REVIEWS OF INFECTIOUS DISEASES • VOL. 12, SUPPLEMENT 6 • JULY-AUGUST 1990
Treatment of Syphilis, 1989 Paul N. Zenker and Robert T. Rolfs
From the Clinical Research Branch, Division of STDIHIV Prevention, Center for Prevention Services, Centers for Disease Control, Atlanta, Georgia
In the first half of this century, syphilis was a major public health problem in the United States: 575,000 cases were reported in 1943, a rate of 4/1,000 population. In contrast, only 68,000 cases were reported in 1986 [1], although the nation's population had doubled. Treatment options available in the early 1940s included mercury, iodine, bismuth, arsenic, and malaria-induced fevers [2]. After World War II, penicillin became widely available. Many studies evaluated different penicillin formulations and regimens; these were reviewed by Idsoe et al. in 1972 [3] and by the Centers for Disease Control (CDC) in 1976 [4-14]. Unfortunately, studies were poorly designed and difficult to compare, and data were scanty in some areas. Thus, CDC recommendations for therapy were based largely on clinical judgment [14]. Despite hopes that future studies would provide definitive answers, few new investigations were performed and the CDC treatment guidelines changed little. Since 1985, however, the incidence of syphilis has increased [15], while case reports of treatment failures have accumulated [16-27]. The CDC guidelines are therefore being questioned, particularly in association with infection caused by the human immunodeficiency virus (HIV). To address these con-
Please address requests for reprints to Technical Information Services (E06), Center for Prevention Services, Centers for Disease Control, Atlanta, Georgia 30333.
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cerns, we review the English-language data both supporting and challenging current syphilis therapy. The evaluation of syphilis treatment trials is complicated by three factors. First, many studies lack the essentials of good design: randomization, blinding, an adequate number of patients (i.e., statistical power), and inclusion of a control group. Second, because Treponema pallidum cannot be cultured routinely, diagnosis of active disease often relies on serologic tests. Third, the natural history of syphilis necessitates long-term follow-up to assess treatment efficacy. Because of the last two factors, studies must have clearly defined entry and outcome criteria, yet these are rarely found. As a result, treatment trials are difficult to evaluate, and optimal treatment regimens are difficult to determine. Diagnosis of Active Syphilis A so-called definite diagnosis of syphilis is based on visualization of the spirochete by dark-field microscopy or direct fluorescent antibody techniques; both procedures are used for lesions of primary or secondary syphilis. Both methods require special equipment and skilled technicians; thus the diagnosis is often made by serologic testing and clinical findings. Since the latter are absent in latent syphilis and are often atypical in late syphilis, these two diagnoses are based on serologic tests only. Antibodies against cardiolipin, known as reaginic or nontreponemal an-
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With the introduction of penicillin after World War II, the incidence of syphilis in the United States decreased. Because of penicillin's great success, clinical trials stopped after an initial period of intensive investigation. Syphilis is a difficult disease to study; the natural history may span decades in an individual, and diagnosis and outcome are usually defined serologically, not clinically or bacteriologically. Although the recommended penicillin regimens changed, clinical trials were not repeated. Furthermore, because the early studies occurred before modern clinical-trial methodology was developed, interpretation of the results is difficult. As a result, while current regimens for syphilis therapy are effective, they mayor may not be optimal. With the accumulation of reports of treatment failures and the recent appearance of human immunodeficiency virus, current regimens for the treatment of syphilis are being questioned. As background for a meeting at which treatment guidelines were reviewed, the available literature on syphilis therapy is summarized herein.
Treatment of Syphilis, 1989
Implications of Natural History In the Oslo study of untreated syphilis, approximately two-thirds of patients never developed late sequelae, and only 6.5070 developed symptomatic late neurosyphilis [43]; yet the CNS is involved in onehalf of patients with early syphilis [44-46]. Clearly, the immune system must affect disease outcome, al-
though this interaction is not understood. Because the development of neurosyphilis (or other sequelae) cannot be predicted, long-term follow-up is needed to measure treatment efficacy. Instead of performing long-term observation, investigators usually monitor titers of nontreponemal antibody to assess the response to treatment. As has been noted, antibody titers are imperfect indicators of disease activity. Twoother factors complicate outcome assessment: the use of antibiotics for other reasons and reinfection. The impact of the former is unknown. The latter is often impossible to distinguish from relapse; most researchers combine these two categories and report rates of re-treatment. Furthermore, previous infections alter the serologic response to new infections [47]. In summary, syphilis treatment trials must use imperfect outcome measures to estimate uncommon events. Since most patients with syphilis are adequately treated, clearly defined outcome criteria, long-term follow-up, and large numbers of patients would be required for full evaluation of a treatment regimen.
Penicillin Therapy for T. pallidum Penicillin is very effective against T. pallidum, but the optimal dose is unknown. Idsoe et al. [3] suggested that effective treatment of early syphilis required maintenance of a minimal serum concentration of 0.03 IU of penicillin/mL (0.018 ug/ml.) for 7-10 days without interruption for more than 24 hours. (The doubling time for T. pa/lidum had been calculated to be 30-33 hours in early disease [48].) Evidence from studies in animals indicates that the duration of treatment and concentration of penicillin in serum are synergistic (as reviewed by Rein [4]). Furthermore, penicillin concentrations of 0.01 ug/ mL are treponemicidal both in rabbit testes and in vitro [49-51]. However, in the same models, a higher concentration of penicillin is more rapidly treponemicidal [52]. The margin between this suggested antibiotic concentration and those required for microbial killing is also less than in most other infectious diseases. Idsoe et al. admitted that the minimal treponemicidal level chosen was somewhat arbitrary [3]; neither the optimal dose nor the optimal duration of administration is known. Despite these caveats, penicillin-resistant strains of T. pallidum have never been isolated, and a concentration of 0.03 IU
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tibodies (e.g., those detected by VenerealDisease Research Laboratory [VDRL] and rapid plasma reagin [RPR] tests), are measured quantitatively, and serum titers usually correlate with disease activity. However, these tests may remain reactive at low titers after treatment (the sero-fast state) or become negative (serorevert) after 5-10 years, even without treatment. Specific treponemal antibody tests (especially the fluorescent treponemal antibody-absorbed [FTAABS] test) are sensitive and specific [28, 29] but usually remain reactive for life despite treatment [30]. Therefore, the positive predictive value of serologic diagnosis is almost 100070 among patients with their first - or any symptomatic - infection. However, serologic diagnosis is less reliable among patients with prior syphilis who are asymptomatic, especially those with low serologic titers. Serologic diagnosis is useful clinically but does not determine the presence of the organism accurately enough for definitive research. FTA-ABS IgM testing makes sense for the monitoring of disease activity but may be unreliable if IgG blocking antibodies' or rheumatoid factor are present, as occurs in congenitally infected infants [31]. Newer tests that reduce this problem, such as column separation of the 19S fraction of serum to remove IgG and rheumatoid factor (FTA-ABS 19S IgM) and IgM capture (ELISA), are becoming available [32-35] and have been reviewed [36]. Although not widely used in the United States, these treponeme-specific IgM assays are considered the best available tests for the diagnosis of active disease [37]. However, even specific IgM may be present for 2 years after treatment [36, 38]. The molecular specificity of antibodies to T. pa/lidum antigen is being examined by immunoblotting and radioimmunoprecipitation; these studies may explain the bases of currently used tests [39-42]. Use of polymerase chain reaction to detect the T. pallidum genome - and therefore the presence of the organism - might also be helpful, especially in research.
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of penicillin/mL is used as a therapeutic gold standard, even in the CSF. Public Health Implications
Persons Exposed to Syphilis Only two controlled studies of therapy for incubating syphilis have been reported [54, 55]. Both found 2.4 million units of benzathine penicillin G (BPG) to be 100% effective in aborting potential syphilis after exposure to a contact with known infectious syphilis (table 1). Within 30 days of exposure, 2.4 million units of procaine penicillin G was also found to be 100% effective. A 3-g dose of tetracycline was only 56% effective, with a 30% infection rate in the placebo control group [55]. In a recent uncontrolled trial, 27 exposed patients received ceftriaxone (125 mg) [59]. On the basis of the seroconversion rate from the trial above, eight infections would have been
Early Syphilis Early syphilis includes primary, secondary, and early latent stages. The last term describes the seropositive, asymptomatic phase during which relapses of secondary syphilis usually occur. In the Oslo study, 90% of relapses of secondary syphilis occurred within 1 year, 95070 within 2 years, and 100070 within 5 years [43]. Stokes originally considered early syphilis to last 4 years [45]. More recently, the duration of early syphilis has been defined as 1 year, in part because 1 year is the interval during which sexually transmitted disease (STD) control programs attempt to ensure partner notification. However, no pathophysiologic or therapeutic reason exists to divide the latent period [3, 7] except for rabbit studies suggesting that increasing amounts of penicillin are necessary with increasing duration of infection [52]. The WHO Expert Committee on Venereal Disease and Treponematoses currently defines the late latent period as ~2 years after the initial infection [37, 61], but 1 year is the cutoff used in the United States [60]. We have divided the latent period for the purpose of reviewing studies and discussing issues, but both the division and its timing are arbitrary. Whether any
Table 1. Efficacy of 2.4 million units of BPG in patients exposed to syphilis and in patients with early syphilis. Type of patient, reference Exposed to syphilis 54 55 Early syphilis 56t
57+ 58t
Stage Contact Contact Primary Secondary Primary Secondary Primary or secondary
No. of patients
Duration of follow-up (no. of patients)
Percentage retreated
131-182* 84
3 mo (83-89) 3 mo (79)
0 0
Primary disease
1.0 5.5
Clinical or serologic failure
0 9.8
Reinfection or failure to become seronegative
119 155 40
80 100
* The number given BPG was not specified; the number
t
All patients had dark-field positive lesions. +Case definition was not stated.
1 Y (60) 1 Y (90) 2 y (37) 1 Y (40) 18-21 mo (?) 1 Y (55) 2 y (25)
5.1 11.4
Retreatment criteria
Failure of titer to respond significantly
shown is the number of patients in each different treatment category.
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Communicable disease control requires effective, simple, inexpensive therapy that assures compliance and minimizes the need for return visits. The preference for depot penicillin preparations for syphilis treatment is an outgrowth of this need. Studies of streptococcal pharyngitis have documented that the rate of compliance with a 10-dayoral regimen of penicillin ranges from 20070 to 90070 [53]. Therefore, multidose outpatient regimens must be superior to single-dose therapy if they are to be recommended.
expected. After 3 months, syphilis developed in two patients. No other drugs have been studied. The effectiveness of combination therapy with ceftriaxone and doxycycline needs to be evaluated, since this is the recommended therapy for gonorrhea [60].
Treatment oj Syphilis, 1989
particular point exists during latency after which more penicillin is needed is not known. eNS Involvement
Penicillin Therapy
Many early treatment regimens used procaine or crystalline penicillin G; these regimens required frequent administration and were no more effective than longer-acting depot preparations [3, 5-7]. Procaine penicillin G in oil with aluminum monostearate was the depot preparation most studied but is no longer available. Studies using 2.4 million units of BPG for the treatment of early syphilis are listed in table 1 [56-58]. (Other studies used BPG but in mixed doses [63, 64, 73].) All of these studies have limitations: no blinding or randomization, varying failure criteria and follow-up, and cumulative retreatment rates that mix relapse and reinfection. However, the re-treatment rates appear to be similar in the different studies and to be higher for secondary than for primary syphilis. This difference may be due to the slower decline in serologic titers in secondary syphilis [74], because patients who did not serorevert within the study period were re-treated. Clinicians claimed not to see clinical relapse [57] and found low serologic relapse rates for primary and secondary disease [56]. Thus, BPG appears to have a low failure rate in early syphilis, but this rate may be higher in the secondary than in the primary stage. No long-term follow-up data exist. Fiumara suggested that early syphilis be treated with two injections of 2.4 million units of BPG given 1 week apart [75-77]. He treated 588 patients with primary syphilis and 623 patients with secondary syphilis with this regimen; all became seronegative within 1 and 2 years, respectively [77]. However, in his studies, patients who developed a fourfold (twodilution; e.g., 1:2-1:8) increase in serologic titers after their lesions had healed and their titers had begun to fall were considered reinfected and excluded from analysis. In the other studies previously cited, these patients would have been counted as needing re-treatment. Durst et al. reported similar results with 40 patients given 6 million units of BPG; however, entry criteria and study methods were not described [78]. The clinical significance of becoming seronegative is unknown, and a controlled comparison study is needed to determine whether a second dose of BPG improves cure rates. No studies of early latent syphilis treated with 2.4 million units of BPG exist. Fiumara reported that 95070 of 368 patients whose latent disease «1 year) was treated with two doses of 2.4 million units of
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The CNS is commonly involved in early syphilis. Among 3t244 patients with early syphilis, 24070 of those with seronegative primary syphilis, 34% of those with early secondary syphilis, and 56070 of those with late secondary syphilis had abnormal CSF findings, as defined by cell count, protein, Wassermann reaction, or colloidal gold test [45]. Furthermore, T. pa//idum has been isolated from the CSF of rv15% of patients with early syphilis and otherwise normal CSF [37t 38]. Thus the CSF is affected in at least one-half of patients with early syphilis. Lukehart et al. [46] confirmed these findings in a carefully performed study: of 43 patients with early syphilis, 12 had T. pallidum isolated from CSF and another 12had pleocytosis. Isolation of T.pa//idum was not wellpredicted by reactive CSF VDRL or CSF FfA-ABS tests in early disease. The meaning of these abnormal CSF findings in asymptomatic patients is unknown, since fewer than 10070 of untreated patients develop symptomatic neurosyphilis [43]. Studies have found the CSF to be normal 9 months and 2 years after treatment with various penicillin regimens, including 2.4 million units of BPG [62-64]. Despite the number of patients with early syphilis who have laboratory evidence of CNS involvement, acute syphilitic meningitis is rare [45, 65]. It is not logically appealing to treat patients differently on the basis of the presence or absence of meningismus; mild neurologic symptoms are common and do not correlate with laboratory parameters [46]. Other modalities, such as auditory brainstem responses, may prove to be better markers of CNS dysfunction [66, 67]. Still, it seems reasonable to treat patients with clinically evident syphilitic meningitis more aggressively, since cranial nerve palsies occur in 44% of such patients [65] and are reversible with therapy [67-72]. Though data are lacking, the current treatment regimens used for neurosyphilis [60] seem reasonable. As has been mentioned, most asymptomatic CNS involvement resolves with or without therapy. Whether subsets of patients exist who are destined to develop neurologic disease despite therapy is unknown. Studies are needed to define the long-term effectiveness of treatment for preventing progression to neurosyphilis.
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Therapeutic Alternatives to Peniclllin
Penicillin is clearly the drug of choice for syphilis. No alternative antibiotics yield lower failure rates, and all require multiple doses. Penicillin should therefore be used except in the presence of true allergy. Skin testing should be available for patients with a history of penicillin allergy. If penicillin cannot be used, alternatives do exist for treatment of early syphilis. Tetracyclines. Older studies of tetracycline therapy for early syphilis have been reviewed [5, 6]. Only three investigations used exclusively oral regimens and followed patients for 1 year [58] (table 2). (Another study also met these criteria but used a high dose so that patients drank milk with their tetracycline [97].)Schroeter et al. compared tetracycline with BPG and found no significant difference in the retreatment rate at 2 years [58]. Taggart et al. used mul-
tiple regimens and found 60 mg/tkg-d) for 8 days to be the best [98]. Fiumara also reported excellent results [99], and - despite previously mentioned caveats about his exclusion policy - his data show that tetracycline can be effective in early syphilis. The cumulative doses used in these studies were 24-32 g, or rv2 g daily for 2 weeks. The efficacy of tetracycline in latent syphilis is probably comparable to that of penicillin. Doxycycline at a dosage of 100mg every 12hours is pharmacologically equivalent to 500 mg of tetracycline every 6 hours [100]. The mean inhibitory and bactericidal concentrations against treponemes are similar for tetracycline and doxycycline [101, 102]. Treatment with doxycycline improves compliance: fewer doses are required, and these can be taken with meals and cause less gastrointestinal irritation [101]. Doxycycline also penetrates the CNS better [102]. However, few relevant studies of the efficacy of this drug in the treatment of syphilis have been done [91-93] (table 2). Despite small numbers of patients, insufficient follow-up, and poor documentation, the outcome of treatment with this agent appears good and there is no theoretical reason for doxycycline to be less effective than tetracycline. Failures with doxycyclinehave not been reported despite its widespread use. While further studies would be desirable, doxycycline may be considered the equivalent of tetracycline for the treatment of early syphilis. Erythromycin. The studies of erythromycin therapy for early syphilis have been reviewed [5, 6]. In the only trial that compared BPG and tetracycline with erythromycin; both 20- and 30-g erythromycin regimens resulted in higher rates of failure (retreatment) [58]. Other investigations with a 20-g total dose have yielded failure rates ranging from to 180/0 [73, 105-107]. Few data exist for a 30-g totaldose regimen. Most studies have been done with the estolate preparation, which is associated with cholestatic hepatitis [108]. Erythromycin is also poorly tolerated, and compliance is likely to be worse than that with tetracycline. The use of erythromycin should be limited to selected patients, who should be closely monitored. Chloramphenicol. In the past, chloramphenicol was used to treat syphilis. Good results were usually reported, especially at higher doses [73,98, 109, 110]. In one series, 105 patients received rv50 mg/tkg-d) for 7-16 days; infection was cured in all who were followed for 3 years, but 12 patients developed agranulocytosis [110]. The treponemicidal activity of
°
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BPG became seronegative within 2 years of treatment [79, 80]. This finding is comparable to that investigator's results with earlier stages, suggesting that primary, secondary, and early latent disease respond similarly. Many case reports have purported to show that BPG fails to prevent progression to late disease [81-85]. However, it is rarely possible to exclude reinfection. A fewreports of cases of clear failure in both primary disease [16] and secondary disease [17, 18] have been published, though at least one of the patients involved had antibody to HIV. That failures occur is not unexpected, given the trials previously reviewed. Although no active surveillance for treatment failures exists, the large number of patients treated for early syphilis and the few reported failures suggest that the failure rate is low. Similarly, gummas and cardiovascular syphilis are now thought to be rare despite treatment of 60,000120,000patients per year [15] with BPG for over 25 years. Cardiovascular syphilis, which occurs in ~10OJo of untreated patients [43, 86], is now found in ~2OJo of patients at autopsy; even these cases are in elderly patients who presumably became infected before penicillin was available, and more than half of these patients were never treated [87, 88]. In summary, the data appear to provide an insufficient basis for change of the current treatment recommendation of 2.4 million units of BPG for early syphilis. Since failures may occur, follow-up of treated patients is recommended.
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Treatment oj Syphilis, 1989
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Table 2. Efficacy of alternatives to penicillin for the treatment of early syphilis.
Drug, reference Tetracycline 58 98 99
93 Ceftriaxone 59 94 95 96
Stage *
No. of patients
Dose 3 g/d x 10 d 60 mg/ikg-d) x 8 d 2 g/d x 12 d 2 g/d x 12 d
(+ )Dark-field (+ )Dark-field Symptoms, (+ )FTA, (+ )RPR
P, S P, S P S
(+ ) Dark-field
(+ )Dark-field
P, S P S Latent Early
19 5 10 16 40
100 100 100 100 100
(+ )Dark-field Symptoms and (+ ) serology Symptoms and (+ )FTA or (+ )Dark-field Not stated Symptoms and (+ ) serology
P S P P, S P, S
16
Either 250 mg/d x 10 d or 500 mg qod# x 5 d 2 gld x 2-5 d 1 g every 3 d x 4 IgqodX4
Not stated
107 36 52 59
8 18 14
mg mg mg mg mg
bid bid bid bid bid
x x x x x
10 d 28 d 28 d 28 d 10 d
2 y (40) 1 Y (19) 1Y 2y
10 2t 0+ 0
6 w-9 mo
It 0 1§ 5§ 011
3 mo
0
1 Y (8) 1 y (18) 1 y (14)
0 1§ It
3 mo 2 mo-7 y
*P
= primary syphilis, S = secondary syphilis. t Reinfections. + Reinfections excluded. § Based on various serologic criteria. II Serologic results not specified clearly. # qod = every other day.
chloramphenicol against T. pallidum has also been questioned: 100 mg/kg does not produce bacteriologic cure in rabbits [110a],and 100J.1g/mL does not immobilize the organism in vitro [110b]. Chloramphenicol should not be used to treat early syphilis. Amoxicillin. Ampicillin and amoxicillin are actively treponemicidal in vitro [102] and appear effective in early syphilis, although data are limited [110c]. However, there is no practical reason to use either drug instead of BPG. Ceftriaxone. Ceftriaxone is active against T.pa/lidum both in vitro [110d] and in the rabbit model [110e]; it has a long half-life and excellent CNS penetration. Four studies with this drug have been reported [59, 94-96] (table 2). It appears to be effective in early syphilis but the optimal dose is unknown. Although specific data for ceftriaxone do not exist, severe allergic reactions to cephalosporins are estimated to occur in 3070-7070 of patients with severe allergy to penicillin [114]. Skin tests for cephalosporin allergy are not available, so it is risky to administer ceftriaxone to patients whose history suggests severe penicillin allergy. Such patients could be given
tetracycline for early disease and, in other stages, could be given skin tests and treated appropriately with penicillin. Because of cost, the need for multiple doses, and possible cross-reactions in penicillinallergic patients, ceftriaxone offers no clear advantage as alternate therapy for syphilis at this time. Neurosyphilis This section includes a discussion of all syphilitic CNS involvement after early disease, including meningovascular syphilis, general paresis, tabes dorsalis, and CNS gummas. Late syphilitic iritis, even without abnormal CSF findings, is wellreported and should also be considered in this group [115, 116]. Diagnosis
The diagnosis of neurosyphilis is difficult without neurologic signs, CSF pleocytosis, and reactive CSF VDRL and serum FTA-ABStests. However, this presentation is rare, and no single gold standard diagnostic test for neurosyphilis exists. In long-standing
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Doxycycline 91 92
Case definition
Duration of follow-up (no. of No. patients) retreated
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cillin therapy in 80% of patients and at 1 year in 90070 (135]. Both reactive CSF VDRL tests and elevated CSF protein concentrations may persist after therapy. Therapy
Trials of neurosyphilis treatment have been reviewed [3, 10]. Despite the inclusion of more than 8,700 patients in these trials, no consensus exists on the optimal dose or duration of penicillin therapy. Moreover, no reported studies with other antimicrobial agents exist. Benzathine penicillin. Smith et al. reported that CSF pleocytosis cleared in 80% of asymptomatic neurosyphilis patients 1year after treatment with one injection of BPG, although the criteria for inclusion of patients were not described [56]. Tho failures of treatment occurred among 26 symptomatic neurosyphilis patients treated with two injections of BPG [136]. No studies have examined three doses of BPG, but many failures of this regimen have been reported [20-24]. BPG does not produce detectable penicillin concentrations in CSF [84, 137-139]. Although the actual failure rate is unknown, sufficient failures have been reported to suggest that BPG should no longer be used alone to treat neurosyphilis. Aqueous penicillin. The optimal penicillin regimen for neurosyphilis is unknown. If a treponemicidallevel of penicillin is present in CSF (although no data correlate such a level with cure), it should also exist in perivascular areas where most organisms are located. A number of regimens produce CSF penicillin concentrations of >0.018 ug/ml, [84, 139-143] (table 3). One regimen (2.4 million units of procaine penicillin and 2 g of probenecid daily) (143] could be adapted to outpatient therapy if good compliance is expected, although one report suggested that this regimen fails to produce treponemicidallevels in some patients (144]. The optimal duration of therapy is also unknown. Idsoe et al. recommended 7-10 days for early syphilis [3]. It has been suggested that spirochetes in late disease divide more slowly, requiring a longer duration of therapy [4], but few data exist to substantiate this theory. Earlier syphilologists thought that prolonged therapy (3 or 4 weeks) was necessary, but those investigators were not using high-dose penicillin (129, 145]. It may be optimal to give high-dose therapy for 14-21 days. However, no failures have been reported with 10 days of high-dose penicillin treatment (often supplemented with BPG). None of these
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disease, serum nontreponemal antibodies may have disappeared although serum treponemal antibodies are usually detectable. The meaning of CSF antibody tests is not always clear. The CSF FTA-ABS test appears more sensitive in detecting neurosyphilis (89070-100070) than the CSF VDRL test (22070-60%) [34, 117-119]. Conversely, the CSF VDRL test appears highly specific (approaching 100070) but the CSF FTA-ABS test appears less so: reactive results are found in patients with syphilis without any other evidence of neurosyphilis [119, 120], presumably due to diffusion of serum antibodies into the CSF, as may occur in infants [121]. Overall, a reactive CSF VDRL test is considered diagnostic of neurosyphilis, and a nonreactive CSF FTA-ABS test is considered strong evidence against this diagnosis (122-124]. Tho other approaches have been used for diagnosis. The FTA-ABSIgM test has been used for CSF, with mixed results [23, 34, 125]. Similarly, IgG and IgM have been measured in CSF, and a CSF/serum ratio has been used to estimate intrathecal antibody production (with correction for the blood-brain barrier by a CSF/serum albumin ratio). Results appear reliable in symptomatic patients but vary in asymptomatic patients (125-128]. Again, with both of these new tests, there is no diagnostic gold standard for comparison. Pleocytosis is the hallmark of active neurosyphilis. Dattner et al. (129] and Thomas (130] believed that CSF pleocytosis occurred in all patients with active neurosyphilis, while Stokes [45] estimated that this occurred in 90% of such patients. Discrepancies were attributed to improper cell-counting techniques, such as failure to analyze the CSF promptly after lumbar puncture, which can result in a lower leukocyte count (131]. Hooshmand et al. reported that 18070 of 243 patients with neurosyphilis had
Treatment of Syphilis, 1989 Paul N. Zenker and Robert T. Rolfs
From the Clinical Research Branch, Division of STDIHIV Prevention, Center for Prevention Services, Centers for Disease Control, Atlanta, Georgia
In the first half of this century, syphilis was a major public health problem in the United States: 575,000 cases were reported in 1943, a rate of 4/1,000 population. In contrast, only 68,000 cases were reported in 1986 [1], although the nation's population had doubled. Treatment options available in the early 1940s included mercury, iodine, bismuth, arsenic, and malaria-induced fevers [2]. After World War II, penicillin became widely available. Many studies evaluated different penicillin formulations and regimens; these were reviewed by Idsoe et al. in 1972 [3] and by the Centers for Disease Control (CDC) in 1976 [4-14]. Unfortunately, studies were poorly designed and difficult to compare, and data were scanty in some areas. Thus, CDC recommendations for therapy were based largely on clinical judgment [14]. Despite hopes that future studies would provide definitive answers, few new investigations were performed and the CDC treatment guidelines changed little. Since 1985, however, the incidence of syphilis has increased [15], while case reports of treatment failures have accumulated [16-27]. The CDC guidelines are therefore being questioned, particularly in association with infection caused by the human immunodeficiency virus (HIV). To address these con-
Please address requests for reprints to Technical Information Services (E06), Center for Prevention Services, Centers for Disease Control, Atlanta, Georgia 30333.
S590
cerns, we review the English-language data both supporting and challenging current syphilis therapy. The evaluation of syphilis treatment trials is complicated by three factors. First, many studies lack the essentials of good design: randomization, blinding, an adequate number of patients (i.e., statistical power), and inclusion of a control group. Second, because Treponema pallidum cannot be cultured routinely, diagnosis of active disease often relies on serologic tests. Third, the natural history of syphilis necessitates long-term follow-up to assess treatment efficacy. Because of the last two factors, studies must have clearly defined entry and outcome criteria, yet these are rarely found. As a result, treatment trials are difficult to evaluate, and optimal treatment regimens are difficult to determine. Diagnosis of Active Syphilis A so-called definite diagnosis of syphilis is based on visualization of the spirochete by dark-field microscopy or direct fluorescent antibody techniques; both procedures are used for lesions of primary or secondary syphilis. Both methods require special equipment and skilled technicians; thus the diagnosis is often made by serologic testing and clinical findings. Since the latter are absent in latent syphilis and are often atypical in late syphilis, these two diagnoses are based on serologic tests only. Antibodies against cardiolipin, known as reaginic or nontreponemal an-
Downloaded from http://cid.oxfordjournals.org/ at East Carolina University on July 7, 2015
With the introduction of penicillin after World War II, the incidence of syphilis in the United States decreased. Because of penicillin's great success, clinical trials stopped after an initial period of intensive investigation. Syphilis is a difficult disease to study; the natural history may span decades in an individual, and diagnosis and outcome are usually defined serologically, not clinically or bacteriologically. Although the recommended penicillin regimens changed, clinical trials were not repeated. Furthermore, because the early studies occurred before modern clinical-trial methodology was developed, interpretation of the results is difficult. As a result, while current regimens for syphilis therapy are effective, they mayor may not be optimal. With the accumulation of reports of treatment failures and the recent appearance of human immunodeficiency virus, current regimens for the treatment of syphilis are being questioned. As background for a meeting at which treatment guidelines were reviewed, the available literature on syphilis therapy is summarized herein.
Treatment of Syphilis, 1989
Implications of Natural History In the Oslo study of untreated syphilis, approximately two-thirds of patients never developed late sequelae, and only 6.5070 developed symptomatic late neurosyphilis [43]; yet the CNS is involved in onehalf of patients with early syphilis [44-46]. Clearly, the immune system must affect disease outcome, al-
though this interaction is not understood. Because the development of neurosyphilis (or other sequelae) cannot be predicted, long-term follow-up is needed to measure treatment efficacy. Instead of performing long-term observation, investigators usually monitor titers of nontreponemal antibody to assess the response to treatment. As has been noted, antibody titers are imperfect indicators of disease activity. Twoother factors complicate outcome assessment: the use of antibiotics for other reasons and reinfection. The impact of the former is unknown. The latter is often impossible to distinguish from relapse; most researchers combine these two categories and report rates of re-treatment. Furthermore, previous infections alter the serologic response to new infections [47]. In summary, syphilis treatment trials must use imperfect outcome measures to estimate uncommon events. Since most patients with syphilis are adequately treated, clearly defined outcome criteria, long-term follow-up, and large numbers of patients would be required for full evaluation of a treatment regimen.
Penicillin Therapy for T. pallidum Penicillin is very effective against T. pallidum, but the optimal dose is unknown. Idsoe et al. [3] suggested that effective treatment of early syphilis required maintenance of a minimal serum concentration of 0.03 IU of penicillin/mL (0.018 ug/ml.) for 7-10 days without interruption for more than 24 hours. (The doubling time for T. pa/lidum had been calculated to be 30-33 hours in early disease [48].) Evidence from studies in animals indicates that the duration of treatment and concentration of penicillin in serum are synergistic (as reviewed by Rein [4]). Furthermore, penicillin concentrations of 0.01 ug/ mL are treponemicidal both in rabbit testes and in vitro [49-51]. However, in the same models, a higher concentration of penicillin is more rapidly treponemicidal [52]. The margin between this suggested antibiotic concentration and those required for microbial killing is also less than in most other infectious diseases. Idsoe et al. admitted that the minimal treponemicidal level chosen was somewhat arbitrary [3]; neither the optimal dose nor the optimal duration of administration is known. Despite these caveats, penicillin-resistant strains of T. pallidum have never been isolated, and a concentration of 0.03 IU
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tibodies (e.g., those detected by VenerealDisease Research Laboratory [VDRL] and rapid plasma reagin [RPR] tests), are measured quantitatively, and serum titers usually correlate with disease activity. However, these tests may remain reactive at low titers after treatment (the sero-fast state) or become negative (serorevert) after 5-10 years, even without treatment. Specific treponemal antibody tests (especially the fluorescent treponemal antibody-absorbed [FTAABS] test) are sensitive and specific [28, 29] but usually remain reactive for life despite treatment [30]. Therefore, the positive predictive value of serologic diagnosis is almost 100070 among patients with their first - or any symptomatic - infection. However, serologic diagnosis is less reliable among patients with prior syphilis who are asymptomatic, especially those with low serologic titers. Serologic diagnosis is useful clinically but does not determine the presence of the organism accurately enough for definitive research. FTA-ABS IgM testing makes sense for the monitoring of disease activity but may be unreliable if IgG blocking antibodies' or rheumatoid factor are present, as occurs in congenitally infected infants [31]. Newer tests that reduce this problem, such as column separation of the 19S fraction of serum to remove IgG and rheumatoid factor (FTA-ABS 19S IgM) and IgM capture (ELISA), are becoming available [32-35] and have been reviewed [36]. Although not widely used in the United States, these treponeme-specific IgM assays are considered the best available tests for the diagnosis of active disease [37]. However, even specific IgM may be present for 2 years after treatment [36, 38]. The molecular specificity of antibodies to T. pa/lidum antigen is being examined by immunoblotting and radioimmunoprecipitation; these studies may explain the bases of currently used tests [39-42]. Use of polymerase chain reaction to detect the T. pallidum genome - and therefore the presence of the organism - might also be helpful, especially in research.
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of penicillin/mL is used as a therapeutic gold standard, even in the CSF. Public Health Implications
Persons Exposed to Syphilis Only two controlled studies of therapy for incubating syphilis have been reported [54, 55]. Both found 2.4 million units of benzathine penicillin G (BPG) to be 100% effective in aborting potential syphilis after exposure to a contact with known infectious syphilis (table 1). Within 30 days of exposure, 2.4 million units of procaine penicillin G was also found to be 100% effective. A 3-g dose of tetracycline was only 56% effective, with a 30% infection rate in the placebo control group [55]. In a recent uncontrolled trial, 27 exposed patients received ceftriaxone (125 mg) [59]. On the basis of the seroconversion rate from the trial above, eight infections would have been
Early Syphilis Early syphilis includes primary, secondary, and early latent stages. The last term describes the seropositive, asymptomatic phase during which relapses of secondary syphilis usually occur. In the Oslo study, 90% of relapses of secondary syphilis occurred within 1 year, 95070 within 2 years, and 100070 within 5 years [43]. Stokes originally considered early syphilis to last 4 years [45]. More recently, the duration of early syphilis has been defined as 1 year, in part because 1 year is the interval during which sexually transmitted disease (STD) control programs attempt to ensure partner notification. However, no pathophysiologic or therapeutic reason exists to divide the latent period [3, 7] except for rabbit studies suggesting that increasing amounts of penicillin are necessary with increasing duration of infection [52]. The WHO Expert Committee on Venereal Disease and Treponematoses currently defines the late latent period as ~2 years after the initial infection [37, 61], but 1 year is the cutoff used in the United States [60]. We have divided the latent period for the purpose of reviewing studies and discussing issues, but both the division and its timing are arbitrary. Whether any
Table 1. Efficacy of 2.4 million units of BPG in patients exposed to syphilis and in patients with early syphilis. Type of patient, reference Exposed to syphilis 54 55 Early syphilis 56t
57+ 58t
Stage Contact Contact Primary Secondary Primary Secondary Primary or secondary
No. of patients
Duration of follow-up (no. of patients)
Percentage retreated
131-182* 84
3 mo (83-89) 3 mo (79)
0 0
Primary disease
1.0 5.5
Clinical or serologic failure
0 9.8
Reinfection or failure to become seronegative
119 155 40
80 100
* The number given BPG was not specified; the number
t
All patients had dark-field positive lesions. +Case definition was not stated.
1 Y (60) 1 Y (90) 2 y (37) 1 Y (40) 18-21 mo (?) 1 Y (55) 2 y (25)
5.1 11.4
Retreatment criteria
Failure of titer to respond significantly
shown is the number of patients in each different treatment category.
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Communicable disease control requires effective, simple, inexpensive therapy that assures compliance and minimizes the need for return visits. The preference for depot penicillin preparations for syphilis treatment is an outgrowth of this need. Studies of streptococcal pharyngitis have documented that the rate of compliance with a 10-dayoral regimen of penicillin ranges from 20070 to 90070 [53]. Therefore, multidose outpatient regimens must be superior to single-dose therapy if they are to be recommended.
expected. After 3 months, syphilis developed in two patients. No other drugs have been studied. The effectiveness of combination therapy with ceftriaxone and doxycycline needs to be evaluated, since this is the recommended therapy for gonorrhea [60].
Treatment oj Syphilis, 1989
particular point exists during latency after which more penicillin is needed is not known. eNS Involvement
Penicillin Therapy
Many early treatment regimens used procaine or crystalline penicillin G; these regimens required frequent administration and were no more effective than longer-acting depot preparations [3, 5-7]. Procaine penicillin G in oil with aluminum monostearate was the depot preparation most studied but is no longer available. Studies using 2.4 million units of BPG for the treatment of early syphilis are listed in table 1 [56-58]. (Other studies used BPG but in mixed doses [63, 64, 73].) All of these studies have limitations: no blinding or randomization, varying failure criteria and follow-up, and cumulative retreatment rates that mix relapse and reinfection. However, the re-treatment rates appear to be similar in the different studies and to be higher for secondary than for primary syphilis. This difference may be due to the slower decline in serologic titers in secondary syphilis [74], because patients who did not serorevert within the study period were re-treated. Clinicians claimed not to see clinical relapse [57] and found low serologic relapse rates for primary and secondary disease [56]. Thus, BPG appears to have a low failure rate in early syphilis, but this rate may be higher in the secondary than in the primary stage. No long-term follow-up data exist. Fiumara suggested that early syphilis be treated with two injections of 2.4 million units of BPG given 1 week apart [75-77]. He treated 588 patients with primary syphilis and 623 patients with secondary syphilis with this regimen; all became seronegative within 1 and 2 years, respectively [77]. However, in his studies, patients who developed a fourfold (twodilution; e.g., 1:2-1:8) increase in serologic titers after their lesions had healed and their titers had begun to fall were considered reinfected and excluded from analysis. In the other studies previously cited, these patients would have been counted as needing re-treatment. Durst et al. reported similar results with 40 patients given 6 million units of BPG; however, entry criteria and study methods were not described [78]. The clinical significance of becoming seronegative is unknown, and a controlled comparison study is needed to determine whether a second dose of BPG improves cure rates. No studies of early latent syphilis treated with 2.4 million units of BPG exist. Fiumara reported that 95070 of 368 patients whose latent disease «1 year) was treated with two doses of 2.4 million units of
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The CNS is commonly involved in early syphilis. Among 3t244 patients with early syphilis, 24070 of those with seronegative primary syphilis, 34% of those with early secondary syphilis, and 56070 of those with late secondary syphilis had abnormal CSF findings, as defined by cell count, protein, Wassermann reaction, or colloidal gold test [45]. Furthermore, T. pa//idum has been isolated from the CSF of rv15% of patients with early syphilis and otherwise normal CSF [37t 38]. Thus the CSF is affected in at least one-half of patients with early syphilis. Lukehart et al. [46] confirmed these findings in a carefully performed study: of 43 patients with early syphilis, 12 had T. pallidum isolated from CSF and another 12had pleocytosis. Isolation of T.pa//idum was not wellpredicted by reactive CSF VDRL or CSF FfA-ABS tests in early disease. The meaning of these abnormal CSF findings in asymptomatic patients is unknown, since fewer than 10070 of untreated patients develop symptomatic neurosyphilis [43]. Studies have found the CSF to be normal 9 months and 2 years after treatment with various penicillin regimens, including 2.4 million units of BPG [62-64]. Despite the number of patients with early syphilis who have laboratory evidence of CNS involvement, acute syphilitic meningitis is rare [45, 65]. It is not logically appealing to treat patients differently on the basis of the presence or absence of meningismus; mild neurologic symptoms are common and do not correlate with laboratory parameters [46]. Other modalities, such as auditory brainstem responses, may prove to be better markers of CNS dysfunction [66, 67]. Still, it seems reasonable to treat patients with clinically evident syphilitic meningitis more aggressively, since cranial nerve palsies occur in 44% of such patients [65] and are reversible with therapy [67-72]. Though data are lacking, the current treatment regimens used for neurosyphilis [60] seem reasonable. As has been mentioned, most asymptomatic CNS involvement resolves with or without therapy. Whether subsets of patients exist who are destined to develop neurologic disease despite therapy is unknown. Studies are needed to define the long-term effectiveness of treatment for preventing progression to neurosyphilis.
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Therapeutic Alternatives to Peniclllin
Penicillin is clearly the drug of choice for syphilis. No alternative antibiotics yield lower failure rates, and all require multiple doses. Penicillin should therefore be used except in the presence of true allergy. Skin testing should be available for patients with a history of penicillin allergy. If penicillin cannot be used, alternatives do exist for treatment of early syphilis. Tetracyclines. Older studies of tetracycline therapy for early syphilis have been reviewed [5, 6]. Only three investigations used exclusively oral regimens and followed patients for 1 year [58] (table 2). (Another study also met these criteria but used a high dose so that patients drank milk with their tetracycline [97].)Schroeter et al. compared tetracycline with BPG and found no significant difference in the retreatment rate at 2 years [58]. Taggart et al. used mul-
tiple regimens and found 60 mg/tkg-d) for 8 days to be the best [98]. Fiumara also reported excellent results [99], and - despite previously mentioned caveats about his exclusion policy - his data show that tetracycline can be effective in early syphilis. The cumulative doses used in these studies were 24-32 g, or rv2 g daily for 2 weeks. The efficacy of tetracycline in latent syphilis is probably comparable to that of penicillin. Doxycycline at a dosage of 100mg every 12hours is pharmacologically equivalent to 500 mg of tetracycline every 6 hours [100]. The mean inhibitory and bactericidal concentrations against treponemes are similar for tetracycline and doxycycline [101, 102]. Treatment with doxycycline improves compliance: fewer doses are required, and these can be taken with meals and cause less gastrointestinal irritation [101]. Doxycycline also penetrates the CNS better [102]. However, few relevant studies of the efficacy of this drug in the treatment of syphilis have been done [91-93] (table 2). Despite small numbers of patients, insufficient follow-up, and poor documentation, the outcome of treatment with this agent appears good and there is no theoretical reason for doxycycline to be less effective than tetracycline. Failures with doxycyclinehave not been reported despite its widespread use. While further studies would be desirable, doxycycline may be considered the equivalent of tetracycline for the treatment of early syphilis. Erythromycin. The studies of erythromycin therapy for early syphilis have been reviewed [5, 6]. In the only trial that compared BPG and tetracycline with erythromycin; both 20- and 30-g erythromycin regimens resulted in higher rates of failure (retreatment) [58]. Other investigations with a 20-g total dose have yielded failure rates ranging from to 180/0 [73, 105-107]. Few data exist for a 30-g totaldose regimen. Most studies have been done with the estolate preparation, which is associated with cholestatic hepatitis [108]. Erythromycin is also poorly tolerated, and compliance is likely to be worse than that with tetracycline. The use of erythromycin should be limited to selected patients, who should be closely monitored. Chloramphenicol. In the past, chloramphenicol was used to treat syphilis. Good results were usually reported, especially at higher doses [73,98, 109, 110]. In one series, 105 patients received rv50 mg/tkg-d) for 7-16 days; infection was cured in all who were followed for 3 years, but 12 patients developed agranulocytosis [110]. The treponemicidal activity of
°
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BPG became seronegative within 2 years of treatment [79, 80]. This finding is comparable to that investigator's results with earlier stages, suggesting that primary, secondary, and early latent disease respond similarly. Many case reports have purported to show that BPG fails to prevent progression to late disease [81-85]. However, it is rarely possible to exclude reinfection. A fewreports of cases of clear failure in both primary disease [16] and secondary disease [17, 18] have been published, though at least one of the patients involved had antibody to HIV. That failures occur is not unexpected, given the trials previously reviewed. Although no active surveillance for treatment failures exists, the large number of patients treated for early syphilis and the few reported failures suggest that the failure rate is low. Similarly, gummas and cardiovascular syphilis are now thought to be rare despite treatment of 60,000120,000patients per year [15] with BPG for over 25 years. Cardiovascular syphilis, which occurs in ~10OJo of untreated patients [43, 86], is now found in ~2OJo of patients at autopsy; even these cases are in elderly patients who presumably became infected before penicillin was available, and more than half of these patients were never treated [87, 88]. In summary, the data appear to provide an insufficient basis for change of the current treatment recommendation of 2.4 million units of BPG for early syphilis. Since failures may occur, follow-up of treated patients is recommended.
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Table 2. Efficacy of alternatives to penicillin for the treatment of early syphilis.
Drug, reference Tetracycline 58 98 99
93 Ceftriaxone 59 94 95 96
Stage *
No. of patients
Dose 3 g/d x 10 d 60 mg/ikg-d) x 8 d 2 g/d x 12 d 2 g/d x 12 d
(+ )Dark-field (+ )Dark-field Symptoms, (+ )FTA, (+ )RPR
P, S P, S P S
(+ ) Dark-field
(+ )Dark-field
P, S P S Latent Early
19 5 10 16 40
100 100 100 100 100
(+ )Dark-field Symptoms and (+ ) serology Symptoms and (+ )FTA or (+ )Dark-field Not stated Symptoms and (+ ) serology
P S P P, S P, S
16
Either 250 mg/d x 10 d or 500 mg qod# x 5 d 2 gld x 2-5 d 1 g every 3 d x 4 IgqodX4
Not stated
107 36 52 59
8 18 14
mg mg mg mg mg
bid bid bid bid bid
x x x x x
10 d 28 d 28 d 28 d 10 d
2 y (40) 1 Y (19) 1Y 2y
10 2t 0+ 0
6 w-9 mo
It 0 1§ 5§ 011
3 mo
0
1 Y (8) 1 y (18) 1 y (14)
0 1§ It
3 mo 2 mo-7 y
*P
= primary syphilis, S = secondary syphilis. t Reinfections. + Reinfections excluded. § Based on various serologic criteria. II Serologic results not specified clearly. # qod = every other day.
chloramphenicol against T. pallidum has also been questioned: 100 mg/kg does not produce bacteriologic cure in rabbits [110a],and 100J.1g/mL does not immobilize the organism in vitro [110b]. Chloramphenicol should not be used to treat early syphilis. Amoxicillin. Ampicillin and amoxicillin are actively treponemicidal in vitro [102] and appear effective in early syphilis, although data are limited [110c]. However, there is no practical reason to use either drug instead of BPG. Ceftriaxone. Ceftriaxone is active against T.pa/lidum both in vitro [110d] and in the rabbit model [110e]; it has a long half-life and excellent CNS penetration. Four studies with this drug have been reported [59, 94-96] (table 2). It appears to be effective in early syphilis but the optimal dose is unknown. Although specific data for ceftriaxone do not exist, severe allergic reactions to cephalosporins are estimated to occur in 3070-7070 of patients with severe allergy to penicillin [114]. Skin tests for cephalosporin allergy are not available, so it is risky to administer ceftriaxone to patients whose history suggests severe penicillin allergy. Such patients could be given
tetracycline for early disease and, in other stages, could be given skin tests and treated appropriately with penicillin. Because of cost, the need for multiple doses, and possible cross-reactions in penicillinallergic patients, ceftriaxone offers no clear advantage as alternate therapy for syphilis at this time. Neurosyphilis This section includes a discussion of all syphilitic CNS involvement after early disease, including meningovascular syphilis, general paresis, tabes dorsalis, and CNS gummas. Late syphilitic iritis, even without abnormal CSF findings, is wellreported and should also be considered in this group [115, 116]. Diagnosis
The diagnosis of neurosyphilis is difficult without neurologic signs, CSF pleocytosis, and reactive CSF VDRL and serum FTA-ABStests. However, this presentation is rare, and no single gold standard diagnostic test for neurosyphilis exists. In long-standing
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Doxycycline 91 92
Case definition
Duration of follow-up (no. of No. patients) retreated
5596
cillin therapy in 80% of patients and at 1 year in 90070 (135]. Both reactive CSF VDRL tests and elevated CSF protein concentrations may persist after therapy. Therapy
Trials of neurosyphilis treatment have been reviewed [3, 10]. Despite the inclusion of more than 8,700 patients in these trials, no consensus exists on the optimal dose or duration of penicillin therapy. Moreover, no reported studies with other antimicrobial agents exist. Benzathine penicillin. Smith et al. reported that CSF pleocytosis cleared in 80% of asymptomatic neurosyphilis patients 1year after treatment with one injection of BPG, although the criteria for inclusion of patients were not described [56]. Tho failures of treatment occurred among 26 symptomatic neurosyphilis patients treated with two injections of BPG [136]. No studies have examined three doses of BPG, but many failures of this regimen have been reported [20-24]. BPG does not produce detectable penicillin concentrations in CSF [84, 137-139]. Although the actual failure rate is unknown, sufficient failures have been reported to suggest that BPG should no longer be used alone to treat neurosyphilis. Aqueous penicillin. The optimal penicillin regimen for neurosyphilis is unknown. If a treponemicidallevel of penicillin is present in CSF (although no data correlate such a level with cure), it should also exist in perivascular areas where most organisms are located. A number of regimens produce CSF penicillin concentrations of >0.018 ug/ml, [84, 139-143] (table 3). One regimen (2.4 million units of procaine penicillin and 2 g of probenecid daily) (143] could be adapted to outpatient therapy if good compliance is expected, although one report suggested that this regimen fails to produce treponemicidallevels in some patients (144]. The optimal duration of therapy is also unknown. Idsoe et al. recommended 7-10 days for early syphilis [3]. It has been suggested that spirochetes in late disease divide more slowly, requiring a longer duration of therapy [4], but few data exist to substantiate this theory. Earlier syphilologists thought that prolonged therapy (3 or 4 weeks) was necessary, but those investigators were not using high-dose penicillin (129, 145]. It may be optimal to give high-dose therapy for 14-21 days. However, no failures have been reported with 10 days of high-dose penicillin treatment (often supplemented with BPG). None of these
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disease, serum nontreponemal antibodies may have disappeared although serum treponemal antibodies are usually detectable. The meaning of CSF antibody tests is not always clear. The CSF FTA-ABS test appears more sensitive in detecting neurosyphilis (89070-100070) than the CSF VDRL test (22070-60%) [34, 117-119]. Conversely, the CSF VDRL test appears highly specific (approaching 100070) but the CSF FTA-ABS test appears less so: reactive results are found in patients with syphilis without any other evidence of neurosyphilis [119, 120], presumably due to diffusion of serum antibodies into the CSF, as may occur in infants [121]. Overall, a reactive CSF VDRL test is considered diagnostic of neurosyphilis, and a nonreactive CSF FTA-ABS test is considered strong evidence against this diagnosis (122-124]. Tho other approaches have been used for diagnosis. The FTA-ABSIgM test has been used for CSF, with mixed results [23, 34, 125]. Similarly, IgG and IgM have been measured in CSF, and a CSF/serum ratio has been used to estimate intrathecal antibody production (with correction for the blood-brain barrier by a CSF/serum albumin ratio). Results appear reliable in symptomatic patients but vary in asymptomatic patients (125-128]. Again, with both of these new tests, there is no diagnostic gold standard for comparison. Pleocytosis is the hallmark of active neurosyphilis. Dattner et al. (129] and Thomas (130] believed that CSF pleocytosis occurred in all patients with active neurosyphilis, while Stokes [45] estimated that this occurred in 90% of such patients. Discrepancies were attributed to improper cell-counting techniques, such as failure to analyze the CSF promptly after lumbar puncture, which can result in a lower leukocyte count (131]. Hooshmand et al. reported that 18070 of 243 patients with neurosyphilis had
