Research
Trends in Fluoroquinolone
(Ciprofloxacin) Resistance in Enterobacteriaceae from Bacteremias,
England and Wales, 1990–1999
David M. Livermore,* Dorothy James,* Mark Reacher,† Catriona
Graham,* Thomas Nichols,* Peter Stephens,‡ Alan P. Johnson,* and
Robert C. George*
*Central Public Health Laboratory, London, United
Kingdom; †Communicable Disease Surveillance Centre, London, United
Kingdom; and ‡IMS-HEALTH UK, Pinner, Middlesex, United Kingdom
The Public
Health Laboratory Service receives antibiotic susceptibility data
for bacteria from bloodstream infections from most hospitals in
England and Wales. These data were used to ascertain resistance
trends to ciprofloxacin from 1990 through 1999 for the most prevalent
gram-negative agents: Escherichia coli, Klebsiella
spp., Enterobacter spp., and Proteus mirabilis.
Significant increases in resistance were observed for all four
species groups. For E. coli, ciprofloxacin resistance rose
from 0.8% in 1990 to 3.7% in 1999 and became widely scattered
among reporting hospitals. The prevalence of resistance in Klebsiella
spp. rose from 3.5% in 1990, to 9.5% in 1996 and 7.1% in 1999,
while that in Enterobacter spp. rose from 2.1% in 1990
to 10.5% in 1996 and 10.9% in 1999. For both Klebsiella
and Enterobacter spp., most resistance was localized in
a few centers. Resistance was infrequent and scattered in P.
mirabilis, but reached a prevalence of 3.3% in 1999.
Fluoroquinolone antimicrobial drugs were a major therapeutic advance
of the 1980s because they have 100-fold greater activity than their
parent compound, nalidixic acid (1). Unlike nalidixic
acid, which is used only for urinary infections and occasionally
shigellosis, the fluoroquinolones have a broad range of therapeutic
indications and are given as prophylaxis, e.g., for neutropenic
patients. In veterinary medicine fluoroquinolones are used as treatment
and metaphylaxis but not as growth promoters. Early researchers
thought that fluoroquinolone resistance was unlikely to evolve,
largely because resistant Escherichia coli mutants are exceptionally
difficult to select in vitro (2) and because plasmid-mediated
quinolone resistance remained unknown even after 30 years of nalidixic
acid usage. Nevertheless, mutational fluoroquinolone resistance
emerged readily in staphylococci and pseudomonads, which are inherently
less susceptible than E. coli. More recently, fluoroquinolone
resistance has emerged in E. coli and other Enterobacteriaceae,
contingent on multiple mutations that diminish the affinity of its
topoisomerase II and IV targets in varying ways, reduce permeability,
and upregulate efflux (3). Plasmid-mediated quinolone
resistance has been reported, but it is exceptional (4).
We report here resistance trends to ciprofloxacin, the most widely
used fluoroquinolone in the United Kingdom, in the prevalent Enterobacteriaceae
species from bacteremias in England and Wales during the 1990s.
Data
Sources
Data Collection
The surveillance, described previously, depends on the voluntary
reporting of bloodstream isolates by hospital laboratories in England
and Wales (5). The number of laboratories reporting
data has grown steadily: by 1998, 208 (91%) of the 229 establishments
in England and Wales listed by the Association of Medical Microbiologists
were participating. Participation by laboratories in Scotland and
Northern Ireland is limited, and their data were excluded from our
analysis. Most laboratories used variants of Stokes’ disc method
(5) for susceptibility tests in the period reviewed,
but a minority used breakpoint tests. Results reported as intermediate
were counted as resistant. Quality control was provided by the laboratories’
participation in the National External Quality Assurance Scheme
and by comparison to results for the smaller numbers of E. coli
isolates from bloodstream infections tested at the Central Public
Health Laboratory (6).
Prescribing Data for
Fluoroquinolones
Prescribing data for fluoroquinolones, as defined daily doses (7),
were estimated for retail pharmacies by using IMS HEALTH’s British
Pharmaceutical Index (BPI) and for hospitals by using Medicare Audit’s
Hospital Pharmacy Audit (HPA). The BPI records pharmaceutical sales
to retail pharmacies and dispensing doctors in the United Kingdom,
Channel Islands, and the Isle of Man. Approximately 97% of wholesaler
sales to retail and physician outlets and >80% of direct sales
by manufacturers are recorded; other sales are estimated from a
sample of approximately 600 pharmacies. The number of pharmacies
represented in the BPI remained constant during the study period.
The HPA provides information on pharmaceutical consumption by National
Health Service hospitals, which account for >95% of hospital
care in the United Kingdom. Most hospitals participate: approximately
93% of beds are currently covered. Since 1995, HPA data have been
collected monthly from the stock control systems of participating
hospitals. Most data are supplied electronically, which minimizes
reporting errors. Data include usage of pharmaceuticals among in-
and outpatient departments and for private patients in NHS hospitals
but not for private patients in designated private hospitals. Before
1995, HPA data were collected from wholesalers, manufacturers, and
a panel of hospitals: approximately 90% of indirect sales to hospitals
were received from wholesalers and approximately 40% of direct sales
from manufacturers. The panel of hospitals covered approximately
80% of beds in 1990 and 84.5% in 1995.
Statistical Analyses
Poisson regression was performed by using the log (total number
of isolates with resistance information) as an offset to determine
if the proportion of ciprofloxacin-resistant isolates was changing
with any type of pattern over time. S-Plus (Mathsoft Inc., Seattle,
WA) was used for calculation.
Results
Species Prevalence and
Reporting Patterns
During the 1990s, the Public Health Laboratory Service received
nearly 392,551 reports of bacteremia in England and Wales, including
132,311 that indicated E. coli, klebsiellae, Enterobacter
spp., and P. mirabilis as the pathogens isolated. These four
species groups thus accounted for 32% to 36% of all bacteremia results
in each year and for 71% to 72% of those concerning gram-negative
bacteria (Table 1). E. coli was
the most frequently reported pathogen, causing 22% to 25% of
all bacteremias in each year, whereas Klebsiella, Proteus,
and Enterobacter spp. were among the 10 most frequent isolates.
The number of bacteremia reports rose each year (Table
1), reflecting improved reporting rather than an increased incidence
of disease. A fall in the proportion of reports with susceptibility
data in 1997 reflected early problems after a switch to electronic
reporting and was not exclusive to ciprofloxacin.
Resistance Trends for
Ciprofloxacin
Among the reports for E. coli, klebsiellae, Enterobacter
spp., and P. mirabilis, 75,168 (56.8%) had susceptibility
data for ciprofloxacin, confirming widespread testing. Ciprofloxacin
resistance was extremely rare when surveillance began but subsequently
increased for all four organisms (Figure 1).
The proportion of E. coli isolates reported as resistant
rose slowly but steadily, from 0.8% in 1990 to 3.7% in 1999. For
Klebsiella spp., the resistance rate rose from 3.5% of reports
in 1990 to 9.5% in 1996, before declining to 7.1% by 1999. Enterobacter
spp. showed a similar pattern to klebsiellae: the prevalence of
resistance rose from 2.1% in 1990 to 10.5% in 1996, then dipped
to 7.9% in 1998 before rising to 10.9% in 1999. Only a few P.
mirabilis isolates were reported resistant in any year before
1999. Poisson regression showed strong evidence of a trend to increasing
resistance for all four organisms and suggested that these increases
had a nonlinear component for E. coli, enterobacters,
and klebsiellae. If the trends nevertheless were approximated
to be linear, the average annual increases in the proportion of
resistant isolates were as follows: E. coli, 21.54% (95%
confidence intervals [CI] 18.86-24.30); Klebsiella spp.,
6.97% (CI 4.41-9.59); Enterobacter spp. 13.97% (CI 10.46-17.58);
and P. mirabilis, 21.31% (CI 11.38-32.13).
Distribution of Resistance
To assess the distribution of resistance, we counted, for each
organism in each year: 1) the number of laboratories reporting resistant
isolates, 2) any laboratories contributing >10% of all reports
of resistance, and 3) the proportion of reports of resistance from
the top three contributors (Table 2). The
last two criteria were applied only when >30 resistant isolates
of a species were reported in a year, so that a hospital would not
appear as a “major contributor” on the basis of three or fewer resistant
isolates.
The number of laboratories reporting resistant E. coli rose
from 25 in 1990 to 89 in 1999, and no single laboratory ever contributed
>10% of all reports of resistance in a year for this species.
Laboratories reporting five or more resistant E. coli
in years before 1998 mostly served major teaching hospitals, but
many district general hospitals reported five or more resistant
E. coli isolates in 1998 and 1999. Resistance was more localized
and more prevalent in Klebsiella and Enterobacter
spp. than in E. coli. The number of laboratories reporting
resistant klebsiellae fluctuated from 36 to 57 after 1992, without
obvious trend. During a peak in resistance prevalence, from 1995
to 1997, one or two laboratories each contributed >10% of all
reports of resistant klebsiellae, and the top three contributors
accounted for 32% to 39% of reports of resistance. For Enterobacter
spp., laboratories reporting resistance increased from 10 in 1990
to 36 in 1992, then fluctuated with little trend until 1997, before
rising to 40 in 1998 and 58 in 1999. In the peak of resistance in
1995 and 1996, two laboratories each accounted for >10% of all
reports of resistant enterobacters, and 30% to 32% of reports of
resistance came from the top three contributors. Resistance was
uncommon in P. mirabilis, and clusters were not evident.
In a further analysis, we identified eight laboratories that frequently
reported large numbers of resistant E. coli, Klebsiella
spp., and Enterobacter spp. during the entire surveillance
period. These were in major metropolitan areas and served
teaching hospitals. These laboratories accounted for 7.7%, 11.2%,
and 10.3% of reports with ciprofloxacin data for E. coli,
Klebsiella, and Enterobacter spp. respectively, but
for 18.2%, 30.9%, and 22.4%, respectively, of reports of resistance
in these organisms, confirming a major excess of resistance.
The prevalence of ciprofloxacin resistance was examined in relation
to patients’ ages for E. coli, since those aged <14
years should not receive fluoroquinolones. Taking the period 1995
through 1999 as a whole, 12 (3.9%) of 305 E. coli with data
from patients 1 to 14 years old were reported as ciprofloxacin resistant,
compared with 778 (3.2%) of 24,302 E. coli isolates from
patients aged >15 years. These data indicated a relative
risk of 1.22 (95% CI 0.7-2.1) for the younger patients. Similar
calculations were not performed for other species because of the
small numbers of source patients aged 1-14 years.
Use of Fluoroquinolones
Fluoroquinolone use increased in the earlier years of surveillance,
nearly doubling from 1990 to 1993. However, usage has been relatively
stable from 1997 onwards, with community use declining slightly
(Figure 2). Although most use is still in
the community, hospital use has grown steadily in absolute terms
and as a proportion, constituting 31.5% of total use in 1999 compared
with 18.9% in 1992. Ciprofloxacin was the dominant fluoroquinolone
throughout the period (not shown).
Conclusion
When this surveillance began in 1990, the ciprofloxacin resistance
rates in E. coli and P. mirabilis were <1%, and
rates for enterobacters and klebsiellae were 2.1% and 3.5%, respectively.
The prevalence of resistance in E. coli subsequently rose
slowly and progressively to reach 3.7% in 1999; this resistance
was widely scattered in hospitals. Resistance also increased significantly
(p<0.01, chi-square test for trend) in enterobacters and
klebsiellas. The prevalence rates for these two genera were strongly
influenced by clusters of resistant isolates reported by a few laboratories.
Thus, the prevalence of ciprofloxacin resistance in klebsiellae
peaked at 9.5% in 1996, when three laboratories accounted for 35%
of reports of resistance. A subsequent decline was associated with
the absence of clusters but not with a decline in the number of
hospitals that reported resistance. For enterobacters, the proportion
of resistant isolates rose from 1990 to 1996, but the number of
laboratories reporting resistance was relatively constant from 1992
to 1997. Peak rates of resistance in 1995 and 1996 were in a period
when the top three contributors accounted for 30% to 32% of reports.
Resistance in P. mirabilis was infrequent and scattered but
rose significantly (p<0.01) in prevalence.
Although our analysis of resistance prevalence depended on the
compilation of susceptibility results obtained at different sites
by different methodologic variants, there is no suggestion that
definitions of resistance to ciprofloxacin have become more conservative
in the United Kingdom. Moreover, a rising prevalence of ciprofloxacin
resistance is evident in the smaller numbers of E. coli isolates
tested by a standardized method at the Central Public Health Laboratory,
supporting the trends found here (6,8).
Several factors may explain the greater prevalence and clustering
of resistance in enterobacters and klebsiellae. Most importantly,
Enterobacter and Klebsiella spp. are primarily hospital
pathogens, whereas E. coli bacteremias are more often community
acquired. Thus, E. coli accounted for 22.8% of all bacteremias
in this surveillance, which included both hospital- and community-acquired
infections, but only 12.5% of hospital-acquired bacteremias, as
recorded by the Nosocomial Infection National Surveillance Scheme
(9). Although most fluoroquinolone use is in the
community (Figure 2), the most intensive
use and therefore the greatest selection pressure relative to numbers
and concentration of patients is in hospitals. Moreover Klebsiella
and Enterobacter infections are more often clonal than those
involving E. coli; single strains, perhaps resistant, spread
to numerous patients (10). Clonal outbreaks seem
the likely explanation when small numbers of hospitals contributed
substantially to resistance totals—as was often the case for Enterobacter
and Klebsiella spp. (Table 2)—but cannot
be proved without retained isolates. Bacteremias caused by quinolone-resistant
E. coli may or may not be clonal, even when multiple cases
occur in a unit (11,12). The laboratories reporting
clusters of resistant Enterobacter and Klebsiella
spp. mostly served major teaching hospitals, where fluoroquinolone
prophylaxis by hematology departments has been associated with a
reduced incidence of bacteremias in neutropenic patients (13)
but with more bacteremias being caused by fluoroquinolone-resistant
strains (14,15).
We did not attempt to comprehensively relate resistance and prescribing,
but three general points can be made. First, the recent decline
in community prescribing of fluoroquinolones (Figure
2) has not affected the upward resistance trend in E. coli,
although most E. coli bacteremia is believed to involve non-nosocomial
strains. Second, the rising hospital use of fluoroquinolones has
not been mirrored by an acceleration in upward trend of resistance
in Klebsiella and Enterobacter spp. Third, the prevalence
of resistant E. coli from bacteremias in patients 1-14 years
old was similar to or higher than that in older patients, although
the younger patients should not receive fluoroquinolones. These
observations imply complex relationships between use and resistance,
demanding prospective investigation.
Except for P. mirabilis, the resistance prevalence rates
found here resemble those for bacteremias in the United States,
a country with much heavier fluoroquinolone use than the United
Kingdom. The Surveillance Network database (http://www.mrlworld.com)
shows resistance trends (with intermediate counted as resistant)
in bloodstream isolates from 250 U.S. hospitals as follows: E.
coli, 1.8% in 1996 and 4.3% in 1999; Klebsiella spp.,
7.1% in 1996 and 6.7% in 1999; Enterobacter spp., 6.6% in
1996 and 6.5% in 1999; and P. mirabilis, 5.7% in 1996 and
12.7% in 1999. Much higher rates are reported from Barcelona, Spain,
where 17% of E. coli isolates from community infections were
ciprofloxacin resistant (16), and India, where
up to 50% of hospital E. coli are reported resistant (17).
High rates in E. coli may reflect contamination via the food
chain: the Spanish study found quinolone-resistant E. coli
in 90% of chicken feces and noted similar fecal carriage rates of
resistant E. coli in children and adults. Acquisition of
resistant E. coli via the food chain may also explain why,
in our study, resistant E. coli were reported from age groups
who should not receive fluoroquinolone therapy and its contingent
selection pressure.
Ciprofloxacin remains a potent antibiotic; but the slow accumulation
of resistant Enterobacteriaceae is disturbing, not least
because resistance is a class effect, affecting all fluoroquinolones.
Ultimately, this resistance may be partly overcome by inhibiting
the efflux pumps that contribute to the resistance (18),
but this strategy is still several years from fruition. In the interim,
the best approach lies in the prudent use of fluoroquinolones in
humans and animals, coupled with an emphasis on preventing patient-to-patient
spread of resistant strains.
Acknowledgments
We are indebted to the hospitals that contributed data. We are
grateful to MRL Inc. of Reston, VA, USA, for permission to cite
The Surveillance Network (TSN) data for the USA.
Dr. Livermore is director of the national reference laboratory
for antibiotic resistance for England and Wales. His interests center
on the prevalence trends and biochemical mechanisms of antimicrobial
resistance.
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Table
1. Ciprofloxacin-resistant Enterobacteriaceae reported
from bacteremias, England and Wales, 1990–1999 |
|
Agent
|
Year
|
|
1990
|
1991
|
1992
|
1993
|
1994
|
1995
|
1996
|
1997
|
1998
|
1999
|
|
Escherichia
coli |
|
Total no. reports
|
7,610
|
7,377
|
7,849
|
7,872
|
8,274
|
8,465
|
9,155
|
10,143
|
11,248
|
11,573
|
|
No. with cipro. results
|
4,171
|
4,456
|
5,036
|
5,071
|
5,136
|
5,143
|
4,559
|
3,706
|
6,282
|
6,708
|
|
No. reported ciproR
|
33
|
32
|
47
|
65
|
88
|
108
|
119
|
144
|
244
|
246
|
Klebsiella spp.
|
|
|
|
|
|
|
|
|
|
|
|
Total no. reports
|
1,544
|
1,634
|
1,710
|
1,725
|
1,791
|
1957
|
2,143
|
2,383
|
2,816
|
2,802
|
|
No. with cipro. results
|
821
|
1,082
|
1,124
|
1,141
|
1,173
|
1,256
|
1,137
|
900
|
1,551
|
1,578
|
|
No. reported ciproR
|
29
|
48
|
55
|
77
|
77
|
115
|
108
|
80
|
125
|
112
|
Enterobacter spp.
|
|
|
|
|
|
|
|
|
|
|
|
Total no. reports
|
895
|
912
|
1013
|
948
|
1,118
|
1,089
|
1,229
|
1,480
|
1,638
|
1,629
|
|
No. with cipro. results
|
582
|
636
|
743
|
759
|
815
|
723
|
617
|
534
|
908
|
949
|
|
No. reported ciproR
|
12
|
26
|
36
|
29
|
54
|
65
|
65
|
55
|
72
|
103
|
Proteus
mirabilis
|
|
Total no. reports
|
868
|
898
|
911
|
925
|
984
|
942
|
1244
|
1,131
|
1,241
|
1,145
|
|
No. with cipro. results
|
454
|
578
|
560
|
573
|
635
|
673
|
578
|
447
|
715
|
658
|
|
No. reported ciproR
|
2
|
3
|
1
|
7
|
14
|
7
|
4
|
5
|
14
|
22
|
No. of other organisms
|
19,866
|
20,458
|
21,335
|
22,968
|
23,559
|
24,545
|
27,908
|
31,258
|
34,517
|
34,216
|
Total bacteremia reports
|
30,783
|
31,279
|
32,838
|
34,438
|
35,726
|
36,948
|
41,679
|
46,395
|
51,100
|
51,365
|
|
Cipro, ciprofloxacin; R, resistant.
|
Table
2. Distribution of reports of ciprofloxacin resistance for
Enterobacteriaceae from bacteremia in hospitals, England
and Wales, 1990–1999 |
|
Agent
|
Year
|
|
1990
|
1991
|
1992
|
1993
|
1994
|
1995
|
1996
|
1997
|
1998
|
1999
|
|
Escherichia
coli
|
|
No. labs reporting ciproR isolates
|
25
|
29
|
39
|
40
|
57
|
52
|
58
|
68
|
94
|
89
|
|
No. labs contributing >10% of ciproR totala
|
1
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
|
% of all ciproR reports from top three contributorsa
|
33
|
19
|
17
|
20
|
13
|
19
|
26
|
17
|
11
|
12
|
Klebsiella spp.
|
|
No. labs reporting ciproR isolates
|
23
|
48
|
38
|
42
|
42
|
47
|
42
|
36
|
57
|
50
|
|
No. labs contributing >10% of ciproR totala
|
-
|
0
|
1
|
0
|
0
|
1
|
2
|
2
|
1
|
0
|
|
% of all ciproR reports from top three contributorsa
|
-
|
17
|
29
|
15
|
21
|
32
|
35
|
39
|
23
|
21
|
Enterobacter spp.
|
|
No. labs reporting ciproR isolates
|
10
|
19
|
36
|
27
|
37
|
30
|
35
|
33
|
39
|
58
|
|
No. labs contributing >10% of ciproR totala
|
-
|
-
|
0
|
-
|
0
|
2
|
2
|
0
|
0
|
0
|
|
% of all ciproR reports from top three contributorsa
|
-
|
-
|
28
|
-
|
22
|
32
|
30
|
22
|
22
|
16
|
Proteus
mirabilis
|
|
No. labs reporting ciproR isolates
|
2
|
2
|
1
|
6
|
12
|
6
|
3
|
6
|
12
|
20
|
|
No. labs contributing
>10% of ciproR totala
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
|
% of all ciproR reports from top three contributorsa
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
-
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-
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aNot calculated if <30
resistant isolates.
Cipro, ciprofloxacin; R, resistant.
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