Double-Blind, Placebo-Controlled Study of Bezlotoxumab in Children Receiving Antibacterial Treatment for Clostridioides difficile Infection (MODIFY III).

BACKGROUND: Therapies to prevent recurrence of Clostridioides difficile infection (CDI) in pediatric patients are needed. Bezlotoxumab is a fully human monoclonal antibody approved for prevention of recurrent CDI in adults. We assessed the pharmacokinetics, safety, tolerability, and efficacy of bezlotoxumab in pediatric patients. METHODS: MODIFY III was a multicenter, double-blind, placebo-controlled study of bezlotoxumab in children (1 to <18 years) receiving antibacterial treatment for CDI. Participants were randomized 3:1 to receive a single infusion of bezlotoxumab (10 mg/kg) or placebo and were stratified by age at randomization (cohort 1: 12 to <18 years, cohort 2: 1 to <12 years). The primary objective was to characterize bezlotoxumab pharmacokinetics to support dose selection for pediatric patients; the primary endpoint was the area under the bezlotoxumab serum concentration-time curve (AUC0-inf). Safety, tolerability, and efficacy were monitored for 12 weeks post-infusion. RESULTS: A total of 148 participants were randomized and 143 were treated: 107 with bezlotoxumab and 36 with placebo (cohort 1 n = 60, cohort 2 n = 83; median age 9.0 years); 52.4% of participants were male and 80.4% were white. Geometric mean ratios (90% CI) for bezlotoxumab AUC0-inf were 1.06 (0.95, 1.18) and 0.82 (0.75, 0.89) h * µg/mL for cohorts 1 and 2, respectively. Bezlotoxumab 10 mg/kg was generally well-tolerated with an adverse event profile similar to placebo, including no treatment discontinuations due to adverse events. CDI recurrence was low and comparable for bezlotoxumab (11.2%) and placebo (14.7%). CONCLUSIONS: The results of this study support the bezlotoxumab dose of 10 mg/kg for pediatric patients. TRIAL REGISTRATION: NCT03182907 at ClinicalTrials.gov.

Unpalatable food for thought: Let marketing research guide effective public obesity interventions.

The prevalence of obesity is growing unabatedly despite the considerable efforts directed at the problem. Although abundant research has contributed to our understanding of the multifactorial causes of obesity, there is less attention to research that is relevant for guiding social marketers, public health professionals and policymakers in delivering public health interventions for countering and/or preventing the problem of obesity. This review offers six points for identifying and developing research relevant for guiding community-wide obesity interventions based on the idea that an applied marketing research perspective offers a better model for identifying effective interventions than more theoretical academic research. Specifically, the research guiding public health and social marketing interventions needs to (1) provide information on ultimate outcomes (weight, health and unintended consequences) more than intermediate outcomes (beliefs, attitudes and behaviour), (2) report on observations collected over the longer term, (3) use natural settings (even at a cost of internal validity), (4) endeavour to overcome observer-effects, (5) report effect sizes (rather than statistical significance) and (6) use moderator analyses to capture variation in how a population responds to interventions.

Transmission, adaptation and geographical spread of the Pseudomonas aeruginosa Liverpool epidemic strain.

The Liverpool epidemic strain (LES) is an important transmissible clonal lineage of Pseudomonas aeruginosa that chronically infects the lungs of people with cystic fibrosis (CF). Previous studies have focused on the genomics of the LES in a limited number of isolates, mostly from one CF centre in the UK, and from studies highlighting identification of the LES in Canada. Here we significantly extend the current LES genome database by genome sequencing 91 isolates from multiple CF centres across the UK, and we describe the comparative genomics of this large collection of LES isolates from the UK and Canada. Phylogenetic analysis revealed that the 145 LES genomes analysed formed a distinct clonal lineage when compared with the wider P. aeruginosa population. Notably, the isolates formed two clades: one associated with isolates from Canada, and the other associated with UK isolates. Further analysis of the UK LES isolates revealed clustering by clinic geography. Where isolates clustered closely together, the association was often supported by clinical data linking isolates or patients. When compared with the earliest known isolate, LESB58 (from 1988), many UK LES isolates shared common loss-of-function mutations, such as in genes gltR and fleR. Other loss-of-function mutations identified in previous studies as common adaptations during CF chronic lung infections were also identified in multiple LES isolates. Analysis of the LES accessory genome (including genomic islands and prophages) revealed variations in the carriage of large genomic regions, with some evidence for shared genomic island/prophage complement according to clinic location. Our study reveals divergence and adaptation during the spread of the LES, within the UK and between continents.

Cost-effectiveness of antibiotic treatment of uncomplicated urinary tract infection in women: a comparison of four antibiotics.

BACKGROUND: Urinary tract infections (UTIs) are one of the most common reasons for women to attend primary care. There are four different antibiotics currently recommended in England for treatment of uncomplicated UTI but little evidence on their comparative cost-effectiveness. AIM: To assess the relative cost-effectiveness of the four antibiotics currently recommended in England for treatment of uncomplicated UTI in adult women. DESIGN & SETTING: A cost-effectiveness model in adult women with signs and symptoms of uncomplicated UTI in primary care in England treated with fosfomycin, nitrofurantoin, pivmecillinam, or trimethoprim. METHOD: A decision tree economic model of the treatment pathway encompassed up to two rounds of treatment, accounting for different resistance levels. End points included recovery, persistence, pyelonephritis, and/or hospitalisation. Prescription, primary and secondary care treatment, and diagnostic testing costs were aggregated. Cost-effectiveness was assessed as cost per UTI resolved. RESULTS: Trimethoprim 200 mg twice daily (for 3 or 7 days) was estimated to be the most cost-effective treatment (£70 per UTI resolved) when resistance was <30%. However, if resistance to trimethoprim was ≥30%, fosfomycin 3 g once became more cost-effective; at resistance levels of ≥35% for trimethoprim, both fosfomycin 3 g once and nitrofurantoin 100 mg twice daily for 7 days were shown to be more cost-effective. CONCLUSION: Knowing local resistance levels is key to effective and cost-effective empirical prescribing. Recent estimates of trimethoprim resistance rates are close to 50%, in which case a single 3 g dose of fosfomycin is likely to be the most cost-effective treatment option.

Recombination is a key driver of genomic and phenotypic diversity in a Pseudomonas aeruginosa population during cystic fibrosis infection.

The Cystic Fibrosis (CF) lung harbors a complex, polymicrobial ecosystem, in which Pseudomonas aeruginosa is capable of sustaining chronic infections, which are highly resistant to multiple antibiotics. Here, we investigate the phenotypic and genotypic diversity of 44 morphologically identical P. aeruginosa isolates taken from a single CF patient sputum sample. Comprehensive phenotypic analysis of isolates revealed large variances and trade-offs in growth, virulence factors and quorum sensing (QS) signals. Whole genome analysis of 22 isolates revealed high levels of intra-isolate diversity ranging from 5 to 64 SNPs and that recombination and not spontaneous mutation was the dominant driver of diversity in this population. Furthermore, phenotypic differences between isolates were not linked to mutations in known genes but were statistically associated with distinct recombination events. We also assessed antibiotic susceptibility of all isolates. Resistance to antibiotics significantly increased when multiple isolates were mixed together. Our results highlight the significant role of recombination in generating phenotypic and genetic diversification during in vivo chronic CF infection. We also discuss (i) how these findings could influence how patient-to-patient transmission studies are performed using whole genome sequencing, and (ii) the need to refine antibiotic susceptibility testing in sputum samples taken from patients with CF.

Automated microscopy, dipsticks and the diagnosis of urinary tract infection.

OBJECTIVES: Automated microscopy is increasingly used to screen urine samples for suspected urinary tract infection (UTI). A 98.8% negative predictive value has been reported in adult studies. The aim of our study was to validate this method in a paediatric population. METHODS: Urine samples were collected from children with known or suspected nephrourological disease attending nephrology and urology clinics over a 6-week period. Samples were tested with dipstick, the UF-100 flow cytometer (automated microscopy) and culture. A gold standard of a positive culture of morethan 10(5) colony forming units per ml (cfu/ml) with a pathogenic organism was used and the sensitivity, specificity and likelihood ratios were calculated. RESULTS: 280 urine samples were collected from 263 patients (143 male, median age 10.2 years, range 0.1-19.75 years). 221 (79%) were midstream or clean-catch samples. Automated microscopy identified 42 of 186 samples as requiring culture and 17 of 19 samples which had a pure growth of more than 10(5) cfu/ml. Two patients were not identified by automated microscopy: one was treated for vulvovaginitis, and one commenced prophylactic antibiotics prior to the culture result being obtained. The sensitivity, specificity, positive and negative likelihood ratios were 0.89, 0.85, 5.98 and 0.17, respectively. This compared to 0.95, 0.72, 3.34 and 0.29, respectively, with urine dipstick. CONCLUSION: Automated microscopy performed comparably to urine dipstick in the diagnosis of UTI with improved specificity and likelihood ratios with slightly reduced sensitivity. The data support the use of automated microscopy for screening urine samples for culture in children, but different automated microscopy methods and algorithms require local evaluation.