Nonparticipation reasons in a randomized international trial of a new latent tuberculosis infection regimen.

BACKGROUND/AIMS: Efficient recruitment of eligible participants, optimizing time and sample size, is a crucial component in conducting a successful clinical trial. Inefficient participant recruitment can impede study progress, consume staff time and resources, and limit quality and generalizability or the power to assess outcomes. Recruitment for disease prevention trials poses additional challenges because patients are asymptomatic. We evaluated candidates for a disease prevention trial to determine reasons for nonparticipation and to identify factors that can be addressed to improve recruitment efficiency. METHODS: During 2001-2009, the Tuberculosis Trials Consortium conducted Study 26 (PREVENT TB), a randomized clinical trial at 26 sites in four countries, among persons with latent tuberculosis infection at high risk for tuberculosis disease progression, comparing 3 months of directly observed once-weekly rifapentine plus isoniazid with 9 months of self-administered daily isoniazid. During March 2005-February 2008, non-identifying demographic information, risk factors for experiencing active tuberculosis disease, and reasons for not enrolling were collected from screened patients to facilitate interpretation of trial data, to meet Consolidated Standards of Reporting Trials standards, and to evaluate reasons for nonparticipation. RESULTS: Of the 7452 candidates screened in Brazil, Canada, Spain, and the United States, 3584 (48%) were not enrolled, because of ineligibility (41%), site decision (10%), or patient choice (49%). Among those who did not enroll by own choice, and for whom responses were recorded on whether they would accept treatment outside of the study (n = 1430), 68% reported that they planned to accept non-study latent tuberculosis infection treatment. Among 1305 patients with one or more reported reasons for nonparticipation, study staff recorded a total of 1886 individual reasons (reason count: median = 1/patient; range = 1-9) for why patients chose not to enroll, including grouped concerns about research (24% of 1886), work or school conflicts (20%), medication or health beliefs (16%), latent tuberculosis infection beliefs (11%), and patient lifestyle and family concerns (10%). CONCLUSION: Educational efforts addressing clinical research concerns and beliefs about medication and health, as well as study protocols that accommodate patient-related concerns (e.g. work, school, and lifestyle) might increase willingness to enter clinical trials. Findings from this evaluation can support development of communication and education materials for clinical trial sites at the beginning of a trial to allow study staff to address potential participant concerns during study screening.

Increased Doses Lead to Higher Drug Exposures of Levofloxacin for Treatment of Tuberculosis.

Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to a weight-banded nominal dose of 11, 14, 17, or 20 mg/kg/day levofloxacin (minimum, 750 mg) in combination with other second-line agents. A total of 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median areas under the concentration-time curve from 0 to 24 h (AUC0-24) were 109.49, 97.86, 145.33, and 207.04 µg · h/ml. Median maximum plasma concentration (Cmax) were 11.90, 12.02, 14.86, and 19.17 µg/ml, respectively. Higher levofloxacin doses, up to 1,500 mg daily, resulted in higher exposures. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.).

Subjects With Diabetes Mellitus Are at Increased Risk for Developing Tuberculosis: A Cohort Study in an Inner-City District of Barcelona (Spain).

Background: Tuberculosis is the leading cause of mortality from lung infectious disease worldwide in recent years, and its incidence has re-emerged in large cities in low-incidence countries due to migration and socioeconomic deprivation causes. Diabetes mellitus and tuberculosis are syndemic diseases, with diabetes being considered a risk factor for developing tuberculosis. Objective: To investigate whether diabetic patients were at increased risk of tuberculosis living in an inner-district of a large city of northeastern Spain. Methods: Observational matched retrospective cohort study based on clinical records from the population of the lowest socioeconomic status in Barcelona (Ciutat Vella district). A cohort including patients with type 1 and type 2 diabetes mellitus in 2007 and new cases until 2016 (8004 subjects), matched 1:1 by sex and age with a non-diabetic cohort. Follow-up period was until December 31st 2018. We evaluated the risk of developing tuberculosis in diabetic patients compared to non-diabetic patients during the follow up period. We used time-to-event analysis to estimate the incidence of tuberculosis, and competing risks regression by clusters and conditional Cox regression models to calculate the hazard ratio (HR) and its 95% confidence intervals (CI). Results: Among the 16,008 included subjects, the median follow-up was 8.7 years. The mean age was 57.7 years; 61.2% men and 38.8% women in both groups. The incidence of tuberculosis was 69.9 per 100,000 person-years in diabetic patients, and 40.9 per 100,000 person-years in non-diabetic patients (HR = 1.90; CI: 1.18-3.07). After adjustment for the country of origin, chronic kidney disease, number of medical appointments, BMI, alcoholism and smoking, the risk remained higher in diabetic patients (1.66: CI 0.99-2.77). Additionally, subjects from Hindustan or with a history of alcohol abuse also showed a higher risk of developing tuberculosis (HR = 3.51; CI:1.87-6.57, and HR = 2.73; CI:1.22-6.12 respectively). Conclusion: People with diabetes mellitus were at higher risk of developing tuberculosis in a large cohort recruited in an inner-city district with a high incidence for this outcome, and low socioeconomic conditions and high proportion of migrants. This risk was higher among Hindustan born and alcohol abusers.

Glycemic control and the risk of tuberculosis in patients with diabetes: A cohort study in a Mediterranean city.

Background: Diabetes mellitus (DM) is one of the leading chronic diseases globally and one of the most common causes of death, morbidity, and poor quality of life. According to the WHO, DM is also one of the main risk factors for developing active tuberculosis (TB). Subjects with DM are at a higher risk of infections, in addition to frequent micro and macrovascular complications, and therefore sought to determine whether poor glycemic control is linked to a higher risk of developing TB. Methods: We used a retrospective cohort of diabetic subjects to predict the incidence of TB. All DM patients were recruited from Ciutat Vella (the inner-city of Barcelona) from January 2007 until December 2016, with a follow-up period until December 2018 (≥2 years). Data were extracted from Barcelona's Primary Care medical record database - SIDIAP, and linked to the Barcelona TB Control Program. The incidence of TB and the impact of glycemic control were estimated using time-to-event curves analyzed by Cox proportional hazard regression. Hazard ratios (HRs) and 95% confidence intervals (CIs), unadjusted and adjusted by potential confounding variables, were also assessed, which included age, sex, diabetes duration, macrovascular and microvascular signs, BMI, smoking habit, alcohol consumption and geographical origin. Results: Of 8,004 DM patients considered for the study (equating to 68,605 person-years of follow-up), 84 developed TB [incidence rate = 70 (95% CI: 52-93) per 100,000 person-years]. DM subjects with TB were younger (mean: 52.2 vs. 57.7 years old), had higher values of glycosylated hemoglobin (HbA1c) (7.66 vs. 7.41%) and total triglycerides (122 vs. 105 mg/dl), and had twice the frequency of diabetic nephropathy (2.08 vs. 1.18%). The calculated incidence rate increased with increasing HbA1c: 120.5 (95% CI 77.2-179.3) for HbA1c ≥ 7.5%, 143 (95% CI 88.3-218.1) for HbA1c ≥ 8% and 183.8 (95% CI 105-298) for HbA1c ≥ 9%. An increase in the risk of TB was also observed according to a poorer optimization of glycemic control: adjusted HR 1.80 (95% CI 0.60-5.42), 2.06 (95% CI 0.67-6.32), and 2.82 (95% CI 0.88-9.06), respectively. Conclusion: Diabetic subjects with worse glycemic control show a trend toward a higher risk of developing TB.

An optimized background regimen design to evaluate the contribution of levofloxacin to multidrug-resistant tuberculosis treatment regimens: study protocol for a randomized controlled trial.

BACKGROUND: Current guidelines for treatment of multidrug-resistant tuberculosis (MDR-TB) are largely based on expert opinion and observational data. Fluoroquinolones remain an essential part of MDR-TB treatment, but the optimal dose of fluoroquinolones as part of the regimen has not been defined. METHODS/DESIGN: We designed a randomized, blinded, phase II trial in MDR-TB patients comparing across levofloxacin doses of 11, 14, 17 and 20 mg/kg/day, all within an optimized background regimen. We assess pharmacokinetics, efficacy, safety and tolerability of regimens containing each of these doses. The primary efficacy outcome is time to culture conversion over the first 6 months of treatment. The study aims to determine the area under the curve (AUC) of the levofloxacin serum concentration in the 24 hours after dosing divided by the minimal inhibitory concentration of the patient's Mycobacterium tuberculosis isolate that inhibits > 90% of organisms (AUC/MIC) that maximizes efficacy and the AUC that maximizes safety and tolerability in the context of an MDR-TB treatment regimen. DISCUSSION: Fluoroquinolones are an integral part of recommended MDR-TB regimens. Little is known about how to optimize dosing for efficacy while maintaining acceptable toxicity. This study will provide evidence to support revised dosing guidelines for the use of levofloxacin as part of combination regimens for treatment of MDR-TB. The novel methodology can be adapted to elucidate the effect of other single agents in multidrug antibiotic treatment regimens. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01918397 . Registered on 5 August 2013.

Blood cultures for women with uncomplicated acute pyelonephritis: are they necessary?

To assess the utility of blood cultures in the management of uncomplicated pyelonephritis in women, we prospectively collected data from 583 cases. Discordant cases were defined as those for which the pathogens isolated from urine and from blood were different. We found that 97.6% of cases were nondiscordant. Clinical and microbiological evolution of infection did not differ between the 2 groups, and no changes of antibiotic therapy were required on the basis of blood culture results. Blood culture may not be routinely required for the evaluation of uncomplicated pyelonephritis in women.

Transrectal prostatic ultrasonography in acute bacterial prostatitis: findings and clinical implications.

To evaluate the role of transrectal ultrasonography (TRUS) in the diagnosis of acute bacterial prostatitis (ABP) and to analyse the possible relationship between sonographic findings and clinical presentation and evolution, a prospective study using TRUS in patients with ABP was conducted. 45 patients (aged 58.2 +/- 14.6 y; mean +/- SD) with a clinical diagnosis of ABP admitted to a university hospital were studied prospectively. Clinical, analytical and microbiological data were recorded. TRUS was performed on admission and after 1 month of antibiotic therapy. Findings were correlated with clinical and evolutive data. The mean prostatic volume on admission was 40.5 +/- 17.9 ml. 21 patients (46.6%) had sonographically demonstrable lesions in peripheral prostatic lobules. One month later, when treatment had ended, lesions had disappeared or improved in 61.1% of patients, and the mean prostatic volume was 24.3 +/- 10.5 ml (p < 0.0005). Clinical, analytical and microbiological data and evolution of ABP were not significantly different in patients with or without sonographically demonstrable lesions. TRUS does not need to be performed in every patient with suspicion of ABP; the only indication for TRUS in ABP is the exclusion of prostatic abscess.

Molecular epidemiology and evolution of resistance to quinolones in Escherichia coli after prolonged administration of ciprofloxacin in patients with prostatitis.

The emergence and evolution of quinolone-resistant Escherichia coli in faeces of patients with prostatitis treated with high-dose oral ciprofloxacin for 1 month were studied. In 11 of 23 patients, from whom only quinolone-susceptible E. coli was isolated before treatment, quinolone-resistant strains, genetically distinct from the quinolone-susceptible ones, predominated during and just after therapy. Two months after treatment, these were completely displaced by quinolone-susceptible E. coli, genetically distinct from the E. coli isolated before and during therapy. Hence, during ciprofloxacin therapy, half of the patients were transiently colonized with new, quinolone-resistant strains of E. coli.

Differences in virulence factors among clinical isolates of Escherichia coli causing cystitis and pyelonephritis in women and prostatitis in men.

Differences in the presence of nine urovirulence factors among clinical isolates of Escherichia coli causing cystitis and pyelonephritis in women and prostatitis in men have been studied. Hemolysin and necrotizing factor type 1 occur significantly more frequently among isolates causing prostatitis than among those causing cystitis (P < 0.0001) or pyelonephritis (P < 0.005). Moreover, the papGIII gene occurred more frequently in E. coli isolates associated with prostatitis (27%) than in those associated with pyelonephritis (9%) (P < 0.05). Genes encoding aerobactin and PapC occurred significantly less frequently in isolates causing cystitis than in those causing prostatitis (P < 0.01 and P < 0.0001, respectively) and pyelonephritis (P < 0.01 and P < 0.0001, respectively). No differences in the presence of Sat or type 1 fimbriae were found. Finally, AAFII and Bfp fimbriae are no longer considered uropathogenic virulence factors since they were not found in any of the strains analyzed. Overall, the results showed that clinical isolates producing prostatitis need greater virulence than isolates producing pyelonephritis in women or, in particular, cystitis in women (P < 0.05). Overall, the results suggest that clinical isolates producing prostatitis are more virulent that those producing pyelonephritis or cystitis in women.