CHAPTER 10 RESOURCES FOR RESEARCH
AND DATA-COLLECTION |
10.1 We have heard
from a succession of clinical academics and other scientists that
little funding is available for applied research into the problems
of antimicrobial resistance, or for the collection of the data
necessary for systematic and effective surveillance. The position
appears to be in marked contrast to the vast resources devoted,
largely by the pharmaceutical companies, to basic research and
different ways of using antibiotics
10.2 According to the
RCGP, research funding for evaluation of different antibiotic
strategies is hard to come by. The College has even taken the
unusual step of providing funds itself (Q 310). Professor
Finch likewise called for more research into antibiotic strategies.
"We need to understand the best regimen for particular infections,
not relying on those which were tested at the time of licensing
in the US where the practice of medicine differs" (Q 386;
cp Griffin p 548).
strategies of professional and public education
|UK PHARMACEUTICAL INDUSTRY
|EXAMPLES OF SURVEILLANCE ACTIVITIES
|Glaxo Wellcome (p 407)
|Glaxo Wellcome tell us that they "co-operate with local health authorities" to provide information on resistance patterns to guide prescribing. They are also "in contact with the WHO surveillance programme with the objective of both contributing to, and reacting to, knowledge of resistance emergence and spread".
|SmithKline Beecham (SKB) (p 476)
|According to SKB, the pharmaceutical industry has been involved in surveillance "for some time", with the aims of evaluating the medical need and commercial value of new products, and of informing appropriate use of existing ones. Industry provides funding; the work is done by clinical microbiology laboratories and research institutions; data from most such studies are published. "Overall, SKB is funding microbial susceptibility surveys in over 50 countries."
|SKB claim to have been "at the forefront of a movement to address the lack of more global, longer-term studies". SKB funded the Alexander Project, to produce and publish high-quality susceptibility data for respiratory pathogens from Europe and the USA. The project began in 1992, and was extended in 1996 to countries in Asia and Africa. Other similar studies supported by industry "are now emerging".
|SKB are among the companies supporting the WHO Antimicrobial Resistance Monitoring Programme. SKB contributed to the funding of WHONET (see paragraph 9.3), and support a Centre-of-Excellence Laboratory Advisory Board to help developing countries' laboratories to produce reliable surveillance data.
|According to SKB, industry is "continuing to explore ways of making surveillance data available...to aid local prescribing decisions"; to aid the interpretation of the data, so as to "reduce the potential for recurrence, relapse, transmission and increase in resistance"; and to use surveillance data, prescribing data and clinical outcome data to model and predict the causes, trends and effects of resistance.
|SKB acknowledge that the industry's resources put it in "a unique position" to fund data-generation. It does so "willingly, and with the goal of an increasingly evidence-based approach to antibiotic usage in mind".
|Zeneca Pharmaceuticals (p 544)
|"In support of our marketed anti-infectives", Zeneca recently conducted a 56-centre surveillance programme in the United Kingdom. They also have studies in Europe, and in the USA, in collaboration with CDC.
10.3 Professor Peter
Borriello of the PHLS, Director of the Central Public Health Laboratory,
observed that, if prescribing practice does indeed affect resistance,
then research is needed into what affects prescribing practice,
and how best to influence it. "It is not usually the easiest
thing...because you are dealing with individuals" (Q 107).
According to Dr Grimshaw, this is in fact a flourishing field,
with "an increasing body of international literature from
rigorous studies", and a "substantive" programme
of research and development funded by the NHS. "Up until
now most of the evidence is North American, but the United Kingdom
is rapidly catching up" (Q 672). Dr Williams of
WHO likewise called for evaluation of programmes of patient/public
education (QQ 119, 138).
10.4 The PHLS are not
in a position to match patterns of prescribing with patterns of
resistance (QQ 71-80, 107). Their resistance data are subject
to acknowledged limitations; and they have no prescribing data
at all, though some data sets exist for parts of the United Kingdom
(Wales, and Tayside as described below). The PHLS have plans to
begin to remedy this deficiency: in a development of TB surveillance
(MYCOBNET), "it is planned to analyse treatment regimens
in relation to acquired resistance"; and they are undertaking
a GP research initiative by which they hope to acquire a network
of sentinel practices. We were surprised to hear that they have
not used PPA data for this purpose, though Professor Duerden said,
"I think they should be made use of".
10.5 The Department
of Health propose to collaborate with the Oxford University Unit
of Health-Care Epidemiology to compare the wide regional variations
in use of antibiotics noted in Chapter 2 with variations
in resistance (p 344). This "will provide a useful first
step in determining whether the level of community antibiotic
utilisation affects the level of antibiotic resistance".
10.6 Dr Davey told
us about his work at the micro-level in Tayside. With some difficulty,
the Tayside Medicines Monitoring Unit have induced GPs and hospitals
to use the same identifying number for each patient, so that individual
records can be linked (Q 237). To improve the usefulness
of the records themselves, the Infectious Diseases Unit at Ninewells
Hospital has produced a stamp or sticker which prompts the doctor
to write essential information in the patient's notes; but they
are having difficulty exporting the concept to other units in
the hospital, let alone elsewhere (p 151, Q 242). Dr Davey
drew our attention to the possible implications, for use of this
sort of information, of the Data Protection Bill [HL] currently
before Parliament, which implements the EU Data Protection Directive
10.7 We have been told
often that, whereas GPs are generally equipped to quite a high
level with information systems suitable for recording and analysing
prescription data, British hospitals are not (DH p 344; AMM
QQ 45, 49; Davey p 150, Q 251). Dr Davey said,
"Probably the single biggest fault...is that the information
systems are not being designed to provide clinically useful information;
they have been designed to provide information on accounting and
throughput" (Q 259). Dr Winyard of the NHS Executive
(Q 784) acknowledged this as "a real issue"; a
few hospitals have now installed computer prescribing systems,
and the Department of Health has commissioned the National Prescribing
Centre to conduct a pilot study with ten of them.
10.8 The preface to
the Cooke Report says, "The group has been very aware of
the continuing need for, and importance of, applied research into
the surveillance, prevention and control of hospital-acquired
infection". Professor Percival agreed (Q 108),
and complained in colourful terms of the difficulty of getting
grants for "pragmatic research" into, for instance,
control of MRSA. Dr Mayon-White would like to see more formal
trials of infection control policies; this would not be easy,
but would be an improvement on "best advice and existing
practice" (Q 173).
denominator data for disease surveillance
10.9 The Public Health
Laboratory Service (PHLS) are the first to admit that their surveillance
data have shortcomings, and one of the biggest is in the area
of denominators (PHLS p 38, cp DH p 335). Generally
speaking, to know that in a certain period laboratories in a certain
area found X isolates of a certain organism to exhibit a certain
resistance is to know little of value, beyond the clinical importance
of each individual result. The laboratories can generally express
X as a percentage of all isolates of that organism tested for
susceptibility; the denominator is the total number of isolates
tested, the number of resistant isolates being the numerator.
10.10 However this
is still defective information, since laboratory isolates are
only a fraction, and an unknown fraction, of all the examples
of the organism at large in the area. What is worse, they are
not normally a representative fraction; generally speaking, laboratories
only see what doctors choose to send them (Q 77). This will
tend to consist of problematical samples, including probably a
higher proportion of resistant strains than is found in the general
population (Q 111). It will consist largely of samples taken
in hospitals (QQ 81, 383): according to the AMM, "Typically
some 40 per cent of the microbiology specimens processed
by a district general hospital laboratory come from the community"
(p 7). It may contain multiple specimens from the same person,
or specimens from persons who have infected each other (AMM p 5).
It will exclude conditions such as pneumonia which do not often
give rise to specimens suitable for susceptibility testing in
vitro (i.e. in the laboratory) (Q 77). Finally, it will
not be randomised for factors such as age and gender (BSAC p 78).
The problem is compounded because, at present, PHLS reference
laboratories only see what peripheral laboratories choose to send
them. Studies funded by the pharmaceutical industry are subject
to the same constraints (SKB p 477). Better denominator data
can be achieved, but only with extra effort and expense.
10.11 The PHLS admit
that their data are largely confined to hospital isolates, and
to isolates from invasive disease. They do not know "the
wider pattern of resistance or susceptibility in the community
at large, where we do not necessarily get the specimens into the
laboratories. We have not conducted special surveys through the
PHLS for those" (Q 71). The ICNA are particularly aware
of the lack of surveillance of "community reservoirs of MRSA,
especially in nursing homes" (p 126).
10.12 Dr Mayon-White
similarly told us, "The study of antimicrobial resistance
outside hospitals in Britain has been highly selective, typically
focused on a single species or group of micro-organisms, often
in one geographical area" (p 107). He advocates "the
collection of comparable data on antimicrobial resistance in a
number of different settings across the country" (Q 173).
He told us, however, that it is difficult to find funding for
such work, since it goes beyond standard service provision but
falls short of research. He suggested that it might find a home
in the NHS R&D programme, as "health services research"
10.13 In general practice,
sentinel or spotter practices can be recruited, and invited to
submit more specimens than would be necessary for purely clinical
reasons (Q 78). Professor Finch considers that a network
of such practices would provide "valuable information"
systems of surveillance
10.14 According to
Dr MacGowan of the BSAC, "We are still not very certain what
the correct method of surveillance is" (Q 109). He would
look to the NHS Directors of R&D to fund such work; but he
fears it is not "fashionable". Likewise Dr Bartlett
of PHLS calls for careful evaluation of new surveillance systems
A funding gap?
10.15 In short, across
the range of our enquiry, there appear to be research needs, and
a lack of public resources to meet them. The research in question
would be highly applied, whether into better ways to use existing
antibiotics, or ways to educate doctors and patients to use antibiotics
more wisely, or means to prevent and control infection, or systems
of disease surveillance. Some of it would amount to sheer data-collection,
whether to collect the denominator data needed to put reported
cases of disease in perspective, or to survey prescribing practice
in order to inform the campaign for prudent use.
10.16 We put this matter
to Professor Roy Anderson, a researcher in his own right in the
basic but highly relevant field of population genetics, and a
Governor of the Wellcome Trust. Speaking for the Trust, he acknowledged
the problem: since 1992 the Trust has put around £90m into
bacteriology (p 306), but only around £4.5m of that
into the area of resistance. He was robustly defensive of the
Trust's position: it was for the Government, not the Trust, to
fund the work of public sector research establishments such as
the PHLS (Q 689), and to support research to improve the
operations of the NHS (Q 710). In any case, the Trust received
few applications of high quality for support for work of this
kind (QQ 706, 711). He acknowledged, however, that the Trust's
panels of reviewers for grant applications tended to be composed
of the best fundamental researchers, who might not fully appreciate
the merit of more down-stream work (Q 710).
10.17 Professor Anderson
indicated that the Wellcome Trust is moving to help to fill the
funding gap. Scientific advances in genome sequencing (see Chapter 6)
and population genetics are attracting researchers and funding
to this area; and the Trust may be going to do more in future
for epidemiology (QQ 686, 706). The Trust attaches importance
to clinical research, and is funding research fellowships in medical
microbiology (QQ 709, 713-5). Although the Trust will not
support the PHLS directly, they are hoping to support university-based
projects involving the PHLS in close collaboration (Q 689).
10.18 According to
Professor S Amyes of Edinburgh University, whose Department
of Medical Microbiology has a large research section devoted to
the study of resistance, the Medical Research Council (MRC) has
been notably reluctant to support bacteriology in general and
resistance-related research in particular (p 544; cp Ayliffe,
p 377). The MRC puts over £60m per year into immunology,
infection and inflammatory disease. But most of this is basic
molecular biology; expenditure specifically addressing resistance
came to only £0.3m in 1995-96. The MRC say (p 429),
"The current scale of research in part reflects the capacity
of the academic science base to develop high quality research
proposals. MRC's view is that there is potential to develop more
high-quality work on resistance in the United Kingdom". In
January, the MRC held an interdisciplinary workshop with the Department
of Health and a number of independent experts on resistance, to
explore ways in which academia might complement the efforts of
industry; this recommended that clinical microbiology and antibiotic
resistance should be priority areas for MRC training schemes and
LINK (academic-industrial research partnership) awards.
10.19 The apparent
lack of high-quality proposals may be deceptive: the Royal College
of Pathologists (p 455) identifies a vicious circle in operation.
"The climate is such that many who would apply, decide not
to do so because they are reluctant to waste their own and funders'
timeand this despite funders' stated wish, at least from
time to time, to support such work."
10.20 We put the matter
to the Minister for Public Health and the Chief Medical Officer,
and they acknowledged the problem. The Minister said (Q 780),
"The way in which research budgets are presently constructed
does not necessarily mean that public health issues are given
a proper opportunity to have a bid for resources". She regards
this as a "fundamental problem about the structure and nature
of public health research". She has already left the MRC
"under absolutely no illusion" as to her view of the
matter, and she intends to pursue it further. The Chief Medical
Officer is similarly anxious (Q 782) that development should
be supported, as well as research (e.g. resistance breakpoints,
as well as basic molecular biology); he considers that this is
appropriate for support from the NHS R&D budget.
The Biotechnology and Biological Sciences Research Council (BBSRC)
also has interests in this area: see p 379. Back