Syphilis, also called Lues, is caused by Treponema pallidum. The risk of transmission is greatest in the early stages of the disease, especially if skin or mucosal ulcers are present. For a single unprotected sexual contact, the risk of transmission is about 30 to 60 %. Like other STDs, syphilis favors the transmission of HIV due to lesions in the genital mucosa. In some European and North-American areas, the incidence of syphilis has increased within the last 10 years to levels last seen in the mid twentieth century. In some metropolitan regions, the rates of newly diagnosed infections has multiplied.. The highest incidence of syphilis in Europe in 2006 was seen in baltic areas.

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Symptoms Classic syphilis progresses in four stages, listed in Table 1: Table 1: Course of classic syphilis Stage Typical clinical appearances Time since infection Lues I Ulcus durum / chancre approx. 3 weeks Lues II Disseminated exanthemas approx. 6-8 weeks Lues III Tuberous syphilis, gumma several years Lues IV Tabes dorsalis, progressive paralysis decades In HIV-infected patients, the latency period between stage II and the late stages III and IV may be significantly shorter than usual. In some cases, symptoms of the different stadiums may be present at the same time. Furthermore, unusual manifestations with dramatic skin ulcers or necrosis, high fever and fatigue are described. Occurrence of these clinical symptoms is called Lues maligna (Gregory 1990). Another unusual aspect in HIV-infected patients is a possible endogenous reactivation after prior Treponema pallidum infection. Diagnosis Routine screening for syphilis with TPHA, TPPA or VDRL may not be reliable in HIV-infected patients. False-negative results can be explained by inadequate production of antibodies or by suppression of IgM production due to exorbitant IgG levels. In case of doubt, specific tests such as FTA-ABS (IgG and IgM) or cardiolipin tests should be carried out. In erosive skin or mucosal lesions, dark field microscopy should be performed to demonstrate Treponema pallidum directly. In cases where infection has been proven serologically, a neurological examination should be performed, especially on HIV-infected patients because of the merging of clinical stages. Patients with neurological symptoms should undergo cerebrospinal fluid examination, which is particularly important for making decisions regarding the type of therapy (intramuscular or intravenous). Therapy Therapy of syphilis should be adapted to the stage of disease. Recommendations for the early stages of syphilis include three intramuscular injections of benzathine penicillin 2.4 MU administered in weekly intervals (Anglo-American recommendations: only twice). In cases of penicillin intolerance, doxycycline (2 x 100 mg), tetracycline (4 x 500 mg) or erythromycin (4 x 500 mg) can be administered orally for 4 weeks, but these drugs are considered to be less effective than penicillin. Consequently, patients should be treated with the same scheme used in neurosyphilis. Neurosyphilis is usually treated with 5 MU benzylpenicillin given intravenously every 4 hours for 21 days. Other recommendations prefer administration of benzylpenicillin for 14 days, followed by three intramuscular doses of 2.4 MU benzathine penicillin given at weekly intervals. In cases of penicillin intolerance, neurosyphilis can also be treated with 2 g intravenous ceftriaxone once daily for 14 days. Observational studies in small groups suggest ceftriaxone to be as effective as penicillin in the treatment of syphilis. However, cross-sensitivity may occur. Alternative treatment options are doxycycline 2 x 100-200 mg per day or erythromycin 4 x 500 mg per day for at least 3 weeks. When treating with macrolides, the possible development of resistance should be considered (Lukehart 2004). On initiation of syphilis therapy, one should be aware of a possible Jarisch-Herxheimer reaction. This reaction is caused by a massive release of bacterial toxin due to the first dose of antibiotic given. By triggering inflammation mediators, patients may experience shivering, fever, arthritis or myalgia. The symptoms of the Jarisch-Herxheimer reaction may be avoided, or at least reduced, by administering 25-50 mg of prednisolone prior to the first dose of antibiotic. Serological controls should be performed at 3, 6 and 12 months after syphilis therapy. Because of a possible endogenous reactivation or reinfection in some patients, annual controls should be considered. References 1. Blocker ME, Levine WC, St Louis ME. HIV prevalence in patients with syphilis, United States. Sex Transm Dis 2000 ; 27:53-9. http://amedeo.com/lit.php?id=10654870 2. Brown TJ, Yen-Moore A, Tyring SK. An overview of sexually transmitted diseases. Part I. J Am Acad Dermatol 1999 ; 41: 511-29. http://amedeo.com/lit.php?id=10495370 3. CDC: Sexually Transmitted Diseases Treatment Guidelines , 2006. MMWR 2006 ; 55, RR-11: 22-33. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5511a1.htm 4. Czelusta A, Yen-Moore A, Van der Staten M, Carrasco D, Tyring SK. An overview of sexually transmitted diseases. Part III. Sexually transmitted diseases in HIV-infected patients. J Am Acad Dermatol 2000 ; 43: 409-32. http://amedeo.com/lit.php?id=10954653 5. Deutsche Gesellschaft für Neurologie: Leitlinien für Diagnostik und Therapie in der Neurologie: Neurosyphilis; 2. überarbeitete und erweiterte Auflage 2003, ISBN 3131324120. http://www.uni-duesseldorf.de/AWMF/ll/030-101.htm 6. Deutsche STD-Gesellschaft.: Diagnostik und Therapie der Syphilis. Elektronische Publikation in AWMF online, 2005. http://www.uni-duesseldorf.de/AWMF/ll/059-002.htm 7. Gregory N, Sanchez M, Buchness MR. The spectrum of syphilis in patients with HIV infection. J Amer Acad Derm 1990 ; 6: 1061-67. http://amedeo.com/lit.php?id=2370332 8. Lukehart SA, Godornes C, Molini BJ et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med 2004 ; 351:154-8. http://amedeo.com/lit.php?id=15247355 9. Marra CM, Boutin P, McArthur JC et al. A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals. Clin Infect Dis 2000; 30:540-4. http://amedeo.com/lit.php?id=10722441 10. Medical Society for the Study of Venereal Diseases (MSSVD). Clinical standards for the screening and management of acquired syphilis in HIV-positive adults. London, 2002. http://www.guideline.gov/summary/summary.aspx?doc_id=3440 11. Peterman TA, Heffelfinger JD, Swint EB, Groseclose SL. The changing epidemiology of syphilis. Sex Transm Dis. 2005 Oct ; 32: S4-S10. http://amedeo.com/lit.php?id=16205291 12. Plettenberg A, Bahlmann W, Stoehr A, Meigel W. Klinische und serologische Befunde der Lues bei HIV-infizierten Patienten. Dtsch Med Wschr 1991 ; 116: 968-72. http://amedeo.com/lit.php?id=2049984 13. Robert Koch-Institut. Zur Situation bei wichtigen Infektionskrankheiten: Syphilis in Deutschland 2005. Epidem Bull 2006 ; 28 : 339-43. 14. Schöfer H. Behandlung der Syphilis. Deutsche und internationale Leitlinien - ein Vergleich. Hautarzt 2005 ; 56: 141-50. http://amedeo.com/lit.php?id=15619079 15. Sellati TJ, Wilkinson DA, Sheffield JS, et al. Virulent Treponema pallidum, lipoprotein, and synthetic lipopeptides induce CCR5 on human monocytes and enhance their susceptibility to infection by HIV type1. J Inf Dis 2000 ; 181: 283-93. http://amedeo.com/lit.php?id=10608777 16. Singh AE, Romanowski B. Syphilis: Review with emphasis on clinical, epidemiologic, and some biologic features. Clin Microbiol Rev 1999 ; 12: 187-209. http://amedeo.com/lit.php?id=10194456 Gonorrhea Gonorrhea, also called the clap, is caused by Neisseria gonorrhea, a diplococcal bacterium. It is typically localized in the genitourinary mucosa, but infection may also occur orally or anally. Transmission is almost exclusively through sexual activity (exception: neonatal conjunctivitis), and the incubation period is about 2 to 10 days. Co-infection with Chlamydia occurs frequently. Symptoms In men, primary symptoms are dysuria and urethral pain. A typical symptom is purulent secretion from the urethra, especially in the morning ("bonjour-drop"). Without treatment, the infection can ascend and cause prostatitis or epididymitis, leading to symptoms such as pain in the perineal region or scrotum or swelling of the scrotum. In women, the course of gonorrhea is often asymptomatic, although vaginal discharge or purulent dysuria may occur. Involvement of the cervix and adnexa is rare, but if left untreated, may lead to pelvic inflammatory disease with subsequent infertility. Extragenital manifestations of gonorrhea occasionally cause pharyngitis or proctitis. Systemic infections with symptoms such as shivering, fever, arthritis or endocarditis are rare (Rompalo 1987). Diagnosis The diagnosis of gonorrhea is confirmed by microscopy. In a dye-staining test with methylene blue or gram stain, the intracellular diplococci of Neisseria gonorrhea are traceable. This kind of diagnosis can directly be performed within several minutes at many sites. Other methods, such as serological examination, PCR or laboratory culture are also accurate, but are more complex and more expensive. Therapy An isolated gonorrhea is usually treated with a single dose of ciprofloxacin 500 mg orally. Other effective antibiotics are Levofloxacin 250 mg or Ofloxacin 400 mg. Recently, some international surveillance authorities reported an increasing number of fluoroquinolone-resistant bacterial isolates. Consequently, the American Centers for Disease Control and Prevention suggest a single dose of cefixime 400 mg orally or ceftriaxone 125 mg as intramuscular injection for the treatment of gonorrhea in high-risk patients. Intramuscular administration of spectinomycin has been an option, but it is effective only in urogenital and anorectal infection, not in pharyngeal gonorrhea (CDC 2004). For these reasons, a pragmatic and sufficient therapy seems to be a single dose of azithromycin 1 g or doxycycline 100 mg twice daily for 7 days. These therapeutic options also treat a possible co-infection with chlamydia species (see following chapter). In all cases of gonorrhea, the sexual partners should also be screened for infection and treated if necessary. References 1. CDC: Increases in Fluoroquinolone-Resistant Neisseria gonorrhoeae Among Men Who Have Sex with Men -United States, 2003, and Revised Recommendations for Gonorrhea Treatment, 2004. MMWR 2004 ; 53: 335-8 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5316a1.htm 2. Handsfield HH, Dalu ZA, Martin DH, et al. Multicenter trial of single-dose azithromycin vs. ceftriaxone in the treatment of uncomplicated gonorrhea. Azithromycin Gonorrhea Study Group. Sex Transm Dis 1994 ; 21:107-11. http://amedeo.com/lit.php?id=9071422 3. Moodley P, Sturm AW. Ciprofloxacin-resistant gonorrhoea in South Africa. Lancet 2005 ; 366: 1159. http://amedeo.com/lit.php?id=16198757 4. Rompalo AM, Hook EW 3rd, Roberts PL, et al. The acute arthritis-dermatitis syndrome. The changing importance of Neisseria gonorrhoeae and Neisseria meningitidis. Arch Intern Med 1987 ; 147: 281-3. http://amedeo.com/lit.php?id=3101626 5. Roy K, Wang SA, Meltzer MI. Optimizing Treatment of Antimicrobial-resistant Neisseria gonorrhoeae. Emerg Infect Dis 2005 ; 11: 1265-73. http://amedeo.com/lit.php?id=16102317 Chlamydia infection Infections with Chlamydia trachomatis are nearly twice as prevalent as gonococcal infections. The serovars D-K cause genitourinary infections and, if vertically transmitted, conjunctivitis or pneumonia in the newborn. The serovars L1-3 cause Lymphogranuloma venereum. This disease is usually considered to be a tropical disease, rarely occurring in industrialized countries. However, for several years, Lymphogranuloma venereum has undergone a renaissance in Europe and USA (Gotz 2004, Krosigk 2004). Actually, the described outbreaks are under investigation by international surveillance authorities, which are working on management strategies. Symptoms In men, a genital infection with Chlamydia is usually asymptomatic. If symptoms occur, they may be present as urethral discharge, burning or unspecific pain in the genital region. As in gonorrhea, an epididymitis, prostatitis or proctitis may occur. Reiter's syndrome with the triad reactive arthritis, conjunctivitis and urethritis is also possible. In women, a chlamydial infection often does not cause any symptoms. But in about 20 % of female patients, unspecific symptoms such as discharge, burning or, more often, polyuria may occur as an expression of urethritis or cervicitis. Some of the patients also suffer from pelvic inflammatory disease involving the adnexa. This disease pattern can lead to later complications such as infertility or ectopic pregnancy due to tubal occlusions. In Lymphogranuloma venereum, a primary lesion occurs at the entry location. Some weeks later, a tender lymphadenopathy develops which is mainly unilateral. These swollen lymph nodes may grow into large bubo that tend to ulcerate, possibly leading to scars and lymphedema. Diagnosis A chlamydial infection may be suspected based purely on clinical symptoms. Gene amplification methods (PCR, LRC) are the best procedures for confirming the diagnosis. Sensitivity is superior to, while specificity is nearly equal to results obtained by culture (Morre 2005). To achieve optimum results, a dry cotton wool wad should be used to collect some epithelioid cells, which should be sent to the laboratory in dry storage. Other direct tests such as ELISA or direct immunofluorescence are also possible, but there is a lack of sensitivity in populations with low prevalence. Therapy The therapy of choice is doxycycline, 2 x 100 mg for 7 days. International guidelines also recommend 1 g azithromycin, given as a single dose, as an equally potent therapy, but which costs nearly twice as much as doxycycline in many countries. Alternatively, ofloxacin 2 x 200 mg or erythromycin 4 x 500 mg for 7 days can be given. Lymphogranuloma venereum requires a longer treatment, with doxycycline being administered for a minimum of 3 weeks. References 1. CDC: Chlamydia - CDC Fact Sheet. http://www.cdc.gov/std/Chlamydia/STDFact-Chlamydia.htm 2. European Guideline for the management of chlamydial infection. Int J STD AIDS 2001 ; 12: S30-3 http://www.iusti.org/Guidelines.pdf 3. Gotz HM, Ossewaarde JM, Nieuwenhuis RF, et al.. A cluster of lymphogranuloma venereum among homosexual men in Rotterdam with implications for other countries in Western Europe. Ned Tijdschr Geneeskd 2004 ; 148: 441-2. http://amedeo.com/lit.php?id=15038207 4. Krosigk A, Meyer T, Jordan S, et al. Auffällige Zunahme des Lymphogranuloma venereum unter homosexuellen Männern in Hamburg. JDDG 2004 ; 8: 676-80. 5. Martin DH, Mroczkowski TF, Dalu ZA, et al. A controlled trial of a single dose of azithromycin for the treatment of chlamydial urethritis and cervicitis. N Engl J Med 1992 ; 327: 921-5. http://amedeo.com/lit.php?id=1325036 6. Morre SA, Spaargaren J, Fennema JS, de Vries HJ, Coutinho RA, Pena AS. Real-time polymerase chain reaction to diagnose lymphogranuloma venereum. Emerg Infect Dis 2005 ; 11: 1311-2. http://amedeo.com/lit.php?id=16110579 7. Nieuwenhuis RF, Ossewaarde JM, van der Meijden WI, Neumann HA. Unusual presentation of early lymphogranuloma venereum in an HIV-1 infected patient: effective treatment with 1 g azithromycin. Sex Transm Infect 2003 ; 79: 453-5. http://amedeo.com/lit.php?id=14663119 8. Paavonen J. Pelvic inflammatory disease. From diagnosis to prevention. Dermatol Clin 1998 ; 16: 747-56. http://amedeo.com/lit.php?id=9891675 9. RKI: Infektionen durch Chlamydien - Stand des Wissens. Epid Bull 1997 ; 18: 121-2. 10. Schachter J, Grossman M, Sweet RL, Holt J, Jordan C, Bishop E. Prospective study of perinatal transmission of Chlamydia trachomatis. JAMA 1986 ; 255: 3374-7. http://amedeo.com/lit.php?id=3712696 Chancroid Chancroid, also called Ulcus molle, is caused by Haemophilus ducreyi, a gram-negative bacterium. It is an endemic infection found primarily in tropical or subtropical regions of the world. In the industrialized countries, it appears to be mainly an imported disease, with only a few cases being reported by the national authorities. Symptoms Usually, the incubation period is about 2-7 days. After transmission, one or more frayed-looking ulcers may appear at the entry location, usually in genitourinary or perianal locations. These ulcers are typically not indurated, unlike the primary ulcers of syphilis (therefore the Latin name Ulcus molle). Characteristically, they cause massive pain. In about half of the patients the inguinal lymph nodes are swollen and painful, mostly unilaterally. Balanitis or phimosis occurs less frequently. Diagnosis Suspected chancroid is difficult to confirm. Clinically, other ulcer-causing STDs such as syphilis or herpes simplex infections have nearly the same symptoms. Microscopy of ulcer smears may demonstrate gram-negative bacteria, but diagnosis should be confirmed from a culture of scrapings from the ulcer or pus from a bubo. Sometimes, a biopsy from the ulcer becomes necessary to differentiate it from a malignoma. Therapy Therapy should be conducted using a single dose of 1 g oral azithromycin (Martin 1995). Ceftriaxone 250 mg intramuscularly, as a single dose, is equally potent. Alternative therapies are ciprofloxacin 2 x 500 mg for three days or erythromycin 4 x 500 mg for 4-7 days. In fluctuant buboes, needle-aspiration of pus may be indicated. References 1. Hammond GW, Slutchuk M, Scatliff J, et al. Epidemiologic, clinical, laboratory, and therapeutic features of an urban outbreak of chancroid in North America. Rev Infect Dis 1980 ; 2: 867-79. http://amedeo.com/lit.php?id=6971469 2. Gesundheitsberichterstattung des Bundes. http://www.gbe-bund.de/ 3. King R, Choudhri SH, Nasio J, et al. Clinical and in situ cellular responses to Haemophilus ducreyi in the presence or absence of HIV infection. Int J STD AIDS 1998 ; 9: 531-6. http://amedeo.com/lit.php?id=9764937 4. King R, Gough J, Ronald A, et al. An immunohistochemical analysis of naturally occurring chancroid. J Infect Dis 1996 ; 174: 427-30. http://amedeo.com/lit.php?id=8699082 5. Lewis DA. Chancroid: clinical manifestations, diagnosis, and management. Sex Transm Infect. 2003 Feb ; 79: 68-71. http://amedeo.com/lit.php?id=12576620 6. Martin DH, Sargent SJ, Wendel GD Jr, et al. Comparison of azithromycin and ceftriaxone for the treatment of chancroid. Clin Infect Dis 1995 ; 21: 409-14. http://amedeo.com/lit.php?id=8562752 7. Ronald AR, Plummer FA. Chancroid and Haemophilus ducreyi. Ann Intern Med 1985 ; 102: 705-7. http://amedeo.com/lit.php?id=3872617 Condylomata acuminata Condylomata acuminata are caused by human papillomaviruses (HPV). They are usually present as genital warts, but other locations (oral) are known to be involved. HIV-infected patients have a higher risk of acquiring genital warts. The typical pathogens, human papillomavirus type 6 or type 11, are not normally considered to be cancerogenic. Although, in both male and female HIV-infected patients, epithelial atypia is seen more often than in uninfected persons. Besides sexual transmission, infection with papillomavirus may be possible via smear infection and perhaps through contaminated objects. But the primary risk factor remains the number of sexual partners (Karlsson 1995). Symptoms Generally, genital warts remain asymptomatic. Pruritus, burning or bleeding is rare and generally caused by mechanical stress. Malignant degeneration of genitourinary papillomavirus infections (HPV 16, 18, etc.) is the most important complication. In contrast to HPV-associated cervical carcinoma, genital or anal carcinoma rarely develops on underlying Condylomata. Diagnosis Condylomata acuminata is a clinical diagnosis. Further diagnostic tests should be considered in case of persistence despite therapy or an early relapse. In addition to histological examination, direct HPV detection, including subtyping, is possible to differentiate between high and low risk types. Actually, this procedure is mainly instrumental in gynecology in case of ambiguous histologies (Ledger 2000). Therapy Treatment of genital warts is performed surgically by electrosurgery, cryotherapy, curettage, or laser. Chemical interventions with podophyllin or trichloroacetic acid are also possible. Other methods have been recommended. In daily clinical practice, a surgical intervention followed by adjuvant immunotherapy with interferon beta or (possibly more effective) with imiquimod reduces the rate of relapse and seems to be the best choice for patients. References 1. Gross G, Von Krogh G. Human Papillomavirus Infections in Dermatovenereology. CRC Press, Boca Raton, New York, London, Tokyo (1997). 2. Hagensee ME, Cameron JE, Leigh JE et al. Human papillomavirus infection and disease in HIV-infected individuals. Am J Med Sci 2004; 328: 57-63. http://amedeo.com/lit.php?id=15254442 3. Karlsson R, Jonsson M, Edlund K, et al: Lifetime number of partners as the only independent risk factor for human papillomavirus-infection: a population based study. Sex Transm Dis 1995 ; 22: 119-26. http://amedeo.com/lit.php?id=7624813 4. Kovach BT, Stasko T. Use of topical immunomodulators in organ transplant recipients. Dermatol Ther 2005; 18:19-27. http://amedeo.com/lit.php?id=15842609 5. Koutsky L. Epidemiology of genital human papillomavirus infection Am J Med 1997; 102: 3-8. http://amedeo.com/lit.php?id=9217656 6. Ledger WJ, Jeremias J, Witkin SS. Testing for high-risk human papillomavirus types will become a standard of clinical care. Am J Obstet Gynecol 2000; 182: 860-65. http://amedeo.com/lit.php?id=10764463 7. Leitlinien für Diagnostik und Therapie, Deutsche STD-Gesellschaft (DSTDG). Condylomata acuminata und andere HPV-assoziierte Krankheitsbilder des Genitale und der Harnröhre; 2000. http://www.uni-duesseldorf.de/AWMF/ll/059-001.htm 8. Maw R. Comparing Guidelines for the management of anogenital warts. Sex Transm Infect 2000; 76: 153. http://amedeo.com/lit.php?id=10961187 9. Von Krogh G, Lacey CJN, Gross G, Barrasso R, Schneider A. European Course on HPV-Associated Pathology: Guidelines for the diagnosis and management of anogenital warts. Sex Transm Inf 2000 ; 76: 162-8. http://amedeo.com/lit.php?id=10961190