La amenaza silenciosa de las resistencias bacterianas / The silent threat of bacterial resistance

Las resistencias bacterianas a antimicrobianos representan uno de los principales problemas en la actualidad, encontrándose dentro de las principales causas de muerte en todo el mundo. Latinoamérica y Argentina, lejos de ser una excepción,presentan incidencias crecientes de infecciones por gérmenes resistentes. Cada día, se conocen mejor los mecanismos de resistencia que presentan los bacilos gram negativos y algunos cocos positivos. El problema no surge sólo por el sobreuso de antimicrobianos en la medicina clínica. Su sobreutilización para maximizar los beneficios productivos en la pesca, la ganadería y la agricultura contribuyen a esta situación. Desde la perspectiva de la atención primaria de la salud,consideramos fundamental conocer todos los aspectos que forman parte de esta problemática para intentar mitigar el daño que las resistencias bacterianas generan a nivel global. Argentina se transformó en el primer país de la región y del continente en contar con una ley para prevenir y controlar la resistencia a los Antimicrobianos. Consideramos de vital importancia que se fomenten más y mejores políticas sanitarias de orden público para enfrentar este creciente desafío. (AU)

Nowadays, bacterial resistance to antimicrobials is one of the main problems, being one of the leading causes of death worldwide. Latin America and Argentina, far from being an exception, have an increasing incidence of infections by resistant germs. Every day, the resistance mechanisms of gram-negative bacilli and some positive cocci are better known. The problem does not arise only because of the overuse of antimicrobials in clinical medicine. Its overuse to maximize productive benefits in fishing, livestock, and agriculture also contributes to this issue. From the perspective of primary health care,it is essential to know all the aspects of this problem to mitigate the damage that bacterial resistance generates at a global level. Argentina became the first country in the region and the continent to have a law to prevent and control antimicrobial resistance. We consider it vitally important that more and better public health policies are promoted to face this growing challenge. (AU)

Resistencia bacteriana, una crisis actual / Bacterial resistance, a current crisis

La resistencia bacteriana es una constante batalla que representa un problema de Salud Pública. Tan es así que la Organización Mundial de la Salud (OMS) la considera de sus prioridades en salud, debido al impacto que genera tanto en la salud (dado que proyecciones recientes indican que para 2050 se producirán más muertes por esta causa que las ocasionadas actualmente por elcáncer), como a su impacto económico (que, de acuerdo a un estudio reciente en el Reino Unido(1), costará a la economía mundialun estimado de 100 billones de dólares anualmente). La veloz aparición de bacterias multirresistentes y panresistentes es unfenómeno de índole mundial, cuestionando la eficacia antibiótica. Implementar protocolos y recomendaciones es vital, de igualforma que es necesario conciencias al personal sanitario, tomando como base el conocimiento de generación de resistencia y suimpacto a través de los años, potenciado por la actual pandemia de la COVID-19.(AU)

Bacterial resistance is a constant battle representing a Public Health trouble. So much, that the World Health Organization consi-derate Public Health as a priority in health, due to the impact that generates as much as in health (giving that recent projectionsindicate that by 2050 it’ll be produced more deaths because of this than the ones occasioned because of cancer) as its economicimpact (which, according to a recent study in the United Kingdom(1), it’ll cost the world’s economy an estimated of 100 trilliondollars). The quick appearance of multidrug-resistant and pandrug-resistant bacteria is a world nature phenomenon, questioningthe antibiotics efficiency. Implement protocols and recommendations is essential, just as essential and necessary as give aware-ness to health personnel, taking as base the knowledge of resistance generation and its impact through the years, empoweredby the actual pandemic of COVID 19.(AU)

Antibiotics: From the Beginning to the Future: Part 1.

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 History of Biomarkers: How Far Have We Come?

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.

The British Pharmacological Society's WDM Paton Memorial Lecture 2019: How doctors were informed about pharmaceutical products through advertising in the British Medical Journal from 1955/6 to 1985/6.

We have reviewed pharmaceutical advertisements in every available issue of the British Medical Journal (BMJ) in 12-month periods during 1955/6, 1965/6, 1975/6, and 1985/6. We have determined the amount of advertising, the therapeutic areas covered, and whether adverts reflected the large number of New Chemical Entities (NCEs) launched during that time. For each product we recorded the therapeutic indications, the marketing company, and the number of adverts appearing. The total number of products advertised fell from 340 in 1955/6 to 260 in 1965/6, 70 in 1975/6, and 16 in 1985/6. Advertisement numbers and companies advertising also fell. Antimicrobial drugs and cardiovascular drugs were the top products advertised over the 30 years, with respiratory, analgesic, and gastrointestinal drugs also in the top five. The number of different drugs advertised by individual companies fell from around eight per company in 1955/6 to one or two in 1985/6. There was good concordance between the most advertised therapeutic areas and NCEs entering the market. From the 1950s to the 1980s prescribers were extensively informed about pharmacological advances in therapeutics through BMJ advertisements. Many novel drugs that were advertised proved to be of lasting value. The Medicines Act 1968 introduced product licensing, regulations requiring demonstration of quality, efficacy, and safety, and restrictions on advertising. Subsequently many companies reduced their advertising or stopped altogether. Since advertising influences prescribing, and since antimicrobial drugs were the most commonly advertised products during 1955-86, we speculate that advertising, resulting in excess use, may have, at least partly, driven bacterial drug resistance.

A brief history of antibiotics and select advances in their synthesis.

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.

History and Current Use of Antimicrobial Drugs in Veterinary Medicine.

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.

Aspectos sociales, técnicos y económicos relativos a la introducción de la penicilina en España (1944-1959) / Social, technical and economic aspects related to the introduction of penicillin in Spain (1944-1959)

Analizamos el proceso de introducción de la penicilina en España desde varios frentes: los proyectos que conllevaron a su fabricación por empresas nacionales, dentro de la política autárquica trazada por las autoridades españolas durante el franquismo; las solicitudes, por parte de empresas españolas, de patentes de invención concernientes a procesos industriales relacionados con la penicilina; su difusión desde los medios de comunicación, la visión que de ella ofrecen los profesionales del medicamento y la repercusión social que la introducción del producto tuvo en España (AU)

We analyze the process of introduction of penicillin in Spain from several sides: the projects that led to its manufacture by national companies as result of the autarkic policy established during the Franco regime; the requests done by Spanish companies for patents of industrial processes related to penicillin; its dissemination by the media, the view offered by the professionals and the social impact that the product had in Spain (AU)

Re-Inventing Infectious Disease: Antibiotic Resistance and Drug Development at the Bayer Company 1945-80.

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.

Cooperative development of antimicrobials: looking back to look ahead.

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 in the 21st century: a multifaceted challenge.

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 history of antibiotics]. / Historien om antibiotika.

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 antibiotics¼. 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.

[Historical notes on the management of infection during the development of surgery]. / Apuntes históricos sobre el manejo de la infección en el desarrollo de la cirugía.

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.

Apuntes históricos sobre el manejo de la infección en el desarrollo de la cirugía / Historical notes on the management of infection during the development of surgery

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.

La cirugía y la medicina no evolucionaron en forma paralela, con discrepancias, reservas, belicosidad, desprecios e incluso estudios universitarios separados durante bastante tiempo. La Cofradía de San Cosme, fundada en Francia en 1260, para supervigilar el ejercicio profesional quirúrgico de los barberos (cirujanos-barberos de toga corta), tuvo la oposición de la Facultad de Medicina de París. Los intereses contrapuestos de la universidad, Cofradía y Barberos, que persistieron hasta fines del siglo XVIII, perjudicaron el progreso de la cirugía. En la primera mitad del siglo XIX, el avance de la cirugía continuó enfrentándose al dolor, la hemorragia y a la infección. El control de ésta debió pasar por la antisepsia, asepsia y finalmente por la aparición de las sustancias antimicrobianas, sulfamidados y antibióticos, que permitirían a los cirujanos abordar y solucionar problemas de mayor relevancia de la especialidad, curativos y preventivos.