2.1     The evidence set out above suggests that one way to tackle drug resistance in the short term is to work towards appropriate and prudent usage of the drugs themselves. In the longer term there may be new drugs and vaccines (see Chapters 6 and 7); but every doctor, dentist and veterinary surgeon can, it seems, affect the situation for better or worse from day to day by more or less appropriate prescribing.[13]

  2.2     It must be recognised at once that, even without the issue of resistance, use of medicines is a three-cornered battlefield. Doctors want the freedom to do the best for their patients; those who pay for health care, whether governments or insurers or the patients themselves, want good care at low cost; and pharmaceutical manufacturers want to maximise the return to their shareholders. Discussion of the impact of usage on resistance cannot be divorced from this context.

Present use in the United Kingdom

  2.3     In the United Kingdom, most antimicrobials used in human medicine are prescribed by GPs (general practitioners, or family doctors). The Association of Medical Microbiologists (AMM - QQ 45-52, p 9) told us that in England alone, GPs prescribe 270m defined daily doses each year—"enough antibiotics to treat every man, woman and child in England for five days a year". This is much more than is administered in hospitals (though data do not permit a precise comparison, and even if they did one would not be comparing like with like). This figure is derived from Prescription Pricing Authority (PPA) data for 1992-94; the same data show an annual increase in prescribing of 5 per cent over the previous three years, with no simultaneous increase in infectious disease to explain it. They also show a tendency to prescribe newer drugs instead of older ones. However the AMM believe around 80 per cent of antimicrobial prescribing in United Kingdom general practice to be "fully justified" (Q 45).

  2.4     The Association of the British Pharmaceutical Industry (ABPI) gave us a different set of figures. In 1996, United Kingdom GPs wrote 51m antibiotic prescriptions, which, though a lot, was 2.5m fewer than the previous year. They conclude, "The message about not prescribing antibiotics in diseases that are probably viral appears to be getting through" (p 177).

  2.5     The Department of Health produce yet more figures, and analyse them in detail (p 343). Between 1991 and 1996 in England, the number of prescription items for antibacterials increased by only 7 per cent, and the net ingredient cost by only 4 per cent, both much less than the figures for all drugs; between 1995 and 1996 both figures went down, as noted by the ABPI. However there were wide variations from drug to drug. The group which gives "most cause for concern" is the fluoroquinolones: over the five years, use rose by 48 per cent, and cost by 81 per cent. "Ciprofloxacin is the market leader in a group of drugs which is heavily promoted". Use of penicillins rose by 13 per cent; the Department find this "disappointing", though they suggest possible innocent explanations.[14] Use of macrolides rose only marginally, but their cost rose by 58 per cent, probably because erythromycin, the original macrolide, lost market share to newer and more expensive macrolides with additional applications (e.g. azithromycin). "The newer macrolides are heavily promoted". The Department produce further figures to show that antibiotic prescribing varies widely between health authorities.

  2.6     From his experience in Oxfordshire, Dr Richard Mayon-White, a Consultant in Communicable Disease Control, considers the antibiotic prescribing of United Kingdom GPs to be "conservative" (p 110). However local monitoring has revealed "wide variations" in prescribing of expensive drugs such as ciprofloxacin. Dr Hugh McGavock, Director of the Drug Utilisation Research Unit at The Queen's University of Belfast, detects a bell-curve (Q 660): "some doctors accepting the guidelines perfectly, the majority moderately well, and some doctors on the far side of the curve hardly paying any attention to them". The Royal College of General Practitioners (RCGP) stand by their profession: "Given the context of diagnostic uncertainty, current prescribing practice of GPs is in general more beneficial than harmful in the care of individual patients" (p 166). However, "There is sufficient evidence of widespread variation in the utilisation of antibiotics to suggest that there is scope for further reduction of their use by some practitioners". Dr Davey is more sceptical about GP prescribing. "We have intense debates about whether children with otitis media should receive antibiotics, or people with sore throats. But our work would suggest that the majority of patients to receive antibiotics...just have runny noses, where there is no evidence that they benefit" (Q 265).

  2.7     There is no equivalent to PPA data for hospitals (DH p 342); all one can say for certain is that hospitals dispense a much smaller volume of antimicrobials than are prescribed in general practice. According to the Department of Health, 15-20 per cent of hospital expenditure on drugs goes on antimicrobials; and around one in-patient in four receives at least one course of antibiotics. The AMM produced, by different routes, two different "ballpark" figures: on the one hand, 1-2m daily doses per year in English hospitals, or on the other the significantly higher figure of something under 5m in the whole United Kingdom (p 9). 20-30 per cent of hospital usage of antimicrobials is for prophylaxis against infection during surgery; and, according to the AMM, "courses given are often longer than necessary". Dr Davey also has doubts about current practice in this area (p 152; QQ 267, 272): "At the moment I do not think we have sufficient debate about what level of benefit [in terms of reduced risk from infection] justifies the use of antibiotics".[15]

Towards more prudent use

  2.8     The AMM believe that, by a significant and sustained campaign of education, it might be possible to eliminate the "small proportion" of United Kingdom GP prescribing which they believe to be completely unjustified, and to reduce the larger proportion which "is perhaps not founded on the best evidence-based practice but may be justified by medical, cultural or psychological reason". They warned us, "The continuing legitimate use of antibiotics in humans may still sustain and might even increase the amount of resistance"[16]; to say nothing of resistance continuing to be generated in animals, and in humans in other countries where imprudent use persists. However, "the medical profession must put its own house in order before it can expect others to do so" (pp 8-13). On the other hand Dr Davey, who believes that more than half of GP prescribing is justified by nothing more than a runny nose, would happily "let the people with the sore throats get antibiotics but concentrate on the people who do not have any clinical signs which warrant antibiotics" (Q 265).

  2.9     These contrasting positions present the question, What constitutes prudence? The RCGP insist that, although doctors have a national, strategic responsibility for public health, this cannot override their primary responsibility to the individual patient (p 167, Q 280). Dr Davey put it more bluntly: "I would much rather...some people received unnecessary treatment than we end up with somebody dying" (Q 268). Dr McGavock was equally blunt on the other side of the dilemma: "[Over-prescription] is a situation that really must be changed if we wish to preserve the antimicrobial era...it may well go on, but if it does our grandchildren will curse us for wasting this limited human resource" (Q 647). Witnesses have pointed to various ways to resolve this dilemma; we consider them below.

Formularies, policies and guidelines

  2.10     A formulary is a list of available drugs, or of drugs recommended from among those available; a policy gives guidance or instruction on when and how they are to be used. In the United Kingdom, most hospitals and some general practices have at least a formulary of antibacterials recommended for local use, and some hospitals have antibacterial policies.

  2.11     The PHLS presented us with the findings of a survey of clinical audit in hospitals in England and Wales, in the context of MRSA (p 41). They found that formularies vary widely in form and content, and "are drawn up with little involvement of the junior staff; comments are often not invited"; that communication of antibiotic policies to new staff is often poor; and that audit of prescribing is often irregular, infrequent and unstructured. The AMM recommend that all hospitals and general practices should have both formularies and policies. These should be produced in a way which gives the doctor "ownership"; and they should be supported by strong encouragement from the health departments, and by audit.

  2.12     Policies may operate at any level, from local to global (RCGP p 167; DH p 344; Petrie Q 669). They may reflect the threat of resistance by recommending rotation or combination of drugs (Davey Q 263, Spencer p 519, Tyrell p 528), or by avoiding certain drugs altogether (PHLS p 52). They may be supported by restrictive reporting,[17] by financial incentives (recommended by Dr McGavock, Q 658) and even by compulsion (resisted by Professor Petrie, Q 674). They may be more or less flexible; Glaxo Wellcome advocate flexibility, "to enable nimble local responses to changes in resistance patterns" (p 407). Box 3 gives examples of good practice in this area which have come to our notice.

Box 3

FORMULARIES, POLICIES AND GUIDELINES:

EXAMPLES OF GOOD PRACTICE

Grampian Formulary

The Grampian Formulary has broad ownership in both hospital and general practice and vigorous monitoring by ward pharmacists and Health Board Prescribing Advisers. Professor Petrie claims that it achieves GP concurrence or compliance of 90-96 per cent (QQ 648, 672, 684). It is commended by the Scottish Microbiology Association (p 471).

Scottish Intercollegiate Guidelines Network (SIGN)

SIGN (Q 663) is a wide group of professionals and others who are working together to produce evidence-based guidelines for a range of conditions. There are formal procedures for proposing a guideline, prioritising projects, literature reviews, grading of evidence and recommendations, and critical appraisal. 21 guidelines have been published, on paper and on the Internet, and 48 are in preparation; infectious diseases are rising up SIGN's list of priorities. Putting the guidelines into practice has involved groups of GPs, associations of patients, and newspapers; and the Royal Colleges and the Scottish Council for Postgraduate Dental and Medical Education use them in the process of accreditation for training. There are arrangements for audit and feedback. Professor Petrie emphasized the importance of local "ownership", and of implementation; "simply sending out a guideline is a waste of time" (Q 664).

PRODIGY

PRODIGY (Prescribing Rationally with Decision Support in General Practice) is a project to develop an electronic guideline (or "decision support") system, intended for use on a GP's desktop computer. Dr Davey commended PRODIGY (Q 250). So did the RCGP (p 167, Q 290); they told us that PRODIGY is being piloted in 200 practices with funding from the Department of Health, and that other similar systems are under development. The Department observe that guidance delivered through PRODIGY is "adjusted to local conditions to reinforce local policies"; and that computer prescribing systems are in use in some hospitals (p 344).

  2.13     A policy is not a panacea. It must be sound in itself, and must be implemented conscientiously and intelligently. It must also be policed: see below, paragraph 2.34. Dr R C Spencer, of the Public Health Laboratory at Bristol Royal Infirmary, points out that policies depend on surveillance, to indicate what the infecting organism is most likely to be, and what resistances it is likely to exhibit (p 513). We consider surveillance in Chapter 5. As for implementation, Professor Percival gave us the example of a policy drawn up for severe community-acquired pneumonia; it was applied to pneumonia of all kinds, and is now blamed for "a tremendous increase in Clostridium difficile side-effects" (Q 104).

  2.14     The pharmaceutical industry strongly prefer evidence-based guidelines for appropriate prescribing, rather than crude injunctions to prescribe less. In some situations, they say, certain drugs should be withdrawn, in others they should be used in combination (particularly for TB and HIV) or rotated; in others new and better agents should be used. Guidelines must be based on evidence, which the industry is willing to provide (see Box 11 below). Glaxo Wellcome and SmithKline Beecham make no bones about it: if use of their anti-infective products were restricted beyond a certain point, they would place their investments somewhere else.[18]

  2.15     In the USA, one of the pressures towards imprudent prescribing is fear of litigation. In United Kingdom law, a doctor who prescribes in accordance with a local policy is unlikely to be successfully sued for negligence (Davey p 156). Professor James Petrie of the University of Aberdeen described the British legal position in this area as "reassuring" (Q 674). Dr McGavock expressed himself more concerned about being sued for prescribing too much than for prescribing too little (Q 642).

Rapid testing

  2.16     Susceptibility testing by the standard methods takes 48 hours; the whole process, from the doctor taking the specimen to receiving the result, may take longer. In the meantime, the doctor must prescribe empirically, and may prescribe inappropriately. Many witnesses have put it to us that the cause of prudent use would be much advanced by more rapid testing. According to the ABPI, rapid testing for routine infections is on the way. "People are working on it, and it will become available in due course"—perhaps in 5-10 years (Q 341). SmithKline Beecham call on the Government to support technology development, possibly through the EU (p 485).

  2.17     The PHLS agreed that faster testing would be helpful (Q 109). "Genotypic" tests, which use the polymerase chain reaction (PCR) to examine the isolate's DNA, are already in use. However, these "will not replace the existing methods entirely", because they are expensive, and because they answer only one question at a time. Professor Roger Finch of the University of Nottingham believes that the expense of genotypic testing for the wide range of infections encountered in general practice will be prohibitive (Q 385). Dr Davey sounded a further note of caution (QQ 269-271): even if rapid analysis were available, it would say only that a certain organism was present, not that it was necessarily the cause of the disease.

  2.18     Even without faster tests, the process could be speeded up if results could be reported electronically. The RCGP told us that systems to do this exist already (Q 294). The recent NHS White Paper The new NHS (Cm 3807) indicates that one immediate application envisaged for the projected "NHSnet", linking all hospitals and GP practices, is to be transmission of test results (paragraph 1.12).

Prescription checking and control

  2.19     A hospital formulary may incorporate controls, whereby certain agents may be prescribed only with certain levels of authority. According to the AMM, "Recent evidence from the USA shows that it is possible by considerable effort (prior approval from an infection specialist for the use of an antibacterial from a restricted list) to influence prescribing without adversely affecting clinical outcomes and with improvements in the sensitivities of bacteria" (p 10).

  2.20     According to the Department of Health (p 344), although routine prescribing of antimicrobials in hospitals is done by junior doctors, "Access to non-routine agents is restricted through the hospital pharmacy", and in most hospitals pharmacists visit the wards every day to check prescriptions and advise.[19] However the PHLS clinical audit project found that practice in this respect, in hospitals in England and Wales, "varied greatly"; and Dr Davey, as a hospital consultant, admitted that prescribing by junior doctors at night is often not reviewed by senior staff in the morning (QQ 245, 268). He suggested that there might be a role here for senior nurses.

  2.21     Senior practitioners whom we met in Boston disagreed as to the appropriate level of control. Dr Sherwood Gorbach favoured requiring that every prescription for a drug associated with a resistance problem be accompanied by a "chit" giving the reason for prescribing. Dr Anton Medeiros considered that this would restrict professional freedom to a degree unacceptable in the USA; he believed that, if surveillance was thorough and its findings were properly communicated, doctors would moderate their practice voluntarily. See Appendix 6.

   2.22     In general practice, there is a long and strong tradition of clinical freedom and responsibility. Dr McGavock considered (QQ 650, 657-660, and p 300) that liberty has degenerated into licence, and that the seriousness of the threat to the effectiveness of antimicrobials justifies extreme measures. He recommended that GPs should be prohibited from prescribing specific new, expensive, broad-spectrum antibiotics without first receiving microbiological advice. Professor Petrie considered this to be unaffordable and impractical. Dr McGavock acknowledged that it would be expensive, but insisted that it was a price worth paying to prolong the "antimicrobial era".

Pharmaceutical licensing

  2.23     It would in principle be possible for a licensing authority, considering a new application, to turn it down on the basis that the new drug, though effective, was no more so than drugs already on the market, and was more likely to induce resistance. This is not however the usual approach. Dr Ross Taylor of the RCGP told us (Q 283), "I think the fundamental problem is that in this country medicines are licensed on the basis of effectiveness, not comparative effectiveness. So, if an antibiotic is licensed, a company can quite legitimately...promote that medicine...whether or not there is another antibiotic already available that might be better". Similarly, it would in principle be possible for a licensing authority to modify or withdraw a licence if resistance induced by the drug rose to a certain level (Finch p 189). Dr McGavock recommended that certain antibiotics should be licensed for hospital use only, so that GPs could not use them at all (p 300).

Pharmaceutical salesmanship

  2.24     The AMM blame the increase in prescribing of antimicrobials, and the tendency to prescribe more expensive drugs where cheaper ones would do, on advertising and salesmanship by the pharmaceutical industry. The comments of the Department of Health on the increased use of ciprofloxacin and the more expensive macrolides, noted above, suggest that they agree—though in oral evidence, the Chief Medical Officer deprecated any suggestion that the industry went beyond reasonable bounds, and said that increased use of macrolides may have been due to a new indication for use (Q 789). Professor Petrie gave a startling example of promotion which he regarded as excessive: provision by a company to a community on-call service of free "starter packs" of the antibiotics co-amoxiclav (Q 654) and clarithromycin (Q 657). The AMM call for "stricter controls" to restrain "over-zealous promotion"; so did Dr Rosamund Williams of WHO (Q 127).

  2.25     Dr Mayon-White considers pharmaceutical salesmanship an "important influence" on GP prescribing, but not necessarily a bad one: "it can be a collaborative process in setting policies and getting educational messages across" (Q 158). For this to happen, he says, health authorities and doctors must be "in control of the process". The RCGP likewise declined to condemn pharmaceutical marketing outright (Q 282); they consider it necessary and useful, and believe that GPs are able to retain control. The ABPI observe that their members' marketing is governed by a code of practice administered by an independent body; they consider that the pressure on GPs to prescribe comes more from patients (see below) and from lack of time than from the industry (Q 333).

14   Demographic factors, or an increase in repeat treatments due to rising resistance. Back

15   Cp BMA: "Antibiotic misuse is common and studies have suggested that up to 70 per cent of treatment courses are unnecessary or inappropriate. Therapy is often unnecessarily prolonged and prophylaxis is often inappropriate or given at the wrong time" (p 381). The National Committee for Microbiology also express concern in this area (p 541). Back

16   Cp Glaxo Wellcome: "The recent lessons learnt from anti-retroviral chemotherapy have demonstrated the very powerful effects that natural selection can have, even when prescribing is entirely appropriate and patients are highly motivated to comply with treatment" (p 407). Back

17   Restrictive reporting: When a doctor sends a specimen to a laboratory for microbiological analysis and susceptibility testing, the microbiologist must decide what to report. Reporting every bacterial isolate would be unhelpful, since it would include normal flora and contaminants; the doctor is interested only in possible pathogens. Reporting the susceptibility of each isolate to every conceivable antimicrobial would be impossible; in practice, only certain susceptibilities are tested or reported. In the United Kingdom, microbiologists turn these facts of life to advantage. According to the AMM, "Reporting is tailored to what is felt to be appropriate for the individual patient and the wider context, and is often made to be concordant with the hospital's formulary and antibacterial policies". Back

18   GW: "The outcome will be a "deprioritisation" of this area in favour of others" (p 407). SKB: "Inappropriate restrictions...would of necessity cause companies to invest their research effort in other, more profitable, therapeutic areas" (p 475). Back

19   The Hammersmith Hospital has appointed a specialist clinical pharmacist working exclusively on antimicrobials. This has led to reduced infection, and annual savings of £77,000 (DH p 345). On the general role of the hospital pharmacist, see the evidence of the Royal Pharmaceutical Society, p 461. Back