Cautious regret minimization: Online optimization with long-term budget constraints

International audienceWe study a class of online convex optimization problems with long-term budget constraints that arise naturally as reliability guarantees or total consumption constraints. In this general setting, prior work by Mannor et al. (2009) has shown that achieving no regret is impossible if the functions defining the agent's budget are chosen by an adversary. To overcome this obstacle, we refine the agent's regret metric by introducing the notion of a "K-benchmark", i.e., a comparator which meets the problem's allotted budget over any window of length K. The impossibility analysis of Mannor et al. (2009) is recovered when K = T ; however, for K = o(T), we show that it is possible to minimize regret while still meeting the problem's long-term budget constraints. We achieve this via an online learning algorithm based on cautious online Lagrangian descent (COLD) for which we derive explicit bounds, in terms of both the incurred regret and the residual budget violations

Longitudinal Study of Dynamic Epidemiology of Extended-Spectrum Beta-Lactamase-Producing Escherichia coli in Pigs and Humans Living and/or Working on Pig Farms

Extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales have been increasingly isolated from pigs, highlighting their potential for transmission to humans living and/or working within pig farms. As longitudinal data on the prevalence and the molecular characteristics of such isolates from the high-risk farming population remain scarce, we performed a long-term study on 39 Dutch pig farms. Fecal samples from pigs, farmers, family members, and employees were collected during four sampling occasions with a 6-month period. The presence of ESBL-producing Enterobacterales and their molecular characteristics (ESBL gene, plasmid, and sequence types) were determined by standard methods. Data on personal and farm characteristics were collected using questionnaires. ESBL-producing Escherichia coli was present in pigs at least once for 18 of 39 farms and in 17 of 146 farmers, family members, and/or employees. Among these 417 E. coli isolates, bla CTX-M-1 was the most frequently observed ESBL gene in pigs ( n  = 261) and humans ( n  = 25). Despite the great variety in plasmid (sub)types and E. coli sequence types (STs), we observed genetic similarity between human- and pig-derived isolates in (i) ESBL gene, plasmid (sub)type, and ST, suggesting potential clonal transmission in seven farms, and (ii) only ESBL gene and plasmid (sub)type, highlighting the possibility of horizontal transfer in four farms. Five pig farmers carried ESBL producers repeatedly, of whom two carried an identical combination of gene, plasmid (sub)type, and ST over time. Human ESBL carriage was associated with both presence of ESBL producers in pigs and average number of hours working on the pig farm per week, while prolonged human carriage was observed only incidentally. IMPORTANCE Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli represents a public health hazard due to reduced therapeutic options for the treatment of infections. Although direct contact with pigs is considered a risk factor for human ESBL-producing E. coli carriage through occupational exposure, nationwide data regarding the occurrence of such isolates among pigs and humans living and/or working on farms remain scarce. Therefore, we determined (i) the longitudinal dynamics in prevalence and molecular characteristics of ESBL-producing E. coli in Dutch pig farmers and their pigs over time and (ii) the potential transmission events between these reservoirs based on genetic relatedness and epidemiological associations in longitudinal data. Our data suggesting the possibility of clonal and horizontal dissemination of ESBL-producing Escherichia coli between pigs and pig farmers can be used to inform targeted intervention strategies to decrease the within-farm human exposure to ESBL-producing E. coli

Living together in a world of extended-spectrum cephalosporin resistance: molecular snapshots of a complex epidemiology

Extended-spectrum cephalosporinase (ESCase)-producing Enterobacteriaceae from human and animal origin have emerged worldwide during the last decades. Although studies documenting direct transmission between humans and animals are rare, the existence of shared reservoirs of extended-spectrum cephalosporinase genes, plasmids and/or STs suggests cross-transmissions and raises the concern of a possible zoonotic source of ESBL/AmpC-producers for humans. The aim of this thesis is to explore the molecular relatedness of extended-spectrum cephalosporin (ESC)-resistant Enterobacteriaceae of human and animal origin and assess their cross-transmission and epidemiology from a “One health” perspective. Chapter 1, as an introduction provides the necessary background information of the extended-spectrum cephalosporinase-producing Enterobacteriaceae and their complex epidemiology, to offer a better understanding of the studies presented in this thesis. Chapter 2 focuses on the emergence and the molecular characteristics of ESC-resistant Salmonella enterica serotype Heidelberg isolates in the Netherlands. Their recent emergence was attributed to food-producing animals and poultry products imported from Brazil, while no human infections linked to these contaminated animals and products have been yet documented in the Netherlands (Chapter 2a). In addition, the potential contribution of Kelp gulls of the southern hemisphere in the dissemination of ESC-resistant S. Heidelberg and other Enterobacteriaceae is presented (Chapter 2b). In Chapter 3, Enterobacteriaceae transmission among humans and between humans and animals is discussed. A cross-sectional study among Dutch preschool children and their parents is presented (Chapter 3a), describing the molecular characteristics of the recovered ESC-resistant Enterobacteriaceae and the frequency of intra-familial colonization with identical isolates. The longitudinal presence and molecular diversity of ESC-resistant E. coli from humans and pigs within the same pig farms are presented, confirming transmission events between farmers and their pigs (Chapter 3b). In Chapter 4, SHV extended-spectrum β-lactamases are discussed. The global epidemiology of Enterobacteriaceae encoding SHV ESCases is reviewed in Chapter 4a, highlighting the ubiquity of these extended-spectrum cephalosporinases. Finally, the recent association of blaSHV-12 with IncX3 plasmids among E. coli isolates in the Netherlands, as well as the genetic and functional characteristics of these plasmids contributing to blaSHV-12 emergence are reported (Chapter 4b). In the general discussion (Chapter 5), the results of the thesis are presented and discussed in relation to the epidemiology of ESC-resistant Enterobacteriaceae and the available international literature. Major outcomes of the studies presented in this thesis, using the available molecular microbiology techniques and the incorporation of human and animal components in a “One Health” approach, provide insights on emerging trends among ESC-resistant Enterobacteriaceae of human and animal origin, their cross-transmission within and between reservoirs, as well as the complexity of their “One Health” epidemiology in order to assess the role of animals as a relevant source of such resistant bacteria for humans

Living together in a world of extended-spectrum cephalosporin resistance: molecular snapshots of a complex epidemiology

Extended-spectrum cephalosporinase (ESCase)-producing Enterobacteriaceae from human and animal origin have emerged worldwide during the last decades. Although studies documenting direct transmission between humans and animals are rare, the existence of shared reservoirs of extended-spectrum cephalosporinase genes, plasmids and/or STs suggests cross-transmissions and raises the concern of a possible zoonotic source of ESBL/AmpC-producers for humans. The aim of this thesis is to explore the molecular relatedness of extended-spectrum cephalosporin (ESC)-resistant Enterobacteriaceae of human and animal origin and assess their cross-transmission and epidemiology from a “One health” perspective. Chapter 1, as an introduction provides the necessary background information of the extended-spectrum cephalosporinase-producing Enterobacteriaceae and their complex epidemiology, to offer a better understanding of the studies presented in this thesis. Chapter 2 focuses on the emergence and the molecular characteristics of ESC-resistant Salmonella enterica serotype Heidelberg isolates in the Netherlands. Their recent emergence was attributed to food-producing animals and poultry products imported from Brazil, while no human infections linked to these contaminated animals and products have been yet documented in the Netherlands (Chapter 2a). In addition, the potential contribution of Kelp gulls of the southern hemisphere in the dissemination of ESC-resistant S. Heidelberg and other Enterobacteriaceae is presented (Chapter 2b). In Chapter 3, Enterobacteriaceae transmission among humans and between humans and animals is discussed. A cross-sectional study among Dutch preschool children and their parents is presented (Chapter 3a), describing the molecular characteristics of the recovered ESC-resistant Enterobacteriaceae and the frequency of intra-familial colonization with identical isolates. The longitudinal presence and molecular diversity of ESC-resistant E. coli from humans and pigs within the same pig farms are presented, confirming transmission events between farmers and their pigs (Chapter 3b). In Chapter 4, SHV extended-spectrum β-lactamases are discussed. The global epidemiology of Enterobacteriaceae encoding SHV ESCases is reviewed in Chapter 4a, highlighting the ubiquity of these extended-spectrum cephalosporinases. Finally, the recent association of blaSHV-12 with IncX3 plasmids among E. coli isolates in the Netherlands, as well as the genetic and functional characteristics of these plasmids contributing to blaSHV-12 emergence are reported (Chapter 4b). In the general discussion (Chapter 5), the results of the thesis are presented and discussed in relation to the epidemiology of ESC-resistant Enterobacteriaceae and the available international literature. Major outcomes of the studies presented in this thesis, using the available molecular microbiology techniques and the incorporation of human and animal components in a “One Health” approach, provide insights on emerging trends among ESC-resistant Enterobacteriaceae of human and animal origin, their cross-transmission within and between reservoirs, as well as the complexity of their “One Health” epidemiology in order to assess the role of animals as a relevant source of such resistant bacteria for humans

A review of SHV extended-spectrum β-lactamases: neglected yet ubiquitous

β-lactamases are the primary cause of resistance to β-lactams among members of the family Enterobacteriaceae. SHV enzymes have emerged in Enterobacteriaceae causing infections in health care in the last decades of the 20st century, and they are now observed in isolates in different epidemiological settings both in human, animal and the environment. Likely originated from a chromosomal penicillinase of Klebsiella pneumoniae, SHV β-lactamases currently encompass a large number of allelic variants including extended-spectrum β-lactamases (ESBL), non-ESBL and several not classified variants. SHV enzymes have evolved from a narrow- to an extended-spectrum of hydrolyzing activity, including monobactams and carbapenems, as a result of amino acid changes that altered the configuration around the active site of the β -lactamases. SHV-ESBLs are usually encoded by self-transmissible plasmids that frequently carry resistance genes to other drug classes and have become widespread throughout the world in several Enterobacteriaceae, emphasizing their clinical significance