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JAC Advance Access originally published online on June 27, 2007
Journal of Antimicrobial Chemotherapy 2007 60(3):629-637; doi:10.1093/jac/dkm225
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Control of extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae in a children's hospital by changing antimicrobial agent usage policy

Jina Lee1,2,{dagger}, Hyunjoo Pai3,{dagger}, Yun Kyung Kim4, Nam Hee Kim1, Byung Wook Eun1, Hyoung Jin Kang1, Kyoung Ho Park5, Eun Hwa Choi1,6, Hee Young Shin1, Eui Chong Kim7, Hoan Jong Lee1,* and Hyo Seop Ahn1

1 Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea 2 Department of Pediatrics, Seoul National University Boramae Hospital, Seoul, Korea 3 Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea 4 Department of Pediatrics, Korea University College of Medicine, Seoul, Korea 5 Department of Pharmacy, Seoul National University Children's Hospital, Seoul, Korea 6 Seoul Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea 7 Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea

* Correspondence address. Department of Pediatrics, Seoul National University Children's Hospital, 28 Yeongeon-dong, Jongro-gu, Seoul 110-744, Korea. Tel: +82-2-2072-3633; Fax: +82-2-745-4703; E-mail: hoanlee{at}snu.ac.kr

Received 25 January 2007; returned 21 March 2007; revised 27 April 2007; accepted 28 May 2007


   Abstract
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 Abstract
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Objectives: This ambidirectional intervention study was performed to examine the impact of a change in antibiotic policy on extended-spectrum ß-lactamase (ESBL) prevalence in a children's hospital with a high prevalence of ESBL production among Escherichia coli and Klebsiella pneumoniae.

Methods: The use of extended-spectrum cephalosporins was restricted and use of ß-lactam/ ß-lactamase inhibitor combinations was encouraged from 2002. All strains of E. coli and K. pneumoniae isolated from sterile body fluids from 1999 to 2005 were analysed for ß-lactamase production and the prevalences of ESBL production were compared at three periods; pre-intervention (1999–2001), transitional period (2002–03) and post-intervention (2004–05).

Results: Comparing the pre- and post-intervention periods, overall piperacillin/tazobactam use increased from 2.2 to 108.0 days on antibiotics/1000 patient admission days/year (AD) (P for trend < 0.001), whereas extended-spectrum cephalosporin use decreased from 175.0 to 96.9 AD (P for trend < 0.001). Among 252 strains of E. coli (n = 128) and K. pneumoniae (n = 124), the overall prevalence of ESBL producers decreased from 39.8% (41/103) to 22.8% (18/79) (P for trend = 0.018). This decreasing trend of ESBL production was more evident for K. pneumoniae (64.1% to 25.6%; P for trend < 0.001) than E. coli (25.0% to 19.4%; P for trend = 0.514). The mortality rates of invasive disease caused by E. coli or K. pneumoniae remained unchanged.

Conclusions: The substitution of piperacillin/tazobactam for extended-spectrum cephalosporins successfully decreased the prevalence of ESBL production of K. pneumoniae and E. coli in an institute for children where ESBLs were endemic. The impact of change in antibiotic policy was more evident in K. pneumoniae than E. coli.

Keywords: cephalosporins , piperacillin/tazobactam , intervention studies


   Introduction
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 Introduction
Materials and methods
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Since extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae were first described in 19831 and 1987,2 respectively, strains of E. coli and K. pneumoniae resistant to broad-spectrum cephalosporins have been increasingly recognized.3,4 There is a universal agreement that increasing antimicrobial resistance is related to selective pressure exerted by the use of these agents,5,6 and the withdrawal of such pressure has been frequently suggested as a means of reversing specific resistance.5,7 It has been demonstrated that restriction of extended-spectrum cephalosporins and the use of piperacillin/tazobactam decrease the incidence of cephalosporin and piperacillin/tazobactam resistance in K. pneumoniae in case of polyclonal spread of ESBL-producing strains.8 However, no study has examined the impact of a change in hospital formulary on the ESBL prevalence in a children's institute with an endemically high prevalence of ESBLs among E. coli and K. pneumoniae.

We have previously reported that the prevalence of ESBL was as high as 17.9% in E. coli and 52.9% in K. pneumoniae among 157 blood isolates from 1993 through 1998 at Seoul National University Children's Hospital.9 This high prevalence rate of ESBL production was maintained throughout the study period, and PFGE analyses of ESBL-producing organisms showed extensive diversity in clonality, implying the endemicity of the ESBL-producing E. coli and K. pneumoniae. In an attempt to reduce the prevalence of ESBL producers, we restricted the use of extended-spectrum cephalosporins and encouraged the use of ß-lactam/ß-lactamase inhibitor combinations (piperacillin/tazobactam or ampicillin/sulbactam) for empirical therapy and/or specific therapy since January 2002.8,10,11 Although piperacillin/tazobactam has not been approved by the Food and Drug Administration for use in children under the age of 12 years, it has been administered to children and did not induce any serious adverse event.12

This study was performed to examine the impact of a change in antibiotic policy on the prevalences of ESBL in a children's hospital with a high prevalence of ESBL production among E. coli and K. pneumoniae. The clinical impact of a change in antibiotic policy was also evaluated by comparing the mortality rates of patients with invasive disease caused by the above strains. In addition, we monitored the emergence of imipenem- or piperacillin/tazobactam-resistant organisms during the study period.


   Materials and methods
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The institute and bacterial strains

The institute concerned is a 300 bed university-affiliated tertiary hospital located in Seoul and has paediatric and surgical wards. The paediatric wards include an oncology ward, a paediatric intensive care unit (ICU), a neonatal ICU and three general wards. Strains of E. coli and K. pneumoniae isolated from normally sterile body fluids such as blood, pleural fluid and cerebrospinal fluid at the paediatric wards during the study period from January 1999 through December 2005 were collected and stored at –70°C. Species identification was carried out using VITEK-GNI cards (bioMerieux, Hazelwood, USA). Only one isolate from each episode was included in this study, but additional microorganisms of different species or with different antibiograms were all included in the microbiological analysis. Because only seven invasive episodes caused by E. coli (n = 3) and K. pneumoniae (n = 4) occurred during the 7 year study period in the surgical wards, the data of surgical wards were not included in this analysis. Blood isolates of Enterobacter species, Pseudomonas aeruginosa and Acinetobacter baumannii were also collected during the study period.

Microbiology

Antimicrobial susceptibility tests. The antibiotic susceptibility of each isolate was determined by the disc diffusion method, as described by the CLSI, USA.13 For isolates that were intermediate or resistant to piperacillin/tazobactam by disc diffusion test, MICs were double-checked using the Etest (AB Biodisk, Solna, Sweden). Isolates with intermediate resistance or resistance were defined as non-susceptible.

Screening and confirmatory tests for ESBL-producing strains. When suspected, according to CLSI screening criteria, ESBL production was confirmed by phenotypic CLSI confirmatory test,13 and/or double disc synergy test using clavulanic acid.14 The production of AmpC type ß-lactamase was phenotypically suspected for isolates that had reduced susceptibility to extended-spectrum cephalosporins and a negative clavulanic acid synergy test, and those that had a cefotetan disc zone diameter of < 16 mm15 and/or a piperacillin/tazobactam disc zone diameter of < 20 mm. These strains were further tested using boronic acid discs to screen for the presence of AmpC ß-lactamase.16

Identification of ESBL types. Types of ESBL or AmpC ß-lactamase (both are designated as ESBLs from here unless otherwise specified) were identified by analytical isoelectric focusing (with or without inhibition with clavulanic and/or cloxacillin), PCR for and/or sequencing of ß-lactamase genes as described previously.9 ESBL types were described based on pI values and the amplification of the suspected class of ß-lactamase genes. ESBLs of the SHV type with pIs of 7.6 and 8.2 were described as SHV with pI 7.6 and SHV with pI 8.2, respectively, and an ESBL of the CTX-M type with a pI 8.0 was described as CTX-M with pI 8.0. Because TEM-type ESBL with a pI 5.9 was found to be either TEM-15 or TEM-52 at the institute during a previous study,9 ß-lactamase genes of this type were sequenced. AmpC-type ß-lactamase genes amplified by primers specific for CMY-1, CMY-2 and DHA-1 were designated as CMY-1-like, CMY-2-like and DHA-1-like, respectively.

Antibiotic regimens and interventions

Antibiotic therapy was mostly prescribed by attending physicians and on requested cases, consultative advice was provided by the hospital's infectious diseases service team which was composed of paediatric doctors with infectious disease speciality. Recognizing the endemicity of ESBLs among E. coli and K. pneumoniae after a previous analysis of strains conducted in 2001,9 the infectious diseases service team had changed the antibiotic policy since January 2002.

Change in antibiotic policy. For intervention, the use of extended-spectrum cephalosporins was discouraged if possible, and instead, prescriptions of ß-lactam/ß-lactamase inhibitor combinations were encouraged. At first, the piperacillin/tazobactam rather than extended-spectrum cephalosporins was encouraged for the empirical and specific treatment of febrile neutropenic cancer patients from January 2002, and the new antibiotic policy was progressively applied for most infections possibly caused by Enterobacteriaceae, such as biliary tract infections or nosocomial infections occurring in ICU and general paediatric wards over 2002–03. For the empirical therapy of community-acquired infections other than meningitis in immunocompetent children, ampicillin/sulbactam was preferred.

Infection control measures. No cohort, isolation ward, or use of gloves with/without gowns was instituted for patients infected with ESBL-producing strains. However, hand hygiene was applied during the whole study period.

Antimicrobial consumption data. The amount of each class of antibiotic used in each study year in the hospital was obtained from the computerized hospital pharmacy database. Antibiotic consumption is presented as days on antibiotic per 1000 patient admission days per year (AD).8

Clinical outcome

To evaluate the impact of antibiotic policy change on the clinical outcome of invasive diseases caused by E. coli or K. pneumoniae, the overall fatality rates in the three study periods (described below) were compared. The following clinical data were collected retrospectively for demographic data comparisons for each time period: patient age, sex, underlying disease, duration of hospitalization, primary site of infection and entities used for determining disease severity. Most definitions were as previously described.9

Statistical analysis

One-way ANOVA was used to compare continuous variables and the {chi}2 test was used to compare categorical variables. The linear-by-linear association was used for trend analysis. All P values were two-tailed and P values of < 0.05 were considered statistically significant. SPSS (version 13.0) software was used for these analyses.


   Results
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Discussion
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Consumption of antibiotics, prevalence of ESBL production in E. coli and K. pneumoniae, and the clinical data of patients with invasive infections caused by these organisms were compared for the three periods, i.e. pre-intervention (1999–2001), transitional period (2002–03) and post-intervention (2004–05). A brief summary of this ambidirectional intervention study is presented in Table 1.


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  		Table 1. Summary table of population, clinical setting, nature and timing of interventions

 
Change of antibiotic consumption (Table 2)

Changes in antibiotic use were more remarkable in the oncology ward; piperacillin/tazobactam use increased from 4.5 to 155.6 AD and the use of extended-spectrum cephalosporins decreased from 170.5 to 26.9 AD, comparing pre- and post-intervention period (both, P for trend < 0.001). In paediatric wards other than the oncology ward, trends of increase in piperacillin/tazobactam use (from 1.4 to 89.2 AD) and decrease in extended-spectrum cephalosporin use (from 176.4 to 124.6 AD) were also observed (P for trend < 0.001 and 0.002, respectively). The consumptions of ampicillin/sulbactam, carbapenems and cephamycins remained stable irrespective of antibiotic policy change. In addition, total amounts of antibiotics used in each time period did not increase significantly; 274.8, 342.3 and 315.4 AD, respectively (P for trend = 0.053).


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  		Table 2. Changes in parenteral antibiotic use from 1999 to 2005 according to changes in antibiotic usage policy

 
Changes in the prevalences of ESBL producers among E. coli and K. pneumoniae isolates (Table 3)

A total of 252 isolates of E. coli (n = 128) and K. pneumoniae (n = 124) grown from the blood (n = 248), cerebrospinal fluid (n = 2) and pleural fluid (n = 2) were identified in the microbiology laboratory database. Strains were isolated from 245 episodes of invasive disease. Of the 252 isolates, 232 [92.1%; E. coli (n = 113) and K. pneumoniae (n = 119)] strains were available for analysis. Of the 232 strains available, 24.8% (28 of 113) of E. coli and 45.4% (54 of 119) of K. pneumoniae were ESBL producers. Additionally, among the 20 isolates that were not available, 2 strains (1 of 15 E. coli strains and 1 of 5 K. pneumoniae) were resistant to all of aztreonam, cefotaxime and ceftazidime by disc diffusion test, and thus were considered ESBL producers; the inhibition zone diameters of the remaining 18 isolates were greater than the ESBL screening criteria suggested by CLSI guidelines,13 and they were considered as non-ESBL producers. Overall, 22.7% (29/128) of E. coli and 44.4% (55/124) of K. pneumoniae isolates were ESBL-producing organisms.


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  		Table 3. The frequency of ESBL producers among E. coli or K. pneumoniae according to the location and time period from 1999 through 2005

 
Overall ESBL prevalences gradually decreased; 39.8% (41/103) during pre-intervention, 35.7% (25/70) during transitional period and 22.8% (18/79) after intervention. Decreasing tendency was more evident in K. pneumoniae {64.1% [25/39] to 25.6% [11/43]; P for trend < 0.001; OR = 5.20 [95% confidence interval (CI), 2.02–13.40]} than in E. coli [25.0% (16/64) to 19.4% (7/36); P for trend = 0.514; OR = 1.38 (95% CI, 0.51–3.76)].

In the oncology ward, the prevalence of ESBL production in strains of K. pneumoniae was successfully decreased from 52.9% (9/17) to 21.4% (6/28) in the pre- and post-intervention periods, respectively [P for trend = 0.029; OR = 4.13 (95% CI, 1.11–15.32)]. However, an increasing tendency was observed in E. coli from 17.1% (6/35) to 28.0% (7/25) even though this was without statistical significance [P for trend = 0.325; OR = 0.53 (95% CI, 0.15–1.84)].

In paediatric wards other than the oncology ward, overall ESBL prevalence decreased gradually; 51.0% (26/51), 39.5% (15/38) and 19.2% (5/26) in each period [P for trend = 0.008; OR = 4.37 (95% CI, 1.43–13.38)]. Comparing the pre- and post-intervention periods, ESBL prevalence decreased from 34.5% (10/29) to 0.0% (0/11) in E. coli (P for trend = 0.031) and from 72.7% (16/22) to 33.3% (5/15) in K. pneumoniae [P for trend = 0.017; OR = 5.33 (95% CI, 1.28–22.19)].

Figure 1 shows annual changes in antibiotic consumption and prevalences of ESBLs in all paediatric wards.


Figure 1
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  		Figure 1. Changes in antibiotic use and ESBL prevalence in paediatric wards, which included oncology, ICUs and general wards. The bar graph represents antibiotic usage presented as days on antibiotics per 1000 patient days each year and the line graph represents prevalence of ESBL among blood isolates of E. coli (open triangles), K. pneumoniae (open squares) or both (open circles).

 
Changes in the prevalences of ESBL types

Of 84 ESBL-producing isolates, 81 strains [E. coli (n = 28) and K. pneumoniae (n = 53)] were available for ESBL-type determination and 88 ESBLs were identified. Types of ESBL according to year of isolation are presented in Table 4. Overall, 5.6% (14/252) of isolates [3.9% (5/128) of E. coli and 7.3% (9/124) of K. pneumoniae] were proved to be plasmid-encoded AmpC-type ß-lactamase producers. No significant increasing trend of plasmid-mediated AmpC producers or any other specific type of ESBL producer such as CTX-M was noted with the increasing use of piperacillin/tazobactam throughout the study period. The annual prevalence of AmpC producers reached 11.1% (4/36) in 2002 and decreased to 4.3% (2/46) in 2005.


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  		Table 4. Annual distributions of ESBL types produced by E. coli or K. pneumoniae strains isolated from children with invasive infections at Seoul National University Children's Hospital from 1999 through 2005

 
Monitoring for the emergence of antibiotic resistance

Blood isolates of Enterobacter species, P. aeruginosa and A. baumannii as well as of E. coli and K. pneumoniae were tested for the emergence of piperacillin/tazobactam or carbapenem resistance.

The susceptibility rates to piperacillin/tazobactam during the three periods were 78.5%, 93.1% and 100.0%, respectively, for E. coli (P = 0.004 by the {chi}2 test) and 76.9%, 80.0% and 93.2% for K. pneumoniae (P = 0.098 by the {chi}2 test). One E. coli isolate was resistant to imipenem and produced CMY-2-like ß-lactamase, but no K. pneumoniae isolate showed imipenem resistance.

Among the 178 blood isolates of A. baumannii, Enterobacter spp. and P. aeruginosa, 107 strains were available for analysis for resistance to piperacillin/tazobactam and imipenem (Table 5). No statistically significant increasing tendency of resistance to each antibiotic was observed in the above species.


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  		Table 5. Total number of isolates and the antibiotic resistance of A. baumannii, Enterobacter species and P. aeruginosa during the study period 1999–2005a

 
Clinical outcome

Medical records of 228 (93.1%) out of 245 episodes were available. Demographic and clinical data for patients infected with E. coli and K. pneumoniae in the different periods are shown in Table 6. Most characteristics were not statistically different during the three periods.


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  		Table 6. Demographic dataa of children with invasive disease due to E. coli or K. pneumoniae at the Seoul National University Children's Hospital from 1999 through 2005

 
Among the 228 episodes, the final outcomes of 10 episodes could not be documented because of discharge or transfer to another hospital. As a result, a total of 218 episodes (108 episodes caused by E. coli; 105 by K. pneumoniae; 5 by both species) were analysed to calculate all-cause fatality rates within 7 and 30 days, respectively, from the onset of invasive disease (Table 7). Comparing the pre-and post-intervention periods, overall fatality rates were not affected by antibiotic policy change; from 9.0% (8/89) to 5.5% (4/73) at the 7th day (P = 0.199, by the {chi}2 test) and from 12.4% (11/89) to 11.0% (8/73) at the 30th day (P = 0.195, by the {chi}2 test). Additionally, adverse events such as severe drug side effects were not observed during this intervention period.


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  		Table 7. Overall 7th- and 30th-day fatality rates for invasive diseases caused by E. coli or K. pneumoniae isolates according to each time period (n = 218)

 

   Discussion
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Previous attempts to decrease ESBL-mediated resistance to cephalosporins in Enterobacteriaceae by changing antibiotic policy have focused on restricting ceftazidime or all extended-spectrum cephalosporins.8,11,17–19 The successful substitutions of imipenem,20 piperacillin/tazobactam11 and cefepime/amikacin21 for empirical therapy to decrease the prevalence of ESBL-producing organisms have already been reported. In other hands, control of ESBL was successfully achieved using strict isolation procedures without placing limitations on antibiotic use.22

In most of the studies, the impact of changes in antibiotic policy on the prevalence of ESBL-producing organisms was observed in outbreak situations caused by ESBL-producing K. pneumoniae and was followed up for relatively short periods. Moreover, this type of study has not been conducted previously in any institute for children to our knowledge. We changed the antibiotic policy in the children's institute, where the endemicity of ESBL-producing E. coli and K. pneumoniae had been demonstrated for at least 8 years from 1993 to 20019 and observed the impact of these changes over a 4 year period from 2002 through 2005. The intervention policy had been implemented immediately in the oncology ward since January 2002 because infectious diseases service teams were more directly involved in selection of antibiotics. However, there was a time lag in the implementation of intervention in the paediatric wards other than the oncology ward because the infectious disease teams were relatively indirectly involved in selection of antibiotics, based on consultation and education of attending staffs or physicians.

In this type of study, the daily defined dose (DDD) is usually used for quantification of antibiotic usage. DDD is the assumed average dose per day for a drug in adults.23 However, in paediatric patients, DDD may not adequately reflect the number of children exposed to antibiotics and consequent antibiotic pressure exerted on children. In this study, antibiotic days per 1000 patient admission days were used to define the antibiotic consumption because it could be used regardless of patients' age, weight or body surface. As a limitation, patient admission day data were not available for the ICU due to a lack of computerization, the impact of antibiotic policy change on ICU settings could not be separately evaluated.

In accordance with our intention, overall ESBL prevalences decreased during this study period without increase of mortality rates in the patients with invasive E. coli or K. pneumoniae infections. However, the change in antibiotic policy did not exert a favourable influence on E. coli but did on K. pneumoniae, especially in the oncology ward. The reason is unclear at the moment. Most studies so far have looked at impact of change in antibiotic pressure on the prevalence of ESBL-producing K. pneumoniae and few studies have focused on ESBL-producing E. coli. In one study executed in an adult ICU setting, increased use of piperacillin/tazobactam instead of extended-spectrum cephalosporins reduced the ESBL prevalence in K. pneumoniae strains, but failed to show a decrease of ESBL prevalence in E. coli.24 In another previously published paediatric trial, substitution of ceftazidime with piperacillin/tazobactam could not reduce the rectal or nasopharyngeal colonization by antibiotic-resistant Gram-negative bacilli in paediatric ICU; in that study, E. coli strains composed 17.5% of the total colonizing isolates, but K. pneumoniae strains were not included because K. pneumoniae was not identifed.25 Moreover, it has been reported that carriage or colonization of ESBL-producing E. coli was more commonly observed than that of K. pneumoniae in the patients who had received antibiotics.26–28 Thus, it is possible that there may be a difference in response to change in antibiotic pressure between E. coli and K. pneumoniae. In order to clarify a delayed effect of antibiotic change in E. coli strains, more prolonged observation is mandatory.

In addition, only parenteral antibiotic use was included in this analysis and oral antibiotics such as cefpodoxime, cefdinir and amoxicillin-clavulanate, most of which were prescribed at the outpatient clinics for low-risk febrile episodes were not considered in the analysis, which might have influenced the prevalence of ESBL producers in the oncology ward.

Although statistically not significant (P for trend = 0.053), the total use of antibiotics has increased from pre- to post-intervention period (Table 2). Thus, the possible influence of increase of total antibiotic usage on the prevalence of ESBL-producers in this study could not be excluded. In order to clarify whether the increase of total antibiotic usage could impact on the ESBL prevalences in this institute, further observation for a longer period would be needed.

The increased use of ß-lactam/ß-lactamase inhibitor combinations has resulted in the emergence of plasmids encoding class C ß-lactamases,29 and may potentially cause spread of organisms with plasmid-encoded AmpC ß-lactamases. Restriction of extended-spectrum cephalosporins has often been associated with increased use of carbapenems and increase of infections caused by carbapenem-resistant organisms.30–32 In this study, however, no increase in piperacillin/tazobactam- or carbapenem-resistant E. coli or K. pneumoniae infections, or in piperacillin/tazobactam- or carbapenem-resistant Pseudomonas, Acinetobacter, or Enterobacter infections has been detected.

It is of particular interest that the susceptibility of E. coli and K. pneumoniae to piperacillin/tazobactam increased despite increased use of piperacillin/tazobactam. The reasons for this are not known, but a similar phenomenon was observed by Patterson et al.8 Similarly, the susceptibility of A. baumannii to piperacillin/tazobactam also increased from 50% during pre-intervention period to 100% during post-intervention period.

In conclusion, the restriction of the use of extended-spectrum cephalosporin and the encouragement of the use of piperacillin/tazobactam were found to be followed by a successful reduction in ESBL-producing K. pneumoniae and E. coli isolates in an institute for children where ESBL-producing E. coli and K. pneumoniae were endemic. The impact of a change in antibiotic policy was more evident in K. pneumoniae than E. coli.


   Funding
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 Abstract
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 Materials and methods
 Results
 Discussion
 Funding
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This work was supported by a grant (grant no. 06-04-087) from Seoul National University Hospital and the grant was financially supported by the Wyeth Research.


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None to declare.


   Footnotes
 
{dagger} The first two authors contributed equally to the study. Back


   Acknowledgements
 
We thank Chang-Hoon Lee for assistance in statistical analysis.


   References
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 Abstract
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 Materials and methods
 Results
 Discussion
 Funding
 Transparency declarations
 References
 
1 Knothe H, Shah P, Krcmery V, et al. Transferable resistance to cefotaxime, cefoxitin, cefamandole and cefuroxime in clinical isolates of Klebsiella pneumoniae and Serratia marcescence. Infection (1983) 11:315–7.[CrossRef][Web of Science][Medline]

2 Bauernfeind A, Horl G. Novel R-factor-borne ß-lactamase conferring resistance to cephalosporins. Infection (1987) 15:257–9.[CrossRef][Web of Science][Medline]

3 Hyle EP, Lipworth AD, Zaoutis TE, et al. Risk factors for increasing multidrug resistance among extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella species. Clin Infect Dis (2005) 40:1317–24.[CrossRef][Web of Science][Medline]

4 Romero L, Lopez L, Rodriguez-Bano J, et al. Long-term study of the frequency of Escherichia coli and Klebsiella pneumoniae isolates producing extended-spectrum ß-lactamases. Clin Microbiol Infect (2005) 11:625–31.[CrossRef][Web of Science][Medline]

5 Duncan RA. Controlling use of antimicrobial agents. Infect Control Hosp Epidemiol (1997) 18:260–6.[Web of Science][Medline]

6 Tenover FC, Hughes JM. The challenges of emerging infectious diseases. Development and spread of multiply-resistant bacterial pathogens. JAMA (1996) 275:300–4.[Abstract/Free Full Text]

7 Jarvis WR. Preventing the emergence of multidrug-resistant microorganisms through antimicrobial use controls: the complexity of the problem. Infect Control Hosp Epidemiol (1996) 17:490–5.[Web of Science][Medline]

8 Patterson JE, Hardin TC, Kelly CA, et al. Association of antibiotic utilization measures and control of multiple-drug resistance in Klebsiella pneumoniae. Infect Control Hosp Epidemiol (2000) 21:455–8.[CrossRef][Web of Science][Medline]

9 Kim YK, Pai H, Lee HJ, et al. Bloodstream infections by extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae in children: epidemiology and clinical outcome. Antimicrob Agents Chemother (2002) 46:1481–91.[Abstract/Free Full Text]

10 Piroth L, Aube H, Doise JM, et al. Spread of extended-spectrum ß-lactamase-producing Klebsiella pneumoniae: are ß-lactamase inhibitors of therapeutic value? Clin Infect Dis (1998) 27:81–3.[Web of Science][Medline]

11 Rice LB, Eckstein EC, DeVente J, et al. Ceftazidime-resistant Klebsiella pneumoniae isolates recovered at the Cleveland Department of Veterans Affairs Medical Center. Clin Infect Dis (1996) 23:118–24.[Web of Science][Medline]

12 Fishman SJ, Pelosi L, Klavon SL, et al. Perforated appendicitis: prospective outcome analysis for 150 children. J Pediatr Surg (2000) 35:923–6.[CrossRef][Web of Science][Medline]

13 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing-Fifteenth Informational Supplement: Approved Standard M100-S15 (2005) Wayne, PA, USA: CLSI.

14 Thomson KS, Sanders CC. Detection of extended-spectrum ß-lactamases in members of the family Enterobacteriaceae: comparison of the double-disk and three-dimensional tests. Antimicrob Agents Chemother (1992) 36:1877–82.[Abstract/Free Full Text]

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16 Coudron PE. Inhibitor-based methods for detection of plasmid-mediated AmpC ß-lactamases in Klebsiella spp. Escherichia coli, and Proteus mirabilis. J Clin Microbiol (2005) 43:4163–7.[Abstract/Free Full Text]

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