The interweaving roles of mineral and microbiome in shaping the antibacterial activity of archaeological medicinal clays.

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal Earths (MEs), natural aluminosilicate-based substances (largely kaolinite and montmorillonite), have been part of the European pharmacopoeia for well over two millennia; they were used generically as antidotes to 'poison'. AIM OF THE STUDY: To test the antibacterial activity of three Lemnian and three Silesian Earths, medicinal earths in the collection of the Pharmacy Museum of the University of Basel, dating to 16th-18th century and following the methodology outlined in the graphical abstract. To compare them with natural clays of the same composition (reference clays) and synthetic clays (natural clays spiked with elements such as B, Al, Ti and Fe); to assess the parameters which drive antibacterial activity, when present, in each group of samples. MATERIALS AND METHODS: a total of 31 samples are investigated chemically (ICP-MS), mineralogically (both bulk (XRD) and at the nano-sized level (TEM-EDAX)); their organic load (bacterial and fungal) is DNA-sequenced; their bioactivity (MIC60) is tested against Gram-positive, S. aureus and Gram-negative, P. aeruginosa. RESULTS: Reference smectites and kaolinites show no antibacterial activity against the above pathogens. However, the same clays when spiked with B or Al (but not with Ti or Fe) do show antibacterial activity. Of the six MEs, only two are antibacterial against both pathogens. Following DNA sequencing of the bioactive MEs, we show the presence within of a fungal component, Talaromyces sp, a fungus of the family of Trichocomaceae (order Eurotiales), historically associated with Penicillium. Talaromyces is a known producer of the exometabolite bioxanthracene B, and in an earlier publication we have already identified a closely related member of the bioxanthracene group, in association with one of the LE samples examined here. By linking fungus to its exometabolite we suggest that this fungal load may be the key parameter driving antibacterial activity of the MEs. CONCLUSIONS: Antibacterial activity in kaolinite and smectite clays can arise either from spiking natural clays with elements like B and Al, or from an organic (fungal) load found only within some archaeological earths. It cannot be assumed, a priori, that this organic load was acquired randomly and as a result of long-term storage in museum collections. This is because, at least in the case of medicinal Lemnian Earth, there is historical evidence to suggest that the addition of a fungal component may have been deliberate.

Terapia antibacteriana: origen y evolución en el tiempo / Antibacterial therapy: origin and evolution in the time

Desde siempre, el ser humano buscó una explicación a los fenómenos y una solución a sus males. El instinto fue quien primero guió al hombre para buscar remedios con los que aliviar sus males lamiendo o limpiando sus heridas. Mediante el método de "ensayo-error", el hombre prehistórico fue encontrando plantas y sustancias minerales que resultaban eficaces. En la Edad Media y el Mundo Moderno, la medicina Hippocrático-galénica tuvo, en relación a la terapéutica, a Dioscórides como el gran referente Con el decurso de los años, científicos como Pasteur, Koch, Cantani, Emmerich, Low, Tiberio, sentaron las bases para que más tarde otros como Freudenreich, Domagk, Fleming, Waksman, entre otros, descubrieran y perfeccionaran la amplia gama de antibióticos que hoy conocemos. A pesar de estos avances, en la actualidad se observan múltiples mecanismos de resistencia bacteriana que ponen en peligro la eficacia antibiótica (AU).

The human beings have always looked for an explanation to the phenomena and a solution to his misfortunes. Firstly the instinct was what guided the man to look for remedies to alleviate his ills licking or cleaning his wounds. By means of the "trial-error" method, the prehistoric man was finding plants and mineral substances that were effective. In the Middle Ages and the Modern World, the Hippocratic-galenic medicine took Dioscorides as the great referent in relation to therapeutic. As the years went by, scientist like Pasteur, Koch, Cantani, Emmerich, Low, Tiberio, set the bases for Freudenreich, Domagk, Fleming, Waksman among others to discover and improve the wide range antibiotics known today. In spite of these advances, multiple mechanisms of bacterial resistance putting in danger antibiotic effectiveness are observed today (AU).

Antibacterial activity of medicinal plants from The Physicians of Myddvai, a 14th century Welsh medical manuscript.

ETHNOPHARMACOLOGICAL RELEVANCE: Antimicrobial drug resistance is a growing threat to global public health. Historical records and herbal texts relating to traditional Celtic medicine indicate an extensive pharmacopeia of plants for treating infections likely caused by microbes. However, a major barrier for successful integration of these remedies into mainstream practice is the current lack of accurate interpretation and scientific validation. MATERIALS AND METHODS: We investigated the flora of the Isle of Arran, Scotland, via in situ targeted screening of 83 out of 138 plants identified in Meddygion Myddvai (a 14th century Welsh manuscript) to treat conditions related to microbial infections, and an additional 18 plants from modern ethnobotanical knowledge on the island (Scottish School of Herbal Medicine). In a follow-up proof-of-concept study, bioassay-guided fractionation was performed to identify bioactive constituents from two high scoring hits that inhibited Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative) bacterial growth. RESULTS: 67 historical plants (80.7%) and 14 modern plants (77.8%) were found to have detectable levels of antimicrobial activity when tested using Mobile Discovery kits, with human saliva as a source of bacteria for screening. Sabinene, a natural bicyclic monoterpene from juniper "berries" (Juniperus communis L.) and alliin, a natural sulfoxide from garlic cloves (Allium sativum L.), were isolated and confirmed as primary antibacterial leads. CONCLUSION: Using historical medical sources such as those associated with traditional Celtic medicine to guide rigorous, evidence-based scientific investigation, provides additional leads for new and alternative bioactive molecules for combating bacterial diseases.

A introduçao da penicilina nos hospitais da universidade de Coimbra, Portugal (1944-1946) / The introduction of penicilin in Coimbra university hospitals, Portugal (1944-1946)

A importação regular de penicilina para Portugal iniciou-se em Setembro de 1944 através da Cruz Vermelha Portuguesa. Até Junho de 1945 a importação e distribuição do medicamento foram controladas por esta instituição humanitária mas a partir desta data, com o aumento da produção mundial, a penicilina começou a ser importada por intermédio da indústria farmacêutica. No Arquivo da Universidade de Coimbra consultamos papeletas (processos individuais) de doentes internados nos Hospitais da Universidade de Coimbra desde Setembro de 1944 até Agosto de 1946. A investigação realizada permitiu-nos recolher informações sobre a introdução da penicilina e sobre os primeiros tratamentos efetuados com o medicamento nestes hospitais. Com base nos dados recolhidos pretendemos, pelo presente artigo, mostrar como foi feita a receção da penicilina num hospital central de grande dimensão, um dos principais hospitais portugueses, saber a frequência com que era prescrita, as patologias mais comuns em que era empregue, as doses administradas, a posologia e o tempo de tratamento assim como os clínicos responsáveis pela sua prescrição (AU)

The Portuguese Red Cross began to import of penicillin regularly following September 1944. Until June 1945, the humanitarian institution controlled the distribution of the antibiotic, subsequently, due to the increase in world production penicillin began to be imported by means of the pharmaceutical industry. We consulted and analyzed files of patients admitted to Coimbra University Hospitals between September 1944 and August 1946. These files, located in Coimbra University Archive, enabled us to collect information on the introduction of penicillin and on the first cases treated with the antibiotic at these hospitals. In the present paper, we aim to shed some light upon how penicillin was received in one of the main Portuguese central hospitals, the frequency with which it was prescribed, the most common diseases in which the antibiotic was utilized, the dosage administrated, the length of the treatment and the physicians responsible for prescribing the antibiotic (AU)

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A 1,000-Year-Old Antimicrobial Remedy with Antistaphylococcal Activity.

UNLABELLED: Plant-derived compounds and other natural substances are a rich potential source of compounds that kill or attenuate pathogens that are resistant to current antibiotics. Medieval societies used a range of these natural substances to treat conditions clearly recognizable to the modern eye as microbial infections, and there has been much debate over the likely efficacy of these treatments. Our interdisciplinary team, comprising researchers from both sciences and humanities, identified and reconstructed a potential remedy for Staphylococcus aureus infection from a 10th century Anglo-Saxon leechbook. The remedy repeatedly killed established S. aureus biofilms in an in vitro model of soft tissue infection and killed methicillin-resistant S. aureus (MRSA) in a mouse chronic wound model. While the remedy contained several ingredients that are individually known to have some antibacterial activity, full efficacy required the combined action of several ingredients, highlighting the scholarship of premodern doctors and the potential of ancient texts as a source of new antimicrobial agents. IMPORTANCE: While the antibiotic potential of some materials used in historical medicine has been demonstrated, empirical tests of entire remedies are scarce. This is an important omission, because the efficacy of "ancientbiotics" could rely on the combined activity of their various ingredients. This would lead us to underestimate their efficacy and, by extension, the scholarship of premodern doctors. It could also help us to understand why some natural compounds that show antibacterial promise in the laboratory fail to yield positive results in clinical trials. We have reconstructed a 1,000-year-old remedy which kills the bacteria it was designed to treat and have shown that this activity relies on the combined activity of several antimicrobial ingredients. Our results highlight (i) the scholarship and rational methodology of premodern medical professionals and (ii) the untapped potential of premodern remedies for yielding novel therapeutics at a time when new antibiotics are desperately needed.

Fevered Decisions: Race, Ethics, and Clinical Vulnerability in the Malarial Treatment of Neurosyphilis, 1922-1953.

Physicians deliberately inoculated marginalized patients with malaria, using them as reservoirs to facilitate malarial fever therapy for syphilitic patients. The history presents ethical questions in an evolving historical context.

Historic perspective: prebiotics, probiotics, and other alternatives to antibiotics.

Applications of antimicrobials in food production and human health have found favor throughout human history. Antibiotic applications in agricultural and human medical arenas have resulted in tremendous increases in food animal production and historically unprecedented gains in human health protection. Successes attributed to widespread antibiotic use have been accompanied by the inadvertent emergence of antibiotic-resistant bacteria. A major problem associated with this emerging resistance is the crossover use of some antibiotics in agricultural settings as well as in the prevention and treatment of human disease. This outcome led to calls to restrict the use of human health-related antibiotics in food animal production. Calls for restricted antibiotic use have heightened existing searches for alternatives to antibiotics that give similar or enhanced production qualities as highly reliable as the antibiotics currently provided to food animals. Agricultural and scientific advances, mainly within the last 100 yr, have given us insights into sources, structures, and actions of materials that have found widespread application in our modern world. The purpose of this presentation is to provide a historic perspective on the search for what are generally known as antibiotics and alternative antimicrobials, probiotics, prebiotics, bacteriophages, bacteriocins, and phytotherapeutics.

Fred Loe, MD, and the history of trachoma.

Trachoma has been one of the most blinding diseases in the history of ophthalmology. From its initial description in antiquity until the late 1930s, no specific treatment or effective cure had been known, and the only expedient had been to destroy the diseased tissue containing the infectious agent, rendering the disease inactive. Virtually all medical, mechanical, and surgical treatments were unsatisfactory, with cure rates of approximately 20%. Therapy for trachoma had barely advanced from the measures used by the ancient Egyptian, Greek, and Roman physicians. All prior therapies became obsolete in 1938 when Fred Loe, MD, working on an American Indian reservation, introduced sulfanilamide as a treatment of trachoma, achieving a 90% cure rate. One of the most unusual aspects of Loe's career was that he had no formal training in ophthalmology and was completely self-taught as an ophthalmologist.

Screening antibiotics: industrial research by CEPA and Merck in the 1950s.

This article is an account of a screening programme in search of new antibiotics established by CEPA (Comparñia Española de Penicilinas y Antibióticos) and Merck in Madrid in 1954. An exploration of the genealogy for such a programme, its narratives and practices, shows that the main inspiration for this programme was the factory system of production, on the one hand, and Selman Waksman's research agenda on microorganisms of the soil, on the other. In this article, the relationship between industrial production of antibiotics and the research program aimed at identifying new candidate drugs is examined. I suggest that this screening program in search of new antibiotics was organised like industrial manufacturing. The research objects and tools came, both materially and conceptually, from industrial production: a line of artisanship put together in order to obtain a product with the collaboration of every member of the production line. Following the style developed by Selman Waksman in Rutgers, the screening program evaluated samples manually, and the microbiological skills were enhanced with every test. The Madrid team's practice of applying instructions for use led to circulation of knowledge and practices, including research material and microbiological methods.

Historical perspectives in critical care medicine: blood transfusion, intravenous fluids, inotropes/vasopressors, and antibiotics.

Significant progress in critical care medicine has been the result of tireless observation, dedicated research, and well-timed serendipity. This article provides a historical perspective for four meaningful therapies in critical care medicine: blood transfusion, fluid resuscitation, vasopressor/inotropic support, and antibiotics. For each therapy, key discoveries and events that have shaped medical history and helped define current practice are discussed. Prominent medical and social pressures that have catalyzed research and innovation in each domain are also addressed, as well as current and future challenges.

Antibacterial discovery and development--the failure of success?

A combination of approaches and compounds-many of which failed to yield immediate results in the past-will ultimately prove invaluable to the drug industry in the ongoing battle against infectious disease.

Observations on the history of the development of antimicrobials and their use in poultry feeds.

Antimicrobials are powerful tools, but controversy and conflict often follow power. The development of antimicrobials was marked by personal attacks, political intrigue, internal conflicts, and lawsuits. Such controversy and conflict has continued. The early history of supplementing animal feeds with antimicrobials parallels the isolation and identification of vitamin B12. Vitamin B12 was isolated and characterized in 1948, but further research showed that several feed ingredients, including dried mycelia of certain fungi, were more potent as growth promoters in the diet of chicks than was vitamin B12 alone. The growth-promoting component in fungal mycelia was shown to have antimicrobial activity. A total of 32 antimicrobial compounds are approved for use in broiler feeds in the U.S. without a veterinary prescription. Fifteen compounds are listed for treatment of coccidiosis, 11 are listed as growth promotants, and six are listed for other purposes. Seven compounds are also used in human medicine. These compounds include bacitracin, chlotetracycline, erythromycin, lincomycin, novobiocin, oxytetracycline, and penicillin. No published estimates of antimicrobial use in animals exist at present, and estimates of that use differ markedly. The Union of Concerned Scientists (UCS) estimates usage at 30.6 million pounds, nearly 50% (49.85%) higher than the Animal Health Institute (AHI) estimate of 20.42 million pounds. AHI surveyed their members (the manufacturers of antimicrobials) to obtain their estimates, whereas USC calculated their estimates using published data and the following general formula: antimicrobial use = number of animals treated x average days treated x average dose.

Historical perspective on the use of otic antimicrobial agents.

Treatment of otorrhea has been described in the literature since 1500 BC. A multitude of therapeutic options have been described, including the use of astringents, antiseptics, alcohol, benzoin and various powders. Since the middle of the 20th century, antibiotic usage has been promoted as the most effective means of therapy. Until recently none of the agents that were used was found to be safe for middle ear use. Since 1990 there have been publications describing the safety and efficacy of fluoroquinolone drops for acute and chronic otorrhea. This article details the transition from treatment of otorrhea with nonspecific means to an era of antimicrobial therapy based on sound scientific evidence.

Medicinals for the millennia: the historical record.

Nature has been a source of medicinal agents for thousands of years, and an impressive number of modern drugs have been isolated from natural sources, many based on their use in traditional medicine. The use of herbal drugs is once more escalating in the form of complementary and alternative medicine. The past century, however, has seen an increasing role played by microorganisms in the production of the antibiotics and other drugs for the treatment of some serious diseases. With less than 1% of the microbial world currently known, advances in procedures for microbial cultivation and the extraction of nucleic acids from environmental samples from soil and marine habitats, and from symbiotic and endophytic microbes associated with terrestrial and marine macro-organisms, will provide access to a vast untapped reservoir of genetic and metabolic diversity. By use of combinatorial chemical and biosynthetic technology, novel natural product leads will be optimized on the basis of their biological activities to yield effective chemotherapeutic and other bioactive agents.

[From the history of wound care]. / Aus der Geschichte der Wundbehandlung.

Wound care in ancient times was based on many techniques: Bandages soaked with antibiotics, Sutures continuous or in separate stitches, apply of poultices around the wounds, honey and propolis as antibiotics in the treatment of wounds, surgical drainage of pus with a piece of tin pipe etc. The oldest wound clamp is shown with the jaws of ants holding together the edges of a wound. Finally are discussed the cauterization and the principles of Antisepsis and Asepsis.