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Evaluation of Sch 29482 in experimental syphilis and comparison with penicillin G benzathine in disseminated disease and localized infection.

The present study was designed to assess the in vivo activity of Sch 29482, a new penem antibiotic, against disseminated and localized Treponema pallidum infections in rabbits. Animals were inoculated either intravenously or intradermally. Randomized groups then received 25 or 50 mg of Sch 29482 per kilogram of body weight twice a day for 7 days, two weekly injections of 200,000 U of penicillin G benzathine for comparative purposes, or no antibiotic therapy. In both infection models, striking differences were noted between the untreated control rabbits and rabbits receiving penicillin G benzathine or high-dose Sch 29482. Intravenously infected rabbits did not develop disseminated lesions or orchitis, and chancres produced by intradermal infection regressed and healed rapidly after both treatment regimens. Infectivity studies also suggested that high-dose Sch 29482 and penicillin G benzathine were effective since the testes and lymph nodes of treated animals were free of infectious organisms. Treatment of animals with the lower dose of Sch 29482 represented borderline or suboptimal therapy, with a failure rate of one in four for each infection model.

Animals↗

Treponema pallidum subsp. pertenue displays pathogenic properties different from those of T. pallidum subsp. pallidum.

The present study described the susceptibility of C4D guinea pigs to cutaneous infection with Treponema pallidum subsp. pertenue Haiti B strain. The general manifestations of the disease in adults and neonates differ, to a certain degree, from those induced by T. pallidum subsp. pallidum Nichols strain. Noticeable differences between the infections were reflected in the character of the skin lesions, their onset and persistence, and the kinetics of the humoral response. The incidence and dissemination of cutaneous yaws lesions in very young guinea pigs were remarkably different from the low frequency observed in a similar age group of syphilis infection, 100 versus 17%, respectively. Moreover, as opposed to T. pallidum subsp. pallidum, T. pallidum subsp. pertenue does not cross the placenta. Offspring born to yaws-infected mothers did not produce immunoglobulin M antibodies and their organs, examined by PCR and rabbit infectivity test (RIT), were all negative. Examination of a large number of tissues and organs in adult, neonate, and maternal yaws by PCR and RIT clearly demonstrated that, unlike syphilis, there was a low incidence and short persistence of the yaws pathogen in internal organs. These findings stress the dermotropic rather than the organotropic character of yaws and provide further evidence of distinctive biological and pathological differences between yaws and venereal syphilis.

Age Factors↗

Pathophysiology of swine dysentery: colonic transport and permeability studies.

Net transport of electrolytes and water, unidirectional Na+ and Cl- fluxes, and mucosal permeability were examined in isolated colonic loops of control pigs and pigs infected with Treponema hyodysenteriae. Results indicated that all net ion and water absorption from the colon was abolished in infected pigs. This abolition of net absorption was almost exclusively the result of a decrease in the lumen-to-blood fluxes of Na+ and Cl-; the blood to lumen fluxes and mucosal permeability were essentially unaffected. The results indicated that the diarrhea observed in these pigs was a consequence of colonic absorptive failure alone. Neither an active nor a passive secretory process could explain the fluid losses under the conditions of these experiments.

Animals↗

OptiSol corneal storage medium and transmission of Treponema pallidum.

This study was conducted to provide experimental information on the probability of syphilis transmission resulting from corneal transplantation. To determine the effects of commonly employed corneal storage conditions on the survival and infectivity of Treponema pallidum, T. pallidum subsp. pallidum (Nichols) was inoculated into OptiSol storage medium or a T. pallidum survival medium at a concentration of 10(6)/ml and incubated in cornea viewing chambers for 24 h at 4 degrees C. When inoculated intradermally into rabbits (0.1 ml per site), none of the 10 sites developed lesions from suspensions incubated in OptiSol in the presence or absence of 100 microgram/ml gentamicin; T. pallidum incubated in the survival medium yielded lesions at one of 10 sites, whereas freshly extracted organisms produced lesions at all 10 sites. In another set of experiments, the infectivity of corneal tissue from rabbits inoculated intratesticularly with 2 x 10(7) T. pallidum 10 days earlier was determined. Corneas from five T. pallidum-infected rabbits were excised, extracted, and tested for infectivity either immediately after removal or after 24-h storage in OptiSol. Recipient rabbits developed lesions at five of 50 intradermal sites when the corneas were neither stored in OptiSol nor rinsed before extraction. Corneas from 10 donor rabbits that were rinsed with phosphate-buffered saline to remove blood and aqueous humor before extraction did not yield lesions at any of 200 sites in the recipient animals. The results of this study indicate that retention of T. pallidum infectivity is poor under typical corneal storage conditions and that rabbit corneal tissue contains few, if any, infectious T. pallidum organisms under the experimental conditions employed.

Animals↗

Association of Trichomonas vaginalis with sociodemographic factors and other STDs among female inmates in Lisbon.

A study on STDs was conducted among 211 female inmates in a prison in Lisbon, Portugal, in order to establish possible associations between Trichomonas vaginalis infection, sociodemographic factors and other STDs. T. vaginalis was found in 31.2% of the women, from whom only 65.1% presented symptoms. It was more frequently isolated in the 20-40 year age group. On univariate analysis there was an association, although not statistically significant, between the existence of T. vaginalis, multiple sexual partners, drug addiction and no condom use. A statistically significant association was found between trichomoniasis, prostitution and other STDs. These were found in 87% of all women. T. vaginalis was detected alone in 23.8% (15/63) of all women with trichomoniasis, while 76.2% (48/63) of them had multiple infections with trichomonas and other STDs. A statistically significant association was present between trichomoniasis and Mycoplasma hominis and infection with Treponema pallidum. This study showed that the prevalence of T. vaginalis is as high as that of multiple infections with other STDs. Therefore, our findings seem to confirm that trichomoniasis serves as a marker for other STDs. Screening for STDs should then be offered to Portuguese inmates, or, at least, these women should be screened for T. vaginalis, as a marker for the other STDs.

Adult↗

Prevalence and incidence of syphilis and its association with HIV-1 infection in a population-based study in the Kagera region of Tanzania.

Population-based prevalence and incidence studies on HIV-1 infection were started in the Kagera region of Tanzania in 1987. The prevalence and incidence of infection with Treponema pallidum was studied to enable development of better strategies for STD control. Serological diagnosis of a past or treated infection with Troponema pallidum was made by seropositivity only to TPHA testing while active syphilis was diagnosed by seropositivity to both VDRL and TPHA tests. Seroconversion was measured in 1989 by finding TPHA serologically positive individuals during the follow-up period among the initially seronegative study population of 1987. The overall prevalence of active syphilis in the total sample of adults in the region was found to be 5.9% while that of past syphilis was 13.5%. The association between the prevalence of HIV-1 infection and syphilis of both types was found to be highly significant. However, the association between one pre-existing infection and seroconversion in the other was present but not statistically significant. The overall incidence of syphilis based on seroconversion in a cohort of adults in the region was found to be 11.6 per 1000 person-years at risk. In view of these findings, syphilis is a significant health problem in the region with a high level of transmission and efforts should be made to control it. Intervention studies should use these base-line data and monitor changes in syphilis incidence which may indicate changes in sexual behaviour. Such indicators could also be useful for evaluating the impact of interventions directed at reducing the transmission of HIV, syphilis and other STDs in the region.

Acquired Immunodeficiency Syndrome↗

Drugs five years later. Spectinomycin.

A single intramuscular injection of 0.2 g of spectinomycin hydrochloride is highly effective for the treatment of uncomplicated anogenital infections with Neisseria gonorrhoeae. Spectinomycin hydrochloride is indicated for uncomplicated anogenital gonococcal infections in men and women who cannot receive penicillin or probenecid, and is the drug of choice for the retreatment of patients with uncomplicated anogenital gonococcal infection who have not responded to other antibiotics. A single dose of spectinomycin does not appear to be reliably effective in the treatment of gonococcal pharyngitis. Preliminary reports indicate that multiple-dose schedules of spectinomycin will prove to be effective in gonococcal pelvic inflammatory disease and disseminated gonococcal infection. In the dosage used for gonococcal infections, spectinomycin has little effect on infection with Treponema pallidum. Evaluation of this antibiotic against other microorganisms suggests little utility for this agent in conditions other than gonococcal infections.

Animals↗

Immunogenicity of three recombinant Treponema pallidum antigens examined in guinea pigs.

The immunogenicity of recombinant treponemal antigens TmpA, TmpB and TmpC incorporated in RIBI adjuvant and injected into inbred strain 2 guinea pigs has been examined. The immune status of these animals has been challenged by infection with Treponema pallidum, Nichols. The immune response evaluated by the fluorescent-antibody test, microhemagglutination test and ELISA demonstrated high titers of antibodies to the T. pallidum antigens. The immunoblot analysis proved that the antibodies were directed to the 43-(Tmp A) 34- (Tmp B) and 35-kdalton (Tmp C) polypeptides. Antibodies cross-reacting with Treponema phagedenis biotype Reiter were, however, also detected. In spite of high titers of antibodies the animals were not protected against challenging infection with 10(8) organisms of T. pallidum.

Adjuvants, Immunologic↗

Neurosyphilis in HIV-infected patients.

To determine the prevalence and the clinical and serological findings of neurosyphilis in HIV-infected patients, Treponema pallidum hemagglutination (TPHA) tests, CD4+ lymphocyte counts and determination of rapid plasma reagin (RPR) titers were performed in 972 HIV-infected patients over a period of 3.5 years. Patients were scored according to the Centers for Disease Control's classification for HIV infection. Reactive serum syphilis tests and positive cerebrospinal fluid (CSF)-Venereal Disease Research Laboratory (VDRL) tests, with or without clinical symptoms, were used as the criteria for diagnosis of neurosyphilis. The TPHA test was positive in 31 patients, representing 3.1% of all HIV-infected patients included in the study. Of these, 13 were intravenous drug addicts, 14 were homosexuals and 4 were heterosexuals. Diagnosis of syphilis was concurrent with HIV infection in 19 patients, prior to HIV infection in 6 patients and after HIV infection in 6 patients. CSF examinations were performed in 28 of the 31 (90.3%) patients with serologically evident syphilis. Four patients had positive CSF-VDRL tests with pleocytosis (23.5% of untreated syphilis patients in whom CSF was examined), three of whom reported mild headache, which was considered a doubtful manifestation of neurosyphilis. Patients with syphilis diagnosed and treated prior to diagnosis of HIV infection did not have evidence of neurosyphilis. Seven patients had pleocytosis with a negative CSF-VDRL test, without any clinical manifestations of neurosyphilis. There was no significant difference in the mean CD4+ lymphocyte count between patients with and without neurosyphilis (p = 0.5). RPR titers in neurosyphilis patients were greater than those in patients previously treated for syphilis and in those with pleocytosis only (p = 0.046 and 0.036, respectively). All neurosyphilis patients had an RPR titer > 1:8. After therapy, neurosyphilis patients had negative CSF-VDRL tests with a lower level of pleocytosis. The prevalence of neurosyphilis was 0.4% in HIV-infected patients and 23.5% in HIV-infected patients with untreated syphilis. This high prevalence of neurosyphilis warrants CSF examination in HIV-infected patients with syphilis, regardless of the stage of syphilis.

Adult↗

Cyclophosphamide-sensitive activity of suppressor T cells during treponemal infection.

When hamsters were infected with Treponema pallidum subspecies endemicum, the composition and activity of the cellular immune components were markedly altered compared to those of sham-infected controls. A population of suppressor T cells (Ts) developed that diminished the ability of the macrophage (M phi) to perform C3b receptor-mediated ingestion (C3bMI) of erythrocytes coated with antibody and complement. Using cyclophosphamide (CY) we examined node and peritoneal cells to determine their role in regulating M phi activity during this infection. In vitro the node and peritoneal T cells from treponemal-infected/CY-treated animals showed considerably less suppressive activity than treponemal-infected/untreated T cells when co-cultured with M phi from infected animals. This response was greater with node T cells compared to peritoneal T cells. Moreover, a quantitative analysis of the mononuclear leucocyte populations from each of these regions showed that CY-treated/uninfected animals had a decreased percentage of node T cells. Despite this reduction of node T cells, peritoneal T-cell populations were only minimally reduced. However, treponemal-infected hamsters concomitantly treated with CY had a significant reduction in the T-cell percentages in both compartments. These results imply that, during this infection, most Ts generated in the node remain there although some are dispersed to supplementary regions. Thus, the development of a suppressor system that effects M phi function may be one way in which treponemes escape total elimination by the host.

Animals↗

Endemic syphilis: transfer of resistance to Treponema pallidum strain Bosnia A in hamsters with a cell suspension enriched in thymus-derived cells.

Direct evidence for involvement of thymus-derived (T) cells in host defense against syphilitic infection is presented. Irradiated, bone marrow-reconstituted hamsters receiving cells from hamsters immune to infection with Treponema pallidum strain Bosnia A had significantly lower weights and fewer treponemes per lymph node than animals that had received normal lymphoid cells or only normal bone marrow cells. Cell suspensions enriched in T cells from immune hamsters were obtained by sequential filtration of pooled spleen and lymph node cells through glass- and nylon-wool columns. The fractionated suspensions of cells responded poorly to stimulation by phytohemagglutinin, Escherichia coli lipopolysaccharide, and dextran sulfate, but responded relatively strongly to the T-cell mitogen, convanavalin A. After fractionation the proportion of cells susceptible to antithymocyte serum and complement increased significantly. These immune cell suspensions depleted of bone marrow-derived cells closely resembled unfractionated suspensions in their ability to confer resistance to challenge with T. pallidium.

Animals↗

Acquired resistance of hamsters to challenge with homologous and heterologous virulent treponemes.

Hamsters infected with Treponema pallidum Nichols (venereal syphilis), T. pallidum Bosnia A (endemic syphilis), or T. pertenue (frambesia, or yaws) developed substantial resistance to homologous reinfection. Hamsters infected for 10 weeks developed no lesions, and their lymph nodes contained fewer treponemes after reinfection with the same strain. The degree of cross-resistance among the treponemes correlated well with pathological changes occurring in infected hamsters and with the persistence of treponemal antigen during primary infection. Only hamsters infected with T. pallidum Bosnia A developed substantial resistance to heterologous reinfection. These animals also had extensive chronic skin lesions and lymph nodes containing measurable numbers of treponemes. Frambesial hamsters had less extensive lesions and were resistant to T. pallidum Nichols and, to a lesser extent, to T. pallidum Bosnia A. Hamsters infected with T. pallidum Nichols developed no cutaneous lesions and were resistant only to reinfection with T. pertenue. Confirmation of these results was obtained in normal hamsters infused with syphilitic (Nichols or Bosnia A) or frambesial immune cells and challenged with homologous or heterologous treponemes.

Animals↗

Low prevalence of human immunodeficiency virus-1 (HIV-1), HIV-2, and human T cell lymphotropic virus-1 infection in Somalia.

A seroepidemiologic survey was conducted to determine the prevalence of human immunodeficiency virus type 1 (HIV-1), HIV-2, human T cell lymphotropic virus type I (HTLV-I), and Treponema pallidum infection among southern Somalis. Sera were collected from 1,269 study subjects in the urban area of the capital city, Mogadishu, and in the rural towns of Merka, Qoryoley, and Kismayo. The subjects included 57 prostitutes, 79 sexually transmitted disease (STD) patients, and 1,133 others, including outpatient and hospitalized patients with leprosy, tuberculosis, other infectious diseases, individuals from rehabilitation camps and secondary schools, and Ethiopian immigrants. Results indicated that none of the sera were positive for HIV-1 and HIV-2 by Western blot, but one was positive for HTLV-I. The prostitutes had a significantly higher prevalence of treponemal antibody (50.8%; P less than 0.0001) than either the STD patients (12.6%) or the other subjects (5.2%). Epidemiologic data indicated that 94% of the males and females were circumcised and only 2.6% of the males used condoms. Overall, the results of this study suggested a very low prevalence of HIV-1, HIV-2, and HTLV-I infections, especially among prostitutes and STD patients, who were considered at greatest risk of contracting these retroviral infections.

Adolescent↗

Passive transfer of resistance to frambesial infection in hamsters.

The immune mechanism by which hamsters acquire resistance to infection with Treponema pertenue, the causative agent of frambesia, or yaws, has not been elucidated. Serum or cells (spleen or lymph node) obtained from hamsters resistant to frambesial infection were transferred to normal syngenic recipients, who are subsequently infected with T. pertenue. The following parameters were used to measure the ability of immune serum of cells to confer resistance on recipient hamsters to frambesial infection: inhibition of the development of cutaneous lesions, decreased weight, and number of treponemes in the inguinal lymph nodes. This investigation demonstrated that immune serum conferred protection on recipient hamsters infected with T. pertenue. Discontinuation of the administration of immune serum (18 days after frambesial infection) did not result in the development of cutaneous lesions. Since the inguinal lymph nodes contained a sizeable number of treponemes (2.6 X 10(5)), immune serum failed to prevent frambesial infection. Recipients of immune spleen or lymph node cells initially developed frambesial lesions 9 days after infection. The frambesial lesions began to resolve 12 to 14 days after infection and by day 21 had completely regressed. These results illustrated that humoral factors and cells are involved in resistance of the hamster to frambesial infection.

Animals↗

Alteration in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus.

Within the past 18 months, we have seen four cases of neurosyphilis at our institution (two of meningovascular syphilis, one of acute syphilitic meningitis, and one of asymptomatic neurosyphilis) in young homosexual men with serologic evidence of exposure to human immunodeficiency virus (HIV). Two of the four patients had neurosyphilis despite previous adequate therapy for early syphilis with benzathine penicillin. Meningovascular syphilis developed in one patient within four months after a primary infection, in a manner consistent with an accelerated course of syphilitic infection. These findings suggest the possibility that HIV infection may alter the natural course of syphilis because of the profound defects in cell-mediated immunity it causes. The possible potentiating effects of HIV on Treponema pallidum infection suggest the need for lumbar puncture in the evaluation of HIV-seropositive patients with syphilis, as well as modifications of the currently recommended treatment regimens for primary, secondary, and latent syphilis and neurosyphilis in this patient population. Neurosyphilis should probably be added to the growing list of infectious complications of the acquired immunodeficiency syndrome (AIDS) and may be the first such complication to appear.

Acquired Immunodeficiency Syndrome↗