Journal of the New Zealand Medical Association, 15-July-2005, Vol 118 No 1218
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.
All 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).
During 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.
During 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 email@example.com
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