巴尔通体 

 

Jane E. Koehler, M.D., David A. Relman, M.D.

 

译者：彭琳一 住院医师

      北京协和医院 内科

      Email: penglinyi@gmail.com

 

审阅者：曹玮 博士

        北京协和医院 内科

        Email: weic1981@gmail.com

 

GENERAL DESCRIPTION

总述  

Microbiology Guided Medline Search 

微生物学

               Bacteria belonging to the Bartonella genus are extremely fastidious, slow-growing gram-negative rods that are dependent on blood or blood products for growth.  There are currently sixteen known species of Bartonella, five of which have been isolated from humans:  B. henselae, B. quintana, B. elizabethae, B. bacilliformis and B. vinsonii subsp. arupensis.  Bartonella henselae, B. quintana, B. vinsonii and B. elizabethae were previously classified in the genus Rochalimaea and considered rickettsiae, but were moved to the genus Bartonella in 1993 (3).   

Berger S.  Emergence of Infectious Diseases into the 21st Century, 2008.

Cadena J, Anstead GM. Carrion's Disease, 2008.

    巴尔通体属的细菌为营养需求苛刻、生长缓慢的革兰氏阴性杆菌，它们依赖血液或血制品生存。现在已知16种巴尔通体，其中自人体分离得到5种：汉氏巴尔通体（B. henselae）、五日热巴尔通体（B. quintana）、伊丽莎白巴尔通体（B. elizabethae）、杆状巴尔通体（B. bacilliformis）和文氏巴尔通体arupensis亚种（B. vinsonii subsp. Arupensis）。汉氏巴尔通体、五日热巴尔通体、文氏巴尔通体和伊丽莎白巴尔通体曾一度被认为是立克次氏体，而归入罗卡利马体属，但在1993年被划分为巴尔通体属（3）。

Epidemiology Guided Medline Search 

流行病学

               Bartonellae alternate between two niches: the gut of obligately hematophagous arthropod vectors and the bloodstream of the mammalian reservoir (18).  Bartonella species usually have both arthropod and mammalian host specificity, e.g., the domestic cat is the host for B. henselae and the cat flea is the vector, whereas the human is believed to be the definitive reservoir for B. quintana and the body louse is the arthropod vector.  In one study of human immunodeficiency virus (HIV)-infected patients with concomitant Bartonella infection (22), patients with B. henselae infection were statistically significantly more likely to have a cat and to have received cat scratches, whereas those with B. quintana were homeless and had exposure to body lice.  B. henselae is now known to be the primary agent of cat scratch disease, and the cat serves as the reservoir and vector for transmission of the bacterium to humans.  It has become evident that numerous mammalian species have persistent bloodstream infection with their own cognate Bartonella species (2).

巴尔通体在两种宿主间交替寄生：嗜血节肢动物媒介的消化道和哺乳动物宿主的血液(18)。巴尔通体通常同时对节肢动物和哺乳动物宿主有特异性，例如家猫是汉氏巴尔通体的宿主，猫蚤则是其传播媒介，而人是明确的五日热巴尔通体贮存宿主，体虱是其节肢动物媒介。有关人免疫缺陷病毒（HIV）感染并发巴尔通体感染的研究发现（22），感染汉氏巴尔通体的患者家中养猫并被猫抓伤的几率显著增高，而并发五日热巴尔通体的患者多是具有体虱暴露的流浪者。已知汉氏巴尔通体是猫抓病的病原体，猫既为贮存宿主，也是向人传播病菌的媒介。已经证实，许多哺乳动物物种都有持续的相应巴尔通体属细菌的血液感染(2)。

Clinical Manifestations Guided Medline Search

临床表现

               The spectrum of disease caused by Bartonella species includes cat scratch disease (B. henselae), bacillary angiomatosis (B. henselae and B. quintana), bacillary peliosis (B. henselae), endocarditis (B. henselae, B. quintana, B. elizabethae), relapsing bacteremia (B. henselae and B. quintana), bacteremia (B. vinsonii subsp. arupensis), trench fever (B. quintana), Oroya fever (B. bacilliformis) and verruga peruana (B. bacilliformis) (17).  Infections occur in both immunocompromised and immunocompetent individuals, but the manifestations and response to treatment are dramatically different, depending on the immune status of the patient.  Cat scratch disease, a benign, self-limited granulomatous lymphadenitis caused by B. henselae, occurs in immunocompetent individuals.  The primary cat scratch disease lesion occurs at the site of a cat scratch, 3-10 days after the inoculation.  Lymphadenopathy develops two weeks after the scratch and regresses spontaneously over the ensuing 2-4 months (26).  

巴尔通体病菌引起的疾病谱包括猫抓病 (汉氏巴尔通体)、杆菌性血管瘤病 (汉氏巴尔通体和五日热巴尔通体)、杆菌性紫癜(汉氏巴尔通体)、心内膜炎 (汉氏巴尔通体、五日热巴尔通体和伊丽莎白巴尔通体)、复发菌血症(汉氏巴尔通体和五日热巴尔通体)、菌血症 (文氏巴尔通体arupensis亚种), 战壕热 (五日热巴尔通体), 奥罗亚热(杆状巴尔通体) 和秘鲁疣 (杆状巴尔通体) (17)。免疫功能低下者与正常者均可发生感染，但其临床表现及治疗反应随着患者的免疫状态而截然不同。猫抓病为汉氏巴尔通体引起的良性、自限性肉芽肿性淋巴结炎，发生于免疫功能正常的个体。原发猫抓病病损于伤后3到10天出现于抓伤部位。淋巴结病变在抓伤后2周发生，2到4个月可自行消退(26)。

               Bacillary angiomatosis and bacillary peliosis are vascular proliferative manifestations of Bartonella infection that occur in immunocompromised patients (35), especially those co-infected with HIV.  Bacillary angiomatosis infections occur most commonly late in HIV infection; in one series, the median CD4 cell count of patients at the time of bacillary angiomatosis diagnosis was 22/mm3 (29).  B. quintana and B. henselae cause bacillary angiomatosis;  these lesions are usually noted in the skin, but also can occur in the brain, bones, subcutaneous tissues, lymph nodes, gastrointestinal and respiratory tracts.  Peliosis is a closely related vascular proliferative lesion caused by B. henselae infection in the liver and spleen of immunocompromised patients (31).  More than half of patients with focal bacillary angiomatosis are bacteremic with the corresponding Bartonella species, emphasizing the systemic nature of this disease (21).  

杆菌性血管瘤病和杆菌性紫癜，是免疫力低下患者（尤其是HIV感染患者）感染巴尔通体时血管增殖的表现（35）。杆菌性血管瘤病最常见发生于HIV感染晚期，某一队列中确诊杆菌性血管瘤病时的CD4细胞中位数为22/mm3（29）。五日热巴尔通体和汉氏巴尔通体引发杆菌性血管瘤病，其病损通常见于皮肤，但脑、骨、皮下组织、淋巴结、胃肠道和呼吸道均可受累。杆菌性紫癜是免疫功能低下者肝脾内的汉氏巴尔通体感染而导致的血管增殖性病变（31）。超过半数的局灶性杆菌性血管瘤患者有菌血症，说明该疾病具有全身受累倾向（21）。

               B. bacilliformis infections occur exclusively in South America, most commonly in the Peruvian Andes at an altitude of between 2,500 and 8,000 feet (45).  The acute infection, Oroya fever, can cause a severe, potentially fatal hemolytic anemia that is often followed by a chronic phase, verruga peruana, or Peruvian warts (11).  These cutaneous lesions may be clinically indistinguishable from those of bacillary angiomatosis and persist for months to years, causing few symptoms.   

    杆状巴尔通体感染只发生在南美洲，在秘鲁的安迪斯山脉海拔2500到8000英尺高度间最为常见（45）。急性感染引起的奥罗亚热，可能导致严重的溶血性贫血，可能致命，随后常发展为慢性阶段的秘鲁疣（11）。这些皮肤感染临床上可能很难与杆菌性血管瘤区分，常持续数月至数年，很少引发症状。

               The Bartonella infections most frequently encountered by physicians in the United States and Europe are bacillary angiomatosis and cat scratch disease (the latter is by far the more common, with greater than 22,000 cases annually in the United States (14)).  Treatment of bacillary angiomatosis has not been studied prospectively or systematically.  The aggregate of anecdotal cases of cat scratch disease treatment do not demonstrate clearly that treatment affects outcome, and virtually all patients recover fully regardless of whether they receive antibiotic treatment or not.  In contrast, bacillary angiomatosis and bacillary peliosis can be fatal if not treated (7), and the response to antibiotic treatment is often dramatic.  This difference in treatment response may be due to the number of Bartonella bacilli present in lesions (fewer in cat scratch disease, more numerous in bacillary angiomatosis) or the immune status of the infected individual, or both.  

Maman E, et al. Musculoskeletal manifestations of cat scratch disease. Clin Infect Dis. 2007 Dec 15;45(12):1535-40.

Breitschwerdt EB, et al.  Bartonella sp. Bacteremia in Patients with Neurological and Neurocognitive Dysfunction.  J Clin Microbiol 2008;46:2856-2861.

    美国和欧洲的医生们最常见的巴尔通体感染是杆菌性血管瘤病和猫抓病（后者更为普遍，美国每年超过22000例（14））。对于杆菌性血管瘤病的治疗尚缺乏前瞻的、系统的研究。病例报告的总结并未明确表明对猫抓病的治疗能影响预后，实际上不管是否接受抗生素治疗，所有病人都会完全康复。与之相反，杆菌性血管瘤病和杆菌性紫癜如不治疗有死亡的风险（7），且抗生素治疗效果显著。这种治疗应答的差异很可能与病损处的巴尔通体杆菌数量（猫抓病数量较少，杆菌性血管瘤病数目远远超过前者）或感染者免疫状态有关。

Laboratory Diagnosis Guided Medline Search  

实验室诊断

               Focal Bartonella infection (cat scratch disease, bacillary angiomatosis) can be diagnosed from biopsied tissue samples using the Warthin-Starry silver stain.  Bartonella species can be isolated from human blood (EDTA (4) or Wampole isolator tubes (37)) and tissue using solid agar containing blood or using endothelial cell co-cultivation (21, 24).  However, these methods are too laborious for most diagnostic microbiology laboratories.  The indirect fluorescence antibody test (9) provides a more accessible means of diagnosing Bartonella infections.  This test is performed at the U.S. Centers for Disease Control and Prevention and at some U.S. State Public Health laboratories.

    通过对组织切片进行Warthin-Starry银染，可诊断局灶性巴尔通体感染（猫抓病、杆菌性血管瘤病）。可自人血液（EDTA（4）或Wampole分离管（37））及组织中分离出巴尔通体菌，其中组织分离可采用含血的固体琼脂或用内皮细胞联合培养（21、24）实现。然而，这些手段对于大多数诊断性微生物学实验室来说难度较大。间接荧光抗体检测（9）为诊断巴尔通体感染提供了更可行的方法。这一检测已用于美国疾病控制预防中心和一些美国州立公共卫生实验室。

Pathogenesis Guided Medline Search  

致病机理

               Very little is known about the pathogenesis of nce in host response between immunocompromised and immunocompetent humans to Bartonella infection.  Patients with immunocompromise develop BA whereas patients with normal immune function develop a granulomatous response devoid of vascular proliferation.  Finally, it was recently demonstrated in an animal model (36) that the Bartonella bacilli circulate within red blood cells (RBC) for prolonged periods of time, but the mechanism of RBC entry and persistence has not been determined.  

[Mege JL, Meghari S, Honstettre A, Capo C, Raoult D.  The Two faces of interleukin 10 in human infectio Guided Medline Searchus diseases.  Lancet Infectious Diseases 2006:7;557-569.]

    目前对于巴尔通体感染免疫功能低下和正常人群的宿主应答发病机制所知甚少。免疫功能低下患者发生杆菌性血管瘤，而免疫功能正常者产生肉芽肿性应答来避免血管增殖。最近在动物模型（36）中证实了巴尔通体杆菌通过在红细胞（RBC）内循环以延长生存时间，但其进入红细胞并存活的机制尚不明确。

Susceptibility in vitro and in vivo Guided Medline Search In Vitro and In Vivo 

体外及体内的药物敏感性 

In Vitro Susceptibilities 

体外药物敏感性

               As for many other fastidious organisms, in vitro susceptibility testing for Bartonella species is not standardized.  Additionally, there is a striking discrepancy between some of the in vitro and in vivo antibiotic susceptibility patterns obtained for Bartonella species.  This discrepancy is especially notable for antibiotics that affect cell wall synthesis, e.g., penicillins.  Most in vitro susceptibility testing reveals MIC90 values of approximately <0.05 µg/ml for penicillin (27), yet clinical failures and even dramatic disease progression have been frequently noted during treatment with this drug (20, 23).  The clinical utility of MICs derived from in vitro susceptibility testing has therefore not been established, and we do not recommend routine susceptibility testing of Bartonella isolates to guide patient therapy.

    与其他多种难以培养的生物一样，对巴尔通体菌种的体外药物敏感性并无标准化测定方法。此外，已知的巴尔通体杆菌对某些抗生素的体外或体内药物敏感性类型有显著差异。这一差异对那些影响细胞壁合成的抗生素尤其明显，如青霉素类。多数体外药物敏感性检测显示巴尔通体杆菌对于青霉素MIC90值约<0.05µg/ml（27），但该药治疗往往出现临床失败甚至显著的病程进展（20、23）。因此，通过体外药物敏感性检测得到的MICs并未确立其在临床中的应用，我们不推荐根据巴尔通体菌分离株的体外药物敏感性检测来指导治疗。 

               The earliest in vitro susceptibility testing for Bartonella species was reported by Myers et al. in 1984 (30).  They tested two B. quintana strains, the Fuller strain (type strain ATCC VR358) and Heliodoro strain using the agar dilution method (antibiotics diluted with agar composed of GC agar base with IsoVitaleX supplementation).  They found a MIC50/MIC90 for penicillin of 0.024/0.035 µg/ml and 0.024/0.044 µg/ml for the 2 strains, respectively.  The Fuller and Heliodoro strains were susceptible to erythromycin (MIC50/MIC90 0.026/0.036 µg/ml and 0.033/0.040 µg/ml, respectively), doxycycline (MIC50/MIC90 0.021/0.036 µg/ml and 0.095/0.115 µg/ml) and tetracycline (MIC50/MIC90 0.040/0.068 µg/ml and 0.35/0.82 µg/ml). Maurin and colleagues (27) reported MICs for 28 antibiotics with 14 Bartonella isolates, also using an agar dilution method, but using Columbia agar supplemented with 5% horse blood.  They also observed susceptibility to penicillin G (MIC90 range of 0.015-0.06 µg/ml) for all Bartonella species:  B. quintana (9 strains), B. vinsonii (1), B. elizabethae (1) and B. henselae (3).  All 14 Bartonella species and strains tested were susceptible to erythromycin, doxycycline and rifampin.  Additionally, they noted susceptibility of all Bartonella isolates to azithromycin and clarithromycin.  Sobraques et al. (38) tested the in vitro susceptibility of four strains of B. bacilliformis and found similar susceptibilities to other Bartonella species, including susceptibility to erythromycin (MIC 0.06 µg/ml), azithromycin (MIC 0.015 µg/ml), clarithromycin (MIC 0.015 to 0.03 µg/ml), doxycycline (MIC 0.03 to 0.06 µg/ml), rifampin (MIC 0.003 µg/ml) and streptomycin (MIC 4 µg/ml). In another study, the susceptibility of B. henselae and B. quintana to five macrolides was tested using in vitro cultivation with Vero cell monolayers:  all five macrolide antibiotics demonstrated activity against both these Bartonella species (13).  All human Bartonella isolates tested to date have been susceptible in vitro to erythromycin and tetracycline except one that was resistant to erythromycin on one testing (MIC >256 µg/ml), but on retesting was susceptible (MIC 0.06 µg/ml) (8).  A subsequent relapse isolate from the same patient also was susceptible at an MIC of 0.06 µg/ml.  

    1984年，Myers等人发表了有关巴尔通体杆菌体外药物敏感性检测的最早报告（30）。他们利用琼脂稀释法（用含有GC琼脂和IsoVitaleX添加剂的琼脂稀释抗生素），检测了两株五日热巴尔通体，Fuller株（菌株号ATCC VR358）和Heliodoro株。他们发现两株菌对于青霉素的MIC50/MIC90分别为0.024/0.035µg/ml和0.024/0.044 µg/ml。Fuller和Heliodoro菌株对红霉素（MIC50/MIC90分别为0.026/0.036µg/ml和0.095/0.115 µg/ml）、多西环素（MIC50/MIC90 0.021/0.036 µg/ml和0.095/0.115 µg/ml）及四环素（MIC50/MIC90 0.040/0.068 µg/ml和0.35/0.82 µg/ml）均敏感。Maurin及其同事（27）报道了14株巴尔通体分离株对28种抗生素的MIC值，他们也使用了琼脂稀释法，但所用的是添加5%马血的Columbia琼脂。他们也观察到所有的巴尔通体菌（五日热巴尔通体（9株）, 文氏巴尔通体 (1), 伊丽莎白巴尔通体(1) 和汉氏巴尔通体 (3)）都对青霉素G敏感（MIC90范围在0.015到0.06µg/ml之间）。检测的所有14株巴尔通体都对红霉素、多西环素和利福平敏感。此外，还发现所有巴尔通体菌株都对阿奇霉素和克拉霉素敏感。Sobraques等人（38）检测了4株杆状巴尔通体的体外药物敏感性，其敏感性与其他巴尔通体相似，对红霉素（MIC 0.06 µg/ml）、阿奇霉素（MIC 0.015 µg/ml）、克拉霉素（MIC 0.015至0.03 µg/ml）、多西环素（MIC 0.03至0.06 µg/ml）、利福平（MIC 0.003 µg/ml）和链霉素（MIC 4 µg/ml）均敏感。另一研究使用Vero单层细胞体外培养的方法检测了汉氏巴尔通体和五日热巴尔通体对五种大环内酯类的敏感度，发现五种大环内酯类抗生素对这些巴尔通体杆菌均有活性（13）。迄今为止，所有感染人类的巴尔通体杆菌都对红霉素和四环素敏感，仅有一株在一次体外检测中对红霉素耐药（MIC>256µg/ml），但重复检测时仍为敏感（MIC 0.06 µg/ml）（8）。同一病人中复发菌株仍敏感，其MIC为0.06µg/ml。

               The E-test (AB Biodisk, Solna, Sweden) was utilized to test the erythromycin, azithromycin, doxycycline, ciprofloxacin, rifampin and vancomycin susceptibilities of 10 B. henselae isolates grown on chocolate agar (47).  The susceptibilities for doxycycline, erythromycin, azithromycin and rifampin correlated with those from agar dilution methods.  Use of E-test strips with Bartonella isolates streaked on fresh chocolate agar is the susceptibility testing method most accessible to a clinical microbiology lab, and may be useful in the specific situation of comparing initial and relapse isolates for changes in susceptibility.  Susceptibility testing with combination drugs has not been performed.

    使用E-检测(AB Biodisk, Solna, Sweden)测试10株由巧克力琼脂培养的汉氏巴尔通体对红霉素、阿奇霉素、多西环素、环丙沙星、利福平和万古霉素的敏感性（47）。其中对多西环素、红霉素、阿奇霉素和利福平的敏感性与琼脂稀释法所得的结果类似。使用E测试试纸条检测新鲜巧克力琼脂上的巴尔通体菌落，是最适用于临床微生物实验室的敏感性检测方法，并可用于比较初发及复发病原体的敏感性差异。联合用药的敏感性检测尚未开展。 

In Vivo Susceptibilities 

体内药物敏感性

               Animal data substantiate the role of macrolides or a tetracycline in the treatment of Bartonella infection.  Regnery and colleagues experimentally infected 25 cats with B. henselae and then treated groups of 5 cats for two weeks with one of four different antibiotics: tetracycline, amoxicillin, erythromycin or enrofloxacin, a fluoroquinolone (34).  They cultured the blood of each animal at intervals after experimental infection, and determined that only tetracycline or erythromycin treatment resulted in a significant decrease in the titer of B. henselae bacilli in the blood at any time during the period after infection.  There were no significant differences among the four antibiotics with regard to the apparent frequency at which bacteremia resolved.  However, the duration of bacteremia did differ: bacteremia resolved at day 71 for tetracycline- and erythromycin-treated cats, at day 83 for control cats and at days 98 and 127 for those treated with enrofloxacin and amoxicillin, respectively. 

    动物数据证实大环内酯类或四环素在治疗巴尔通体感染中的作用。Regnery及同事用汉氏巴尔通体试验性感染了25只猫，以5只猫为一组，使用四环素、阿莫西林、红霉素或恩氟沙星（氟喹诺酮）等四种不同抗生素之一治疗2周（34）。试验性感染后，他们定期培养每只猫的血液，发现只有四环素或红霉素治疗能显著降低感染后病程中任意时间点汉氏巴尔通体的血液滴度。观察发现4种抗生素对菌血症的治愈率没有明显差别。然而，菌血症的持续时间有所差别：四环素和红霉素治疗的猫，治愈菌血症需要71天；对照组需要83天；恩氟沙星和阿莫西林组分别需要98天和127天。

Antimicrobial therapy Guided Medline Search  

抗生素治疗

Bartonella Infection in the Immunocompromised Patient 

免疫功能低下患者的巴尔通体感染

Bacillary Angiomatosis and Bacillary Peliosis:  Stoler et al. described the first patient with bacillary angiomatosis in 1983, and although neither the disease had been named nor the infecting bacillus identified, they treated the patient successfully with erythromycin (41).  In 1987, we treated the cutaneous and osseous bacillary angiomatosis lesions of the first prospectively identified patient at San Francisco General Hospital with erythromycin; the lesions resolved completely (20).  We have now treated more than 65 patients with biopsy-proven bacillary angiomatosis, and from our experience and from reviewing the published literature on treatment of anecdotal bacillary angiomatosis cases (summarized in (23) and (28)), either one of two drugs can be confidently recommended for first line therapy:  erythromycin or doxycycline.  The response to treatment appears to be equivalent whether erythromycin or doxycycline is prescribed and whether the bacillary angiomatosis is caused by B. henselae or B. quintana.   

杆菌性血管瘤病和杆菌性紫癜：Stoler等人于1983年描述了首例杆菌性血管瘤病病人，尽管当时既没有命名这一疾病也没有鉴定出病原体，但他们成功地利用红霉素（erythromycin）治疗了患者（41）。1987年我们在旧金山总医院用红霉素治疗了首例皮肤和骨受累的杆菌性血管瘤病患者，病变彻底痊愈（20）。我们现已治疗了超过65例活检证实的杆菌性血管瘤病患者，根据我们的经验并综合已发表的经验性治疗杆菌性血管瘤病例的文献（总结见(23)和(28)），红霉素或多西环素（doxycycline）中的任意一种都可推荐为有效的一线治疗。无论是使用红霉素或多西环素，也无论是由汉氏巴尔通体或五日热巴尔通体引起的杆菌性血管瘤病，其治疗反应等同。

               For treatment of Bartonella infection in the immunocompromised patient, the drug of first choice is either erythromycin 500 mg Q6H PO or IV, or doxycycline 100 mg Q12H PO or IV.  We usually initiate therapy for bacillary angiomatosis with oral erythromycin, but favor oral doxycycline over erythromycin in several situations:  when poor patient compliance dictates twice daily dosing, to achieve potentially superior CNS antibiotic delivery for focal CNS Bartonella infection, or when severe gastrointestinal symptoms are present that could be exacerbated by oral erythromycin therapy.  Rifampin also appears to have in vivo activity in patients with bacillary angiomatosis lesions, but because in general, bacteria spontaneously develop rifampin resistance at a high rate, we do not recommend use of this antibiotic alone.  

    治疗免疫力低下患者巴尔通体感染的首选药物为红霉素500mg Q6H 口服或静注，或多西环素100 mg Q12H口服或静注。起始治疗杆菌性血管瘤病常使用口服红霉素，但在几种情况下更优选口服多西环素而不是红霉素，即当患者依从性不佳需要每日两次用药时、为实现较高的CNS药物浓度以治疗局灶性CNS巴尔通体感染，或口服红霉素会加重已有的严重胃肠道症状时。利福平也对杆菌性血管瘤病具有体内活性，但由于细菌自发产生利福平抗性的几率很高，不推荐单独使用该抗生素。

               Combination therapy, with the addition of rifampin to either erythromycin or doxycycline is recommended for immunocompromised patients with acute, life-threatening Bartonella infection, including bacillary peliosis, endocarditis or CNS disease.  Failure to respond to antibiotic treatment after 7-10 days should prompt change of drug therapy to the other first line drug, addition of rifampin, change of route of antibiotic administration to intravenous, or all of these.  The intravenous route is especially important in those patients with severe Bartonella infection of the gastrointestinal tract who may have inadequate absorption of the antibiotic and symptom exacerbation by oral erythromycin therapy.   

对于免疫功能低下患者的急性的危及生命的巴尔通体感染，包括杆菌性紫癜、心内膜炎或中枢神经系统疾病，推荐使用红霉素或多西环素加利福平的联合治疗。若抗生素治疗7－10天后无效，应更换另一种一线药物加利福平，换为静脉途径给药或静脉加口服给药。静脉途径给药对于胃肠道有严重巴尔通体感染者尤其重要，这些患者可能抗生素吸收不佳或口服红霉素导致症状加重。

               Penicillins and first generation cephalosporins lack efficacy and should not be used to treat Bartonella infection in immunocompromised patients (20, 23).  Although some anecdotal reports describe a response of Bartonella infection to ciprofloxacin, we have observed progression of bacillary angiomatosis lesions in patients treated with ciprofloxacin (43).  In addition, we have isolated Bartonella species from immunocompromised patients treated with gentamicin or trimethoprim/sulfamethoxazole and would therefore not recommend treatment of patients with bacillary angiomatosis infection with either of these antibiotics.  

青霉素类和一代头孢菌素疗效欠佳，不推荐用于治疗免疫功能低下者巴尔通体感染（20, 23）。尽管一些经验性研究报道巴尔通体感染对环丙沙星（ciprofloxacin）敏感，但我们曾观察到环丙沙星治疗巴尔通体感染病情加重的情况（43）。此外，我们也从用庆大霉素或甲氧苄氨嘧啶/磺胺甲基异噁唑治疗后的免疫抑制患者体内分离出巴尔通体菌，因此也不推荐使用这几种抗生素治疗杆菌性血管瘤病感染患者。

               It is evident that the majority of patients with cutaneous bacillary angiomatosis have systemic disease, and a short duration of treatment is frequently associated with relapse.  At least three months antibiotic treatment is recommended for patients with cutaneous bacillary angiomatosis, and four months for patients with bacillary peliosis (23).  For patients with bacillary angiomatosis of the bone or CNS, treatment should continue for at least four months.  After discontinuation of antibiotic therapy, patients should be monitored carefully for relapse of Bartonella infection in the same organ or at a new site.  If relapse occurs, the patient should receive treatment and lifelong secondary prophylaxis with either doxycycline or a macrolide (15).  

显然，大多数皮肤杆菌性血管瘤病患者具有全身疾病，短期治疗经常复发。推荐皮肤杆菌性血管瘤病患者至少接受3个月的抗生素治疗，而杆菌性紫癜患者需至少4个月（23）。骨或CNS杆菌性血管瘤病患者应至少进行4个月治疗。停止抗生素治疗后，应密切监视病人同一器官或新部位巴尔通体感染的复发。如果复发，病人应该接受治疗并终生使用多西环素或大环内酯类抗生素进行二级预防 (15)。

Alternative Therapy

其他治疗方案

               For patients unable to tolerate erythromycin or doxycycline, alternative antibiotics include minocycline (100 mg PO Q12H), used to treat bacillary angiomatosis successfully in an immunocompetent adult (44) or tetracycline (500 mg PO Q6H), used to treat an HIV-infected patient with bacillary angiomatosis successfully (21).  There also is very limited experience with azithromycin; this antibiotic could be considered if a patient is incapable of complying with BID doxycycline. Azithromycin (500 mg PO Q24H) for 28-90 days was used to treat five of the ten immunocompetent patients with B. quintana bacteremia reported by Spach et al. (40), and one immunocompromised patient with bacillary angiomatosis was successfully treated with 1 gm PO Q24H (12).  

    对于不能耐受红霉素或多西环素的患者而言，备选抗生素包括米诺环素（100 mg PO Q12H）(曾成功治疗免疫功能低下成人的杆菌性血管瘤病（44）)，或四环素(500 mg PO Q6H)（曾成功治疗HIV感染患者的杆菌性血管瘤病（21））。使用阿奇霉素的经验很有限；当病人无法执行每日两次多西环素治疗时可考虑使用。Spach等人报道了阿奇霉素(500 mg PO Q24H)使用28－90天以治疗免疫功能正常患者的五日热巴尔通体菌血症（40），10名患者中治愈5人。他们还用1 gm PO Q24H剂量的阿奇霉素成功治愈了1例免疫功能低下患者的杆菌性血管瘤病（12）。

Bartonella Infection in the Immunocompetent Patient 

免疫功能正常患者的巴尔通体感染

Uncomplicated Cat Scratch Disease:  The only prospective, double-blind, placebo-controlled study of treatment of immunocompetent patients with uncomplicated cat scratch disease was reported by Bass et al (1).  They treated patients with 5 days of azithromycin or placebo and found no statistically significant difference between the two groups in the duration of lymphadenopathy.  However, they did find a statistically significant difference between the number of patients achieving 80% reduction of lymph node volume (by sonography) at 30 days after initiation of treatment in the azithromycin group.  Because the natural course of cat scratch disease is relatively benign, self-limited and extremely variable, the data for treating uncomplicated CSD are not currently compelling.  More important, as antibiotic resistance of many bacteria is increasing dramatically, treatment of uncomplicated cat scratch disease does not appear to be justified either from the standpoint of the individual patient who is likely to experience little benefit yet would be exposed to potential antibiotic side effects, or from a public health standpoint.   

无并发症的猫抓病：Bass等人报道了免疫功能正常患者中无并发症的猫抓病治疗的唯一一个前瞻、双盲、安慰剂对照的研究（1）。他们用阿奇霉素或安慰剂治疗患者5天，发现两组间淋巴结病的持续时间没有统计学显著差异。然而，在阿奇霉素治疗开始30天后，两组内淋巴结体积缩小80%（超声检查）的病人数量有明显的统计学差异。因为猫抓病的自然病程相对良性、自限且多变，对无并发症的猫抓病进行治疗的意义很有限。更重要的是，细菌的对抗生素耐药性正在显著增加，对无并发症的猫抓病进行治疗似乎缺乏其合理性，从患者个人角度而言有可能收益甚小却面临潜在的抗生素副作用，从公共卫生角度而言也缺无益处。

Complicated Cat Scratch Disease:  Retinitis, CNS Infection and Granulomatous Hepatitis: Treatment of complicated cat scratch disease, including retinitis, granulomatous hepatitis and encephalitis with a number of different antibiotics has been reported by a number of authors.  As with cat scratch disease, however, it is not clear that antibiotics have any efficacy in the treatment of these manifestations in immunocompetent patients.  Wong et al. (48) report one patient with stellate neuroretinitis from whose blood B. henselae was isolated.  However, despite receiving doxycycline and rifampin for one month and experiencing resolution of ophthalmologic symptoms, B. henselae could still be cultured from the blood of this patient.  Many clinicians elect to administer oral antibiotics to patients with visual impairment or to give intravenous antibiotics to those ill enough to require hospitalization.  Clinical experience with doxycycline and rifampin in immunocompromised patients makes this combination a reasonable choice if treatment of these immunocompetent patients is elected.  

有并发症的猫抓病：视网膜炎、中枢神经系统感染及肉芽肿性肝炎：很多作者报道了利用多种不同抗生素治疗猫抓病并发症，包括视网膜炎、肉芽肿性肝炎和脑炎。然而，和猫抓病一样，尚不明确抗生素对于免疫功能正常患者这些症状是否有效。Wong等人(48)报道了一例星芒状视神经视网膜炎患者，其血液中可以分离到汉氏巴尔通体菌株。然而，虽然该患者接受了一个月的多西环素和利福平的治疗后眼部症状得以缓解，其血液中仍能培育出汉氏巴尔通体。许多临床医师选择口服抗生素治疗视觉受损患者，或静脉抗生素治疗需要住院的患者。应用多西环素和利福平治疗免疫功能低下患者得到的临床经验是使用这个组合于免疫功能正常者的主要根据。

Relapsing Bacteremia:  Clinical experience with treatment of isolated Bartonella bacteremia also is limited.  Historically, soldiers with B. quintana relapsing bacteremia (trench fever) during World War I cleared the infection in the absence of antibiotic treatment.  In contemporary times, one immunocompetent patient with B. henselae bacteremia and meningitis was treated with amoxicillin for five days, then doxycycline for two weeks, and finally ceftriaxone for ten days, but had positive blood cultures for the subsequent six weeks, despite resolution of symptoms (25).  Although treatment did not eliminate the bacteremia in this patient, patients with Bartonella bacteremia should be treated, probably with doxycycline for 2-4 weeks.  An important caveat should be kept in mind:  the patient must first be evaluated carefully for endocarditis because this will change the duration and follow-up of antibiotic treatment.  

复发性菌血症：对于独立的巴尔通体菌血症的治疗经验十分有限。一战期间，患有五日热巴尔通体复发性菌血症（战壕热）的士兵在没有抗生素治疗情况下也能清除感染。在当代，患有汉氏巴尔通体菌血症和脑膜炎的免疫功能正常患者，用阿莫西林治疗5天，再以多西环素治疗2周，最后经头孢曲松治疗10天，虽然其症状缓解，但其后6周内血培养仍为阳性（25）。尽管治疗没有清除该患者的菌血症，但巴尔通体菌血症的患者应接受治疗，可以用多西环素治疗2-4周。不过，首先应仔细评估患者是否具有心内膜炎，因为这会影响抗生素治疗的持续时间和随访。

Endocarditis:  Spach et al. (39) described four patients with Bartonella endocarditis, all of whom received antibiotic therapy with multiple drugs, three of whom had valve replacement and all of whom were cured.  The one patient who did not require valve replacement received treatment with ceftriaxone, doxycycline and erythromycin.  The other three patients who required valve replacement did not receive treatment with a first line antibiotic against Bartonella species prior to valve replacement, and whether surgery was required due to ineffective antibiotic treatment or the natural course of Bartonella endocarditis in these three patients is not known.  In these three patients, valve replacement may have been curative. 

心内膜炎：Spach等人（39）描述了4例巴尔通体心内膜炎病例，他们都接受了多种抗生素的治疗，其中3人进行了瓣膜置换，都获得了痊愈。没有进行瓣膜置换的患者接受了头孢曲松、多西环素和红霉素的治疗。其他3位需要瓣膜置换的患者在置换前没接受巴尔通体一线抗生素治疗，且没有明确说明手术的必要性是由于这3人的抗生素治疗无效还是其巴尔通体心内膜炎的自然病程所致。对于这3名患者而言，瓣膜置换是有疗效的。

               In a series of 33 Bartonella endocarditis patients (32), only one surviving patient did not require valve replacement, and this patient was treated with ceftriaxone and doxycycline.  The remainder of the patients received numerous other antibiotics before and after valvular surgery.  B. henselae was isolated from one patient after completion of a course of amoxicillin and gentamicin, and we have isolated Bartonella species from a patient receiving similar treatment.  Thus, the culture-negative endocarditis regimen using gentamicin plus penicillin or amoxicillin is unlikely to treat Bartonella endocarditis adequately.  Patients with Bartonella endocarditis should receive six weeks of antibiotic therapy, probably with two drugs (doxycycline plus rifampin or erythromycin plus rifampin), because neither first line drug is bactericidal.  

    在对33个巴尔通体心内膜炎患者的研究中（32），仅有一名存活患者没有进行瓣膜置换，而该患者接受了头孢曲松和多西环素的治疗。其他病人在瓣膜手术前后接受了其他多种抗生素的治疗。一名患者在完成一个阿莫西林和庆大霉素疗程后，仍能分离出汉氏巴尔通体；我们也从接受类似治疗的患者体内分离出巴尔通体菌。因此，使用庆大霉素加青霉素或阿莫西林的方案似乎不能用于治疗巴尔通体心内膜炎。巴尔通体心内膜炎患者应接受6周的抗生素治疗，由于一线药物均不杀菌，很可能需要两种药物（多西环素加利福平或红霉素加利福平）。

Oroya Fever and Verruga Peruana:  Antibiotic treatment of patients infected with B. bacilliformis has been documented to decrease the morbidity and mortality associated with both acute and chronic stages of infection with this pathogen.  Mortality due to Oroya fever was estimated to be 40% prior to the era of antibiotics and is now estimated to be approximately 8% (11).  Some patients who survive the acute anemia succumb to intercurrent infection with intracellular pathogens such as Salmonella, Toxoplasma and Mycobacterium because of an immunodeficient state that may develop during Oroya fever (11).  Thus, although penicillin treatment can attenuate the lysis of erythrocytes during the acute phase, patients in the endemic regions of South America often are treated with chloramphenicol to reduce the mortality from intercurrent Salmonella infection.  Antibiotic treatment of Oroya fever may not prevent subsequent development of verrugae (45), and once verruga peruana develops, the currently favored treatment is streptomycin (38).  Macrolides have also been used successfully, but with much less experience (38).  

奥罗亚热和秘鲁疣：抗生素治疗杆状巴尔通体感染患者，可减轻该病原感染的急性或慢性期的病情和降低死亡率。在没有抗生素的年代，奥罗亚热的致死率约为40%，而现在约为8%（11）。一些病人度过了急性贫血期，但死于其他胞内生长的病原体如沙门氏菌、弓形虫及分枝杆菌并发感染，这是由于奥罗亚热可能导致免疫缺陷状态（11）。虽然青霉素治疗能减少急性期红细胞的裂解，在南美区域患者常用氯霉素（chloramphenicol）治疗以防并发沙门氏菌感染。抗生素治疗奥罗亚热可能并不能预防随后的秘鲁疣（45），而一旦出现秘鲁疣，目前优选使用链霉素治疗（38）。大环内酯类也有成功的病例，但其使用经验较少（38）。

Bartonella elizabethae:  Only one human infection with B. elizabethae has been reported, in a patient with endocarditis (10).  This patient defervesced during treatment with nafcillin and gentamicin but developed progressive congestive heart failure and required valve replacement.    

伊丽莎白巴尔通体：迄今为止仅报道了一例伊丽莎白巴尔通体人类感染病例，为心内膜炎患者（10）。该患者接受奈夫西林（nafcillin）和庆大霉素治疗后体温正常，但发生了进行性充血性心力衰竭，需要进行瓣膜置换。

Bartonella vinsonii subsp. Arupensis:  This species has been isolated from only one human, a cattle rancher, with bacteremia and fever (46).  The patient defervesced after a single dose of ceftriaxone and did not appear to have endocarditis by cardiac echocardiography. 

文氏巴尔通体 Arupensis亚种：仅自一名家畜饲养员中分离出该菌，表现为菌血症和发热（46）。该病人接受单剂头孢曲松后体温即正常，超声心动图没有发现心内膜炎。

(Printable Version of Antimicrobial Therapy for  Bartonella)

ADJUNCTIVE THERAPY Guided Medline Search  

辅助治疗

               The majority of patients with Bartonella endocarditis require valve replacement, in addition to antimicrobial therapy.  However, the contribution of valve replacement to the cure of Bartonella infection has not been studied prospectively, and most patients reported in the literature received no treatment or were treated with an inadequate regimen before diagnosis of Bartonella endocarditis.

大多数巴尔通体心内膜炎病人除了抗菌治疗外还需要瓣膜置换。然而，有关瓣膜置换治疗巴尔通体感染的作用尚无前瞻性研究，而文献中报道的绝大多数病例是在确诊为巴尔通体心内膜炎之前并未接受治疗或者治疗不得当。 

Endpoints for monitoring therapy Guided Medline Search  

治疗监控的终点  

               Patients with cutaneous bacillary angiomatosis lesions should be evaluated for presence of Bartonella infection at other sites that would alter therapy duration, e.g., for osseous lesions or endocarditis.  Cutaneous lesions usually improve in the first several weeks of antibiotic therapy and resolve completely in one to two months, depending on the size and number of lesions.  Patients with peliosis hepatitis can be monitored by abdominal CT scanning, and those with osseous lesions by 99mtechnetium bone scans.  Patients in whom antibiotic therapy has been stopped should be followed closely for recurrence of Bartonella infection at the original site as well as at new sites, e.g., a patient treated for osteomyelitis may recur with bacteremia (21).  

对于皮肤杆菌性血管瘤病患者应评估其他部位巴尔通体感染，如骨病变或心内膜炎，因而治疗时间将有所改变。皮肤病变通常在抗生素治疗的头几周内得以改善，随病变大小和数量不同而在1－2个月内痊愈。紫癜性肝炎患者应行腹部CT扫描监测，而骨病变患者应行99m锝骨扫描监测。停用抗生素治疗的患者应密切随访其原位复发以及新部位的感染，例如因骨髓炎而接受治疗的患者可能复发菌血症（21）。

               A Jarisch-Herxheimer-like reaction has been described in immunocompromised patients after receiving the first several doses of antibiotics (21).  Physicians should advise patients of this possible treatment complication, and patients with severe respiratory and/or cardiovascular compromise should be monitored carefully following institution of antimicrobial therapy.  This reaction has occasionally been mistaken for an adverse drug reaction.

有报道称免疫功能低下患者的病人接受前几剂抗生素治疗后出现了雅里施-赫克斯海默样（Jarisch-Herxheimer-like）反应（21）。医生应提示患者该可能出现的治疗并发症，而对于严重呼吸和/或心血管功能不全的患者，应该进行相应的监护。该反应有时被误认为是药物不良反应。

               An additional concern is the propensity for doxycycline to cause pill-associated ulcerative esophagitis (16).  This complication is most frequently reported when a dose is taken with only a small amount of liquid or at night just before retiring, and can be prevented by taking doxycycline several hours before bedtime with copious amounts of water. 

    多西环素有导致药物相关溃疡性食管炎的倾向（16）。这一并发症最常见于服药时仅饮少量液体或晚上睡前服药时。睡前几小时服药并大量饮水可有效防止其发生。

VACCINES Guided Medline Search  

疫苗

               There are no vaccines available for prevention of Bartonella infection in either humans or animals.  

    目前没有能有效预防巴尔通体感染的人或动物疫苗。

PREVENTION AND PROPHYLAXIS Guided Medline Search   

预防   

Prevention of Bartonella Infection

预防巴尔通体感染 

               Bartonella species are vector borne, and control of the associated vector may help decrease incidence of these infections.  The cat flea efficiently transmits B. henselae from cat to cat (6), and this is hypothesized to facilitate creation of the large reservoir of infected cats (as many as 41% of cats are infected in the San Francisco Bay area (19)).  Fleas could potentially transmit B. henselae directly to humans, but this has not been documented to date, and the vast majority of human B. henselae infections occur following a cat scratch or bite (26).  Control of cat flea infestation is recommended, especially for the pets of immunocompromised patients (33).  This strategy may reduce the transmission of B. henselae by decreasing feline infection, reducing contamination of cat claws due to scratching, and reducing the potential of direct transmission to humans via fleas.  Additional recommendations for decreasing risk of B. henselae infection include acquiring a mature cat, which is less likely to scratch and less likely to be bacteremic (5, 19), washing cat wounds immediately with soap and water and avoiding rough play with the cat (15, 33).

        巴尔通体杆菌是通过媒介传播的，控制相应的昆虫媒介有助于降低该感染的发病率。猫蚤能在猫之间高效传播汉氏巴尔通体，这有助于建立巨大的感染猫宿主库（在旧金山海湾区多达41%的猫被感染（19））。跳蚤具有将汉氏巴尔通体直接传播给人的潜能，但是尚无证实，而绝大部分人汉氏巴尔通体感染都是由于猫抓或咬伤引起的（26）。建议控制猫蚤感染，尤其是对免疫功能低下的患者（33）。这一策略可以降低猫科动物的感染、减少抓伤后猫爪的污染、并降低跳蚤直接传播给人的可能性，从而降低汉氏巴尔通体的传播。其他减少汉氏巴尔通体感染风险的建议包括饲养不易伤人不易携带病菌的成年猫（5, 19）；一旦被抓伤要及时用肥皂和清水冲洗伤口；避免和猫过度嬉闹（15, 33）。

               Antibiotic treatment of cats belonging to immunocompromised individuals has been proposed, but it is not evident that Bartonella infection can be permanently eradicated from the feline reservoir (34).  In addition, treatment usually involves orally force-feeding antibiotics to the cat, which incurs substantial risk of cat scratches and bites and is likely to increase risk of transmission of B. henselae to the humans involved.

对于免疫功能低下的患者，有人建议使用抗生素预防性治疗其饲养的猫，但是并不确定能将猫体内的巴尔通体感染永久清除（34）。此外，治疗涉及给猫强制口服抗生素饲喂，从而大大增加了被猫抓伤和咬伤的风险，也可能增加了相关人员传染汉氏巴尔通体的风险。

               Bartonella quintana is transmitted from human to human by the body louse (42); homeless individuals are at increased risk for infestation with the body louse and thus for infection with B. quintana.  Avoiding infestation with and exposure to the body louse is the only current recommendation for prevention of B. quintana infection.  For B. bacilliformis, the substantial decrease of infection in endemic regions of the Peruvian Andes has been attributed not only to antibiotic treatment of humans but also to reduction of the sandfly vector for this Bartonella species (45).  For B. elizabethae and B. vinsonii subsp. arupensis, the reservoirs are apparently rodents (46), but the vectors are as yet unknown.  There currently are no recommendations about prevention of infection with these two species.

五日热巴尔通体通过体虱在人与人之间传播（42）；流浪人群由于体虱的感染，感染五日热巴尔通体的风险也大。避免体虱感染和暴露是目前唯一推荐的防止五日热巴尔通体感染方法。对于杆状巴尔通体而言，其在秘鲁安第斯山区域感染的大幅下降不仅是由于抗生素对患者的治疗，也与白蛉的减少有关（45）。伊丽莎白巴尔通体和文氏巴尔通体Arupensis亚种的宿主显然为啮齿类（46），但是其媒介尚不明确。目前还没有预防这两种细菌的推荐方法。

Antibiotic Prophylaxis 

抗生素预防 

               Antibiotics of the macrolide, tetracycline and rifamycin classes have shown good in vivo activity against Bartonella species.  Treatment with macrolide antibiotics was protective against B. henselae and B. quintana infection in HIV-infected patients in one study (22).  It is therefore likely that Mycobacterium avium complex prophylaxis or treatment regimens that include an antibiotic of the macrolide, rifamycin or tetracycline class will provide adequate prophylaxis against Bartonella infection.   

    大环内酯类、四环素类和利福霉素类抗生素对巴尔通体都有很好的体内活性。有研究发现大环内酯类抗生素治疗能够预防HIV感染患者的汉氏巴尔通体和五日热巴尔通体感染（22）。因此，包括大环内酯类、利福霉素类或四环素类抗生素的鸟型分枝杆菌复合体的预防或治疗方案，都可以预防巴尔通体感染。

 

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