Escherichia coli associated with urinary tract infections and bacteremia has been intensively investigated, including recent work focusing on the virulent, globally disseminated, multidrug-resistant lineage ST131. To contextualize ST131 within the broader E. coli population associated with disease, we used genomics to analyze a systematic 11-yr hospital-based survey of E. coli associated with bacteremia using isolates collected from across England by the British Society for Antimicrobial Chemotherapy and from the Cambridge University Hospitals NHS Foundation Trust. Population dynamics analysis of the most successful lineages identified the emergence of ST131 and ST69 and their establishment as two of the five most common lineages along with ST73, ST95, and ST12. The most frequently identified lineage was ST73. Compared to ST131, ST73 was susceptible to most antibiotics, indicating that multidrug resistance was not the dominant reason for prevalence of E. coli lineages in this population. Temporal phylogenetic analysis of the emergence of ST69 and ST131 identified differences in the dynamics of emergence and showed that expansion of ST131 in this population was not driven by sequential emergence of increasingly resistant subclades. We showed that over time, the E. coli population was only transiently disturbed by the introduction of new lineages before a new equilibrium was rapidly achieved. Together, these findings suggest that the frequency of E. coli lineages in invasive disease is driven by negative frequency-dependent selection occurring outside of the hospital, most probably in the commensal niche, and that drug resistance is not a primary determinant of success in this niche.

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Serratia marcescens, a member of the Enterobacteriaceae family, is a Gram-negative bacterium responsible for a wide range of nosocomial infections. The emergence of multidrug-resistant strains is an increasing danger to public health. To design effective means to control the dissemination of S. marcescens, an in-depth analysis of the population structure and variation is required. Utilizing whole-genome sequencing, we characterized the population structure and variation, as well as the antimicrobial resistance determinants, of a systematic collection of antimicrobial-resistant S. marcescens associated with bloodstream infections in hospitals across the United Kingdom and Ireland between 2001 and 2011. Our results show that S. marcescens is a diverse species with a high level of genomic variation. However, the collection was largely composed of a limited number of clones that emerged from this diverse background within the past few decades. We identified potential recent transmissions of these clones, within and between hospitals, and showed that they have acquired antimicrobial resistance determinants for different beta-lactams, ciprofloxacin, and tetracyclines on multiple occasions. The expansion of these multidrug-resistant clones suggests that the treatment of S. marcescens infections will become increasingly difficult in the future.

Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens. Individualised dosing, based on population PK models and patient factors (e.g. renal function and weight) known to influence antimicrobial PK, increases the probability of achieving therapeutic drug exposures while at the same time avoiding toxic concentrations. When therapeutic drug monitoring (TDM) is applied, early dose adaptation to the needs of the individual patient is possible. TDM is likely to be of particular importance for infected critically ill patients, where profound PK changes are present and prompt appropriate antibiotic therapy is crucial. In the light of the continued high mortality rates in critically ill patients with severe infections, a paradigm shift to refined dosing strategies for antimicrobials is warranted to enhance the probability of achieving drug concentrations that increase the likelihood of clinical success.

Klebsiella pneumoniae is a human commensal and opportunistic pathogen that has become a leading causative agent of hospital-based infections over the past few decades. The emergence and global expansion of hypervirulent and multidrug-resistant (MDR) clones of K. pneumoniae have been increasingly reported in community-acquired and nosocomial infections. Despite this, the population genomics and epidemiology of MDR K. pneumoniae at the national level are still poorly understood. To obtain insights into these, we analyzed a systematic large-scale collection of invasive MDR K. pneumoniae isolates from hospitals across the United Kingdom and Ireland. Using whole-genome phylogenetic analysis, we placed these in the context of previously sequenced K. pneumoniae populations from geographically diverse countries and identified their virulence and drug resistance determinants. Our results demonstrate that United Kingdom and Ireland MDR isolates are a highly diverse population drawn from across the global phylogenetic tree of K. pneumoniae and represent multiple recent international introductions that are mainly from Europe but in some cases from more distant countries. In addition, we identified novel genetic determinants underlying resistance to beta-lactams, gentamicin, ciprofloxacin, and tetracyclines, indicating that both increased virulence and resistance have emerged independently multiple times throughout the population. Our data show that MDR K. pneumoniae isolates in the United Kingdom and Ireland have multiple distinct origins and appear to be part of a globally circulating K. pneumoniae population.