dh_4047165_the path of least resistance synopsis)

8/6/2019 Dh_4047165_the Path of Least Resistance Synopsis)

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1 INTRODUCTION

In July 1997, the Chief Medical Officer asked the Stand ing Med ical

Advisory Comm ittee (SMAC) to examine the issue of antimicrobial resistance

in relation to medical prescribing. SMAC responded by setting up an inter-

disciplinary Sub-Group with th e following Terms of Reference:

BOX 1. TERMS O F REFERENCE

In the light of the increasing clinical importance of resistance to antimicrobial

dru gs, to:

q identify the major and emerging problems of antimicrobial resistance in

clinical practice

q identify clinical practices that may predispose to the development of

resistance

q identify practices in antimicrobial use that might help to limit the

development and spread of resistance

q identify priorities for changing practice in the use of antimicrobial agents

q advise on how such changes might most effectively be achieved for both

professionals and the pu blic

Membership of the Sub-Group includ ed cross-representation from the Standing

Advisory Committees for Dentistry, Pharmacy, Nursing and Midwifery an d

consumer, veterinary m edicine and phar maceutical industry representation.

The main rep ort, of which this is the synop sis, reviews the problem at

several levels:

Case-studies explore day-to-day antimicrobial prescribing problems faced by

doctors.

The b asis and impact of resistance are reviewed. Aspects of antimicrobial use

and misuse that exacerbate resistance are identified, together with strategies to

conserve the usefulness of antimicrobial agents.

Recommend ations are made . These recognise that the decisions concerning

antimicrobial prescribing are often complex, and are as m uch abou t minimising

harm as about maximising benefit.

Introduction 3


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Methods for implementation of the recommendations are reviewed. The

Report d oes not claim to add ress all the issues, or to make recommend ations

that will solve all the problems associated with antimicrobial use. Nevertheless,

key areas are identified w here innovative app roaches may lessen a p roblem

that affects us all.

This Synopsis presents the k ey points from the main Report. It follows the

same section n umb ering as the main Report to ease cross-referral. The main

Report also contains a fu ll set of references and a glossary of terms.

In introdu cing th e Report, it may be helpful to d raw attention to specific

features that distinguish antimicrobial therapy from all other forms of

medicinal treatment.

FIRST The majority of the population will take antimicrobial agents at

some time or other in their lives. Apart from simple analgesics,

no other drugs are in such widespread use.

SECOND The efficacy of an antim icrobial in any ind ividu al patient is

affected by its previous use in other individu als, which mayhave selected for resistance to the d rug. This does not ap ply to an y other k ind

of medicine: taking a d rug to lower blood pressure in the w rong d ose, or

unnecessarily, may be deleterious for that individual, but it will not affect the

efficacy of the m edication for others.

THIRD There is probably no other area of prescribing in which

patients expectations, and doctors perceptions of those

expectations, play such a role in determining w hether or not to p rescribe.

Any strategy to red uce unn ecessary prescribing cannot be targeted only at

professionals. It must also address the needs of the consumer for clear

information about the risks and benefits of antimicrobial agents and about th ecircumstances in which it is appropriate for the doctor notto prescribe.

FOURTH Resistance is a natural evolutionary result of exposing

microbes to antimicrobials. Arealistic expectation would be

that redu cing inapp ropriate prescribing would p revent the situation

deteriora ting fur ther. While certain clinical prescribing practices exacerbate the

development of resistance, it is much less clear that changing those practices

4 The Path of Least Resistance


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will achieve a decline in the p revalence of resistance. Unrealistic expectations

should n ot be generated by the recommend ations in this Report.

FIFTH The part played by veterinary pr escribing in the d evelopmen t

of antimicrobial resistance in h um an p athogens is importan t

with some (although not all) pathogens. This is the subject of review by the

Governm ents Advisory Com mittee on the Microbiological Safety of Food.

Debate over the relative contributions of med ical and veterinary prescribing to

the development of antimicrobial resistance in hum an p athogens mu st not be

allowed to delay the implementation of initiatives to improve clinical

prescribing practices.

SIXTH The use of antimicrobials as animal growth prom oters is

distinct from veterinary p rescribing an d is not p erformed

un der v eterinary su pervision. Its role in the selection of resistance is a major

concern, especially its potential to genera te resistance to antibiotics wh ich are

under development for use in humans.

SEVENTH It is importan t to recognise that ou r best efforts, in this country,to minimise resistance may be frustrated by a lack of

comparable initiatives abroad. Some early and demonstrable successes in

modifying clinical prescribing practice in the UK may provide a helpful model

for others.

FINALLY Good antimicrobial prescribing will have other beneficial

effects in pa rticular, a reduction in th e incidence of adverse

effects. Adverse effects are always unwelcome, but an adverse event arising

from an u nnecessary p rescription is doubly so.

The recommen dations in th is Report are directed towards en suring that b est

practice in antimicrobial prescribing becomes routine practice. This will

require a willingness, on the part of health care professionals and th e pu blic

alike, to treat antimicrobials as a valuable and non-renewable resource, to be

treasured and conserved in everyones interest.

Introduction 5


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2 RECOMMENDATIONS

There is a huge literature on an timicrobial resistance in relation to clinical

prescribing. Not all of it is sound ly evidence-based and many fundam ental

questions have not been add ressed. Hence, the Sub-Group h as not attempted

to prod uce an exhau stive set of recommen dations for minimising th e

developm ent of antimicrobial resistance in every clinical situation.

Rather, since the aim of this Report is to make a genu ine difference, wehave taken the p ragmatic approach of concentrating on recomm endations

where the pay-back in terms of potential benefit seems to us, on the evidence

currently available, likely to be greatest. Thus, we have concentrated on

recommend ations related to prescribing for the most common ly encountered

conditions and on prop osals for developing sup port systems that help

prescribers make evidence-based d ecisions and which involve patients an d

carers in the decision-making process.

In the light of research on behavioural change, the Report p roposes a

co-ordinated app roach with various incentives ranging from edu cational

program mes, through organisational changes, to financial inducements to

indu stry. The recommendations are pr esented in a framework wh ich is

add ressed to p olicy and d ecision makers including ind ustry and to

prescribers and the pu blic. Within th at framework, there are recommendations

aimed at helping general medical practitioners (who undertake 80% of all

antimicrobial prescribing) make a real difference to the development of

resistance, by optimising their own prescribing practices.

PRESCRIBING IN THE COMMUNITY

Patients with minor infections mostly present to general practitioners (GPs);

consequen tly, 80% of UK hu man antim icrobial prescribing is in the comm un ity.

This Report, therefore, concentrates on community prescribing ofantimicrobials. We recommen d that there should be a national Camp aign on

Antibiotic Treatmen t (CAT) in primary care on the theme of Four things you

can do t o m ake a difference.



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BOX 2. FOUR THIN GS YOU CAN D O:

q no prescribing of antibiotics for simple coughs and colds

q no p rescribing of antibiotics for viral sore throats

q limit prescribing for uncomplicated cystitis to three days in otherwise fit

women

q limit prescribing of antibiotics over the telephone to exceptional

cases

In making recommen dations aimed at influencing doctors prescribing

habits, we acknowledge the importance and influence of patients expectations

and deman ds on the d ecision-making process. We see these as two sides of the

same coin; modifying patients expectations, through a process of public

edu cation, will make it easier for GPs to adhere to the recommend ations.

Hence, we recommen d that the CAT mu st be matched by a National Advice to

the Pu blic (NAP) campaign aimed at sup porting the initiative in primary care.

A key feature of the NAP campaign shou ld be to highlight the benefits of

cherishing and preserving your normal bacterial flora.

We recommen d that further sup port for app ropriate prescribing in primary

care be provided by developing and promu lgating evidence-based national

guidelines for the management of certain infections, under the aegis of the

National Institute for Clinical Excellence. Guid elines wou ld aim to m inimise

unn ecessary antimicrobial use, and to ensure that, wh en needed , the most

app ropriate antimicrobial and regimen is pr escribed, so as to ensure the best

possible clinical outcome and reduce the risk of resistance developing.

We recommend that such national guidelines be adapted for local use du ring

the d evelopm ent of Health Improvem ent Plans. Health Authorities will need

to co-ordinate ideas on guid eline development an d u se with Primary Care

Groups/ Local Health Group s and with local microbiological andepidemiological advice.

The best of gu idelines are of no value if they are not u sed. To make the

incorporation of the guidelines into everyday practice as effort-free as possible,

we recommen d that they shou ld be integrated within compu terised d ecision-

making support systems. A number of these are under d evelopment and some

are currently being piloted in general practice. The guidelines should also be

prom ulgated wid ely through the med ical literature.

Recommendations 7


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PRESCRIBING IN H OSPITALS

Hospital prescribing accounts for only about 20% of all human prescribing

of antimicrobials in the UK. Nevertheless, resistance problems are greatest in

hosp itals, reflecting th e facts that (i) the p rescribing is concentrated in a sm all

locale, intensifying selection p ressure for resistance, (ii) many hosp italised

patients have severe und erlying d iseases that render th em susceptible to

infection by otherwise harmless opp ortunist p athogens that h ave been ad eptat acquiring resistance and (iii) the high concentration of susceptible patients

facilitates the spread of infection. Thu s, prescribing in hosp itals poses some

different issues from those in primary care. However, hospital clinicians would

benefit as much as GPs from the availability of computer-aided decision-

supp ort systems, into wh ich su itably adap ted national prescribing gu idelines

could be integrated. IT for clinical use tends not to be as well developed in

hospitals as in p rimary care, although systems are being d eveloped. Therefore,

we recommen d that stud ies be und ertaken in selected hosp itals to develop and

test one or more proto type decision-supp ort systems. To be fully effective,

these computer-based ad visory systems shou ld include information from local

antim icrobial sensitivity profiles. These, in tu rn, shou ld feed into regional and

national surveillance databases.

PRESCRIBING GUIDELINES

We recommen d that local prescribing information sh ould, w herever

possible, be harmonised with that in the British National Formulary (BNF) and

other formularies. Guidelines and formularies should also take account of th e

prop osed national evidence-based gu idelines to be produ ced und er the aegis of

the N ational Institu te for Clinical Excellence. All local prescribing gu idelines

should take their cue from these national guidelines to avoid re-invention of

the wh eel. We recommen d that all such local guidelines should include, as aminimum , certain standard items of information on d rug, regimen and

duration.



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EDUCATION

The development of gu idelines and their widescale introdu ction into

clinical practice will have impor tant and beneficial spin-offs for the edu cation

of health care professionals involved in antimicrobial prescribing. We

recommend that greater emphasis than h itherto should be placed on teaching

about antimicrobial prescribing in medical and dental schools, as well as in the

un dergrad uate curricula for phar macists and nu rses. We recommend also thatteaching abou t antimicrobials should be better integrated with teaching about

the infections for wh ich th ey are u sed. This enhan ced emph asis on edu cation

in antimicrobial use shou ld be carried over into continuing m edical, dental and

professional edu cation an d development. Similar concepts ap ply in the field of

veterinary m edicine.

The whole pop ulation, not just th ose destined to become health care

professionals, would benefit from enhan ced edu cation abou t the benefits and

disadvantages of antimicrobials. We recommend that, in add ition to h ealth

edu cation m aterial aimed at ad ults, teaching abou t antibiotics should be

includ ed as p art of the health education in the National Curriculum.

SURVEILLANCE OF RESISTAN CE

Effective surveillance is critical to understanding and controlling the spread

of resistance. Not on ly does su rveillance monitor th e existing situat ion, it

allows the effects of interventions to be tested . We recommen d that a strategic

system for surveillance of antimicrobial resistance should be developed as

swiftly as possible, and that this should cover the whole of the UK. Discussions

to develop su ch a system are taking place between the Pu blic Health

Laboratory Service (PHLS), the British Society for An timicrobial Chemoth erap y

and various par ties in Scotland an d Ireland . It is vital that the system being

developed is ad equately fun ded , also that PH LS and NH S microbiologylaboratories, whose routine data will be collected, are adequately staffed and

resourced to provide high-quality information and we so recommend .

RESEARCH

National and local surveillance will give invaluable guidance to th e man y

Health Service and University projects needed to investigate the drivers of

Recommendations 9


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resistance and th e effects of interven tions. Aside from these studies, more basic

research is needed on the mechanisms of antimicrobial resistance and their

spread. We recommen d that research into antimicrobial resistance should

become a high p riority for all fund ing bodies concerned with h ealth care and

biomedical research. We note, with grave concern, the dow ngrad ing of med ical

microbiology as an academic speciality in many teaching hospitals, including

several with distinguished records of work on antimicrobial resistance.

HYGIENE, INFECTION CON TROL AND

CROSS-INFECTION

Not all problems merit the u biquitous more research needed

recommendation. In some cases the solutions are well known; it is

implementation that is faulty or deficient. This is true for certain aspects of

infection control. In h ospitals, guidance is available to be followed . At its heart

is the issue of attention to cleanliness and hygiene in all their manifestations.

These extend from th e thorough ness of the work d one by cleaning staff to

simple hand washing by health care p rofessionals in contact with p atients. The

issue of infection control, although intimately boun d up with p roblems of

antimicrobial resistance, particularly in hospitals and other health care

environments, was outside the Terms of Reference of our Sub-Group.

Nevertheless, we believe that it is so fund amental to p reventing the spr ead

of resistant organisms, not only in hospitals but also in the commun ity, that

we recommen d consideration be given to p rodu cing gu idance on infection

control in the commu nity, especially in n ursing an d residential hom es. This

may need to await clarification of the roles and responsibilities of Health and

Local Authorities in the control of infection.

VETERINARY AND AGRICULTURALUSE

Antimicrobials are used und er veterinary supervision for the treatment and

prophylaxis of infection in animals. Some agents are also used, without this

supervision, as growth promoters. These aspects were, strictly, outside our remit

although ou r Sub-Group had cross-representation from the Adv isory

Comm ittee on the Microbiological Safety of Food , whose Work ing Grou p on

Microbial Antibiotic Resistance in Relation to Food Safety is expected to rep ort

later this year. Neverth eless, we recognise that th e use of antimicrobials in



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animals has a p rofound influence on the d evelopm ent of antimicrobial

resistance in hum an path ogens and our general recommendation would be

that the u se of antibiotics in veterinary p ractice should be gu ided by the same

principles as those for prescribing in hu mans nam ely, they should be used

only for clinical conditions where their use is likely to provide a genuine health

benefit. We recommen d that alternative means of animal husband ry be

developed so that the use of antimicrobials as growth p romoters can be

discontinued.

IMPLICATION S FOR IND USTRY

If our recommend ations are followed, they shou ld h ave the effect, inter alia,

of redu cing antibiotic usage. There m ay be financial imp lications for the

ph armaceutical industry, up on w hose profitability the d evelopm ent of new

antibiotics depends. Therefore, we recommen d that consideration be given by

the app ropriate bodies to finding ways through pricing and other

mechanisms of ensuring that investment in the d evelopm ent of new

antibiotics remains commercially viable for the industry.

In addition, we recommen d that indu stry should be encouraged to

und ertake stud ies of optimum prescribing regimens for new antimicrobials, for

each of their indications and in adu lts and children as app ropriate. This

evidence-based information should be included in the Summary of Product

Characteristics (SPC) for each product as set out in the product licence and the

product data sheet. We recommen d that the licensing au thorities should have

du e regard to an an timicrobials poten tial to select for resistance as well as to

its efficacy and safety.

INTERNATIONAL CO-OPERATION

In the field of antibiotic prescribing, this count ry cannot consider itself an

island. International prescribing practices have a major influence on the

development and spread of antimicrobial-resistant organisms and their genes.

Resistant organisms in Europe enjoy as much freedom of movement only in

larger num bers as their hu man hosts. Hence, we recommen d that every

effort is mad e by the Govern ment to raise the profile of antimicrobial resistance

as a major public health issue meriting priority action from all Member States

of the Europ ean Union.

Recommendations 11


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EXPECTATIONS

We wish to emp hasise that our Report should not generate un realistic

expectations. Even stopping altogether the prescribing of certain antimicrobials

may not lead to an app reciable reduction in the levels of resistance to those

dru gs, even over a p eriod of several years. However, we hop e to achieve a

slowing of the rate at w hich resistance develops. This may buy a few m ore

years of therapeutic usefulness for certain antimicrobials, until such time,hopefully, as they may be replaced by new and novel compound s. Different

considerations may then ap ply, so as to build in, from th e outset, safeguard s to

minimise the d evelopm ent of resistance.

NATIONALSTRATEGY

Our aim has been to pr odu ce recommendations that can constitute the first

phase of a national strategy for minimising the d evelopm ent of antimicrobial

resistance. We recommend , as part of this phase, the establishment of a small

National Steering Grou p (NSG) charged with ensu ring that these

recommend ations are imp lemented an d their effects, on p rescribing practice

and on the development of resistance, are monitored. The NSG, which might

need to establish a small nu mber of expert group s to take forward specific

aspects of the recommendations, should report to the Chief Medical Officer

within a year on progress with and lessons learned from implementing

Phase 1 of the strategy. Thereafter, the CMO may w ish to consider asking

SMAC to reconvene this Sub-Group, in order to provide a suitable inter-

disciplinary forum for the development of the next phase of the strategy,

building on the results of various p ilot and other stud ies to evaluate the

effectiveness of the recommendations in this Report.


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Recommendations 13

Figure 1 Recommend ations for the p rofessions and the p ub lic: CATNAP


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3 LOOKING INTO THE ABYSS

KEY POINTS

q Antibiotics enable hu ge advances in medicine

q Antib iotic use selects for resistant bacteria

q Resistant b acteria accumulate an d spread

qResistance increases clinical complications, lengthens hospital stay andadds cost

q Development of n ew antibiotics is slow, expensive and cann ot be

guaranteed

q With m ore resistance and few n ew antimicrobial agents, modern medicine

is threatened

For two generations, antimicrobial agents have altered exp ectations of life

and death. The fever hospitals and tu berculosis sanatoria hav e gone. In the

early 1930s, deaths from sepsis after childbirth in the UK were 100120 per

100,000 births; after antibiotics were introdu ced th is rate fell to almost zero.

Antimicrobials have enabled operations and treatments such as tran splantationto be und ertaken that were pr eviously un thinkable because they exposed the

patient to a huge infection risk.

Unfortunately however, antimicrobial use exerts an inevitable Darwinian

selection for resistance. Once selected, resistant bacteria sp read or tran sfer their

resistances to other bacteria. The resu lt has been erosion of antim icrobial

efficacy, pu tting the p ast half-centu rys med ical progress at risk.

Until recently, man kept ah ead an d new an timicrobials were d eveloped

faster than bacteria developed resistance. Gradu ally, though , a change

occurred: while the 1950s and 60s saw the discovery of numerous new classes of

antim icrobials, the 1980s and 90s yielded on ly relative improvements within

classes. Now, in the closing years of the centu ry, micro-organisms ar e getting

ahead, and therapeutic options are narrowing.

In the UK there are bacteria resistant to man y antim icrobials. Elsewhere th e

situation is often w orse. In Japan, strains ofStaphylococcus aureus an d

Pseudomonas aeruginosa are resistant to a ll established antim icrobials. There is

every reason to fear that such p athogens will be imp orted to the UK, or will

evolve ind epend ently here.

The spread of resistance threatens a return to darker times, when surgery

was restricted to simple operations on the otherwise healthy, and when organ



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transplants, joint replacements and imm unosu pp ressive therapies were

unthinkable.

Even when resistance does not prevent effective therapy, it adds cost. The

initial antimicrobials mu st be replaced w ith agents that are more expensive or

have undesirable side-effects. More generally, patients whose therapy proves

inappropriate as a result of resistance are more likely to experience

complications .

In one stud y, reoperation, abscess formation and wou nd infection w ere all

commoner in th ose surgical patients who received inapp ropriate therapy.

Figure 2 Complications (%) after appropriate and in approp riate therapy in

surgical peritonitis

The th reats to health p osed by antimicrobial resistance are:

q Some cond itions may become untreatable

q Empirical treatment m ay be inap propriate and time may be lost in

critically ill patien tsq Length of hospital stay, antimicrobial use, morbidity, mortality and costs

may b e increased

q More toxic, less effective or more expen sive alternative d rugs may h ave to

be used.

Looking into the abyss 15


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4 ANTIMICROBIAL AGENTS

The range of ant imicrobial agents available and their activities are

summ arised in this section of the m ain Report, to which the reader is referred.

The terms antimicrobial agent and antimicrobial are u sed in th is Repor t

principally to encompass an tibiotics (substances prod uced by m icro-organisms

that selectively destry or inhibit other micro-organisms) and chemically

prod uced antibacterial dru gs, and also to include, where ap prop riate, antiviraland antifungal agents.



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5 BASIS OF RESISTANCE

KEY POINTS

q Darwinian selection

q Antimicrobial agents kill sen sitive organisms, resistant ones survive

q Sensitive organisms m ay become resistant b y mu tation

qResistances can transfer among different organisms

q Some species are inherently resistant and are selected b y antimicrobial

agents

q Bacteria accumulate multiple resistances to unrelated antibiotics

The great pr inciple of antimicrobial resistance is Surv ival of the Fittest.

Antimicrobials kill susceptible bacteria but r esistant ones su rvive to infect

other patients. At the same time, advan ces in med icine enlarge the pool of

patients susceptible to infection by organisms that historically were harmless,

but w hich are adept at developing resistance.

Resistance can arise via mu tation, gene transfer or by the selection ofinherently resistant species. The importance of these processes varies with the

organism, the antimicrobial agent and the clinical setting.

Figure 3 Mechanisms of antimicrobial resistance

The antimicrobial, draw n as a

bullet, heads tow ards its target.

Resistance may arise (i) if it is

inactivated before it reaches

the ta rget, (ii) if the bacterial

cell becomes imperm eable,

(iii) if the cell becomes able to

pu mp the antibiotic back out,

(iv) if the target is altered so

that it no longer recognises the

antimicrobial, or (v) if the

bacterium acquires an alternative

metabolic pathw ay, by-passing the

site of action.

Basis of resistance 17


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BOX 3. MULTI-RESISTAN CE

Organ isms resistant to one an timicrobial are more likely to be resistant

to un related agents. It is not the m ethicillin resistance of methicillin-

resistant Staphylococcus aureus ( MRSA) that m atters; rather, that m any

MRSA are also resistant to alternative d rugs. Likewise, the vancom ycin

resistance of increasing numbers of enterococci would not matter if

many enterococci were not already resistant to all other dru gs.



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Does antimicrobial use cause resistance? 19

6 DOES USE OF ANTIMICROBIALAGENTS CAUSE RESISTANCE?

KEY POINTS

q Resistance has repeatedly emerged to new drugs after clinical use

q Most resistance occurs in countries and un its where use is h eaviest

q Resistance may be selected in the target organism d uring th erapyq Resistant commensal bod y flora may also emerge during th erapy

q Evidence linkin g antimicrobial use in man and resistance is clear and

overwhelming, bu t mostly circumstantial

Key facts are:

i) Acquired resistance is absent from bacteria ante-dating the antimicrobial era.

The only resistances seen are those inherent to particular species.

ii) Introduction of new antimicrobials has been followed repeatedly by resistance.

The time scale has varied, reflecting the complexity of the evolution, but the

pattern is constant.

iii) Resistance often develops in the normal bacterial flora of individuals receivingantimicrobial therapy. If a further infection arises from this flora, it is more likely

to be resistant than in patients who have not received prior therapy.

iv) Resistance is greatest in countries and hospital units where antimicrobial use is

heaviest. The clearest example is the excess of resistance in intensive care units


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7 TO PRESCRIBE ORNOT TO PRESCRIBE?

KEY POINTS

q In m any common in fections the d ecision to prescribe is finely b alanced

q Infections are often viral and un affected b y antibiotics

q Decisions to prescribe are influenced by patientsexpectationsq Patients believe that antimicrobials will work for th em

q Unn ecessary or margin al use exacerbates th e selection of resistance

q Reducing un necessary antibiotic use must involve health care workers,

patients and the p harmaceutical industry

Microbial pathogens are increasingly resistant to the available drugs.

However, the anxious parent and the unw ell adu lt continue to expect the

doctor to prescribe a pill to cure th eir ill. GPs, hosp ital physicians, sur geons,

paed iatricians, or obstetricians continue to prescribe antibiotics, sometimes for

inappr opriate indications, in inapprop riate doses, for inapp ropriate lengths oftime. Why is this so, and how can it be changed ?

The unn ecessary prescription an d consumption of antimicrobials is

everyones responsibility. Effective treatmen t of infectious disease can

only be preserved through a determination on the p art of policy makers,

manu facturers, prescribers and consumers to m inimise un necessary

consum ption . There may be d ifficult clinical decisions, as exemplified in Boxes

5-8, but th ere are also circum stances when pr escription of an antim icrobial is

clearly wrong. A patient with a common cold should not receive an an tibiotic

and women with u ncomplicated cystitis should not receive antibiotics for m ore

than three days.



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BOX 4. THE ANTIM ICROBIAL TUG O F WAR

What st im ula te s p rescr ib ing ? What inh ib it s p rescr ib ing ?

Prescribers Prescribers

Failing to prescribe may lead to Adv ice from specialists in

clinical complications or litigation microbiology and infectious disease,

Applying rules learned as a who discourage excessive prescribing

studen t which may no longer be Good basic training on risks and

app ropriate benefits of antimicrobial treatment

Clinical jud gement

Scientific and promotional

literature

A prescription is an easy way to

end a consultation

Patients Patients

Patients expectations dr ive Some pat ients are averse to

prescribing prescription, and seek reassurance

Many patien ts expect a script that they will recover withou t an

Belief that they need an antibiotic antibiotic

to stop a cold going to th eir chest

Anxiety over sick childr en

Nurses Nurses

May not fully app reciate the risks See the problems associated with

associated with inapp ropriate over-prescription resistance, ward -

use of antimicrobials closures, antibiotic-associated

diarrhoea and try to edu cate

prescribing colleagues an d patients

Pharmacists Pharmacists

Often first commu nity contact; Particularly in hosp itals, have anmay advise that a prescription important role in controlling

is necessary prescribing and identifying

inapp ropriate prescribing

Pharmaceutical industry Pharmaceutical industry

Wan ts to sell its p rod ucts Wan ts to en su re long p rod uct life

To prescribe or not t o prescribe? 21


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This is the antimicrobial tug of war, and what is required is action that will

ensure that every prescription is justified, is of the approp riate drug, d ose and

regimen, and is reassessed in the light of clinical response and microbiological

results, if necessary.

Prescription of an antibiotic should b e seen as a serious step, similar to the

prescription of steroids or any other p otentially hazardous medicament.

BOX 5. THE PAINFUL EAR

Acute otitis med ia (AOM infection of the mid dle ear) is common in

childh ood. A child with AOM is distressed, unh app y and febrile. The

parents are concerned and eager for the GP to act. The GP may feel

und er pressure to prescribe. It is easy to write the p rescription and see

the family leave satisfied. When the symptoms improve this is

attribu ted to th e antibiotic, reinforcing the cycle of expectation. A GP

will see many children w ith AOM each year and most will receive an

antibiotic.

Reviews on AOM suggest that the benefit of routine antimicrobial use

is unproved or m odest. A prop ortion of children d o benefit but it is

difficult to predict which ones. Countries with lower rates of antibiotic

prescribing for AOM do not have any increase in the nu mber of

complications comp ared w ith those where a prescription is usu al.

Even if antibiotics are prescribed, there is d ebate about th e app ropriate

length of treatment: three and ten day courses were equally effective in

one study.

Antibiotics are p robably u nn ecessary in AOM. Reassurance, time

and adequ ate pain relief are required. If antibiotics are prescribed, the

course should be limited to three days.



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BOX 6. THE SO RE THRO AT

Sore throats are common, particularly in children. Most are viral and can

be left to run their course without antibiotics. Indeed, recurrence and

relapse may be more common in those who have h ad early treatment

with an tibiotics.

Nevertheless, the GP can come un der considerable pressure to

prescribe an antibiotic for a sore throat. A r ecent stud y showed thatpatients with sore throats w ere more likely to leave the consultation

satisfied if they received a p rescription. However, they were no m or e

likely to be satisfied at th e end of the illness. Those wh o received

antibiotics were m ore likely to return for treatment in futu re attacks and

were more likely to believe in the efficacy of antibiotics.

A minority of sore throats are caused by a bacterium, Streptococcus

pyogenes. It is not easy to distingu ish a strep tococcal sore throat from a

sore throat caused by viral infection. Streptococcus pyogenes can lead to

local abscesses and, rarely, to kidney problems and rheumatic fever.

Therefore, many doctors prescribe antibiotics for a sore throat with the

intention of preventing th e consequences ofStreptococcus pyogenes

infection.

Sore throats should n ot be treated with antibiotics, unless there is

good evidence that they are caused by Streptococcus pyogenes.

BOX 7 SINUSITIS

Several studies, including rand omised controlled trials, have show n

antibiotics to be effective in proven acute sinusitis. Most of these stud ies

have u sed ten d ay courses of antibiotics. One comparative study

showed that three days of antibiotics were as effective as ten days.Recent overviews of the treatment of acute sinusitis-like symptoms in

adu lts in the primary care setting suggest that th ere is no benefit from

antibiotic treatment.

The adu lt with sinusitis-like symp tomsin p rimary care does n ot

need im mediate antibiotics.

In proven acute sinusitis three days of antibiotics are as effective as

ten.

To prescribe or not to prescribe? 23


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BOX 8 CYSTITIS

Each year about one wom an in 20 will present to her GP with symptoms

of cystitis; abou t half of these women will have an infection (defined by

the p resence of a significant n um ber of bacteria in the ur ine). Most of

these infections in otherwise healthy women are caused by coliform

bacteria.

Uncomplicated cystitis can be treated empirically with trimethoprim.If resistance is common locally, the med ical microbiologist can ad vise on

an ap prop riate alternative. Several stud ies have shown that a three d ay

course of treatmen t is as effective as a five or seven day course.

Limiting the prescription of antibiotics for uncomplicated cystitis in

otherwise healthy wom en to th ree days reduces selection pressure for

resistance.



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8 WHERE ARE ANTIMICROBIALAGENTS USED?

KEY POINTS

q 50% of antib iotic use in th e UK is in man , 50% in an imals

q 80% of human use is in the commu nity

q 50% of commun ity use is in respiratory tract infection, 15% in u rinarytract infection

q Considerable local and regional variation exists in levels of commun ity

prescribing

q In hospitals, antimicrobial agents account for 1030% of the drugs budget

COM MUN ITY PRESCRIBING

About 50 million prescriptions for antibiotics are dispensed in England

every year an average of one prescription per p erson per year. Most human

antibiotic prescribing in the UK (80%) is of oral an tibiotics in th e comm un ity.Abou t half of this commu nity u se is in respiratory tract infection (RTI),

with a further one-sixth in urinary tract infection (UTI). Most community

antim icrobial prescribing is by GPs, but d entists account for abou t 7%. Usage

is subject to approximately two-fold variation between Districts with the

lowest and highest prescribing, with no obvious explanation.

PRESCRIBING IN HO SPITALS

Although hospital prescribing accounts for only 20% of human usage, it is

of key importance because it is concentrated in a small pop ulation brough t

together in a confined environment. Also hospitals with high popu lations of

immun ocompromised p atients are fertile breeding groun ds for opp ortunist

bacteria that ar e ad ept at accum ulating resistance.

Audits at a teaching hospital trust showed that 2025% of patients had

received an an tibiotic with in the p revious 24 h, with a ran ge from 40 to 50% in

ICU to less than 10% in ENT surgery. As in the comm un ity, most p rescribing is

for RTI.

Where are antimicrobial agents used? 25


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Figure 4 Hospital and commu nity use of some an timicrobial agents

Data kindly provided by IMS Health UK, Maxims Database

Figure 5 The p yramids of an timicrobial use an d selection for an timicrobial

resistance

Most p rescribing of antimicrobials (80%) takes place in the com mu nity; 20% of

prescribing is for small numbers of patients, often in specialised hospital units.

Both intense pressure in a small nu mber of hospitalised p atients and less

intense selection pressure in large nu mbers of patients in the commu nity cause

problems w ith resistance.


ANTIMICROBIAL RETAIL (COMMUNITY) HOSPITAL

AGENTS (kg) (kg)

Total Systemic Antibiotics 385600 80900

Broad spectrum penicillins 160406 25556

Med/ narrow-spectrum penicillin 59800 17200

Tetracyclines + combinations 45900 1600

Cephalosporins + combinations 35900 15100

Trimethoprim combinations 10900 3500

Fluoroquinolones 10300 3600

Nitrofurantoin 742 45

Nalid ixic acid 588 59

Fusidic acid 354 454

Aminoglycosides 109 5300

Chloramphenicol + combinations 25 88

Rifampicin/ rifamycin 12 14

Other -lactams 9 527

Glycopeptides 9 493


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9 TH E EXTEN T O F BACTERIALRESISTANCE IN THE UK

NB: This table has many simplifications and ignores variation within

antim icrobial classes; it aims to give only an overall, broad -brush p icture.

The extent of bacterial resistance in the UK 27

S. aureus MethS q r r 7 7 7 7 7 7! q r 7!

MRSA q q q 7 q q q q 7! q r 7!

Enterococci 7 7 q q q q q 7

-haem. streps r r r 7 7 7 7 r 7

S. pneumoniae 7 7 r 7 7 7 r 7!

Viridans strep s 7 7 r 7 7 q q 7 r 7! E. coli q 7 r q q 7 7 q

Klebsiella sp p 7 r q q 7 7 q

Enterobacter q q! r q q 7 7 q

Pseudomonas 7! 7! 7! 7! 7!

Acinetobacter q q 7 q q q 7

N. meningitidis r r r r q r 7 7

N . gonorrhoeae 7 r r 7 r 7 7 7 7

H. influenzae 7 7 7 7 7 7 7

M. tuberculosis 7 7

Inherently resistant.

7 Acquired resistance in 20% of isolates.

r Acquired resistance unkn own, or virtually so.

! Resistance emerges readily by mutation.


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10 CURRENT RESISTANCEPROBLEMS IN THE UK AND

WORLD-WIDE

KEY POIN TS

q Resistance is accumulating w orld-wide in many bacteria

q The UK situation is n ot as bad as that in many countries, bu t the trend is

to more resistance

q A major problem in th e UK is methicillin-resistant Staphylococcus aureus

(MRSA)

q Other major prob lems include pn eumococci, enterococci and hospital

gram-negative opp ortunists

q Resistance is emerging in viruses and fungi

STAPHYLOCOCCUS AUR EUS

When pen icillin w as introd uced in l944, over 95% ofStaphylococcus aureus

isolates were susceptible, but this proportion has since shrunk to 10%. The

introd uction of -lactamase-stable pen icillins (e.g. methicillin and

flucloxacillin) in th e early l960s w as swiftly followed by the emergence of the

first m ethicillin-resistant Staphylococcus aureus (MRSA). Subsequently, a series

of epidemic MRSA(EMRSA) strains have evolved and spread, som e locally,

others internationally. Many are resistant to a number of antibiotics, with only

glycopeptides (vancomycin and teicoplanin) remaining active. Recently there

have been reports of MRSAwith intermediate resistance to vancomycin and

teicoplanin. These are resistant to all available antimicrobials and, un like other

organisms where pan-resistance is seen, have considerable pathogenicity for

those not severely immu nocompromised.



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Figure 6 Proportion (%) ofStaphylococcus aureus isolates from blood and

CSF that w ere resistan t to meth icillin, 198997

ENTEROCOCCI

Enterococci are a p art of the norm al hum an gu t flora, where they are

harmless. They have little virulence but can cause infection in patients whose

health is impaired, particularly in specialised hospital settings (eg renal dialysis

and bone marrow transplant units). Serious infections are extremely difficult to

treat because of resistance.

Enterococci are intrinsically resistant to quinolones and cephalosporins and

clinical use of these agen ts may explain the rising imp ortance of enterococci. In

addition, enterococci readily gain resistance to other antim icrobials. Recent

concern has centred on the emergence and spread of enterococci with

resistance to the glycopeptides (vancomycin and teicoplanin) (Figure 7).

Many glycopept ide-resistant ent erococci (GRE) are resistant to all established

antimicrobials, forcing clinicians to use untested agents or combinations with

no guarantee of success.

Current resistance problems in the UK and world-wide 29


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Figure 7 Number of hospitals submitting enterocococci resistant to

glycopeptides to the PHLS Antibiotic Reference Unit: England and Wales,

198796

STREPTOCOCCUS PNEUMO NIA E

Streptococcus pneumoniae is most important as a cause of commu nity-

acquired p neum onia, which may lead to bacteraemia. It is also a frequent cause

of otitis media and is one of the commonest causes of bacterial meningitis.

Historically, Streptococcus pneumoniae was exqu isitely susceptible to p enicillin,

which could be u sed in most p neum ococcal infections, including m eningitis.

Macrolides (eg erythrom ycin), tetracyclines and co-trimoxazole w ere

alternatives in respiratory tract infection, whereas several cephalosporins and

meropenem were an d are alternatives in meningitis. Pneumococci with

low-level penicillin resistance were recorded in the late l960s and som e with

high-level resistance began to be seen in th e late l970s. These are now

increasing, both in frequen cy and in the level of their resistance (Figure 8).

There is also concern about the risk of importation of resistant strains from

those coun tries (eg Spain ) where th e rate of resistance is mu ch higher.



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Figure 8 Prevalence of resistance in pn eum ococci from b lood an d CSF in

England and Wales, 198995.

HO SPITAL-ACQUIRED GRAM -NEGATIVE OPPORTUN ISTS

Many different gram-negative bacteria can cause opportunistic infection in

immun ocompromised p atients. The organisms most often involved includ e

members of the genera Escherichia, Klebsiella, Proteus, Enterobacteran d

A cinetobacter. Escherichia coli is also the commonest cause of cystitis in the

community. Resistance to many antibiotics is increasing in these pathogens,

notably to cephalosporins, quinolones and trimethop rim.

ENTERIC PATHOG ENS SALMONELLA

Several bacterial genera are imp ortant in food poisoning. At present

mu ltiple dr ug resistance is a major problem in Salmonella, particularly

Salmonella typhimurium, where an imp ortant recent factor was epidemic spreadof multi-resistant Salmonella typhimurium DT 104 in bovines and its increasing

recovery from m an.

Current resistance problems in the UK and world-wide 31

PREVALENCE (%) OF RESISTAN CE

YEAR PENICILLIN G ERYTHROMYCIN

1989 0.3 3.3

1990 0.5 5.1

1991 0.7 6.4

1992 1.9 8.61993 1.7 10.8

1994 2.5 11.2

1995 2.9 10.9

1996 3.7 9.9

1997 7.5 11.8


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Figure 9 Isolation of Salmonella typhimurium DT 104 from man , 198296

CAMPYLOBACTER SPECIES

These organisms, which are the commonest cause of bacterial

gastrointestinal infection, can cause severe food poisoning requiring antibiotic

treatment. Macrolides and ciprofloxacin are used. Emerging resistance to

ciprofloxacin is a concern.

NEISSERIA GONORR HOEAE

Sulphonamides were effective against gonorrhoea on introduction in 1937

and almost inv ariably ineffective by 1944. Penicillin r esistance was slow er to

emerge, but the agents activity has been gradu ally eroded , with higher d oses

being needed. Strains that produce -lactamases (penicillin-degrading

enzym es) were first detected in 1974 in gon ococci from the Far East and from

West Africa. These penicillin-destroying strains are rar e in the UK.Ciprofloxacin is very effective against penicillin-resistant isolates and is

now u sed for this purp ose in the UK and elsewhere, but this is resulting in a

slow increase in the proportion of frankly resistant strains.



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NEISSERIA MENINGITIDIS

This organism is the commonest cause of bacterial meningitis. Frank

penicillin resistance is not yet a problem, but the proportion of isolates with

decreased susceptibility increased from


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VIRAL INFECTION

Resistance has been d ocumented to virtually all the antiviral dru gs

available in the UK. Resistance generally accrues by step-w ise muta tion, and

often leads to a v irus with red uced su sceptibility rather than one with frank

clinical resistance.

Combination therapy may militate against the d evelopm ent of resistance in

HIV, but th e risk cannot be d iscounted .

What next for antimicrobial resistance ?

FIRST, it seems inevitable that vancomycin-intermediate MRSAwill spread.

Worse, gene exchange occurs betw een stap hylococci and enterococci and it is

likely that the high-level glycopeptid e resistance of enterococci will spread to

MRSA. Its spread to p neumococci is also possible. The consequen ces would be

severe: glycopeptides are th e dru gs of last resort against many serious gram -

positive pathogens (eg resistant pneumococci in meningitis).

SECOND , it is also common to see gram -negative bacteria susceptible only to

the carbapenems, imipenem and meropenem. Unfortunately, carbapenem

resistance is now seen increasingly in hospital opportunists such as

Pseudomonas aeruginosa an d Acinetobacter.

OTH ER RESISTANCES to be feared includ e those in species that h ave, thus

far, remained r emarkably susceptible. Obvious risks are pen icillin resistance in

Neisseria meningitidis an d Streptococcus pyogenes.

Penicillin resistance in Streptococcus pyogenes is remarkable by its continued

absence. This species, once the most feared of hospital wound pathogens, has

remained exquisitely sensitive to pen icillin since the 1940s. Neverth eless, gene

exchange occurs between Streptococcus pyogenes and staphylococci and there isa risk that -lactamase prod uction may sp read from the latter to the former.

In short, evolution hasn t finish ed yet ...



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11 AREAS OF CLINICALPRACTICE WHERE

ANTIMICROBIAL RESISTANCEHAS, OR IS LIKELY TO HAVE,

THE GREATEST IM PACT

KEY POINTS

q Resistance is greatest where antimicrobial use is heaviest

q Major problem areas in hosp itals include ICUs, transplant u nits

q Key patient group s includ e the immu nocompromised

q Resistance is also rising in common commu nity path ogens

Resistance is most frequent where there are large numbers of susceptible

patients. These are also the situations where antimicrobial chemotherapy is

most essential. Neverth eless, the consequ ences of resistance are not r estricted

to specialised un its but are also seen in general in-patients and in thecommunity.

INTENSIVE CARE UNITS

Resistance is most common in patients receiving mechanical ventilation and

in u niversity or teaching h ospitals. Intensive care and similar u nits present

special problems. Ventilator-associated pneumonia due to antimicrobial-

resistant bacteria often follows prior antimicrobial exposure and is a

particularly important p roblem.

Heavy an timicrobial use probably lies behind th e high rates of

antim icrobial resistance in ICUs. Fur therm ore, ICU patient s often require

invasive support activities which increase the risk of infection, demanding

more antimicrobial treatment and exacerbating the risk of selecting resistance.

Areas of clinical practice where antimicrobial resistance... 35


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ADMISSIONS WARDS

Over the last decade there has been a 50% increase in emergency

admissions to general hospitals in the UK. General hospitals increasingly

accept emergency p atients on an ad missions ward , where a p re-registration

house p hysician makes a diagnosis, orders investigations, and p rescribes

treatment. Most of these patients have medical rather than surgical problems

and so are admitted und er physicians.Infection is often considered , but may be d ifficult to d iagnose. The

diagn osis of infection relies on microbiological investigation. Meanw hile the

junior doctor has to decide whether to prescribe empirically. This provides

many opp ortunities for inapp ropriate or u nnecessary antimicrobial prescribing.

IMMUNOCOMPROMISE

Immun ocomp romised p atients may p resent with d ifficult-to-diagnose or

occult infections. They are vulnerable to a wide range of opportunist infections

and often require urgent em pirical treatment, without the op portu nity to take

appropriate microbiological samples. Broad-spectrum antibiotics are used,

selecting for broad resistance.



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12 WHAT PRACTICES BYCLINICIANS AND THE PUBLIC

PREDISPO SE TO THEDEVELOPMENT OF

ANTIM ICROBIAL RESISTANCE ?

KEY POIN TS

q Some antimicrobials are more selective than others for resistance

q Selection varies with the dosage and du ration of therapy

q Unnecessary antimicrobial use selects resistance without any gain

q Unnecessary use in cludes over-long p rophylaxis and th erapy of infections

that are trivial, self-limiting, or viral

q Public expectations of A pill for every ill encourage over-prescribing

Spread of resistant bacteria is aided by:

i) crowding of children and the elderly

ii) increased travel

iii) increased bed-efficiencyin hospitals

iv) increased hospital throughput

v) antimicrobial use

Health care practitioners and the public both carry a responsibility. Claims that

the entire responsibility lies elsewhere with veterinary antimicrobial use do

not w ithstand scrutiny, since resistance is widespread to antimicrobials used

only in man .

This is not to absolve veterinary u se it is a major driver of resistance

among enteric pathogens and , maybe, enterococci but it is important to stress

that the whole responsibility cannot be passed to another grou p.

Ultimately, resistance is an inevitable consequ ence of use, as micro-

organisms are selected in an environment of antimicrobials. Nevertheless the

practices of prescribers and consum ers affect the rate of this evolution. Key

factors ar e:

What are the practices by clinicians... 37


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ANTIMICROBIAL USED

Some antimicrobials are more prone to select resistance than oth ers, either

by encouraging overgrow th of an un desirable flora (eg yeasts or Clostridium

difficile) or by favouring resistant mu tants within the original infection.

Oral cephalosporins and clindamycin are both associated with selection of

Clostridium difficile; fusidic acid and rifampicin notoriously select resistant

mu tants in their target species, as do cephalosporins w ithEnterobacteran dCitrobacterspp.

REGIMEN

Dosage and du ration of therapy are key factors in mod ulating selection

pressure. Regimens var y greatly from h ospital to hospital and practice to

practice, often w ith no und erlying rationale. Ar eview of prescribing gu idelines

showed that simple information su ch as dose, frequency and total length of

course was often missing.

BOX 9. ANTIM ICROBIAL GUID ELINES SHO ULD:

q be evidence-based

q be dated

q contain information on the antimicrobial, dose, frequency and length of

course

q indicate the strength of the evidence for the recommendation

q show local variation from national recommend ations

Necessary antimicrobial use whether prophylactic, empirical or therapeutic

exerts selection for resistance. The qu estion is always wh ether th e gainoutweighs the risk; whether the choice of antimicrobial maximises the benefit

and minimises the risk. Unnecessary use exerts selection pressure with n o gain.

PRESCRIBING UNNECESSARILY OR INAPPRO PRIATELY

Antimicrobials are prescribed unnecessarily and empirically for trivial

complaints where no treatment is necessary, or w here culture and sensitivity



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results could safely be aw aited. The use of emp irical antimicrobials in

community upper respiratory tract infections is a key concern, since 50% of

clinical antimicrobial usag e is for infections a t th is site and 70% of infections

are viral.

A surv ey of 21,400 pa tient encoun ters revealed tha t over 80% of patients

were p rescribed an antim icrobial for upp er RTI, including 7080% not actually

seen by the doctor. Even where the diagnosis was coryza (common cold), 42%

of patients were prescribed an antimicrobial.

PROPHYLAXIS

Prophylactic antimicrobial use, ie use to prevent infection, carries a

selection risk, whether the use is warranted or not. This risk is increased where

the p rophylaxis is prolonged . In m ost cases effective surgical prop hylaxis can

be achieved with on e or tw o d oses at operation, yet proph ylaxis is sometimes

continued for several days, without an y evidence of need.

EMPIRICAL THERAPY

Empirical antibacterial therapy should be given when bacterial infection is

suspected, and poses a sufficient health risk to demand immediate treatment. Clear

examples include fever of unknown origin in n eutropenic patients, pneumon ia,

meningitis and tuberculosis.

In reality, empirical therapy is used far more widely. In community practice,

microbiological examination of specimens is rarely undertaken before initiating

therapy and , in hospitals, therapy that begins empirically remains so owing to

difficulty in obtaining a specimen or disinclination to do so.

The specific problems with empirical therapy are:

it is often given to patients who do not have bacterial infections; inappropriate antimicrobials may be selected;

it is common to use broad-spectrum agents or combinations.

Where warran ted, empirical regimens shou ld be based on knowledge of the

likely pathogens and their antimicrobial susceptibilities. This depends on

access to good LOCAL surveillance data.



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pn eum ococci rose swiftly, from being virtua lly unkn own to 20% of all

pneumococci isolated. This reflected the spread of a resistant strain previously

prevalent in Spain. It seems that children w ere colonised by the strain w hilst

on h oliday and that it then spread among them in child-care facilities, which

most attend.

VETERINARY ANTIMICROBIAL USE AND

THE EMERGENCE OF RESISTAN CE

Disease is inevitable in farm and companion animals. Moreover, healthy

animals can be carriers and asymptom atic excretors of pathogens.

Antimicrobial resistance rates vary with the animal species, the type of

hu sbandry, environmental pressure, the standard of stockmanship and the

patterns in trad e. Antimicrobial use in an imals has been prop osed as a factor in

the emergence of resistance in hu man pathogens.

Resistant bacteria selected in animals may be transferred to man via the

food chain, or may transfer their resistance genes to hum an p athogens.

TYPES OF ANTIMICRO BIAL USAGE IN ANIMALS

The main reasons for antimicrobial use in an imals are therapy, p rophylaxis

and , in farm an imals only, performance enhancement (growth p romotion).

Therapy involves individual animals or d efined group s with iden tified

disease. Its justification is not d ifficult; disease can cause d eath or m orbidity.

Prophylaxis aims to contain the spread of infection in herds or flocks.

Following diagn osis of illness in one or m ore of the mem bers of a herd or flock,

the whole herd may be treated to prevent spread.

Performance enhan cement (growth prom oting) is the most contentious

usage. Antimicrobials imp rove the prod uctivity of healthy an imals by

increasing growth rate, feed conversion or yield. They are given continuously

at sub-therapeutic doses, usually as feed additives or, occasionally, by addition

to the drinking water.

Antimicrobials that are u sed in man cannot be used as grow th p romoters in

the UK. Nevertheless there is concern that:

growth promoters may select cross-resistance to antibiotics used in man

antibiotics for human u se are now being sought among classes previously

used only as growth p romoters; it is feared that th e prior u se of the agents

as growth p romoters may have u nd ermined their activity even before they

become available for hu man use.



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These concerns are echoed wor ld-wid e: in 1994 the WH O Scientific Working

Group on the Monitoring and Management of Bacterial Resistance to

Antimicrobial Agents recommend ed that th e u nnecessary an timicrobial use for

prop hylaxis in food animals shou ld be d iscouraged , and that antimicrobials

should n ot be used as a su bstitute for adequate h ygiene in animal hu sbandry.

To this we would add the desirability of ph asing out use as growth

promoters.



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13 PREVENTINGTHE DEVELOPMENT OF

ANTIM ICROBIAL RESISTANCE

KEY POINTS

q Without a guarantee of n ew antimicrobials, conservation of present agents

is desirable

q Careful an timicrobial use shou ld slow th e emergence of new resistance

q Reduced use may but cannot b e guaranteed to reduce present

resistance

q Prevention of spread of resistant strains is also critical, especially for

MRSA

SHO ULD RESISTANCE DECLINE IF ANTIM ICROBIAL

USE IS RESTRICTED?

Whilst the relationship betw een antimicrobial use and the emergence of

resistance is clear, if circum stantial, its corollary that resistance shou ld d ecline

if use is restricted is much less certain. Stud ies of disu sed an timicrobials are

useful since they examine agents w here d irect selection is no longer sign ificant

and where n o active steps are being taken to redu ce resistance. Neither

streptomycin nor chloramp henicol has been u sed against Enterobacteriaceae

for over 25 years. Yet, a recent survey in Lond on foun d that 20% ofEscherichia.

coli isolates remained resistant to streptomycin and chloramphenicol resistance

occur red in 510% of isolates. These stud ies show h ow d ifficult it is to displace

accumulated resistance.

DO GO OD PRESCRIBING PRACTICES PREVENT OR

SLOW DEVELOPM ENT OF RESISTANCE?

Intensive control or mon itoring of prescribing has been accomp anied by an

increase in susceptibility in a few institutions. Co-operative multicentre studies

are needed to assess fully the value of control measures.

One investigation from Finland has caused mu ch comment. An increase

Preventing the development of antimicrobial resistance 43


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was n oted in resistance to macrolides amongst Streptococcus pyogenes isolates in

Finland through the late 1980s and early 1990s. Nationwide recommendations

calling for a reduction in macrolide use were introduced. Macrolide

prescriptions an d the incidence of erythromycin resistance among Streptococcus

pyogenes isolates halved over the next 3 years. A causal relationship was

assumed, but this is arguable, not least because the incidence of macrolide

resistance increased in pneumococci in the same period.

Although reducing antimicrobial use may not redu ce rates of resistance, it

should limit the rate at which n ew resistance accumu lates, and this may b e

critical.



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14 DEVELOPMENT OF NEWANTIMICROBIAL AGENTS

KEY POINTS

q Antimicrobial research is more efficient th an previously

q New an timicrobials are under d evelopment, but success cannot b e

guaranteedq Develop men t cost is high (350 m) and paten t life brief (17 years)

q Anti-infectives are not am ongst the most p rofitable p harmaceuticals

q Vaccines may b e an an swer to pn eum ococci, bu t little advan ce against

other key pathogens

q Little progress achieved in developing non-antimicrobial treatments of

infection

NEW STRATEGIES IN ANTIM ICROBIAL DEVELOPMENT

Despite the recent dearth of new antimicrobials there are several promising

factors for antim icrobial developm ent, on a 10-year view :

the new science of genomics may yield n ew families of antimicrobials

methods of synthesising new candidate drugs have become vastly more

efficient

methods of screening antimicrobial activity have been improved

These strategies may (although this is not certain) yield whole new families

of antimicrobials toward s the end of the next decade.

How ever, even if this optimism is warranted , there will be a window with

resistance accumulating and a dearth of new antimicrobials. Furthermore, it isvirtually certain that resistance will develop to any new compoun ds, therefore

good p rescribing h abits will help preserve their value when they app ear.

Development of new antimicrobials 45


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15 PROMOTING GO OD PRACTICE

KEY POINTS

We need :

q Faster diagnosis to allow iden tification of those p atients needing

antimicrobial th erapy

qFaster susceptibility testing to allow better-tailored therapy

q Guid elines for theraby of common infections

q Computer-assisted antimicrobial prescribing

q Better surveillance as background to empirical therapy and to monitor

effects of in terventions to alter an timicrobial usage patterns

q Better communication of resistance surveillance data to GPs and in

hospitals

q Better control of infection to stop sp read of resistant b acteria

q Education of prescribers, health care staff and consumers

q Greater pu blic awareness of antimicrobial resistance

q A higher p rofile for research on the epid emiology and bases of resistance

From the precedin g sections of th is synop sis, it is clear that:

Resistance is increasing to many antimicrobials and in many species

We face the prospect of having no useful antimicrobials for some infections

Development of new antimicrobials is in progress, but will take time and

success cannot be gu aranteed

Careful antimicrobial use, and p revention of cross-infection, can minimise

the emergence and accum ulation of resistance

Once resistance has accumulated, it cannot readily be displaced

The recommend ations that we m ake are based on th ese premises.



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16 PROMOTING BETTERPRESCRIBING

KEY POINTS

Improved p rescribing can be encouraged by:

q evidence-based guidelines for prescribing (or n ot prescribing)

q compu ter-assisted systems to aid antimicrobial choice and to help theph ysician and patient avoid an antimicrobial when it is not needed

q swifter microbiological diagnosis to min imise inapp ropriate therapy

BOX 10. BETTER PRESCRIBIN G

q Stop unnecessary antimicrobial use

eg viral upper respiratory tract infection

q Shorten unnecessarily long courses

eg cystitis; surgical prophylaxis

qAvoid inapp ropriate broad -spectrum antibioticseg ciprofloxacin for URTI

q Avoid inappr opriate repeat prescriptions w ithout microbiological

confirmation

eg repeat courses

q Further research into inapp ropriate prescribing

GUIDELINES FOR ANTIMICROBIAL USE

The hu ge variation and incompleteness of current p rescribing guidelines in

many centres has already been noted. Evidence-based guidelines are urgently

needed for antimicrobial use, particularly for the treatment of common

conditions in th e commun ity. Local guidelines should take their cue from these

national guidelines to avoid re-invention of the wheel.

Guidelines should be sufficiently flexible to accommod ate regional and

local differences in th e p revalence of an timicrobial resistance, especially in

hospitals. Such differences would be informed by an antimicrobial resistance

surveillance program me.

Promoting better prescribing 47


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It is not suggested that there shou ld, say, be a national standard regimen

for UTI; rather, that there should be a series of potent ial regimens, designed to

optimise success and minimise the emergence of resistance, with the choice between

these based on local circumstances.

COMPUTER-ASSISTED PRESCRIBING (or non-prescribin g!)

Improved prescribing can potentially be encouraged by compu ter-basedadvisory systems.

Systems are being developed, piloted an d used. They are designed to

enable clinicians to augment their clinical decision-making skills rather than to

replace or control them an d to use locally derived d ata (with respect to the

epidemiology of resistance) to guide the selection of drugs.

Potential for the use of such systems exists in primary care, where there is

likely to be less local variation in p athogen p revalence and resistance, as well

as in hospitals. Use of these systems deserves urgent investigation.

Prescribing guidelines should be incorporated into th e compu ter-aided

decision-supp ort systems, improving their availability an d implementation. If

the computer systems can be made relevant to both the prescriber and the

patient this will assist in their interaction and help the prescriber to explain

why a p rescription may not be n ecessary.

IMPROVING EMPIRICAL THERAPY THROUG H

SWIFTER DIAG NO SIS

Empirical therapy is often given w hen on ly a few p atients the minority

with bacterial infections are likely to ben efit.

Simple path ogen d etection tests can be introdu ced into GPs surgeries and

are valuable if they give an instant result, identifying those who may benefit

from antimicrobial theraby. Examples include dipsticks and leucocyte esterasetests to iden tify UTI. A rap id antigen-detection test for Streptococcus pyogenes

led to a r edu ction in th e prop ortion of culture-negative patients with sore

throa ts wh o were g iven an timicrobials from 53% to 32%. The savings on

antim icrobial costs offset the costs of the tests, irrespective of any lon g-term

gain achieved by redu cing antimicrobial usage.


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ROLE OF THE MEDICAL MICROBIOLOGIST

All major acute hosp itals in the UK are served by d epartments of m edical

microbiology, under the direction of a medically qualified consultant

microbiologist. Most med ical microbiologists have close links w ith their

hospital and GP colleagues and collect information on the su sceptibility

patterns of their local bacterial isolates. Many departments provide prescribing

information for use in hospitals and general practice, based up on th ese localpatterns.

The local med ical microbiology dep artm ent also can offer ad vice on

infection control matters. As GPs u nd ertake increasing nu mbers of p rocedu res

in their surgeries, it is especially important to ensure that responsible and

thorough infection control advice is provided.

The diagn ostic facilities of the local laboratory can assist in the rational

choice of antim icrobials by ad vising on th e subm ission of specimens. Some

laboratories have gu idelines as to w hether, for example, sputu m sh ould be

examined from all p atients who have a respiratory tract infection, or on ly those

patients in wh om pr evious therapy has failed.

It is vital that hosp ital doctors and GPs form strong links w ith their med ical

microbiology colleagues in the battle against an timicrobial resistance, with the

aim of optimising p rescribing patterns.

IMPROVING MEDICAL EDUCATION

Education on antimicrobials and resistance often takes place in the early

pre-clinical years of medical and dental training and is divorced from clinical

situations where students are exposed to prescribing decisions. There is a

paucity of experts available to teach antimicrobial prescribing in the context of

clinical medicine and microbiology and this is less than ideal. Greater exposure

of medical and d ental students, hou se staff and postgradu ates in all specialitiesto the issues of antimicrobial prescribing, and the threat posed by antimicrobial

resistance, is desirable.



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COMMUNICATION

Data on local rates of pathogen prevalence and resistance are often poorly

disseminated from the laboratory to physicians, both within h ospitals and in

the commu nity. This information shou ld be th e key to th e choice of therapy

and better communication is essential.

ROLE OF HEALTH CARE PROFESSION ALS,

OTH ER THAN M EDICAL PRESCRIBERS

Although doctors are responsible for most antimicrobial prescribing, other

professionals also have a role. The roles of dentists, nurses and pharmacists are

described below . In hosp itals and comm un ity care facilities ALL staff have a

role in controlling cleanliness and hygiene, which impact hugely on the

transmission of infection and on the need for antimicrobial chemotherapy.

DENTISTS

Dentists are p rescribers, albeit for only a sm all fraction of total antim icrobial

usage. Dental practice is significant for certain antimicrobials wh ich dentists

prescribe frequently, eg metronidazole.

NURSES

Nu rses should be familiar with p rescribing p rotocols so that they can alert

doctors, wh en for examp le, antim icrobials are being p rescribed for excessively

long periods. Nurses help patients to und erstand the n ature of their illness and

the actions and sid e-effects of medications. They are in an excellent p osition to

maximise concordance and to edu cate patients. They may be able to identify

those individu als and families in w hom concordance is likely to be a p roblem

and where single-dose therapy is desirable if available.

Most of all, nurses have a key role in the pr evention and control ofinfection, especially in hosp itals.

PHARMACISTS

The pharm acist is frequently the point of contact for the p atient when a

prescription is collected an d thus can help ed ucate the p ublic about

concordan ce. Within th e commun ity, the role of the pharm acist in p roviding

services to nu rsing homes is d eveloping, and is one wh ere pharm acists could



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have an important role in influencing change in the p rescribing of

antimicrobials.

Hospital pharm acists are involved in a n um ber of key areas. They are w ell

qualified to advise prescribers on choice and change of agent as well as

suitable routes and du rations of therapy. Pharmacists commonly have an inpu t

into the ed ucation of jun ior hospital doctors about prescribing. They may also

be able to help in the enforcement of prescribing p olicies.

VETERINARY SURGEONSVeterinary su rgeons have a respon sibility to use antimicrobials pruden tly.

We recommend that the use of antimicrobials in veterinary practice should be

guided by the same principles as in hum an pr escribing viz antimicrobials

should be used only where their use is likely to yield a specific health benefit.

PUBLIC EXPECTATIONS AN D ATTITUD ES TO

ANTIMICROBIALS

Over-prescribing o f antimicrobials part ly reflects pu blic expectation. If

campaigns to red uce prescribing are aimed only at h ealth care professionals,

then these professionals w ill be left facing d issatisfied p atients or carers, not all

of whom take refusal to prescribe kindly.

We therefore propose a National Advice to the Public (NAP) campaign, to

run concurrently with the efforts to reduce and rationalise prescribing. Since

most inappropriate community use of antimicrobials is for upper RTI, this

usage should be targeted, with key messages that:

Patients should not expect antimicrobials for trivial infections

GPs may give post-dated p rescriptions wh en the n eed for an antimicrobial is

doubtful

Antimicrobials are magic bu llets invaluable bu t not to b e taken lightlyTaking an timicrobials unn ecessarily does you n o good and damages them

for everyone else

For serious infections eg meningitis swift antimicrobial therapy is

essential



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Various ways of communicating these messages could be envisaged, from

simple slogan-based advertising:

Antimicrobials cure serious diseases not colds, cough s and wh eezes...Save them for wh en its important

through billboard ad vertising, and on to p atient information leaflets such as

those produced in America by the Alliance for the Prudent Use of Antibiotics.These messages should also be communicated in schools, with information

on an timicrobials includ ed in health edu cation, maybe as p art of the N ational

Curriculum. It is highly desirable that children are taugh t the difference

between bacteria, which antibiotics kill, and viruses, which they do not kill.

The failure of many adu lts, and of the national press, to make this d istinction is

an obstacle to un derstand ing the p roblem of resistance.

Those who d esign school curricula should consider including antimicrobial

resistance as an eloquent d emonstration of evolution in action and of

evolution with very d irect consequences for man kind.

CHERISHING YOUR FLORA THE BENEFICIAL

NATURE OF BACTERIA

The normal hu man microflora comprises more bacteria than there h ave

ever been peop le upon the p lanet. The microflora has a role in the metabolism

of nutrients, vitamins, drugs, end ogenous h ormones an d carcinogens. This role

is poorly u nd erstood, but probably largely beneficial. Furtherm ore, the

microflora is probably p rotective against invasion by pathogens.

Unnecessary insults to the n ormal microflora through the injud icious use of

antibiotics can lead to adverse health outcomes. These may be transient and

self-limiting, such as the diarrhoea that may accompany a course of antibiotics,

but m ore serious p roblems may also arise (eg p seudom embranou s colitis).

The role of our normal resident microflora is now beginning to be

un derstood, and w ith und erstanding comes a realisation that we should be

cherishing ou r nor mal bacterial flora.



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17 SURVEILLANCEOF RESISTANCE

To measure the public health impact of antimicrobial resistance and of

interven tions to minim ise antimicrobial usage, requires close surveillance. The

PHLS, in liaison with th e British Society for Antimicrobial Chemotherap y and

other interested parties, is developing a multi-faceted national surveillance

scheme.

It is critical that th is receives sup por t, both financially and in term s of

encouragement to laboratories to participate.

Alert organism reporting and reference laboratory activities will identify

unu sual resistances deserving priority work, but w ill provide minimal

denom inator data. Sentinel laboratory surv eys and those where isolates are

collected centrally will provide high quality microbiology and quantitative

measu remen t of levels of resistance, but w ith small samp le sizes. Collection of

routine data will provide mass information, suitable for relation to prescribing

and pop ulation denom inators, but w ill be based on rou tine susceptibility tests,

which are poorly standard ised in th e UK.

Collectively, how ever, these activities will validate each oth er to give acomprehensive picture. The sentinel laboratory and ad hoc studies will test the

quality of the routine d ata, whilst the app earance of trend s (or unexpected

results) in the routine d ata will advise the choice of organisms deman ding

enhanced surveillance.

Surveillance of resistance 53


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18 RESEARCH ON RESISTANCEAND ON NEW ANTIM ICROBIALS

KEY POINTS

q Research on resistance has been un fashionable and u nd erfund ed

q Research is k ey to the developmen t of new antimicrobials

q Research is key to u nd erstanding h ow to preserve the value of currentantimicrobials

Whilst the prob lem of resistance is clear, there are man y aspects on w hich our

un derstand ing is limited. Consequently, there is much scope for useful

research.

BOX 11. ASPECTS MERITING FURTHER RESEARCH

q Factors driving resistance

q Mathematical modelling of resistance

q Geographical information systems

q Basic research on m echanisms of resistance

q Links between p rescribing an d resistance at ind ividu al and p opu lation

levels

q Beliefs concerning antimicrobial use, their influence on demand and

concordance

q Factors leading to inapp ropriate pr escribing

q The role of social change, pa rticularly day-care of the elder ly and children

q Compu terised d ecision-support systems

q Investment versus restriction in antimicrobial use

ANTIMICROBIAL DEVELOPMENT

The thrust of this Report is upon the conservation of present antimicrobials.

Past resistance problems have been overcome (if only temporarily) by the

development of new antimicrobials. In recent years, the p harmaceutical



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indu stry has d eveloped vastly more efficient systems for seeking new

antim icrobials. These strategies will, hop efully, yield new generat ions of

antimicrobials by the end of the next decade. It is vital that research on new

antimicrobials is encouraged and not mad e uneconomic.

If the recommend ations of this Report are followed, they shou ld red uce

overall antimicrobial usage. As a result there may be financial implications for

the ph armaceutical industry, up on wh ose profitability the development of new

antimicrobials d epend s. Consideration m ay, therefore, need to be given to

find ing ways, through pricing an d oth er mechanisms (eg, extended patents), ofmaking investment in the d evelopm ent of new antimicrobials commercially

attractive.

Research on resistance and on new antimicrobials 55

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