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| Journal of the New Zealand Medical Association,
15-July-2005, Vol 118 No 1218
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Extended-spectrum beta-lactamase-producing
Enterobacteriaceae at Middlemore
Hospital
Simon Briggs, James Ussher, Susan Taylor
Extended-spectrum beta-lactamase-producing
Enterobacteriaceae (ESBLPE) were first
described in Europe in 1983.1 In the subsequent
20 years, bacteria with this resistance mechanism have become increasingly
important. ESBLPE are not only resistant to penicillins and cephalosporins but
are often also resistant to a wide range of other antibiotic classes (including
fluoroquinolones, aminoglycosides, and trimethoprim/sulfamethoxazole) due to
accumulation of other resistance genes. This limits effective treatment options.
ESBLPE were first identified in New Zealand in
19942 but were only isolated in low numbers
nationwide (less than 30 per year) until 2001.3
Since then, there has been a significant increase in the number of isolates
received by the Institute of Environmental Science and Research Limited (ESR),
with 83 in 2001, 230 in 2002, 305 in 2003,3 and
182 in the first 6 months of 2004 (personal communication, H Heffernan,
Senior Scientist, ESR, 2004).
This review was undertaken to assess the demographics and
microbiology of patients colonised or infected with ESBLPE at Middlemore
Hospital and the treatment and outcome of patients with ESBLPE
bacteraemia.
MethodsAll patients who had an ESBLPE
isolated at the Middlemore Hospital Microbiology Laboratory from January 2001 to
June 2004 were included in this review. Potential ESBLPE were identified by any
of the following: reduced susceptibility to a third-generation cephalosporin;
resistance to two or more classes of antibiotics excluding beta-lactams; synergy
between ceftriaxone and amoxycillin/clavulanic acid on routine disc
susceptibility testing, or resistance to cefaclor or cefuroxime while retaining
susceptibility to amoxycillin/clavulanic acid.
Isolates were confirmed as ESBL-producers by either the
National Committee on Clinical Laboratory Standards (NCCLS)
method4 (modified to include cefpodoxime and
cefpirome discs with and without clavulanic
acid)5 and/or the double disc synergy
test.6 It is common practice for ESBL-producing
isolates in New Zealand to be referred to ESR for surveillance purposes. All
isolates included in this review were also confirmed as ESBL-producing by
ESR.
Data were retrospectively collected on patient
demographics, organism isolated, antibiotic susceptibility profiles, specimen
type, day of admission when ESBLPE was first isolated, and potential risk
factors for ESBLPE acquisition (a hospital admission in the previous 6 months,
residence in a long-term care facility [LTCF], and admission to an intensive
care unit [ICU]). Antibiotic susceptibilities were performed by either the disc
diffusion method or by the Vitek 2 system (AST-NO19 card, bioMerieux), and
interpreted using NCCLS breakpoints.4
For patients in whom an ESBLPE was isolated from
peripheral blood culture, data were also collected on source of bacteraemia, day
post admission when ESBLPE bacteraemia was first detected, antibiotics received,
and treatment outcome (‘cure’ defined as no clinical deterioration
following completion of antibiotic treatment; ‘relapse’ defined as
clinical deterioration following completion of treatment and/or isolation of the
same organism from blood following treatment; or ‘death’).
In addition to the antibiotic susceptibility testing
methods described above, the minimum inhibitory concentrations (MIC) of
ciprofloxacin, meropenem, ertapenem, imipenem, and amikacin were determined
(E-test, AB Biodisk, Solna, Sweden).
ResultsDuring the 3½-year period of
this review, ESBLPE were isolated from 132 patients admitted to Middlemore
Hospital. The median age was 67 (range 1 to 93) years, and 72 (55%) were female.
The ethnicities of these patients were recorded as European (n=85), Maori
(n=14), Samoan (n=5), Chinese (n=3), Fijian (n=3), Fijian Indian (n=3), Indian
(n=3), Rarotongan (n=3), Tongan (n=3), and Other (n=10)
There were 12 patients colonised or infected with an ESBLPE
in 2001, 34 in 2002, 43 in 2003, and 43 in the first 6 months of 2004. The
Service primarily responsible for patient care before the isolation of an ESBLPE
was Medicine (n=27), Surgery (n=25), Orthopaedics (n=23), Plastics/Burns (n=18),
Geriatrics (n=11), Intensive Care Unit [ICU] (n=9), Paediatrics
(n=3), and Other
(n=13).
Of the 132 patients, 129 had an ESBLPE first isolated as an
inpatient and 3 as an outpatient. The median number of days after admission when
an ESBLPE was first isolated was 11 (range 0 to 94) days. Thirty-three (25%)
patients had an ESBLPE isolated in the first 48 hours of admission to hospital.
Of these 33 patients, 21 had one or more hospital admissions in the previous 6
months; 7 of these 21 patients were also LTCF residents. Of the remaining 12
patients, 5 were LTCF residents and 7 were neither LTCF residents nor had
hospital admissions in the previous 6 months. Thirty-six of the 132 patients
(27%) had an ICU admission before the first isolation of an ESBLPE.
Overall, during the review period, 31 patients (23%) resided
in a LTCF before the admission when an ESBLPE was isolated. Eleven LTCFs had one
patient, six LTCFs had two patients, one LTCF had three patients, and one LTCF
had five patients colonised or infected with an ESBLPE.
The isolates from the five patients residing in the same
LTCF were all Escherichia coli. These
five patients were admitted to hospital between June 2003 and March 2004. DNA
analysis using pulsed-field gel electrophoresis (PFGE) after restriction
digestion with Xba I was performed on
these isolates by ESR. Four of the five isolates had an indistinguishable
pattern and the remaining isolate had a very closely related pattern with one
band difference only. An ESBLPE was first isolated from two of these patients on
the day of admission and from the others on days 7, 8, and 16 after admission.
Four of these five patients had a hospital admission in the previous 6
months.
The species producing an ESBL included
E. coli (n=56),
Enterobacter cloacae (n=48),
Klebsiella pneumoniae (n=21) and
Enterobacter spp. (n=7). During the
review period, the Middlemore Hospital Microbiology Laboratory isolated
E. coli from approximately 7370
patients, Enterobacter spp. from
approximately 790 patients, and K.
pneumoniae from approximately 810 patients.
Thus ESBL-production was detected in 0.8% of
E. coli, 7% of
Enterobacter spp., and 3% of
K. pneumoniae at Middlemore Hospital.
Many patients had an ESBLPE isolated from more than one specimen type.
The most clinically significant isolate came from peripheral
blood culture (n=18), catheter blood culture (n=2), central venous catheter tip
(n=2), tissue/abscess (n=6), drainage fluid (n=2), epidural catheter tip (n=1),
joint aspirate (n=1), pleural aspirate (n=1), sputum/tracheal aspirate (n=5),
wound swab (n=25), midstream urine/catheter urine (n=63), and faeces (n=6).
The antibiotic susceptibilities for all isolates are shown
in Table 1. Seventy-eight of 80 (98%) isolates tested were susceptible to
amikacin. All 115 isolates that were tested were susceptible to imipenem.
Sixty-seven of 68 (99%) isolates tested were susceptible to ertapenem.
Table 1. Antibiotic susceptibilities for all
isolates
The ertapenem resistant isolate was an
E. cloacae that was first isolated from
the urine of a 75-year-old European man with a history of Duke’s C
adenocarcinoma during an admission to another hospital for ureteric stenting.
One month later, it was again isolated from his urine when he presented to
Middlemore Hospital with a bowel obstruction. This isolate had an ertapenem MIC
of 8 mg/L (susceptible ≤2 mg/L, intermediate 4 mg/L, resistant ≥8
mg/L),4 meropenem MIC of 0.5 mg/L (susceptible
≤4 mg/L)4 and imipenem MIC of 4 mg/L
(susceptible ≤4 mg/L).4
Eighteen patients had an ESBLPE isolated from a peripheral
blood culture during their admission. Two of these patients remained well,
despite receiving no effective antibiotic against the isolate so were excluded
from further analysis. Of the remaining 16 patients, 6 (38%) were female and
their median age was 63 (range 17 to 91) years. The organisms isolated were
E. cloacae (n=7),
E. coli (n=6), and
K. pneumoniae (n=3). There were
approximately 750 episodes of Gram-negative bacteraemia during the review
period, thus ESBLPE were responsible for 2% of all Gram-negative bacteraemia.
Characteristics of the bacteraemic patients and their
isolates are shown in Table 2. Four patients (25%) presented to hospital
bacteraemic with an ESBLPE. Of the 12 patients who developed ESBLPE bacteraemia
in hospital, 8 (67%) had previously been admitted to ICU.
All bacteraemic isolates were susceptible to all
carbapenems. The MIC50 and
MIC90 were 0.064 and 0.125 mg/L respectively for
meropenem; 0.064 and 0.5 mg/L for ertapenem; and 0.25 and 1 mg/L for imipenem.
All isolates were susceptible to amikacin with a
MIC50 and MIC90 of
4 and 8 mg/L respectively (susceptible ≤16
mg/L).4 Fourteen (88%) of the isolates were
susceptible to piperacillin/tazobactam by disc diffusion (MICs were not
determined).
Twelve patients received more than 48 hours of antibiotic as
treatment for ESBLPE bacteraemia; the majority of antibiotic treatment these
patients received was with a carbapenem (n=6), a quinolone (n=4),
piperacillin/tazobactam (n=1), or amikacin (n=1). Six patients (38%) died; there
were no relapses.
DiscussionDuring the 3½ years of this
review, the number of ESBLPE isolated at Middlemore Hospital have increased
significantly. In the first 6 months of 2004, there was the same number of
ESBLPE isolated as for all of 2003. During the review period, ESBL production at
Middlemore Hospital was detected in 7% of
Enterobacter spp., 3% of
K. pneumoniae, and 0.8% of
E. coli.
ESBLPE were isolated from all departments at Middlemore
Hospital; particular departments did not appear to be over-represented in the
number of patients from whom an ESBLPE was isolated, however one-quarter of
patients had been admitted to ICU before the isolation of an ESBLPE. While
almost half of the ESBLPE at Middlemore Hospital were isolated from urine,
ESBLPE were also responsible for invasive disease (including 16 patients with
bacteraemia).
Originally K.
pneumoniae and E. coli were the
most common ESBL-producing bacteria worldwide, although in recent years ESBL
production amongst Proteus mirabilis
and AmpC-producing Enterobacteriaceae
has become more prevalent.7
As the genes encoding ESBLs are contained on plasmids,
horizontal gene transfer to many species of bacteria is possible. ESBL
production has rarely been transferred to
non-Enterobacteriaceae; ESBL-producing
Pseudomonas aeruginosa and
Acinetobacter spp. have been reported
in Europe.8,9
Nationwide, during the review period,
E. coli (responsible for 73% of all
isolates), Enterobacter spp.
(responsible for 15% of all isolates), and K.
pneumoniae (responsible for 8% of all isolates) were the most common
ESBLPE referred to ESR (personal communication, H Heffernan, 2004).
The numbers of E.
coli are bolstered by a clonal outbreak in a North Island Hospital. At
Middlemore Hospital, ESBL-producing
Enterobacter spp. are as common as
ESBL-producing E. coli (both
responsible for 42% of all isolates) with ESBL-producing
K. pneumoniae responsible for only a
small number of isolates (16%).
ESBLPE were responsible for 2% of all Gram-negative
bacteraemia that occurred at Middlemore Hospital during the review period. While
the majority of patients with ESBLPE bacteraemia developed this during their
hospital stay, a quarter of these patients presented to hospital with
bacteraemia. Two-thirds of the patients who developed bacteraemia during their
hospital stay had previously been admitted to ICU. The majority of bacteraemic
patients were treated with either a carbapenem or a quinolone.
Carbapenems are recommended as the treatment of choice for
ESBLPE bacteraemia.7,10 The meropenem,
ertapenem, and imipenem MICs for all isolates causing bacteraemia were well
within the susceptible range. The MIC50 and
MIC90 were lowest for meropenem, followed closely
by ertapenem. The choice of carbapenem may be influenced by cost and dosing
interval.
Ertapenem, being the narrowest spectrum carbapenem, may be
an attractive option in terms of reducing pressure on the development of
resistance. However, while all the bacteraemic isolates were
ertapenem-susceptible, an E. cloacae
isolated from urine was found to be ertapenem-resistant. Rare
ertapenem-resistance in
Enterobacteriaceae has been described
previously.11 Therefore, susceptibility to
ertapenem should not be assumed on the basis of susceptibility to meropenem or
imipenem.
The use of ciprofloxacin (to treat ESBLPE bacteraemia) has
been associated with increased rates of treatment failure and mortality when
compared to treatment with a carbapenem.10,12
This is thought, at least in part, to be related to ESBL-producing isolates that
have ciprofloxacin MICs close to the susceptibility breakpoint (susceptible
≤1mg/L)4 and the inability to achieve
adequate tissue levels of this drug above these MICs.
Of the seven bacteraemic isolates that were
ciprofloxacin-susceptible, five (71%) had MICs close to the susceptibility
breakpoint (MICs of 0.25 to 1 mg/L). Two patients (patients 7 and 10), who were
almost exclusively treated with ciprofloxacin, had ciprofloxacin-susceptible
isolates with MICs close to the susceptibility breakpoint (MICs of 1 and 0.25
mg/L respectively). The source of bacteraemia in these patients was
ventilator-associated pneumonia and intravascular-catheter sepsis, respectively.
Both patients were cured. Given the above concerns, we are not currently using
ciprofloxacin as treatment for patients with ESBLPE bacteraemia or invasive
disease.
All of the blood culture isolates, and 98% of the total
isolates, were susceptible to amikacin. Treatment with this aminoglycoside is
currently a treatment option at Middlemore Hospital, especially for patients
with a urinary tract source of infection. The other possible treatment option is
piperacillin/tazobactam, although there are concerns that treatment failure may
occur (as the piperacillin/tazobactam MIC can increase with a large inoculum of
infecting organisms).13
ESBLPE bacteraemia at Middlemore Hospital has a significant
mortality rate (38%). This compares to mortality rates from other series of 19
to 50%.12,14,15
One of the major risks (for colonisation and infection with
an ESBLPE) is prolonged hospitalisation,16
however acquisition in LTCFs,17,18 and more
recently community acquisition of these organisms, has been
reported.19,20 The PFGE results for the five
patients with an ESBL-producing E. coli
(residing in one LTCF during a 10-month period) suggest that acquisition of
ESBLPE in LTCFs may well be occurring in Auckland, although four of these five
patients had been hospitalised in the previous 6 months and may have become
colonised at that time.
There is transmission occurring in the Auckland community,
as 7 of the 33 patients who had an ESBLPE isolated in the first 48 hours of
admission to hospital had no hospital admission in the previous 6 months and
were not LTCF residents. Given these findings, all patients are at risk of
colonisation and infection with an ESBLPE.
Previous antibiotic use is a well-recognised risk factor for
colonisation and infection with an ESBLPE. Hospital- and community-based studies
have found an association with previous use of penicillin, a second- or
third-generation cephalosporin, or a fluoroquinolone and ESBLPE
infection.14,19–21
The use of third-generation cephalosporins and ciprofloxacin
is not restricted at Middlemore Hospital, and inappropriate use of these
antibiotics may be contributing to the recent increase in ESBLPE isolations. We
are currently considering ways in which to limit the use of these antibiotics at
Middlemore Hospital.
The transfer of ESBLPE to non-colonised patients in
hospitals and LTCFs occurs mainly via the hands of healthcare
workers.7 Therefore, efforts to prevent
patient-to-patient transmission (via the hands of healthcare workers) are
necessary to reduce the transmission of ESBLPE in these facilities.
Since many ESBLPE-colonised patients are likely to go
undetected, attention to standard precautions (particularly hand hygiene) is
essential for all healthcare workers. Standard precautions plus contact
precautions are used at Middlemore Hospital for patients known to be colonised
or infected with an ESBLPE. An electronic ‘multidrug-resistant organism
alert’ is placed in the clinical record of colonised patients so that
staff will be aware of this at the time of any future admission.
Specific screening for ESBLE colonisation is performed at
Middlemore Hospital when previously colonised patients are readmitted, when
transmission within a multi-bedded room or ward is suspected, and in the ICU
where ongoing surveillance occurs. Colonisation is detected using faeces or a
rectal swab cultured onto media that selects for Gram-negative bacilli with
reduced susceptibility to aztreonam or ceftazidime.
Colonisation and infection due to ESBLPE are increasing at
Middlemore Hospital and in the Auckland community. Currently ESBLPE are
responsible for only a small percentage of invasive disease or bacteraemia
caused by Gram-negative bacilli at Middlemore Hospital. However we anticipate
that ESBLPE will become more common in the near future; this may have
implications for empirical antibiotic treatment.
Useful treatment options in our hospital for proven ESBLPE
infection include amikacin or a carbapenem. Strategies that may reduce the rate
of increase of ESBLPE-colonisation and infection in Auckland will include
careful infection-control practices in hospitals and LTCFs, avoidance by all
prescribers of unnecessarily broad spectrum antibiotics, and avoidance of the
use of antibiotics in situations where they are not required.
Author information:
Simon Briggs, James Ussher, Susan Taylor, Departments of Infectious Diseases and
Microbiology, Middlemore Hospital, Auckland.
Correspondence:
Simon Briggs, Infectious Diseases Department, Auckland City Hospital, Private
Bag 92-024, Auckland, New Zealand. Fax: (09) 307 4940. Email sbriggs@adhb.govt.nz
References:
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