomized study, AIDS patients with MAC bacteremia who received GM-CSF in combination with azithromycin had evidence of increased monocyte activation and mycobactericidal activity as compared those randomized to receive azithromycin alone (40).

　　免疫调节细胞因子和GM-CSF（粒-巨噬细胞集落刺激因子）在严重感染的难治病例中的辅助治疗，正在被研究当中(69)。免疫调节细胞因子可抑制巨噬细胞中MAC的生长(65)。GM-CSF和TNF-α均可显著减少巨噬细胞内的病原体数量。在一项小型随机研究中，MAC菌血症的艾滋病患者在接受GM-CSF和阿奇霉素联合治疗后，体内单核细胞及其抗分枝杆菌活性与仅接受阿奇霉素治疗的对照组相比，均有更显著提高(40)。

               The combination of interferon-γ ( INF-γ ) with IL-2 has been used as adjunctive therapy to routine MAC treatment in a refractory case of disseminated MAC in a pediatric AIDS patient (63). CD4 cells produce interferon-γ in vivo, and patients with mutations in INF-γ receptors are exquisitely susceptible to tuberculosis and mycobacterial infections (20, 51). This suggests that INF-γ is integral to host defense to MAC infections. In the aforementioned case, IL-2 was used to increase the number of circulating CD4 cells, which in turn led to sustained increased INF-γ levels. The use of these cytokines in addition to antimicrobials led to eradication of disseminated MAC.

　　一个患有顽固MAC播散感染的艾滋病儿童，在常规MAC治疗的基础上接受了γ-干扰素(INF-γ)与白介素-2(IL-2)联合辅助治疗(63)。CD4细胞在体内产生INF-γ，而INF-γ受体突变的患者对结核和其他分枝杆菌具有易感性(20,51)。这说明INF-γ是宿主对MAC感染的防御机制的组成部分。在上述病例中，IL-2的作用是增加循环CD4细胞的数量，从而导致INF-γ水平持续升高。在抗菌治疗的基础上使用这些细胞因子，能够促进MAC播散感染的清除。

Milanes-Virelles MT, Garcia-Garcia I, et al.  Adjuvant interferon gamma in patients with pulmonary atypical Mycobacteriosis: a randomized, double-blind, placebo-controlled study.  BMC Infect Dis. 2008 Feb 11;8(1):17 [Epub ahead of print].

 

ENDPOINTS FOR MONITORING THERAPY Guided Medline Search

治疗监测的终点

Disseminated MAC in HIV-Positive Patients

HIV阳性者的MAC播散感染

               Response to therapy for disseminated MAC is monitored by clinical symptoms and qualitative blood cultures. Patients should respond with resolution of fevers and chills, decreases in abnormal alkaline phosphatase levels, and a feeling of well being within approximately 4 to 8 weeks (13). Quantitative blood cultures are a research tool used to describe the types of response to certain therapies and are not used in routine clinical practice. Response to therapy should result in a negative blood culture for MAC by 12 to 16 weeks (13). However, while the blood may be free of MAC, tissues (including the bone marrow) may still harbor the infection (18, 41). Failure to clear the blood of MAC should lead the clinician to perform sensitivity testing on the clinical isolate to direct future therapeutic choices.

　　MAC播散感染对治疗的反应是通过临床症状和定性血培养进行监测的。治疗反应表现为治疗开始约4～8周后，发热寒战的消退、ALP水平的回落和主诉感觉的好转(13)。定量血培养作为研究工具用来描述治疗反应的情况，但不用于临床实践。治疗反应还表现在12～16周后血培养转阴(13)。然而，即使血液中已没有MAC存在，组织（包括骨髓）中仍可能包藏感染(18,41)。血液中MAC清除失败时，临床医生应该对分离株进行药敏试验，以指导下一步治疗葯物选择。

Pulmonary MAC in HIV-Negative Patients

HIV阴性者的MAC肺病

               Responses for pulmonary MAC should be measured by negative sputum cultures. Since this is such a difficult disease to treat, as evidenced by Wallace et al. (51% sputum negative at 4 months), the approach to monitoring is similar to that for pulmonary tuberculosis (72). Symptomatic and radiologic improvement should be seen within 4 months. If it is not, individualized therapy decisions should be made on the basis of results of sputum culture and isolate susceptibility testing.

　　MAC肺病对治疗的反应一般用痰培养来衡量。由于治疗困难，如Wallace等人所报道（治疗4个月时痰培养转阴率仅51％），MAC肺病的疗效监测采用与肺结核类似的方法(72)。症状和影像学缓解应在治疗开始4个月内出现；若未出现，则个体化治疗的方案应依据痰培养和分离物药敏试验来制定。

               Given the prolonged duration of therapy for pulmonary and disseminated MAC , serial evaluations for the emergence of complications due to medications should be employed (4) [Table 4]. Monitoring should include visual acuity (ethambutol and rifabutin) (30), red-green color discrimination (ethambutol), liver enzymes (clarithromycin, azithromycin, rifabutin, rifampin, isoniazid, ethionamide) (12), auditory and vestibular function (streptomycin, amikacin, clarithromycin, azithromycin), renal function (streptomycin and amikacin), and leukocyte and platelet counts (rifabutin).

　　由于MAC肺病和播散感染的疗程很长，应对药物副反应进行持续监测(4)[表4]。监测指标应包含视力（乙胺丁醇、利福布丁）(30)，红绿分辨力（乙胺丁醇），肝酶（克拉霉素、阿奇霉素、利福布丁、利福平、异烟肼、乙硫异烟胺）(12)，听力和前庭功能（链霉素、阿米卡星、克拉霉素、阿奇霉素），肾脏功能（链霉素、阿米卡星），以及白细胞和血小板计数（利福布丁）。

               Ototoxicity due to streptomycin is often irreversible. Patients who receive both a macrolide and rifabutin must be monitored for the development of toxicity related to the interaction of these drugs. Clarithromycin enhances rifabutin toxicity (especially uveitis) (64) while the rifamycins, rifampin more than rifabutin, lower clarithromycin serum drug levels.

　　链霉素的耳毒性常常是不可逆的。同时接受大环内酯和利福布丁治疗的患者必须时刻警惕药物相互作用产生的毒性。克拉霉素可增加利福布丁的毒性（尤其是葡萄膜炎）(64)，而利福霉素和利福平（非利福布丁）则降低克拉霉素的血药浓度。

 

VACCINES Guided Medline Search

疫苗

               There are currently no vaccines in use against MAC. However, there is increasing interest to develop a vaccine against tuberculosis, which may provide immunity against MAC (19, 55). Mycobacterium tuberculosis, MAC, and other mycobacteria have homologous PPE and PE genomes that express proteins of unknown function, but believed to be related to virulence of the organism (42). Researchers have determined that a PE protein expressed by MAC is an effective T-cell immunogen in the mouse model (56). While these studies are promising, it has already been established that HIV infected patients have variable response rates to vaccines and loss of immunity as T-cell counts decline. This makes it unclear how effective a vaccine with activity against MAC would be for the severely immunocompromised HIV infected population at greatest risk for developing disseminated MAC.

　　目前尚无针对MAC的疫苗。结核疫苗的研发却引起广泛兴趣，该疫苗同时也可能对MAC感染具有保护效应(19,55)。结核分枝杆菌、MAC和其他分枝杆菌具有同源的编码未知功能蛋白（被认为与病原体毒力有关）的PPE和PE基因组(42)。研究者们发现，其中一种MAC表达的PE蛋白在小鼠模型中是一种有效力的T细胞免疫原(56)。尽管这方面的研究卓有成效，但事实表明HIV感染者对疫苗反应各异，且该免疫效应随T细胞数降低而丧失。这使得疫苗对重度免疫缺陷的HIV感染人群，即最可能发生MAC播散感染的人群的效果无法预测。

 

PREVENTION OR INFECTION CONTROL MEASURES CINES Guided Medline Search Smart search

预防或感染控制手段

Primary Antibiotic Prophylaxis

抗生素一级预防

               Prior to the introduction of macrolides, nearly 50% of AIDS patients developed disseminated MAC disease within two years of AIDS diagnosis. Primary prophylaxis against MAC disease in severely immunocompromised HIV positive patients is now the standard of care (5, 52). Prophylactic therapy is recommended in an effort to reduce the significant morbidity and mortality associated with disseminated MAC in HIV-positive individuals. Currently, the CD4 cell count is used as an indicator for the initiation of prophylactic therapy. Prophylaxis is indicated for patients with a CD4 count below 50 cells/mm3. Azithromycin 1200 mg once a week is the preferred first line regimen (54). Azithromycin's efficacy, long half life, weekly dosing, and its high concentration within intracellular compartments make it the preferred agent. GI intolerance is the most common adverse effect of the high dose of azithromycin. Alternative regimens include clarithromycin 1 gm daily (in two divided doses or 1000mg extended release formulation) or rifabutin 300 mg daily. Care must be taken to insure dose adjustments are made for any possible medication interactions especially with the use of rifabutin.

　　在大环内酯类出现之前，近50％艾滋病患者在确诊后两年内会发生MAC播散感染。对重度免疫缺陷者实施MAC一级预防是目前的标准治疗(5,52)。推荐预防性治疗的目的是减少HIV阳性者MAC播散感染的致病率和死亡率。目前，CD4细胞计数被作为判断预防性治疗起始的指标。CD4细胞低于50/uL时应开始预防性治疗；阿奇霉素1200mg每周一次是其首选方案(54)。阿奇霉素的良好药效、长半衰期、宽用药间隔和较高细胞内浓度使它成为理想的选择。胃肠道反应是大剂量阿奇霉素的最常见副作用。替代方案可选用克拉霉素每日1g（分两次服用或采用1000mg缓释制剂），或每日利福布丁300mg。应时刻小心可能存在的药物相互作用并适当调整剂量，尤其在使用利福布丁时。

               Prior to the initiation of MAC prophylaxis, symptomatic patients with unexplained fever, malaise, or cachexia should have blood cultures to rule out disseminated MAC infection. If there is a high clinical suspicion of disseminated MAC, the clinical should consider empiric combination therapy while awaiting final culture results. This strategy would prevent the emergence of resistance as the result of partial treatment with monotherapy.

　　在MAC预防性治疗起始前，有不明原因发热、不适或消瘦的患者应留取血培养以除外MAC播散感染。当临床高度怀疑已有MAC播散感染时，应开始经验性联合药物治疗，同时等待血培养结果。该策略可避免单药的不完全治疗，从而减少耐药性的产生。

               Several double blind, placebo controlled trials have investigated the optimal parameters for the discontinuation of primary MAC prophylaxis for patients who have increased CD4 cell counts with antiretroviral therapy in the absence of prior documented disease (17, 24). The conclusions in these studies were comparable. The current recommendations are that primary MAC prophylaxis in HIV infected patients whose CD4 cell count has been greater that 100 cells/mm3 for at least 3 months in response to antiretroviral therapy may discontinue the antimycobacterial therapy(ies).

　　对于那些尚未发生MAC感染，且ART后CD4细胞数升高的患者，若干双盲对照试验研究旨在找出停止MAC一级预防的最佳指征(17,24)。这些研究得到的结果相互吻合。目前的推荐是，当HIV感染者在ART后CD4细胞升高至超过100/uL并持续至少3个月时，MAC一级预防即可停止。

 

Infection Control Guided Medline Search 

感染控制

               Although MAC is found in environmental samples, there are currently no recommendations regarding avoidance of exposure.

　　虽然MAC被发现存在于环境标本中，但目前尚不推荐用减少暴露来控制感染。

 

TABLES

Table 1.  Diagnostic Criteria for Mycobacterium avium complex Pulmonary Disease [Download PDF]

Table 2.  Treatment and Prophylaxis of AIDS associated Mycobacterium avium complex disease [Download PDF]

Table 3.  Treatment of Mycobacterium avium complex Pulmonary Disease  [Download PDF]

Table 4.  Antimycobacterial Agents Commonly Used in the Treatment of MAC Infections [Download PDF]

 

 

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