Rectal Sites Research Articles

A prospective study of the immune system activation biomarker neopterin and colorectal cancer risk.

Neopterin may be relevant for colorectal cancer (CRC) development, as a biomarker of cellular immune activity exerting pleiotropic effects on cellular ageing, oxidative stress, and inflammation. So far, the association between prediagnostic neopterin and colon and rectal cancer risk has not been evaluated in human populations. A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort using data on plasma concentrations of total neopterin (T-N, sum of neopterin and 7,8-dihydroneopterin) in 830 incident CRC case patients (561 colon and 269 rectal) matched within risk sets to 830 control participants. A subsequent replication study used data from the Hordaland Health Study, where 173 CRC case patients have been diagnosed among 6594 healthy participants over 12 years of follow-up. After multivariable adjustment for a priori chosen CRC risk factors, a "U-shaped" association of T-N with CRC was revealed. Compared with the second quintile of the T-N distribution, the relative risks for the first, third, fourth, and fifth quintiles were 2.37 (95% CI = 1.66 to 3.39), 1.24 (95% CI = 0.87 to 1.77), 1.55 (95% CI = 1.08 to 2.22), and 2.31 (95% CI = 1.63 to 3.27), respectively. Replication of these associations within the Hordaland Health Study yielded similar results. No differences have been observed when the associations were explored by colon and rectal cancer site (two-sided P difference = .87) and after excluding case patients diagnosed within the first four follow-up years. These novel findings provide evidence of the role of both suppressed and activated cell-mediated immunity as reflected by prediagnostic T-N concentrations in the development of CRC.

143. The State of Sexual Health Services at U.S. Colleges & Universities

143. The State of Sexual Health Services at U.S. Colleges & Universities

Infection with neisseria gonorrhoeae and association between rising ceftriaxone minumum inhibitory concentration and men who have sex with men

Objectives The aim of this study was to review patients presenting with Neisseria gonorrhoeae over a 5 year period. Methods We performed a retrospective cohort study, using a prospective database and retrospective review of medical records, of patients with gonorrhoea infection presenting between January 2008 and November 2013. Results 215 patients screened positive by NAAT and treatment failure occurred in 2 patients after both initially received treatment with ciprofloxacin. of the 106 culture positive Neisseria gonorrhoeae isolates, 37 had ceftriaxone MIC >0.008. In addition, there were 4 penicillinase producing Neisseria gonorrhoeae (PPNG) isolates, 30 quinolone resistant Neisseria gonorrhoeae (QRNG) isolates, 9 tetracycline resistant Neisseria gonorrhoeae (TRNG) isolates and 4 isolates resistant to azithromycin. On a multivariate model, an association was seen between ceftriaxone MIC >0.008 and a history of men who have sex with men (MSM, OR 11.81, 95% CI 2.51–55.59, p = 0.02). Univariate analysis was statistically significant for infection involving either rectal or pharyngeal sites (OR 3.02, 95 CI 1.24–7.34, p = 0.02). Conclusion Screening for Neisseria gonorrhoea in rectal and pharyngeal sites is important amongst patients presenting with a history of MSM. Rising ceftriaxone MIC is associated with MSM and infection in rectal or pharyngeal sites.

Topical Mucosal Vaccination with Angiotensin (1-7) and Feline Immunodeficiency Virus Induces Secretory IgA Responses

Background: Pre-existing mucosal generated secretory IgA antibodies may prevent transmission of HIV. The present study aimed to characterize mucosal antibodies generated following topical vaccination with a novel mucosal adjuvant, angiotensin (1-7), in combination with a killed feline immunodeficiency virus (FIV) vaccine used as a model antigen. Methods: Female outbred cats were vaccinated with Fel-O-Vax FIV vaccine agent combined with increasing concentrations of angiotensin (1-7) [A (1-7)] applied topically to oral, vaginal and rectal surfaces weekly for six weeks. Control animals received intramuscular vaccinations with the Fel-O-Vax FIV alone or with A (1-7). Mucosal secretions were evaluated for antibody responses against FIV-p24 antigen or HIV-gp120 antigen. Results: Topical application of whole killed FIV virus with A (1-7) induced substantial secretory IgA (SIgA)-antigp120 antibodies in oral, vaginal and rectal secretions across a wide ranges of A (1-7) dose levels. Intramuscular vaccination of FIV antigen with A (1-7) induced high levels of SIgA-anti-gp120 antibodies at vaginal and rectal sites. The topical application vaccination strategy elicited only very weak systemic immune responses. Conclusion: Angiotensin (1-7) is a potent mucosal vaccine adjuvant.

Rectal site and suboptimal nodal yield predict systemic recurrence in resected colorectal carcinoma: a case-control study.

We assessed the contribution of histopathological features to systemic recurrence (SR) in patients with colorectal cancer, using a case-control design: 71 cases and 184 controls were included, with a mean time until SR of 1.4 ± 0.1 years and a mean follow-up of controls of 1.6 ± 0.06 years. Cases had significantly greater odds of rectal site (odds ratio [OR] = 1.82), stage ≥ pT3 (OR = 2.11), suboptimal (<12) lymph node yield (OR = 4.6), stage ≥ pN1 (OR = 2.46), KRAS mutation (OR = 2.76), and extramural venous invasion (OR = 1.97). By multiple regression analysis, rectal site, stage ≥ pT3, suboptimal lymph node yield, and lymph node positivity independently predicted SR. Rectal cancers were more likely to have a suboptimal node yield than nonrectal cancers (relative risk = 1.6) among the entire cohort. We conclude that rectal cancers have greater risk of SR than colon cancers. A lower yield of lymph nodes in rectal cancer specimens may contribute to this.

P0018 Prognostic value of total number of lymph nodes identified and ratio of lymph nodes in resected colorectal cancer

<h3>Background</h3> The extent of lymph node involvement is the most significant prognostic indicator in resected locoregional colorectal cancer. This study aimed to investigate the prognostic value of the total number of lymph nodes identified and the ratio of lymph nodes in resected colorectal cancer. <h3>Methods</h3> A total of 275 patients with histologically proven resected locoregional invasive colorectal adenocarcinoma were included between 2003 and 2011. All patients were treated with standard surgical resection for their colorectal cancer. Patients with incomplete data, or unresectable tumours or distant metastases, were excluded from the study. All potential prognostic variables were evaluated for their impact on local control and disease-free and overall survival rates. <h3>Findings</h3> Of 275 patients, 162 were men and 113 were women, with a median age of 54years (range 23–84). The mean total number of lymph nodes was significantly higher in colon cancer than in rectal cancer (11 versus 7.5, <i>p</i>=0.001). In node-positive (stage III) patients, the mean lymph node ratio was 0.5 for rectal cancers and 0.37 for colon cancers, showing a non-significant trend (<i>p</i>=0.05) toward a higher lymph node ratio in rectal cancer patients. In univariate analysis, the mean total number of lymph nodes identified was a prognostic factor for 5-year disease-free (<i>p</i>=0.04) and overall survival (<i>p</i>=0.02) rates. In node-positive patients, the lymph node ratio was a prognostic factor for 5-year local control (<i>p</i>=0.04), disease-free survival (<i>p</i>=0.01), and overall survival (<i>p</i>=0.01) rates. On multivariate analysis, advanced primary tumour stage, rectal primary site, and the presence of perineural invasion were independent adverse prognostic factors for overall survival. <h3>Interpretation</h3> The total number of lymph nodes identified and ratio of lymph nodes are associated with oncological outcomes in patients with colorectal cancer.

Methods and Devices of Temperature Measurement in the Neonate: A Narrative Review and Practice Recommendations

There are a number of measurement devices available for use. However agreement about the effectiveness of the various types of thermometers in the neonatal population remains unclear. The review indicates that the axilla method continues to be the site of choice for preterm and term infants. However, it has been noted in some studies that very little work has been done on the sensitivity and specificity of each method of temperature measurement, making it difficult to identify any negative or positive results in relation to measuring temperature at the axilla, rectal, skin, forehead and tympanic sites. Nurses need to be aware of the various temperature measurement methods, devices and factors influencing neonatal temperature recordings. New thermometers should be rigorously tested for suitability in the neonatal population. Evidence based practice remains important and studies need to continue into the accuracy and reliability of different temperature measurement devices and methods.

Determining fever in children: the search for an ideal thermometer

Body temperature measurement is most commonly taken to confirm the presence or absence of fever. Many decisions concerning the investigation and treatment of children are based on the results of temperature measurement alone. Determining the presence of fever in young children is particularly important. A missed fever is serious, but a false-positive fever reading can result in unnecessary septic workups. The axillary, rectal, oral and tympanic membrane sites are most commonly used to record body temperature, and electronic and infrared thermometers are the devices most commonly used. Each site and device has numerous advantages and disadvantages, which are described in this article. The search for the means of measuring body temperature that best combines accuracy, speed, convenience, safety and cost-effectiveness goes on. The infrared thermometer and the tympanic site appear to offer such a combination. Electronic thermometers are also suitable when used orally or at the axilla in newborn babies.

Phase II clinical trial of pasireotide LAR in patients with metastatic neuroendocrine tumors.

241 Background: Pasireotide LAR is a novel somatostatin analog (SSA) with avid binding to somatostatin receptor subtypes (SSTR) 1, 2, 3 and 5. It has been studied in patients who are refractory to SSAs, but has not yet been investigated in treatment naïve patients. Methods: We performed a phase II trial of first-line pasireotide LAR 60mg q4 weeks in patients with metastatic low and intermediate grade NETs. Prior systemic therapy, including octreotide and lanreotide, was not permitted. The primary endpoint was PFS. Immunohistochemical SSTR subtype analysis was performed on archival tissue. Results: 29 patients were enrolled of whom 28 patients were assessable for response. Primary sites included small intestine (14 pts), pancreas (6), rectal (2), unknown (4) and other sites (3). 13 patients had low-grade and 16 patients had intermediate-grade tumors. Best radiographic response was stable disease in 17 patients (60%), progressive disease in 10 patients (36%) and partial response in 1 patient (4%). Median PFS was 12.2 months (95% CI 7.7-17.5). The 1 year OS rate was 92% (CI 72%-98%). Although generally well tolerated, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia. 4 patients (14%) developed grade 3 hyperglycemia. 6 patients were started on insulin during the trial period, and at least 2 have remained on long-term insulin therapy despite discontinuation of pasireotide. Conclusions: Although the median PFS of 12.2 months in a heterogeneous population of NET patients is encouraging, the high rate of hyperglycemia requiring intervention represents a significant concern. Future studies of pasireotide should explore specific populations such as octreotide refractory patients. Clinical trial information: NCT01253161.

Expressed Breast Milk as a Predictor of Neonatal Yeast Colonization in an Intensive Care Setting.

Yeast colonization is a predictor for invasive infection in neonates. Candida albicans and Candida parapsilosis are leading causes of invasive fungal infection (IFI) in this population. This study examines maternal breast milk as a predictor of colonization of infants with yeast. Inclusion criteria were admission longer than 72 hours to the neonatal intensive care unit and parental consent. Cultures of expressed breast milk, when available, and swabs from oral, rectal, and inguinal sites were obtained weekly for 12 weeks, or until discharge, transfer, or death. Cultures were analyzed using standard laboratory methods. Clinical information was extracted from medical records. One hundred thirty infants were enrolled from February 2011 to November 2012. Cultures were obtained in 129 patients. The median (interquartile range [IQR]) gestational age was 34.4 weeks (33.1-37.1 weeks). The median (IQR) birth weight was 2157.5 g (1740-3060 g). No infants developed IFIs. Twenty-nine (22%) infants were colonized with yeast. Potential correlates for colonization in univariate analysis included exposure to antenatal steroids, postnatal antibiotics, and receipt of breast milk containing yeast. Potential correlates that remained after multivariable logistic regression included exposure to antenatal steroids and receipt of breast milk containing yeast. In cases in which yeast was recovered from an individual infant and from the breast milk received by that infant, there was only 30% concordance between yeast species. Recovery of yeast from breast milk is associated with colonization with yeast in the neonate. Because Candida transmission via breast milk had a 30% concordance, breast milk is only one of several ways colonization occurs. Further study is needed on mechanisms of colonization.

High rates of sexually transmissible infections in HIV-positive patients in the Australian HIV Observational Database: a prospective cohort study

Background In HIV-positive people, sexually transmissible infections (STIs) probably increase the infectiousness of HIV. In 2010, we established a cohort of individuals (n=554) from clinics in the Australian HIV Observational Database (AHOD). We calculated retrospective rates for four STIs for 2005-10 and prospective incidence rates for 2010-11. At baseline (2010), patient characteristics were similar to the rest of AHOD. Overall incidence was 12.5 per 100 person-years. Chlamydial infections increased from 3.4 per 100 person-years (95% confidence interval (CI): 1.9-5.7) in 2005 to 6.7 per 100 person-years (95% CI: 4.5-9.5) in 2011, peaking in 2010 (8.1 per 100 person-years; 95% CI: 5.6-11.2). Cases were distributed among rectal (61.9%), urethral (34%) and pharyngeal (6.3%) sites. Gonococcal infections increased, peaking in 2010 (4.7 per 100 person-years; 95% CI: 5.6-11.2; Ptrend=0.0099), distributed among rectal (63.9%), urethral (27.9%) and pharyngeal (14.8%) sites. Syphilis showed several peaks, the largest in 2008 (5.3 per 100 person-years; 95% CI: 3.3-8.0); the overall trend was not significant (P=0.113). Genital warts declined from 7.5 per 100 person-years (95% CI: 4.8-11.3) in 2005 to 2.4 per 100 person-years (95% CI: 1.1-4.5) in 2011 (Ptrend=0.0016). For chlamydial and gonococcal infections, incidence was higher than previous Australian estimates among HIV-infected men who have sex with men, increasing during 2005-2011. Rectal infections outnumbered infections at other sites. Syphilis incidence remained high but did not increase; that of genital warts was lower and decreased.

Challenges presented by re-emerging sexually transmitted infections: an observational study of lymphogranuloma venereum in the UK

BackgroundLymphogranuloma venereum (LGV) is a rare sexually transmitted infection (STI), a biovar of Chlamydia trachomatis, which re-emerged in 2003 and mainly affects HIV-positive men who have sex with men (MSM). A diagnostic service at the National Reference Laboratory was established in response to the LGV outbreak in the UK, which has been the largest documented in Europe. Surveillance protocol operates through testing patients with symptoms indicative of the infection and their sexual contacts. Additionally, a voluntary enhanced surveillance system was ongoing in 2004–10 in the UK. We assess the utility of the novel surveillance system in light of its strengths and limitations. MethodsWe described data on samples tested for LGV in 2004–10 in the diagnostic service. These data were analysed together with the LGV enhanced surveillance dataset and we undertook a cross-sectional analysis of clinical and behavioural characteristics between HIV-positive and HIV-negative or unknown cases diagnosed in MSM in 2004–10. We used multivariable logistic regression models with generalised estimating equations to control for repeat infections. The final model was adjusted for clinical and behavioural variables chosen through selection of variables based on a-priori hypotheses and statistical associations. FindingsOverall, 11 196 C trachomatis-positive samples were tested for LGV, most of which were from men (10 035 of 11 196 [89·6%]), and most of these were from rectal sites (9138 of 10 035 [91·1%]); 1523 (15·2%) of 10 035 samples in men and four (0·8%) of 531 samples in women were confirmed as LGV. Of those confirmed to have the disease, 1370 (86·7%) of 1581 had a LGV enhanced surveillance form. The enhanced surveillance included 1342 episodes of infection in 1281 MSM and most were known to be HIV positive (1028 of 1281 [80·2%]). In comparison with HIV-negative and unknown cases, HIV-positive men were more likely to report unprotected receptive anal intercourse in the preceding 3 months (adjusted odds ratio [aOR] 2·7, 95% CI 1·3–5·8). However, HIV-positive men were also more likely to report a shorter duration of symptoms before clinic presentation (aOR 0·5, 95% CI 0·3–0·8 for reporting more than a week compared with a week or less), and the recorded information on the clinical variables was more complete for HIV-positive MSM. InterpretationThere has been good coverage with the enhanced surveillance data, probably because of its link to a centralised diagnostic capacity. The surveillance was able to focus on the subpopulation at greater risk of infection because risk behaviour was more common in HIV-positive than in HIV-negative or unknown LGV cases. Furthermore, the surveillance has shown a stable epidemiological profile of cases over time, and LGV seems to remain confined to a small subpopulation of HIV-positive MSM. However, diagnostic bias was suggested in favour of HIV-positive cases with LGV who presented with a shorter duration of symptoms than HIV-negative or unknown cases. This factor is probably a result of the protocol used for testing together with clinical requests for tests. Surveillance for LGV may be systematically missing asymptomatic cases as well as there being a delay in recognising cases in HIV-negative men. Control of the disease needs targeted prevention messages that are suitable for the key population affected, including outreach and direct contact to key venues and networks via the internet. Because LGV has established itself in the UK and is present at low levels, surveillance might benefit from supplemented periodic case finding and collection of detailed information of patients to monitor the epidemiology of the disease. FundingThe work was produced as part of the PhD study of MR, who was funded by the Osk Huttunen Foundation (Finland) and by the Wellcome Trust (090285/Z/09/Z). HW has received funding for research on LGV from the UK Medical Research Council and support from the National Institute for Health Research Imperial Biomedical Research Centre. PW thanks the Medical Research Council for centre funding.

Prognostic Value of Total Lymph Node Identified and Ratio of Lymph Nodes in Resected Colorectal Cancer

Background The extent of lymph node involvement is the most significant prognostic indicator in resected locoregional colorectal cancer. Objectives This study aimed to investigate the prognostic value of total lymph nodes identified and ratio of lymph nodes in resected colorectal cancer. Patients and Methods Two hundred seventy five patients with histologically proven resected locoregional invasive colorectal adenocarcinoma from 2003 to 2011 were included. All patients were treated with standard surgical resection for their colorectal cancer. Patients with incomplete data, or unresectable tumors or distant metastases were excluded from the study. All potential prognostic variables were evaluated for their impact on the local control, disease-free, and overall survival rates. Results Of the 275 patients, 162 were men and 113 were women with a median age of 54 (range 23-84) years. The mean total lymph nodes were significantly higher in colon cancer than rectal cancer (11 versus 7.5, P = 0.001). In node positive (stage III) patients, the mean lymph nodes ratio was 0.5 for rectal cancers and 0.37 for colon cancers respectively showing a nonsignificant (P = 0.05) trend toward higher lymph nodes ratio in rectal cancer patients. In univariate analysis, the mean total number of lymph node identified was a prognostic factor for 5-year disease free (P = 0.04) and overall survival (P = 0.02) rates. In node positive patients, lymph nodes ratio was a prognostic factor for 5-year local control (P = 0.04), disease free survival (P = 0.01), and overall survival (P = 0.01) rates. On multivariate analysis, advanced primary tumor stage, rectal primary site and the presence of perineural invasion were independent adverse prognostic factors for overall survival. Conclusions Total lymph nodes identified and ratio of lymph nodes are associated with oncological outcomes outcomes in patients with colorectal cancer.

Self-collected versus clinician-collected sampling for sexually transmitted infections: a systematic review and meta-analysis protocol

BackgroundThree meta-analyses and one systematic review have been conducted on the question of whether self-collected specimens are as accurate as clinician-collected specimens for STI screening. However, these reviews predate 2007 and did not analyze rectal or pharyngeal collection sites. Currently, there is no consensus on which sampling method is the most effective for the diagnosis of genital chlamydia (CT), gonorrhea (GC) or human papillomavirus (HPV) infection. Our meta-analysis aims to be comprehensive in that it will examine the evidence of whether self-collected vaginal, urine, pharyngeal and rectal specimens provide as accurate a clinical diagnosis as clinician-collected samples (reference standard).Methods/DesignInclusion and exclusion criteria: Eligible studies include both randomized and non-randomized controlled trials, pre- and post-test designs, and controlled observational studies. Search strategy: The databases that will be searched include the Cochrane Database of Systematic Reviews, Web of Science, Database of s of Reviews of Effects (DARE), EMBASE and PubMed/Medline. Data collection and analysis: Data will be abstracted independently by two reviewers using a standardized pre-tested data abstraction form. Heterogeneity will be assessed using the Q2 test. Sensitivity and specificity estimates with 95% confidence intervals as well as negative and positive likelihood ratios will be pooled and weighted using random effects meta-analysis, if appropriate. A hierarchical summary receiver operating characteristics curve for self-collected specimens will be generated.DiscussionThis synthesis involves a meta-analysis of self-collected samples (urine, vaginal, pharyngeal and rectal swabs) versus clinician-collected samples for the diagnosis of CT, GC and HPV, the most prevalent STIs. Our systematic review will allow patients, clinicians and researchers to determine the diagnostic accuracy of specimens collected by patients compared to those collected by clinicians in the detection of chlamydia, gonorrhea and HPV.

Colon and Rectal Cancer Survival by Tumor Location and Microsatellite Instability

Cancers in the proximal colon, distal colon, and rectum are frequently studied together; however, there are biological differences in cancers across these sites, particularly in the prevalence of microsatellite instability. We assessed the differences in survival by colon or rectal cancer site, considering the contribution of microsatellite instability to such differences. This is a population-based prospective cohort study for cancer survival. This study was conducted within the Colon Cancer Family Registry, an international consortium. Participants were identified from population-based cancer registries in the United States, Canada, and Australia. Information on tumor site, microsatellite instability, and survival after diagnosis was available for 3284 men and women diagnosed with incident invasive colon or rectal cancer between 1997 and 2002, with ages at diagnosis ranging from 18 to 74. Cox regression was used to calculate hazard ratios for the association between all-cause mortality and tumor location, overall and by microsatellite instability status. Distal colon (HR, 0.59; 95% CI, 0.49-0.71) and rectal cancers (HR, 0.68; 95% CI, 0.57-0.81) were associated with lower mortality than proximal colon cancer overall. Compared specifically with patients with proximal colon cancer exhibiting no/low microsatellite instability, patients with distal colon and rectal cancers experienced lower mortality, regardless of microsatellite instability status; patients with proximal colon cancer exhibiting high microsatellite instability had the lowest mortality. Study limitations include the absence of stage at diagnosis and cause-of-death information for all but a subset of study participants. Some patient groups defined jointly by tumor site and microsatellite instability status are subject to small numbers. Proximal colon cancer survival differs from survival for distal colon and rectal cancer in a manner apparently dependent on microsatellite instability status. These findings support the premise that proximal colon, distal colon, and rectal cancers are clinicopathologically distinct.

S02.3 Extra-Genital CT/GC Testing by NAATS: Use in Screening and Prevalence of Infection in MSM, Issues in Validation

Most Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) infections in men who have sex with men (MSM) are not in the urethra. This has been confirmed often since it was...

P3.121 Are We Seeing a True Rise in Neisseria Gonorrhoeae and Chlamydia Trachomatis in England in Men Who Have Sex with Men?

BackgroundThe Health Protection Agency (HPA) in England have reported the number of sexually transmitted infections (STIs) diagnosed in men who have sex with men (MSM) continues to rise. Of note,...

The effect of maternal flora on Candida colonisation in the neonate

Colonisation may be the first step for the development of Candida infection. The source of neonatal colonisation is thought to be the hospital environment or the maternal vaginal tract. This study investigated to what extend Candida isolates in neonates are similar to isolates from their mother's vaginal tract. Vaginal samples were collected from 347 pregnant women within 48h before delivery. Samples from oral and rectal mucosa of their neonates were collected within 24-72h after delivery, were cultured and yeast species were identified. Antifungal susceptibility tests against six antifungal agents were performed. All paired isolates from mother and infant were genotyped by pulse field gel electrophoresis. A total of 82 mothers and of 16 infants were found colonised by Candida spp. C.albicans was the most common species in pregnant women (n=68) followed by C.glabrata (n=11). Only C.albicans was isolated from infants, mainly (14/16) from rectal site. All colonised neonates were born to mothers colonised by C.albicans. Candida genotyping revealed identical strains in all investigated neonate-mother pairs. All isolates were susceptible to amphotericin B. Our findings strongly suggest that vertical transmission has the principal role in the neonatal colonisation by C.albicans in the very first days of life.

MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

BackgroundOral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development.ObjectiveMTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design.Methods and FindingsWe enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03).ConclusionsCompared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir’s antiviral effect substantially influence PrEP efficacy.Trial RegistrationClinicalTrials.gov NCT00592124

Neisseria gonorrhoeae Treatment Failure and Susceptibility to Cefixime in Toronto, Canada

Although cephalosporins are the cornerstone of treatment of Neisseria gonorrhoeae infections, cefixime is the only oral antimicrobial option. Increased minimum inhibitory concentrations (MICs) to cefixime have been identified worldwide and have been associated with reports of clinical failure. To assess the risk of clinical treatment failure of N. gonorrhoeae infections associated with the use of cefixime. A retrospective cohort study of culture-positive N. gonorrhoeae infections at a single sexual health clinic in Toronto, Canada, that routinely performs test of cure. The cohort comprised N. gonorrhoeae culture-positive individuals identified between May 1, 2010, and April 30, 2011, treated with cefixime as recommended by Public Health Agency of Canada guidelines. Cefixime treatment failure, defined as the repeat isolation of N. gonorrhoeae at the test-of-cure visit identical to the pretreatment isolate by molecular typing and explicit denial of reexposure. There were 291 N. gonorrhoeae culture-positive individuals identified. Of 133 who returned for test of cure, 13 were culture positive; 9 patients were determined to have experienced cefixime treatment failure, involving urethral (n = 4), pharyngeal (n = 2), and rectal (n = 3) sites. The overall rate of clinical treatment failure among those who had a test of cure was 6.77% (95% CI, 3.14%-12.45%; 9/133). The rate of clinical failure associated with a cefixime MIC of 0.12 μg/mL or greater was 25.0% (95% CI, 10.69%-44.87%; 7/28) compared with 1.90% (95% CI, 0.23%-6.71%; 2/105) of infections with cefixime MICs less than 0.12 μg/mL, with a relative risk of 13.13 (95% CI, 2.88-59.72; P < .001). The rate of clinical failure following treatment of N. gonorrhoeae infections with cefixime was relatively high at a Toronto clinic and was associated with elevated MICs.