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Ciprofloxacin-resistant E. coli in TRUS
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Prevalence of ciprofloxacin-resistant Enterobacteriaceae in
the intestinal flora of patients undergoing trans-rectal
prostate biopsy in Norwich, UK
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Marcelino Yazbek Hanna1*, Catherine Tremlett2, Gurvir Josan1, Robert Mills1, Mark Rochester1,
David M Livermore3.
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1Urology
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and 2Microbiology Departments. Norfolk and Norwich University Hospital. Colney Lane
Norwich. UK NR4 7UYand 3Norwich Medical School, University of East Anglia, Norwich NR4 7TJ
[email protected],[email protected],
[email protected],[email protected], [email protected],
[email protected]
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Keywords: Prostate biopsy, sepsis, infection, rectal swabs, fluoroquinolone.
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Running head: TRUS, ciprofloxacin prophylaxis and sepsis
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*Corresponding author
Ciprofloxacin-resistant E. coli in TRUS
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Abstract
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Objective. To determine the efficacy of fluoroquinolone prophylaxis in patients
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undergoing trans-rectal ultrasound scan (TRUS)-guided biopsy of the prostate in the
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Norwich population, and its correlation with ciprofloxacin resistance in the faecal
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flora. We also aimed to determine the usefulness of a pre-biopsy rectal screen for
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resistant bacteria in these patients.
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Patients and methods The incidence and microbiology of sepsis after TRUS-guided
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prostate
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Subsequently, in 2012, a prospective study was performed, collecting the same data
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but also culturing rectal swabs from all patients undergoing TRUS biopsy, with a
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post-biopsy follow-up period of 6 months. All patients were given prophylactic oral
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ciprofloxacin, as per Trust policy (750 mg 1 hour pre-biopsy, followed by 250 mg
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q12h for 3 subsequent days).
biopsies
between
2007
and
2011
was
audited
retrospectively.
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Results: Between 2007 and 2011, 3600 patients underwent TRUS biopsy. Among
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these, 11 (0.3%) were admitted to hospital for post-biopsy related sepsis but only 4
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(0.1%) had ciprofloxacin-resistant Escherichia coli confirmed from blood cultures:
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three
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ciprofloxacin susceptibility data. In 2012, 10 (3.7%) of 267 patients sampled pre-
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biopsy had ciprofloxacin-resistant E. coli recovered on rectal swab culture but none
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of these men presented with post-biopsy sepsis; during the 6-month follow-up period,
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seven patients were diagnosed with urinary tract infections.
had
ciprofloxacin-susceptible
Enterobacteriaceae,
and
four
had
no
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Conclusion: Ciprofloxacin-resistant Enterobacteriaceae remain rare in the intestinal
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flora of the Norwich TRUS population, meaning that the drug remains adequate as
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prophylaxis. Pre-biopsy rectal swabs may be useful for individual departments to
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periodically assess their own populations and to ensure their antibiotic policy remains
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valid. In populations where resistance is known to be highly prevalent, pre-biopsy
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rectal swabs can help guide addition of further antibiotics to prevent post-biopsy
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septicaemia.
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Ciprofloxacin-resistant E. coli in TRUS
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Introduction
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Trans-rectal Ultrasound (TRUS)-guided prostate biopsy is a common procedure in
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the diagnosis of prostate cancer, performed on approximately 75,000 men every year
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in the UK alone (1).The procedure is relatively safe, except for the risk of infection, in
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particular bacteraemia (2,3). Several studies have shown the benefits of antibiotic
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prophylaxis in reducing infective complications, and fluoroquinolones are the
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preferred agents owing to good penetration into the prostatic cytosol (4-6). A
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randomised control study by Aron et al. (3) observed a significant decrease in post-
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biopsy infection when fluoroquinolones were used compared with placebo (8% vs
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25%) whilst other studies reported reductions to 1% (5) and 0.5% (7). Such findings
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led both the American Urological Association (AUA) and European Association of
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Urology (EAU) to recommend fluoroquinolones as routine prophylactic antibiotics for
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TRUS biopsy (7,8). This strategy is however being undermined by the international
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proliferation of fluoroquinolone-resistant faecal Enterobacteriaceae, which are carried
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into the bloodstream by the biopsy procedure. These are widely reported as agents
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of post-biopsy bacteraemias (9-13) leading several authors, nationally and
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internationally, to question the continued utility of fluoroquinolones as the preferred
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prophylactic agents. These experiences led us to review both TRUS outcomes and
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carriage of resistant Escherichia coli in Norwich, UK, a relatively isolated city with a
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population of 213,166 some, 118 miles north of London.
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Material and Methods
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Case review 2007-11
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All patients who underwent TRUS biopsy of the prostate between 2007 and 2011 at
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the Norfolk and Norwich University Hospital were retrospectively audited. The Trust
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antibiotic policy for TRUS biopsy remained unchanged, including oral administration
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of 750 mg ciprofloxacin 1 hour before the biopsy followed by 250 mg q12h for 3
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subsequent days. A review of subsequent sepsis cases resulting in hospital
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admission was made, including any microbiological data for E. coli or other
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Enterobacteriaceae recovered.
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Prospective study, 2012
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For the 9 months from April to December 2012 (inclusive), rectal swabs were taken
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immediately prior to the TRUS biopsy from 267 men who presented to our prostate
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specific antigen (PSA) one-stop clinic. Ciprofloxacin prophylaxis continued to be
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given to all patients as above.
Ciprofloxacin-resistant E. coli in TRUS
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Patient details including age, race, medical history, medications and past history
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infections were recorded, as well as any history of recent hospitalisations,
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procedures, travel and antibiotic treatments in the previous year.
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Swabs were cultured onto CLED agar with a 1-g ciprofloxacin disc applied on the
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first set of streaks after the primary inoculum.
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ciprofloxacin zone were recovered, identified, and confirmed as ciprofloxacin
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resistant by BSAC disk diffusion testing or using the Vitek 2 (bioMerieux, La Balme
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les Grottes, France). Patients’ hospital admissions within 31 days of the biopsy were
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recorded and correlated to the swab result. All patients were followed up, for a period
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of 6 months (by enquiring about urinary tract infections though general practitioners
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and tracking hospital admission due to related symptoms), to identify post-biopsy
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infective complications. Any urine cultures received by the hospital laboratory during
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this period were reviewed, with identification of the reason for culture submission, the
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culture results, and the antibiotic resistance of any organism grown.
Colonies that grew within the
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Results
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From the 3600 TRUS procedures done between 2007 and 2011, 18 patients were
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hospitalised due to biopsy-related complications, and 11 (0.3%) of these involved
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sepsis.
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for nine patients (Fig 1): four had ciprofloxacin-resistant E. coli recovered from blood
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whereas two had ciprofloxacin-susceptible E. coli, one had a ciprofloxacin-
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susceptible Enterobacter cloacae and two had isolates that were not tested with
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ciprofloxacin. One patient with bacteraemia due to a ciprofloxacin-resistant E. coli
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was known to be long-colonised with this organism (previous bacteriuria), whereas
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the patient with the Ent. cloacae bacteraemia suffered a further bacteraemia with the
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same species 2 months later, followed by two episodes of bacteraemia with
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ciprofloxacin-resistant E. coli, 4 and 7 months post-TRUS. One patient had vascular
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surgery a month after readmission and grew Bacteroides spp. from pus and aortic
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tissue, possibly seeded by the TRUS procedure.
Microbiology for the corresponding blood and urine cultures was available
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Only 10 (3.7%) of the 267 patients sampled pre-biopsy in 2012 had
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ciprofloxacin-resistant E. coli recovered from the swab cultures. Five of the 267
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(1.87%) were admitted to the hospital within 31 days of the procedure with
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complications, comprising haematuria (n=1) and urinary retention (n=4); none had
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infection.
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The mean (SD) age of the 10 patients carrying ciprofloxacin-resistant
Ciprofloxacin-resistant E. coli in TRUS
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Enterobacteriaceae from the 2012 series was 68.7 (SD, 9.2) years vs. 68 (SD=6.8)
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for the rest of the cohort. Three of the ten patients with ciprofloxacin-resistant isolates
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had a possible risk factor (2 travel abroad, 1 with previous antibiotic treatment) as
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shown in Table 1. Full antimicrobial susceptibility patterns of the 10 ciprofloxacin-
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resistant isolates are shown in Table 2: meropenem retained activity against all 10
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isolates as did ertapenem, amikacin and tigecycline, with gentamicin active against
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9/10 tested.
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.Within the 6-month follow-up period, seven patients were diagnosed with
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uncomplicated urinary tract infections.
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resistant
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Enterobacteriaceae on urine culture but none of these showed multiple resistance;
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the remaining two patients yielded heavy mixed growth, meaning that infection was
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not microbiologically confirmed (Table 3).
Enterobacteriaceae
in
None of these patients had ciprofloxacin-
their
original
rectal
swabs.
Five
grew
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Discussion
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Ciprofloxacin is widely used as the prophylactic antibiotic of choice for TRUS biopsy
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(14), reflecting its efficacy and good prostatic penetration. However reports of
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increasing resistance to the drug, and a rise in Clostridium difficile infections linked to
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fluoroquinolone use (15-17), have led some hospitals to replace or supplement
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ciprofloxacin with other antibiotics, though not always successfully. In Cambridge, 56
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miles from Norwich, the incidence of post-TRUS infections rose to 12.9% among
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patients receiving amoxicillin-clavulanate plus gentamicin as prophylaxis compared
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with 2.4% among those receiving ciprofloxacin in the immediately previous period.
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This finding led to the re-adoption of the ciprofloxacin regimen (18). Similarly, at Bury
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St Edmunds 42 miles from Norwich and 28 miles from Cambridge, ciprofloxacin
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prophylaxis was more effective in comparison to amoxicillin-clavulanate (infection
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rate 1.68% for ciprofloxacin vs 7.27% amoxicillin-clavulanate) and, again, these
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findings led to the re-adoption of the fluoroquinolone regimen (19). On the other
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hand, a London hospital that had a post-TRUS biopsy infection rate of 8% despite
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fluoroquinolone prophylaxis achieved a reduction to 2% after supplementation with a
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single pre-procedure dose of gentamicin (20); similar findings were reported in a
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second London study (21).
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These data demonstrate that simple replacement of fluoroquinolones with
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other broad-spectrum antibiotics has limitations, as these alternative agents may
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have inferior efficacy, perhaps owing to poor prostatic penetration.
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alternatives appear to be (i) to adapt prophylaxis to local resistance rates, with
Two better
Ciprofloxacin-resistant E. coli in TRUS
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supplementation of fluoroquinolone regimens where resistance is prevalent, and (ii)
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to identify patients carrying ciprofloxacin-resistant organism pre-procedure, by
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culturing rectal swabs (22), and to adapt prophylaxis individually..
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Local variation is well illustrated by comparing the studies for East Anglia
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versus those for London. In East Anglia, post-TRUS infection rates with
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fluoroquinolone prophylaxis ranged from 0.3% (Norwich, this study) to 1.6% (Bury St
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Edmunds) to 2.4% (Cambridge) and, at Norwich in 2012, just 3.7% of patients
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carried ciprofloxacin-resistant E. coli, with none of these individuals suffering from
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post-TRUS infective complications warranting hospital admission. In London, by
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contrast, 1.5-8% of patients developed infections and up to 10% carried
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ciprofloxacin-resistant Enterobacteriaceae (16). Even between Norwich and
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Cambridge there was a 0 vs 2.4% range in post-procedure infections. A possible
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explanation is that Norwich is a more isolated city than Cambridge, which has a more
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fluid population, with greater ethnic diversity and a higher rate of intercontinental
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travel, possibly with a higher carriage rate of resistant Enterobacteriaceae. In
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Birmingham, Wickramasinghe et al. found that carriage rates for resistant
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Enterobacteriaceae varied among ethnic groups, perhaps reflecting the frequency of
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travel to and from South Asia, where these organisms are extremely prevalent (23);
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this view is supported by a study done by Patel et al. in London (24).
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Based on these findings we conclude that ciprofloxacin remains an
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appropriate prophylactic antibiotic for TRUS in our local setting. Whether or not it
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should be supplemented or changed elsewhere must depend on the local population.
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We suggest that periodic rectal swab cultures should be taken to ascertain the
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prevalence of ciprofloxacin resistance and to confirm its continued appropriateness.
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In regions with high fluoroquinolone resistance, pre-procedure screening could also
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be used to identify individual patients carrying resistant organisms, who might benefit
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from supplementary antibiotics. According to The Department of Health (25) an A&E
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admission costs, on average, £108, plus £400 per 24 hours of hospital stay. On this
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basis, screening becomes cost-effective even if only one patient in a hundred would
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otherwise experience an infection necessitating hospitalisation, even before
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individual suffering and economic costs are considered.
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Conclusion
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Ciprofloxacin resistance remains rare in the intestinal Enterobacteriaceae flora in our
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local TRUS population. Due to the geographical location of Norwich and the limited
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access of our patients to other hospitals, we are confident with this result genuinely
Ciprofloxacin-resistant E. coli in TRUS
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reflects the local situation.
Prophylaxis may need review in settings of higher
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resistance or for individual high-risk patients.
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Ciprofloxacin-resistant E. coli in TRUS
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Table 1 Risk factors in patients with ciprofloxacin-resistance isolates
Patients
Travel History
Hospitalisation for
Antibiotic treatments
over 48 h
(Past 12 months)
(Past 3 months)
(Past 12 months)
P1
No
Yes
No
P2
No
No
No
P3
No
No
No
P4
USA
No
No
P5
France
No
No
P6
No
No
No
P7
No
No
No
P8
No
No
Unknown
P9
No
No
N
P10
Greece
No
Amoxicillin
+Flucloxacillin
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Ciprofloxacin-resistant E. coli in TRUS
Table 2: Antimicrobial susceptibility of ciprofloxacin-resistant isolates recovered from 10 patients in 2012.
Nbr Patients
Amp
Pip
Ptz
Clt
Cxm
Fox
Ctx
Caz
Cpm
Azt
Ert
Mem
Aug
Amk
Gen
Tob
Cip
Tig
Tmp
Susceptible
4
8
2
2
4
6
7
8
8
7
8
9
10
7
9
7
0
9
7
Intermediate
0
0
0
1
2
0
2
0
1
1
0
0
0
2
0
0
0
0
0
Resistant
6
2
5
0
3
4
0
2
1
1
1
0
0
0
1
2
10
0
0
Not Tested
0
0
3
7
1
0
1
0
0
1
1
1
0
1
0
1
0
1
3
Abbreviations: Amp. ampicillin; Aug, co-amoxiclav; Pip, piperacillin; Ptz, piperacillin-tazobactam; Cltn, cephalothin; Cxm, cefuroxime; F
Fox, cefoxitin; Ctx, cefotaxime; Caz, ceftazidime; Cpm, cefepime; Azt, aztreonam; Ert, ertapenem; Mem, meropenem; Amk, amikacin;
Gen, gentamicin; Cip, ciprofloxacin; Tig, tigecycline and Tmp, trimethoprim. Susceptibility testing methods: 9 isolates tested by Vitek. 1
patient tested by BSAC disc diffusion
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