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Optimizing the management of community-acquired respiratory tract infections in the age of antimicrobial resistance.

Community-acquired respiratory tract infections (CARTIs) are the most common reason for prescribing antibiotics in the primary care setting. However, over the last decade, the management of CARTIs has become increasingly complicated by the steady increase in prevalence of drug-resistant pathogens responsible for these infections. As a result, significant attention has been directed at understanding the mechanisms of pathogen acquisition of resistance, drivers of resistance and methods for preventing the development of resistance. Data from recent surveillance studies suggest a slowing or decline in resistance rates to agents, such as beta-lactams, macrolides, tetracyclines and folic acid metabolism inhibitors. However, resistance to one antimicrobial family--the fluoroquinolones--while still low, appears to be on the increase. This is of significant concern given the rapid increase in resistance noted with older antibiotics in recent history. While the clinical implications of antibacterial resistance are poorly understood, the overall rates of antimicrobial resistance, as reported in recent surveillance studies, do not correspond to current rates of failure in patients with CARTIs. This disconnection between laboratory-determined resistance and clinical outcome has been termed the in vitro-in vivo paradox and several explanations have been offered to explain this phenomenon. Solving the problem of antimicrobial resistance will be multifactorial. Important factors in this effort include the education of healthcare providers, patients and the general healthcare community regarding the hazards of inappropriate antibiotic use, prevention of infections through vaccination, development of accurate, inexpensive and timely point-of-care diagnostic tests to aid in patient assessment, institution of objective treatment guidelines and use of more potent agents, especially those with a focused spectrum of activity, earlier in the treatment of CARTIs as opposed to reserving them as second-line treatment options. Ultimately, the single-most important factor will be the judicious use of antibiotics, as fewer antibiotic prescriptions lead to fewer antimicrobial-resistant bacteria.

Anti-Bacterial Agents↗

Novelty, diversity, and genetic dark matter in enterococci of invertebrates.

Enterococci appear to have originated in the guts of early terrestrializing arthropods and invertebrates over 425 million years ago-hosts that are now highly diverse and widespread in nature today. Yet most knowledge of the genus comes from human infection-associated lineages with genomes swollen by the recent accretion of foreign DNA conveyed by mobile elements. Because invertebrates dominate terrestrial animal diversity and biomass, they would be predicted to constitute a major but little-explored reservoir of enterococcal diversity. We therefore systematically examined Enterococcus association and species diversification in invertebrate hosts of the comparatively natural, isolated, but well-characterized environment of the Azorean island of Terceira. Over 100 invertebrate specimens were examined for associated enterococci, which were taxonomically classified by whole-genome sequencing. Supporting the existence of a large pool of uncharacterized enterococci and Enterococcus-adapted genes, 40% (eight of 20) of the Enterococcus species identified were either undescribed, including four candidate new species described here, or very recently discovered. In contrast, control isolates from vertebrates were exclusively of known species typical of sampling elsewhere, discounting geographic isolation as a main driver of the novelty observed. Further, because of the abundance of E. casseliflavus and E. flavescens in this collection, we obtained the resolution necessary to quantify the divergence and decipher the drivers of speciation in the controversial division between these naturally vancomycin-resistant species. These findings provide robust support for the existence of a large pool of new species and unexplored adaptive traits in invertebrate-associated enterococci-diverse environmental survival traits optimized for expression in an enterococcal background, and well positioned for transmission into human-associated enterococcal strains.IMPORTANCEEnterococci are auxotrophic gut-associated bacteria that co-evolved with their terrestrial hosts over many eons. In the last 75 years-the "antibiotic era"-E. faecalis and E. faecium gained genes for antibiotic resistance and enhanced virulence, emerging as leading causes of multidrug-resistant infection. Little is known about the source of those genes or the pathway by which they entered human-associated strains. A recent global survey suggested a potentially large repository of uncharacterized genetic diversity in the enterococci of invertebrates. We directly tested this prospect by examining enterococci of invertebrate hosts in a largely natural and pastoral environment. Our findings provide clear evidence that invertebrates naturally harbor vast unexplored enterococcal diversity. Moreover, associations are likely driven by intrinsic host selection factors rather than geographic isolation. This expands our knowledge of Enterococcus biodiversity, including the identification of four novel species, identifying a vast reservoir of enterococcal genes available to species that colonize and infect humans.

Animals↗