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 million units daily for 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. In fact, the CDC discourages performing a lumbar puncture in early syphilis unless the patient has optic, auditory, cranial nerve, meningeal symptoms, or other indications of.
The rationale is that although early invasion of the CNS by T. 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.
Although this failure can be at times attributed to re-infection 26, 31 , many of those cases are convincingly due to failure of initial therapy Some patients, especially those with HIV, will go on to develop late neurosyphilis in years.
Unfortunately, the diagnosis is difficult to establish and penicillin therapy after the diagnosis of syphilis rarely reverses neurological deficits The clinician must weigh the risk of CNS invasion in each individual patient in deciding whether or not benzathine penicillin is adequate. This assessment should take into account immunocompetent of the host and stage of disease. Since the most reliable form of treatment is one that is reaches treponemicidal levels in the CNS, the most reliable therapy for any form of syphilis in any type of patient is 3 - 4 million units of aqueous crystalline penicillin G given intravenously iv every 4 hours million units daily for days Table 3 since between 5 and 24 million units of intravenous penicillin G consistently achieves levels in the CSF that are treponemicidal 80, Hence, it would follow that treatment failures would be rare when compared to regimens that failed to reliably penetrate the CNS This regimen is the most likely to prevent late neurological deficits which is rarely reversed even after treatment.
However, it is rarely used even in immunocompromised patients except after neurological deficits have developed since inpatient hospital treatment is not always practical from a reimbursement or lifestyle perspective. If outpatient therapy that achieved treponemicidal levels in the CNS is desired, 2. Treponemicidal levels of penicillin have not been achieved as reliably with procaine penicillin but supplementation with probenecid will achieve treponemicidal levels This option is uncommonly used since patient compliance is problematic because of the pain associated with repeated injections.
The semi-synthetic penicillin, amoxicillin, when given with probenecid given 3. Probenecid inhibits renal excretion of natural and semi- synthetic penicillins.
As previously noted, amoxicillin is treponemicidal in the rabbit model, and when 2 gm of amoxicillin plus mg of probenecid is administered to fasting adults, the MIC for T. Clinical trials, albeit small, have confirmed the utility of this regimen 29 , 90 , The first- and third- generation cephalosporin antibiotics, in particular ceftriaxone, are also effective in treating syphilis.
Ceftriaxone has been recommended as an alternative for treatment of early disease and "might be effective for treating late latent syphilis or syphilis of unknown duration" Table 3 This drug is particularly attractive since it readily crosses the blood brain barrier. Both serum and CSF levels exceeding those needed to kill T. It has been used clinically to successfully to treat incubating syphilis 55 , primary syphilis 55 , 81 , 96 , , , secondary syphilis 55 , 96 , , latent syphilis 24 , and neurosyphilis 24 , 53 , However, there have been reports of treatment failures in HIV infected patients, similar to those found with benzathine penicillin 24 , 96 , Doxycycline mg twice daily is also an effective alternative for treatment of immunocompetent adults with syphilis.
Although there is limited data on late latent syphilis, doxycycline is another alternative but the course of therapy should be extended to 28 days The enthusiasm for this regimen is restrained because it is bacteriostatic in vitro and not bacteriocidal 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 Other regimens that are less desirable because of poor CSF penetration and reports of resistance are the macrolide antibiotics.
Another macrolide, azithromycin, has been shown in a recent meta-analysis to be more effective than benzathine penicillin G for treating early syphilis 1. However, in addition to its probable inadequate penetration into the CSF , it has been associated with resistance and treatment failures and therefore it can only be recommended when there are no other alternatives 17 , 63 , 70 , 77 , 79 , 83 , 97 , , , 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 hours instead of every 8 or 12 hours 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 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 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 Because of excellent CNS penetration, chloramphenicol in a dose of 2 gm daily for 30 days is another alternative for optic syphilis.
As is the case of penetration into the anterior chamber of the eye, penicillin does not easily penetrate the labyrinth of the inner ear 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 16 , 23 , Oral prednisone mg daily or every other day for at least 7 to 8 days should be given as tolerated by the patient 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.
Although treatment failures and progression to syphilis appear to be less common in HIV infected patients on effective antiretroviral therapy ART 40 , 41 , immunosuppression associated with HIV infection and its deleterious effect on syphilis outcomes has been well described. More florid clinical manifestations, including multiple and more frequent genital ulcers and symptomatic neurosyphilis, occurring early in the course of syphilis suggestive of a high spirochete burden 61 , 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 5 , 61 , 71 , For example, T.
In addition, in a study of 59 patients with neurosyphilis, HIV infected patients were 2. Furthermore, unlike many treatment failures in immunocompetent hosts, these failures are more likely to be associated with clinical disease, especially neurosyphilis 22 , 24 , 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. Treatment for syphilis is not necessarily benign. It is rarely seen in latent syphilis and occurs in varying amounts in the various forms of tertiary syphilis 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 4.
It has been correlated with the release of heat stable "pyrogens" from T. 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 12 , 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 It lasts hours and is generally safe and self-limited The exceptions are during the second half of pregnancy when there a risk of premature labor and fetal distress 12 and during cardiovascular, neurosyphilis and otosyphilis when reactions are more severe and can be life threatening 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 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 In addition, the vast majority of patients who report a history of penicillin allergy will not have an allergic reaction upon re-challenge.
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 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 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.
Optimally, skin testing should include diluents with both the major and minor determinants of penicillin Because minor determinants of penicillin are not commercially available in the U. Although desensitization can be done both orally and intravenously, oral desensitization is probably safer and certainly less expensive and easier 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.
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. 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 , 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.
Fiumara found that all patients with treated primary syphilis had non-reactive RPR titers at one year 31 and all patients with treated secondary syphilis by two years However, some studies have shown that low but positive titer VDRL or RPR tests of or less may persist despite no other evidence of treatment failure the "serofast reaction" 12 , This may represent a false positive result or, especially when the titer is , persistent active infection or reinfection 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 to is significant while a change from to 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 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 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 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 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 7 , 31 , 32 , 33 , 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 7.
In contrast, patients with no prior history of syphilis re-infection have a more rapid decline in titers 7 , 31 , 32 , In addition, patients with macular rashes during the secondary stage revert to negative quicker than those with papular rashes In adequately treated congenital syphilis, titers should decline by three months of age and should be non-reactive by six months of age 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. 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 nontreponemal antibodies disappear If the CSF cell count is not decreased by six months or remains abnormal two years after therapy, re-treatment is indicated 8.
Although HIV infected patients may have similar non-treponemal VDRL and RPR response as non-HIV infected persons 43 , 49 , 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 Furthermore, HIV infected patients are more likely to have high non-treponemal antibody titers in secondary syphilis, e.
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 Obviously, 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.
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 Treatment with 2.
Transmission occurs only when mucocutaneous lesions are present, which is usually within one year after initial infection , so contact with persons with syphilis greater than one year in duration is not an immediate indication for treatment 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. Azithromycin vs. Cochrane Database Syst Rev. Efficacy of cefmetazole in the treatment of active syphilis in the rabbit model. Antimicrob Agents and Chemother. Beall GN. In: Saxon A, moderator. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med ; Neurological relapse after benzathine penicillin therapy for secondary syphilis in a patient with HIV infection.
N Engl J Med. Relative efficacy of clindamycin, erythromycin, and penicillin in treatment of Treponema pallidum in skin syphilomas of rabbits. J Infect Dis. Serological response to syphilis treatment: a new analysis of old data.
Evaluation of an enzyme immunoassay technique for detection of antibodies against Treponema pallidum. J Clin Microbiol. Centers for Disease Control and Prevention. Infectious Diseases Laboratories. Test Order: Treponema pallidum Molecular Detection. Sexually Transmitted Disease Surveillance.
Sexually Transmitted Treatment Guidelines RR Summary of Notifiable DiseasesUnited States, MMWR ;57 32 Primary and Secondary Syphilis — United States, — MMWR ;63 18 Syphilitic labyrinthitis - an update.
J Laryngol Otol. High prevalence of azithromycin resistance to Treponema pallidum in geographically different areas in China.
Clin Microbiol Infect. Treatment of Syphilis: A Systematic Review. Comparison of methods for the detection of Treponema pallidum in lesions of early syphilis. Sex Transm Dis. Diagnostics Direct, LLC.
Acquired ocular syphilis: diagnosis and treatment. Ann Ophthalmol. Recrudescence of treated neurosyphilis in a patient with human immunodeficiency virus. Mayo Clin Proc. Otosyphilis and hearing loss: response to penicillin and steroid therapy. Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus. Am J Med. Ducas J, Robson HG. Cerebrospinal fluid levels during therapy for latent syphilis.
Penicillin levels in blood and CSF achieved by treatment of syphilis. The effective concentrations of penicillin in vitro and in vivo for streptococci, pneumococci, and Treponema pallidum.
J Bacteriol. The localisation of treponemes and characterisation of the inflammatory infiltrate in skin biopsies from patients with primary or secondary syphilis, or early infectious yaws. Genitourin Med. Treponemicidal levels of amoxicillin in cerebrospinal fluid after oral administration. Sexually Transm Dis. Fitzgerald TJ. Later signs and symptoms may include deafness, teeth deformities and saddle nose — where the bridge of the nose collapses.
However, babies born with syphilis can also be born too early, may die in the womb before birth or can die after birth. Call your doctor if you or your child experiences any unusual discharge, sore or rash — particularly if it occurs in the groin area.
Vivien Williams: Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum. Stacey Rizza, an infectious diseases specialist at Mayo Clinic, says syphilis affects men and women and can present in various stages.
Stacey Rizza, M. Vivien Williams: It may then progress to latent stage syphilis and, finally, the most serious stage: tertiary. Pregnant women are not immune to syphilis. Congenital syphilis can lead to miscarriage, stillbirth or infant deaths.
That's why all pregnant women should be screened. Syphilis is preventable and treatable. As for prevention, Dr. Rizza recommends barrier protection during sex. Rizza: And that's during oral sex, anal sex, vaginal sex — using condoms, dental dams and any other barrier protection.
The cause of syphilis is a bacterium called Treponema pallidum. The most common way syphilis is spread is through contact with an infected person's sore during sexual activity. The bacteria enter the body through minor cuts or abrasions in the skin or mucous membranes.
Syphilis is contagious during its primary and secondary stages, and sometimes in the early latent period. Less commonly, syphilis may spread through direct contact with an active lesion, such as during kissing. It can also be passed from mothers to their babies during pregnancy or childbirth. Syphilis can't be spread by using the same toilet, bathtub, clothing or eating utensils, or from doorknobs, swimming pools or hot tubs.
Once cured, syphilis doesn't return on its own. However, you can become reinfected if you have contact with someone's syphilis sore.
Without treatment, syphilis can lead to damage throughout your body. Syphilis also increases the risk of HIV infection and can cause problems during pregnancy. Treatment can help prevent future damage but can't repair or reverse damage that's already occurred.
In the late stage of syphilis, bumps gummas can develop on the skin, bones, liver or any other organ. Gummas usually disappear after treatment with antibiotics. These may include bulging and swelling of the aorta — your body's major artery — and of other blood vessels. Syphilis may also damage heart valves. Adults with sexually transmitted syphilis or other genital ulcers have an estimated two- to fivefold increased risk of contracting HIV.
A syphilis sore can bleed easily, providing an easy way for HIV to enter the bloodstream during sexual activity. If you're pregnant, you may pass syphilis to your unborn baby. Congenital syphilis greatly increases the risk of miscarriage, stillbirth or your newborn's death within a few days after birth. Syphilis can cause serious health sequelae if not adequately treated.
During , there were , reported new diagnoses of syphilis all stages , compared to 37, new diagnoses of HIV infection in and , cases of gonorrhea in Congenital syphilis syphilis passed from pregnant women to their babies continues to be a concern in the United States. According to preliminary data, more than 2, cases of congenital syphilis were reported, compared to 65 cases of perinatal HIV infection during Syphilis is transmitted from person to person by direct contact with a syphilitic sore, known as a chancre.
Chancres can occur on or around the external genitals, in the vagina, around the anus , or in the rectum, or in or around the mouth. Transmission of syphilis can occur during vaginal, anal, or oral sex. In addition, pregnant women with syphilis can transmit the infection to their unborn child. The average time between acquisition of syphilis and the start of the first symptom is 21 days, but can range from 10 to 90 days. However, syphilis typically follows a progression of stages that can last for weeks, months, or even years:.
The appearance of a single chancre marks the primary first stage of syphilis symptoms, but there may be multiple sores. The chancre is usually but not always firm, round, and painless.
It appears at the location where syphilis entered the body. These painless chancres can occur in locations that make them difficult to notice e. The chancre lasts 3 to 6 weeks and heals regardless of whether a person is treated or not. However, if the infected person does not receive adequate treatment, the infection progresses to the secondary stage. This stage typically starts with the development of a rash on one or more areas of the body.
Rashes associated with secondary syphilis can appear when the primary chancre is healing or several weeks after the chancre has healed. The rash usually does not cause itching. The characteristic rash of secondary syphilis may appear as rough, red, or reddish brown spots both on the palms of the hands and the bottoms of the feet.
However, rashes with a different appearance may occur on other parts of the body, sometimes resembling rashes caused by other diseases. Sometimes rashes associated with secondary syphilis are so faint that they are not noticed. Large, raised, gray or white lesions, known as condyloma lata, may develop in warm, moist areas such as the mouth, underarm or groin region.
In addition to rashes, symptoms of secondary syphilis may include fever, swollen lymph glands, sore throat, patchy hair loss, headaches, weight loss, muscle aches, and fatigue. The symptoms of secondary syphilis will go away with or without treatment. However, without treatment, the infection will progress to the latent and possibly tertiary stage of disease. The latent hidden stage of syphilis is a period of time when there are no visible signs or symptoms of syphilis.
Without treatment, the infected person will continue to have syphilis in their body even though there are no signs or symptoms. Early latent syphilis is latent syphilis where infection occurred within the past 12 months. Late latent syphilis is latent syphilis where infection occurred more than 12 months ago. Latent syphilis can last for years. Tertiary syphilis is rare and develops in a subset of untreated syphilis infections;, it can appear 10—30 years after infection was first acquired, and it can be fatal.
Tertiary syphilis can affect multiple organ systems, including the brain, nerves, eyes, heart, blood vessels, liver, bones, and joints. Symptoms of tertiary syphilis vary depending on the organ system affected. Syphilis can invade the nervous system neurosyphilis , visual system ocular syphilis , or auditory system otosyphilis at any stage of infection. These infections can cause a wide range of symptoms. When a pregnant woman has syphilis, the infection can be transmitted to her unborn baby.
All pregnant women should be tested for syphilis at the first prenatal visit. Some women need to be tested again during the third trimester 28 weeks gestation and at delivery.
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