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In the past 100 years, thanks to the discovery and development of antimicrobial therapies, human and veterinary medicine have made a leap forward in treating infectious diseases. However, resistance mechanisms quickly appeared and spread in all sectors - human, animal and environmental - throughout the world, thus jeopardising the progress made. Awareness has been raised only gradually but is now prominent at the global level, due in large part to the action of international organisations such as the World Organisation for Animal Health (WOAH), the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO), and antimicrobials are considered a global public health good to be preserved. Under the leadership of WOAH in particular, the actions undertaken in research, surveillance, information, training, awareness and communication are moving in the right direction towards responsible and prudent use of antimicrobials. In the next 100 years, the fight against antimicrobial resistance will undeniably remain a crucial challenge for public health, veterinary public health and agriculture. Concerted efforts and scientific innovations, such as in functional genomics and artificial intelligence, could offer solutions to mitigate the impact of this growing threat. A multidisciplinary and comprehensive One Health approach is necessary to successfully address antimicrobial resistance. International collaboration remains crucial, and international organisations such as WOAH, WHO, FAO and the United Nations Environment Programme must continue their essential role in coordinating these efforts.

Sepsis is one of the oldest and most elusive syndromes in medicine that is still incompletely understood. Biomarkers may help to transform sepsis from a physiologic syndrome to a group of distinct biochemical disorders. This will help to differentiate between systemic inflammation of infectious and noninfectious origin and aid therapeutic decision making, hence improve the prognosis for patients, guide antimicrobial therapy, and foster the development of novel adjunctive sepsis therapies. To reach this goal requires increased systematic investigation that includes twenty-first century scientific approaches and technologies and appropriate clinical evaluation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The first written record of intervention against what later came to be known as an infectious disease was in the early seventeenth century by a Buddhist nun. She dried 3 to 4 wk old scabs from patients with mild smallpox and asked well people to inhale the powder. More than a century later in 1796, Edward Jenner described vaccination against smallpox by using cowpox that later was found to be caused by cowpox virus which is non-pathogenic for humans. Another century later in 1890, Robert Koch published the Koch's Postulates allowing the study of pathogenic bacteria and subsequently the study of agents to fight them. The first chemical cure for disease was reported by Paul Erhlich in 1909 in the form of an arsenic compound to treat syphilis. One hundred and ten years since then a lot has happened in the area of preventing and treating infectious diseases with significant contribution to increase in human lifespan. This is the only area of medicine in which treatment (antimicrobial agent) is used to eradicate a replicating biological agent inside the human host. The potential of this second biological agent to mutate under the selection pressure of antibiotics making them resistant was recognized in the 1940s. But the indiscriminate use of antibiotics for over 70 y has led to the present crisis of resistance in major pathogens with increased morbidity and mortality. In this review, we have incorporated all the possible avenues that might be useful in the future. However, none is more important than relearning the judicious use of antibiotics based on microbiology, pharmacology, and genetics.

The advent of modern antibiotics contributed enormously to the dramatic extension of human lifespan since their discovery by virtue of their lethal and selective action against pathogenic microbes. And yet despite our powerful arsenal of weapons against these pathogens, the war against them has not been won. And it may never be. Drug resistance is still menacing the society with many lives being lost due to deadly infections caused by continuously evolving strains spread beyond our means to eradicate them or prevent their spreading. Herein, the emergence and evolution of antibiotics is briefly reviewed, and a select number of total syntheses of naturally occurring antibiotics from the authors' laboratories are highlighted. The article concludes with a strong endorsement of the current efforts to intensify our fight against these dangerous pathogens with the hope that, this time, these initiatives will be sufficiently focused and serious enough so as to achieve our set goals of, at least, being prepared and ahead of them as part of our drive to improve humanity's healthcare and wellbeing.

This chapter briefly reviews the history and current use of antimicrobials in animals, with a focus on food animals in the more economically developed countries. It identifies some of the differences between human medical and food animal use, particularly in growth promotional and "subtherapeutic" use of medically-important antibiotics in animals. The public health impact of the extensive use of antibiotics in food animals for these purposes, differences internationally in such usage, and the major changes in current practices now underway in agricultural use are summarized. The emerging framing of the dimensions of antimicrobial resistance within a "One Health" framework is focusing global efforts to address the antimicrobial resistance crisis in a collaborative manner. The rapidly evolving development and application of practices of antimicrobial stewardship in animal is a critical part of the huge global effort to address antimicrobial resistance. The outcome is still uncertain.

This paper analyses how research on antibiotic resistance has been a driving force in the development of new antibiotics. Drug resistance, while being a problem for physicians and patients, offers attractive perspectives for those who research and develop new medicines. It imposes limits on the usability of older medicines and simultaneously modifies pathologies in a way that opens markets for new treatments. Studying resistance can thus be an important part of developing and marketing antibiotics. The chosen example is that of the German pharmaceutical company Bayer. Before World War Two, Bayer had pioneered the development of anti-infective chemotherapy, sulpha drugs in particular, but had missed the boat when it came to fungal antibiotics. Exacerbated by the effects of war, Bayer's world market presence, which had been considerable prior to the war, had plummeted. In this critical situation, the company opted for a development strategy that tried to capitalise on the problems created by the use of first-generation antibiotics. Part and parcel of this strategy was monitoring what can be called the structural change of infectious disease. In practice, this meant to focus on pathologies resulting from resistance and hospital infections. In addition, Bayer also focused on lifestyle pathologies such as athlete's foot. This paper will follow drug development and marketing at Bayer from 1945 to about 1980. In this period, Bayer managed to regain some of its previous standing in markets but could not escape from the overall crisis of anti-infective drug development from the 1970s on.

As foundations and governments mobilize to tackle antimicrobial resistance (AMR), several experiments in academic-industrial collaboration have emerged. Here, I examine two historical precedents, the Penicillin Project and the Malaria Project of the Second World War, and two contemporary examples, the Tuberculosis Drug Accelerator programme and the Tres Cantos Open Lab. These and related experiments suggest that different strategies can be effective in managing academic-industrial collaborations, and that such joint projects can prosper in both multisite and single-site forms, depending on the specific challenges and goals of each project. The success of these strategies and the crisis of AMR warrant additional investment in similar projects.

Antimicrobial resistance, the ability of (pathogenic) bacteria to withstand the action of antibiotic drugs, has recently been rated of having an impact on humans similar to that of global climate change. Indeed, during the last years medicine has faced the development of highly resistant bacterial strains, which were, as a consequence of worldwide travel activity, dispersed all over the globe. This is even more astonishing if taking into account that antibiotics were introduced into human medicine not even hundred years ago. Resistance covers different principle aspects, natural resistance, acquired resistance and clinical resistance. In the modern microbiology laboratory, antimicrobial resistance is determined by measuring the susceptibility of micro-organisms in vitro in the presence of antimicrobials. However, since the efficacy of an antibiotic depends on its pharmacokinetic and pharmacodynamics properties, breakpoints are provided to translate minimal inhibitory concentration to categorical efficacy (i.e. susceptible or resistant). Resistance in one microorganism against one particular drug may drive treatment decisions of clinicians, thereby fostering selection pressure to resistance development against another antibiotic. Thereby, bacteria may acquire more and more resistance traits, ending up with multi-resistance. To this end, antimicrobial resistance becomes a public health concern, not only in terms of limited treatment options but also due to its economic burden. The current paper provides a summary of the main topics associated with antimicrobial resistance as an introduction to this special issue.

The development of chemical compounds for the treatment of infectious diseases may be divided into three phases: a) the discovery in the 1600s in South America of alkaloid extracts from the bark of the cinchona tree and from the dried root of the ipecacuanha bush, which proved effective against, respectively, malaria (quinine) and amoebic dysentery (emetine); b) the development of synthetic drugs, which mostly took place in Germany, starting with Paul Ehrlich's (1854-1915) discovery of salvarsan (1909), and crowned with Gerhard Domagk's (1895-1964) discovery of the sulfonamides (1930s); and c) the discovery of antibiotics. The prime example of the latter is the development of penicillin in the late 1920s following a discovery by a solitary research scientist who never worked in a team and never as part of a research programme. It took another ten years or so before drug-quality penicillin was produced, with research now dependent on being conducted in large collaborative teams, frequently between universities and wealthy industrial companies. The search for new antibiotics began in earnest in the latter half of the 1940s and was mostly based on soil microorganisms. Many new antibiotics were discovered in this period, which may be termed «the golden age of antibiotics». Over the past three decades, the development of new antibiotics has largely stalled, while antibiotic resistance has increased. This situation may require new strategies for the treatment of infectious diseases.

Surgery and medicine have not evolved in parallel. There have been discrepancies, bellicosity, contempt and even separate university studies during a long time. The Saint Cosme Brotherhood, founded to supervise the professional practice of barbers (short robe surgeon-barbers) in France in 1260, was opposed by the Faculty of Medicine in Paris. The conflicting interests of the university, Brotherhood and Barbers, that persisted until the 18 th century, impaired the progress of surgery. In the first half of the 19 th century, the advance of surgery continued facing pain, hemorrhage and infection. The control of the latter had to consider antisepsis, asepsis and finally the appearance of antimicrobial substances, sulfonamides and antibiotics that allowed surgeons to approach and solve major problems of the specialty.

Introduction: Not so long ago, back in the 1900s, infectious diseases were the leading cause of death world wide. The doubling of our life span in the 20th century was achieved, first of all, by using bioactive natural products, their secondary metabolites or their derivates. These substances have prolonged our life span, reduced the pain and suffering and, at the same time, revolutionized medical science., History of Antibiotics: Antibiotics are among the most important classes of bioactive products and as much as 78% of antimicrobial drugs are extracted from nature. This paper follows the history of progress of antimicrobial drugs, which runs parallel to the history of a man's struggle against the diseases.The golden age of progress of antimicrobial drugs went on between the 1940s and 1970s. Thereafter, there is a gradual decrease in the number of newly discovered antimicrobial drugs. During the time period between 2003 and 2007 only four antibiotics were registered., Conclusion: The current situation in the field of antimicrobial therapy should send off a global alarm .for the creation of a well coordinated, sound and all-encompassing monitoring of the resistance, consumption of antimicrobials and investment in the new trials.

Background: Silver has been used extensively throughout recorded history for a variety of medical purposes., Methods: A review of the literature in English was undertaken, primarily using PUBMED, to identify the medical uses of silver before the clinical introduction of antibiotics in the 1940s., Results: Silver has been used for at least six millennia to prevent microbial infections. It has been effective against almost all organisms tested and has been used to treat numerous infections and noninfectious conditions, sometimes with striking success. Silver also has played an important role in the development of radiology and in improving wound healing., Conclusion: Silver was the most important antimicrobial agent available before the introduction of antibiotics.

In the decade 1935-45 the treatment of lobar pneumonia in the developed and warring world underwent a series of evolutions-anti-sera, specific anti-sera, refinement of sulpha drugs, sulpha and anti-sera, the introduction of penicillin for bacteriology, then ophthalmology, and then for penicillin-sensitive bacterial infections such as lobar pneumonia with its many Cooper types of Streptococcus pneumoniae. Penicillin for civilian use was essentially banned in World War II, a ban that early in 1941 two Musgrave Park physicians tried to circumvent. Strict secrecy on the details of penicillin production was enforced. The treatment option chosen by the Musgrave Park physicians in 1941, and the non-availability of penicillin led to sequelae affecting the post-Belfast careers of both patient and physicians.

In the late Fifties and early Sixties the regulation of food additives represented a remarkable turning point in German consumer politics, establishing a debate about decision making and policy advice, altering the discourse of purity and contamination, and inaugurating a new political actor, the organized critical consumer. The amendment of the Food Law in December 1958 functioned as a negotiation process between representatives of science, industry and the state, which was institutionalized in the Senate Commissions of the German Research Foundation. While these Commissions for preservatives, foreign matter and colorants worked behind closed doors, a public discourse about the "toxic condition" of modern life and the negative role of the pharmaceutical and chemical industry gained strength. The debate about the admission of hexamethylenetetramine (hexa) took part at a crucial moment. Hexa was used as a preservative in the fish industry. But its anti microbial effectiveness was caused by the decomposition of hexa to formaldehyde. Despite the commission's verdict against hexa, the lobbying activities of the industry granted it a reprieve. In the media, the case of hexa was seen as a touchstone for the capacity of negotiated decision making and the ability of rational scientists to resist the demands of industry. Finally, in 1963 it was the new political actor of the organized critical consumer, heir and successor to the housewife federations as well as to "purists" advocating life reform, who, supported by the media, enforced the prohibition of hexa as a preservative.

The 100th anniversary of the Nobel Prize for Medicine to Paul Ehrlich and Elie Metchnikoff gives us a good opportunity to reflect on their research about infectious diseases. Elie Metchnikoff was not only the first to describe phagocytosis of invading pathogens by specialized blood cells - macrophages and neutrophils - he also was interested in the impact of normal flora on well-being and in pre- and probiotic diet and their influence on the normal flora. Paul Ehrlich not only developed the concept of the side-chain theory of antibody formation but also discovered the first chemotherapeutic agent against microbial pathogens through a combination of chemical modification of a lead substance and experimental animal screening on a broad-scale. Hence, they are not only the founders of immunology but also were the first to envisage infection biology as the result of an interplay between host and pathogen.

Among the PELARGONIUM-based herbal remedies that are widely used in traditional medical systems in the Southern African region is a highly valued root medicine (commonly termed UMCKALOABO) of initially unknown botanical origin for the treatment of infectious conditions of the respiratory tract including tuberculosis. Nowadays, a modern aqueous-ethanolic formulation of the roots of Pelargonium sidoides (EPs 7630), developed from this traditional medicine, is successfully employed for the treatment of bronchitis. The article summarizes the fascinating story of this herbal medicine including its way to Europe, identification of the botanical origin, and provides background information of the many profound anti-infectious actions and clinical studies. In spite of considerable effort, the underlying chemical principle is still not clear.

When the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) was established in the mid-1970s, it represented an innovative institutional formula in terms of its structure and the manner in which scientists were convened from both developed and developing countries to address some of the world's most neglected parasitic diseases. A review of TDR's historical record sheds light not only on some important milestones in tropical-disease research, but also on how future challenges could be approached and hopefully surmounted.

Ozone, an allotropic form of oxygen, is successfully used in the treatment of different diseases for more than a hundred years. It is highly valued for various effects, such as antimicrobial, antihypoxic, analgesic, immunostimulating etc. on biological systems. These mechanisms of action supported with a lot of case reports and scientific studies allow using it in different fields of medicine. This review of literature is another attempt to summarize different modalities of ozone application in dentistry. Further studies are necessary to standardize indications and treatment protocols of this promising medical agent.

Background: Acute diarrhoea management has progressed from largely ineffective measures in the early years to a more effective physiologic approach in recent years., Aim: To review the history of acute diarrhoea management., Methods: Citations in PubMed were reviewed on 'acute diarrhoea treatment' along with an extensive file maintained by the corresponding author., Results: Freedom from diarrhoea was equated in early military conflicts with bravery and strength where diarrhoea-free soldiers had the 'guts' to fight. Until early 20th century, colonic irrigants, purgatives and emetic drugs were used to help eliminate undesired intestinal contents. Only a few early authorities suggested the need for replacement of fluids and salt, now standard treatment. Drugs aimed at diarrhoea symptom control have been broadly used for more than 100 years. The evolving history of one of those drugs, kaopectate is unappreciated. Once understanding the pathophysiology and infectious aetiology of acute diarrhoea, new oral fluids, pharmacologic agents designed to block specific secretory alterations and anti-infective drugs have been identified., Conclusions: Physiologic and antimicrobial approaches to controlling diarrhoea can lead to reduction of stool number and enteric complaints, important in industrialized areas, with the potential for decreasing threat of fatal illness among infants in developing regions.

Antimicrobial peptides are among the most ancient effectors of host defense. Intersecting lines of research demonstrate that life forms as diverse as plants, insects, and vertebrates employ antimicrobial peptides to kill or neutralize a wide variety of microbial species. Defensins, of which there are three structural sub-families, constitute a major category of host defense peptides in vertebrates. Presented here is a brief history of the emergence of the defensin field with an emphasis on the role of these peptides in mammalian innate immunity.

In ancient India and Persia surgeons were highly respected and their operating skill with nose plastic and catatact couching is documented. In mediaeval Europe surgery was classified as a handicraft profession and belonged to the barbers guild with the soapcup as symbol, much inferior to the academic trained medical doctors. In war surgery leg amputation after shotwounds demanded great rapidity, since no anestetic but alcohol was available. In the 18th century surgeons becamea accepted as medical doctors e.g. John Hunter in London and OlofAcrel in Stockholm. A great step in the development of surgery was Mortons introduction of eter narcosis 1846. Now surgeons could work carefully without hurry. The next step took Joseph Lister. Born in 1827 he studied medicine in London and then qualified as surgeon at the famous James Syme's clinic in Edinburgh- In 1860 he became professor of surgery in Glasgow. His clinic like all others was afflicted with suppuration, septicemia, erysipelas and gangrene. He happened to read a thesis by Louis Pasteur, who proved that fermentation and putrefaction in wine production were caused by bacteria. Lister saw the similarity with wound suppuration. Carbolic acid was used in wood industri to prevent putrefaction and Lister now introduced this as a mean to cure or prevent suppuration and septicemia. He washed the wound and soaked the bandage with carbolic acid, which he also sprayed in the air of the operation theatre to prevent air carried infection. In 1867 he published his experiences in the Lancet: Out of 11 complicated fractures (where the bone-ends penetrated the skin) 9 healed without complications. Earlier such fractures ended with dead or amputation. The wards were now free from infected wounds. Abroad Listers findings were received with entusiasm, Ernst von Bergmann i Berlin modified the antiseptic method into a aseptic one and sterilized the room, the instruments and clothes and could so avoid the carbolic acid spray, which was irritating for the surgeons breath. Lister applied the aseptic method from 1887. Abdominal and thoracic surgery now became possible and developed rapidly. In England his ideas were accepted with some delay. In 1877 he was appointed professor in London, was made a peer and president of the Royal Society nad was celebrated all over the world. He died 1912, 85 years old.

Artemisinin is currently used for treating drug-resistant malaria. It is found in Artemisia annua and also in A. apiacea and A. lancea. Artemisia annua and A. apiacea were known to the Chinese in antiquity and, since they were easily confused with each other, both provided plant material for the herbal drug qing hao (blue-green hao). This article shows, however, that since at least the eleventh century Chinese scholars recognized the difference between the two species, and advocated the use of A. apiacea, rather than A. annua for 'treating lingering heat in joints and bones' and 'exhaustion due to heat/fevers'. The article furthermore provides a literal translation of the method of preparing qing hao for treating intermittent fever episodes, as advocated by the eminent physician Ge Hong in the fourth century CE. His recommendation was to soak the fresh plant in cold water, wring it out and ingest the expressed juice in its raw state. Both findings may have important practical implications for current traditional usage of the plant as an antimalarial: rather than using the dried leaves of A. annua in warm infusions, it suggests that fresh juice extraction from A. apiacea may improve efficacy.

When Joe Burchenal started studying medicine at the University of Pennsylvania in 1934, antibiotics had not been discovered and the survival of patients diagnosed with acute leukaemia was < 4 months. By the time he retired in 1983, 58% of children with acute lymphoblastic leukaemia survived 5 years with the majority being cured of their disease. His early work in infectious diseases and antimicrobials equipped him well, both clinically and scientifically. The approach to developing antibiotics to conquer previously incurable infection was an inspiration and model for his pioneering work when searching for drugs with activity against cancer. Trials of sequential and then combination chemotherapy followed. Success in treating lymphoid malignancies in children led him to develop treatment regimens for other more resistant cancers, and as an advocate of collaborative working he introduced multimodal therapy to tackle bulky or metastatic cancers, replacing inevitable relapse with a chance of true cure.

Antimicrobial peptides are effectors of innate immunity in phagocytes, body fluids and epithelia. In mammals, defensins, peptides with a characteristic six-cysteine framework, are particularly abundant and widely distributed in various animal species and tissues. The first part of this review provides a historical overview of the ideas that led to the current state-of-the-art in antimicrobial peptides, and the second part is an update on mammalian defensins and their role in host defense to infections.

Born from growing organic chemistry laboratories, dyes were extensively used par textile industry before to be applied in field of biology and therapeutics. Besides their interest for diagnostic techniques due to cell visualization (Virchow, Papanicolaou), dyes allowed scientists to propose scientific hypothesis founding, in conjunction with new microscopy tools, modern basis for biology : tissue constitution, cellular and sub cellular structure, s.o. One of the brightest illustrations of these progresses is the birth of neuronal theory which due to silver print of brain tissue allowed to see intimacy of cerebral structures et propose an operating scheme (Golgi, Cajal). Therapeutic progresses born from dyes chemistry are multiple. First concentrated on the research of antimalarial drugs (Ehrlich) following the use of methylene blue, then generally, anti-infectious drugs, they gave birth to various chimiotherapeutic families: antiseptics, antiparasitic drugs, antibacterial, among which one of the most spectacular illustrations remain sulphonamides preparation.

Tularemia is a complex clinical disorder caused by the ubiquitous intracellular parasite Francisella tularensis, which has many mammalian and insect hosts. The peak observed incidence of tularemia occurred in 1939, and most present-day clinicians have never seen a case of this disease. Tularemia manifests several different clinical syndromes, depending on the portal of entry. F. tularensis has been used in biological warfare experimentation and it has been weaponized and stockpiled in the past by the United States and other countries. It is classified as a category A critical biological agent by the Centers for Disease Control and Prevention. This article reviews the history, clinical features, diagnostic evaluation, and treatment of this organism with an emphasis placed on its potential role as an agent of biological warfare.

The pyrrole alkaloids of the prodigiosin family make up an unusual chapter in the chemistry of natural products. Owing to the characteristic red color of these secondary metabolites, colonies of the Gram-negative-producing bacteria may strikingly resemble droplets of blood. This phenomenon caused considerable confusion in the past and was likely responsible for many seemingly miraculous (prodigious) events. After the eventual transition from superstition to science, the prodigiosins started to attract considerable attention because of their promising physiological properties. Most interesting are the immunosuppressive activities at doses that are not cytotoxic, in particular since in vivo studies suggest that the prodigiosins act synergistically with cyclosporine A or FK 506, which are presently the dominant drugs in clinical immunosuppressive regimens. Furthermore, the chemistry of the closely related and structurally rather unique alkaloid roseophilin is summarized, a cytotoxic agent that recently became the focal point of many innovative total syntheses.