Professional Documents
Culture Documents
Antimicrobial Resistance
Antimicrobial Resistance
Antimicrobial
Resistance in 2000
England and Wales
Acknowledgements
This report was prepared by Dr Patricia Prendiville*, L. Bishop#, T. Lamagni#, R. Dattani# and G.
Duckworth#, but brings together contributions from very many different units and datasets. It
would not have been possible without the help of many colleagues who contributed information
and data from their units. We are very grateful for their help in the production of this report. We
apologise unreservedly if any contribution has been inadvertently omitted. The unsung heroes are
the microbiology, communicable disease control and regional epidemiology staff who were
responsible for reporting, collecting and collating reports or putting the systems in place to make
this possible. Thank you.
Joan Birkin
Jon Brazier
Tom Cheasty
Barry Evans
Kevin Fenton
Jenny Frost
Rob George
Iain Gillespie
Douglas Harding
Alan Herring
Cathy Ison
Dorothy James
Elizabeth Johnson
Alan Johnson
Sue Le Baigue
David Livermore
Harry Mallinson
Sarah O’ Brien
Robert Owen
Andrew Pearson
Deenan Pillay
Mary Ramsay
Peter Ridout
Ian Simms
Mary Slack
Alistair Story
Louise Teare
John Threlfall
Andrew Turner
Martin Wale
Simon Ward
John Watson
*Communicable Disease Officer, South East Health Board, Ireland, on secondment to PHLS Communicable Disease
Surveillance Centre
#Division of Healthcare Associated Infection & Antimicrobial Resistance, PHLS Communicable Disease
Surveillance Centre
antimicrobial resistance in England & Wales 2000
Key Points
3
antimicrobial resistance in England & Wales 2000
ceftazidime and imipenem susceptibility was reported far less frequently than for gentamicin
and ciprofloxacin.
• Gentamicin resistance was indicated in 8% of Pseudomonas aeruginosa bacteraemia reports.
Ciprofloxacin and ceftazidime resistance were indicated in 15% and 8% of these reports.
However, there was wide regional variation in these levels with 21% gentamicin and 27%
ciprofloxacin resistance in Wales and 19% ceftazidime resistance in London.
• Detailed examination of antimicrobial susceptibilities of Acinetobacter spp was not undertaken,
given the difficulties laboratories face in speciation. This means that A. baumannii/calcoaceticus
and A. lwoffii (species with very different susceptibilities) are not adequately differentiated.
However, a survey of 54 hospitals including non-bacteraemia as well as bacteraemia isolates
indicated that over 90% of isolates were susceptible to carbapenems, colistin and minocycline,
between 70-90% were susceptible to sulbactam, piperacillin/tazobactam and amikacin, but
fewer than 20% were susceptible to cephalosporins or tetracycline. Although carbapenem
resistance is very rare, it is emerging, but tends to be over-reported by referring clinical
laboratories.
Tuberculosis
• Over 40% of all tuberculosis cases in England and Wales occur in London.
• Resistance to anti-tuberculous drugs has remained relatively stable in 2000, 6.4% of isolates
being isoniazid resistant, 1.5% rifampicin resistant, 6.8% resistant to at least one first-line
drug, 1.2% resistant to more than one first line drug and 1.1% resistant to at least isoniazid
and rifampicin. London accounts for most cases of isoniazid resistance.
Gastrointestinal infections
• Campylobacter is the commonest reported enteric pathogen (106/100,000), numbers of
reported cases continuing to rise, as does resistance to ciprofloxacin (18% in C. jejuni and
26% in C. coli). Erythromycin resistance remains low at 1% and 5% in C. jejuni and C. coli
respectively.
4
antimicrobial resistance in England & Wales 2000
• The commonest Salmonella enteritica serotypes are prone to multiple resistance, which was
recorded in 67% and 49% of S. Typhimurium and S. Virchow isolates respectively. Ciprofloxacin
resistance was reported in 11% of S. Enteritidis, 12% of S. Typhimurium, 52% of S. Virchow
and 48% of S. Hadar.
• Multiple resistance is commoner in non-sonnei shigella cases, usually imported infections,
than in S. sonnei. Ampicillin resistance is high in both types (61% and 62%), with
chloramphenicol resistance being high in non-sonnei (59%) and low in S. sonnei (3%).
• Antimicrobial resistance in E. coli 0157 is at 2% or under for ampicillin, chloramphenicol,
gentamicin and ciprofloxacin, but higher for tetracyclines and sulphonamides (13% and 14%).
• Culture is not routinely undertaken for the diagnosis of C. difficile infection and this hampers
monitoring of antimicrobial susceptibility. Susceptibility testing of 50 random isolates submitted
to the Reference Unit in 1996 showed no resistance to metronidazole, vancomycin or
Augmentin. Resistance was reported to piperacillin-tazobactam (4%), chloramphenicol (6%),
tetracycline (8%), penicillin (14%), clindamycin (20%), erythromycin (46%), imipenem (96%)
and cefoxitin (100%). Metronidazole resistance was subsequently reported in a hospital
environmental isolate, the first such report in England and Wales.
• There is no surveillance network for monitoring H. pylori susceptibility. Studies in Essex and
London show a variable rate of resistance of Helicobacter pylori to standard recommended
treatment between the regions.
5
antimicrobial resistance in England & Wales 2000
Fungal Infections
• There is no surveillance network for monitoring antifungal drug resistance in the UK.
• Although Candida albicans remains the predominant yeast pathogen, there are increasing
numbers of other yeast species which are less susceptible to fluconazole, such as C. krusei and
C. glabrata, possibly associated with the use of azole derivatives. Of 194 blood culture isolates
of C. glabrata tested by the Mycology Reference Laboratory, 12% were resistant to fluconazole,
a further 25% were in an intermediate category and 43% were at the top concentration of
the currently accepted susceptible range.
• Fluconazole resistance in C. albicans appears to be less of a serious problem since the introduction
of HAART for HIV infection, fewer than 1% of referred isolates are resistant.
• There are emerging mould pathogens such as Scedosporium spp, Fusarium spp and some of
the zygomycetes that are resistant in vitro to many or all of the available antifungal agents.
Summary points
• There are many caveats associated with the reporting of infections for surveillance purposes
and these must be considered when interpreting the data. Thus the consistency and
completeness of reporting may vary within and between laboratories.
• This would be significantly improved through electronic automated reporting from laboratory
IT systems, but this is hampered by a multiplicity of laboratory systems, including many old
systems that have difficulty exporting data, and different specimen coding by laboratories,
which makes mapping individual laboratory codes labour-intensive and time-consuming.
• Standardised methods for culture and susceptibility testing (including “core” sets of antibiotics
tested by all laboratories) would address many of the issues around speciation of micro-organisms
and inaccurate susceptibility results. This should then be validated through regular surveys
involving a network of representative laboratories.
• Sentinel networks of laboratories are required for the culture and susceptibility testing of
organisms that are not routinely cultured for the diagnosis of infection, such as Clostridium
difficile, Chlamydia trachomatis and Helicobacter pylori.
• Surveillance systems are required where there is not currently a formalised programme of
susceptibility testing, such as HIV, hepatitis B and C and invasive fungal infections.
• More information is required regionally and nationally on the susceptibility of organisms causing
less serious infections in the community e.g. organisms causing urinary and respiratory tract
infections.
• There is a need to link antimicrobial susceptibility information with prescribing information.
For the community population, this is hampered by the lack of readily accessible information
regionally and nationally on the susceptibility of organisms causing less serious infections
occurring in the community, but information on prescribing is generally available. For the
hospital population, there is more easily available information on infections, but a paucity of
information on antimicrobial prescribing regionally and nationally.
6
antimicrobial resistance in England & Wales 2000
Overview
This report reviews surveillance information available within the PHLS on antimicrobial resistance
in a wide variety of micro-organisms in England and Wales for the year 2000.
Introduction
Controlling antimicrobial resistance has been assuming greater priority over the past few years,
following publication of various reports, such as “The Path of Least Resistance”1 from the Standing
Medical Advisory Committee Sub-Group on Antimicrobial Resistance and “Resistance to antibiotics
and other antimicrobial agents”2,3 from the House of Lords Select Committee on Science and
Technology. These led to the NHS Executive’s Health Service Circular in 1999 on “Resistance to
Antibiotics and Other Antimicrobial Agents”4 and a national strategy and action plan to limit the
development and spread of further resistance. This latter included a national public awareness
campaign aimed at reducing inappropriate antimicrobial prescribing. Subsequently a national
Specialist Advisory Committee on Antimicrobial Resistance (SACAR) has been established to advise
the Government on future strategy in this area. It has an overarching role covering the medical,
veterinary and agricultural use of antimicrobials.
Surveillance is central to the control of antimicrobial resistance. Unlike other therapeutic agents,
the efficacy of antimicrobials in individuals may be affected by previous use in other people, where
the development of resistance may have occurred.5 The monitoring of changing patterns of
resistance may signal emerging problems, which should facilitate the introduction of appropriately
targeted interventions and control measures, as well as indicating areas for further research. At
the individual patient level information from laboratory susceptibility testing allows informed
decisions on therapeutic options for patients where samples have been submitted. Surveillance
data can provide guidance that may help to inform the development of prescribing policies (for
both hospitals and the community), which in turn provide information to guide empirical prescribing.
This report reviews surveillance information on antimicrobial resistance in England and Wales for
the year 2000, with occasional reference to other periods as appropriate for particular studies. The
7
antimicrobial resistance in England & Wales 2000
aims are to outline the current situation in antimicrobial resistance for important pathogens and
identify areas where more information is required.
Data included in this report are primarily derived from surveillance programmes co-ordinated by
the Public Health Laboratory Service’s (PHLS) Communicable Disease Surveillance Centre (CDSC),
complemented, whenever possible, by information available from relevant reference laboratories.
8
antimicrobial resistance in England & Wales 2000
Sources of data
A review of PHLS publications and surveillance reports, as well as ad hoc analyses from relevant
databases, were undertaken for the year 2000, as the most recent year for which complete data
was available. The main sources of information are identified below.
The data on bacteraemias were mainly obtained from routine laboratory reports to CDSC,
maintained within the database ‘LabBase’. It was estimated in 1998 that 91% of laboratories in
England and Wales were reporting laboratory diagnoses to CDSC.6 Other laboratories have begun
reporting to CDSC since then, making this an underestimate of coverage. Where other sources
were used, e.g. sentinel surveys, this is stated.
Data on pathogens sampled from the community were obtained from the PHLS Antimicrobial
Susceptibility Surveillance Unit (AmSSU) based at CDSC (East Midlands). AmSSU has developed an
electronic system to facilitate the monthly import of Routinely Generated Susceptibility Data (RGSD)
from hospital microbiology departments. RGSD can be interrogated for a given organism-antibiotic
combination over a defined time frame for a specified population. Repeat results (i.e. those relating
to the same disease episode) are removed at analysis for any interval from 0 to 90 days and
duplicate reports are excluded on import.
The data source for tuberculosis infections was the Tuberculosis Enhanced Surveillance database
and Mycobnet (the UK Mycobacterial Resistance Network).
For enteric diseases, the source of data was the database of the PHLS Laboratory of Enteric Pathogens
(LEP). In addition, information on C. difficile was obtained from the Anaerobe Reference Unit in
Cardiff.
For sexually transmitted infections (STIs), antimicrobial resistance data were derived from the
genitourinary medicine clinics and laboratories participating within the Gonococcal Resistance to
Antimicrobials Surveillance Programme (GRASP). Background data on clinical STI diagnoses were
obtained from statutory KC60 statistical returns.
Community prescribing and cost data (PACT) referred to in this report were from prescriptions
redeemed at community pharmacies. PACT data were supplied to AmSSU by the Prescribing Support
Unit and further analysed by AmSSU. PACT data were analysed on the basis of the number of
prescriptions per 1000 population. It has been assumed that patients have complied with the
administration instructions given by the prescriber.
9
antimicrobial resistance in England & Wales 2000
Surveillance data should always be interpreted in cognisance of its potential biases and caveats.
Variations in practice account for inherent biases in antimicrobial resistance rates. These variations
occur at all stages of the process, from the type of patient who seeks a General Practitioner (GP)
consultation, to whether a specimen is taken, how the laboratory processes the specimen for the
isolation, and the identification and susceptibility testing of any organisms found. In addition,
different laboratories test different drugs or vary in their selection of first or second line agents,
complicating the pooling of data. And finally, variations in practice can occur at the final step: that
of laboratory reporting for surveillance purposes, where laboratories vary in terms of the datasets
that they report.
Particular biases arise from the fact that mid-stream urine (MSU) specimens are often taken for
conditions other than suspected infections. In comparison few sputum specimens are sent for
microbiological investigation although much antibiotic prescribing in the community is related to
respiratory tract infections. Thus specimens sent to the laboratory may identify that the patient
has an organism that is not improving on therapy. Consequently the organisms isolated may not
reflect the more prevalent susceptible infections, which may have responded to the initial empiric
treatment without microbiological investigation. Therefore, there is a lack of information on the
actual susceptibility of the primary causative agents of chest infections. This has important
implications for basing a change in local antibiotic policies on evidence obtained from local
susceptibility patterns.
More generally, laboratory reports indicate areas where lack of speciation or mis-speciation of
some organisms may occur. Lack of speciation is widespread for isolates from urinary tract infections,
where different species with differing inherent antimicrobial susceptibilities are often lumped
together as “coliforms”. Mis-speciation is notable in enterococci, where reporting of ampicillin
and vancomycin resistance indicates that many Enterococcus faecium isolates are reported as
Enterococcus faecalis. Also, there is little standardisation of how susceptibility testing is carried out
and which antimicrobials are tested. For practical reasons in the laboratory, particularly when
there is heavy reliance on an overburdened workforce, it is often more cost effective to test all
organisms against a wide range of antimicrobials rather than targeting antimicrobials against
particular organisms. This means that “irrelevant” antimicrobial susceptibilities may be reported
to surveillance systems. An example of this is Stenotrophomonas maltophilia, where susceptibilities
to a range of antimicrobials to which the organism is inherently resistant are reported, whilst
susceptibility to cotrimoxazole is infrequently reported. This is compounded by the fact that
laboratories in England and Wales tend to test very few drugs, usually only three to six per isolate,
compared to other countries, for example, 16 per isolate in France.7
Apart from the above factors that affect surveillance of antimicrobial susceptibility, reporting
behaviour may not be consistent within or between laboratories. Laboratories may vary in their
11
antimicrobial resistance in England & Wales 2000
definition of clinically significant isolates and in terms of whether microbiological expertise is applied
to differentiating contaminants from clinically significant isolates, as well as completeness of
reporting. Thus all significant isolates may not be reported and the information on antimicrobial
susceptibilities may be incomplete in those that are reported. Analysing data without knowledge
of the population served by the laboratory and factors that may influence the analysis, could lead
to erroneous conclusions. And, of course, there are always opportunities for transcription errors,
as was recently highlighted following an enquiry into reported penicillin resistance in group A
streptococci. Such errors would be reduced through automatic capture and transmission of
surveillance data from laboratory IT systems.
12
antimicrobial resistance in England & Wales 2000
Results
Much of the information in this section is a collation and abridging of the monthly bacteraemia
reports that appeared in the Communicable Disease Report throughout 2000. Fuller descriptive
accounts of the epidemiology of these organisms can be found in these reports (http://
www.phls.org.uk/publications/cdr/archive/bacteraemiaarchive.html). In some instances, the
incidence of these infections will have changed due to the arrival of subsequent finalised laboratory
reports after the production of the reviews. The bacteraemias have been sub-divided into those
caused by Gram-positive (table 1) and Gram-negative (table 2) organisms.
All bacteraemia reports concern isolates cultured from blood with or without CSF. Reports are
analysed according to the date of the specimen. Rates are calculated using 1999 mid-year resident
population estimates as denominators for each region and age group for reports prior to the
availability of the 2000 mid-year population estimates from the Office for National Statistics in
September 2001. Subsequent reports use the 2000 denominators. Poisson exact 95% confidence
intervals were calculated using STATA v7 (StataCorp. 2001. Stata Statistical Software: Release 7.0.
College Station, TX: Stata Corporation).
Gram-positive bacteria
Staphylococcus aureus
13
antimicrobial resistance in England & Wales 2000
Eighty three per cent (83%) of the 12,187 S. Figure 1: Methicillin resistance in
Staphylococcus aureus bacteraemia reports:
aureus bacteraemia reports included information England & Wales, 2000
on the methicillin (flucloxacillin) susceptibility of
the isolate. Methicillin resistance was present in Overall
42%
4,301 (42%) of 10,180 S. aureus reports for
which methicillin susceptibility was available
(table 1). Methicillin resistance ranged from 34% 45%
41% 42%
No vancomycin resistant S. aureus were
confirmed during this period in England and
Wales.
As the total number of isolates tested for Health Authority B has remained reasonably stable over
the time period covered, a gradual increase in resistance suggests that no major change in sampling/
testing policy has occurred. In contrast, for Health Authority A, the number of isolates tested has
varied whilst maintaining an increase in resistance comparable to Health Authority B. As the increase
in prescribing for flucloxacillin was of similar magnitude between the two health authorities this
14
antimicrobial resistance in England & Wales 2000
therefore raises the question of why the resistance rates to flucloxacillin should be so much higher
in Health Authority A than Health Authority B.
Figure 2: Illustrates the percentage resistance and total isolates tested for S. aureus vs flucloxacillin as
well as presciptions per thousand population for the given antibiotic from GP practices within health
authorities A and B
20 17.2
15
10.8
10 8.6
5 3.5
0
1998 1999 2000
2388 2483
2500
2059
Total Number Tested
2000 1606
1500 1221
1000 709
500
0
1998 1999 2000
Figure 2c: Total number of prescriptions per thousand population for flucloxacillin
64 62.6
62 60.2
Prescriptions/1000
60 57.9
58 55.4
56 54.7
52.8
Population
54
52
50
48
46
1998 1999 2000
HA A Prescriptions/1000 HA B Prescriptions/1000
Population Population
15
antimicrobial resistance in England & Wales 2000
Some of the reasons that may influence the differences between the health authorities have been
covered under “Interpretation of Data” on page 13. Influencing factors may include:
• Health Authority B testing almost double the number of isolates potentially “diluting” out the
effect of any resistant strains.
• Health Authority A possibly having more focused patient sampling or testing protocols thereby
appearing to inflate resistance rates.
• Flucloxacillin resistance in the community could also be influenced by local hospital policy i.e.
pre-operative screening of patients for methicillin resistant Staphylococcus aureus (MRSA), or
early discharge of patients with MRSA to be treated in the community.
Analysis on a contiguous regional or national basis would provide a more balanced picture.
Streptococci
Streptococcus pneumoniae
Pneumococci were the third most commonly reported cause of bacteraemia in 2000, accounting
for 4,744 reports (8.96 per 100,000 population).
Information on penicillin susceptibility was available on 75% of isolates overall, and to erythromycin
on 70% of isolates. Of the isolates for which susceptibility information was given, 7% were resistant
to penicillin, and 15% to erythromycin (table 1).
Figure 3: Antimicrobial resistance among
invasive Streptococcus pneumoniae isolates:
Resistance to penicillin among S. pneumoniae
England & Wales, 2000
has been gradually increasing from less than 1%
in 1990 and 1991 to 3.6% in 19981 and 7% in Overall
Penicillin 7%
2000. The picture for invasive pneumococcal Erythromycin 15%
16
antimicrobial resistance in England & Wales 2000
Enhanced surveillance
Laboratories reporting invasive pneumococcal disease in children under 6 years to CDSC are actively
requested to send the isolate to the Respiratory and Systemic Infection Laboratory (RSIL) for
serotyping. Antimicrobial resistance testing is carried out by the Antimicrobial Resistance Monitoring
and Reference Laboratory (ARMRL). Serotyping is strongly associated with resistance in pneumococci:
resistance is associated internationally with clones of types 19, 23, 6, 9, 14 and 15. In 1999 in
England and Wales, 33 different serogroups/types were noted among invasive pneumococcal
disease (IPD) isolates for that year. The vast majority of isolates belonged to serogroups covered in
current vaccines (seven-valent conjugate and 23-valent plain polysaccharide vaccines). However a
small number of isolates were to non-vaccine serogroups.11 Continued monitoring of disease
burden and serogroup distribution in IPD will be required to assess whether the less common, but
potentially invasive, non-vaccine serogroups expand to fill the ecological space that may be created
following widespread use of conjugate vaccines.
Pyogenic streptococci
Figure 4: Erythromycin resistance in group A, C
& G streptococci, England & Wales, 2000
Group A, C and G streptococci
Group A, C and G streptococci accounted for
far fewer bacteraemias than S. pneumoniae in Overall
Group A 4%
2000, with 845 reports of group A streptococcal Group C 11%
Group G 12%
bacteraemia, 528 reports of group G
3%
streptococcal bacteraemia and 158 reports of 10%
9%
group C streptococcal bacteraemia. 13 This 9%
0%
translated into an overall reporting rate for 5% 7%
25%
England and Wales of 1.6/100,000 population 12%
0%
for group A streptococcal bacteraemia, 0.3/ 0%
3% 6% 7%
100,000 for group C streptococcal bacteraemia 0%
0%
13%
and 1.0/100,000 for Group G streptococcal 12% 0%
12%
bacteraemia. 3% 1%
14%
31% 25%
11% 19%
Thirty-six to 40% of reports lacked penicillin or
erythromycin susceptibility information. To date,
there have been no validated reports of penicillin
resistance in the Group A, C and G streptococci in the UK or elsewhere. Of the reports with
erythromycin susceptibility information, 3.7%, 11% and 12% of the isolates were reported resistant
to erythromycin among group A, C and G streptococci respectively (table 1). There were no reports
of erythromycin-resistant group A streptococcal bacteraemias in London or the West Midlands.
17
antimicrobial resistance in England & Wales 2000
Non-pyogenic streptococci
The non-pyogenic streptococci were assigned to groups based on genetic similarities, rather than
using the traditional Lancefield serological groupings or haemolytic properties. They accounted
for 2403 reported bacteraemias in 2000,14 with a reporting rate of 4.5/100 000 population. Mitis
group organisms were the most commonly reported group of identified non-pyogenic streptococci,
accounting for 25% of these reports. Anginosus group streptococci accounted for the second
most common group (18% of reports), followed by the sanguinis group (10%), the bovis group
(7%), the salivarius group (6%) and lastly the mutans group (2%). The remaining non-pyogenic
streptococcal bacteraemias were caused by a small number of other identified streptococci (1%)
and related genera (5%) not fitting into these groups and a substantial number of streptococci
that were not fully identified (30%).
Reporting of antibiotic susceptibility was very poor for these streptococci, fewer than 15% of
reports for any of these groups containing susceptibility information. Consequently, it is difficult to
interpret them meaningfully and regional breakdowns of antibiotic data were not performed.
There were a small number of reports of penicillin and tetracycline resistance. However, most
penicillin resistance in these and other streptococci is low level and accrues stepwise, meaning
that variation in definition is likely among laboratories. There were more reports indicating
gentamicin resistance; however, all streptococci are gentamicin resistant but most only have low
level resistance, so the drug can still be used as a synergist with penicillin.
Enterococcus spp
Enterococci were the fourth commonest reported cause of bacteraemia, with 3501 reports in
2000 – an overall reporting rate of 6.6/100,000 population. The West Midlands had the highest
reporting rate (10.3/100,000) and South East the lowest (5.4/100,000). Twenty per cent of isolates
were reported as Enterococcus spp and the remainder as E. faecalis (49%), E. faecium (18%),
18
antimicrobial resistance in England & Wales 2000
Vancomycin susceptibility data was only available on about 33% of E. faecium and E. faecalis
isolates. Twenty seven per cent of E. faecium reports with vancomycin susceptibility data were
reported as vancomycin resistant, compared to 11% of E. faecalis reports. The E. faecium data is
consistent with the aforementioned sentinel survey,16 which found 24% of E. faecium isolates to
be vancomycin resistant. However, the sentinel survey found much lower levels of vancomycin
resistance in confirmed E. faecalis isolates (0.5%), further suggesting some mis-identification of E.
faecium as E. faecalis, although this figure might be lowered by UTI isolates. The small numbers of
E. faecium and E. faecalis reports with vancomycin susceptibility data hinder any meaningful inter-
regional comparisons.
Teicoplanin susceptibility data was available for 35% and 28% of E. faecium and E. faecalis isolates
respectively. Eighteen per cent of reports for E. faecium and 3% of reports for E. faecalis indicated
teicoplanin resistance. As with vancomycin and amoxycillin/ampicillin, these data are consistent
with sentinel survey data for E. faecium (20% resistance), but indicate a higher rate of resistance
in E. faecalis than that (0.3%) found in the sentinel study.16 This discrepancy reinforces the view
that some reported ‘E. faecalis’ are actually E. faecium. Wales reported the highest levels of
teicoplanin resistance in E. faecium (74%). This may reflect local susceptibility testing practice,
only those isolates already resistant to other agents being tested against teicoplanin.
Gentamicin susceptibility information was only available in less than 10% of reports. Of these
reports, 73% of E. faecium and 66% of E. faecalis reports indicated gentamicin resistance, but it
is unclear whether high level acquired resistance or low level inherent resistance was meant.
19
antimicrobial resistance in England & Wales 2000
Sentinel surveys indicate 25%-33% high-level gentamicin resistance in both species. In such cases,
gentamicin cannot be used as a synergist. Laboratories are encouraged to report only high-level
gentamicin resistance.
tested % resistant tested % resistant tested % resistant tested % resistant tested % resistant tested % resistant tested % resistant
* unconfirmed
Source: routine laboratory reporting to CDSC
Gram-negative bacteria
Escherichia coli
There were 11,032 E. coli bacteraemia reports in 2000, making it the second most commonly
reported cause of bacteraemia.13 The overall E. coli bacteraemia reporting rate for England and
Wales was 19.5/100,000 population.
The proportions of E. coli bacteraemia reports lacking susceptibility information ranged from 43%
(ciprofloxacin) to 38% (gentamicin).
Of the E. coli bacteraemia reports including susceptibility information, 55% indicated ampicillin/
amoxycillin resistance, 30% trimethoprim resistance, 3% gentamicin resistance, and 5%
ciprofloxacin resistance (table 2). There was significant regional variation, London having the highest
20
antimicrobial resistance in England & Wales 2000
meropenem resistance.
This section will deal with those Enterobacteriaceae which are commonly hospital-acquired:
Klebsiella spp, Enterobacter spp, Serratia spp, and Citrobacter spp. Care must be taken when
interpreting Citrobacter data, as the two main Citrobacter spp (C. freundii and C. diversus/koseri)
are very different in their susceptibility to β-lactams.
There were 5,876 bacteraemia reports for these Figure 8: Antimicrobial resistance in
Klebsiella spp: England & Wales, 2000
genera in 2000. Of the Enterobacteriaceae being
reviewed, Klebsiella spp bacteraemia were the
most commonly reported, accounting for 53% Overall
Gentamicin 5%
of the total (3,147, reporting rate 5.67/ 100,000 Ciprofloxacin 10%
21
antimicrobial resistance in England & Wales 2000
Ciprofloxacin resistance rose from 8% to 10% in Klebsiella, 11% to 13% in Enterobacter, 22% to
29% in Serratia and 6% to 10% in Citrobacter spp between 1999 and 2000. However, again this
masked big inter-regional variations, London reporting ciprofloxacin resistance levels of 21% and
29% in Klebsiella and Citrobacter spp, whilst 22% of Enterobacter spp in the North West were
resistant. The highest rate of ciprofloxacin-resistance was seen in Serratia spp in Wales in both
these years though: 44% and 55% respectively, compared to a maximum of 38% in any other
region in 2000. This reflected a problem with Serratia spp in two tertiary referral hospitals.
These bacteraemia reports were also examined Figure 10: Antimicrobial resistance in
Serratia spp: England & Wales, 2000
for susceptibility to antimicrobials other than
gentamicin and ciprofloxacin, such as the third-
generation cephalosporins, the carbapenems Overall
Gentamicin 4%
and piperacillin/tazobactam. Information on the Ciprofloxacin 29%
22
antimicrobial resistance in England & Wales 2000
Pseudomonas spp
There were 2,105 Pseudomonas spp bacteraemias reported in 2000.10 The majority (74%) of the
reports were specified as P. aeruginosa, which probably also accounted for most of the 20% of
reports where the species name was not given. Numerically this makes Pseudomonas spp
bacteraemias slightly less common than Klebsiella spp bacteraemia and about five times less
common than E. coli bacteraemia.
Figure 12: Antimicrobial resistance in
P. aeruginosa: England & Wales, 2000
The overall Pseudomonas spp bacteraemia
reporting rate for England and Wales was 4.0/
100,000 population, with the West Midlands Overall
Gentamicin 8%
having the highest reporting rate (5.7/100,000) Ciprofloxacin 15%
Ceftazidime 8%
and the North West the lowest (2.9/100,000).
4%
15%
7%
The proportions of reports with susceptibility 4%
9%
information were generally highest for P. 10% 8%
15%
aeruginosa and much lower for other speciated 1%
1%
and non-speciated pseudomonads. Gentamicin 9%
21% 3% 8%
was the antimicrobial for which there was most 27%
14%
10%
complete reporting, followed by ciprofloxacin and 9% 17%
24%
ceftazidime, 62%, 49% and 53% of reports 3% 4%
19%
12% 10%
respectively including information on 2% 6%
susceptibility to these agents. Information on
23
antimicrobial resistance in England & Wales 2000
Acinetobacter spp
There were 745 reports of Acinetobacter spp Figure 13: Antimicrobial resistance in
Acinetobacter spp: England & Wales, 2000
bacteraemias in 2000, a rate of 1.4/100,000
population. To put this in context with other
bacteraemia reports, these numbers are slightly Overall
Gentamicin 11%
higher than those for Serratia spp (592) and Ciprofloxacin 19%
Reviewing susceptibility reports of Acinetobacter spp bacteraemias as a whole, in the light of the
low proportion of reports containing susceptibility information for some antimicrobials, gentamicin
resistance was indicated in 11% of reports with susceptibility information. The reported resistance
24
antimicrobial resistance in England & Wales 2000
rates for ciprofloxacin, ceftazidime and imipenem ranged across the regions from 3% to 44%,
14% to 53%, <4% to 16% for these antimicrobials respectively.
Given the limitations detailed above, a more realistic picture of antimicrobial susceptibility in
Acinetobacter spp is likely to be obtained from the survey of resistance in Acinetobacter spp
undertaken in 2000 by the Antibiotic Resistance Monitoring & Reference Laboratory (ARMRL) in
collaboration with Nottingham PHL.19 Organisms from all clinical sites were included. Over 600
isolates were collected from 54 hospitals and identified to species level. Over 90% of isolates were
susceptible to carbapenems, colistin and minocycline, and between 70-90% were susceptible to
sulbactam, piperacillin/tazobactam and amikacin. Fewer than 20% were susceptible to
cephalosporins or tetracycline. Until recently, imipenem and meropenem (carbapenems) have
retained universal activity against Acinetobacter spp. However, carbapenem-hydrolysing ß-
lactamases have begun to emerge in the genus worldwide, a disturbing phenomenon given the
frequent resistance of acinetobacters to other antibiotics.20 The survey found that although
carbapenem resistance remained very rare, it was over-reported by referring clinical laboratories
such that the positive predictive values of “resistant” designations (compared to relevant MIC
breakpoints) were only 19% for imipenem and 2% for meropenem. More generally, the sensitivity
of the susceptibility tests performed in clinical laboratories was moderate: 89% of ciprofloxacin-
resistant isolates (by MIC) were reported resistant by the referring clinical laboratories, but this
proportion fell to ≤66% for amikacin, ceftazidime, gentamicin, piperacillin and piperacillin/
tazobactam. The survey concluded that carbapenems, colistin and minocycline retained greatest
activity against the Acinetobacter spp isolates collected. There is an urgent need to improve the
standards of identification and susceptibility testing for Acinetobacter spp in clinical laboratories.
tested % resistant tested % resistant tested % resistant tested % resistant tested % resistant tested % resistant tested % resistant
E. coli 6,055 55% 5,111 0.02% 6,347 3.1% 6,241 5.0% 4276 29.8%
(n = 11,032)
P. mirabilis 759 28% 588 0.3% 774 1.3% 720 2.6%
(n=1,255)
P. aeruginosa 517 5% 807 7.6% 418 4.7% 946 7.7% 910 14.7%
(n=1,549)
Non speciated & other
Pseudomonas spp 26 4% 43 4.6% 19 5% 61 6.5% 53 9.4%
(n=556)
S. maltophilia 157 91 192 189 56 30%
(n=400)
Klebsiella spp 1,221 8.4% 723 0.4% 1,770 5% 1,693 10.0%
(n=3,147)
Enterobacter spp 717 28% 470 1.9% 1,018 6% 962 13.0%
(n=1,721)
Serratia spp 255 7.4% 182 1% 345 4% 333 29%
(n=592)
Citrobacter spp 185 21% 105 1.9% 261 4% 243 10%
(n=416)
A. baumannii
A. calcoaceticus
} 85 51% 60 3% 111 14% 109 30%
(n=198)
A. lwoffii 35 17% 23 0% 47 4% 45 6%
(n=107)
25
antimicrobial resistance in England & Wales 2000
Fungal infections
Despite their well-documented imperfections, the introduction of standardized methods for the
susceptibility testing of yeasts and moulds has meant that epidemiological analyses and national
and even international comparisons of susceptibility trends are now possible. Moreover, limited in
vitro-in vivo correlation studies have led to the introduction of tentative breakpoints for some of
the systemic agents. Both intrinsic and emergent antifungal drug resistance are encountered and
the need for accurate and predictive susceptibility testing with antifungal agents is becoming
more acute due to the increasing numbers of agents becoming available for both the topical and
systemic treatment of fungal infection. The broadening choice of agents means that clinicians will
need guidance as to the most appropriate agent for a particular infection.
Currently no surveillance network exists to monitor trends in antifungal drug resistance in the UK,
and the value of most current epidemiological data is limited by sample selection. It is important
that mechanisms are introduced with the capacity to identify potential problems as they occur.
This is especially necessary with the increasing use of prolonged antifungal regimens as prophylaxis,
empirical or maintenance therapy and the lack of control engendered by the availability of over-
the-counter antifungal agents.
To date, antifungal drug resistance has not proved to be as problematic as that experienced with
antibacterial agents. However, intrinsic resistance, which is generally consistent and predictable, is
encountered in an increasing number of yeast and mould species and highlights the need for
accurate speciation of infecting organisms. Treatment with azole derivatives has been associated
with the emergence of isolates of Candida krusei that are innately resistant to fluconazole and the
haploid yeast Candida glabrata which often demonstrates either innate or rapidly emergent
resistance. Of 194 blood culture isolates of C. glabrata tested by the Mycology Reference Laboratory
(MRL) in 1999-2001, 12% were resistant to fluconazole, a further 25% were in an intermediate
category and 43% were at the top concentration of the currently accepted susceptible range
(table 3). A significant proportion of Candida tropicalis isolates also demonstrate in vitro resistance
to azoles (19% of 78 isolates tested by the MRL were resistant to both fluconazole and itraconazole).
An important consequence of innate azole resistance may therefore have been the reported
Table 3: Susceptibility profiles of referred yeast isolates from deep infections 1999-2001
Candida glabrata (n=194) 100% 99% 1% 63% 25% 12% 4% 44% 52%
Candida tropicalis (n=142) 100% 90% 10% 75% 6% 19% 44% 31% 25%
Cryptococcus neoformans (n=56) 95% 5% 46% 54% 89% 11% 11% 86% 3%
26
antimicrobial resistance in England & Wales 2000
epidemiological shift away from Candida albicans as the predominant yeast pathogen towards
these other less susceptible yeast species.
One concern over the availability of over-the-counter (OTC) fluconazole for the treatment of vaginal
candidosis has been the possibility that it may select for azole resistance and there are suggestions
that there is an increasing incidence of vaginal infections with less azole-susceptible C. glabrata.
Of interest is MRL data to suggest that the background fluconazole resistance of this species
isolated from blood culture is 11% whereas a level of 28% has been recorded in 82 isolates from
high vaginal specimens. However this could be a reflection of sampling bias as it is only in the
more refractory vaginal infections that an isolate is likely to be sent to the reference laboratory for
testing. Moreover, this would not necessarily implicate OTC medicines, as azoles are often used as
first line therapy in primary healthcare.
Currently there are few problems with emergent resistance during a course of treatment, a
potentially more serious scenario than the more predictable innate resistance. Far more likely to
occur in yeast rather than mould infections, this has been encountered predominantly with
flucytosine and fluconazole, mainly as a consequence of inappropriate prescribing practices for
specific infections in certain patient groups. Flucytosine is now rarely used as monotherapy, which
was associated with a high incidence of emergent resistance. Emergent resistance to fluconazole
among isolates of C. albicans from the oral cavities of patients with HIV infection was a serious
problem until the introduction of HAART for the treatment of HIV infection in the late 1990s,
which led to declining rates of oropharyngeal candidosis. Less than 1% of the last 1,291 isolates
of C. albicans referred to the MRL since 1998 have been fluconazole resistant.
There have also been reported cases of emergent resistance in isolates of Cryptococcus neoformans
from HIV-infected patients on prolonged fluconazole maintenance therapy. However, despite the
widespread use of lifelong suppressive fluconazole therapy in this group of patients this has not
emerged as a serious clinical problem and resistance is rarely the cause of relapse.
There have been some reports that suggest Candida lusitaniae and Trichosporon spp are less
susceptible to amphotericin B than other yeast species. Reference laboratory testing of blood
culture isolates suggests that amphotericin B resistance in C. lusitaniae is not a common finding. It
was not encountered in any of the 26 isolates tested in 2001. However there are still issues over
the reliability of current methodology for detecting amphotericin B resistance.
27
antimicrobial resistance in England & Wales 2000
Tuberculosis remains an important source of morbidity and mortality in the UK. Notifications declined
throughout the last century until 1988, after which a rise in incidence was observed. As a surveillance
response to the increased numbers of reported cases, the five yearly national TB survey was
superseded by continuous Enhanced Tuberculosis Surveillance in 1999. In 2000, the number of
cases reported through Enhanced Tuberculosis Surveillance was 6323, a reporting rate of 11.94
per 100,000 population.
Resistance to anti-tuberculous drugs has been Figure 14: First line drug resistance in initial
isolates of M. tuberculosis complex by region:
observed since the advent of effective England & Wales, 2000
chemotherapy and is now a global public health
problem.21 Although drug resistance occurs Overall
Isoniazid 6.4%
spontaneously through random mutation, by far Rifampicin 1.5%
MDR 1.1%
the most important factor driving the emergence
3.2%
of drug resistant tuberculosis internationally is 0.9%
0.9%
inadequate treatment. High levels of drug 5.7%
1.6%
resistance reflect a failure to control the disease. 1.6% 4.3%
2.0%
Drug resistant tuberculosis complicates treatment 6.5%
2%
Of 4094 M. tuberculosis isolates reported for England and Wales in 2000, 6.4% were isoniazid
resistant, 1.5% demonstrated rifampicin resistance, 6.9% were resistant to at least one first line
drug, 1.2% were resistant to more than one first line drug and 1.1% were MDR, i.e. resistant to
at least isoniazid and rifampicin, with or without resistance to other drugs. Resistance to isoniazid
and to any first line drug was highest in England (6.5% and 7% respectively).
In England, isoniazid resistance occurred in all regions, and ranged from 3.2% in Northern and
Yorkshire to 8.2% in London. All other measures of resistance, except MDR, were highest in
London. In Trent region 2% (6/301) of isolates were reported as MDR.
28
antimicrobial resistance in England & Wales 2000
Over 40% of all tuberculosis cases and almost 40% of all organism isolates in England and Wales
now occur in London. The latter account for 52% of all isoniazid resistant isolates, 54% of all
isolates resistant to at least one first line drug and 42% of all MDR isolates. Nearly two thirds of
the cases in London were among individuals born abroad, over half arriving within the previous
five years. More than 60 linked cases of isoniazid resistant tuberculosis have been identified in
London since mid-2000. Some of these cases appear to have acquired tuberculosis while in prison.
The 15 to 34 year age group accounted for approximately half of all the drug resistant isolates.
This is because 60% of cases in the UK occur in persons born overseas, many arriving from areas
where rates of anti-tuberculous drug resistance are much higher than those found in the UK; thus
the higher rates of resistance in the 15-34 age group is a reflection of the situation in more than
60% of these cases’ country of origin. Resistance was also commoner in males than females in all
categories of resistance examined, and all types of resistance were commoner in those born abroad.
Resistance to any first line drug occurred in 4.3% of UK-born patients, compared to 7.4% of
foreign-born patients, and MDR in 0.5% of the UK-born, compared to 1.3% of the foreign-born
group.
The overall trend in levels of anti-tuberculous drug resistance in England and Wales is relatively
stable. Factors associated with drug resistance include foreign birth, diagnosis in London, HIV
seropositivity and previous tuberculosis treatment. A disproportionately high level of drug resistance
is seen in the London region. This is related to increasing tuberculosis case numbers, immigration
from countries where rates of drug resistant tuberculosis are high, co-infection with HIV and social
problems including overcrowding and poverty.
Limitations in the drug susceptibility data about previous infection and treatment make estimates
of primary and acquired resistance problematic. Levels of resistance in initial isolates from individuals
known to and those not known or reported to have ever suffered tuberculosis previously also
remain stable.
Neisseria meningitidis
During 2000, there were 2,653 cases of meningococcal infection with isolates or clinical samples
confirmed at the PHLS Meningococcal Reference Laboratory. A total of 2,778 cases of meningococcal
meningitis or septicaemia were notified by clinicians.
Clinically significant resistance to the antimicrobials used in the treatment of invasive disease has
not been observed in England and Wales. All isolates of N. meningitidis referred to the PHLS
Meningococcal Reference Unit (MRU) are tested for susceptibility to penicillin, sulphonamides,
rifampicin and ciprofloxacin. Although the drug is no longer used for carriage eradication,
sulphonamide resistance is used as an additional phenotypic marker, whilst rifampicin and
ciprofloxacin susceptibility are used to inform prophylaxis for contacts of cases. Reduced susceptibility
to penicillin (MIC > 0.1mg/l) has been observed and has increased from <1% in 1984 to 18% in
2000 and this is reflected in the upward trend of the geometric mean MIC (figures 15 and 16).
29
antimicrobial resistance in England & Wales 2000
Figure 15: All meningococcal clinical isolates, geometric mean penicillin MIC. England & Wales 1984-2000
0.08
Geometric mean MIC (mg/l)
0.06
0.04
0.02
0
1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000
(prov)
Year
Figure 16: Meningococcal clinical isolates – geometric mean penicillin MIC for serogroup B, C2a and C2b
strains. England & Wales, selected years 1986-2000
0.2
Group B
0.16
Geometric mean MIC (mg/l)
Group C2a
Group C2b
0.12
0.08
0.04
0
1987 1992 1994 1995 1996 2000
Year
Since 1989, only a handful of strains with penicillin MICs of 1.28mg/l have been identified. These
have not been beta-lactamase producers and such strains would still be expected to respond
clinically to the currently recommended dose of penicillin. Analysis of clinical outcomes of patients
from whom samples were submitted between 1993 and 2000 showed that this reduced
susceptibility is not of clinical significance currently and is mainly related to strain phenotype.
Particular strains, for example the phenotypes C2b and W135 2a P1.5, 1.2 associated with
30
antimicrobial resistance in England & Wales 2000
importation from the Hajj in Saudi Arabia, have a particularly high rate of reduced penicillin
susceptibility.
Local diagnostic laboratories test strains against other antibiotics used in treatment (mainly penicillin
and cephalosporins). The MRU and CDSC are not aware of any resistance having been reported
for cephalosporins to which organisms remain highly susceptible with MICs in the range 0.001 –
0.08mg/l.
Haemophilus influenzae
There were 113 cases of invasive H. influenzae type b infection reported to the PHLS Haemophilus
Reference Unit (HRU) in 2000. Of these, 22 (19%) were resistant to ampicillin, 1 (0.9%) was
resistant to chloramphenicol, and 5 (4%) were resistant to trimethoprim (table 4).
The level of chloramphenicol resistance has remained very low since 1992, and trimethoprim
resistance has tended to stay at or below 5%, apart from 1999. The level of resistance to ampicillin
is higher (at around 20%), but this has also not changed significantly over the past decade. Almost
all of the ampicillin resistance in H. influenzae type b is beta-lactamase mediated.
Enteric infections
This section includes information on campylobacter, salmonella, shigella, VTEC (E. coli 0157), C.
difficile and Helicobacter pylori infections. For campylobacter, salmonella, shigella, VTEC and H.
pylori, the source of data was the database of the PHLS Laboratory of Enteric Pathogens (LEP).
Campylobacter spp
There were 55,887 campylobacter reports from laboratories in England and Wales, 106 per 100,000
31
antimicrobial resistance in England & Wales 2000
population, in 2000, making this the commonest reported enteric pathogen. Further information
on campylobacter isolates was available from a pilot project in Wales and the North West Region
of England between 1997 and 1999, which was later developed into a sentinel surveillance scheme.
In 2000 this encompassed approximately 16% of all campylobacter isolates in England and Wales
(data from this active surveillance will be published later this year). Table 5 shows the antimicrobial
susceptibility of the isolates from this sentinel surveillance scheme.
Table 5: Resistance to antimicrobial agents in Campylobacter spp. Human isolates from laboratories collaborating
in the Campylobacter Sentinel Surveillance Scheme, May 2000 to April 2001
% resistant % resistant
Nalidixic to one to four or
Antimicrobial Ampicillin Chloramphenicol Erythromycin Gentamicin Kanamycin Neomycin Tetracyclines acid Ciprofloxacin agent more agents
Salmonella spp
The total number of reports of Salmonella spp (excluding S. typhi and S. paratyphi) in 2000 was
14844, a reporting rate of 28.04 per 100,000 population. In these reports, the two most common
serotypes were S. Typhimurium and S. Enteritidis, which together accounted for 75% (18% and
57% respectively) of the total number of cases in 2000.
The four most common non-typhoidal Salmonella enterica serotypes in England and Wales in
1999 were S. Enteritidis, S. Typhimurium, S. Virchow, and S. Hadar.31 Resistance in these serotypes
(table 6) is partly related to food animal reservoirs and the pattern of antimicrobial resistance due
to the use of antimicrobials in specific species. For example, S. Typhimurium has a strong bovine
association and multiple resistance is known to be associated with the use of antimicrobials in
cattle. These serotypes are also prone to multiple resistance (four or more antimicrobials), although
the incidence of multiple resistance in serotypes Typhimurium, Virchow and Hadar fell between
1996 and 1999, and remained virtually the same in S. Enteritidis. The most noticeable reduction
was in S. Typhimurium, from 81% in 1996 to 59% in 1999. However, this trend was not continued
in 2000 for S. Typhimurium and S. Virchow, with multiple resistance recorded in 67% and 49% of
isolates respectively. Decreased susceptibility to ciprofloxacin has increased in S. Enteritidis, S.
Virchow and S. Typhimurium; in 2000 52% of S. Virchow exhibited decreased susceptibility to
ciprofloxacin.
32
antimicrobial resistance in England & Wales 2000
Table 6: Resistance (%) to antimicrobial agents in salmonellae: England and Wales, 2000 (provisional figures for each serotype)
Ampicillin Chloramphenicol Gentamicin Kanamycin Streptomycin Sulphonamides Tetracyclines Trimethoprim Furazolidone Ciprofloxacin (L)
There were 1079 reports of shigella infection in 2000, of which 632 were Sh. sonnei and 447 non-
sonnei (table 7). Since 1995/6, resistance to all the antimicrobials listed in table 7 has increased in
Sh. sonnei.32 In non-sonnei species resistance has remained high but stable over this time period.
The majority of non-sonnei shigella cases are imported from countries where antibiotics are freely
available without prescription, with 56%-80% of cases (depending on the species) in 1995-6
associated with recent travel outside of the United Kingdom. There was little difference in the
incidence of multiple resistance between travellers and non-travellers. In contrast, S. sonnei is
indigenous to the UK and more common in patients who have not travelled abroad, but multiple
resistance is more common in recent travellers. In 1996 73% of isolates from travellers were multi-
resistant compared to only 32% in non-travellers.
The overall incidence of resistance to antimicrobials in E. coli 0157 has remained relatively low in
comparison to shigellas, Campylobacter spp and salmonellas (with the exception of S. Enteritidis).
However, it is noteworthy that about 14% of isolates were resistant to streptomycin, sulphonamides
or tetracycline, which may reflect the usage of these antimicrobials in bovine animals.
Table 7: Resistance (%) to antimicrobial agents in Escherichia coli O157 and shigellae: England and Wales, 2000
Ampicillin Chloramphenicol Gentamicin Kanamycin Streptomycin Sulphonamides Tetracyclines Trimethoprim Furazolidone Ciprofloxacin (L)
Helicobacter pylori
33
antimicrobial resistance in England & Wales 2000
Resistance to metronidazole was 58% in London and 37% in mid-Essex, whilst that to clarithromycin
was 12% in London and 4.2% in mid-Essex. The resistance pattern in mid-Essex remained stable
over the 5 years of the study. The majority of clarithromycin resistant strains were also resistant to
metronidazole. As dual resistant strains are difficult to eradicate, their prevalence should be
monitored. The variation between the two areas was thought to be due to ethnic differences.
Further studies are being undertaken. The rate of clarithromycin resistance is similar to that in
other European countries, but the rate of metronidazole resistance is higher (European range 7%
- 49%; mean 27.5%). Resistance to amoxycillin or tetracycline was not detected.
As resistance lowers the rate of successful eradication of infection, it becomes increasingly important
to know local susceptibility patterns in order to inform therapeutic approaches in affected patients.
Culture and susceptibility testing become increasingly cost-effective as resistance rates increase.
Clostridium difficile
The number of toxin positive stools recorded by CDSC for 2000 was 15,812, a reporting rate of
29.87 per 100,000 population. A further 5,180 reports were reported just as C. difficile. It is
assumed that most of these reports reflected a diagnosis based on toxin-testing rather than culture,
as surveys have indicated that very little C. difficile culture is undertaken.
The susceptibility of 50 random C. difficile isolates submitted for typing in 1996 (representing 18
PCR ribotypes and about 14% of the total number of isolates) was assessed by the Anaerobe
Reference Laboratory in Cardiff. This showed no resistance to metronidazole, vancomycin or
Augmentin. Resistance was reported to piperacillin/tazobactam (4%), chloramphenicol (6%),
tetracycline (8%), penicillin (14%), clindamycin (20%), erythromycin (46%), imipenem (96%) and
cefoxitin (100%). Since then metronidazole resistance was reported in an environmental isolate
from an elderly care ward in Leeds, which was typed as PCR ribotype 10, a non-toxigenic ribotype.34
This is the first such report in England and Wales, although metronidazole resistance has been
reported in other countries. This finding emphasises the need for susceptibility testing by sentinel
laboratories to monitor changing susceptibility in this organism where routine susceptibility testing
is not undertaken.
The continued rise in infections with N. gonorrhoeae and C. trachomatis is an enormous public
health challenge. Reports of both these infections doubled in the past five years. The burden of
infection falls mostly on the young.
34
antimicrobial resistance in England & Wales 2000
Chlamydia trachomatis
In 2000, genital chlamydia infection was the commonest bacterial STI reported by genitourinary
(GUM) clinics in England and Wales, with 63,037 diagnoses made of uncomplicated infection and
a further 2,784 of complicated genital chlamydia infection, giving an overall rate of 124/100,000
population.35 This data does not include those cases treated outside of genitourinary medicine
(possibly 16% of male cases and 36% of female cases36), nor does it included the significant
burden of undiagnosed infection.36
Neisseria gonorrhoeae
N. gonorrhoeae is the second most common bacterial STI in England and Wales. In 2000 there
were 20,520 diagnosed episodes at GUM clinics, an overall rate of 39/100,000 population. It is
estimated that up to 90% of cases are seen at GUM clinics.35
Classification Definition
35
antimicrobial resistance in England & Wales 2000
Sentinel surveillance
A sentinel surveillance scheme for monitoring N. gonorrhoeae antimicrobial resistance in England
and Wales was established in 2000 by the PHLS Communicable Disease Surveillance Centre (CDSC)
in association with the PHLS Genitourinary Infections Reference Laboratory (GUIRL) and the
Department of Infectious Diseases & Microbiology at Imperial College.40 This programme, known
as the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP), is funded by the
Department of Health for a further 3 years. It combines prospective susceptibility testing of isolates
from 30 laboratories (13 within and 17 outside London), using standardised methodology, with
retrospectively collected clinical and behavioural data from recruited GUM clinic patients. For this
review, the data from the GRASP report for 2000 was used, comprising all consecutive gonococcal
isolates (one from each patient episode) identified in participating laboratories during the months
of June, July and August 2000. MICs were determined to the following antimicrobial concentrations:
penicillin (0.03-4.0mg/l), ciprofloxacin (0.002-0.125mg/l - extended range 0.125 – 32mg/l tested
as necessary), spectinomycin (2-64mg/l), tetracycline (1-32mg/l). Ceftriaxone was tested at a single
concentration (0.12mg/l).
3325 isolates were collected by the 30 GRASP collaborating laboratories during the three-month
data collection period. Ninety-five per cent (3166) of all isolates were retrieved successfully and
confirmed to be N. gonorrhoeae. Of the confirmed isolates, 94.7% (2998) were from patients
who had attended a GUM clinic, and the rest were primarily from GPs. A large proportion (65%)
of isolates were from the London region, due to greater sampling of this region.
Gonorrhoea remains highly concentrated within demographic and behavioural risk groups in
England and Wales. Twenty-three per cent of infections were among gay and bisexual men. Black
and ethnic minority groups were also disproportionately affected: 29% of diagnoses of infection
in women and 24% in men occurred in Black Caribbeans.
Table 9 summarises the proportion of resistant isolates from all GRASP clinics and table 10
summarises the mechanisms of resistance for penicillin and tetracycline. Nine per cent of all isolates
from GRASP clinics were resistant to penicillin. Plasmid-mediated resistance (PPNG or PP/TRNG)
accounts for about half of penicillin resistance with a prevalence of 5.0%. Decreased susceptibility
or resistance to ciprofloxacin was observed in 4.2% of all isolates. Overall, 1.8% of isolates showed
Table 9: Number and proportion (%) of isolates resistant to specific antibiotics from all GRASP
laboratories, June to August 2000 (GUM patients only).
Outside
Antibiotic London London Total GRASP
Penicillin ≥1mg/l or β−lactamase positive 168 (8.45) 110 (11.01) 278 (9.31) [8.29,10.41]
Tetracycline ≥2mg/l 931 (46.83) 204 (20.42) 1135 (38.00) [36.25,39.77]
Ciprofloxacin: ≥1mg/l 18 (0.91) 37 (3.70) 55 (1.84) [1.39,2.39]
Ciprofloxacin decreased susceptibility:
≥0.125mg/l 65 (3.27) 61 (6.11) 126 (4.22) [3.53,5.00]
Spectinomycin 1 (0.05) 1 (0.10) 2 (0.07) [0.00,0.24]
Ceftriaxone 0 (0.00) 0 (0.00) 0 (0.00) ---
Source: GRASP
36
antimicrobial resistance in England & Wales 2000
Table 10: Number and per cent (%) of isolates resistant to penicillin and tetracycline, by resistance
classification type from all GRASP laboratories, June to August 2000 (GUM patients only).
Outside
Classification* London London Total GRASP
Source: GRASP
* see glossary in table 8 for definitions
Despite the high burden of disease in London, resistance to penicillin and ciprofloxacin was more
likely to be observed outside London. This is of concern as the national surveillance data suggests
that between 1998 and 1999 the largest increases in gonorrhoea reports were observed outside
London. Early indications are that the higher than predicted levels of ciprofloxacin resistance outside
London, particularly in Northern and Yorkshire region, which were observed mainly among
heterosexuals, may be a direct result of earlier outbreaks of ciprofloxacin resistant gonococcal
disease reported in the north of England during 1999/2000.
Along with penicillin, the current UK guidelines for the treatment of uncomplicated gonorrhoea
now recommend the use of fluoroquinolones (either ciprofloxacin or ofloxacin)41 as first line therapy.
37
antimicrobial resistance in England & Wales 2000
However, ciprofloxacin resistance, first seen in the UK in the early 1990s, has been increasingly
reported over recent years.42,43,44 Quinolone resistant gonococci are more prevalent in countries in
the Western Pacific region.45 Many such infections seen in the UK were acquired abroad, although
recent data suggest more than half are also acquired through heterosexual contact within England
and Wales. There were no reports of resistance to ceftriaxone.
HIV
Over 15 antiretroviral drugs are now available for use in HIV infection, encompassing three classes,
nucleoside reverse transcriptase (RT) inhibitors (nRTI), non-nucleoside RT inhibitors (nNRTI), and
protease inhibitors (PI). Standard therapy now includes triple drug regimens, which are more effective
than double or single treatment at suppressing virus replication, monitored by the amount of viral
genome (RNA) in plasma. In general, a rise in viral load while on therapy is associated with disease
progression, and thus, is increasingly termed “virological failure”. Such failure is multi-causal, but
the single most important factor is patient adherence to therapy. Very recent single clinic cohort
studies within the UK suggest that the incidence of such failure is 10-15% per year, although this
figure is likely to be variable depending on clinic size, patient support infrastructure, and clinician
expertise. Further, results of a large US cohort study of patients initiating therapy in 1996-7 suggest
that 80% of patients were failing by the year 1999. Since HIV drug resistance is common in
patients failing therapy, a key determinant of the prevalence of resistance is, indeed, the success
of therapy.
Resistance to drugs used in treatment of HIV infection can be ascertained by genotypic assays
(looking for mutations in the reverse transcriptase or protease genes known to be associated with
resistance to particular drugs) or phenotypic assays when the susceptibility threshold of the drug
has to be defined. However, the nature of resistance is highly complex, such that over 250 mutations
are associated with resistance. Since they can appear singly or in combination, and confer variable
levels of decreased drug susceptibility and cross-resistance, then classification of these data for
epidemiological purposes is difficult. Further, the continual high-level replication of virus means
that the “predominant” species at any one time-point in plasma may change, and a single time
point assessment of resistance will not represent all resistant viruses present within the body.
Consequently, in untreated patients infected with drug resistant virus, gradual replacement with
drug susceptible virus may occur, although the drug resistant virus will still be archived. Such
archived resistant virus may emerge under drug pressure and thus compromise treatment.
Two key sets of epidemiological data to monitor and assess emergence and transmission of HIV
drug resistance are currently available in the UK. Firstly, an assessment of resistance in 300 viral
isolates, obtained in a non-selective manner from 3 different clinic types across England, through
1998, 1999 and 2000 to identify the prevalence of resistance in patients failing antiretroviral
therapy. The criteria for such samples were that they be from individuals receiving antiretroviral
therapy, and with a viral load >1000 copies RNA/ml. The national dataset is being compiled through
an NHS R&D funded project based at the MRC Clinical Trials Unit, in collaboration with the PHLS
and all major clinical units within the UK. This initiative has the potential to describe HIV drug
resistance within the UK in great detail, and its association with therapy and clinical response.
38
antimicrobial resistance in England & Wales 2000
Figure 18: Proportion of treated UK patients with detectable viral load with resistance: 1998-2000
80%
% patients
60%
40%
20%
0%
none NRTI nNRTI PI
drug class
Source: PHLS AVSRU (unpublished and preliminary data)
However, grant funding for this finishes in 2003. Around £70,000/annum is required to maintain
the data collection and support ongoing analyses and co-ordination with CDSC epidemiological
data.
The second data set addresses the important issue of transmission of drug resistance by assessing
the prevalence of resistant virus in untreated individuals. This can be derived from newly infected
individuals (seroconverters), and/or new diagnoses. By definition, the seroconverters dataset is
small, since the vast majority of HIV diagnoses are made some time after initial infection, and the
majority species of virus in the plasma of such individuals may not truly represent transmitted (and
thus archived) resistance. Information on a proportion of newly infected individuals is captured
within the UK Seroconverter Register/PHLS collaboration. As this is only a small fraction of all new
diagnoses, it would be desirable to generate resistance data on all of the >4000 new diagnoses/
year, but this has significant resource implications (~ £1m/yr) - a small fraction of the antiretroviral
drug budget.
Figure 18 represents data from the 300 surveillance isolates from patients failing on therapy, by
year. Resistance to each of the three current classes of drug is defined as the presence of one or
more mutations, which clearly compromises activity of at least one drug within that class. This
does not mean that all drugs within the class are compromised, although this may be the case.
The key message is that the majority of patients failing therapy have some degree of drug resistance.
Secondly, year on year differences are apparent, and relate to the trends in use of specific drugs
e.g. the increasing use of nNRTI drugs within first line therapy from 1999. These data are preliminary,
with formal statistical analysis now being undertaken.
39
antimicrobial resistance in England & Wales 2000
Table 11 represents data to the end of 200046,47 on prevalence of resistance (defined as one or
more key resistance mutations) in patients with early infection, who have not yet received
antiretroviral therapy. This therefore represents transmitted drug resistance. Although the numbers
1994 1 (0)
1995 5 (0)
1996 15 (0) 0
1997 3 (1)
1998 10 (1) 10
1999 9 (1) 11
2000 36 (9) 25
are by definition small, there appears to be an increasing prevalence of such resistance over time.
These data are similar to those published recently from the US and France. However, with the
apparent reduction in resistance in prevalent infections (figure 18), and improved suppression of
viral replication over time, we cannot assume that transmitted resistance will continue to grow.
Although lamivudine is now licensed for treatment of chronic hepatitis B, treatment is not widely
used and so lamivudine resistance is not of public health significance yet, although it can be an
issue in the treatment of individual patients. Chronic hepatitis infection is not reported routinely to
PHLS CDSC and therefore no data on resistance is available. New anti-virals are becoming licensed
but the cost of therapy is likely to limit the more widespread use of treatment for the short to
medium term.
Treatment of hepatitis C involves the use of alpha-interferon with or without ribavirin. Treatment
is generally short term for six or twelve months and emergence of resistance per se is not a clinical
issue. Failure to respond is more associated with pre-existing host or viral factors rather than
resistance to antimicrobials.
40
antimicrobial resistance in England & Wales 2000
Discussion
Antimicrobial resistance commonly follows the advent of new antimicrobials and may even antedate
them. However, after a period of several new antimicrobials becoming available in the late 1990s,
the pace of developing new antimicrobials appears to be slowing and so the challenge of keeping
ahead of the organisms is growing. Couple this with the widespread use of powerful agents to
treat infections in special groups of patients, such as the immunocompromised, and the balance is
in danger of tipping in favour of the micro-organisms. Concern over this situation has led to the
production of many reports on the issues and a campaign to restrict antibiotic use in the community.1-
4, 48,49
However, the main problem area for resistance is with the newer, more powerful antimicrobials
used in hospitals or the spread of resistance associated with infection control difficulties, as is the
case with MRSA. But, unlike the situation in the community where prescribing information is
routinely available through the Prescription Pricing Authority (Prescribing Analyses and Cost, PACT,
data), information on the prescribing of antimicrobials is not routinely available from hospitals.
41
antimicrobial resistance in England & Wales 2000
The issues around the surveillance of susceptibility trends in organisms which are not normally
cultured or where there are difficulties in undertaking susceptibility testing in general microbiology
laboratories or where there are as yet no formalised programmes for susceptibility testing probably
require addressing through the development of a network of representative sentinel laboratories
to collect isolates for referral or to undertake culture and susceptibility testing routinely. Thus in
these recognised laboratories, all or a representative sample of specimens for C. difficile and C.
trachomatis identification would be routinely cultured and susceptibility testing then undertaken.
There is also a place for regular nationally representative surveys of other, less difficult, micro-
organisms, to validate the routine ‘broad brush’ surveillance data. For instance, these would be
useful to assess the extent to which mis- or lack of speciation of an organism might be skewing
the antimicrobial susceptibility picture, as is the case with Acinetobacter spp, E. faecalis and E.
faecium. Mechanisms also need to be in place to keep a watching brief on the situation as regards
new antimicrobials, such as linezolid, quinupristin/dalfopristin and lamivudine for hepatitis B.
Laboratories have sent ARMRL several groups of suspected linezolid-resistant enterococci for
confirmation, which has enabled rapid methods of detecting the responsible mutation to be
established.
This review has not been able to focus in any detail on the corollary of antimicrobial susceptibility:
antimicrobial prescribing. However, it is easy to identify areas requiring further attention, such as
the routine collation of hospital prescribing information in an analogous way to GP prescribing,
the need to agree the use of appropriate denominators for antimicrobial prescribing analyses
nationally and consideration of methods of assessing the appropriateness of antimicrobial
prescribing.
42
antimicrobial resistance in England & Wales 2000
43
antimicrobial resistance in England & Wales 2000
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antimicrobial resistance in England & Wales 2000
Appendix
Number of Reports
Gram-negative bacteria
Acinetobacter spp 774 (8)
Aeromonas spp 71 (0)
Alcaligenes spp 56 (2)
Campylobacter spp 120 (14)
Citrobacter spp 416 (2)
Comamonas spp 18 (0)
Enterobacter spp 1721 (11)
Escherichia coli 11032 (33)
Fusobacterium spp 55 (2)
Haemophilus influenzae 317 (13)
H. influenzae type b 21 (4)
Klebsiella spp 3147 (14)
Moraxella spp 82 (1)
Morganella morganii 275 (0)
Neisseria meningitidis 823 (211)
Proteus spp 1646 (4)
Providencia spp 69 (0)
Pseudomonas spp 2105 (13)
P. aeruginosa 1544 (12)
Salmonella spp 394 (2)
S. typhi and S. paratyphi 191 (0)
Serratia spp 592 (3)
Stenotrophomonas maltophilia 402 (2)
Gram-positive bacteria
Bacillus sp 143 (18)
Corynebacterium spp 188 (4)
Enterococcus spp1 3606 (28)
Gemella spp 39 (1)
Listeria monocytogenes 53 (6)
Micrococcus spp 89 (5)
Propionbacterium spp 157 (9)
Staphylococci:
S.aureus 12187 (101)
coagulase negative 4334 (224)
Streptococci:
pyogenic streptococci 2527 (52)
group A 897 (6)
group B 912 (43)
group C/G 718 (3)
‘Streptococcus anginosus group’ 431 (7)
‘Streptococcus bovis group’ 161 (1)
‘Streptococcus mitis group’ 612 (14)
‘Streptococcus mutans group’ 58 (0)
S. pneumoniae 3657 (160)
‘Streptococcus salivarius group’ 151 (3)
‘Streptococcus sanguins group’ 238 (0)
Anaerobic bacteria
Anaerobic cocci2 155 (0)
Bacteroides spp 881 (2)
Clostridium spp 402 (3)
46