Mathematical modelling for antibiotic resistance control policy: do we know enough?

BACKGROUND: Antibiotics remain the cornerstone of modern medicine. Yet there exists an inherent dilemma in their use: we are able to prevent harm by administering antibiotic treatment as necessary to both humans and animals, but we must be mindful of limiting the spread of resistance and safeguarding the efficacy of antibiotics for current and future generations. Policies that strike the right balance must be informed by a transparent rationale that relies on a robust evidence base. MAIN TEXT: One way to generate the evidence base needed to inform policies for managing antibiotic resistance is by using mathematical models. These models can distil the key drivers of the dynamics of resistance transmission from complex infection and evolutionary processes, as well as predict likely responses to policy change in silico. Here, we ask whether we know enough about antibiotic resistance for mathematical modelling to robustly and effectively inform policy. We consider in turn the challenges associated with capturing antibiotic resistance evolution using mathematical models, and with translating mathematical modelling evidence into policy. CONCLUSIONS: We suggest that in spite of promising advances, we lack a complete understanding of key principles. From this we advocate for priority areas of future empirical and theoretical research.

Effectiveness of travel restrictions in the rapid containment of human influenza: a systematic review.

OBJECTIVE: To assess the effectiveness of internal and international travel restrictions in the rapid containment of influenza. METHODS: We conducted a systematic review according to the requirements of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Health-care databases and grey literature were searched and screened for records published before May 2014. Data extraction and assessments of risk of bias were undertaken by two researchers independently. Results were synthesized in a narrative form. FINDINGS: The overall risk of bias in the 23 included studies was low to moderate. Internal travel restrictions and international border restrictions delayed the spread of influenza epidemics by one week and two months, respectively. International travel restrictions delayed the spread and peak of epidemics by periods varying between a few days and four months. Travel restrictions reduced the incidence of new cases by less than 3%. Impact was reduced when restrictions were implemented more than six weeks after the notification of epidemics or when the level of transmissibility was high. Travel restrictions would have minimal impact in urban centres with dense populations and travel networks. We found no evidence that travel restrictions would contain influenza within a defined geographical area. CONCLUSION: Extensive travel restrictions may delay the dissemination of influenza but cannot prevent it. The evidence does not support travel restrictions as an isolated intervention for the rapid containment of influenza. Travel restrictions would make an extremely limited contribution to any policy for rapid containment of influenza at source during the first emergence of a pandemic virus.

Understanding Antibiotic Use in Companion Animals: A Literature Review Identifying Avenues for Future Efforts.

Addressing antibiotic use is essential to tackle antimicrobial resistance, a major human and animal health challenge. This review seeks to inform stewardship efforts in companion animals by collating research insights regarding antibiotic use in this group and identifying overlooked avenues for future research and stewardship efforts. The development of population-based methods has established that antibiotics are frequently used in companion animal care. Research insights are also contributing toward an in-depth comprehension of the contexts to antibiotic use. Qualitative approaches, for example, have enabled a nuanced understanding in four key areas: interactions with owners, clinical and financial risk management, time pressures, and clinic dynamics. This review identifies that much of the existing research frames antibiotic use as the result of choices made by the individuals at the interface of their use. Future research and policy endeavours could look beyond the moment of prescribing to consider the societal structures and networks in which companion animal antibiotic use is entangled. A diversification in research approaches and frameworks through which antibiotic use is understood will facilitate the identification of additional targets for stewardship initiatives beyond providing information and awareness campaigns.

Unsafe "crossover-use" of chloramphenicol in Uganda: importance of a One Health approach in antimicrobial resistance policy and regulatory action.

Since the introduction of antibiotics into mainstream health care, resistance to these drugs has become a widespread issue that continues to increase worldwide. Policy decisions to mitigate the development of antimicrobial resistance are hampered by the current lack of surveillance data on antibiotic product availability and use in low-income countries. This study collected data on the antibiotics stocked in human (42) and veterinary (21) drug shops in five sub-counties in Luwero district of Uganda. Focus group discussions with drug shop vendors were also employed to explore antibiotic use practices in the community. Focus group participants reported that farmers used human-intended antibiotics for their livestock, and community members obtain animal-intended antibiotics for their own personal human use. Specifically, chloramphenicol products licensed for human use were being administered to Ugandan poultry. Human consumption of chloramphenicol residues through local animal products represents a serious public health concern. By limiting the health sector scope of antimicrobial resistance research to either human or animal antibiotic use, results can falsely inform policy and intervention strategies. Therefore, a One Health approach is required to understand the wider impact of community antibiotic use and improve overall effectiveness of intervention policy and regulatory action.

What drives antimicrobial prescribing for companion animals? A mixed-methods study of UK veterinary clinics.

Antimicrobial use in companion animals is a largely overlooked contributor to the complex problem of antimicrobial resistance. Humans and companion animals share living spaces and some classes of antimicrobials, including those categorised as Highest Priority Critically Important Antimicrobials (HPCIAs). Veterinary guidelines recommend that these agents are not used as routine first line treatment and their frequent deployment could offer a surrogate measure of 'inappropriate' antimicrobial use. Anthropological methods provide a complementary means to understand how medicines use makes sense 'on-the-ground' and situated in the broader social context. This mixed-methods study sought to investigate antimicrobial use in companion animals whilst considering the organisational context in which increasing numbers of veterinarians work. Its aims were to i) to epidemiologically analyse the variation in the percentage of antimicrobial events comprising of HPCIAs in companion animal dogs attending UK clinics belonging to large veterinary groups and, ii) to analyse how the organisational structure of companion animal practice influences antimicrobial use, based on insight gained from anthropological fieldwork. A VetCompassTM dataset composed of 468,665 antimicrobial dispensing events in 240,998 dogs from June 2012 to June 2014 was analysed. A hierarchical model for HPCIA usage was built using a backwards elimination approach with clinic and dog identity numbers included as random effects, whilst veterinary group, age quartile, breed and clinic region were included as fixed effects. The largest odds ratio of an antimicrobial event comprising of a HPCIA by veterinary group was 7.34 (95% confidence interval 5.14 - 10.49), compared to the lowest group (p < 0.001). Intraclass correlation was more strongly clustered at dog (0.710, 95% confidence interval 0.701 - 0.719) than clinic level (0.089, 95% confidence interval 0.076 -0.104). This suggests that veterinarians working in the same clinic do not automatically share ways of working with antimicrobials. Fieldwork revealed how the structure of the companion animal veterinary sector was more fluid than that depicted in the statistical model, and identified opportunities and challenges regarding altering antimicrobial use. These findings were organised into the following themes: "Highest priority what?"; "He's just not himself"; "Oh no - here comes the antibiotics police"; "We're like ships that pass in the night"; and "There's not enough hours in the day". This rigorous mixed-methods study demonstrates the importance of working across disciplinary silos when tackling the complex problem of antimicrobial resistance. The findings can help inform the design of sustainable stewardship schemes for the companion animal veterinary sector.

Identifying hotspots for antibiotic resistance emergence and selection, and elucidating pathways to human exposure: Application of a systems-thinking approach to aquaculture systems.

Aquaculture systems are highly complex, dynamic and interconnected systems influenced by environmental, biological, cultural, socio-economic and human behavioural factors. Intensification of aquaculture production is likely to drive indiscriminate use of antibiotics to treat or prevent disease and increase productivity, often to compensate for management and husbandry deficiencies. Surveillance or monitoring of antibiotic usage (ABU) and antibiotic resistance (ABR) is often lacking or absent. Consequently, there are knowledge gaps for the risk of ABR emergence and human exposure to ABR in these systems and the wider environment. The aim of this study was to use a systems-thinking approach to map two aquaculture systems in Vietnam - striped catfish and white-leg shrimp - to identify hotspots for emergence and selection of resistance, and human exposure to antibiotics and antibiotic-resistant bacteria. System mapping was conducted by stakeholders at an interdisciplinary workshop in Hanoi, Vietnam during January 2018, and the maps generated were refined until consensus. Thereafter, literature was reviewed to complement and cross-reference information and to validate the final maps. The maps and component interactions with the environment revealed the grow-out phase, where juveniles are cultured to harvest size, to be a key hotspot for emergence of ABR in both systems due to direct and indirect ABU, exposure to water contaminated with antibiotics and antibiotic-resistant bacteria, and duration of this stage. The pathways for human exposure to antibiotics and ABR were characterised as: occupational (on-farm and at different handling points along the value chain), through consumption (bacterial contamination and residues) and by environmental routes. By using systems thinking and mapping by stakeholders to identify hotspots we demonstrate the applicability of an integrated, interdisciplinary approach to characterising ABU in aquaculture. This work provides a foundation to quantify risks at different points, understand interactions between components, and identify stakeholders who can lead and implement change.

Pig farmers' perceptions, attitudes, influences and management of information in the decision-making process for disease control.

The objectives of this study were (1) to explore the factors involved in the decision-making process used by pig farmers for disease control and (2) to investigate pig farmers' attitudes and perceptions about different information sources relating to disease control. In 2011 a qualitative study involving 20 face-to-face interviews with English pig farmers was conducted. The questionnaire was composed of three parts. The first part required farmers to identify two diseases they had experienced and which were difficult to recognize and/or control. They were asked to report how the disease problem was recognized, how the need for control was decided, and what affected the choice of control approach. For the latter, a structure related to the Theory of Planned Behaviour was used. Their verbal responses were classified as associated with: (1) attitude and beliefs, (2) subjective norms, or (3) perceived behavioural control (PBC). In the second part, five key sources of information for disease control (Defra, BPEX, research from academia, internet and veterinarians) and the factors related to barriers to knowledge were investigated. Interviews were recorded and transcribed. A qualitative analysis of the text of the interview transcripts was carried out using templates. Drivers for disease control were 'pig mortality', 'feeling of entering in an economically critical situation', 'animal welfare' and 'feeling of despair'. Veterinarians were perceived by several participating farmers as the most trusted information source on disease control. However, in particular non-sustainable situations, other producers, and especially experiences from abroad, seemed to considerably influence the farmers' decision-making. 'Lack of knowledge', 'farm structure and management barriers' and 'economic constrains' were identified in relation to PBC. Several negative themes, such as 'lack of communication', 'not knowing where to look', and 'information bias' were associated with research from academia. This study identified a range of factors influencing the decision-making process for disease control by pig farmers. In addition, it highlighted the lack of awareness and difficult access of producers to current scientific research outputs. The factors identified should be considered when developing communication strategies to disseminate research findings and advice for disease control.

Qualitative study of factors associated with antimicrobial usage in seven small animal veterinary practices in the UK.

Responsible use of antimicrobials by veterinarians is essential to contain antimicrobial resistance in pathogens relevant to public health. Inappropriate antimicrobial use has been previously described in practice. However, there is scarce information on factors influencing antimicrobial usage in dogs and cats. We investigated intrinsic and extrinsic factors influencing decision-making of antimicrobial usage in first opinion small animal practices in the UK through the application of qualitative research methods. Semi-structured interviews were conducted with 21 veterinarians from seven veterinary first opinion practices in the UK in 2010. Topics investigated included: a) criteria used for selection of antimicrobials, b) influences by colleagues, c) influences by clients, d) pet characteristics, e) sources of knowledge, f) awareness of guidelines and g) protocols implemented in practice that may affect antimicrobial usage by veterinarians. Hypothetical scenarios selected to assess appropriateness of antimicrobial usage were: a) vomiting in a Yorkshire Terrier due to dietary indiscretion, b) deep pyoderma in a Shar-Pei, c) Feline Lower Urinary Tract disease in an 7 year-old male neutered cat and d) neutering of a 6-months dog. Interviews were recorded and transcribed by the interviewer. Thematic analysis was used to analyse content of transcribed interviews. Data management and analysis was conducted with qualitative analysis software NVivo8 (QSR International Pty Ltd). Antimicrobial usage by participants was influenced by factors other than clinical evidence and scientific knowledge. Intrinsic factors included veterinarian's preference of substances and previous experience. Extrinsic factors influencing antimicrobial selection were; perceived efficacy, ease of administration of formulations, perceived compliance, willingness and ability to treat by pet owners, and animal characteristics. Cost of therapy was only perceived as an influential factor in low, mixed socioeconomic areas. Veterinarians had limited awareness of current recommendations for responsible use in small animal practice. Social norms, particularly verbally agreed protocols influenced veterinarians. Inappropriate antimicrobial usage was identified in the therapy of non-infectious diseases and prophylaxis of routine clean surgical procedures. Discussion of clinical cases with peers and effectiveness meetings in the workplace were useful to veterinarians to share scientific knowledge. Effectiveness meetings can be a common ground for veterinarians to discuss and agree protocols for clinical conditions and surgical procedures. Protocols should be evidence-based, follow current recommendations and take into account the resources available in the workplace. Targeted training of veterinarians in the workplace with peer support should be used to promote responsible antimicrobial usage.