Self-medication and antibiotic resistance: Crisis,current challenges,and prevention

The present study aims to explore the crisis of antibiotic resistance and discover more about the current challenges related to self-medication. The current challenges related to antibiotic resistance are unique and differ from the challenges of the past since new bacterial pathogens are involved and continue to evolve. Strains with resistance to multiple antibiotic classes have emerged which the discovery of new antibiotics has failed to match. The consequences of antibiotic resistance are grave with mortality and morbidity continually on the rise. This paper also highlights the possible interventions that can be effective at the micro or individual level in the prevention of development of antibiotic resistance.     

Using Interactive Family Science Shows to Improve Public Knowledge on Antibiotic Resistance: Does It Work?

The public plays an important role in controlling the emergence and spread of antibiotic resistance. A large British survey showed that there is still public misunderstanding about microbes and antibiotics. e-Bug, a European DG Sanco sponsored project, aims to disseminate a school antibiotic and hygiene educational pack and website across Europe. Interactive science shows based on the e-Bug educational packs were developed to take the key health and hygiene messages from the e-Bug school resources to families. The science show was evaluated to assess public knowledge and understanding of antibiotics and antibiotic resistance pre and post intervention. An interactive stall comprised of a 3×2 m backing stand with background information, an interactive activity and discussions with a trained demonstrator was on display at a family holiday resort. Pre-piloted knowledge questionnaires were completed by parents and children pre and post intervention. Adult (≥19 years) baseline knowledge regarding antibiotics and antibiotic resistance was high although significant knowledge improvement was observed where baseline knowledge was low. Children''s (5–11 years) knowledge around antibiotics and antibiotic resistance was significantly improved for all questions. The science show can be viewed as a success in improving parents'' and children''s knowledge of antibiotic use thereby highlighting the importance of educating the public through interaction.     

Effects of Long Term Antibiotic Therapy on Human Oral and Fecal Viromes

Viruses are integral members of the human microbiome. Many of the viruses comprising the human virome have been identified as bacteriophage, and little is known about how they respond to perturbations within the human ecosystem. The intimate association of phage with their cellular hosts suggests their communities may change in response to shifts in bacterial community membership. Alterations to human bacterial biota can result in human disease including a reduction in the host''s resilience to pathogens. Here we report the ecology of oral and fecal viral communities and their responses to long-term antibiotic therapy in a cohort of human subjects. We found significant differences between the viral communities of each body site with a more heterogeneous fecal virus community compared with viruses in saliva. We measured the relative diversity of viruses, and found that the oral viromes were significantly more diverse than fecal viromes. There were characteristic changes in the membership of oral and fecal bacterial communities in response to antibiotics, but changes in fecal viral communities were less distinguishing. In the oral cavity, an abundance of papillomaviruses found in subjects on antibiotics suggests an association between antibiotics and papillomavirus production. Despite the abundance of papillomaviruses identified, in neither the oral nor the fecal viromes did antibiotic therapy have any significant impact upon overall viral diversity. There was, however, an apparent expansion of the reservoir of genes putatively involved in resistance to numerous classes of antibiotics in fecal viromes that was not paralleled in oral viromes. The emergence of antibiotic resistance in fecal viromes in response to long-term antibiotic therapy in humans suggests that viruses play an important role in the resilience of human microbial communities to antibiotic disturbances.     

Improved annotation of antibiotic resistance determinants reveals microbial resistomes cluster by ecology

Antibiotic resistance is a dire clinical problem with important ecological dimensions. While antibiotic resistance in human pathogens continues to rise at alarming rates, the impact of environmental resistance on human health is still unclear. To investigate the relationship between human-associated and environmental resistomes, we analyzed functional metagenomic selections for resistance against 18 clinically relevant antibiotics from soil and human gut microbiota as well as a set of multidrug-resistant cultured soil isolates. These analyses were enabled by Resfams, a new curated database of protein families and associated highly precise and accurate profile hidden Markov models, confirmed for antibiotic resistance function and organized by ontology. We demonstrate that the antibiotic resistance functions that give rise to the resistance profiles observed in environmental and human-associated microbial communities significantly differ between ecologies. Antibiotic resistance functions that most discriminate between ecologies provide resistance to β-lactams and tetracyclines, two of the most widely used classes of antibiotics in the clinic and agriculture. We also analyzed the antibiotic resistance gene composition of over 6000 sequenced microbial genomes, revealing significant enrichment of resistance functions by both ecology and phylogeny. Together, our results indicate that environmental and human-associated microbial communities harbor distinct resistance genes, suggesting that antibiotic resistance functions are largely constrained by ecology.     

Subsistence and complexity of antimicrobial resistance on a community-wide level

There are a multitude of resistance strategies that microbes can apply to avoid inhibition by antimicrobials. One of these strategies is the enzymatic modification of the antibiotic, in a process generally termed inactivation. Furthermore, some microorganisms may not be limited to the mere inactivation of the antimicrobial compounds. They can continue by further enzymatic degradation of the compounds' carbon backbone, taking nutritional and energetic advantage of the former antibiotic. This driving force to harness an additional food source in a complex environment adds another level of complexity to the reasonably well-understood process of antibiotic resistance proliferation on a single cell level: It brings bioprotection into play at the level of microbial community. Despite the possible implications of a resistant community in a host and a lurking antibiotic failure, knowledge of degradation pathways of antibiotics and their connections is scarce. Currently, it is limited to only a few families of antibiotics (e.g. β-lactams and sulfonamides). In this article, we discuss the fluctuating nature of the relationship between antibiotic resistance and the biodegradation of antibiotics. This distinction mainly depends on the genetic background of the microbe, as general resistance genes can be recruited to function in a biodegradation pathway.     

Antibiotic Use in Animal Agriculture: What Have We Learned and Where are We Going?

Antibiotics are enormously important for the humane and efficient production of food animals. These benefits are somewhat offset by the human and animal health antibiotic resistance risks posed by their use in animals. This article provides an overview of what we have learned about antibiotic resistance as an issue in animal agriculture and where that knowledge could lead us in the future. To preserve the effectiveness of antibiotics, more action is needed to ensure their prudent use, particularly in the case of antibiotic growth promoters and antibiotics deemed critically important for human and animal health.     

Antibiotic use in animal agriculture: what have we learned and where are we going?

Antibiotics are enormously important for the humane and efficient production of food animals. These benefits are somewhat offset by the human and animal health antibiotic resistance risks posed by their use in animals. This article provides an overview of what we have learned about antibiotic resistance as an issue in animal agriculture and where that knowledge could lead us in the future. To preserve the effectiveness of antibiotics, more action is needed to ensure their prudent use, particularly in the case of antibiotic growth promoters and antibiotics deemed critically important for human and animal health.     

Antibiotic susceptibility of faecal bacteria in Antarctic penguins

Faecal bacteria from 49 Gentoo penguins on the Antarctic Peninsula were identified by biochemical methods and sequencing, and tested for antibiotic susceptibility using agar dilution. Of the 42 Enterobacteriaceae isolates found, 39 belonged to the genus Edwardsiella. All isolates were susceptible to the 17 antibiotics tested. This implies that antibiotic selection pressure is a prerequisite to a high prevalence of antibiotic resistance, and in the absence of contact with human activities, antibiotic resistance in Enterobacteriaceae remains undetectable.     

The Use of Machine Learning Methodologies to Analyse Antibiotic and Biocide Susceptibility in Staphylococcus aureus

Background

The rise of antibiotic resistance in pathogenic bacteria is a significant problem for the treatment of infectious diseases. Resistance is usually selected by the antibiotic itself; however, biocides might also co-select for resistance to antibiotics. Although resistance to biocides is poorly defined, different in vitro studies have shown that mutants presenting low susceptibility to biocides also have reduced susceptibility to antibiotics. However, studies with natural bacterial isolates are more limited and there are no clear conclusions as to whether the use of biocides results in the development of multidrug resistant bacteria.

Methods

The main goal is to perform an unbiased blind-based evaluation of the relationship between antibiotic and biocide reduced susceptibility in natural isolates of Staphylococcus aureus. One of the largest data sets ever studied comprising 1632 human clinical isolates of S. aureus originated worldwide was analysed. The phenotypic characterization of 13 antibiotics and 4 biocides was performed for all the strains. Complex links between reduced susceptibility to biocides and antibiotics are difficult to elucidate using the standard statistical approaches in phenotypic data. Therefore, machine learning techniques were applied to explore the data.

Results

In this pioneer study, we demonstrated that reduced susceptibility to two common biocides, chlorhexidine and benzalkonium chloride, which belong to different structural families, is associated to multidrug resistance. We have consistently found that a minimum inhibitory concentration greater than 2 mg/L for both biocides is related to antibiotic non-susceptibility in S. aureus.

Conclusions

Two important results emerged from our work, one methodological and one other with relevance in the field of antibiotic resistance. We could not conclude on whether the use of antibiotics selects for biocide resistance or vice versa. However, the observation of association between multiple resistance and two biocides commonly used may be of concern for the treatment of infectious diseases in the future.     

Silver bullets: A new lustre on an old antimicrobial agent

Silver was widely used in medicine to treat bacterial infections in the 19th and early 20th century, up until the discovery and development of the first modern antibiotics in the 1940s, which were markedly more effective. Since then, every new antibiotic introduced to the clinic has led to an associated development of drug resistance. Today, the threat of extensive bacterial resistance to antibiotics has reignited interest in alternative strategies to treat infectious diseases, with silver regaining well-deserved renewed attention. Silver ions are highly disruptive to bacterial integrity and biochemical function, with comparatively minimal toxicity to mammalian cells. This review focuses on the antimicrobial properties of silver and their use in synergistic combination therapy with traditional antibiotic drugs.     

In Silico Analysis of Antibiotic Resistance Genes in the Gut Microflora of Individuals from Diverse Geographies and Age-Groups

The spread of antibiotic resistance, originating from the rampant and unrestrictive use of antibiotics in humans and livestock over the past few decades has emerged as a global health problem. This problem has been further compounded by recent reports implicating the gut microbial communities to act as reservoirs of antibiotic resistance. We have profiled the presence of probable antibiotic resistance genes in the gut flora of 275 individuals from eight different nationalities. For this purpose, available metagenomic data sets corresponding to 275 gut microbiomes were analyzed. Sequence similarity searches of the genomic fragments constituting each of these metagenomes were performed against genes conferring resistance to around 240 antibiotics. Potential antibiotic resistance genes conferring resistance against 53 different antibiotics were detected in the human gut microflora analysed in this study. In addition to several geography/country-specific patterns, four distinct clusters of gut microbiomes, referred to as ‘Resistotypes’, exhibiting similarities in their antibiotic resistance profiles, were identified. Groups of antibiotics having similarities in their resistance patterns within each of these clusters were also detected. Apart from this, mobile multi-drug resistance gene operons were detected in certain gut microbiomes. The study highlighted an alarmingly high abundance of antibiotic resistance genes in two infant gut microbiomes. The results obtained in the present study presents a holistic ‘big picture’ on the spectra of antibiotic resistance within our gut microbiota across different geographies. Such insights may help in implementation of new regulations and stringency on the existing ones.     

Combating bacteria and drug resistance by inhibiting mechanisms of persistence and adaptation

Antibiotics have revolutionized the treatment of infectious disease but have also rapidly selected for the emergence of resistant pathogens. Traditional methods of antibiotic discovery have failed to keep pace with the evolution of this resistance, which suggests that new strategies to combat bacterial infections may be required. An improved understanding of bacterial stress responses and evolution suggests that in some circumstances, the ability of bacteria to survive antibiotic therapy either by transiently tolerating antibiotics or by evolving resistance requires specific biochemical processes that may themselves be subject to intervention. Inhibiting these processes may prolong the efficacy of current antibiotics and provide an alternative to escalating the current arms race between antibiotics and bacterial resistance. Though these approaches are not clinically validated and will certainly face their own set of challenges, their potential to protect our ever-shrinking arsenal of antibiotics merits their investigation. This Review summarizes the early efforts toward this goal.     

微生态学与后抗生素时代

本文简述了抗生素产生的历史背景,和对人类感染性疾病作出的贡献。但由于抗生素的泛用、滥用和过度治疗,引起了机体的菌群失调、二重感染和更为严重的细菌耐药性。为解决抗生素的弊端,解决菌群失调等问题,促使了微生态学的兴起和发展。本文还阐述了细菌耐药性的现状及危害,细菌产生耐药性的动因,后抗生素时代对细菌的防控措施。提出用微生态制剂、肠道正常菌群、中药、抗菌肽、噬菌体、研制新型抗菌药和规范用药等措施,防控细菌感染。同时阐述了常用中药的抗菌谱,及与微生态制剂合并应用的可能性。     

On the possible ecological roles of antimicrobials

The Introduction of antibiotics into the clinical use in the middle of the 20th century had a profound impact on modern medicine and human wellbeing. The contribution of these wonder molecules to public health and science is hard to overestimate. Much research has informed our understanding of antibiotic mechanisms of action and resistance at inhibitory concentrations in the lab and in the clinic. Antibiotics, however, are not a human invention as most of them are either natural products produced by soil microorganisms or semisynthetic derivatives of natural products. Because we use antibiotics to inhibit the bacterial growth, it is generally assumed that growth inhibition is also their primary ecological function in the environment. Nevertheless, multiple studies point to diverse nonlethal effects that are exhibited at lower levels of antibiotics. Here we review accumulating evidence of antibiosis and of alternative functions of antibiotics exhibited at subinhibitory concentrations. We also speculate on how these effects might alter phenotypes, fitness, and community composition of microbes in the context of the environment and suggest directions for future research.     

The global regulator Crc modulates metabolism,susceptibility to antibiotics and virulence in Pseudomonas aeruginosa

The capacity of a bacterial pathogen to produce a disease in a treated host depends on the former's virulence and resistance to antibiotics. Several scattered pieces of evidence suggest that these two characteristics can be influenced by bacterial metabolism. This potential relationship is particularly important upon infection of a host, a situation that demands bacteria adapt their physiology to their new environment, making use of newly available nutrients. To explore the potential cross‐talk between bacterial metabolism, antibiotic resistance and virulence, a Pseudomonas aeruginosa model was used. This species is an important opportunistic pathogen intrinsically resistant to many antibiotics. The role of Crc, a global regulator that controls the metabolism of carbon sources and catabolite repression in Pseudomonas, was analysed to determine its contribution to the intrinsic antibiotic resistance and virulence of P. aeruginosa. Using proteomic analyses, high‐throughput metabolic tests and functional assays, the present work shows the virulence and antibiotic resistance of this pathogen to be linked to its physiology, and to be under the control (directly or indirectly) of Crc. A P. aeruginosa strain lacking the Crc regulator showed defects in type III secretion, motility, expression of quorum sensing‐regulated virulence factors, and was less virulent in a Dictyostelium discoideum model. In addition, this mutant strain was more susceptible to beta‐lactams, aminoglycosides, fosfomycin and rifampin. Crc might therefore be a good target in the search for new antibiotics.     

Crossroads of Antibiotic Resistance and Biosynthesis

The biosynthesis of antibiotics and self-protection mechanisms employed by antibiotic producers are an integral part of the growing antibiotic resistance threat. The origins of clinically relevant antibiotic resistance genes found in human pathogens have been traced to ancient microbial producers of antibiotics in natural environments. Widespread and frequent antibiotic use amplifies environmental pools of antibiotic resistance genes and increases the likelihood for the selection of a resistance event in human pathogens. This perspective will provide an overview of the origins of antibiotic resistance to highlight the crossroads of antibiotic biosynthesis and producer self-protection that result in clinically relevant resistance mechanisms. Some case studies of synergistic antibiotic combinations, adjuvants, and hybrid antibiotics will also be presented to show how native antibiotic producers manage the emergence of antibiotic resistance.     

Antibiotic use: present and future

Antibiotics were initially viewed as "wonder drugs" primarily because they were introduced at a time when only surgical drainage or spontaneous cures were available to treat serious bacterial infections. During the five or six decades since their introduction, several classes of these drugs became available including sulfonamides and trimethoprim, penicillins, cephalosporins, chloramphenicol, tetracyclines, colimycins, macrolides, lincosamides, streptogramins, rifamycins, glycopeptides, aminoglycosides, fluoroquinolones, oxazolidinones, glycylglycines, lipoglycopeptides, and variations on these themes. Unfortunately, through a variety of mechanisms and perhaps as a result of their profligate use, many bacterial groups are exhibiting resistance to these antibiotics. At present, most bacterial infections can still be treated with available antibiotics used alone or in combination, but increasing numbers of clinical failures with the current armamentarium can be expected. Optimizing drug dosing and duration might help minimize the emergence of resistance in some situations. However, the future could look dim, as there are relatively few new agents on the horizon. A bold new look for antibacterial targets is needed. Surely our scientific abilities are up to this challenge. New approaches to antimicrobial chemotherapy are needed if we are to survive the increasing rates of antibiotic resistance predicted for the future.     

Phage-resistant mutations impact bacteria susceptibility to future phage infections and antibiotic response

Bacteriophage (phage) therapy in combination with antibiotic treatment serves as a potential strategy to overcome the continued rise in antibiotic resistance across bacterial pathogens. Understanding the impacts of evolutionary and ecological processes to the phage-antibiotic-resistance dynamic could advance the development of such combinatorial therapy. We tested whether the acquisition of mutations conferring phage resistance may have antagonistically pleiotropic consequences for antibiotic resistance. First, to determine the robustness of phage resistance across different phage strains, we infected resistant Escherichia coli cultures with phage that were not previously encountered. We found that phage-resistant E. coli mutants that gained resistance to a single phage strain maintain resistance to other phages with overlapping adsorption methods. Mutations underlying the phage-resistant phenotype affects lipopolysaccharide (LPS) structure and/or synthesis. Because LPS is implicated in both phage infection and antibiotic response, we then determined whether phage-resistant trade-offs exist when challenged with different classes of antibiotics. We found that only 1 out of the 4 phage-resistant E. coli mutants yielded trade-offs between phage and antibiotic resistance. Surprisingly, when challenged with novobiocin, we uncovered evidence of synergistic pleiotropy for some mutants allowing for greater antibiotic resistance, even though antibiotic resistance was never selected for. Our results highlight the importance of understanding the role of selective pressures and pleiotropic interactions in the bacterial response to phage-antibiotic combinatorial therapy.     

Antibiotic Resistance in Bacteria Isolated from the Deep Terrestrial Subsurface

Various natural environments have been examined for the presence of antibiotic-resistant bacteria and/or novel resistance mechanisms, but little is known about resistance in the terrestrial deep subsurface. This study examined two deep environments that differ in their known period of isolation from surface environments and the bacteria therein. One hundred fifty-four strains of bacteria were isolated from sediments located 170–259 m below land surface at the US Department of Energy Savannah River Site (SRS) in South Carolina and Hanford Site (HS) in Washington. Analyses of 16S rRNA gene sequences showed that both sets of strains were phylogenetically diverse and could be assigned to several genera in three to four phyla. All of the strains were screened for resistance to 13 antibiotics by plating on selective media and 90% were resistant to at least one antibiotic. Eighty-six percent of the SRS and 62% of the HS strains were resistant to more than one antibiotic. Resistance to nalidixic acid, mupirocin, or ampicillin was noted most frequently. The results indicate that antibiotic resistance is common among subsurface bacteria. The somewhat higher frequencies of resistance and multiple resistance at the SRS may, in part, be due to recent surface influence, such as exposure to antibiotics used in agriculture. However, the HS strains have never been exposed to anthropogenic antibiotics but still had a reasonably high frequency of resistance. Given their long period of isolation from surface influences, it is possible that they possess some novel antibiotic resistance genes and/or resistance mechanisms. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

The role of natural environments in the evolution of resistance traits in pathogenic bacteria

Antibiotics are among the most valuable compounds used for fighting human diseases. Unfortunately, pathogenic bacteria have evolved towards resistance. One important and frequently forgotten aspect of antibiotics and their resistance genes is that they evolved in non-clinical (natural) environments before the use of antibiotics by humans. Given that the biosphere is mainly formed by micro-organisms, learning the functional role of antibiotics and their resistance elements in nature has relevant implications both for human health and from an ecological perspective. Recent works have suggested that some antibiotics may serve for signalling purposes at the low concentrations probably found in natural ecosystems, whereas some antibiotic resistance genes were originally selected in their hosts for metabolic purposes or for signal trafficking. However, the high concentrations of antibiotics released in specific habitats (for instance, clinical settings) as a consequence of human activity can shift those functional roles. The pollution of natural ecosystems by antibiotics and resistance genes might have consequences for the evolution of the microbiosphere. Whereas antibiotics produce transient and usually local challenges in microbial communities, antibiotic resistance genes present in gene-transfer units can spread in nature with consequences for human health and the evolution of environmental microbiota that are largely ignored.