Skip to search form Skip to main content. The topics covered include mechanisms of resistance, resistance of bacterial fish pathogens, resistance to antibacterial agents associated with use in aquaculture, and factors causing selection of resistant variants.
View PDF. Save to Library. Create Alert. Share This Paper. Figures and Tables from this paper. Figures and Tables. Citations Publications citing this paper. Polysaccharide fraction from the Indian mistletoe, Dendrophthoe falcata L. Ettingsh enhances innate immunity and disease resistance in Oreochromis niloticus Linn. We excluded studies when they focused on drug administration only no prescribing decision. Following analysis of the literature from the main search and discussions with the stakeholder group, an additional search was undertaken to allow the review to focus on issues emerging as significant.
This additional search focused on social and professional influences in clinical training, and more specifically related to hierarchies, team-working and decision-making. It was not intended to be exhaustive, but to purposefully draw together relevant literature from a different range of disciplines and provide an explanatory backbone for the wider contextual influences identified as important from the analysis of the literature in the main search.
The additional search strategy was developed in a similar way to the main search. Studies were included when they discussed the role of hierarchies, teamwork and decision-making, in relation to doctors-in-training any specialty and level , regardless of study design or setting hospital or primary care. We had no pre-specified exclusion criteria. Included studies were not necessarily linked to prescribing as we were looking to understand the wider context in which doctors-in-training practise.
The results of both searches were exported to Endnote X7 bibliographic management software Thomson Reuters Corporation, Toronto, Ontario and de-duplicated using automated and manual checking. All citations were reviewed by C. The selection process primarily focused on the extent to which articles included data that could contribute to the development and refinement of programme theory.
For those articles that met the inclusion criteria, C. At the point of inclusion based on relevance, the trustworthiness and rigour of each study was also assessed. Once the core dataset was established, initial manual coding was carried out chronologically from the most recent article for familiarization with the data. In the first rounds of analysis the content was classified in broad descriptive, conceptual categories. By looking at each of the conceptual categories more closely, C.
As the review progressed we iteratively refined the programme theory driven by interpretations of the data in articles included in the review. The characteristics of the documents were extracted into an Excel spreadsheet see Part S3.
How to educate prescribers in antimicrobial stewardship practices
The aim of the analysis was to reach theoretical saturation, such that sufficient information has been captured to explain the wide range of antimicrobial prescribing experiences of doctors-in-training reported in the included articles. Excerpts coded under specific concepts in NVivo were exported into Word documents, to provide a more flexible space to examine the viability of different CMOCs, experiment with different formulations and work towards building the narrative of the synthesis.
To develop a programme theory of the antimicrobial prescribing experiences of doctors-in-training we moved iteratively between the analysis of particular examples, stakeholder interpretations, refinement of programme theory, and further iterative searching for data in our existing dataset to refine particular subsections of the programme theory for more details on the analysis and synthesis processes, see Part S4. We continued to apply a realist logic of analysis to synthesize the data.
This means that we followed a process of constantly moving from data to theory abductive analysis defined in Part S1 to refine explanations about why certain behaviours are occurring and tried to frame these explanations at a level of abstraction that could cover a range of phenomena or patterns of behaviour in different settings. This included inferences about which mechanisms may be triggered in specific contexts, as these often remained hidden or were not articulated adequately in the literature.
Relationships between contexts, mechanisms and outcomes were sought not just within the same articles, but also across sources. For example, mechanisms inferred from one article could help explain the way contexts might be seen to influence outcomes in a different article.
Beyond analysis and synthesis, the writing process also helped us finalize the programme theory, as it allowed us to bring together the different CMOCs and to create a narrative that synthesizes and explains the data presented in the literature. This process also enabled us to fine-tune our interpretations, to debate the meaning and relevance of different aspects of the programme theory, and to develop shared understandings of our arguments.
By drawing on a range of social science and learning theories identified in the literature reviewed or separately we were able to substantiate the inferences made about mechanisms, contexts, outcomes and the configurations between these elements, and to enhance the plausibility and coherence of the arguments. The process of screening and article selection resulted in references. Of those, 81 references came from the main literature search and 35 references from the additional search.
The remaining 15 articles resulted from citation-tracking, targeted searches and expert suggestions, on the basis of relevance to programme theory.
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Of the references, 78 used quantitative methods, 37 used qualitative methods, 12 were mixed methods papers, and there were also 3 position papers and 1 report. Part S3 provides more details on the characteristics of the studies included in the dataset for the review. On their own, these articles did not provide enough information to adequately develop and refine an in-depth programme theory about how antimicrobial prescribing intervention components contributed to particular outcomes.
Therefore, we chose to focus on explaining how antimicrobial prescribing works for trainees as a process more generally. In this way, we were able to overcome limitations of poor description and lack of comprehensive evaluations and develop findings that can be transferable across different settings.
Through systematic coding and analysis of the included papers we were able to reach theoretical saturation on the concepts emerging as important for the development of programme theory on antimicrobial prescribing behaviours of doctors-in-training. We attempted to build explanations of how and why trainees engage with antimicrobial prescribing differently under different circumstances.
To do this, we focused on situations where antimicrobial prescribing decisions appear more challenging and where there is increased uncertainty about what course of action to take compared with when decisions are clear-cut, e. Instead of identifying barriers and facilitators to antimicrobial prescribing, we focused on what trainees do in the presence of challenges, such as diagnostic uncertainty, inexperience and lack of knowledge, to reach antimicrobial prescribing decisions. The following parts of the Results section provide a narrative overview of the programme theories on antimicrobial prescribing practices of doctors-in-training, based on the realist analysis and explanatory CMOCs developed from the literature reviewed.
The narrative presents the programme theories organized under four categories: i influence of the medical hierarchy on prescribing decisions; ii influence of the hierarchy on balancing conflicting priorities and using sources of support; iii assistance seeking and challenging decisions; and iv changing contexts. These four categories emerged following analysis and clustering of the data from the literature. Only selected CMOCs are presented in this section due to space constraints. Part S5 includes the full list of all 28 CMOCs along with examples of data excerpts from the literature.
For a more detailed account of the review, we would direct readers to the full report from this project published on the NIHR Journals library link provided in the Methods section. The literature describes hierarchies as a core and pervasive aspect of professional socialization in medicine, with senior clinicians e. Analysis of the literature suggests this compliance results primarily from fear of criticism and fear of individual responsibility for patients deteriorating.
Findings related to the role of medical hierarchy on prescribing decisions are synthesized in CMOCs 1 and 2 the illustrative data excerpts used to develop and refine these may be found in Part S5 and a detailed example of how we developed a CMOC is illustrated in Part S6 : 27 , 46—66 , CMOC 1: In a context of learning through role-modelling within hierarchical relationships C , junior doctors passively comply with the prescribing habits and norms set by their seniors O , due to fear of criticism M and fear of individual responsibility for patients deteriorating M. CMOC 2: In a context where career progression depends on hierarchical power relationships C , junior doctors feel they have to preserve their reputation and position in the hierarchy fitting-in M , by actively following the example of their seniors and avoiding conflict O.
According to the articles reviewed, perceptions of responsibility and accountability also play a role in influencing the extent to which doctors-in-training follow the norms set by the hierarchy. When trainees perceive that it is their seniors who have responsibility for patient outcomes, they tend to follow the practices indicated as legitimate by those seniors who have ultimate responsibility CMOC 4 in Part S5.
Role-modelling from senior to junior levels of the hierarchy extends to how conflicting goals should be prioritized CMOC 5 in Part S5. The way senior clinicians engage in decision-making indicates to trainees how they should prioritize between more immediate, individual short-term goals of patient recovery e. In examples included in the literature, it is suggested that seniors also role-model how to find a balance between the need for antimicrobial prescribing against the risk of side effects e. Clostridium difficile infection.
In such a context of learning through implicit or explicit role-modelling within hierarchical relationships, junior doctors follow the example of seniors, not just in their prescribing decisions, but also in what they count as legitimate sources of support for making prescribing decisions CMOCs 6—8 in Part S5.
The primary influence behind guideline use seems to be whether these are adopted and perceived as credible by senior colleagues CMOC 9 in Part S5 for factors influencing guideline credibility and use. Besides the role of guidelines and patient expectations, the literature suggests that senior doctors also role-model how the opinions of other health professionals should be taken into account. By creating a legitimate role for other health professionals in the antimicrobial prescribing process, senior doctors signal to their trainees what is appropriate behaviour to follow, whose opinion counts, in what cases and to what extent CMOCs 11—12 in Part S5.
For example, newly qualified doctors may turn to the pharmacist as a source of support external to the medical hierarchy, as they will feel less fear of appearing ignorant or experiencing negative repercussions CMOC 13 in Part S5. Analysis of the data in the included studies shows that role-modelling may result in positive learning, when for example senior doctors follow appropriate prescribing behaviours and clearly explain the rationale of their decisions e. According to the literature, optimal role-modelling means explicitly setting the rules about how hierarchical relationships operate in different environments and how trainees should expect to be embedded within them CMOC 14 in Part S5.
In hierarchical environments, rules on how to interact with other healthcare professionals and on how to effectively apply knowledge in practice at different training levels often remain implicit or unspoken.
Detailed analysis of the literature highlights how trainees make detailed judgements about: i whether or not it would be acceptable to ask for assistance when making certain antimicrobial prescribing decisions; ii what types of topics would be acceptable to ask about; iii who they should address their questions to; and iv how they should frame and communicate their questions. Doctors-in-training make judgements on these points, depending on the condition of the patient, whether they feel a case falls within their remit or knowledge, and depending on what they think the consequences of seeking assistance from particular colleagues would be CMOCs 18—20 in Part S5.
Similar dynamics seem to apply in cases where trainees consider challenging the decisions of their seniors. The literature discusses how reluctance to challenge stems from the belief that it is unlikely that the senior would change their decision, that any error would not be major enough to result in direct patient harm, and that it would be more appropriate for someone else at a different position in the hierarchy to identify and intercept the error CMOCs 21—22 in Part S5.
This shows that collective hierarchical norms are often more powerful than norms or rules set by individual senior doctors CMOC 25 in Part S5 , while discrepancies in perceptions of communication openness between hierarchical levels are prevalent CMOC 26 in Part S5. As training progresses, doctors become more comfortable negotiating the boundaries of responsibility, knowledge expected and its application in practice at different stages.
Through professional socialization in different environments they learn how to operate under different rules set by the local hierarchies. Their ability to ask questions and confidently argue alternative positions changes over time, as with increasing seniority they are expected to assume more autonomy and responsibility CMOCs 27—28 in Part S5.
Figure 2 provides an overarching programme theory which consolidates the relationships between the 28 detailed explanations i. CMOCs emerging from the data, organized around the important outcomes identified. The IMPACT review adds to a growing literature that acknowledges the importance of the wider context in which an intervention is implemented and attempts to explain how and why trainee prescribing practices differ under different circumstances.
In doing this, the review does not aim to produce evidence about the relative advantages of different interventions. Given the complexity and clinical uncertainty inherent in antimicrobial prescribing, it is likely that a context-sensitive combination of top-down and bottom-up, multifaceted solutions and ongoing support will be required to improve practice. The programme theory also explains what drives reluctance or willingness to ask questions about antimicrobial prescribing or to challenge the decisions made by seniors, as well as how this changes as training progresses.
As discussed in the literature reviewed, these outcomes result from complex interrelationships between the contexts in which doctors-in-training practice i. Despite recognition of the significant influence of social norms in trainee prescribing, there is still emphasis on purely knowledge- or skills-based interventions. When education and feedback interventions are disjointed from how prescribing decisions are made in the workplace, they are less likely to result in meaningful and sustainable change.
Therefore, there is a need to incorporate an understanding of local prescribing norms and power dynamics in the design and delivery of context-sensitive education and feedback programmes, including training on teamwork, communication, error awareness and management that addresses the influence of hierarchical teams. Based on the findings of the review, we have focused our recommendations on six key areas for consideration when designing and implementing antimicrobial prescribing interventions for doctors-in-training Figure 3.
These recommendations have been developed so that they are transferable and generic enough to allow local tailoring of different types of interventions for different environments.
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Areas to consider when designing or implementing antimicrobial prescribing interventions that include or target doctors-in-training. Given the importance of hierarchical dynamics in influencing prescribing decisions, it would not be adequate to implement interventions that target one specific group of prescribers, especially when this group is considered to have a lower status in the hierarchy. A wider cultural shift is necessary across all professional groups and levels of training. Having commonly agreed roles and responsibilities for appropriate antimicrobial prescribing e.
In addition to setting particular roles and responsibilities, it would also be important to ensure appropriate knowledge and skills e. Developing explicit processes for seeking assistance, i. As senior doctors play a significant role in setting prescribing norms and influencing junior clinicians, any interventions that do not match accepted norms may not translate to better practice. In addition, progress and the current status in the development of new vaccines to prevent diseases caused by N.
Future progress will likely bring to the clinic passive immunotherapies based on monoclonal antibodies and new adjuvants, especially for use in vaccines against intracellular pathogens. Recent Advances in Vaccine Adjuvants. Infectious disease remains one of the main causes of mortality and morbidity worldwide. Vaccination has had the greatest impact of any medical intervention technique in controlling infectious diseases. Most notably, eradication of smallpox was achieved through concerted and rigorous mass vaccination programs, and the incidence of diphtheria, pertussis, polio and other childhood diseases have been significantly reduced through routine infant immunization.
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However, with a move away from whole-killed vaccines for safety reasons, a key challenge in realizing the full potential of vaccination has been the lack of immunogenicity of many novel vaccines especially in certain populations such as the elderly and the immunocompromised. Adjuvants are a key component in enhancing immunogenicity of vaccines. Furthermore, adjuvants can play a vital role in facilitating the induction of the appropriate type of immunity that is required to either prevent, such as in prophylactic vaccines, or to treat, such as in therapeutic vaccines.
Therefore, careful consideration of the choice of adjuvants becomes quintessential for developing an effective vaccine. This chapter focuses on the importance of choosing the correct adjuvant or adjuvant combination to induce the appropriate immune responses to control the target pathogen. The increasing problem of resistance to antimicrobial agents, combined with the limited development of novel agents to treat infectious diseases is a serious threat to human morbidity and mortality around the world.
Among the available strategies available to create new therapeutic agents is the enhancement of the multifunctional properties of the natural anti-infectives, cationic host defense antimicrobial peptides HDPs. This chapter will provide a summary of our current understanding of the different types of HDPs including natural and synthetic peptides and their antimicrobial and immunomodulatory modes of action. Additionally, we will describe new approaches to peptide design and discuss both the therapeutic potential and prospective challenges in the utilization of peptides for antibacterial.
Antibodies for Antibacterials. Prior to the use of antibiotics, antibody or serum therapy was used with some success to treat bacterial infections.
Antibacterial Chemotherapy-Theory, Problems, And Practice (Oxford University Press)
Antibiotics almost completely replaced the use of antibody therapies for bacterial disease with few exceptions. Based upon the information available at the time, this was an obvious progression given the broader spectrum activity of antibiotics. Antibiotics revolutionized medicine and the approach to treating infectious disease. In addition to their broad spectrum, they exhibited few side-effects relative to the potential for serum sickness following the administration of equine immune serum and they were inexpensive.
But bacterial resistance to antibiotics became evident in the decades to follow, and we are now faced with a shortage of effective antibiotics and a need for alternative approaches to stand-alone antibiotic therapy.
One such approach which could supplement antibiotic use, thereby removing some of the selective pressure from antibiotics, is monoclonal antibody therapy or prophylaxis. Although this technology has yet to yield an antibacterial product, many clinical and preclinical programs are underway to explore varied and novel approaches to monoclonal antibody-based anti-infectives. Integrated pharmacokinetic-pharmacodynamic models are commonly used to study the in vivo dynamics of antimicrobial agents and bacterial pathogens.
These models are extremely useful for understanding the properties of antimicrobial agents such as absorption, transport, rate of binding, etc. However, they fail to consider within-host aspects of the infectious process that are likely to affect the bacterial-host interactions. For example, immune-mediated mechanisms to contain bacteria or limit their access to nutrients can also affect the access of a drug to its bacterial target. Alternatively, pathogens have various strategies to sequester themselves from host immune mechanisms that can also affect the access of therapeutic agents.
The search for new antibacterial agents that will be effective in vivo can be substantially informed by an understanding of the within-host dynamics of bacterial pathogens. Mathematical modeling of immune responses can assist in this process by providing new predictions, by offering mechanistic understanding and by revealing the gaps in our current understanding.
Such models are based on experiments that reveal the components of the immune system that play important roles during infections. But knowing the components alone usually provides only a static picture of bacterium-host interactions. Mathematical models aim to use the information obtained from experiments to construct the interactions and dependencies between various components. Thus mathematical models offer a mechanistic understanding of the interplay between various immunological processes and simulations of these models give a dynamic view of the entire process.
In this chapter we will first provide an overview of pharmacokinetic and pharmacodynamic models followed by a review of some of the immunological processes involved in bacterial infections which are generally ignored in pharmacodynamic models but are likely to affect access or activity of treatments.
We will then discuss the development of mathematical models by different approaches. We will end the chapter by exploring implications of these models in the discovery of new antibacterial agents. Despite the rising numbers of multidrug resistant pathogens, and their continuously emerging resistance patterns, few novel antibacterial agents have been approved or released recently. In order to combat this problem, efforts are being made to extend the utility of existing antibiotics as long as possible, while attempting to develop new drugs.
The clinical practice of evidence-based therapy, based on diagnosing early and narrowing antimicrobial coverage, with timely administration of an antibiotic, may help alleviate the problem. Diagnostic procedures optimized for accuracy and turn-around time further improve patient therapy. We review techniques currently in use in diagnostic microbiology, such as direct microscopic examination, rapid biochemical and antigen testing, microorganism culture, serologic diagnosis, and a variety of molecular diagnostic techniques.
In addition, we introduce various emerging diagnostic techniques, which show promise in their application towards a more exact antibacterial practice. Such emerging technologies include ultra high-throughput sequencing, microarray science, quantum dots, PCR electrospray ionization mass spectrometry, atomic force microscopy, and carbon nanotubes.
Point-of-care testing devices are also reviewed. As diagnostic methods have changed over the years, the novel applications of these technologies hold promise in their rapidity and accuracy, while showing potential application in drug target testing and drug discovery. At the beginning of the 21 st century the therapeutic paradigm for the treatment of infectious diseases can be summarized by three words: kill the bug.
This strategy has been termed the second age of antimicrobial therapy and was preceded by the era of serum therapy, which differed in the fundamental manner that serum was primarily an immunotherapeutic agent than enhanced host defenses Casadevall, First and second age therapeutics differed in other ways including the chemistry of the therapeutic agent, their specificity and the form of manufacturing Table 1.