Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections.

The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A series of N-benzyl-substituted 3'-(R)-3'-aminomethyl-3'-hydroxy spectinomycins was developed on the basis of a computational analysis of the aminomethyl spectinomycin binding site and structure-guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against the common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis, as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome-binding 3'-(S) isomers of the lead compounds demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target against the ribosome. Compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series exhibited excellent chemical stability superior to spectinomycin; no interaction with a panel of human receptors and drug metabolism enzymes, suggesting low potential for adverse reactions or drug-drug interactions in vivo; activity in vitro against a panel of penicillin-, macrolide-, and cephalosporin-resistant S. pneumoniae clinical isolates; and the ability to cure mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate that N-benzyl aminomethyl spectinomycins are suitable for further development to treat drug-resistant respiratory tract and sexually transmitted bacterial infections.

HIV-1 DNA levels in peripheral blood mononuclear cells and cannabis use are associated with intermittent HIV shedding in semen of men who have sex with men on successful antiretroviral regimens.

BACKGROUND: Few data exist on the efficacy of combined antiretroviral therapy (cART) in semen of human immunodeficiency virus type 1 (HIV-1) infected men who have sex with men (MSM) with sustained control of HIV replication in blood. METHODS: HIV-1 infected MSM on successful cART for >6 months were enrolled. HIV-RNA was quantified in seminal plasma (spVL) and in blood plasma (bpVL) from 2 paired samples collected 4 weeks apart. Relationship between spVL and bpVL (measured by an ultrasensitive assay, LOQ 10 copies/mL), total peripheral blood mononuclear cells (PBMC)-associated HIV-DNA, sexually transmitted infections (STIs), and self-reported socio-behavioral characteristics was assessed using GEE logistic regression. RESULTS: In total, 157 patients were included. Median time with bpVL <50 copies/mL was 3.3 years. spVL was detectable in 23/304 samples (prevalence 7.6%). Median spVL was 145 cp/mL (100-1475). spVL was detectable on the first, on the second, and on both samples in 5, 14, and 2 men, respectively. In sum, 33 individuals (21%) had STIs (asymptomatic in 24/33). Residual bpVL was undetectable by ultrasensitive assay in 225/300 samples (75%). After multivariable adjustments, PBMC-associated HIV-DNA (OR 2.6[1.2; 6.0], for HIV-DNA > 2.5 log10 cp/10(6) PBMC, P = .02), and cannabis use during sexual intercourse (OR 2.8[1.2; 6.7], P = .02) were the only factors associated significantly with spVL. CONCLUSION: We show that HIV-RNA can be detected intermittently in semen of HIV-1 infected MSM despite successful cART. The size of blood HIV-1 reservoir predicted spVL detection. Our results indicated also that the possible effect of cannabis should be taken into account when developing prevention interventions targeted toward HIV-infected MSM on successful cART.

[Antibiotic resistance as a public health problem: the case of genital mycoplasmoses]. / L'antibiotico resistenza un problema di sanità pubblica: il caso delle micoplasmosi genitali.

Antibiotic resistance is an emerging public health problem especially due to the continuous use of antibiotics that selects more aggressive and resistant species. In the present study the authors determined the antibiotic sensitivity of 128 Mycoplasma hominis strains obtained from urethral swabs of male patients (mean age 36 years). The Mycoplasma IST 2 strip was used to test antibiotic susceptibility: 88% of analysed strains were found to be resistant to erythromycin and azithromycin, 75% to clarithromycin, 50% to ofloxacin and ciprofloxacin, and 12% to tetracycline. All strains were susceptible to josamycin, doxycycline and pristinamycin. Results were comparable to those of a recent study by Savarino-Mattei which also showed high resistance of M hominis to macrolide antibiotics and to ciprofloxacin and susceptibility to tetracyclines. Doxycycline is currently the antibiotic of first choice for treating M hominis infections.

The use of an integrated care pathway for evidence-based practice and clinical governance in abortion care.

The aim of the study was to assess the effectiveness of an integrated care pathway (ICP) for delivery of evidence-based practice in abortion care. All women re-admitted after an abortion had their records audited for adherence to national and local guidelines using information in the ICP and general gynaecology case notes. A total of 100 women were re-admitted into the gynaecological wards of hospitals in Hull and East Riding of Yorkshire after an abortion, between January 2000 and December 2006. Out of 8,476 medical or surgical induced abortions undertaken at 14 weeks gestation or under, the overall readmission rate was 1.2%. The ICP showed that 97% of women had chlamydia screening prior to the abortion; all women had a contraceptive discussion and 43% left using a long-acting reversible method of contraception (LARC). However, data outside the care pathway was not documented, and hence the standard of care given on readmission was difficult to locate and variable in quality. The ICP clinical record is demonstrated to be a useful tool for high quality record-keeping and ensuring all patients receive the same standard of pre-assessment care. Although this service has an acceptably low-risk profile in terms of re-admission, we propose the addition of a re-admission episode to the current ICP to further enhance clinical care post-abortion.

[Update on the epidemiology, diagnosis and treatment of sexually-transmitted infections]. / Panorama actual de la epidemiología, diagnóstico y tratamiento de las infecciones de transmisión sexual.

In the last decade, cases of sexually-transmitted infections (STIs) have progressively increased in Europe. The reasons for this increase are unclear, but may involve changes in social behavior, migration and international travel, coupled with the emergence of risk groups that have not been taken into sufficient consideration to date. The routine use of molecular diagnostic techniques for many of these infections has solved many problems of sensitivity and the suitability of samples for microbiological diagnosis: non-invasive samples can be used, which has undoubtedly contributed to the increase in the number of cases. Moreover, molecular methods have also been introduced for antibiotic and antiviral susceptibility testing, as well as for molecular characterization of clinical isolates. All of these factors, together with the approval of the vaccine against the human papillomavirus, have changed the landscape of STIs across Europe.

Prevalence of sexually transmitted infections among adolescents in Kampala, Uganda, and theoretical models for improving syndromic management.

PURPOSE: To estimate the prevalence of treatable sexually transmitted infections (STI) in adolescents visiting a youth health clinic. To evaluate the algorithm for management of the abnormal vaginal discharge (AVD) syndrome recommended in Uganda's national guidelines and compare it with other theoretical flowchart models. METHODS: Sexually experienced adolescents who were visiting an urban youth health clinic in Kampala, Uganda were examined and interviewed (with their consent) about their socio-demographic background, sexual risk factors, and genital symptoms. Samples taken for Chlamydia trachomatis (CT), Neisseria gonorrhoea (NG), and Trichomonas vaginalis (TV) were analyzed by polymerase chain reaction (PCR). Rapid plasma reagin (RPR) was used with confirming treponema pallidum hem agglutination (TPHA) for syphilis diagnosis. One hundred ninety-nine females and 107 males were examined. Performance of the national algorithm was compared with different theoretical algorithms. RESULTS: Prevalence of CT, NG, TV and syphilis was 4.5%, 9.0%, 8.0%, and 4.0%, respectively, for girls and 4.7%, 5.7%, 0%, and 2.8%, respectively, for boys. We found that 20.6% of the females and 13.2% of the males had at least one STI. The national AVD flow chart had a sensitivity of 61%, a specificity of 38.5% and a positive predictive value (PPV) of 11.6%. All the models had PPV of less than 20% and sensitivity less than 85%. The best performing algorithm using risk and protective factors, rather than symptoms, implicated a sensitivity/specificity and PPV of 82.6%/47% and 17.3%, respectively (p = .012). CONCLUSIONS: An algorithm for management of STI using behavioral and demographic factors in this population demonstrated enhanced sensitivity, specificity, and PPV.

Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina.

BACKGROUND: Factors that influence shedding of HIV-1 infected cells in cervical and vaginal secretions may be important determinants of sexual and vertical transmission of the virus. We investigated whether hormonal contraceptive use, vitamin A deficiency, and other variables were risk factors for cervical and vaginal shedding of HIV-infected cells. METHODS: Between December, 1994, and April, 1996, women who attended a municipal sexually transmitted diseases (STDs) clinic in Mombasa, Kenya, and had previously tested positive for HIV-1, were invited to take part in our cross-sectional study. Cervical and vaginal secretions from 318 women were evaluated for the presence of HIV-1 infected cells by PCR amplification of gag DNA sequences. FINDINGS: HIV-1 infected cells were detected in 51% of endocervical and 14% of vaginal-swab specimens. Both cervical and vaginal shedding of HIV-1 infected cells were highly associated with CD4 lymphocyte depletion (p = 0.00001 and p = 0.003, respectively). After adjustment for CD4 count, cervical proviral shedding was significantly associated with use of depot medroxyprogesterone acetate (odds ratio 2.9, 95% CI 1.5-5.7), and with use of low-dose and high-dose oral contraceptive pills (3.8, 1.4-9.9 and 12.3, 1.5-101, respectively). Vitamin A deficiency was highly predictive of vaginal HIV-1 DNA shedding. After adjustment for CD4 count, severe vitamin A deficiency, moderate deficiency, and low normal vitamin A status were associated with 12.9, 8.0, and 4.9-fold increased odds of vaginal shedding, respectively. Gonococcal cervicitis (3.1, 1.1-9.8) and vaginal candidiasis (2.6, 1.2-5.4) were also correlated with significant increases in HIV-1 DNA detection, but Chlamydia trachomatis and Trichomonas vaginalis were not. INTERPRETATION: Our study documents several novel correlates of HIV-1 shedding in cervical and vaginal secretions, most notably hormonal contraceptive use and vitamin A deficiency. These factors may be important determinants of sexual or vertical transmission of HIV-1 and are of public health importance because they are easily modified by simple interventions.

PIP: Correlates of HIV-1 shedding in cervical and vaginal secretions were investigated in a cross-sectional study of 318 women previously diagnosed with HIV who presented to a sexually transmitted disease clinic in Mombasa, Kenya, during 1994-96. HIV-infected cells were detected in 51% of endocervical and 14% of vaginal swab specimens. Both cervical and vaginal shedding of HIV-1 infected cells were highly associated with CD4 lymphocyte depletion. After adjustment for CD4 count, cervical proviral shedding was significantly associated with use of depo medroxyprogesterone acetate (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.5-5.7) and of low- and high-dose oral contraceptives (OR, 3.8; 95% CI, 1.4-9.9 and OR, 12.3; 95% CI, 1.5-101, respectively). After adjustment for CD4 count, severe vitamin A deficiency, moderate deficiency, and low-normal vitamin A status were associated with 12.9, 8.0, and 4.9-fold increased odds of vaginal shedding, respectively. Finally, gonococcal cervicitis (OR, 3.1; 95% CI, 1.1-9.8) and vaginal candidiasis (OR, 2.6; 95% CI, 1.2-5.4), but not Chlamydia trachomatis and Trichomonas vaginalis, were correlated with significant increases in HIV-1 DNA detection. These risk factors, easily modifiable by simple interventions, may be important determinants of sexual or vertical HIV transmission.