梅毒螺旋体（梅毒）

Updated March, 2009

Lori E. Fantry, M.D., M.P.H., Edmund C. Tramont, M.D., F.A.C.P.

译者：杨德彦 住院医师                     

            北京协和医院 内科

            北京市东城区帅府园1号

            100730

            Email：swallow_sums@tom.com

校对者：张峣 博士                     

GENERAL DESCRIPTION

               Syphilis has been known afflict mankind at least since the discovery of the “New World” by Christopher Columbus. Before the advent of antibiotics, it was one of the most common infections, afflicting up to 10% of the adult populations in the Western World. Although, it was one of the first infections to be treated successfully with antibiotics (83), debate remains with regards to what constitutes optimal treatment. The fundamental reason for this controversy is the inability to culture Treponema pallidum in vitro on routine culture media or in tissue culture. The only means of laboratory culture remains in laboratory animals. This requirement has made it extremely difficult to correlate clinical signs and symptoms with the presence or absence of replicating spirochetes or perform simple in vitro antimicrobial susceptibility testing which in turn has forced clinicians to rely on non-specific serological tests to gage the effectiveness of therapy.

Rothschild BM.  History of Syphilis. Clin Infect Dis 2005;40:1454-1463.

Laura J. McGough.[ Demons, Nature or God? Witchcraft Accusations and the French Disease in Early Modern Medicine ]

Paul A. Lombardo and Gregory M. Dorr. [ Eugenics, Medical Education, and the Public Health Service: Another Perspective on the Tuskegee Syphilis Experiment ]

概论

　　梅毒至少从克里斯托弗·哥伦布发现“新大陆”的时候就开始折磨人类。在抗生素广泛应用之前，梅毒是最常见的感染性疾病，西方成年人曾有高达10%的感染率。虽然梅毒是最早被抗生素成功治疗的感染之一[83]，但其最佳治疗方案的确定依旧存在争议。其根本原因在于梅毒的病原体——梅毒螺旋体，难以进行体外常规培养或组织培养，只能通过实验动物接种。因此临床医生难以将临床症状、体征和有否正在复制的螺旋体联系起来，并且难以进行体外抗微生物药物敏感试验，只能依靠非特异性的血清学试验来衡量治疗的效果。

Microbiology Guided Medline Search

               Syphilis is caused by a thin, tightly coiled spirochete, Treponema pallidum subspecies pallidum (84). It is a member of the family Spirochaeticea and is related to other spirochete genera associated with the capacity to infect man, namely Borrelia and Leptospira. Other pathogenic treponemes for man include T. pallidum subspecies pertenue, the causative agent of yaws; T. carateum, the causative agent of pinta; and T. pallidum subspecies endemicum, the agent associated with non-venereal or endemic syphilis.

Harper KN, et al.  On the origin of the trepanomatoses: a phylogenetic approach.  PLOS Neglected Tropical Diseases 2008;2:e148

微生物学

　　梅毒的病原体是苍白密螺旋体种苍白亚种，是一种小而纤细的螺旋状微生物[84]，属于螺旋体科。其他可造成人类感染的螺旋体还包括疏螺旋体、钩端螺旋体等。其他致病性密螺旋体包括苍白螺旋体种极细亚种（引起雅司病）、品他密螺旋体（引起人类品他病）及苍白螺旋体地方亚种（引起非性传播的或地方性梅毒）。

Epidemiology Guided Medline Search

               Although syphilis can be spread by passage through the birth placenta (congenital syphilis), by kissing or other close contact with an active lesion, transfusion of fresh human blood, or by direct inoculation, the vast majority of cases are transmitted by sexual contact (84). Persons are most infectious early in disease when a chancre, mucous patch, or condyloma latum is present and by 4 years after acquiring the disease, an immunocompetent person is essentially non-infectious. The disease is worldwide in distribution, occurring primarily in persons between the ages of 15 and 30 years. In the United States, up to 10% of persons living in urban areas were infected until the advent of penicillin treatment when the incidence plummeted to very low levels by the mid-1950s (83).  Rates have declined dramatically since then reaching an all time low in the year 2000 (9).  However, since 2000 there has been a slight upward trend in large part because of circumscribed outbreaks in men who have sex with men (7, 9).

[BenedeK TG: Biography of Neisser]

流行病学

　　虽然梅毒可以通过胎盘（先天性梅毒）、接吻等密切接触活动（特别是有破损的情况下）、输血、直接种植等途径传播，但最主要的传播途径是性接触[84]。在疾病的早期，当出现硬下疳、粘膜斑及湿疣时，传染性最强，而免疫力正常的患者在感染4年后基本没有传染性。梅毒在全世界范围内广泛分布，主要累及15～30岁人群。在青霉素应用之前，美国曾有高达10%的城市人口感染梅毒，而到了50年代中期，其发病率已显著降低[83]，而到了2000年则降至更低的水平[9]。然而2000年以来，由于男性同性性行为显著增多，梅毒的发病率有轻度上升的趋势[7，9]。

Clinical Manifestations Guided Medline Search

               The clinical disease manifestations have been well characterized for over 100 years and are traditionally divided into five stages: incubating, primary, secondary, latent (early latent and late latent), and late or tertiary syphilis (neurosyphilis, cardiovascular syphilis and gummatous syphilis) (84). The incubation period may vary from 3 to 90 days with a median of 3 weeks.

               Primary syphilis is by definition a painless chancre or ulcer that develops at the site of inoculation (84). However, in some persons, it doesn't develop at all; in other persons, it is so small that it may go completely unnoticed; and in others, especially those with human immunodeficiency virus (HIV) infection, multiple ulcers may develop (71, 72). The untreated lesion or lesions usually heal spontaneously in 2 to 8 weeks (range 1 to 12 weeks).

               Untreated secondary syphilis, the result of the interaction between a large spirochete load and the immune response, is classically characterized by cutaneous manifestations, especially a widely disseminated maculopapular rash involving the hands and soles , and is often associated with a variety of secondary clinical manifestations ranging from general malaise to organ failure. It becomes evident a mean of 6 weeks (range 2 to 16 weeks) after inoculation.

               Latent syphilis is characterized by a period of months to years in which there are no outward clinical manifestations of disease despite viable organisms. Clinical relapses can occur during the first year of the latent stage (referred to as the early latent phase) and is felt to be the result of waning cellular immunity.

               Tertiary syphilis occurs in up to 35% of untreated patients ten to twenty-five years after the initial infection and today is manifested primarily as a neurological disease reflecting the generally poor penetration of antibiotics into the CNS. Cardiovascular disease and granulomatous lesions, referred to as gummas , are very uncommon in the antibiotic era (4, 11, 49, 74, 88).

临床表现

　　梅毒的临床表现在100年前已被详细描述，传统上分为五个阶段：潜伏期、一期梅毒、二期梅毒、潜伏梅毒（早期潜伏梅毒和晚期潜伏梅毒）、三期梅毒或称为晚期梅毒（包括：晚期神经梅毒、晚期心血管梅毒和梅毒树胶肿）[84]。梅毒的潜伏期从3天到90天不等，中位潜伏期是3周。

　　一期梅毒主要表现为无痛性硬下疳或梅毒螺旋体侵入部位的溃疡[84]。部分病人无症状或因表现过于轻微而未被注意，而在部分病人中，尤其对于人类免疫缺陷病毒（HIV）感染患者，可以表现为多发溃疡[71，72]。未经治疗的病灶常在2～8周（1～12周）自行愈合。

　　由于大量梅毒螺旋体和人体免疫反应的相互作用，未经治疗的二期梅毒的典型表现为皮肤粘膜损害，突出表现为广泛性斑丘疹，常累及手及足底。二期梅毒常伴有继发性临床表现，从全身不适到器官衰竭不等，一般在感染后6周（2～16周）表现明显。

　　潜伏梅毒是指在梅毒螺旋体感染后一段时期内无任何临床症状。潜伏阶段的第1年（称为早期潜伏梅毒）可以出现临床复发，可能和细胞免疫逐渐减弱有关。

　　有35%未经治疗的病人在初始感染后10～25年发生三期梅毒。由于抗生素难以透过血脑屏障，目前三期梅毒主要表现为神经系统受累。在抗生素广泛应用之后，心血管梅毒及梅毒树胶肿已经很罕见[4，11，49，74，88]。

Laboratory Diagnosis Guided Medline Search

Direct Microscopic Examination: Dark field microscopy is a sensitive, direct and the quickest method for diagnosing syphilis (84). However, it requires a special dark field equipped microscope and skilled technicians that are not usually available at most medical facilities today, including many large hospitals in the United States. Specimens for microscopic examination are best obtained from serous transudate of moist lesions such as such as a primary chancre, condyloma latum (wart like lesions, sometimes extensive), or mucous patches (shallow ulcers on mucous membranes, non-painful unless secondarily infected). However, they also can be collected from dry skin or lymph nodes by non-bactericidal saline aspiration. When obtaining a sample, the surface should be cleaned with non-bactericidal saline and gently abraded with dry gauze, just enough so that a few scattered red blood cells are seen on the slide. The cleaning should be performed without soap, a topical antiseptic or bactericidal saline because dead and non-motile organisms are difficult to visualize. The specimen should be placed on a glass slide with a cover slip placed on top. When using serous exudates, a drop of non-bactericidal saline may be added if the serous preparation is too thick. Under dark field microscopy, T. pallidum will appear as corkscrew shape in spiraling motion with a 90^o undulation about its midpoint. At least three specimens should be examined before deciding that a lesion is non-syphilitic.

实验室诊断

直接显微镜检查：暗视野显微镜检查是一种敏感、直接、快速的诊断方法[84]。但目前在大多数医疗机构包括美国许多大医院均不具备有暗视野显微镜和熟练的观察者。显微镜观察的标本最好采自潮湿病灶的浆液性渗出物，例如原发性硬下疳、扁平湿疣（疣样病灶，有时更为扁平）或粘膜斑（无痛性粘膜浅表溃疡，继发感染者除外）。然而，也可以用生理盐水从干燥的皮肤或淋巴结采集。在采集标本时，应使用生理盐水清洁病灶表面，并用干纱布轻轻擦拭，若在载玻片上看到少许散在红细胞即表示采够。不能用肥皂、局部消毒液或杀菌盐水清洁病灶表面，因为可造成梅毒螺旋体死亡或不运动从而影响观察。标本应用盖玻片覆盖。若待观察的浆液性渗出性标本太厚，可加入1滴生理盐水稀释。在暗视野显微镜下，梅毒螺旋体表现为螺旋状，以其中点作波状曲折螺旋运动。至少观察3份标本才可作出阴性诊断。

Immunofluorescent and Immunoperoxidase Antibody Staining and Polymerase Chain Reaction (PCR): Specific immunofluorescent or immunoperoxidase antibody staining can be used to visualize organisms, including nonviable spirochetes, from mucocutaneous lesions, lymph nodes, or dry skin (12, 84). In addition, it can be used for examining non-frozen biopsy material (84). PCR is available through the CDC (Center for Disease Control, Atlanta, GA.) but as yet is not available for routine clinical practice in the United States (30,40,45,65).

免疫荧光、免疫过氧化物酶联抗体染色及聚合酶链反应（PCR）：特异性免疫荧光标记或免疫过氧化物酶联抗体染色试验可用于观察梅毒病原体，包括采自皮肤粘膜病变处、淋巴结或干燥皮肤的不活动螺旋体[12，84]。此外，还可以用于检测非冰冻活检标本[84]。尽管PCR法已经获得美国疾病控制中心批准，但在美国仍未作为常规的检测方法[30，40，45，65]。

Serological Tests: Serological blood tests remain the mainstay for the diagnosis of syphilis. There are two types of tests: the nonspecific nontreponemal reagenic antibody and the specific antitreponemal antibody (see Table 1) (84). The nontreponemal test is inexpensive, rapid, and convenient for screening large numbers of sera. If the nonspecific test is positive and when there is a suspicion of syphilis, then the specific tests are used for confirmation.

梅毒血清学试验：血清学试验仍是梅毒检测的主要方法，包括非特异性的非梅毒螺旋体抗原血清试验及特异性的梅毒螺旋体抗原血清试验2种（见表1）[84]。前者对于大量血清标本的筛查具有便宜、快速、方便的优点。若非特异性试验阳性并怀疑感染梅毒，应进行特异性试验确证。

Non-treponemal Reaginic Tests: Syphilis reaginic antibodies are IgG and IgM antibodies directed against a lipoidal antigen resulting from the interaction of host tissues with T. pallidum or from T. pallidum itself (84). The earliest cardiolipin antigens used to measure reagenic antibody were crude extracts from beef livers or hearts and false-positive tests were common. However, today’s preparation, the cardiolipin-cholesterol-lecithin, is much purer and hence there are less false-positive reactions. The nontreponemal test first developed was the Venereal Disease Research Laboratory (VDRL) slide test (84). In this test, serum is heated to 56^o C and tested to seer if it can flocculate a suspension of a cardiolipin-cholesterol-lecithin antigen. Except for its use in diagnosing neurosyphilis, it has now been largely replaced by the modifications such as the rapid plasma reagin (RPR) card test, automated regain test (ART), and the toluidine red unheated test (TRUST).

非梅毒螺旋体抗原血清试验：梅毒抗心磷脂抗体（反应素抗体）是IgG和IgM抗体，其直接针对梅毒螺旋体和宿主组织相互作用而产生的或梅毒螺旋体本身产生的脂类抗原[84]。最早用于检测抗心磷脂抗体的心磷脂抗原来源于牛肝脏或牛心脏的粗提取物，容易产生假阳性，而目前应用的心磷脂-卵磷脂-胆固醇纯度已大大提高，故假阳性减少。非梅毒螺旋体抗原血清试验源自性病研究实验室玻片试验[84]，其方法是将患者血清加热到56^○C，看其是否能凝集加入的心磷脂-卵磷脂-胆固醇抗原。目前除用于神经梅毒的诊断外，大部分已经被快速血浆反应素环状卡片试验（RPR）、自动反应素试验（ART）以及甲苯胺红卡片不加热血清反应试验（TRUST）等改良试验所取代。

               False negatives can occur in up to 2% of these tests, especially during secondary syphilis, due to the prozone phenomenon (84). If the clinical index of suspicion is high, appropriate serum dilutions should be performed. Nontreponemal tests become positive shortly after initial infection, peak during the secondary or early latent stage, and then decline with time (33). Virtually 100% of infected persons have positive serological tests for syphilis during the secondary stage of disease. They decline, usually to <1:4, and actually become negative in 25% of untreated persons during later stages.

　　由于前带现象的存在，这些试验有2％的假阴性，尤其对于二期梅毒[84]。如果临床高度怀疑梅毒，应对血清进行合理稀释后重复检测。非梅毒螺旋体抗原血清试验在感染后短期即表现阳性，在二期梅毒以及早期潜伏梅毒时阳性率达到高峰，此后逐渐下降[33]。事实上，二期梅毒患者100%表现为梅毒血清试验阳性。然而随着病程延长，反应滴度通常逐步下降到小于1：4，有25%未经治疗的患者在疾病后期表现为阴性。

               Whenever there is a strong immunologic stimulus (e.g., acute bacterial or viral infection, vaccination, HIV infection), a “false” positive nontreponemal reagenic test may develop (42,84). In addition, persons who use injection drugs have autoimmune or connective tissue diseases (especially systemic lupus erythematosus) and hypergammaglobulinemic states may have “false” positive results. These persons often also have blood tests positive for other factors frequently associated with autoimmune disease such as antinuclear, antithyroid, or antimitochrondrial antibodies; rheumatoid factor; and cryoglobulins. A negative specific treponemal test will confirm that the test is a false positive and that syphilis can be excluded.

　　任何强的免疫刺激（例如：急性细菌或病毒感染、疫苗接种、HIV感染）均可造成非梅毒螺旋体抗原血清试验假阳性[42，84]。此外，自身免疫性疾病、结缔组织疾病（例如：系统性红斑狼疮）或高丙种球蛋白血症患者在应用注射药物时，也可能出现假阳性。这类患者通常也会出现其他自身免疫性疾病相关检查阳性，例如抗核抗体阳性、抗甲状腺抗体阳性、抗着丝点抗体阳性、类风湿因子阳性及冷球蛋白阳性等。若特异性梅毒螺旋体抗原血清试验阴性，则可明确假阳性，并排除梅毒。

Specific Treponemal Tests: The specific antitreponemal antibody tests currently performed are the fluorescent treponemal antibody-absorption (FTA-abs), T. pallidum haemagglutination assay (TPHA), microhemagglutination assay for antibodies to T. pallidum (MHATP), and the T. pallidum immobilization (TPI) tests (84).

特异性梅毒螺旋体抗原血清试验：目前应用的特异性抗梅毒螺旋体抗体检测技术包括：荧光螺旋体抗体吸收试验（FTA-abs）、梅毒螺旋体血凝试验（TPHA）、梅毒螺旋体微量血凝试验（MHATP）及梅毒螺旋体固定试验（TPI）[84]。

               The FTA-abs uses. T. pallidum harvested from rabbit testes as the antigen in a standard indirect immunofluorescent antibody test. The first step is to remove so called “natural” cross-reacting antibody that may have been raised against saprophytic treponemes of the oral cavity or genital tract by absorbing the patient’s serum with nonpathogenic treponemal antigen (referred to as “sorbent”). The next step is to place the patient’s “absorbed” serum on a slide which contains that has fixed T. pallidum as the antigen. If specific antibody to T. pallidum is in the patient’s serum, then it is detected when fluorescein-labeled antihuman gamma globulin is added to the slide and examined under a fluorescence microscope. Although this test is very specific, its interpretation can be quite subjective. The TPHA also measures specific treponemal antibody. It is easier to perform than the FTA-abs and is as specific but not as sensitive, especially in early disease. The MHATP test is similar to the TPHA test except it uses a microtiter plate. “Sorbent” is always used to increase its specificity. The TPI test is now available in only a few research laboratories because it is expensive (requires abstracting living treponemas from infected laboratory animals), time-consuming, and difficult to perform.

　　荧光螺旋体抗体吸收试验的应用： 标准的间接免疫荧光抗体试验以采自兔睾丸的梅毒螺旋体作为抗原。试验首先要去除所谓的非特异性（自然）交叉反应抗体。此抗体由口腔或生殖道腐物中寄生的螺旋体产生。将非致病性螺旋体抗原加入患者的血清（作为吸收剂），可将其吸收清除。然后，将患者血清滴到已经固定了作为抗原的梅毒螺旋体的载玻片上。若患者血清中存在特异性抗梅毒螺旋体抗体，当免疫荧光标记的抗人丙种球蛋白加入载玻片上的时候，其就会被荧光显微镜发现。虽然此试验非常特异，但其解释较主观。TPHA也用于检测特异性梅毒螺旋体抗体，其检测方法较FTA-abs简单，而特异性和FTA-abs类似，但敏感性不足，尤其在疾病的早期。MHATP除了需应用微滴定盘之外，和TPHA基本类似，一般需应用吸收剂来提高其特异性。TPI由于昂贵（需要从感染的实验动物中提取活性的梅毒螺旋体）、耗时及难以施行，目前仅在少数实验室应用。

Tests for Congenital Syphilis: The diagnosis of congenital syphilis is best made by testing the mother at the time of birth since infant serum titers, even when the infant is infected, may be non-reactive, especially if the mother has low titers or the mother was infected late in pregnancy (7, 84). If the mother has reactive syphilis serology, then the infant’s serum should be evaluated with a RPR or VDRL. Infants should also have physical exam including darkfield microscopy or direct fluorescent staining of any suspicious lesions and radiological and ultrasound studies (8). IgM-specific antibodies (ELISA, Relispot, FTA-abs, or immunoblotting/Western blot) combined with antigen detection (darkfield, immunofluorescence or immunoperoxidase labeled antibody staining, or PCR) are also recommended when the diagnosis of congenital syphilis is considered (8,54,84). Any positive tests requires treatment except if the infant’s nontreponemal serology is the same or less than fourfold that of the mother, the mother was known to have been adequately treated with penicillin during pregnancy, and all other tests are negative.

先天性梅毒的检测：对于先天性梅毒的患儿，最好在分娩时对其母亲进行检测，因为即使婴儿受到感染，其血清滴度仍可能很低，从而导致检测阴性，尤其在其母亲血清滴度低或在怀孕后期感染梅毒时[7，84]。若母亲梅毒血清学检测阳性，应使用RPR或VDRL来检测婴儿的血清，而暗视野显微镜检查、可疑病变直接荧光染色检查及放射线、超声检查也应该进行[8]。当考虑先天性梅毒的时候，也推荐联合应用特异性IgM抗体检测（ELISA、Relispot、FTA-abs或免疫印迹法）及特异性抗原检测（暗视野显微镜检查、免疫荧光或免疫过氧化物酶标记抗体染色检查或PCR）[8，54，84]。任何阳性结果均提示需要治疗，除非婴儿的非特异抗体滴度小于或等于其母亲的四倍，其母亲在怀孕期间已经接受足够的青霉素治疗，而且其他检测均为阴性。

Tests for Neurosyphilis: A lumbar puncture with the CSF sent for VDRL, cytology, and protein is the most commonly used method for making the diagnosis (8). In the appropriate clinical setting, a reactive CSF-VDRL is considered diagnostic of syphilis while a negative test does not rule out disease, e.g., it is specific but not very sensitive test (84). If the CSF-VDRL is a negative, a finding of more than five mononuclear cells per cubic millimeter, a protein value of 46 mg/dL or greater, or a glucose of 45 mg/dL or less all are suggestive of neurosyphilis (16,47). However, the limitations of these tests have been well known for over 80 years and were most recently dramatically illustrated in a 1988 study (47).  Four of twelve patients (33%), in whom T. pallidum was cultured from the CSF using rabbits had normal cellular and protein studies, as well as a non-reactive CSF-VDRL (RPR), attesting to the low sensitivity for all of these tests, even in combination.  In addition, there were a significant number of patients in whom T. pallidum was not isolated from the CSF despite CSF abnormalities including four patients with reactive VDRL’s. A serum VDRL (RPR) titer greater than 1:32 most closely correlates with a positive T. pallidum isolation in rabbits (culture) and this was found most commonly in secondary syphilis.

神经梅毒的检测：脑脊液（CSF）VDRL检查、细胞学检查和蛋白质检查是神经梅毒最常用的检测方法[8]。若临床表现符合神经梅毒，脑脊液VDRL检查阳性，而其他检测不能排除梅毒，则可以作出神经梅毒的诊断，因此这是一个特异但不敏感的检查[84]。在CSF-VDRL检测阴性时，每立方毫米超过5个单核细胞、CSF蛋白大于等于46mg/L、CSF葡萄糖小于等于45mg/L均提示神经梅毒[16，47]。然而，人们至少在80年前就发现上述试验的局限性，在1988年的一个研究中，此局限性被充分表明[47]。此研究发现，在12例CSF培养阳性（接种兔子）患者中，有4例（33%）CSF细胞、蛋白检测均正常，且CSF-VDRL（RPR）阴性，证实了上述试验即使联合应用，其敏感性仍较低。此外，有相当一部分患者虽然CSF异常，包括有4例VDRL阳性，但CSF却不能分离出梅毒螺旋体。血清VDRL（RPR）滴度大于1:32与CSF培养阳性（接种兔子）相关性最好，此相关性在二期梅毒中最为普遍。

               Other methods with greater sensitivity and specificity than the CSF-VDRL are the intrathecal T. pallidum antibody (ITPA) and TPHA indices but these are seldom used in clinical practice (84). A FTA-abs test is usually not performed on CSF because it is difficult to interpret because a positive test may represent passive transfer of antibody from serum to the CSF and not active CNS disease (84). However, it is highly sensitive. Marra and co-workers found it, along with a determination of a percent CSF cells that were B lymphocytes, to be useful in excluding or establishing a diagnosis of neurosyphilis (52).

　　其他敏感性、特异性更高的检测包括鞘内梅毒螺旋体抗体检测（TIPA）及TPHA指数，但均很少应用于临床[84]。FTA-abs通常不用于CSF检测，因为阳性结果可能由血清中的抗体被动进入CSF导致，而非活动性的CNS病变造成[84]。然而，其敏感性很高。Marra及其同事发现FTA-abs联合CSF中B淋巴细胞比例有助于排除或诊断神经性梅毒[52]。

Ghanem KG et al. Lumbar Puncture in HIV-infected Patients with Syphilis and No Neurologic Symptoms.Clin Infect Dis. 2009 Mar 15;48(6):816-21.

Pathogenesis Guided Medline Search

               T. pallidum divides every 30-33 hours (84). It has an outer membrane composed of a phospholipids bilayer that is similar to those of mammalian cells. This sheath is unique in that it has few protruding antigenic proteins. Both the slow dividing time and the paucity of antigenic proteins allow the organism to successfully evade an effective host immune response for prolonged periods of time and hence enable it to establish a chronic infection in at least 1 out of 4 victims. Antigenic variation may result in a subpopulation of spirochetes that are resistant to macrophage phagocytosis. As with many other chronic infections, prolonged persistence in a given host depends at least in part on the switch from a predominant Th 1 (cellular) to Th2 (humoral) host response, as is the case in many other chronic infections.

发病机制

　　梅毒螺旋体每30－33小时分裂1次[84]。和哺乳动物的细胞类似，梅毒螺旋体也有一层由磷脂双分子层组成的外膜。这层膜的特殊之处在于其很少突起的抗原蛋白。缓慢的分裂以及极少的抗原蛋白令其可以长时间逃避宿主免疫反应，从而在1/4的感染者中造成慢性感染。抗原变异可导致能抵抗巨噬细胞的亚群出现。和其他慢性感染类似，要延长在宿主中的生存，至少在一定程度上依靠宿主免疫反应由Th1细胞介导（细胞免疫）为主转变为Th2细胞介导（体液免疫）为主。

               Infection begins when T. pallidum penetrates the host, usually through intact or abraded mucous membranes (84). Although, the exact infectious dose in humans is not known, in rabbits, an infectious inoculum can be as few as four spirochetes. The incubation period is directly proportional to the size of the inoculum since clinical lesions do not appear until a concentration of approximately 107 organisms per milligram of tissue in rabbits is reached (19). In early disease, spirochetes can be found in the chancre, the usual first manifestation of syphilis.

　　梅毒螺旋体通常从完整或经常摩擦的粘膜侵入宿主引起感染[84]。虽然尚未能精确确定多少梅毒螺旋体才能导致人体感染，但仅4个梅毒螺旋体即可引起兔子感染，梅毒潜伏期的长短和侵入的数量直接成正比，当每毫克组织中达到大约107个病原体时，临床病变即可出现[19]。在疾病的早期，梅毒螺旋体可从硬下疳中找到，硬下疳通常是梅毒的首发症状。

               Invasion into the bloodstream and lymphatics occurs within hours to days of penetration of T. pallidum as evidenced by the fact that patients who received blood transfusions from syphilitic donors in the seronegative incubation period have become infected (84). All organs of the body can be invaded but organisms are prone to most commonly invade the skin, lymph nodes, and the central nervous system (CNS). In the skin, T. pallidum is found in the dermal-epidermal junction zone or throughout the dermis (20). In most cases, the cellular immune response is predominately T (CD3 positive) cells rather than B (CD22 positive) (20). Up to 40% of patients have evidence of CNS invasion, including the eye, as evidenced by either abnormal laboratory tests or direct culture of the treponemes in laboratory animals.

　　梅毒螺旋体进入人体后数小时到数天之内即可侵入血流及淋巴系统。其证据是，健康人输入处于梅毒血清学阴性潜伏期的梅毒患者的血液后，也会发生感染[84]。梅毒螺旋体可侵犯所有脏器，但最常见的是皮肤、淋巴结及中枢神经系统。侵犯皮肤时，可以在表皮真皮连接处或全层真皮找到梅毒螺旋体[20]。在大多数病例，细胞免疫反应主要由T细胞介导（CD3 阳性）而非B细胞介导（CD22 阳性）[20]。高达40％的患者有中枢神经系统（包括眼睛）受累的证据，包括异常的实验室检查及实验动物直接梅毒螺旋体接种培养阳性。

               Initially, the host develops an intense cellular immune response and as with most other infections, it is the ensuing inflammation that is responsible for most of the disease pathology (84). Spirochetes may remain alive and continue to replicate in immunologically sequestered sites in the body even when there are no outward clinical manifestations of disease. When the host is not able to eliminate replicating spirochetes, chronic disease manifestations can develop.

　　正如大多数其他感染一样，机体首先表现出强烈的细胞免疫反应，而随后继发的炎症反应则是梅毒感染病理改变的主要原因[84]。尽管无外在的临床表现，但在被免疫细胞隔离的组织中，梅毒螺旋体仍保持活性并持续复制。当机体无法清除复制中的梅毒螺旋体时，便会出现慢性感染的表现。

               Chronic disease is most often manifested by invasion of the vasa vasorum of the aorta and/or the arteries of the CNS by T. pallidum (84). In addition, gummas, granulomatous lesions with coagulated or amphous centers, form most commonly in the skin, liver, bones, and spleen.

　　慢性感染最常表现为梅毒螺旋体侵犯大动脉系统和/或中枢神经系统的动脉[84]。此外，梅毒树胶肿、中心凝固性坏死性肉芽肿病变在皮肤、肝、骨及脾最为常见。

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

Single Drug

               Early susceptibility testing of various antibiotics against T. pallidum in experimental rabbit models established the principles of anti-treponemal syphilis therapy. Using the rabbit model, Eagle and co-workers in the 1940’s found that established later stage disease required a longer course of therapy but cure could be accomplished with relatively low dose therapy (19) given over a prolonged period of time. These early studies have served as the basic tenants in our approach to syphilis therapy.

体内及体外药物敏感性

单药

　　早期在实验兔子模型上进行的梅毒螺旋体药物敏感试验建立了抗梅毒螺旋体的治疗原则。通过实验兔子模型，Eagle及其同事在40年代发现，越晚期的梅毒疗程应越长，而通过延长疗程，相对低的药物剂量也可达到治愈的目的[19]。这些早期研究是我们治疗梅毒的基础。

               Penicillin, the first antibiotic developed, was the first known effective antibiotic for T. pallidum and remains the treatment of choice today (8,22,66). The maximally treponemicidal serum concentration of penicillin is 0.36 µg/ml which can kill the organism in 6 to 9 hours (19). However, a concentration as low as 0.005 µg/ml can clear T. pallidum from chancres if it is maintained for 48 to 96 hours (19). In the rabbit model, viable treponemas may persist in the lymph nodes even after early lesions have been cleared. T. pallidum can regenerate if the serum penicillin concentration falls to sub-inhibitory levels for 18-24 hours (36).

　　作为第一个应用于临床的抗生素，青霉素也是第一个被发现对梅毒螺旋体有效的抗生素，其至今仍为治疗的选择之一[8，22，66]。青霉素在最大杀菌浓度0.36ug/ml时，可在6到9小时内杀灭梅毒螺旋体[19]。当浓度降低到0.005ug/ml时，持续48到96小时仍可将梅毒螺旋体从硬下疳中清除[19]。在实验兔子模型中，即使早期病变被清除，在淋巴结里仍存在存活的梅毒螺旋体。如果青霉素血液浓度下降到亚抑菌浓度达18到24小时，梅毒螺旋体可以再次复制[36]。

               Resistance to penicillin has not yet been found among clinical isolates (84) but there is the potential for the acquisition of extrachromosomally mediated antibiotic resistance since at least one strain has been shown to contain plasmid DNA (62).

　　至今仍未发现对青霉素耐药的梅毒螺旋体菌株[84]，但获得性染色体外介导性耐药的潜在可能是存在的，因为已经发现至少有1个菌株存在质粒DNA[62]。

               T. pallidum is also susceptible to virtually all other β-lactam antibiotics. Based on studies done with the time honored in vivo rabbit model, amoxicillin (57), ceftriaxone (44), ceftizoxime (43), cefmetazole (1) and cefetamet (22) have been shown to be curative. Azithromycin, which has the advantage of once daily dosing, also has activity against T. pallidum (46,80).

　　事实上梅毒螺旋体对所有其他β内酰胺类抗生素均敏感。根据著名的实验兔子体内药敏试验结果，阿莫西林[57]、头孢曲松[44]、头孢唑肟[43]、头孢美唑[1]、头孢他美酯[22]均可用于治疗梅毒。一天一次的阿奇霉素同样有抗梅毒螺旋体活性[46，80]。

               Macrolide antibiotics are also able to inhibit T. pallidum but not as efficiently as the β-lactam antibiotics and unlike penicillin, clinical resistance to macrolides have been described (36). Thus, they are relegated to second line antibiotic treatment status. For example, when erythromycin was directly compared to penicillin G for the treatment of rabbit skin syphilomas, a single injection of penicillin decreased the motile T. pallidum count by more than 250-fold, whereas single doses of erythromycin did not decrease the count significantly (5). Only after multiple injections of erythromycin was the motile treponema count decreased in amounts similar to that of penicillin.

　　大环内酯类抗生素也有抑制梅毒螺旋体的作用，但不如β内酰胺类抗生素有效。此外它和青霉素不同的是，梅毒螺旋体已经有对大环内酯类抗生素耐药的临床报道[36]。因此，大环内酯类抗生素仅作为二线药物。在直接比较红霉素和青霉素对治疗兔子皮肤梅毒效果的实验中，单次注射青霉素可以减少活动性梅毒螺旋体250倍以上，然而，单次注射红霉素效果并不明显[5]，只有多次注射才能达到和青霉素相似的效果。

               Chloramphenicol, an antibiotic no longer available in the USA, also has activity against T. pallidum but has failed to eradicate infection in the rabbit model (36). Never the less, because it concentrates in the CNS, it has utility to treat neurosyphilis.

　　氯霉素（美国已经不再应用）也有抗梅毒螺旋体活性，但在实验兔子模型中无法根除梅毒螺旋体感染[36]。然而，由于其在中枢神经系统浓度较高，故可用于治疗神经性梅毒。

               Spectinomycin (66), the quinolone class of antibiotics (82), and clindamycin (5) have negligible activity against T. pallidum and are contraindicated.

　　大观霉素[66]（喹诺酮类抗生素）[82]及克林霉素[5]几乎无抗霉素螺旋体活性，故对治疗梅毒无效。

Combination Drugs Guided Medline Search

               Because of the exquisite success of single drug therapy, combination therapy for syphilis is not required and has not been studied.

Review Article:  Stamm LV.  Global Challenge of Antibiotic-Resistant Treponema pallidum.  Antimicrobial Agents and Chemotherapy 2010;54:583-589.

联合用药

　　由于单药治疗效果明显，故联合用药并无必要也无相关研究。

ANTIMICROBIAL THERAPY Guided Medline Search Smart search

               The following points are important to note before a discussion of antimicrobial therapy for syphilis. First, as in the case of many infections, a natural immune response can clear T. pallidum independent of antibiotic usage (28). On the other hand, in states of immune impairment, especially with cell-mediated deficits such as occurs in the Acquired Immunodeficiency Syndrome (AIDS), even the most effective antibiotics may fail to eradicate T. pallidum (48). Hence, antibiotics augment clearance and subsequent cure but do not guarantee it. Furthermore, the pharmacology of the antibiotic preparation must be considered, specifically whether it reliably reaches the CNS in adequate amounts to inhibit T. pallidum because the CNS is invaded in up to 40% of patients (47). Unfortunately, many of the current therapies recommended for syphilis do not sufficiently penetrate into the CNS to best assure a cure of incubating neurosyphilis (17, 18, 55).

抗生素治疗

　　在讨论梅毒的抗生素治疗之前首先要明确以下几点。第一，和许多感染一样，机体自身的免疫反应可以在无抗生素应用的情况下清除梅毒螺旋体[28]。另一方面，在免疫缺陷的情况下，尤其是细胞免疫缺陷，比如获得性免疫缺陷综合征（AIDS），即使应用最有效的抗生素也无法根除梅毒螺旋体[48]。因此，抗生素提高了治愈率及清除率，但不一定都能达到治愈的目的。进一步来讲，由于有高达40％的患者有中枢神经系统受累，因此必须考虑抗生素的药理学特点，特别是能否在中枢神经系统达到足够的抑菌浓度[47]。遗憾的是，目前推荐用于治疗梅毒的药物中，许多并不能有效透过血脑屏障因此难以治愈潜伏神经梅毒[17，18，55]。

               Penicillin is the best studied and still remains the recommended therapy for syphilis (84). However, after nearly 60 years, there still remains much debate as to what dosing schedules and which preparations are appropriate for the various stages and types of persons infected with T. pallidum (68). The original studies of penicillin treatment were performed before the establishment of the standard double-blinded placebo or comparison controlled randomized clinical trials to evaluate the efficacy of therapy. In other words, there have been no rigorous studies of penicillin or any other antibiotics to evaluate dose, duration, and preparation of antibiotic that would achieve cure with minimal toxicity and cost. Hence, all recommendations of treatment for syphilis must be regarded with a degree of skepticism.

　　青霉素治疗梅毒已被充分论证，其目前仍作为推荐药物[84]。然而近60年来，针对梅毒感染的不同类型、不同阶段，青霉素剂量的选择、其制剂类型的选用依旧存在争论[68]。在最初进行青霉素治疗梅毒临床试验的时候，用于评价药物疗效的标准安慰剂随机双盲对照临床试验方法尚未建立。也就是说，尚无严格的临床试验去评估青霉素或其他抗生素在何种剂量、何种制剂及多长疗程的情况下，才能最经济、最小副作用地治愈梅毒。因此，所有推荐的梅毒治疗方案在一定程度尚存在疑问。

               Because therapy should be tailored according to the benefit that a person will receive from a particular therapy balanced with the inconvenience and cost of alternative forms of therapy, the following discussion will focus on therapeutic preferences rather than rigorous recommendations.

　　由于最佳治疗方案的制定须综合考虑治疗收益、治疗费用以及患者依从性，接下来的论述主要从治疗效果出发，而非严格意义上的最佳方案。

Centers for Disease Control and Prevention (CDC) Recommendations

               The CDC periodically reviews the recommended treatments for syphilis (Table 2) (8). The CDC treatment guidelines are based on the premise that different stages or forms of the disease should be treated with different preparations and doses of penicillin. Following the principles of public health or population based guidelines, their goal is to provide therapeutic recommendations that will cure the greatest number of patients with minimal expense, easy administration, and high compliance (36). In contrast, treatment of the individual patient rests with the treating clinician who must weigh the risk of failing to cure a curable disease.

美国疾病预防控制中心（CDC）的推荐

　　CDC会定期更新梅毒治疗的推荐方案（表2）[8]，其制定的前提是针对不同类型、不同阶段的疾病，应使用不同剂量、不同制剂的青霉素治疗。基于公共卫生及人群保健的考虑，其目标是应用最经济、最方便、最容易接受的方法治疗最多的病人[36]。相反，对于个体治疗而言，临床医生须衡量治疗失败的风险。

               The CDC recommends that non-pregnant women and men with early syphilis, which includes primary syphilis (the stage that occurs immediately after infection characterized by an ulcer or chancre); secondary syphilis (the later stage corresponding to spirochete dissemination and characterized by skin rash); and early latent syphilis (the stage up to one year after initial infection when positive serology’s are the only indication of infection), should be treated intramuscularly with one injection of 2.4 million units of benzathine penicillin G (8). This is based primarily on animal data showing that the minimal inhibitory concentration that cures primary lesions is easily achieved with this dose of benzathine penicillin (36). However, this does not take into consideration the fact that in 40% of cases of early syphilis there is CNS invasion which can result in the development of late neurosyphilis (47) and that this dose of benzathine penicillin does not reliably penetrate the CNS (17,18, 55, 67, 90). Furthermore, a failure rate of up to 5% was suggested in the early clinical trials.

　　CDC推荐对于男性及非妊娠女性的早期梅毒，包括一期梅毒（感染后随即发生，以溃疡和硬下疳为特征）；二期梅毒（对应于梅毒螺旋体扩散，以皮疹为特征）；及早期潜伏梅毒（初始感染后1年内，血清学阳性为感染的唯一表现）应肌肉注射240万单位苄星青霉素G 1次[8]。其主要根据是，动物试验表明当应用上述剂量苄星青霉素时，较容易达到治愈原发病灶所需要的最小抑菌浓度[36]。然而，上述剂量的制定并未考虑到实际上有40％的病例存在中枢神经受累，可以导致迟发的神经梅毒[47]，而上述剂量并不能在中枢神经系统达到有效浓度[17，18，55，67，90]。甚至，在早期的临床试验中，有高达5％的治疗失败率。

               The CDC also recommends that non-pregnant women and men with late latent syphilis (syphilis of more than 1-year in duration), latent syphilis of unknown duration, and tertiary syphilis except neurosyphilis) also receive benzathine penicillin (Table 2) but at an increased total dose of 7.2 million units given as 2.4 million units weekly for three weeks (8) to account for the possible longer dividing time of the spirochete at this stage of disease (36). However, as noted above, CNS concentrations of benzathine penicillin are not reliably achieved (47).

　　CDC也推荐对男性及非妊娠女性晚期潜伏梅毒（病程超过1年）、未知病程的潜伏梅毒及三期非神经梅毒应用苄星青霉素（表2），但不同之处在于为了治疗这种情况下可能存在的更长分裂时间的梅毒螺旋体[36]，其剂量须提高到240万单位每周1次共3次，累计剂量720万单位[8]。但正如上文所述，苄星青霉素并不一定能在中枢神经系统达到有效浓度[47]。

               Acknowledging the well-recognized fact the neurosyphilis is the most difficult manifestation to treat, the CDC recommends that persons with neurosyphilis be treated with 3 - 4 million units of aqueous crystalline penicillin G given intravenously every 4 hours (18-24 million units daily) for 10-14 days. However, who should be included in this classification of “neurosyphilis” is vague and ill defined. Patients with a reactive cerebrospinal fluid VDRL or RPR test are the easiest to classify and are accepted as definitely having neurosyphilis. But most patients have either no symptoms or ill-defined symptoms and most have nonspecific CSF abnormalities. Furthermore, despite the fact that T. pallidum invades the CNS in 40% of patients (47), a lumbar puncture is seldom performed unless the signs and symptoms of acute meningitis are manifested as part of the signs and symptoms of secondary syphilis. In fact, the CDC discourages performing a lumbar puncture in early syphilis unless the patient has optic, auditory, cranial nerve, or meningial symptoms (8). The rationale is that although early invasion of the CNS by T. pallidum is common, it does not predict treatment failure with benzathine penicillin and that the lumbar puncture often yields little additive information.

　　由于神经梅毒最难治疗，CDC推荐静脉应用水剂青霉素300-400万单位每4小时1次（每天1800-2400万单位）持续10-14天。然而，神经梅毒的诊断常模棱两可，其定义也并不完善。脑脊液VDRL或RPR阳性的患者最容易被认为是神经梅毒患者，并常被确认存在神经梅毒。但大多数患者既无明确相关症状，也无特征性的脑脊液改变。进一步来讲，尽管有40％的患者存在中枢神经系统受累[47]，但很少患者接受腰椎穿刺检查，除非有作为二期梅毒临床表现之一的急性脑膜炎的症状及体征。事实上，CDC并不推荐对早期梅毒患者行腰椎穿刺检查，除非有视觉、听觉、颅神经或脑膜炎症状[8]。原则上说，虽然梅毒螺旋体早期侵犯中枢神经系统比较普遍，但并不意味着苄星青霉素治疗无效，而腰椎穿刺并不能提供太多额外的帮助。

               In summary, the CNS is invaded soon after infection in up to 40% of patients and some will go on to develop late neurosyphilis 10-25 years later. Unfortunately, the diagnosis is difficult to establish, and benzathine penicillin does not reliably reach the CNS in the majority of cases, setting the stage for well-documented treatment failures. The clinician must weigh this risk in each individual patient.

　　总而言之，40％的患者在梅毒感染后短期会出现神经系统受累，部分在10-25年后会进展为神经梅毒。遗憾的是，其诊断比较困难，而苄星青霉素在大多数患者中不能很好地透过血脑屏障，从而有时难免治疗失败。临床医生在诊治每位患者时须权衡此风险。

Treatment Failures

               Although benzathine penicillin is effective therapy for the vast majority of persons with syphilis, there are multiple reports of treatment failures, especially in patients co-infected with Human Immunodeficiency Virus (HIV). It has long been established that benzathine or low dose aqueous or procaine penicillin is not 100% successful in preventing neurosyphilis in non-HIV infected persons, so it not surprising that these immune dysfunctional patients would be particularly vulnerable to this complication, especially when one considers that re-treatment is necessary in at least 5% of immunocompetent patients with primary or secondary syphilis treated with low dose aqueous benzathine procaine penicillin (6, 68, 76, 77). Although this failure can be at times attributed to re-infection (23, 24), at least half of those cases are convincingly due to failure of initial therapy (76).

治疗失败

　　虽然苄星青霉素可以有效治疗大多数患者，但是仍有许多治疗失败的报告，尤其在重叠感染人类免疫缺陷病毒（HIV）的时候。早已证明在非HIV感染者中，苄星青霉素、低剂量水剂青霉素或普鲁卡因青霉素均不能100％预防梅毒侵犯神经系统，故对免疫缺陷患者而言，神经系统更容易受累，例如接受低剂量水剂苄星普鲁卡因青霉素治疗的免疫力正常的一期或二期梅毒患者至少有5％需要再次治疗[6，68，76，77]。虽然治疗失败有时是由于再次感染造成的[23，24]，但是至少有一半的病例是明确由初始治疗失败导致的[76]。

               The most likely reason for treatment failures is that at least 40% of patients with early syphilis are infected with T. pallidum in the CNS (47), a site that is poorly penetrated by benzathine penicillin (17,18,25,41,47,55,59,67). In most cases of syphilis, the CNS infection and poor penetration of penicillin is inconsequential since an immunocompetent host is usually capable of clearing the infection before any neurological damage occurs.

　　治疗失败的最可能原因是至少40％的早期梅毒患者存在中枢神经系统受累[47]，而苄星青霉素并不能很好透过血脑屏障[17，18，25，41，47，55，59，67]。但在大部分患者中并不出现上述情况，因为免疫正常的宿主可以在任何神经系统损害发生之前清除感染。

               Since the most reliable form of treatment is one that is reaches treponemicidal levels in the CNS, the most reliable preferred therapy for any form of syphilis in any type of patient is 2 - 4 million units of aqueous crystalline penicillin G given intravenously (iv) every 4 hours (12-24 million units daily) for 10-14 days (Table 3) since between 5 and 24 million units of intravenous penicillin G consistently achieves levels in the CSF that are treponemicidal (55,67). Hence, it would follow that treatment failures would be rare when compared to regimens that failed to reliably penetrate the CNS (58).

　　由于最可靠的治疗方法是令药物在中枢神经系统里达到杀灭梅毒螺旋体的浓度，因此对于任何患者任何类型的梅毒的最佳治疗是静脉应用200-400百万单位水剂青霉素G每4小时1次（1200-2400万单位/天）持续10-14天（表3），因为静脉应用500-2400万单位青霉素G可以在CSF中保持杀灭梅毒螺旋体浓度[55，67]。因此，和其他药物不能很好透过血脑屏障的治疗方法相比，此方法治疗失败很少见[58]。

Oral Regimens

               Because inpatient hospital treatment is not always practical from a reimbursement or lifestyle perspective, other treatment regimens have been developed. The oral regimen most thoroughly studied is the semi-synthetic penicillin, amoxicillin, given 3.0 gm orally twice a day with probenecid 500 mg orally for 10-14 days (See Table 3). Probenecid inhibits renal excretion of natural and semi- synthetic penicillins. As previously noted, amoxicillin is treponemicidal in the rabbit model , and when 2 gms of amoxicillin plus 500mg of probenecid is administered to fasting adults, the MIC for T. pallidum can be exceeded for at least eight hours (57). Clinical trials, albeit small, have confirmed the utility of this regimen (63, 69).

口服疗法

　　鉴于住院治疗会影响患者的生活，也可以考虑其他更方便的口服治疗方法。其中研究最充分的是阿莫西林，一种半合成青霉素，剂量是3g口服1天2次，并联用丙磺舒500毫克口服持续10-14天（表3）。丙磺舒能抑制肾脏对天然或半合成青霉素的排泄。正如既往所知，阿莫西林在兔子模型里有杀灭梅毒螺旋体的作用，当空腹口服2克阿莫西林联合500毫克丙磺舒可以超过梅毒螺旋体MIC至少8小时[57]。小规模的临床试验也证实了此疗法的有效性[63，69]。

               Both of these regimens can be used in adults at any stage of syphilis. However, in neurosyphilis, even these regimens may fail and re-treatment may be required (87), especially in HIV infected patients (59). Hence, diligence of follow-up must be the order of the day.

　　所有这些疗法均可应用于任何阶段的成人梅毒。然而对于神经梅毒，这些疗法可能无效，可能需要再次治疗[87]，尤其对于HIV感染的患者[59]。因此需要密切随访。

               Unfortunately, reversal of late neurological deficits due to syphilis is rarely obtained (36).

　　遗憾的是，梅毒造成的晚期神经系统损害难以修复[36]。

Alternative Therapy Guided Medline Search

               2.4 million units of aqueous procaine penicillin G have been given intramuscularly daily with probenecid 500mg orally 4 times per day for 10-14 days. Treponemicidal levels of penicillin have not been achieved as reliably with procaine penicillin but supplementation with probenecid will achieve treponemicidal levels (18). Furthermore, patient compliance is problematic because of the pain associated with the injections. Since this therapy avoids the need for frequent dosing and thus hospitalization, it is recommended as an alternative in compliant patients in whom the local discomfort is tolerable.

备选治疗

　　240万单位水剂普鲁卡因青霉素G肌注一天一次联合丙磺舒500mg口服一天四次持续10-14天。普鲁卡因青霉素单用并不能达到有效灭菌浓度，但联用丙磺舒后则可以达到[18]。进一步而言，由于青霉素注射会有疼痛感，患者的依从性是一个需要考虑的问题。由于这种治疗方案避免了住院频繁注射青霉素，因此可以作为备选方案应用于能耐受局部不适的患者。

               The first- and third- generation cephalosporin antibiotics, in particular ceftriaxone, are also effective in treating syphilis. Ceftriaxone has been recommended for treatment of early disease and neurosyphilis (8) (Table 3). This drug is particularly attractive since serum and CSF levels exceeding those needed to kill T. pallidum are easily obtained with standard dosing (44). It has been used clinically to successfully to treat incubating syphilis (37), primary syphilis (37,56,75), secondary syphilis (37,75), latent syphilis (16), and neurosyphilis (50, 66,74). However, there have been reports of treatment failures in HIV infected patients, similar to those found with benzathine penicillin (16).

　　第一及第三代头孢菌素类抗生素，尤其是头孢曲松，对治疗梅毒螺旋体同样有效。头孢曲松推荐应用于早期梅毒及神经梅毒[8]（表3）。头孢曲松的优势在于在标准剂量情况下，可以轻易在血液及脑脊液中超过杀灭梅毒螺旋体所需的浓度[44]。头孢曲松已经在临床上成功治疗潜伏期梅毒[37]、一期梅毒[37，56，75]、二期梅毒[37，75]、潜伏梅毒[16]及神经梅毒[50，66，74]。但如苄星青霉素一样，同样有头孢曲松治疗HIV感染梅毒患者失败的报道[16]。

            Doxycycline (100 mg twice daily for 21 days) is also an effective alternative for treatment of the non-HIV infected adult with syphilis. The enthusiasm for this regimen is also restrained because it is bacteriostatic in vitro and not bacteriocidal (84). Furthermore, tetracycline and doxycycline are contraindicated in pregnant women and children under the age of 8 because of potential damage to developing bones and teeth (61). Since tetracycline and doxycycline have similar spectrums of antibacterial activity, most data in support of doxycycline has been extrapolated from previous trials with tetracycline, a drug that one is less inclined to recommend because of its poor CSF penetration. Patients treated with 24-32 grams of tetracycline for 10 -12 days have had similar serological and symptomatic response to therapy when compared to penicillin (23,24,76). One study reported a failure rate at 12 months of below 4%, which was similar to that obtained with benzathine penicillin therapy (75). However, one small prospective observational study showed that doxycycline (100 mg bid for 28 days) resulted in 100, 90, 68, and 90% success rates in treating primary, early, late, and congenital syphilis, respectively (64).

　　对于非HIV感染的成人梅毒患者，多西环素（100mg 1天2次共21天）也是一种有效的选择。但此方案的不足之处在于多西环素在体外试验中是抑菌剂而非杀菌剂[84]。进一步而言，由于对生长发育中的骨骼、牙齿有潜在的损害，故四环素、多西环素禁用于孕妇及8岁以下儿童[61]。由于四环素及多西环素有相似的抗菌谱，支持多西环素的临床数据大多数由之前四环素的临床试验外推而来。由于对血脑屏障的穿透能力不良，四环素目前已经很少作为推荐用药。应用四环素治疗10-12天总剂量24-32克在血清学及症状方面和青霉素治疗效果相似[23，24，76]。一项研究表明，四环素治疗12个月治疗失败率低于4％，这和苄星青霉素的效果类似[75]。然而，一项小规模的前瞻性观察性研究表明，多西环素（100mg bid共28天）对于一期、早期、晚期及先天性梅毒的治疗成功率分别为100％、90％、68％及90％[64]。

               Other regimens that are less desirable because of poor CSF penetration include benzathine penicillin, as previously discussed, and the macrolide antibiotics. Erythromycin had a failure rate of 14% after a follow up of 18 months (75). Another macrolide, azithromycin, has been shown to be effective multiple, small case series (28, 53, 85). In one nonrandomized study, non-HIV infected patients with primary or secondary syphilis were treated with azithromycin (500 mg per day), with cure in 11 of 13 patients for at least 3 months (85). In another similar study of early syphilis, the 10 of 14 patients had negative VDRL tests after 6 months treated with azithromycin showed more rapid resolution both clinically and serologically those treated with azithromycin showed more rapid resolution both clinically and serologically than the other treatment groups with no evidence of chronic sequelae (53). However, it is unclear if azithromycin at standard doses achieves therapeutic levels in the CSF (78) and therefore it can only be recommended when there are no other alternatives. Because of excellent CNS penetration, chloramphenicol, when available, (2 gm daily for 30 days) is another alternative that can be used for treatment of neurosyphilis. In every instance, prolonged treatment will result in a cure since, with the exception of erythromycin, antibiotic resistance has not yet evolved.

　　由于透过血脑屏障的能力不良，其他治疗方案难以令人满意，包括苄星青霉素及大环类酯类抗生素。例如，随访18个月发现红霉素的治疗失败率高达14％[75]。其他大环类酯类药物，例如阿奇霉素，在几个小的病例系列中显示有效[28，53，85]。在一项对非HIV感染一期或二期梅毒患者应用阿奇霉素治疗（500mg qd）的非随机研究表明，至少在3个月内13例患者中有11例治愈[85]。另一项针对早期梅毒的类似研究发现，应用阿奇霉素治疗6个月后，14例患者中有10例VDRL转阴，表明应用阿奇霉素治疗较研究中其他方案有更快的临床及血清学缓解，而不伴有慢性后遗症[53]。然而，目前并不清楚阿奇霉素在标准治疗剂量时能否在脑脊液中达到治疗浓度[78]，因此仅在无其他药物选择的情况下才选用阿奇霉素。由于有良好的血脑屏障透过能力，氯霉素（2g 1天1次共30天）可以作为神经梅毒治疗的另一种备选方案。除红霉素外，由于耐药性尚未出现，延长疗程可以提高治愈率。

Bai ZG,et al. Azithromycin vs. benzathine penicillin G for early syphilis: a meta-analysis of randomized clinical trials. Int J STD AIDS. 2008 Apr;19(4):217-21.

Stoner BP. Current controversies in the management of adult syphilis. Clin Infect Dis. 2007 Apr 1;44 Suppl 3:S130-46.

Special Situations

Congenital Syphilis: For newborns, the treatment is 50,000 units/kg of aqueous crystalline penicillin G intravenously every 12 hours for a total of 100,000-150,000 units/kg/day for the first 7 days of life and then every 8 hours for a total of 10 days (8). The alternative regimen is 50,000 units/kg of procaine penicillin intramuscularly daily for 10 days. If treatment is interrupted for more than 24 hours, then the full course of therapy is restarted. Children diagnosed beyond the newborn period with congenital syphilis should also be treated presumptively for CNS involvement with therapy as described above except that aqueous crystalline penicillin needs to be administered every 4-6 hours instead of every 8 or 12 hours.

特殊情况

先天性梅毒：对于新生儿，出生后第1-7天的治疗方案为水剂青霉素G 5万单位/kg，静脉滴注每12小时1次，总量10-15万单位/kg/天，随后每8小时1次，总疗程10天[8]。备选方案是普鲁卡因青霉素5万单位/kg，肌注1天1次共10天。如果治疗中断超过24小时，治疗应重新开始。新生儿期过后的儿童先天性梅毒需按中枢神经系统受累来治疗，除了水剂青霉素应每4-6小时给药而不是每8小时或12小时给药1次之外，其余治疗同上述。

Optic Syphilis: Syphilitic involvement of the eye, a relatively common occurrence in HIV co-infected persons, should be treated with penicillin G 12 to 24 million units per day for 10 to 14 days regardless of CSF findings (13). Penicillin, however, regardless of dose or preparation, does not easily achieve treponemicidal levels in anterior chamber of the eye and hence, requires high doses and prolonged treatment (14 days) to improve the chances of adequate aqueous fluid levels (84). An illustrative case is that of a newborn with congenital syphilis receiving penicillin G potassium 50,000 units/kg body weight given intramuscularly at 12 hour intervals for 17 days after birth and T. pallidum were found in both the aqueous humor and ground eye tissue at autopsy (32). Hence, it may also be prudent to consider chloramphenicol or cephalothin, antibiotics that do achieve adequate levels in the anterior chamber of the eye, as possible first line agents (84).

眼梅毒：梅毒累及眼睛在HIV重叠感染的患者中相对常见，无论有否脑脊液异常发现，其治疗为青霉素G 1200－2400万单位/天共10-14天[13]。然而，无论应用何种剂量或何种制剂的青霉素均不易在眼前房达到灭菌浓度，因此需要提高剂量及延长疗程（14天）以提高达到灭菌浓度的机会[84]。例如，1例先天性梅毒的新生儿接受青霉素G钾5万单位/kg，肌注每12小时1次共17天的治疗后，在尸解中仍能在体液及眼底组织中发现梅毒螺旋体[32]。因此，也可以谨慎考虑使用能在眼前房达到灭菌浓度的氯霉素或头孢菌素类抗生素作为可能的一线用药[84]。

Otosyphilis: As is the case of penetration into the anterior chamber of the eye, penicillin does not easily penetrate the labyrinth of the inner ear (84). Hence, a neurosyphilis regimen is warranted. Patients are usually treated with a prolonged course of penicillin for six weeks to three months with the addition of steroids (10,15,91) Oral prednisone 30-60 mg daily or every other day for at least 7 to 8 days should be given as tolerated by the patient (91). The utility of the steroids has never been proven but has become the standard of care to guard against the sudden worsening of hearing loss attendant to an acute reaction to released antigens form lysing organisms (Jarish-Herxheimer Reaction).

耳梅毒：正如青霉素难以透入眼前房一样，青霉素也不易透入内耳迷路[84]。因此，需考虑治疗神经梅毒的方案。通常需延长青霉素疗程到6周至3个月并联用糖皮质激素[10，15，91]。对于能耐受的患者，应口服泼尼松30-60mg 每天1次或隔天1次持续至少7-8天[91]。使用糖皮质激素于上述的临床情况尚未得到证实，但已广泛的使用于机体对病原体溶解后释放的抗原产生的急性反应（Jarish-Herxheimer吉赫反应）所造成的听力急剧下降的治疗。

HIV Infected Patients: More florid clinical manifestations, including multiple and more frequent genital ulcers (72) and symptomatic neurosyphilis, occurring early in the course of syphilis suggestive of a high spirochete burden (41), have been well documented in persons co-infected with HIV. In addition, multiple case reports suggest that HIV infected patients are more likely to fail antibiotic therapy than non-HIV infected patients (3, 41, 47, 60). For example, T. pallidum was isolated in three of three HIV infected patients evaluated after single dose benzathine penicillin therapy for early syphilis but could be cultured in the only patient without HIV infection (47). In addition, in a study of 59 patients with neurosyphilis, HIV infected patients were 2.5 and AIDS patients were 3.7 times less likely to normalize CSF-VDRL (51). Multiple retrospective chart reviews have documented treatment failures in up to 20% of HIV infected patients (16,48), significantly higher than the 5-10% failure rate reported prior to the AIDS era. Furthermore, unlike many treatment failures in immunocompetent hosts, these failures are more likely to be associated with clinical disease, especially neurosyphilis (14,16,48).

HIV感染患者：已经证明在HIV重叠感染的患者中，具有更严重的临床表现，包括多发、频发的生殖器溃疡[72]、症状性神经梅毒等，上述情况在疾病早期即可出现表明此类患者有梅毒螺旋体的高负荷[41]。此外，多个病例报道提示HIV感染患者较非HIV感染患者更容易有抗生素治疗的失败[3，41，47，60]。例如，在单剂量苄星青霉素治疗早期梅毒后，3例HIV感染患者均能分离出梅毒螺旋体，而在非HIV患者中只有1例分离出梅毒螺旋体[47]。此外，在1项纳入59例神经梅毒患者的研究中表明，脑脊液VDRL恢复正常的可能性在HIV感染者及AIDS患者中分别降低2.5或3.7倍[51]。多个回顾研究发现HIV感染患者治疗失败率高达20％[16，48]，比HIV流行前的5-10%治疗失败率高得多。进一步而言，和免疫功能正常患者的治疗失败不同，HIV感染患者的治疗失败多数有临床症状，尤其是神经梅毒[14，16，48]。

               More florid clinical manifestations and the higher frequency of treatment failures are most likely due to immune dysfunction coincident with HIV that results in a significantly higher spirochete load. There is a greater likelihood that spirochetes will remain active in sequestered sites. Hence, in HIV infected patients, it is prudent that only antibiotics that more reliably penetrate the CNS, such as high dose penicillin or amoxicillin with probenicid, for 10-14 days.

[Review Article: Lynn WA, Lightman S. Syphilis and HIV: a dangerous combination. Lancet Infect Dis. 2004 Jul;4(7):456-66.]

　　免疫功能异常导致了更严重的临床表现及更高的治疗失败率，这与HIV感染导致病原体负荷显著增加相一致。梅毒螺旋体更容易在机体免疫隔离的组织保持活力。因此，在HIV感染患者中，只有能有效透过血脑屏障的治疗方案才能选用，例如高剂量青霉素、阿莫西林联用丙磺舒治疗14天等。

Ghanem KG et al. Lumbar Puncture in HIV-infected Patients with Syphilis and No Neurologic Symptoms.Clin Infect Dis. 2009 Mar 15;48(6):816-21.

Jarisch-Herxheimer reaction: Treatment for syphilis is not necessarily benign. Along with the discomfort of intramuscular or intravenous therapy and the possibility of a drug reaction, an acute febrile response to therapy is seen in 10-25% of all patients and 70-90% of patients with secondary syphilis (84). It is rarely seen in latent syphilis and occurs in varying amounts in the various forms of tertiary syphilis (73). This reaction, called the Jarisch Herxheimer reaction, is most commonly associated with penicillin therapy but also has been associated with other antibiotics used to treat syphilis (2). It has been correlated with the release of heat stable “pyrogens” from T. pallidum and other spirochete infections (84) probably resulting in a rapid high release of inflammatory cytokines and chemokines. The clinical course is marked by the abrupt onset of symptoms usually beginning within two hours, occasionally as late as 24 hours, after initiation of therapy (8, 84). Besides fever, clinical signs and symptoms may include chills, headache, nausea, vomiting, myalgias, tachycardia, hyperventilation, mild hypotension, vasodilatation with flushing, and the exacerbation and new onset of skin lesions (73). It lasts 12-24 hours and is generally safe and self-limited (84). The exceptions are during the second half of pregnancy when there a risk of premature labor and fetal distress (8) and during cardiovascular, neurosyphilis and otosyphilis when reactions are more severe and can be life threatening (84). Acetaminophen or aspirin can be used for symptomatic relief. In severe cases or those associated with cardiovascular syphilis or neurosyphilis, prednisone 60 mg can be given. When given intravenously, this usually results in a prompt and dramatic decrease in fevers (84).

Jarisch-Herxheimer 反应（吉赫反应）：梅毒的治疗是有一定副作用的。除了肌肉注射或静脉点滴造成的不适以及可能发生的药物反应之外，10-25%的梅毒患者、70-90%的二期梅毒患者可在治疗后出现急性发热反应[84]。此反应在潜伏梅毒患者中很少出现，而在三期梅毒患者中形式、程度各不相同[73]。此反应被称为吉赫反应，其多数和青霉素治疗有关，但也与其他治疗梅毒的抗生素有关[2]。吉赫反应与梅毒螺旋体及其他螺旋体释放的热稳定球蛋白有关[84]，热稳定球蛋白可以导致炎性细胞因子及化学因子的高速释放。此临床过程通常在开始治疗后2小时内突然出现，但偶见于治疗后24小时[8，84]。除了发热，临床表现也包括了寒战、头痛、恶心、呕吐、肌肉疼痛、心动过速、过度通气、轻度血压下降、由于血管扩张导致的皮肤潮红以及爆发性的新发皮损[73]。其持续12-24小时后逐渐平稳并自限[84]。但在怀孕后期，吉赫反应有可能造成早产及胎儿窘迫[8]，在心血管梅毒、神经梅毒、眼梅毒的患者中，吉赫反应表现更为严重并有可能是致命的[84]。对乙酰氨基酚或阿司匹林可用于对症治疗。在严重病例或心血管梅毒、神经梅毒的患者中，可予泼尼松60mg。静脉应用激素可迅速有效控制体温[84]。

Penicillin Desensitization: Since penicillin is the optimal therapy for syphilis, penicillin should be seriously considered even in patients with penicillin allergies, except in those with a history of Stevens-Johnson syndrome, or alternatives are limited. These situations include syphilis in pregnant women, infants with congenital syphilis and adults with symptomatic neurosyphilis since treatment must be effective as soon as possible to prevent irreversible neurological disease. In addition, in syphilis in pregnancy and congenital syphilis, the toxicities associated with the tetracyclines make this option undesirable not only in terms of possible treatment failures but also in terms of damage to bone and teeth development (61).

青霉素脱敏：由于青霉素是治疗梅毒的最佳药物，即使在青霉素过敏的患者中，仍需认真考虑应用，尤其是替代药物受到限制时，但曾有Stevnes-Johnson综合征者除外。这些情况包括妊娠梅毒、先天性梅毒婴幼儿以及治疗需尽快起效以预防不可逆神经系统损害的有症状的成人神经梅毒。此外，对于妊娠梅毒及先天性梅毒患者，四环素治疗不但有治疗失败的风险，而且有影响骨骼及牙齿生长发育的可能，故于上述情况中，不应使用[61]。

               Allergic skin reactions to penicillin are the principle toxicity associated with this antibiotic, are much less frequent with the pure preparations used today and occurred in at most 4% treatment courses in the past with less pure product (86). In addition, the vast majority of patients who report a history of penicillin allergy will not have an allergic reaction upon re-challenge.

        皮肤过敏反应是青霉素过敏的主要表现，在过去青霉素纯度不足的情况下，治疗过程中的发生率不到4％，而目前在青霉素纯化制备后，其发生率就更低了[86]。此外，在大部分有青霉素过敏病史的患者中，在再次应用青霉素时并不过敏。

               Anaphylactic reactions are extremely rare today. The most reliable method of distinguishing those who will have a future reaction from those who will not is skin testing. Prior to skin testing, patients should be instructed not to take antihistamines, tricyclic antidepressants, and adrenergic drugs within a time interval appropriate for the corresponding half-life of the medication (8). For instance, chlorpheniramine maleate or terfenadine should not have been taken within 24 hours; diphenhydramine HCL or hydroxyzine within 4 days; and astemizole within 3 weeks. Testing is begun by injecting skin test reagents, including a negative diluent and positive histamine controls, in the epidermis on the volar surface of the forearm with a 26 gauge needle without drawing blood (86). If there is no reaction, then the same reagents are injected intradermally and if the diameter of induration is greater than 5 mm after 15 minutes, then the test is positive.

        目前，过敏反应已经很少发生。皮试是判定是否出现过敏反应的最可靠方法。在皮试前，应根据不同药物的相应半衰期在一定时间内停用抗组胺药物、三环类抗抑郁药物及肾上腺素能药物[8]。例如，在皮试24小时内不应用马来酸氯苯那敏或特那定，4天内不应用苯海拉明或羟嗪，3周内不应用阿斯咪唑。皮试首先应用26G针头在前臂掌侧皮内（回抽未见血）注射皮试试剂，并注射阴性对照及组胺作为阳性对照[86]。若无反应，相同的皮试剂在皮内注射，若15分钟后硬结直径大于5mm，则皮试阳性。

               Optimally, skin testing should include diluents with both the major and minor determinants of penicillin (86). If the skin test is negative, then there is no risk of anaphylaxis but 1-3 percent of patients will develop a mild cutaneous reaction. If the skin test is positive, then desensitization should be carried out prior to treatment since there is a 50-70% risk for an acute reaction. Because minor determinants of penicillin are not commercially available in the United States, skin testing is often done with the major determinants only. In this case, if the test is negative then patients should still receive gradually increased doses of penicillin in monitored setting since there still is at least a 3% risk of a reaction (2).

　　皮试时最好应用含有主要抗原决定簇及次要抗原决定簇的青霉素稀释液[86]。若皮试阴性则无过敏风险，但仍有1-3%的患者会出现轻度的皮肤反应。若皮试阳性，则有50-70%的可能发生急性反应，故在青霉素治疗前需先行脱敏。由于美国并无含有次要抗原决定簇的青霉素试剂，所以只能应用含有主要抗原决定簇的青霉素试剂来皮试。在此情况下，由于仍有至少3％的过敏风险，所以即使皮试阴性，青霉素剂量仍需在监护下逐渐增加[2]。

               Although desensitization can be done both orally and intravenously, oral desensitization is probably safer and certainly less expensive and easier (86). It should be performed in an intensive care setting with continuous electrocardiogram monitoring. Doses of penicillin should be gradually increased until the dose required for therapy is achieved. One-third of patients will develop a transient allergic reaction during desensitization but it is usually mild and self-limited. If mild symptoms occur, then the dose of penicillin should be stabilized until there are no signs or symptoms. If it is more sever, such as hypotension, laryngeal edema, or asthma, then the dose should be reduced at least ten-fold. There should be no interruption between desensitization and treatment since there the risk of an allergic reaction increases as the time from desensitization increases.

(Printable Version of Antimicrobial Therapy for Treponema Pallidum)

　　虽然青霉素脱敏可以通过口服或静脉给药，但口服给药更安全、简便、便宜[86]。青霉素脱敏需在持续心电监护下进行。青霉素须逐渐增加至治疗剂量。在脱敏过程中，三分之一的患者会出现一过性的过敏反应，但通常是轻微及自限性的。若出现轻微过敏反应，青霉素须暂停加量，直到反应消失。若过敏反应强烈，例如出现低血压、喉部水肿或喘息，则青霉素剂量须至少降低10倍。由于脱敏中断时间越长，过敏反应的风险越大，故脱敏及治疗须连续进行。

ENDPOINTS FOR MONITORING THERAPY Guided Medline Search

Non-HIV Infected Patients

               As in any disease, the primary endpoint of therapy is clinical and a carefully taken medical history, physical exam and appropriate laboratory tests will determine if therapy has been successful. In primary syphilis, the patient should be examined for resolution of the chancre; in secondary syphilis, for resolution of the skin rash and any of the other protean disease manifestations that the patient may experience; and in early neurosyphilis for resolution of signs and symptoms of neurological disease. In late neurosyphilis, there is usually no reversal of signs and symptoms that are present prior to therapy but patients should be monitored carefully for further progression of disease. During any stage of syphilis and at any time, if there is persistence or recurrence of clinical disease, the person should be retreated. He or she should also be questioned about the possibility of re-infection to ease the concern about antibiotic resistance.

治疗终点：

非HIV感染患者

        正如其他疾病一样，治疗的终点取决于临床情况，仔细的病史采集、体格检查以及恰当的实验室检查均有助于判定治疗是否有效。对于一期梅毒，需检查硬下疳是否消退；对于二期梅毒，需检查皮疹及其他多种症状是否消退，对于早期神经梅毒，需检查神经系统受累的表现是否消退，对于晚期神经梅毒，在治疗前通常无可逆的症状及体征，但仍需密切监测是否有疾病进展。无论任何时候或在梅毒的任何阶段，若出现疾病持续或复发的临床证据，需再次治疗。同时，需明确患者有否再感染的可能，以协助辨别是否是梅毒螺旋体耐药的发生。

               However, since the disease process is clinically silent at many stages and we are unable to grow in routine culture, it is necessary to follow disease activity with surrogate markers of infection. Treponemal antibody tests such as the FTA-abs are not helpful for measuring response to therapy since they are not quantified, usually remain positive for life, and do not correlate with disease activity (70,79). In contrast, nontreponemal tests such as the RPR and VDRL are quantifiable, revert to negative in the vast majority of patients given effective therapy, and do correlate with disease activity. In fact, without therapy, 25% of patients eventually have non-reactive VDRL tests (33). With therapy, nearly 100% of non-HIV infected persons change from reactive to non-reactive.

        由于在许多阶段疾病的进展是隐匿的，而我们无法反复进行病原体培养，故需采用其他一些提示感染存在的指标来监测疾病的活动。由于FTA-abs等梅毒螺旋体抗原血清试验并非定量检测，而且通常终生阳性，和疾病的活动无关，故无法用于评估治疗的反应[70，79]。相反，RPR、VDRL等非梅毒螺旋体抗原血清试验则是定量检测，和疾病活动相关，在大部分治疗有效患者中可以转阴。事实上，即使不经过治疗，有25%的患者最终VDRL检测阴性[33]。治疗后，接近100％的非HIV感染梅毒患者转阴。

               Fiumara found that all 196 patients with treated primary syphilis had non-reactive RPR titers at one year (23) and all 204 patients with treated secondary syphilis by two years (24). In addition, he found that only 44% of 275 patients treated for late latent syphilis became seronegative (25). In another series, all patients with primary syphilis had resolution both clinically and serologically but only 55% of patients with secondary syphilis (58). However, some studies have shown that low but positive titer VDRL or RPR tests of 1:16 or less may persist despite no other evidence of treatment failure (the “serofast reaction”) (8,76). This may represent a false positive result or, especially when the titer is >1:4, persistent active infection or reinfection (84). HIV-infected patients are more likely to have a persistently high-titer RPR or VDRL.

　　Fiumara在一项研究中发现，196例一期梅毒患者在治疗1年后检测RPR全部转阴[23]，204例二期梅毒患者在治疗2年后全部转阴[24]，而275例晚期潜伏梅毒患者在治疗后只有44％转阴[25]。在另一项研究中，所有一期梅毒患者治疗后均得到临床及血清学缓解，而在二期梅毒患者中只有55％[58]。然而，一些研究发现即使无其他治疗失败的证据，VDRL或RPR仍可持续表现≤1:16的低滴度阳性，称之为“抗血清反应”[8，76]。此现象可能是假阳性的表现，但也可能代表感染的持续活动或再感染，尤其当滴度＞1:4时[84]。HIV感染的梅毒患者更容易出现RPR或VDRL的持续高滴度阳性。

               Since VDRL titers are often slightly lower than RPR titers and there is significant variation in values between laboratories, either a RPR or VDRL, is best obtained from the same laboratory each time to monitor therapy (8). A fourfold change in titers, equivalent to a two dilution change, is considered a significant change and implies a change in disease activity. For instance, a change from 1:64 to 1:8 is significant while a change from 1:64 to 1:32 is not. The frequency of obtaining serological testing after treatment depends on the stage of disease and characteristics of the patients. Non-HIV infected adults with syphilis should be tested at three, six, and twelve months (84). If syphilis is greater than one year in duration or of unknown duration, then serologic testing should also be checked at 24 months. Pregnant women who are infected should have follow up serology in the third trimester and at delivery (8). If a pregnant woman is at a high risk for re-infection or in an area where the prevalence of syphilis is high, she should be retested every month (8). Infants with congenital syphilis and those who are sero-positive only because of passive transfer of maternal antibodies and are not infected should be checked with serological testing every two to three months (8).

        由于VDRL滴度通常略低于RPR滴度，不同实验室测定值之间也有差异，因此RPR或VDRL每次检测最好在同一实验室进行[8]。滴度4倍改变，相当于2倍稀释，有临床意义，提示疾病活动的变化。例如，滴度由1:64降低到1:8是有意义的，而从1:64到1:32则是无意义的。治疗后血清学检测的频率取决于疾病的分期及患者的特点。非HIV感染成人梅毒患者应在治疗3、6、12个月后进行检测[84]。若梅毒病程超过1年，或病程不明确，应在治疗24个月后再次检测。妊娠梅毒妇女需每3个月检测1次并在分娩时检测[8]。若孕妇再次感染的风险高，或在梅毒高发区生活，需每月检测1次[8]。先天性梅毒婴儿以及那些由于被动获得母体抗体而仅仅表现出血清学阳性但非感染的婴儿需每2-3个月检测1次[8]。

               The rate of decline after treatment of nontreponemal titers appears to be related to the stage of disease, height of the initial titers, and a prior history of syphilis (6, 23, 24, 25, 26). Brown and co-workers found a fourfold decrease in RPR titers at 6 months and eightfold decrease at 12 months in successfully treated patients with primary and secondary syphilis but there was a slower decline in patients with early latent disease and longer duration of symptoms (6). In contrast, patients with no prior history of syphilis (re-infection) have a more rapid decline in titers (6, 23, 24, 27). In addition, patients with macular rashes during the secondary stage revert to negative quicker than those with papular rashes (26). When titers do not decline fourfold by six months in primary or secondary syphilis or patients have a positive RPR/VDRL reaction beyond 12 months in primary syphilis, 24 months in secondary or latent syphilis, or 5 years in late syphilis, then patients should have a CSF examination and be retreated (66).

　　治疗后非梅毒螺旋体抗原血清滴度下降率似乎和疾病的分期、治疗前滴度的高低以及是否有梅毒既往史有关[6，23，24，25，26]。Brown及其同事发现在治疗有效的一期及二期梅毒患者中，治疗6个月后RPR滴度下降4倍，12个月后下降8倍，但在早期潜伏梅毒及症状持续时间长的患者中，滴度下降较慢[6]。相反，无梅毒既往史的患者（再感染），滴度下降更快[6，23，24，27]。此外，表现为斑点样皮疹的二期梅毒患者较表现为乳头样皮疹的患者转阴快[26]。若一期或二期梅毒患者治疗6个月后滴度下降小于4倍，或一期梅毒患者治疗超过12个月后，或二期及潜伏梅毒患者治疗24个月后，或迟发梅毒治疗5年后RPR/VDRL仍阳性，需行脑脊液检查并再次治疗[66]。

               In adequately treated congenital syphilis, titers should decline by three months of age and should be non-reactive by six months of age (8). Titers, however, may decline slower if treatment is not initiated in the neonatal period and, occasionally, titers are still positive up to one year after birth. If titers are found to be stable or increasing or are still present after one year of age, then the child should be re-evaluated fully, including a CSF examination, and retreated.

        经过充分治疗的先天性梅毒患儿，在3个月龄时滴度会下降，而在6个月龄时转阴[8]。然而，若并非从新生时即开始治疗，滴度会下降得较慢。在偶然情况下，滴度可持续阳性到1岁。若滴度无下降、甚至升高，或在1岁时仍阳性，则应再次充分评估病情，包括脑脊液检查，并再次治疗。

               Besides following serum nontreponemal test, a lumbar puncture is recommended every six months after treatment for neurosyphilis, including infants with abnormal CSF analyses, until the pleocytosis has resolved or CNS non-treponemal antibodies disappear (84). Pleocytosis usually resolves before CSF protein declines and CSF-VDRL tests may remain reactive for more than one year (36). If the CSF cell count is not decreased by six months or remains abnormal two years after therapy, re-treatment is indicated (8). In addition, in infants if the CSF-VDRL is still positive at six months of age, the infant should be retreated.

        在神经梅毒（包括脑脊液检查异常的婴幼儿）治疗后，除了检查血请非梅毒螺旋体抗体，也推荐每6个月检测1次脑脊液，直到脑脊液淋巴细胞计数恢复正常及脑脊液非梅毒螺旋体抗体消失[84]。脑脊液淋巴细胞计数通常在脑脊液蛋白下降前恢复正常，而脑脊液VDRL检测可持续阳性超过1年[36]。若脑脊液细胞计数在治疗6个月后仍未下降或治疗2年后仍异常，则需再次治疗[8]。此外，若婴幼儿脑脊液VDRL检测在6月龄时仍阳性，则需再次治疗。

               PCR could potentially become the principle end point marker of disease if and when markers of active replication or viable spirochetes are validated so as to make the test adequately specific for active disease (30, 40, 45, 66).

        若梅毒螺旋体活动复制的标志物或活性梅毒螺旋体的标志物得到验证，从而令PCR对梅毒活动的判定有足够特异性时，PCR可能成为判定治疗终点的一项有效指标[30，40，45，66]。

HIV Infected Patients

HIV感染患者

               Although HIV infected patients may have similar non-treponemal (VDRL and RPR) response as non-HIV infected persons (29,39), HIV infected patients are more prone to have a delayed serological response to infection or therapy and greater likelihood of having persistently reactive non-treponemal titers after treatment (87). Furthermore, HIV infected patients are more likely to have high non-treponemal antibody titers in secondary syphilis, e.g. >1:128 dilution (38), an increased rate of false positive non-treponemal antibody titers (32) and are less likely to have a fourfold decrease in titers within 6 months than matched non-HIV infected patients (81,89). In addition, specific treponemal tests (FTA-ABS, TPHA and MHA-TP) more often become non-reactive in HIV infected patients than in non- HIV infected patients and, as would be expected, this loss of reactivity is associated with lower CD4 lymphocyte counts (31,39).

        虽然HIV感染患者和非HIV感染患者有着类似的非梅毒螺旋体抗原血清检测（VDRL及RPR）反应[29，39]，但HIV感染患者更容易对感染及治疗出现延迟的血清学反应，更容易在治疗后出现非梅毒螺旋体抗体的持续阳性[87]。进一步而言，和非HIV感染患者相比，HIV感染患者在二期梅毒感染时更容易出现高滴度的非梅毒螺旋体抗体，例如＞1:128[38]，更容易出现非梅毒螺旋体抗体检测的假阳性[32]，而治疗6个月内滴度4倍下降的几率较小[81，89]。此外，和非HIV感染患者相比，在HIV感染患者中，特异性梅毒螺旋体检测（FTA-ABS、TPHA及MHA-TP）经常表现为阴性，其原因可能和较低的CD4＋T淋巴细胞计数有关[31，39]。

               This abnormal response to therapy is most likely due to immune dysfunction related to the increased polyclonal B cell activation found in HIV infection rather than a true change in disease activity, although the resultant loss of effective T-cell function could result in less ability to clear the spirochete (81).

        尽管有效T淋巴细胞功能的缺失可能导致梅毒螺旋体清除能力下降，但是这些对治疗的异常反应，很可能源于免疫缺陷和相关的HIV感染患者中多克隆B细胞活化增加，而不是疾病活动的真正改变[81]。

VACCINES Guided Medline Search

               Currently, there are no vaccines available.

疫苗

    目前尚无梅毒疫苗。

PREVENTION Guided Medline Search Smart search

               The most effective prophylaxis against contracting syphilis is avoidance of sexual contact with persons who harbor the spirochete. Condoms use during sexual intercourse can also be inferred to be protective from studies of HIV infection. Currently, prophylactic drugs are not recommendations in any group of patients with syphilis except those who have been exposed to a person with syphilis and in this population, it is unclear whether medicines prevent infection or treat very early disease, e.g. “incubating” syphilis.

预防

        预防梅毒感染的最有效方法是避免和梅毒携带者发生性接触。从对HIV感染的研究中可以外推使用避孕套也可对梅毒感染提供保护作用。目前不推荐任何病人保护性用药，除了和梅毒患者有性接触的人，但在这种情况下，很难界定药物是预防感染还是治疗非常早期的梅毒，例如种植的梅毒病原体。

               We recommend that persons sexually exposed to primary, secondary, or latent syphilis of less than 1- year’s duration within the previous 90 days be treated for syphilis even if they have negative serological tests for syphilis because there is data to suggest that therapy is most successful when initiated early and the treponemal burden is relatively low (32). This is the one instance where treatment with 2.4 million units of benzathine penicillin is acceptable. A possible alternative is a single 1.0-g dose of azithromycin (34).

        对于和一期、二期或病程小于1年的潜伏梅毒患者有性接触的人，即使梅毒血清学试验阴性，仍推荐在90天内接受治疗，这是因为有数据显示及早开始治疗，由于梅毒螺旋体载荷相对较低，有更高的成功率[32]。建议240万单位苄星青霉素治疗，也可予1.0g阿奇霉素1次[34]。

               Transmission occurs only when mucocutaneous lesions are present, which is usually within one year after initial infection (84), so contact with persons with syphilis greater than one year in duration is not an immediate indication for treatment (8). Instead, it is recommended that these persons be followed clinically and serologically for syphilis. Persons with exposure greater than 90 days prior to evaluation need not have immediate treatment, unless they have positive serological test, serological results will be delayed or follow up is uncertain.

Blood transmission is rare today because of the low incidence of disease and blood storage procedures.

        只有存在皮肤损害的时候才会出现传染，这种情况通常出现在感染后1年内[84]，所以和梅毒感染超过1年的患者接触后并不需要立即治疗[8]，而应该监测其临床表现及梅毒血清学试验。接受评估时已经暴露超过90天的患者不需要立即治疗，除非有血清学试验阳性，血清学试验会延迟或无法随访等情况。

        由于梅毒发病率较低以及血液采集储存程序的规范化，血液传播目前很罕见。

Table 1:  Serological Tests (Modified from reference 83) [Download PDF]

表1：血清学检测（根据参考文献83修改）

Table 2:  CDC Guidelines for Syphilis Treatment [Download PDF]

表2：CDC梅毒治疗指南

Table 3:  Therapeutic Preferences and Alternatives [Download PDF]

*Treatment of exposed persons is not included in this table since in many cases it is prevention rather than treatment of active disease (See text for further discussion).

**Not acceptable in pregnancy, congenital syphilis, or symptomatic neurosyphilis.

***Not acceptable in any form of neurosyphilis.

表3：推荐治疗及备选方案

*表格不包括仅有暴露病史病人的治疗，因为在许多病例中应归为对疾病活动的预防而非治疗（进一步讨论见正文）

**不可用于妊娠患者、先天性梅毒及症状性神经梅毒

***不可用于任何形式的神经梅毒

CDC，INH，IDSA 2005：Recommendation for treatment of syphilis among HIV exposed and infected infant

HIV暴露者及婴儿梅毒的治疗

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