Walter Marget and a brief history of paediatric infectious diseases in Munich, Germany

Theodor Escherich (1857–1911) was one of the key players in early paediatric infectious diseases (PID). In fact, he can be regarded as the first paediatric infectious diseases physician and the founder of this subspecialty. During his long years in service for children, he spent 6 years at the Dr von Hauner children’s hospital (1884–1890), laying the foundations for PID clinical care and research in Munich. Walter Marget, founder of this journal and co-founder of the German Society for Infectious Diseases (DGI) graduated from medical school in 1946 and practised in Munich since 1967. His tireless efforts went into establishing close links between clinical paediatrics and microbiological diagnostics culminating in the foundation of the Department of Antimicrobial Therapy and Infection Epidemiology at the Dr von Hauner children’s hospital. Walter Marget was a key figure for PID in Germany having trained and supported many clinician scientists who followed in his footsteps. This article gives a brief overview of the history of PID in Munich while commemorating Walter Marget and his achievements in this field and for INFECTION.

"Marantic Thrombosinusitis in Cholera Infantum"). He met with Rudolf Emmerich from Munich in 1884 and spent 2 weeks as his scientific assistant investigating the large cholera epidemic in Naples, Italy. He used his newly acquired knowledge in bacteriology to find Vibrio cholerae in stool samples of victims of this epidemic. Since the discipline of paediatrics was yet in its infant stages in Germany at that time, Escherich travelled to Vienna, Austria, to learn from the famous Hermann von Widerhofer , the first Chair of Pediatrics at the University of Vienna, today considered to have been the first "Ordinarius" of the Diseases of Childhood. During this time, he decided to devote his career to child health and began his first bacteriologic investigations of the intestinal microbiological flora of neonates as well as breast milk samples-of what can be today considered as the beginning of microbiome research.
From 1884 he spent a full 6 years at the Dr von Hauner children's hospital. During these years, he obtained his habilitation [the post-doctoral qualification and licence to lecture in Germany's universities]. His main area of research covered the normal bacterial flora of the neonatal gastrointestinal tract and its changes after birth, the physiology of digestion and the role of bacteria involved and, finally, characterization of the interdependence of these 1 3 findings to neonatal disease. Escherich developed close collaborative bonds with the Max von Pettenkofer hygienic institute and Otto Bollinger's microbiology laboratory where he got more and more familiar with the developing techniques of bacteriology specializing in the characterization of microorganisms. Eventually he isolated almost 20 different bacteria from infant stool samples including various bacilli and cocci. Notably the most important outcome of his works can be considered the detailed descriptions of what he called the Bacterium coli commune (today known as Escherichia coli) and the Bacterium lactis aerogenes (known to us as Klebsiella pneumoniae). He was the first paediatrician who took a sincere research and clinical interest in infectious diseases and the study of the normal gastrointestinal flora, today called the gut "microbiome". In July 1885, Escherich presented the results of his studies on the Bacterium coli commune to the Society of Morphology and Physiology in Munich. In 1886 his habilitation thesis "The Intestinal Bacteria of the Infant and Their Relation to the Physiology of Digestion" was published [3]. An English version of this manuscript was reprinted in Reviews of Infectious Diseases in 1988 and 1989 [4,5].
Escherich himself might have been very impressed by the pivotal role of E. coli as prototypical bacterium used in the development of modern molecular biology. At least 10 Nobel prizes have been awarded to scientists for their work on different aspects of E. coli biology [1].
Based on these studies and his dedicated service to children and young people, he was regarded as the foremost expert in bacteriology in paediatrics [2]. From 1887, he was a lecturer in Paediatric at the Ludwig-Maximilians-University in Munich, balancing clinical and scientific activities with amazing accuracy and dedication. In 1890, Escherich moved to Austria where he continued his studies and clinical activities in Graz (1890Graz ( -1902 and Vienna (1902Vienna ( -1911 where he succeeded Hermann von Widerhofer as Chair of Paediatrics at the University of Vienna and Director of the St. Anna Children's Hospital in Vienna, the most prestigious European position in paediatrics at that time. Those years were spent with a great variety of activities where Escherich demonstrated extraordinary leadership, vision and enthusiasm mirrored in structural developments and modernization as well as the establishment of key services such as the training of nurses in infant care and in providing nursing care to children with tuberculosis or founding the infant welfare society (Säuglingsschutz) as well as the foundation of several scientific societies and the construction of the Imperial Institute for Maternal and Infant Care supported by Emperor Franz Joseph of Austria. It is fair to state that he was well ahead of his time, a true pioneer, in continuously working towards raising awareness about social welfare of children, thus being a great example on multiple levels for us today.
Being an outstanding teacher, clinician and researcher Escherich attracted many brilliant and talented students, such as Meinhard von Pfaundler  or Ernst Moro (1874-1951) who both practised in Munich at the Ludwig-Maximilians-University (LMU) from 1907 and 1906, respectively. He continued to serve the welfare of children until he eventually passed away in Vienna in 1911.
Nine years later, Walter Marget (1920-2013) was born in Stuttgart, Germany. He began his medical studies in 1939 with periods spent in Innsbruck, Vienna and Heidelberg. Due to the turmoil of World War II, it took until 1946 until he was able to complete his medical studies and to start a specialisation in microbiology and hospital hygiene in Heidelberg, culminating in his medical thesis in 1951. His key interest in clinical paediatrics led him to the university children's hospital in Freiburg where he specialised in paediatrics and put an enormous effort into the establishment of an in-house microbiology laboratory focussed on paediatric infectious diseases. He was a pioneer in this area and the very laboratory still exists today. This activity of structurally and educationally combining clinical paediatrics and microbiology can be highlighted as a hallmark of his professional activity throughout his active years.
His dedicated scientific work focussed on the exploration of nosocomial Staphylococcus aureus infections in neonatal units with a specific focus on infection control and the thorough investigation and elucidation of transmission events. Making use of the relatively new method of lysotyping, the characterization of different bacterial species by bacteriophage standards [6], he was one of the very first clinical researchers to publish evidence on the reservoir of those pathogens as well as the line of transmission events, results that he published in his habilitation in 1961. In 1962, Marget followed Prof Klaus Betke to Tubingen where he also established a microbiology laboratory in the Children´s hospital, and subsequently moved to Munich in 1967, following Prof. Betke who was appointed as Physician in Chief at the Dr von Hauner Children´s Hospital. Here again, his effort went into establishing close links between clinical paediatrics and microbiological diagnostics mirrored in the establishment of a diagnostic microbiological laboratory and the foundation of the Department of Antimicrobial Therapy and Infection Epidemiology, still existing today. One of Marget's particular academic interests in later life were the mechanisms of host-defence and specific role that endotoxins, the lipopolysaccharides of Gram-negative bacteria, play in causing clinical disease. His multiple research activities are demonstrated in hundreds of scientific publications and many contributions to medical text books.
Besides his various clinical and academic activities Walter Marget was a great teacher and spent much time and effort on education of students and younger clinicians and researchers. In addition, he founded this very scientific journal, INFECTION, in 1973, a jubilee celebrated in this special edition. INFECTION has since succeeded in becoming one of the leading European journals for Infectious Diseases and clinical microbiology, also serving as the official organ of the German Society for Infectious Diseases (DGI, https:// www. dgi-net. de/) that Marget co-founded.
Marget's educational efforts are also mirrored in him being a co-founder of the European Society for Paediatric Infectious Diseases (ESPID, https:// www. espid. org) in 1983 in Munich. Today this scientific society has successfully connected researchers from around the world in joint collaborative efforts in both the clinical and scientific area. ESPID today counts a total of > 1600 members and commemorates Walter Marget by holding an educational workshop at each annual meeting called the Walter-Marget-Educational-Workshop. Finally, Marget supervised over a hundred MD / PhD students and numerous post-doctoral works.
The long tradition of paediatric infectious diseases at the Dr von Hauner Children´s hospital is also a testament of Walter Marget being a great mentor. Several of his coworkers were influenced by him and went on to become important members of the Infectious Disease community in Germany, reflecting in their chosen fields the wide-ranging interests and curiosity of Marget. The following paragraphs as well as Table 1 intend to acknowledge a selection of them.
Dieter Adam studied medicine and pharmacy and received a doctorate in both fields. From 1983 to 2001 he served as head of the Department of Antimicrobial Therapy and Infection Epidemiology at the University Children's Hospital in Munich, succeeding Walter Marget. Adam, who is still an active member of the scientific community today, pioneered pharmacological studies and helped to elucidate pharmacokinetics and pharmacodynamics of antimicrobials. He served as president of the Paul Ehrlich Society for Chemotherapy from 1982 to 1986 and as president of the Bernd Belohradsky succeeded Dieter Adam as head of the Department of Antimicrobial Therapy and Infection Epidemiology. His clinical and scientific focus, most likely encouraged by Walter Marget, was laid on inborn and acquired immunodeficiencies, an important and newly emerging field at that time. Belohradsky established the Immunodeficiency Outpatient Clinics (Immundefektambulanz, IDA) still an important specialty service in our days for children with rare genetically mediated immunological diseases as well as acquired immunodeficiency, such as an HIV infection.
Currently the legacy of paediatric infectious diseases at the Dr von Hauner children's hospital is carried on by two authors of this manuscript, Johannes Huebner and Ulrich von Both. One major joint clinical and research area of these clinician scientists revolves around antimicrobial resistance and the implementation of antibiotic stewardship (ABS) interventions. Since 2015, an ABS team consisting of paediatric ID physicians, pharmacists and supporting scientists has been established at the children's hospital and been actively growing ever since. Until today many junior doctors have been trained in ABS and infectious diseases of childhood following an educational curriculum. Research Since the time of Theodor Escherich, paediatric infectious disease specialists at the Dr von Hauner Children's Hospital have been pioneers exploring new areas of infectious diseases research and medical care (Fig. 1). From the first description the Bacterium coli commune and the beginning of microbiome research via the implementation of close links between clinical paediatrics and microbiological diagnostics and an in-depth exploration of fundamental principles and their practical implications of hospital hygiene to a current innovative telemedical approach to broaden the scope of antibiotic stewardship service to paediatric patients in Germany-this pioneering journey is ever continuing at the Dr von Hauner Children's hospital and its PID department once established by the founding father of the INFEC-TION journal: Walter Marget.
Author contributions UvB and JH drafted the concept of the manuscript. UvB wrote the first draft and both UvB and JH modified text and figures in a revision process. DA critically reviewed and complemented text and figures. All authors have read the final version of the manuscript and are thus responsible for its content. There are no conflicts of interest to be declared.
Funding Open Access funding enabled and organized by Projekt DEAL.
Data availability Not Applicable.

Conflict of interest The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. E. coli / gut microbiome: The normal gastrointesƟnal flora is highly complex with 500 to 1000 different species in one individual, many of these are non-culturable with standard techniques. New-borns iniƟally do not have in individual gut microflora but subsequently acquire bacteria during their first months of life, primarily from their mothers and their environment. T. Escherich was the first clinician scienƟst to systemaƟcally study gut flora of children during their first years of life and correlate the individual composiƟon of this flora to health and disease. Recently, this field has received parƟcular interest since the advent of genomic analysis. The complex gut microflora and its relaƟon to disease is now a rapidly growing area of microbiome research.
InfecƟon journal: The Journal "InfecƟon" was founded by Walter Marget in 1973 because he realized that infecƟous diseases as a medical field in Germany needs its own scienƟfic plaƞorm. While publishing in infecƟous diseases was (and sƟll is) dominated by Anglo-American publicaƟons, "InfecƟon" presented the possibility for German (and European) infecƟous diseases physicians to publish their results and observaƟons, evaluated predominantly by their European peers. From the very beginning, the journal aimed to cover a broad range of topics that were close to Marget´s interests, such as pharmacology, paediatric and adult infecƟons, clinical microbiology as well as infecƟon control and hospital epidemiology. The successful development that the journal has demonstrated since and its growing significance in the field of internaƟonal journals is a testament to Walter Marget's vision.

Hospital Hygiene & InfecƟon Control:
Early studies in outbreak control, related to S. aureus in new-born nurseries and elucidaƟon of transmission by phage typing paved the way for the field of infecƟon control and hospital hygiene. Nowadays, no hospital can care for paƟents without carefully monitoring infecƟon rates, surveillance of specific mulƟ-resistant bacteria, and established cleaning and disinfecƟon procedures, regularly monitored by specialist personnel, such as infecƟon control pracƟƟoners and hospital epidemiologists. While many of these procedures involve toxic compounds (i.e. disinfectants) and lead to considerable addiƟonal waste (disposable gowns, masks, gloves etc.) it is important to carefully evaluate these to minimize environmental harm without endangering paƟents and personnel.
PharmacokineƟcs / pharmacodynamics: Measuring concentraƟons of anƟbioƟcs in different compartments and understanding the kineƟcs of these drugs has always been an important part of infecƟous disease treatments. Nowadays this is reflected by the requirement of anƟbioƟc stewardship to include hospital pharmacists, and therapeuƟc drug monitoring is an essenƟal part of the treatment of complicated infecƟons in high-risk paƟents.

AnƟbioƟc Stewardship (ABS):
The conƟnuous and worrying increase in mulƟresistant pathogens worldwide has been shown to be predominantly due to uncriƟcal and excessive use of anƟbioƟcs. As many as 30-50% of anƟbioƟc prescripƟons are not jusƟfied. UncriƟcal use involves prescribing anƟmicrobials with a spectrum that is too broad, treatment duraƟons longer than required, incorrect dosing as well as administraƟon of anƟbioƟcs in the absence of bacterial infecƟon. ABS refers to mulƟ-level programs monitoring anƟbioƟc treatments, guiding medical decision on the bed-site by opƟmizing raƟonal anƟbioƟc use. An ever-increasing number of specific educaƟonal courses are now available and ABS teams should eventually be established in all hospitals.