gms | German Medical Science

GMS Hygiene and Infection Control

Deutsche Gesellschaft für Krankenhaushygiene (DGKH)

ISSN 2196-5226

From antiseptics to antibiotics – and back?

Von der Antiseptik zur Antibiotik – und zurück?

Original Contribution

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  • corresponding author Ojan Assadian - Clinical Department for Hospital Hygiene, Clinical Institute for Hygiene and Microbiology of the Medical University of Vienna, General Hospital of Vienna, Austria

GMS Krankenhaushyg Interdiszip 2007;2(1):Doc26

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/journals/dgkh/2007-2/dgkh000059.shtml

Veröffentlicht: 13. September 2007

© 2007 Assadian.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Abstract

There is no straight line to trace the trajectory of antiseptics; rather, this has been manifested more as a fluctuating line, a backwards and forwards movement, seen in the wake of major discoveries but of colossal mistakes too. While today no one would allow their prophylactic policies to be guided by miasma or contagia, there continues to be some uncertainly about how to manage anti-infectives effectively even today.

When in 1941 the first human being was successfully treated with penicillin, interest in antiseptics gradually waned. From that time onwards, everything was treated with antibiotics, unleashing a race for the discovery of novel antibiotics, as witnessed decades earlier in the case of antiseptics. The significance of antiseptics declined to such an extent that among physicians they were associated merely with cleaning agents or sanitary disinfection. Today, at the beginning of the 21st century we know that the euphoria generated by antibiotics was just another station along the pathway of discoveries. Bacterial infections and new, hitherto unknown infectious diseases continue to play a major role. Several viral infections continue to be refractory to successful treatment and bacterial antibiotic resistance has become a problem worldwide. The most effective countermeasures no longer entail only the development of new antibiotics but above all responsible management of antibiotics and strict observance of infection control measures in the hospital setting. Set against that background, interest in antiseptics has been rekindled. In that spirit we can look eagerly forward over the coming years to further developments in antisepsis.

Zusammenfassung

Es ist keine gerade Linie, die die Entwicklung der Antiseptik kennzeichnet, sondern wohl eher ein Auf und Ab, ein Hin und Her, eine Folge großer Erkenntnisse und ebenso großer Irrtümer. Niemand würde heute mehr sein Handeln an “Miasmen“ oder „Contagien“ ausrichten, wenn es um die Infektionsprophylaxe geht, wirklich sicher ist man sich aber auch heute noch nicht immer im Verständnis und Umgang mit Antiinfektiva.

Als 1941 der erste Mensch erfolgreich mit Penicillin behandelt wurde, nahm das Interesse an Antiseptika sukzessive ab. Fortan wurde alles mit Antibiotika behandelt und ähnlich wie Jahrzehnte zuvor bei Antiseptika, setzte ein Rennen um die Entdeckung von neuen Antibiotika ein. Antiseptika rutschen so sehr in ihrer Bedeutung ab, dass sie unter Medizinern lediglich mit Putzmittel oder Sanitärdesinfektion assoziiert wurden. Heute, zu Beginn des 21. Jhd. wissen wir, dass die Antibiotika-Euphorie auch nur eine Zwischenstufe in der Erkenntnishirarchie war. Bakterielle Infektionen und neue, bisher unbekannte Infektionskrankheiten spielen eine unverändert große Rolle. Viele Virusinfektionen entziehen sich nach wie vor einer erfolgreichen Behandlung und die bakterielle Antibiotikaresistenz hat sich zu einem weltweiten Problem entwickelt. Zu den wirksamen Gegenmaßnahmen gehören heute wieder nicht nur die Entwicklung neuer Antibiotika, sondern vor allem das verantwortungsvolle Umgehen damit und die strikte Beachtung krankenhaushygienischer Maßnahmen. Das Interesse an Antiseptika ist dafür wieder neu belebt. In diesem Sinne können wir in den nächsten Jahren mit Spannung auf die Weiterentwicklung der Antiseptik blicken.


Text

Professor Josef Nowak, chairman of the newly introduced professorship for infection control in Vienna in 1881 wrote the following sentence in this publication, the very first Austrian Textbook for Infection Control (Lehrbuch der Hygiene): “One of the most important aims of infection control research is to ascertain the causes of infectious diseases and to identify means and ways to prevent or attenuate them.”

His summary of the prevailing perceptions of the causes of infectious diseases cast the deep-seated and controversially discussed views held at that time into sharp relief: “Since from the divergent opinions expressed above, it must be concluded that to date it has not been possible to classify the causes of diseases and infectious diseases in the light of the latest research, we have no choice at present but to continue to content ourselves with the designations miasma and contagium.”

In particular, perceptions of the causes of infectious diseases had fundamental implications for the ways and means used to combat such infectious diseases. During the Middle Ages people were of the opinion that the quality of well water was one of the chief determinants of whether or not epidemics were going to take place. Hence at that time it was only logical to conclude that a well that had previously supplied safe water could become toxic only if it had first been poisoned. And of course all too soon scapegoats were pinpointed, against whom the common anger could be unleashed. But once the anger had been appeased, the epidemics continued.

Later, it was believed that dangerous vapors in the air were the cause of epidemics and infirmity. But the publications by Louis Pasteur marked the first steps on the scientific and systematic pathways that would eventually prove decisive for the major breakthroughs in the prevention and treatment of infectious diseases.

After reading Pasteur’s germ theory in 1865, Sir Joseph Lister concluded that if infections were caused by microorganisms then the most effective way to prevent postsurgical wound infections was to kill these microorganisms before they could reach the open wound. In pursuit of this, Lister did not opt for heat or filtration as Pasteur had done; rather, he decided to use a chemical antiseptic in the form of carbolic acid which had already been used elsewhere for disinfection. In his book “Antiseptic Principle of the Practice of Surgery”, published in 1867, Lister described the use of carbolic acid as follows “The material which I have employed is carbolic or phenic acid, a volatile organic compound, which appears to exercise a peculiar destructive influence upon low forms of life, and hence is the most powerful antiseptic with which we are at present acquainted.”

Following this, Lister incorporated the strict implementation of antisepsis into hospital routine activities. Such measures included, in particular, antiseptic handwashing with carbolic solutions, instrument disinfection and the use of wound dressings impregnated in carbolic acid, albeit they also included the vaporization of carbolic acid into the ambient air. Despite the fact that the latter procedures posed risks not only to the person implementing them but also to the patients, they soon became widespread practice worldwide thanks to their enormous success, while ensuring that Lister’s teachings of antiseptic surgery became renowned in Europe and the USA.

On a purely speculative note, one wonders to what extent Lister based his method solely on the contagium theory or to what degree belief in miasmatic causes continued to play a role. While disinfection of hands, instruments and wounds continue to be important right up to the present day, albeit using other substances rather than carbolic acid, vaporization of carbolic acid is probably the most ineffective, but most hazardous, method of infection prevention. Although Lister puts forward arguments claiming that this measure is in complete harmony with his initial perceptions of preventing the introduction of low life forms into the wound already at the outset, in other publications he admits that the “bad air” in itself can cause disease.

But Lister’s association with preventive antisepsis remains undisputed up to the present day. However, this impression reflects only part of the total potential application spectrum of antiseptics, bearing in mind that Lister, himself, had successfully used antiseptics for treatment of existing infections.

Once antiseptics began to become established as an important factor despite scientific disputes, it was not surprising that in the aftermath of their discovery a hectic search was launched for more antiseptics. Indeed, some of the proposals and formulations put forward were so highly adventurous that Otto Nägeli could not resist issuing the following warning: “For some people the fact that something is a poison is justification enough to justify its use as a disinfectant. How it works and the amount of it needed for a particular effect is something to which no one has devoted any thought. There are disinfectant formulations that give the experienced researcher the impression, such as for example the opinion of a semi-educated person, he could kill himself with a bitter almond since it contains cyanic acid”. This quotation from Nägel can be extrapolated without any significant modification to a whole range of what are known today as novel antiinfective products.

A recurring protagonist in these endeavors is silver. Since early times silver-containing compounds have been used in medicine, with silver-based formulations enjoying a sharp upswing in popularity in the late 19th century. Around 1940 well over 4 dozen different silver preparations were being offered on the market as oral, injectable or topical preparations for treatment of all infectious diseases known. These had impressive names, e.g. Albargin, Argonin, Argyn, Argyrol, Largin, Lunosol, Novargan, Proganol, Electrargol or Silvol. Some of these products differed considerably from each other; some consisted of colloidal silver, others of colloidal silver salt compounds, while others were not used at all in colloidal form but rather in solid form. The silver content ranged from minimal concentrations up to a 30% silver content of the entire weight. Accordingly, there were also marked differences in their effectiveness and side effects depending on the manufacturing conditions, galenics, preparation, age and quality of ingredients. However, none of these products were as effective as silver nitrate or silver acetate, which continued to be used successfully up till the recent past in several countries in the form of Crede’s prophylaxis for prevention of neonatal ophthalmia. In the meantime, other substances are being used today for this indication too, due to the cytotoxic side effects well known to midwives as chemical conjunctivitis. Noteworthy here is the trajectory via the initial use of antibiotics back to antiseptics again for this indication in the form of 1.25% povidone-iodine.

It is most fortuitous that the antiseptic principle came on the scene precisely at a time when the first inroads were being made into bacteriology. Up till then, virtually none of the important microbes was known. It was only as from the mid1870s when more and more bacteria were being discovered that it was possible to conduct experiments to investigate the effects exerted by certain substances on these bacteria. Soon it was noted that a range of substances exerted an inhibitory, or even in some cases a lethal, effect on different microorganisms. These agents proved effective only in certain concentrations and only when they were in very close contact with microorganisms. Likewise, soon it could not be overlooked that regardless of how successful a substance had proved to be in certain cases, it could not be assumed that it would generate a microbicidal effect in other cases too. For example, Buchholz in Vienna published the results of experiments that revealed that the following substances in certain concentrations were able to prevent bacterial growth in a nutrient liquid: sublimate in a dilution of 1:20000, thymol 1:2000, benzoic acid, sodium hydroxide solution 1:2000, creosote 1:1000, benzoic acid 1:1,000, salicyl acid 1:666, carbolic acid 1:200, quinine 1:200, alcohol 1:50, chlorine 1:25000, sulfurous acid 1:666,and vapors of nitric acid 1:666.

According to Nowak, of the aforementioned “disinfectants” only very few could be used in practice due to toxicity or high cost; these were carbolic acid, sulfurous acid and chlorine.

The investigations carried out by Robert Koch at the Imperial Health Office played a trailblazing role. In addition to other substances, Koch also investigated the effects mediated by carbolic acid and was able to demonstrate that in its conventional 2% dilution it had no effect on anthrax spores. Only a 4%, or better a 5%, carbolic solution reliably killed the spores. But the spores had to be exposed to the carbolic acid for a long time to achieve these results. If the items to be disinfected were merely sprinkled, sprayed, washed or wetted in another way, all viable bacteria were not killed even after repeating this test on ten occasions, making Koch realize that any form of disinfection conducted in this manner would prove unreliable. In other experiments he was able to demonstrate that carbolic acid dissolved in oil or alcohol did not have the slightest disinfectant effect. Using the same method as for carbolic acid, further experiments were conducted with sulfurous acid and with zinc chlorine, which among other things had been recommended as one of the most effective disinfectants in the 1870s. The outcome of all these tests was none of the disinfectants in whose use much confidence had been hitherto vested was able to meet the requirements now addressed by bacteriology to such agents. Koch stressed that it was not enough to destroy the living forms of bacteria; rather, what was important was to render unviable the spores which were much more resistant. He then turned his attention to other methods with the hope of discovering more reliable forms of disinfection. What a fateful interpretation by one of the real key players of bacteriology! Apart from his subsequent misinterpretation of being able to use tuberculin as a remedy against tuberculosis, Koch drew his second incorrect conclusion in the demands he addressed to antisepsis. While by placing the emphasis on spores, he made a significant contribution to spurring on the development of sterilization processes, without which asepsis would not at all have been possible, ongoing trends in antisepsis damaged Koch’s new line of research at least to a certain extent and for some time.

Oddly enough present-day research into antisepsis consists of, among other things, conducting simple microbiological tests in a systematic manner, which a heavyweight like Koch would no doubt have carried out himself were he to place the main emphasis of his activities on preventive and therapeutic aspects of antisepsis, while excluding the effects exerted on spores. Apart from the “spores’ gap“, a shortcoming that can be imputed to many if not all antiseptics, already in the early 20th century there was a need for “antiseptics“ that could be also introduced into the bloodstream so as to inactivate pathogens in body regions that could not be accessed with the available substances.

Koch offered some insights into what was possible in 1906 when during his Africa expedition he detected the favorable effects exerted by atoxyl (natrium-4-aminophenylhydrogenarsonate) on sleeping sickness. However, Koch did not pursue this line of research since non-toxic doses exerted only a slight effect.

Nonetheless, this reference helped to draw Paul Ehrlich’s attention to atoxyl, who, however, recognized that pentavalent arsenic compounds exerted only a weak in vitro effect against microbes, thus concluding that it was only within the human organism that the substance was converted into the actually active substance. Hence Ehrlich concentrated his attention on the quest for a “magic pill”, on trivalent arsenic compounds. In 1909 salvarsan (preparation 606, dioxy-diamino-arsenobenzol-dihydrochloride) was developed by Ehrlich and Sahachiro Hata and was available on the market already as from 1910. However, since the substance was so toxic that it could be injected intravenously only at most every 7 days while taking utmost precautions, the quest continued for products with better tolerability profiles.

This vision lent momentum to the working activities of the Scottish physician Alexander Flemming carried out in London during the 1920s. To begin with, Flemming investigated human tear fluid and discovered to his amazement that this was capable of killing bacteria. Flemming called the ingredients responsible for this “lysozyme“. But his expectations were soon to be undermined by further investigations. It soon emerged that while lysozyme was able to destroy bacteria, it could kill only those that in principle were harmless to humans. None of the bacteria known at that time to be pathogenic were even remotely affected by lysozyme, not to speak of being killed by it.

Thanks to the now most famous bacteriological error, contamination of a staphylococci culture with Penicillium chrysogenum, Flemming made an amazing discovery in 1928. Penicillin was (re-) discovered. Since already back in 1897 Ernest Duchesne working at the Ecole du Service de Santé Militaire de Lyon defended the views expressed in his doctorial thesis “Contribution à l’étude de la concurrence vitale chez les micro-organismes: antagonisme entre les moisissures et les microbes“ (A contribution to the study of the vital competition among microorganisms: antagonism between moulds and microbes), by giving a detailed account of the bactericidal activity of Penicillium glaucum. His work elicited little attention and was soon forgotten again.

Years were to go by before Howard Florey and Ernst Chain succeeded in producing penicillin as a pure substance. When in 1941 the first human being was successfully treated (with an antibiotic), interest in antiseptics gradually waned. From that time onwards, everything was treated with antibiotics, unleashing a race for the discovery of novel antibiotics, as witnessed decades earlier in the case of antiseptics.

The significance of antiseptics declined to such an extent that among physicians they were associated merely with cleaning agents or sanitary disinfection. For many decades, courage, a robust character, farsightedness and vision were needed to take on the topic of antiseptics. Accordingly, even today compared with antibiotics there is a paucity of literature explaining the principle of action, application fields and potential interactions of antiseptics with other substances.

After many years of euphoria, Sir Macfarlane Burnet wrote towards the end of the 1960s that infectious diseases would be largely eradicated by the close of the 20th century. Today, at the beginning of the 21st century we know that this optimistic view has proved to be incorrect. Bacterial infections and new, hitherto unknown infectious diseases continue to play a major role. Several viral infections continue to be refractory to successful treatment and bacterial antibiotic resistance has become a problem worldwide. Furthermore, the competition between bacteria and antibiotics now appears to be slanted in favor of the bacteria on reaching an economic plateau. The most effective countermeasures no longer entail the development of new antibiotics but above all responsible management of antibiotics and strict observance of infection control measures in the hospital setting. Dennis Maki summed up the situation in a succinct manner: “The development of new antibiotics without having mechanisms to endure their appropriate use is much like supplying your alcoholic patients with a finer brandy!”

Even though antiseptics were temporarily overshadowed by antibiotics, the broad spectrum and non-critical use of antiseptics helped to draw attention to new and serious problems. Since we can now clearly foresee the limitations of antibiotics, it is not surprising that interest in antiseptics is being rekindled. Deployed for prophylactic or therapeutic purposes, antisepsis can inactivate or impede the growth of microorganisms. Potential application sites coincide with the portals of entry of microbes or of manifest infection foci on the body surface (skin, mucosa, wounds), in body cavities (punctures, catheters) and with surgically exposed or opened areas. Tailored to the different application sites, skin, mucosal and wound antiseptics are available.

One hundred and thirty years later we return to Professor Josef Nowak: “One of the most important aims of infection control research is to ascertain the causes of infectious diseases and to identify means and ways to prevent or attenuate them.” In this spirit we can look eagerly forward over the coming years to further developments in antisepsis.

Of imminent importance and as the basis for further concrete research and development, clarification of the definitions used hitherto is needed first of all. Today, we find ourselves in a situation where it is becoming increasingly more difficult to clearly and concisely distinguish between terms such as antibiotic, antiseptic, chemotherapeutic, biocide, disinfectant or antiinfective. Development of new substances, new fields of application and the discovery of new pathogens cause obfuscation of the terms used hitherto. To avoid confusing ourselves, our students and patients in the future our nomenclature must be brought into line with new developments while reaching a broad consensus.


Curriculum Vitae

a.o. Univ.-Prof. Dr. med. Ojan Assadian

Figure 1 [Fig. 1]

DTM&H (London)
Specialist for Hygiene and Microbiology
Assistant Director of the Clinical Department for Hospital Hygiene, Clinical Institute for Hygiene and Microbiology of the Medical University of Vienna, General Hospital of Vienna – University Clinic Centres

Study visits to Thailand and London (recessed education in diagnostics and therapy of tropical diseases) and Australia, further special educations a.o. antibiotics therapy, differential diagnosis of infection diseases, clinical and experimental microbiology. In 2004 he habilitated at the Vienna University, venia legendi on the subjects of hygiene and microbiology.

Called member of the Scientific Educational Council of the Kammerlander-WFI Wound Management Consulting, regular reviewer of the Critical Care Medicine (IF: 3,486), Infection Control and Hospital Epidemiology (IF: 2,620) and Artificial Intelligence in Medicine (IF: 1,474)