Critical knowledge gaps and research needs related to the environmental dimensions of antibiotic resistance

There is growing understanding that the environment plays an important role both in the transmission of antibiotic resistant pathogens and in their evolution. Accordingly, researchers and stakeholders world-wide seek to further explore the mechanisms and drivers involved, quantify risks and identify suitable interventions. There is a clear value in establishing research needs and coordinating efforts within and across nations in order to best tackle this global challenge. At an international workshop in late September 2017, scientists from 14 countries with expertise on the environmental dimensions of antibiotic resistance gathered to define critical knowledge gaps. Four key areas were identified where research is urgently needed: 1) the relative contributions of different sources of antibiotics and antibiotic resistant bacteria into the environment; 2) the role of the environment, and particularly anthropogenic inputs, in the evolution of resistance; 3) the overall human and animal health impacts caused by exposure to environmental resistant bacteria; and 4) the efficacy and feasibility of different technological, social, economic and behavioral interventions to mitigate environmental antibiotic resistance.(1)Peer reviewe

Neural mechanisms for the control of posture, locomotion and steering : a behavioral, electrophysiological and modeling study in lamprey

When animals move around interacting with the environment, the nervous system has to solve several tasks simultaneously in order to produce and control the movements - notably propulsion, posture, balance, and associated movements. Basic motor tasks are controlled by neuronal networks organized into central pattern generators (CPGs) and reflexes, located in the spinal cord and brainstem. The overall aim of this work has been to study how supraspinal descending control systems for locomotion, including control of movement direction, and postural control interact with each other, and with the spinal locomotor CPG in order to produce purposeful and economic movements. Locomotion and postural corrections were studied in the lamprey, a lower vertebrate, in which the reticulospinal (RS) system is responsible for sensori-motor integration and descending control. Different aspects of locomotor activity - initiation, termination, and regulation of the intensity of locomotion, as well as steering and maintenance of a proper posture - were reflected in the activity of RS neurons in intact, freely swimming lampreys. In vitro studies have shown that groups of RS neurons in the middle and posterior rhombencephalic reticular nuclei are activated by vestibular and visual stimuli. Here, the activity of these neurons was correlated to the direction of fictive turns in a novel in vitro preparation. Commands for lateral turns can be initiated in rhombencephalon and are mediated by ipsilateral descending spinal pathways. Asymmetric descending command signals, such as the commands for turning and postural corrections, are amplified by a system of crossed reciprocal inhibition in the spinal cord and phasically modulated by the locomotor activity. The alternating locomotor pattern is also dependent on crossed reciprocal inhibition between the two sides of the spinal cord. Crossing inhibitory neurons are subject to inhibition from a class of propriospinal neurons, the lateral interneurons (LINs), which have been considered as a possible burst terminating factor in the locomotor CPG. The LIN activity, however, is only weakly correlated to the output of the locomotor network. LINs receive input from RS neurons and may mediate descending commands related to motor function instead. Inhibitory mechanisms were also investigated in a light and electron microscopic study. A proportion of synaptic terminals in the lamprey spinal cord display immunoreactivity against two co-localized inhibitory neurotransmitters: glycine and GABA. Computer modeling of the neural mechanisms of lateral turns showed that locomotor models depending on LINs for burst termination did not generate turn-like patterns when LINs were activated. A strong activation of crossing inhibitory neurons by the descending turn command was necessary to generate turns in models of the locomotor network in which bursts are terminated by intrinsic properties of the crossing inhibitory neurons. In many species of fish, the paired pectoral and pelvic fins are the main effector organs for stabilizing and changing the body orientation in the roll and pitch planes. Lampreys lack paired fins but the dorsal fin may provide better stability in the roll plane. Primary afferents from the fin appear to take part in a local monosynaptic resistance reflex that activates fin motoneurons

Turning behaviour in lamprey in response to descending unilateral commands: experiments and modelling

Steering manoeuvres in vertebrates are characterised by asymmetric modulation of the cycle duration and the intensity of the symmetric rhythmic locomotor activity. In the lamprey in vitro model system, turns can be evoked by electrical skin stimuli applied to one side of the head, which give rise to descending unilateral excitatory commands. Turns are observed as increased activity on one side of the spinal cord, followed by a rebound on the other. We investigated the generation of turns in single-segment models of the lamprey locomotor spinal network, and were able to reproduce all main experimental results. Sufficient mechanisms to explain changes in the locomotor rhythm, including rebound, are asymmetric activation of crossing inhibitory neurons, accompanied by a calcium influx in these neurons

Key considerations on the potential impacts of the COVID-19 pandemic on antimicrobial resistance research and surveillance

Antibiotic use in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients during the COVID-19 pandemic has exceeded the incidence of bacterial coinfections and secondary infections, suggesting inappropriate and excessive prescribing. Even in settings with established antimicrobial stewardship (AMS) programmes, there were weaknesses exposed regarding appropriate antibiotic use in the context of the pandemic. Moreover, antimicrobial resistance (AMR) surveillance and AMS have been deprioritised with diversion of health system resources to the pandemic response. This experience highlights deficiencies in AMR containment and mitigation strategies that require urgent attention from clinical and scientific communities. These include the need to implement diagnostic stewardship to assess the global incidence of coinfections and secondary infections in COVID-19 patients, including those by multidrug-resistant pathogens, to identify patients most likely to benefit from antibiotic treatment and identify when antibiotics can be safely withheld, de-escalated or discontinued. Long-Term global surveillance of clinical and societal antibiotic use and resistance trends is required to prepare for subsequent changes in AMR epidemiology, while ensuring uninterrupted supply chains and preventing drug shortages and stock outs. These interventions present implementation challenges in resource-constrained settings, making a case for implementation research on AMR. Knowledge and support for these practices will come from internationally coordinated, targeted research on AMR, supporting the preparation for future challenges from emerging AMR in the context of the current COVID-19 pandemic or future pandemics

Key considerations on the potential impacts of the COVID-19 pandemic on AMR research and surveillance

Antibiotic use in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients during the COVID-19 pandemic has exceeded the incidence of bacterial coinfections and secondary infections, suggesting inappropriate and excessive prescribing. Even in settings with established antimicrobial stewardship (AMS) programmes, there were weaknesses exposed regarding appropriate antibiotic use in the context of the pandemic. Moreover, antimicrobial resistance (AMR) surveillance and AMS have been deprioritised with diversion of health system resources to the pandemic response. This experience highlights deficiencies in AMR containment and mitigation strategies that require urgent attention from clinical and scientific communities. These include the need to implement diagnostic stewardship to assess the global incidence of coinfections and secondary infections in COVID-19 patients, including those by multidrug-resistant pathogens, to identify patients most likely to benefit from antibiotic treatment and identify when antibiotics can be safely withheld, de-escalated or discontinued. Long-term global surveillance of clinical and societal antibiotic use and resistance trends is required to prepare for subsequent changes in AMR epidemiology, while ensuring uninterrupted supply chains and preventing drug shortages and stock outs. These interventions present implementation challenges in resource-constrained settings, making a case for implementation research on AMR. Knowledge and support for these practices will come from internationally coordinated, targeted research on AMR, supporting the preparation for future challenges from emerging AMR in the context of the current COVID-19 pandemic or future pandemics