CHAPTER 2 PRUDENT USE IN HUMAN
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.
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"
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.
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"
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".
Towards more prudent
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
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.
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
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, 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.
|FORMULARIES, POLICIES AND GUIDELINES:
|EXAMPLES OF GOOD PRACTICE
|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 (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.
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).
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).
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.
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
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).
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 agreethough 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).
What we have to say about doctors should be taken to apply mutatis
mutandis to dentists. Veterinary practice is discussed separately
in the next chapter. Back
Demographic factors, or an increase in repeat treatments due to
rising resistance. Back
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
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
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
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
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