Bacteriophage Resistance Alters Antibiotic-Mediated Intestinal Expansion of Enterococci.

Enterococcus faecalis is a human intestinal pathobiont with intrinsic and acquired resistance to many antibiotics, including vancomycin. Nature provides a diverse and virtually untapped repertoire of bacterial viruses, or bacteriophages (phages), that could be harnessed to combat multidrug-resistant enterococcal infections. Bacterial phage resistance represents a potential barrier to the implementation of phage therapy, emphasizing the importance of investigating the molecular mechanisms underlying the emergence of phage resistance. Using a cohort of 19 environmental lytic phages with tropism against E. faecalis, we found that these phages require the enterococcal polysaccharide antigen (Epa) for productive infection. Epa is a surface-exposed heteroglycan synthesized by enzymes encoded by both conserved and strain-specific genes. We discovered that exposure to phage selective pressure favors mutation in nonconserved epa genes both in culture and in a mouse model of intestinal colonization. Despite gaining phage resistance, epa mutant strains exhibited a loss of resistance to cell wall-targeting antibiotics. Finally, we show that an E. faecalisepa mutant strain is deficient in intestinal colonization, cannot expand its population upon antibiotic-driven intestinal dysbiosis, and fails to be efficiently transmitted to juvenile mice following birth. This study demonstrates that phage therapy could be used in combination with antibiotics to target enterococci within a dysbiotic microbiota. Enterococci that evade phage therapy by developing resistance may be less fit at colonizing the intestine and sensitized to vancomycin, preventing their overgrowth during antibiotic treatment.

Adjunct clinical interventions that influence vaginal birth after cesarean rates: systematic review.

BACKGROUND: Rates of cesarean deliveries have been increasing, and contributes to the rising number of elective cesarean deliveries in subsequent pregnancies with associated maternal and neonatal risks. Multiple guidelines recommend that women be offered a trial of labor after a cesarean (TOLAC). The objective of the study is to systematically review the literature on adjunct clinical interventions that influence vaginal birth after cesarean (VBAC) rates. METHODS: We searched Ovid Medline, Ovid Embase, Wiley Cochrane Library, CINAHL via EBSCOhost; and Ovid PsycINFO. Additional studies were identified by searching for clinical trial records, conference proceedings and dissertations. Limits were applied for language (English and French) and year of publication (1985 to present). Two reviewers independently screened comparative studies (randomized or non-randomized controlled trials, and observational designs) according to a priori eligibility criteria: women with prior cesarean sections; any adjunct clinical intervention or exposure intended to increase the VBAC rate; any comparator; and, outcomes reporting changes in TOLAC or VBAC rates. One reviewer extracted data and a second reviewer verified for accuracy. Two reviewers independently conducted methodological quality assessments using the Mixed Methods Appraisal Tool (MMAT). RESULTS: Twenty-three studies of overall moderate to good methodological quality examined adjunct clinical interventions affecting TOLAC and/or VBAC rates: system-level interventions (three studies), provider-level interventions (three studies), guidelines or information for providers (seven studies), provider characteristics (four studies), and patient-level interventions (six studies). Provider-level interventions (opinion leader education, laborist, and obstetrician second opinion for cesarean sections) and provider characteristics (midwifery antenatal care, physicians on night float call schedules, and deliveries by family physicians) were associated with increased rates of VBAC. Few studies employing heterogeneous designs, sample sizes, interventions and comparators limited confidence in the effects. Studies of system-level and patient-level interventions, and guidelines/information for providers reported mixed findings. CONCLUSIONS: Limited evidence indicates some provider-level interventions and provider characteristics may increase rates of attempted and successful TOLACs and/or VBACs, whereas other adjunct clinical interventions such as system-level interventions, patient-level interventions, and guidelines/information for healthcare providers show mixed findings.

Obesity Outweighs Protection Conferred by Adjuvanted Influenza Vaccination.

UNLABELLED: Obesity is a risk factor for developing severe influenza virus infection, making vaccination of utmost importance for this high-risk population. However, vaccinated obese animals and adults have decreased neutralizing antibody responses. In these studies, we tested the hypothesis that the addition of either alum or a squalene-based adjuvant (AS03) to an influenza vaccine would improve neutralizing antibody responses and protect obese mice from challenge. Our studies demonstrate that adjuvanted vaccine does increase both neutralizing and nonneutralizing antibody levels compared to vaccine alone. Although obese mice mount significantly decreased virus-specific antibody responses, both the breadth and the magnitude of the responses against hemagglutinin (HA) and neuraminidase (NA) are decreased compared to the responses in lean mice. Importantly, even with a greater than fourfold increase in neutralizing antibody levels, obese mice are not protected against influenza virus challenge and viral loads remain elevated in the respiratory tract. Increasing the antigen dose affords no added protection, and a decreasing viral dose did not fully mitigate the increased mortality seen in obese mice. Overall, these studies highlight that, while the use of an adjuvant does improve seroconversion, vaccination does not fully protect obese mice from influenza virus challenge, possibly due to the increased sensitivity of obese animals to infection. Given the continued increase in the global obesity epidemic, our findings have important implications for public health. IMPORTANCE: Vaccination is the most effective strategy for preventing influenza virus infection and is a key component for pandemic preparedness. However, vaccines may fail to provide optimal protection in high-risk groups, including overweight and obese individuals. Given the worldwide obesity epidemic, it is imperative that we understand and improve vaccine efficacy. No work to date has investigated whether adjuvants increase the protective capacity of influenza vaccines in the obese host. In these studies, we show that adjuvants increased the neutralizing and nonneutralizing antibody responses during vaccination of lean and obese mice to levels considered "protective," and yet, obese mice still succumbed to infection. This vulnerability is likely due to a combination of factors, including the increased susceptibility of obese animals to develop severe and even lethal disease when infected with very low viral titers. Our studies highlight the critical public health need to translate these findings and better understand vaccination in this increasing population.