EDITORIAL

Chemotherapy: yesterday, today and tomorrow

The title of this Editorial is taken from the paperdelivered by Sir Alexander Fleming, First President ofthe Society for General Microbiology, in 1946 andreprinted1 in 1995 to mark the Society's 50thanniversary. The year, 1946, was one of great hopeand enthusiasm. The Second World War had justended and great advances were being made in thedevelopment of medicine. The antibiotics, penicillin inparticular, that had been discovered by Fleming re-presented one of the most exciting areas of develop-ment. Penicillin had been of vital importance in thetreatment of war wounded and its availability hadbeen strictly restricted as supplies were quite limited.Fleming said that soon penicillin would be on sale inchemists' shops and hoped that it would not be abusedas had been the sulphonamides, to which resistancehad developed following their widespread use.

It is now 70 years since Fleming's observation ofthe interaction between Penicillin notatum andstaphylococci which led to the subsequent puri®ca-tion of penicillin. The antibiotic era which followedhas lasted 50 years and we have come to expect thatthe great majority of bacterial infections will be easilycured both in human and veterinary medicine.Antibiotics are often administered as a matter ofcourse. If the animal recovers, we take the credit forhaving used an appropriate treatment. If it does not,we often assume that there is antibiotic resistance andchange the antibiotic. There is no doubt that in manycases an antibiotic is not required or has little e�ecton the outcome of the case. But does it matter? Afterall, one could argue that it is safer to give anantibiotic than to risk infection.

The answer to this question is that it does matter.Modern epidemiological evidence on the develop-ment and spread of antibiotic resistance shows that amajor factor determining its emergence and intensityis the resistance selection density2,3 which is de®nedas follows:

selection density=amount of antibiotic per indivi-dual per geographical area

Use of antibiotics selects for resistant bacteria andeliminates susceptible organisms. The e�ect is im-portant not only on the pathogens but also on non-pathogens which contribute to the diversity of theecosystem and the natural balance between suscep-tible and resistant strains. Provided that the originalsusceptible bacteria survive or are available torepopulate the treated individual from other sources,the selection process will be reversible. The ecologicalchallenge which tends to eliminate the resistantorganisms comes from a range of di�erent competing

bacteria. If these have been eliminated or if exposureto antibiotics continues then the resistant organismswill persist. The more antibiotics administered andthe longer the exposure, the greater the damage to thenormal ecosystem. Eventually a point may be reachedwhere the ecology of the treated animal is so changedthat the original ¯ora cannot recover. This e�ectextends beyond the treated animal ± hence therelationship between selection density and totalantibiotic use in a particular geographical area. Thetreatment e�ect extends over all forms of antibioticuse including human medicine, veterinary medicineand the use of antibiotics for industrial purposesincluding growth promotion.

The resistance depends on the genetics of thebacteria. Mutants arising with enhanced antibioticresistance are selected and proliferate but resistancecan also be transferred by the exchange of resistancegenes using a variety of mechanisms. Resistance isinduced by antibiotic exposure in both pathogens andnonpathogens and can be transferred rapidly notonly within the same genus and species but alsobetween genera. Thus elimination of the pathogendoes not necessarily eliminate the antibiotic resis-tance. Worse, plasmids may carry episomes posses-sing several resistance determinants and enablingsimultaneous transmission of multiple resistance.Such episomes may also encode systems whichpromote their own conjugative transmission and themobilization of other plasmids. Here the organismhas adapted its biology to take advantage ofantibiotic treatment and promote its survival in avery e�ective manner. Repeated antibiotic therapyeliminates competing bacteria and selects for in-creased ability to resist and transfer resistance to awidening range of antibiotics. Worryingly, transfer ofresistance to antiseptics including chlorhexidine is agrowing problem and hence the e�ectiveness ofchemical disinfection procedures are also at risk.

This is the situation with the methicillin-resistantStaphylococcus aureus (MRSA) which is now begin-ning to be recognized in both small and large animalveterinary practice as it migrates from infectedhuman populations. Isolates are commonly resistantto all available antibiotics with the exception ofvancomycin, and the appearance of vancomycin-resistant strains is now being recognized. At the sametime, discovery of new antibiotic classes has virtuallyceased and there is little hope that we will developnew wonder drugs to deal with this threat. It ispossible that we are just entering the post-antibioticera. The menace to human medicine poses a specialthreat to veterinary use of antibiotics and it is already

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being suggested that our employment of these drugsshould be greatly curtailed to reduce antibioticselection density. Dermatological use of antibioticsrepresents one of the biggest markets for these drugsin the veterinary ®eld. Curtailment thus represents aparticular threat to our discipline. The threat fromthe MRSA may seem quite distant at present and wecan comfort ourselves that the major pathogen insmall animal dermatological practice, Staphylococcusintermedius, has shown little propensity to developresistance to much used antibiotics, such as oxacillin,coamoxyclav and cephalexin. Nevertheless, it be-hoves us to take care with our use of these precioussubstances. Alexander Fleming expressed the view in1946 that there was `probably no chemotherapeuticdrug to which in suitable circumstances the bacteriacannot react in some way by acquiring `fastness'. Wemust ensure that we do not provide Staphylococcus

intermedius with circumstances which may enable itto become `fast'.

D. H. Lloyd

REFERENCES

1. Fleming, A. Chemotherapy. yesterday, today andtomorrow. The Linacre Lecture, May 6th 1946.

Reprinted in: Hunter, P.A., Darby, G.K., Russell,N.J., eds. Fifty Years of Antimicrobials: PastPerspectives and Future Trends. Cambridge: Cambridge

University Press, 1995: 1±18.2. Levy, S.B. Antibiotic resistance: an ecological

imbalance. In: Chadwick, D.J., Goode, J., eds.Antibiotic Resistance: Origins, Evolution, Selection and

Spread. Chichester: John Wiley & Sons, 1997: 1±9.3. Chadwick, D.J., Goode, J., eds. Antibiotic Resistance:

Origins, Evolution, Selection and Spread. Chichester:

John Wiley & Sons, 1997.

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