International Journal of Antimicrobial Agents 23 (2004) 209–212

Commentary

Antibiotic resistance from two perspectives: man and microbe

J.M.T. Hamilton-Miller∗

Department of Medical Microbiology, Royal Free and University College Medical School, Royal Free Campus, London NW3 2PF, UK

Abstract

Despite much effort, antibiotic resistance continues to increase. Looking back, it is clear that this was an inevitable consequence of antibioticuse. From a bacterial viewpoint, the introduction of antibiotics was a tremendous stimulus to evolution. As a survival reaction to stress (selectionpressure) bacteria, by means of their extreme biochemical and genetic versatility, have adapted to 21st Century conditions. Resistance can beto some extent contained by less and better use of antibiotics, but ultimately novel approaches to the treatment and prevention of infectiousdiseases will have to be forthcoming. This will only be achieved if best use is made of alternative resources presently available and mostimportantly, man’s ingenuity must be fully engaged.© 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Keywords:Antibiotic resistance; Selection pressure; Alternatives to antibiotics

1. Introduction

The problem of bacterial resistance to antibiotics has beenaddressed in literally thousands of scientific articles duringthe past decade. A Medline search using keywords drugresistance and antibiotic resistance gave 12,260 hits for theperiod January 1996–March 2003, with the mean annual rateof publication increasing year by year.

2. Bacterial resistance to antibiotics

2.1. A brief history

Looking back over more than 40 years’ involvement withantibiotics, the surprising thing is that it appears to havecome as such a surprise to many workers that resistancearose to such an extent as to become serious. Perhaps theassumption was that new antibiotics would continue to ap-pear as if by magic, thus extending permanently the ‘goldenage’ of the 1960s–1980s (‘we are overwhelmed as it is, withan infinite abundance of vaunted medicaments, and herethey add a new one’—Thomas Sydenham MD 1624–1689);perhaps there was naivety in underestimating the extremeversatility of bacteria (‘micro-organisms can do anything,

∗ Tel.: +44-20-7940500; fax:+44-20-74359694.E-mail address:j.hamilton-miller@rfc.ucl.ac.uk

(J.M.T. Hamilton-Miller).

micro-organisms are cleverer than chemists’—David Perl-man, 1980); perhaps there was just a state of denial (‘thestaphylococcus is beaten’—Sir Ernst Chain, Nobel Laure-ate, during a lecture given shortly after the introduction ofmethicillin, c.1962). Whatever the reason, it should havebeen clear from the outset of the antibiotic era that resis-tance was not only possible but inevitable. The messagesfrom history were plain to read: as early as 1887 Kossiakoffhad shown thatBacillus subtilisand other bacteria couldadapt to boric acid and 2 years later Abbott reported resis-tance to HgCl2 in Staphylococcus aureus[1]. The Father ofChemotherapy, Paul Ehrlich, realising that resistance mightprove an obstacle to successful chemotherapy, suggested in1908 an avoidance strategy involving hitting the pathogenwith a high dose for the shortest time and using two ormore drugs with different modes of action. The start of theantibiotic era was followed by the acquisition of resistancesoon after the introductions of, respectively, sulphonamidesby the gonococcus, streptomycin byMycobacterium tuber-culosisand penicillin byS. aureus. This situation moved LPGarrod to write in his Kettle Memorial Lecture for 1950 ‘sofar the supply of new antibiotics has more than matched thecapacity of bacteria to resist them, but if this supply shouldcease—and presumably the number yet to be discovered islimited—the time may come when a few of the more enter-prising species will flourish more or less unhindered’. Thescenario had deteriorated further by the late 1950s, by whichtime the phage type 80/81 hospital staphylococcus had be-come resistant to all the antibiotics in common use at that

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210 J.M.T. Hamilton-Miller / International Journal of Antimicrobial Agents 23 (2004) 209–212

time (penicillin, sulphonamides, tetracycline, streptomycinand erythromycin), the situation being saved in the nick oftime by the introduction of methicillin in 1961.

2.2. Resistance today

Thus, the writing was already firmly on the wall as the‘golden era’ dawned, and should have been heeded, butlike a Greek Tragedy the inevitable happened, and we areconsequently now faced with an uphill struggle to maintaintherapeutic supremacy over pathogenic bacteria. Reversingexisting levels of resistance by conventional means appearsto be extremely difficult if not impossible. While thereare many measures that should in theory reduce antibioticuse—the prime driver of resistance emergence—when putinto practice, while they may succeed briefly in this lim-ited primary objective (and thus save money), the mainobjective—reducing resistance rates—has been broughtabout only very rarely[2,3]. While we must persist withsuch obvious objectives as using antibiotics rationally (inthe context of medicine, veterinary practice and all formsof agriculture), Infection Control and education at all lev-els, control of resistance is not possible without a furtherunderstanding of the basic biological processes involved.

It seems to me that we have been guilty of reductionism(definition: the doctrine that a system can be fully under-stood in terms of its isolated parts) in looking at the questionof how to address the matter of resistance. We have failedover the years to consider first all the component parts ofthe problem, and second to integrate them into an interac-tive whole, i.e. to adopt a holistic approach. We have inves-tigated the problem from the points of view of the doctor,the patient, the public and the antibiotic, but have almostentirely neglected the aspect of the other main player, thebacterium. It is my intention here to enlarge upon a previoustheme[4], and to try to view antibiotic use and its effectsfrom the viewpoint of a bacterium.

2.3. Resistance from the point of view of a bacterium

The introduction of antibiotics was initially a disaster forbacteria, as it created a highly stressful situation. The imper-ative to react to this stress became literally a matter of lifeand death. All earthly systems, be they living or inanimate,have the capacity to react to stress in a such a way as toreduce that stress; this concept was first put forward by theFrench chemist Le Chatelier in 1884. Thus, a chemical reac-tion where a diminution in volume occurs (as in the classicHaber–Bosch synthesis of ammonia) will proceed faster ifpressure is applied, humans produce adrenaline in the clas-sic ‘fight or flight’ situation, and bacteria make heat shockprotein when the temperature rises, and show the stringentresponse if starved of aminoacids. In the case under con-sideration, antibiotics caused stress by applying selectionpressure and the reaction of bacteria, in order to reduce theapplied stress, was to acquire resistance. The extent of the

stress is difficult to overestimate: combining some simpleassumptions as to antibiotic production, the total number ofbacteria carried by the world’s population and the molecu-lar weight of the average antibiotic, I calculated some yearsago [5] that every bacterium associated with man has en-countered about 1011 molecules of antibiotic.

The generation time of many pathogenic bacteria is, un-der favourable circumstances, about 20 min, that is approx-imately 500,000 times faster than that of man (about 20years). Thus, a bacterium of the pre-antibiotic era (say 70years ago) bears the same evolutionary relationship to itspresent day counterpart as does modern man to Dryopithe-cus, the common ancestor of man and apes, that lived some30 million years ago[5]. Added to this, one should considerthe amazing biochemical versatility of bacteria. For exam-ple, different genera can:

• survive for thousands of years as spores;• grow at extremes of temperature—0◦C for psychrophiles,

100◦C for thermophiles;• tolerate extremes of pH—0 forAcetobacter, >9 forVibrio

cholerae;• tolerate extremes of osmolarity—some halophiles can

grow in 20–30% NaCl;• tolerate high radiation levels—Deinococcus radiodurans;• utilise substances toxic to man and animals—H2S, NH3,

CO, methanol;• use penicillins as a sole source of C and N—Burkholderia

cepacia, Pseudomonas fluorescens.

Combine these extraordinary properties with a life stylethat involves frequent and promiscuous exchange of ge-netic material and it seems clear that, from a bacterial pointof view, acquiring resistance to antibiotics must be a rela-tively simple matter. However, not all species have provedequally adept at evolving. There is a clear hierarchy, the up-per echelons of which can be described in general terms,with apologies to William Shakespeare, as ‘Some bacteriaare born great (P. aeruginosa), some acquire greatness (M.tuberculosiswith one-step mutation to high level resistanceto rifampicin or streptomycin), some have greatness thrustupon them (receipt of R-factor)’. The introduction of an-tibiotics may have started as a catastrophe for bacteria, butit has ended as a powerful evolutionary lever, fitting manypathogens for survival in the 21st Century. For some species,indeed, it has been a blessing—who would have predicted 30years ago that the humbleAcinetobacterwould, by virtue ofacquiring multiple resistance, deservedly achieve the soubri-quet ‘the Gram-negative MRSA’?

Finally, it should not be forgotten that some species havethrived without having had to acquire resistance—for exam-ple, Streptococcus pyogenesremains a common pathogendespite being still fully sensitive to penicillin, the an-tibiotic of choice for its treatment for the past 50 years.This shows that there is more to bacterial survival underantibiotic-induced stress than the acquisition and spread ofresistance.

J.M.T. Hamilton-Miller / International Journal of Antimicrobial Agents 23 (2004) 209–212 211

3. Can we hope to contain resistance?

It should be plain from the above considerations that re-sistance cannot be prevented and that all we can do is to at-tempt to modulate its progress; what we have observed overthe past 70 years is the Darwinian concept of ‘survival ofthe fittest’ being acted out—in a way, we have been privi-leged to have been able to watch evolution in progress. Asstated above, much has been written about possible ways inwhich resistance may be tackled practically. The search fornew targets for antimicrobial agents through scrutiny of bac-terial genomes has not yet born fruit, and the longer successis delayed the more unlikely it is to occur.

3.1. Reducing antibiotic use

The only practical option we have at present to stem thetide is by reducing antibiotic use; conventional wisdom hasit that this might be achieved by reducing numbers of in-fections by Infection Control, immunisation, public healthmeasures at both individual and societal levels, curbing ofhigh risk behaviour and eradication of world poverty. Whereantibiotics have to be used, ‘use less, less better’ should bethe theme; possible interventions include refining of dosageregimens, targeting, improving compliance, restricting pro-phylaxis to where it is of proven value, continuing educationof the profession and the public and reduction of excessiveusage outside medical and veterinary practice. Less conven-tional approaches might involve application of better under-standing of immunomodulating agents[6,7] and advancesin chronobiology[8,9].

3.2. Alternatives to antibiotics

A separate approach to reducing antibiotic use is to bearin mind possible alternatives to antibiotics. Some of theseideas are as follows:

• Immunotherapy for staphylococcal infections has beenwidely used in Russia[10].

• Phage therapy is attracting increasing attention[11,12].• The discovery that bacteria contain the apparatus to bring

about apoptosis perhaps points to novel targets[13].• ‘Bacteriotherapy’, best recognised as the use of probi-

otics, has been commended inThe British Medical Jour-nal [14]. Probiotics have been reported to be effective ina remarkably wide variety of clinical conditions, by nomeans restricted to the intestinal tract.

• Attacking virulence mechanisms rather than the wholebacterial structure offers a wide range of possibilities. Agreat attraction of this type of approach is that it seemsless likely to apply selection pressure. Targets that havebeen investigated include receptor sites[15], P-fimbriae[16], sortases[17], quorum sensing signals[18], Shigatoxin [19] and staphylococcal enterotoxin B[20].

• The use of therapies derived from complementary andalternative medicine (CAM). These are very widely used

by the general public, a fact now recognised by The WorldHealth Organisation, who in 2002 launched its first globalstrategy on CAM. The world market is estimated to beworth at least US$ 60 billion annually and a recent studyfound that up to 70% of US Residents had used someform of CAM [21]. It would be unwise of the medicaland scientific communities to ignore these facts[22]. Twosubstances that would seem worth exploiting more fullyin infectious disease are manuka honey[23] and tea treeoil [24].

4. Can we reverse resistance?

The strategies mentioned above have been devised inorder to reduce antibiotic use thereby, we hope, tending todecrease the rate of emergence of resistance. Reduced selec-tion pressure should have this effect, but to go further andactually bring about a decline in the incidence of resistancerequires more radical measures, as many resistant bacteriaseem to be as fit as their sensitive counterparts[25]. Certainlines of research offer some optimism that this could beachieved:

• Blocking of a known, existing resistance mechanismwill convert resistance to sensitivity. This has been welldemonstrated in the case of certain�-lactamases byclavulanate, sulbactam and tazobactam. A similar type ofapproach is offered by the action of the tea componentepicatechin gallate on methicillin-resistantS. aureus,whereby production of PBP2’ is suppressed and sen-sitivity to methicillin regained[26]. Inhibition of theefflux pumps that confer resistance to tetracycline, flu-oroquinolones and other antibiotics, with consequentreversal of resistance, has been reported[27].

• Components of tea have also been shown to prevent de-velopment of antibiotic resistance in vitro[28] by exertingan anti-mutagenic effect.

• The antibiotic flavophospholipol (also known as flavomy-cin, bambermycin and moenomycin) inhibits the transferof conjugative R plasmids, both in vitro[29] and in ani-mal feeding experiments[30]. The tea component epigal-locatechin gallate had a similar effect in vitro[31].

• A surprisingly neglected finding[32] is that the antimalar-ial quinacrine preferentially killed bacteria containing Rplasmids.

5. Conclusions

Some authorities have seriously suggested the end of theantibiotic era[33], but although resistance rates continueinexorably to creep upwards this seems unnecessarily pes-simistic in the short term. However versatile bacteria may be,they are pitted against an apparatus of enormous complexityand power, namely the human brain. When antibiotics do

212 J.M.T. Hamilton-Miller / International Journal of Antimicrobial Agents 23 (2004) 209–212

eventually, as seems inevitable, fail to offer therapeutic effi-cacy against agents of infectious disease, I feel confident thatalternative measures will have been found as the result ofhuman ingenuity. For if we do not succeed in this endeavournot only will the rate of progress of medical advances be setback, but we will have failed the giants, such as Erhlich, Do-magk, Waksman, Florey and Fleming who made possible thechemotherapeutic era.

Acknowledgements

I am most grateful to Professor David Greenwood for hisadvice about studies of resistance in the 19th Century.

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