Safety and pharmacokinetics of XOMA 3AB, a novel mixture of three monoclonal antibodies against botulinum toxin A.

Botulinum neurotoxin A is a category A bioterrorism agent. Current antitoxin therapies are scarce and produce adverse reactions. XOMA 3AB consists of 3 IgG1 monoclonal antibodies (MAbs), each with a distinct human or humanized variable region, which bind to distinct epitopes on botulinum neurotoxin serotype A. This first-in-human study evaluated the safety and pharmacokinetics (PK) of escalating doses of XOMA 3AB administered intravenously (i.v.) to healthy adults. In this double-blind placebo-controlled dose escalation study, 3 cohorts of 8 healthy subjects received a single intravenous dose of XOMA 3AB or placebo at a 3:1 ratio. Follow-up examinations included physical examinations, hematology and chemistry blood tests, electrocardiograms, and pharmacokinetics. Pharmacokinetic parameters were estimated using noncompartmental methods. There were no infusion discontinuations or hypersensitivity reactions. Two or more subjects experienced headache, hyperglycemia, or anemia; none was dose related. All adverse events (AEs) were mild to moderate except for an episode of exercise-induced elevation of a subject's creatine phosphokinase (CPK) level, unrelated to XOMA 3AB. Concentration-time plots demonstrated a peak in MAb concentrations 1 to 2 h after completion of the infusion, after which the levels declined in a biexponential decay pattern for all analytes. For each MAb, the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve from 0 to infinity (AUCinf) increased as the dose increased. Clearance of the humanized mouse MAb was more rapid than that of the two fully human MAbs, particularly at the lowest dose. None of the MAbs was immunogenic. At the doses administered, XOMA 3AB was well tolerated. These safety findings support further investigation of XOMA 3AB as a potential agent for botulism treatment and postexposure prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. NCT01357213.).

What do we need to learn for policy decision-making on sexually transmitted infections prevention and treatment in Israel?

The rising trend of sexually transmitted infections (STIs) reported in several western countries has also affected Israel. To review epidemiological trends and to address additional issues needed for a wider overview on STIs in Israel, we analysed notified data on infectious syphilis, gonorrhoea, Chlamydia trachomatis and HIV/AIDS during 1998-2007, by age groups, and each available publication on STIs in Israel. The trend of each disease had a unique pattern, probably influenced by different screening procedures, case definition, mix of populations and better access to care for high-risk populations. Higher rates were found among patients aged 25-34 years. Rates found in different peak years for gonorrhoea, HIV, chlamydia and infectious syphilis reached 43.6, 18.9, 10.8 and 8.1 cases per 100,000 population, respectively. We compare trends to those of countries from World Health Organization (WHO) European Region and discuss interventions for subpopulations on which additional data are needed for evidence-based policy-making. Incidence rates of syphilis, gonorrhoea, chlamydia and HIV/AIDS are still low in Israel. We propose additional components needed for a more comprehensive evidence-based policy on STIs.

PCR offers no advantage over culture for microbiologic diagnosis in cellulitis.

PURPOSE: Most cases of cellulitis are traditionally attributed to ß-hemolytic Streptococcus and Staphylococcus species, although in most cases, no organism is identified. Development of PCR using the conserved bacterial 16 S rRNA DNA permits identification of bacteria independent of conventional culture approaches and prior use of antibiotics. METHODS: We used PCR-based techniques to identify cellulitis etiology using aspirate samples from affected skin. Saline was infiltrated and aspirated at the site of greatest erythema or at the cellulitic border. Samples were tested for 16 S rRNA DNA, and organism-specific probes used to identify bacteria commonly seen in skin infections. RESULTS: Aspirates from 32 patients were studied, and 16 S rRNA DNA was detected in nine of these patient samples (28.1%). Bacterial species were identified by PCR methods in six of these nine samples (66.6%), with S. aureus and methicillin-resistant S. aureus (MRSA) identified in four and two, respectively, of these samples. Of the patients with positive aspirate bacterial cultures (3/9, 33.3%), S. aureus and coagulase-negative Staphylococcus (CoNS) were present on cultures of two of the three (both 66.6%) positive samples. Only in one of the three positive bacterial cultures did the PCR method detect the same organism as was detected by culture. Among patients with positive provider-collected clinical cultures, MRSA was the predominant organism (11/18, 61.1%) and when present, it was found as the sole organism. Where S. aureus or Streptococcus species were detected by molecular methods, clinical cultures yielded a positive result as well. CONCLUSIONS: PCR-based techniques do not appear to be more sensitive than aspirate cultures for the detection of pathogens in cellulitis.

Prostate involvement during sexually transmitted infections as measured by prostate-specific antigen concentration.

BACKGROUND: We investigated prostate involvement during sexually transmitted infections by measuring serum prostate-specific antigen (PSA) as a marker of prostate infection, inflammation, and/or cell damage in young, male US military members. METHODS: We measured PSA before and during infection for 299 chlamydia, 112 gonorrhoea, and 59 non-chlamydial, non-gonococcal urethritis (NCNGU) cases, and 256 controls. RESULTS: Chlamydia and gonorrhoea, but not NCNGU, cases were more likely to have a large rise (40%) in PSA than controls (33.6%, 19.1%, and 8.2% vs 8.8%, P<0.0001, 0.021, and 0.92, respectively). CONCLUSION: Chlamydia and gonorrhoea may infect the prostate of some infected men.

New horizons for cutaneous microbiology: the role of biofilms in dermatological disease.

Human skin is colonized by bacteria. The development of new genomic microbiological techniques has revealed that the bacterial ecology of human skin is far more complex than previously imagined and includes many fastidious or noncultivable bacterial species which are found on both normal and diseased skin. In nature, the predominant bacterial phenotype on epithelial surfaces is that of organisms organized within a biofilm. This contrasts with the widely held belief that bacteria are planktonic, i.e. free-floating single cells. Biofilms are sessile bacterial communities encased in an extracellular matrix that have a well-developed communication system and can regulate bacterial growth and metabolism, confer resistance to antimicrobials and to host inflammatory cells, and alter host metabolism. Biofilms have been observed on healthy skin and in a number of dermatological conditions, including some that were previously thought not to have an infectious aetiology. Here we review the concept of biofilms and their role in cutaneous health and disease.

Real-time PCR assays compared to culture-based approaches for identification of aerobic bacteria in chronic wounds.

Chronic wounds cause substantial morbidity and disability. Infection in chronic wounds is clinically defined by routine culture methods that can take several days to obtain a final result, and may not fully describe the community of organisms or biome within these wounds. Molecular diagnostic approaches offer promise for a more rapid and complete assessment. We report the development of a suite of real-time PCR assays for rapid identification of bacteria directly from tissue samples. The panel of assays targets 14 common, clinically relevant, aerobic pathogens and demonstrates a high degree of sensitivity and specificity using a panel of organisms commonly associated with chronic wound infection. Thirty-nine tissue samples from 29 chronic wounds were evaluated and the results compared with those obtained by culture. As revealed by culture and PCR, the most common organisms were methicillin-resistant Staphylococcus aureus (MRSA) followed by Streptococcus agalactiae (Group B streptococcus) and Pseudomonas aeruginosa. The sensitivities of the PCR assays were 100% and 90% when quantitative and qualitative culture results were used as the reference standard, respectively. The assays allowed the identification of bacterial DNA from ten additional organisms that were not revealed by quantitative or qualitative cultures. Under optimal conditions, the turnaround time for PCR results is as short as 4-6 h. Real-time PCR is a rapid and inexpensive approach that can be easily introduced into clinical practice for detection of organisms directly from tissue samples. Characterization of the anaerobic microflora by real-time PCR of chronic wounds is warranted.

Risk of Chlamydia trachomatis infection during pregnancy: effectiveness of guidelines-based screening in identifying cases.

Our goal was to define the risk factors for Chlamydia trachomatis (CT) infection among pregnant women at a large urban medical centre. In a retrospective study, clinical records at a US maternity unit from July 2005 through February 2008 were reviewed. The study population included all pregnant women with a singleton newborn of at least 20 weeks gestation and antenatal care information. Logistic regression was used to analyse the association between a positive CT test and demographic, behavioural and prenatal care variables. A total of 2127 women were included in this analysis. The prevalence of CT infection was 4.7%. Cases were more likely to be younger, black and single. Other risk factors included tobacco use and Neisseria gonorrhoeae infection. Our findings suggest that factors other than age may impact upon the diagnosis of CT in pregnant women and that a more comprehensive testing strategy should be considered.

Chlamydia trachomatis infection during pregnancy and the risk of preterm birth: a case-control study.

Our goal was to define the risks of preterm birth associated with Chlamydia trachomatis (CT) and other sexually transmitted infections (STIs) among pregnant women. We accessed clinical records from July 2005 to February 2008. The study population included all pregnant women who gave birth to a singleton newborn of at least 20 weeks' gestation, and who had antenatal care information. We estimated the impact of CT and other STI on the odds of preterm birth using logistic regression. Overall, 2127 women were included in this analysis. The prevalence of CT infection was 4.7%. CT diagnosis was not associated with preterm birth. In conclusion, this study did not find an association between CT and preterm birth. The lack of an association may be explained by early treatment. Future studies evaluating the timing of screening for STIs may help clarify whether pregnant women would benefit more from earlier screening.

Concordance of chlamydia trachomatis infections within sexual partnerships.

OBJECTIVES: The enhanced sensitivity of nucleic acid amplification tests (NAAT) provides an opportunity for estimating the prevalence of untreated Chlamydia trachomatis infections. The transmissibility and public health significance of some NAAT-identified infections are, however, not known. METHODS: Adults attending an urban emergency department provided specimens for C trachomatis screening using NAAT. Participants testing positive were offered follow-up including re-testing for C trachomatis using NAAT and traditional methods, eg culture and direct fluorescent antibody, and were treated. Partners were offered identical evaluation and treatment. Overall, 90 C trachomatis-positive participants had one or more sexual partners enrolled. RESULTS: Evidence of transmission, as defined by infection concordance between partnerships, was observed among 75% of partners of index cases testing positive by both NAAT and traditional assay but only 45% of partners of index cases testing positive by NAAT only (prevalence ratio 1.7, 95% CI 1.1 to 2.5). Among index participants returning for follow-up, 17% had no evidence of C trachomatis infection by NAAT or traditional assay (median follow-up three weeks). CONCLUSIONS: A substantial proportion of positive NAAT results for chlamydial infection may be of lower transmissibility and may not persist after a short follow-up. The long-term health effects of some positive NAAT are uncertain.

Relative prevalence of different sexually transmitted infections in HIV-discordant sexual partnerships: data from a risk network study in a high-risk New York neighbourhood.

OBJECTIVES: To determine infection patterns of sexually transmitted infections that facilitate HIV transmission among HIV-discordant couples. METHODS: 112 initial respondents were recruited in an impoverished neighbourhood of Brooklyn, New York. Their sexual (and injection) partners were recruited in up to four additional network sampling waves for a final sample of 465 persons aged 18 years or older. After separate informed consent had been obtained, blood and urine were collected and tested for HIV, type-specific antibodies to herpes simplex virus (HSV-2), syphilis, chlamydia and gonorrhoea. RESULTS: Of 30 HIV-discordant partnerships, five were same-sex male partnerships and 25 were opposite-sex partnerships. No subjects tested positive for syphilis or gonorrhoea. Two couples were chlamydia-discordant. For HSV-2, 16 couples were double-positive, eight discordant, four double-negative, and two comprised a HSV-2-negative with a partner with missing herpes data. CONCLUSIONS: HSV-2 was present in 83% of the HIV-discordant couples, chlamydia in 7%, and syphilis and gonorrhoea in none. HSV-2 is probably more important for HIV transmission than bacterial sexually transmitted diseases because it is more widespread. Even given the limited generalisability of this community-based sample, there seems to be an important HIV-prevention role for herpes detection and prevention activities in places where HIV-infected people are likely to be encountered, including sexually transmitted disease clinics, HIV counselling and testing programmes, prisons, needle exchanges, and drug abuse treatment programmes. The effects of HSV-suppressive therapy in highly impacted groups should also be investigated.

Audio computer assisted interviewing to measure HIV risk behaviours in a clinic population.

OBJECTIVES: To examine whether audio computer assisted survey interviewing (ACASI) influenced responses to sensitive HIV risk behaviour questions, relative to interviewer administration of those questions (IAQ), among patients attending a sexually transmitted infection (STI) clinic and whether the impact of interview mode on reporting of risk behaviours was homogeneous across subgroups of patients (defined by age, sex, and previous STI clinic experience). METHODS: 1350 clinic patients were assigned to complete a detailed behavioural survey on sexual risk practices, previous STIs and symptoms, condom use, and drug and alcohol use using either ACASI or IAQ. RESULTS: Respondents assigned to ACASI were more likely to report recent risk behaviours such as sex without a condom in the past 24 hours (adjusted OR = 1.9), anal sex (adjusted OR = 2.0), and one or more new partners in the past 6 months (adjusted OR = 1.5) compared to those interviewed by IAQ. The impact of ACASI varied by sex but, contrary to expectations, not by whether the patient had previously visited an STI clinic. Mode of survey administration made little difference within this population in reports of STI knowledge, previous STIs, STI symptoms, or illicit drug use. CONCLUSION: ACASI provides a useful tool for improving the quality of behavioural data in clinical environments.

Audio computer assisted self interview and face to face interview modes in assessing response bias among STD clinic patients.

BACKGROUND: Audio computer assisted self interview (ACASI) may minimise social desirability bias in the ascertainment of sensitive behaviours. The aim of this study was to describe the difference in reporting risk behaviour in ACASI compared to a face to face interview (FFI) among public sexually transmitted diseases (STD) clinic attendees. STUDY DESIGN: Randomly selected patients attending a public STD clinic in Baltimore, Maryland, sequentially took an ACASI formatted risk behaviour assessment followed by an FFI conducted by a single clinician, with both interview modalities surveying sexual and drug use behaviours. Binary responses were compared using the sign test, and categorical responses were compared using the Wilcoxon signed rank test to account for repeated measures. RESULTS: 671 (52% men, mean age 30 years, 95% African American) of 795 clinic attendees screened consented to participate. Subjects affirmed sensitive sexual behaviours such as same sex contact (p = 0.012), receptive rectal sexual exposure (p < 0.001), orogenital contact (p < 0.001), and a greater number of sex partners in the past month (p < 0.001) more frequently with ACASI than with an FFI. However, there were no differences in participant responses to questions on use of illicit drugs or needle sharing. CONCLUSIONS: Among STD clinic patients, reporting of sensitive sexual risk behaviours to clinicians was much more susceptible to social desirability bias than was reporting of illegal drug use behaviours. In STD clinics where screening of sexual risk is an essential component of STD prevention, the use of ACASI may be a more reliable assessment method than traditional FFI.

The prevalence of abnormal cervical cytology in a sexually transmitted diseases clinic.

Women seeking sexually transmitted disease (STD) services are at high risk of human papillomavirus infections. Cervical cytological screening with Papanicolau staining (Pap smear) is not consistently offered at public STD clinics. We reviewed Pap smear results on a series of 1000 female STD clinic attendees, abstracted demographics, risk behaviours and STD diagnosis from the clinical record and tested for associations with abnormal Pap smear. In all, 5.7% of the satisfactory specimens (56/993) were abnormal; increasing age category, genital warts, and chlamydia infections were independently associated with an abnormal Pap smear in multivariate analysis. Routine Pap smear screening provided satisfactory results in the STD clinic and, where population-based programmes are not available, should be fully integrated into public STD care, (particularly in settings serving younger women).

Prevalence and risk factors of chlamydia and gonorrhea among rural Nepali women.

OBJECTIVES: The epidemiology of sexually transmitted infections (STI) in rural, developing world populations is poorly understood. We estimated the prevalence and risk factors of Neisseria gonorrhoeae and Chlamydia trachomatis in a female population in rural Nepal. METHODS: We conducted a cross sectional study in a sample of 1177 postpartum women participating in a micronutrient supplementation trial in Nepal. Urine samples were collected to test for the two infections using the ligase chain reaction (LCR). RESULTS: C trachomatis was detected in 1.0% (95% confidence intervals (CI): 0.4 to 1.5) and N gonorrhoeae in 2.3% (95% CI: 1.2 to 3.4) of women. None of the women tested positive for both. Self report of all three symptoms of lower abdominal pain, pain and burning on urination, and vaginal discharge was associated with the presence of gonorrhoea (odds ratio (OR): 12.1, 95% CI: 1.3 to 115.0). Neonatal eye discharge was associated with maternal gonococcal infection (OR = 5.2, 95% CI: 1.1 to 24.9). Incidence of low birth weight was not related to these maternal infections, but very preterm delivery (<32 weeks) was higher among women positive for gonorrhoea (OR = 4.7, 95% CI: 1.0 to 22.0). In a multivariable analysis, low body mass index (<18.5) and cattle ownership were associated with gonorrhoea (p <0.05), whereas woman's literacy was associated with chlamydia (p = 0.06). CONCLUSION: We found the rates of N gonorrhoeae and C trachomatis to be low among women in this rural population of Nepal.

Patient, provider, and clinic characteristics associated with public STD clinic patient satisfaction.

OBJECTIVES: There is a lack of information describing levels of patient satisfaction among patients seeking sexually transmitted diseases (STD) care in a public clinic setting. We sought to identify patient, provider, and clinic characteristics associated with patient satisfaction within public STD clinics. METHODS: A cross sectional survey with random sampling was conducted among patients attending two public STD clinics. Satisfaction was assessed using questions from validated national surveys. Outcomes for multivariate logistic regression analysis were ratings of overall health care and clinician. RESULTS: 499/605 (82%) patients were enrolled. Patients were mean age 29 years, 51% male, 94% black. Lower rating of clinician technical skills (OR = 15.6 clinic A, OR = 7.9 clinic B) and clinic environment (OR = 3.9 clinic A, OR = 9.6 clinic B) were associated with lower healthcare rating, as was lower rating of television/video in waiting room (OR = 10.2, clinic A) and dysuria (OR = 4.2, clinic B). Higher clinician rating (OR = 0.58, clinic A) and receiving written materials (OR = 0.44, clinic B) were protective of lower healthcare rating. Risks for lower clinician rating at clinic A were greater pain, problems getting care, lower rating of clinician technical skill, and overall health care, while receiving written materials was protective. At clinic B, lower rating of clinician technical skill and clinic environment were risks for lower clinician rating. CONCLUSIONS: Patient satisfaction was associated with modifiable provider and clinic characteristics. Results from our study indicate a need to examine whether health outcomes of STD management vary by patient satisfaction.

Following-up for HIV test results: what limits return in an STD clinic population?

HIV testing is routinely performed in sexually transmitted disease (STD) clinics, but many tested do not follow up for results. We analysed data on STD clinic patients undergoing HIV testing between 1994-1998 who tested HIV-negative to describe characteristics associated with 'non-return' for results. Among 31,777 patients testing HIV-negative, male gender (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.19, 1.33), age <30 years (OR 1.72, 95% CI 1.43, 1.82), and a diagnosis of gonorrhoea at the testing visit (OR 1.72, 95% CI 1.43, 1.82) were all independently associated with 'non-return.' Presentation to clinic specifically for HIV testing (OR 0.70, 95% CI 0.63, 0.77) or reporting a partner with HIV (OR 0.63, 95% CI 0.53, 0.74) were factors independently protective against 'non-return.' Operational changes to improve test results notification, or enhanced counselling at the initial test visit, particularly focusing on young men with gonorrhoea, may optimize prevention outcomes in this high risk population.

LCR testing for gonorrhoea and chlamydia in population surveys and other screenings of low prevalence populations: coping with decreased positive predictive value.

OBJECTIVE: Nucleic acid amplification tests have facilitated field based STD studies and increased screening activities. However, even with highly specific tests, the positive predictive value (PPV) of such tests may be lower than desirable in low prevalence populations. We estimated PPVs for a single LCR test in a population survey in which positive specimens were retested. METHODS: The Baltimore STD and Behavior Survey (BSBS) was a population based behavioural survey of adults which included collecting urine specimens to assess the prevalence of gonorrhoea and chlamydial infection. Gonorrhoea and chlamydial infection were diagnosed by ligase chain reaction (LCR). Nearly all positive results were retested by LCR. Because of cost considerations, negative results were not confirmed. Predicted curves for the PPV were calculated for a single testing assuming an LCR test sensitivity of 95%, and test specificities in the range 95.0%-99.9%, for disease prevalences between 1% and 10%. Positive specimens were retested to derive empirical estimates of the PPV of a positive result on a single LCR test. RESULTS: 579 participants age 18-35 provided urine specimens. 20 (3.5%) subjects initially tested positive for chlamydial infection, and 39 (6.7%) tested positive for gonococcal infection. If positive results on the repeat LCR are taken as confirmation of a "true" infection, the observed PPV for the first LCR testing was 89.5% for chlamydial infection and 83.3% for gonorrhoea. This is within the range of theoretical PPVs calculated from the assumed sensitivities and specificities of the LCR assays. CONCLUSIONS: Empirical performance of a single LCR testing approximated the theoretically predicted PPV in this field study. This result demonstrates the need to take account of the lower PPVs obtained when such tests are used in field studies or clinical screening of low prevalence populations. Repeat testing of specimens, preferably with a different assay (for example, polymerase chain reaction), and disclosure of the non-trivial potential for false positive test results would seem appropriate in all such studies.

Gonorrhoea reinfection in heterosexual STD clinic attendees: longitudinal analysis of risks for first reinfection.

OBJECTIVES: Gonorrhoea is associated with adverse reproductive health outcomes, including pelvic inflammatory disease and increased HIV transmission. Our objective was to determine the association of demographic factors, sexual risk behaviours, and drug use with incident gonorrhoea reinfection among public STD clinic clients. METHODS: A retrospective cohort study conducted from January 1994 through October 1998, of heterosexual public STD clinic attendees age >/=12 years having at least one gonorrhoea infection in Baltimore, MD. The outcome was first incident gonorrhoea reinfection over a maximum 4.8 years, compared in STD clinic clients with or without sexual risk behaviours and drug use at initial gonorrhoea infection. RESULTS: 910 reinfections occurred among 8327 individuals and 21 246 person years of observation, for an overall incidence of 4.28 reinfections per 100 person years (95% CI 4.03 to 4.53). Median time to reinfection was 1.00 year (95% CI 0.91 to 1.07 years). In multivariate Cox regression, increased reinfection risk was associated with male sex, younger age, greater number of recent sex partners, and having a sex partner who is a commercial sex worker. Injection drug use and coming to the clinic as an STD contact were protective. Among risk factors that differed significantly between men and women, injection drug use was protective of reinfection in men, and "any" condom use was a risk factor for reinfection in women CONCLUSIONS: Reinfection represents a significant proportion of STD clinic visits for gonorrhoea. Prevention counselling and routine screening for patients at high risk for reinfection should be considered to maximally reduce transmission and resource utilisation.