Typology of interventions for antimicrobial use and antimicrobial resistance in aquaculture systems in low- and middle-income countries.

Indiscriminate antimicrobial use (AMU) in aquaculture to treat and prevent diseases is common and can lead to the emergence of antimicrobial-resistant micro-organisms, potentially impacting public health and connected ecosystems. This study aimed to develop a typology to classify and characterise interventions to reduce AMU in aquaculture and identify points of action. Seventeen aquaculture and animal health professionals in Asian and African countries were interviewed to gather information on characteristics of interventions in different contexts to develop a typology. Seven types of interventions were defined: (i) legislation and regulations; (ii) industry rules and standards; (iii) voluntary instruments; (iv) commercial technology and alternatives to antimicrobials; (v) on-farm management; (vi) learning and awareness-raising; and (vii) activities with co-benefits. Types were based on intervention function, scope of implementation, implementer, compulsion, strength of the intervention, AMU/antimicrobial resistance (AMR) objective and stakeholder to influence. For each type, examples were described and discussed. The most common interventions to address AMU and AMR were legislative and regulatory frameworks and voluntary instruments, including National Action Plans. Interventions addressing AMU/AMR specifically were scarce. Other interventions focused on indirect effect pathways to AMU and AMR reduction aiming to improve good aquaculture practices, disease prevention and improved management. Monitoring and evaluation of these interventions were found to be rare, only present for interventions driven by development projects and international agencies. The presented typology of existing strategies and interventions addressing AMU/AMR in aquaculture systems can guide evaluation of AMR-sensitive interventions that promote responsible AMU, and informs the design and implementation of future interventions.

Setting occupational exposure limits for antimicrobial agents: A case study based on a quaternary ammonium compound-based disinfectant.

Antimicrobial agents have become an essential tool in controlling the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and guidelines on their use have been issued by various public health agencies. Through its Emerging Viral Pathogen Guidance for Antimicrobial Pesticides, the US Environmental Protection Agency has approved numerous surface disinfectant products for use against SARS-CoV-2. Despite their widespread use and range of associated health hazards, the majority of active ingredients in antimicrobial products, such as surface disinfectants, lack established occupational exposure limits (OELs) to assist occupational health professionals in characterizing risks from exposures to these chemicals. Based on established approaches from various organizations, a framework for deriving OELs specific to antimicrobial agents was developed that relies on a weight-of-evidence evaluation of the available data. This framework involves (1) a screening-level toxicological assessment based on a review of the existing literature and recommendations, (2) identification of the critical adverse effect(s) and dose-response relationship(s), (3) identification of alternative health-based exposure limits (HBELs), (4) derivation of potential OELs based on identified points of departure and uncertainty factors and/or modification of existing alternative HBELs, and (5) selection of an appropriate OEL. To demonstrate the use of this framework, a case study is described for selection of an OEL for a disinfectant product containing quaternary ammonium compounds (quats). Three potential OELs were derived for this product based on irritation toxicity data, developmental and reproductive toxicity (DART) data, and modification of an existing HBEL. The final selected OEL for the quats-containing product was 0.1 mg/m3, derived from modification of an existing HBEL. This value represented the lowest resulting value of the three approaches, and thus, was considered protective of irritation and potential DART.

Soap and syndets: differences and analogies, sources of great confusion.

OBJECTIVE: Soap has been used by humankind since ancient times and was probably already known to the Sumerians. It is a fatty acid salt obtained from the reaction of a strong base with a fatty substance of animal (tallow) or plant origin (oil). This reaction is called saponification. Syndets, on the other hand, are much more recent and have been in use for about a century. In the case of liquid syndets, they are mainly alkyl sulphates and their derivatives alkyl ether sulphates while isethionates and sarcosinates are more commonly found in solid syndets. Synthetic soaps and detergents are surfactants and, as such, they have detergent properties. The way soap works accounts for its antimicrobial properties. Thanks to its amphiphilic structure, it is able to interact with the lipid membranes of microorganisms (viruses, bacteria, etc.) and inactivate them. In this coronavirus pandemic period, health authorities worldwide recommend hand washing with soap and water. We therefore wanted to provide a summary of the chemical characteristics and applications of soaps, on the one hand, and synthetic detergents, on the other. Soap is not the only product used for hand hygiene and, given the current situation, alternatives are complex and varied.

Antimicrobial De-Escalation in the ICU: From Recommendations to Level of Evidence.

Antimicrobial de-escalation (ADE) is a component of antimicrobial stewardship (AMS) aimed to reduce exposure to broad-spectrum antimicrobials. In the intensive care unit, ADE is a strong recommendation that is moderately applied in clinical practice. Following a systematic review of the literature, we assessed the studies identified on the topic which included one randomized controlled trial and 20 observational studies. The literature shows a low level of evidence, although observational studies suggested that this procedure is safe. The effects of ADE on the level of resistance of ecological systems and especially on the microbiota are unclear. The reviewers recommend de-escalating antimicrobial treatment in patients requiring long-term antibiotic therapy and considering de-escalation in short-term treatments.

Exploring the Relevance of Senotherapeutics for the Current SARS-CoV-2 Emergency and Similar Future Global Health Threats.

The higher death rate caused by COVID-19 in older people, especially those with comorbidities, is a challenge for biomedical aging research. Here we explore the idea that an exacerbated inflammatory response, in particular that mediated by IL-6, may drive the deleterious consequences of the infection. Data shows that other RNA viruses, such as influenza virus, can display enhanced replication efficiency in senescent cells, suggesting that the accumulation of senescent cells with aging and age-related diseases may play a role in this phenomenon. However, at present, we are completely unaware of the response to SARS-CoV and SARS-COV-2 occurring in senescent cells. We deem that this is a priority area of research because it could lead to the development of several therapeutic strategies based on senotherapeutics or prevent unsuccessful attempts. Two of these senotherapeutics, azithromycin and ruxolitinib, are currently undergoing testing for their efficacy in treating COVID-19. The potential of these strategies is not only for ameliorating the consequences of the current emergence of SARS-CoV-2, but also for the future emergence of new viruses or mutated ones for which we are completely unprepared and for which no vaccines are available.

Antimicrobial Effectiveness in Eye Drops: Limited Sterility versus Reduction in Microbial Count.

Eye drops are sterile preparations intended for instillation into the eye. All major pharmacopoeias require these products to pass the antimicrobial effectiveness test (AET). This test is similar to that used for an oral dosage form despite the fact that both product categories differ in their microbiological specifications. The eye drops might pass the official requirements of the AET, but in practice, contaminants introduced into the preparation might not be killed before its next use by the patient and this may compromise ocular health. The objective of this work was to investigate the possible application of a limited sterility testing in a multichallenge test that mimics more closely real life use of eye drops. The AET was performed on 12 brands of eye drops, and results were compared with the suggested pass criteria of various pharmacopoeias. The multichallenge test was designed and used to demonstrate the ability of each tested product to kill the entire challenge organism population within a few hours. The results demonstrated that all products investigated complied with the AET acceptance requirements of the USP <51> and the "B" criteria of the European Pharmacopoeia (Ph Eur) <5.1.3>. Only two of the tested products did not comply with the no recovery term of Ph Eur <5.1.3> "A" criteria. Products repeatedly challenged with Pseudomonas aeruginosa ATCC 9027 (103 CFU/mL) were found to be self-sterilizing within 2 h of each inoculation. In conclusion, all tested products passed the acceptance criteria of the USP <51>, class B of the Ph Eur <5.1.3>, and the multichallenge test. The size of the challenge organism population in the AET seems to be severe for eye drops, and the pass criteria of the British Pharmacopoeia Appendix XVI are the most stringent. The no recovery term given in the Ph Eur <5.1.3> should be defined to a specified range.

How to start an antimicrobial stewardship programme in a hospital.

BACKGROUND: Antimicrobial stewardship (AMS) describes a coherent set of actions that ensure optimal use of antimicrobials to improve patient outcomes, while limiting the risk of adverse events (including antimicrobial resistance (AMR)). Introduction of AMS programmes in hospitals is part of most national action plans to mitigate AMR, yet the optimal components and actions of such a programme remain undetermined. OBJECTIVES: To describe how health-care professionals can start an AMS programme in their hospital, the components of such a programme and the evidence base for its implementation. SOURCES: National and society-led guidelines on AMS, peer-reviewed publications and experience of AMS experts conducting AMS programmes. CONTENT: We provide a step-by-step pragmatic guide to setting up and implementing a hospital AMS programme in high-income or low-and-middle-income countries. IMPLICATIONS: Antimicrobial stewardship programmes in hospitals are a vital component of national action plans for AMR, and have been shown to significantly reduce AMR, particularly when coupled with infection prevention and control interventions. This step-by-step guide of 'how to' set up an AMS programme will help health-care professionals involved in AMS to optimally design and implement their actions.

Comparison of Anti-Microbial Effects of Low-Level Laser Irradiation and Microwave Diathermy on Gram-Positive and Gram-Negative Bacteria in an In Vitro Model.

Background and Objectives: The aim of this study was to compare the effects of low-level laser therapy and continuous microwave diathermy on the growth of Gram-negative and Gram-positive bacteria and to establish their efficacy as an alternative therapeutic modality. MATERIALS AND METHODS: Laser fluence of 13 Joules (J)/cm2, 18 J/cm2 and 30 J/cm2 were used against several bacterial strains. Microwave dosages of 25, 50 and 100 watts (W) were used, respectively. RESULTS: A significant difference between the three groups was observed using repeated analysis of variance (RANOVA) (F value: 0.74, and p value: 0.001). The Greenhouse-Geisser correction (GG) revealed significant results for laser irradiation alone. However, effect size calculation showed effects with microwave diathermy as well as laser fluence. CONCLUSIONS: Low-level laser therapy appears to be an effective modality of treatment when compared with continuous microwave diathermy on the Gram-negative and the Gram-positive bacterial strains tested. Microwave diathermy revealed large and medium effects on the bacterial cell counts with dominant effects on Gram-negative strains.

Government policy interventions to reduce human antimicrobial use: A systematic review and evidence map.

BACKGROUND: Growing political attention to antimicrobial resistance (AMR) offers a rare opportunity for achieving meaningful action. Many governments have developed national AMR action plans, but most have not yet implemented policy interventions to reduce antimicrobial overuse. A systematic evidence map can support governments in making evidence-informed decisions about implementing programs to reduce AMR, by identifying, describing, and assessing the full range of evaluated government policy options to reduce antimicrobial use in humans. METHODS AND FINDINGS: Seven databases were searched from inception to January 28, 2019, (MEDLINE, CINAHL, EMBASE, PAIS Index, Cochrane Central Register of Controlled Trials, Web of Science, and PubMed). We identified studies that (1) clearly described a government policy intervention aimed at reducing human antimicrobial use, and (2) applied a quantitative design to measure the impact. We found 69 unique evaluations of government policy interventions carried out across 4 of the 6 WHO regions. These evaluations included randomized controlled trials (n = 4), non-randomized controlled trials (n = 3), controlled before-and-after designs (n = 7), interrupted time series designs (n = 25), uncontrolled before-and-after designs (n = 18), descriptive designs (n = 10), and cohort designs (n = 2). From these we identified 17 unique policy options for governments to reduce the human use of antimicrobials. Many studies evaluated public awareness campaigns (n = 17) and antimicrobial guidelines (n = 13); however, others offered different policy options such as professional regulation, restricted reimbursement, pay for performance, and prescription requirements. Identifying these policies can inform the development of future policies and evaluations in different contexts and health systems. Limitations of our study include the possible omission of unpublished initiatives, and that policies not evaluated with respect to antimicrobial use have not been captured in this review. CONCLUSIONS: To our knowledge this is the first study to provide policy makers with synthesized evidence on specific government policy interventions addressing AMR. In the future, governments should ensure that AMR policy interventions are evaluated using rigorous study designs and that study results are published. PROTOCOL REGISTRATION: PROSPERO CRD42017067514.

Phage Therapy Regulation: From Night to Dawn.

After decades of disregard in the Western world, phage therapy is witnessing a return of interest. However, the pharmaceutical legislation that has since been implemented is basically designed for regulating industrially-made pharmaceuticals, devoid of any patient customization and intended for large-scale distribution. Accordingly, the resulting regulatory framework is hardly reconcilable with the concept of sustainable phage therapy, involving tailor-made medicinal products in the global perspective of both evolutionary and personalized medicine. The repeated appeal for a dedicated regulatory framework has not been heard by the European legislature, which, in this matter, features a strong resistance to change despite the precedent of the unhindered implementation of advanced therapy medicinal product (ATMPs) regulation. It is acknowledged that in many aspects, phage therapy medicinal products are quite unconventional pharmaceuticals and likely this lack of conformity to the canonical model hampered the development of a suitable regulatory pathway. However, the regulatory approaches of countries where phage therapy traditions and practice have never been abandoned are now being revisited by some Western countries, opening new avenues for phage therapy regulation. As a next step, supranational and international organizations are urged to take over the initiatives originally launched by national regulatory authorities.

High Rates of Prescribing Antimicrobials for Prophylaxis in Children and Neonates: Results From the Antibiotic Resistance and Prescribing in European Children Point Prevalence Survey.

BACKGROUND: This study was conducted to assess the variation in prescription practices for systemic antimicrobial agents used for prophylaxis among pediatric patients hospitalized in 41 countries worldwide. METHODS: Using the standardized Antibiotic Resistance and Prescribing in European Children Point Prevalence Survey protocol, a cross-sectional point-prevalence survey was conducted at 226 pediatric hospitals in 41 countries from October 1 to November 30, 2012. RESULTS: Overall, 17693 pediatric patients were surveyed and 36.7% of them received antibiotics (n = 6499). Of 6818 inpatient children, 2242 (32.9%) received at least 1 antimicrobial for prophylactic use. Of 11899 prescriptions for antimicrobials, 3400 (28.6%) were provided for prophylactic use. Prophylaxis for medical diseases was the indication in 73.4% of cases (2495 of 3400), whereas 26.6% of prescriptions were for surgical diseases (905 of 3400). In approximately half the cases (48.7% [1656 of 3400]), a combination of 2 or more antimicrobials was prescribed. The use of broad-spectrum antibiotics (BSAs), which included tetracyclines, macrolides, lincosamides, and sulfonamides/trimethoprim, was high (51.8% [1761 of 3400]). Broad-spectrum antibiotic use for medical prophylaxis was more common in Asia (risk ratio [RR], 1.322; 95% confidence interval [CI], 1.202-1.653) and more restricted in Australia (RR, 0.619; 95% CI, 0.521-0.736). Prescription of BSA for surgical prophylaxis also varied according to United Nations region. Finally, a high percentage of surgical patients (79.7% [721 of 905]) received their prophylaxis for longer than 1 day. CONCLUSIONS: A high proportion of hospitalized children received prophylactic BSAs. This represents a clear target for quality improvement. Collectively speaking, it is critical to reduce total prophylactic prescribing, BSA use, and prolonged prescription.

Outpatient parenteral antimicrobial therapy (OPAT) in the UK: a cross-sectional survey of acute hospital trusts and health boards.

This study reviews the current OPAT service provision in the UK and evaluates concordance with the national OPAT practice guidelines (standards of care). We conducted a survey of acute hospital trusts and health boards in the UK regarding OPAT practices between June and September 2017. 165 (93%) of the 178 acute hospital trusts/health boards that were contacted responded to the survey. 100 (61%) indicated they had an OPAT service. Ten (10%) OPAT services did not involve an infection specialist. Bone and joint infections, and skin and soft-tissue infections were the most common conditions treated. Most OPAT services (74%) hold weekly multidisciplinary meetings/virtual ward rounds to review patient's progress. 73% had a dedicated OPAT database. We identified variations in practice and concordance with the national OPAT good practice guidelines. In an era of increasing demand for home-based care, further studies are required to identify the optimal configuration of OPAT services with regards to quality and patient safety.

Comparison of knowledge to antimicrobial stewardship institution policies targeting Staphylococcus aureus bacteremia and candidemia between medical doctors and pharmacists in an academic teaching hospital in Japan.

Staphylococcus aureus bacteremia (SAB) and candidemia have significant impacts on mortality. Both have important implications for antimicrobial stewardship programs (ASPs). However, there are limited data regarding who should be educated and what components should be considered for the ASPs. Hence, we investigated the possibility of the key elements for implications of SAB and candidemia managements for ASPs. We conducted a cross-sectional study on the knowledge of antimicrobial stewardship institution policies targeting SAB and candidemia for all medical doctors (MDs) and pharmacists to using an E-learning system. To compare the differences in proportions of appropriate knowledge between junior residents and other MDs, and all MDs and pharmacists, we performed bivariate analyses using Fisher's exact test and χ2 test with odds ratios (ORs) with 95% confidence intervals (CIs). In total, all 395 MDs (71 junior residents, 137 senior residents and fellows, and 187 attending doctors) and all 63 pharmacists including 4 antimicrobial stewardship teams pharmacists responded to survey. MDs other than junior residents responded significantly inappropriately to the questions on the candidemia than junior residents (OR = 0.6, 95% CI: 0.4-1.0). Pharmacists had a significantly lower proportion of appropriate knowledge to the candidemia than MDs (OR = 0.4, 95% CI: 0.2-0.8). The major pitfall was failure to consult an ophthalmologist (82.5%). Next step, we will conduct educational intervention about institution policies, and evaluate whether to improve the knowledges and practices by pre-post test and chart review.

Poor compliance with antimicrobial guidelines for childhood pneumonia.

INTRODUCTION: Antimicrobial stewardship programmes recommend use of narrow-spectrum antibiotics as first-line treatment of childhood pneumonia in secondary care. The primary aim of the present study was to assess whether current guidelines are followed. A secondary aim was to assess if tracheal aspiration is a useful tool in the diagnostic process of suspected childhood pneumonia. METHODS: This was a retrospective descriptive single-centre cohort study. Children between three months and 17 years with a pneumonia diagnosis were included. The children were divided into two groups based on whether or not they had been treated with antibiotics (TWA) by their general practitioner. We obtained information on blood samples, treatment and microbial findings. Finally, we compared the use of antibiotics and the microbiological diagnosis of children TWA prior to admittance with those of drug-naïve children (DN). RESULTS: Guidelines were followed in 55% (n = 78) of the cases, which is comparable to results reported by other studies. Tracheal aspiration culture identified a bacterial pathogen in 54% (n = 77) of the cases; Haemophilus influenzae was the most prevalent. A larger percentage of tracheal aspirations was positive in the TWA group than in the DN group (66%; n = 31 versus 48%; n = 46). CONCLUSIONS: Compliance with local guidelines was comparable to findings reported in similar single-centre studies. Airway aspiration may be a useful supplement to other investigations. FUNDING: none. TRIAL REGISTRATION: not relevant.

Licensing and Approval of Antimicrobial Agents for Use in Animals.

The importance of antimicrobial resistance and the urgent need to combat it has increased the already existent complexity of licensing and approval of antimicrobial agents for use in animals due to its possible impact on animal and public health. VICH-the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products-is the trilateral (European Union-Japan-United States) program that has the goal of harmonizing technical requirements for veterinary product registration. This article aims to describe the data requirements and testing necessary to build a registration file to obtain marketing authorization for a new antimicrobial agent for use in animals. This information is needed in the context of the risk assessment framework currently used in the approval of veterinary medicinal products containing antimicrobial substances. This framework considers the consequences of the uncontrolled quality of the antimicrobial product, the direct exposure of people to the antimicrobial product (human occupational safety and consumer safety), inadvertent exposure of organisms to the antimicrobial product (environmental safety), the antimicrobial product causing harm in the treated animals (target animal safety), and failure to achieve claims (efficacy). Approved veterinary medicines need to have a clear positive benefit associated with their use because of the risk to public health, animal health, and the environment. However, the presence of antimicrobials in the environment exerts a selective pressure for resistance genes in bacteria, and there is growing worldwide concern about the role of polluted soil and water environments in spreading antimicrobial resistance and the role of the contaminant resistome due to food-producing animal antimicrobial treatment. Additionally, the international developments regarding the categorization of critically important antimicrobials with the possible restrictions of use and the monitoring and surveillance of antimicrobial resistance in animals are reviewed.

Bioprofiling for the quality control of Egyptian propolis using an integrated NIR-HPTLC-image analysis strategy.

Quality control of propolis being a complex mixture of compounds that are very difficult to analyze and standardize is certainly challenging. Shown on the example of 35 Egyptian propolis samples, a strategy for an improved quality control was demonstrated in which efficacy-directed fingerprint analysis of high-performance thin-layer chromatography (HPTLC) fingerprints were evaluated in combination with Near Infra-Red spectrometry (NIRS) to realize precise discrimination and high quality assessment of chemical and effective consistency of propolis samples that are collected from various geographical locations in Egypt. The fingerprints obtained after derivatization and fluorescence detection (FLD) at λ 366 nm were analyzed by using multivariate data analysis and data were used to identify nine marker ingredients of the different propolis samples. These markers were then quantified by a new validated HPTLC method and an attempt to classify the samples by using a targeted approach was implemented. All investigated propolis samples were initially divided into two types in the untargeted and targeted HPTLC image multivariate analysis. The antimicrobial activities of propolis samples were then evaluated and the results showed that there was significant variation in the biological activities of the different samples. The quantitative data of marker compounds as well as the samples bioactivity results were then subjected to partial least squares regression (PLS-R) analysis which revealed that chrysin, galangin­5­O­methylether, pinostrobin, and islapinin were the main bioactive markers. Based on the efficacy-associated marker ingredients, pretreated spectral patterns of NIRS were selected as a complementary evaluation technique directed to the comprehensive efficacy-directed discrimination of the different Egyptian propolis samples which could successfully classify the propolis samples tested into three different types. Hierarchical cluster analysis and orthogonal projection to latent structures discriminant analysis (OPLS-DA) were applied to the quantitative results from the efficacy-associated markers only. From this systematic method, the 35 samples were subsequently divided into three types; orange, green and blue, displaying a more intricate division than OPLS-DA which is based only on the untargeted HPTLC analysis or the full NIR spectral data. This study initiated the research on the Egyptian propolis and confirmed the existence of three different types of Egyptian propolis, the blue, green and orange types. The study also emphasizes how it is critical to implement the fingerprint- efficacy relationship analysis in finding out the main health-relevant biomarkers for the quality assessment especially for samples displaying delicate differences in their chemical composition and bioactivity.

Monitoring Antimicrobial Drug Usage in Animals: Methods and Applications.

Monitoring antimicrobial drug usage in animals at the national and international levels is important for identification and tracking if and how often quantities are used. This information can be used for many purposes, including raising awareness, comparing use patterns across countries, identifying trends over time, integrating with antimicrobial resistance data, conducting risk assessment, and evaluating the effectiveness of measures to manage antimicrobial usage. The goal of this article is to describe how monitoring systems for antimicrobial drug usage in animals are set up and conducted, using examples from specific countries as well as international efforts. Several key figures and variables are used to describe and evaluate antimicrobial consumption in animals, including the amount in kilograms of active ingredient, standardized units (e.g., number of defined daily dose animals, DDDAs) and number of treatments (e.g., number of used daily doses, UDDA). Data can be collected from a variety of sources including pharmaceutical sales, pharmacy dispensing, veterinary prescriptions, and farm records. In many countries, data analysis and reporting at the national level provide statistics on overall quantities used in animals, in some cases by animal species. Antimicrobial consumption data should be contrasted to the respective animal population, for example, the weight of different categories of livestock and slaughtered animals. Several countries have established antimicrobial usage monitoring systems. Most report overall sales data, but some provide usage data to the levels of animal species and production type. At the international level, several organizations (e.g., European Union, World Organization for Animal Health, World Health Organization) have initiatives to support the development of antimicrobial consumption data collection and reporting. However, these initiatives are ongoing and so far lack harmonization, which will be the biggest challenge for the future.