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JAC Advance Access published online on April 28, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn184
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© The Author 2008. 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

Original research

Trends in antimicrobial susceptibility of Gram-negative isolates from a paediatric intensive care unit in Warsaw: results from the MYSTIC programme (1997–2007)

Jan A. Patzer1,*, Danuta Dzierzanowska1 and Philip J. Turner2

1 Department of Clinical Microbiology and Immunology, Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland 2 Infection Discovery Department, AstraZeneca, Alderley House, Alderley Park, Macclesfield, Cheshire SK10 47G, UK

* Corresponding author. Tel: +48-22-815-72-71; Fax: +48-22-815-72-75; E-mail: j.patzer{at}czd.pl

Received 14 February 2008; returned 15 February 2008; revised 26 March 2008; accepted 1 April 2008


   Abstract
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Objectives: The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) programme is a longitudinal global surveillance study to monitor in vitro data on microbial susceptibility in centres that prescribe meropenem. This overview provides data on the susceptibility of Gram-negative bacteria (n = 1300) isolated from clinical specimens of children hospitalized in a paediatric intensive care unit (ICU) during 1997–2007.

Methods: MICs of meropenem and eight other antibiotics were determined using the CLSI agar dilution method.

Results: Meropenem, imipenem and ciprofloxacin were most active (>90% susceptibility) against the tested isolates. A greater proportion of Pseudomonas aeruginosa isolates was susceptible to meropenem compared with imipenem. Antibiotic susceptibility of Enterobacteriaceae and Acinetobacter baumannii showed an increase in 2007. Only susceptibility of P. aeruginosa to ceftazidime and cefepime increased. The incidence of extended-spectrum β-lactamase (ESBL) producers among Enterobacteriaceae isolates decreased from 37% in 1997 to 21.8% in 2007, and AmpC β-lactamase producers decreased from 24.6% to 5.7%. Consumption of cephalosporins remained the same and piperacillin/tazobactam increased 3-fold. During 11 years, despite an increase in carbapenem consumption, meropenem and imipenem have retained excellent activity against the majority of isolates studied.

Conclusions: The comparison of antibiotic susceptibility of Gram-negative isolates in 1997 and 2007 showed a trend of increase, and the number of β-lactamase-producing isolates among Enterobacteriaceae showed a trend of decrease possibly related to changes in antibiotic policy.

Key Words: MICs , antimicrobial agents , ICU


   Introduction
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Antimicrobial resistance is a significant and increasing problem worldwide. In particular, resistance of Gram-negative bacilli is a serious problem in some geographical regions mainly due to the appearance of multidrug-resistant (MDR) Pseudomonas aeruginosa and Enterobacteriaceae that produce extended-spectrum β-lactamases (ESBLs) or stably derepressed AmpC β-lactamases.1–3 The antimicrobial surveillance programmes that provide extensive information on the pattern, development and prevalence of bacterial resistance in different geographical regions are vital in the fight against bacterial resistance. In 1997, the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) programme was set up to monitor the in vitro activity of meropenem and other broad-spectrum antimicrobials against bacterial isolates causing serious infections in hospital units that are actively prescribing meropenem.4,5 The aim of this analysis was to assess the in vitro activity of meropenem and eight other antimicrobials against Gram-negative isolates from a paediatric intensive care unit (ICU) obtained over 11 years and the prevalence of ESBL- and AmpC-producing organisms among members of the Enterobacteriaceae.


   Materials and methods
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Setting

The Children's Memorial Health Institute is a 575 bed paediatric hospital located in Warsaw, Poland. It has an ICU with a total of 30 beds (20 beds until 2000). It is the reference paediatric hospital where children are hospitalized not only from Warsaw, but also serious cases from the whole of Poland.

Bacterial strains

Gram-negative isolates were obtained from various clinical specimens of children hospitalized in the ICU. Each year, 100 consecutive clinically relevant, non-duplicate Gram-negative isolates between 1997 and 2003 and 140 consecutive isolates between 2004 and 2007 were collected. The isolates were identified to species level using conventional methods.5

Antimicrobial susceptibility testing

MICs of meropenem, imipenem, piperacillin/tazobactam, cefotaxime, ceftazidime, cefepime, gentamicin, tobramycin and ciprofloxacin were determined using the agar dilution method as recommended by the CLSI (formerly the NCCLS).6 Percentage susceptibilities were determined using CLSI susceptibility breakpoints: ciprofloxacin, ≤1 mg/L; meropenem, imipenem, gentamicin and tobramycin, ≤4 mg/L; cefotaxime, ceftazidime and cefepime, ≤8 mg/L; piperacillin/tazobactam, ≤16 mg/L, except for P. aeruginosa for which the breakpoint was ≤64 mg/L.7 Quality control was performed using the following strains supplied by AstraZeneca: Acinetobacter baumannii (T18), Enterobacter aerogenes (IC5), P. aeruginosa ATCC 27853, Klebsiella pneumoniae #911 (ESBL non-producer), #1204 (low-level ESBL producer) and #1951 (high-level ESBL producer).

Detection of ESBL and AmpC β-lactamase producers

Enterobacteriaceae (Escherichia coli, Citrobacter spp., Klebsiella spp., Enterobacter spp., Serratia spp.) were tested to determine if they were ESBL- or AmpC β-lactamase-producing strains. For ESBL producers, an in vitro synergy test was performed between ceftazidime and clavulanic acid (4 mg/L) on any Enterobacteriaceae isolates with an MIC for ceftazidime of ≥2 mg/L. A positive result was indicated by a ≥8-fold reduction of the ceftazidime MIC in the presence of clavulanic acid. During 2006–07 synergy between cefotaxime and cefepime and clavulanic acid was tested in addition. Hyper- or derepressed production of AmpC β-lactamase was identified by high-level resistance to cefotaxime, ceftazidime and piperacillin/tazobactam, with no change in susceptibility to ceftazidime in the presence of clavulanic acid.

Antibiotic consumption

Total antibiotic consumption in the hospital and in the ICU was recorded in the hospital pharmacy on a monthly basis using a computer-based pharmacy documentation system.


   Results
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Susceptibility testing

During 1997–2007, a total of 1300 aerobic Gram-negative isolates were tested. Among these isolates 841 (64.7%) were Enterobacteriaceae and 459 (35.3%) were non-fermenters. The most commonly reported Enterobacteriaceae were Enterobacter cloacae (n = 233; 28%), K. pneumoniae (n = 211; 25%) and E. coli (n = 187; 22%). The most commonly isolated non-fermenting Gram-negative bacteria were P. aeruginosa (n = 253; 55%) and A. baumannii (n = 137; 30%).

Over the 11 year observation period, meropenem, imipenem and ciprofloxacin were the most active antibiotics with 94.1%, 92.1% and 95.2% of Gram-negative isolates being susceptible, respectively (Table 1). The highest activity of meropenem, imipenem and ciprofloxacin was against Enterobacteriaceae, with 99.6%, 99.6% and 98.1% of isolates susceptible, respectively. Cefepime inhibited 89.4% of the Enterobacteriaceae isolates, but only 79.1% of non-fermenters. A different situation was observed in the case of ceftazidime and piperacillin/tazobactam, which had higher activity against non-fermenters. Cefotaxime was the least active β-lactam tested (53.8% susceptibility). Aminoglycosides, gentamicin and tobramycin (1997–2005) were active against 67.1% and 64.5% of all Gram-negative isolates, respectively. They showed higher activity against non-fermenters than Enterobacteriaceae.


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  		Table 1. Susceptibility (%) of Gram-negative bacteria isolated in the ICU during 1997–2007 to nine antibiotics

 
MDR strains

During the 11 year surveillance, 12 MDR isolates (11 A. baumannii and 1 P. aeruginosa) were seen. All 11 A. baumannii strains were susceptible to both carbapenems and 7 were susceptible to tobramycin, but they were non-susceptible to all other agents. The one P. aeruginosa strain was resistant to all agents.

If MDR is defined as the resistance to ceftazidime, gentamicin and piperacillin/tazobactam (to reflect the low usage of ciprofloxacin in this ICU), then the following 20 such strains are found: two E. coli (both susceptible to the carbapenems and ciprofloxacin and one of the strains susceptible to cefepime), four K. pneumoniae (all susceptible to carbapenems and ciprofloxacin, one susceptible to cefotaxime and two susceptible to cefepime), five Klebsiella oxytoca (all susceptible to carbapenems and ciprofloxacin), four E. cloacae (all susceptible to carbapenems and ciprofloxacin, two susceptible to cefepime), one Serratia marcescens (susceptible to carbapenems and ciprofloxacin), one A. baumannii (susceptible to carbapenems only), two P. aeruginosa (susceptible to ciprofloxacin only) and one Chryseobacterium indologenes (non-susceptible to all tested agents). Overall, these are very low numbers suggesting that in this paediatric ICU there is not a great problem of MDR strains.

Prevalence of ESBL- and AmpC-producing Enterobacteriaceae

ESBL and AmpC producers among Enterobacteriaceae isolates still remain a serious problem among nosocomial isolates. Therefore, the incidence of β-lactamase producers amongst Gram-negative isolates in 1997–2007 was studied. In general, a trend of decreasing incidence of AmpC β-lactamase- and ESBL-producing strains from 61.6% in 1997 to 27.6% in 2007 was found (Table 2). The percentage of ESBL producers decreased from 37% to 21.8% and AmpC producers from 24.6% to 5.7%.


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  		Table 2. Incidence of β-lactamase-producing strains among Enterobacteriaceae from the ICU in 1997–2007

 
Trends in antimicrobial susceptibility (1997–2007)

Table 3 presents the activity of meropenem and comparator antimicrobials against selected Gram-negative bacteria isolated from the ICU. Susceptibility of Enterobacteriaceae to ceftazidime and other β-lactams reflects the prevalence of β-lactamase producers among isolates of particular species. Between 1997 and 2007, the percentage of E. coli strains producing ESBLs decreased from 33% to 15%. E. coli isolates characterized consistently high susceptibility to cefepime (93–100%) and increases in susceptibility to ceftazidime (66.7–85%), cefotaxime (53.3–90%), piperacillin/tazobactam (66.7–90%) and gentamicin (53.3–65%). In the case of K. pneumoniae strains, isolated between 1997 and 2007, the percentage of ESBL-producing strains slightly decreased from 58.8% to 35%. As a consequence, the susceptibility to ceftazidime increased from 29.4% to 80%, piperacillin/tazobactam from 52.9% to 85%, cefotaxime from 64.7% to 70% and gentamicin from 35.3% to 55%. Only cefepime MIC90 increased from 4 to 32 mg/L and susceptibility decreased from 100% to 80%. In the period 1997–2007, the percentage of K. oxytoca ESBL-producing strains changed from 41.7% to 36.4%. The susceptibility to cefepime remains on the highest level of 100%, ceftazidime increased from 66.7% to 100%, cefotaxime changed from 83% to 73% and gentamicin from 50% to 73%. In 1997, a very high incidence of E. cloacae isolates producing an elevated amount of AmpC β-lactamase equal to 85.6% was found. During the subsequent years of study, the percentage of AmpC producers among E. cloacae isolates decreased to 55% in 2001 and 20% in 2007. In consequence, an increase in susceptibility to cefotaxime from 14.3% in 1997 to 65% in 2007 and to piperacillin/tazobactam from 50% to 90% was observed. The susceptibility to ceftazidime, cefepime and gentamicin remained nearly identical in 1997 and 2007. Meropenem retained very high activity against Enterobacteriaceae, in the whole period, with the MIC90 values 0.03–0.12 mg/L, ~4-fold lower than imipenem (Table 3). Imipenem also retained its high activity against Enterobacteriaceae (MIC90, 0.12–0.5 mg/L). Ciprofloxacin characterized the identical MIC90 values of 0.015–0.5 mg/L for Enterobacteriaceae in years 1 and 11 of our studies.


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  		Table 3. Activity of nine antibiotics against Gram-negative bacteria isolated in the ICU in 1997 and 2007

 
Infections due to the reported organisms present in the ICU were on an ongoing basis. Since 2004, the infection control team has not detected any outbreak in this ICU.

Non-fermenting Gram-negative bacteria

The susceptibility results for P. aeruginosa and A. baumannii isolates and other non-fermenting Gram-negative bacteria between 1997 and 2007 are shown in Table 1. Ciprofloxacin, meropenem and imipenem were the most active antibiotics against non-fermenters, with susceptibilities 90%, 84.9% and 78.4%, respectively. Susceptibilities for the other antimicrobials used in this study were: piperacillin/tazobactam 83.9%, ceftazidime 80.8%, cefepime 79.1%, gentamicin 78.4%, tobramycin (1997–2005) 82.8% and the lowest for cefotaxime 39%.

During 1997–2007, the MIC90 values of ciprofloxacin for A. baumannii decreased from 4 to 1 mg/L and for P. aeruginosa increased from 0.25 to 1 mg/L (Table 3). Simultaneously, the susceptibility to ciprofloxacin of A. baumannii increased to 100%, and of P. aeruginosa, decreased to 92%. The MIC90 values of carbapenems for A. baumannii were 0.25–1 mg/L, and the susceptibility was 100%. In 1997 and 2007, P. aeruginosa isolates characterized the identical MIC90 values equal to 8 mg/L for meropenem and 16 mg/L for imipenem. A greater proportion of P. aeruginosa isolates was susceptible to meropenem than to imipenem: 89.5% and 73.7% in 1997 and 72% and 68% in 2007, respectively. In 2007, the susceptibility of A. baumannii isolates to the remaining antibiotics, with the exception of gentamicin, increased: piperacillin/tazobactam, from 60% to 83.3%; cefotaxime, from 40% to 77.8%; ceftazidime, from 80% to 83.3%; and cefepime, from 80% to 88.9%. In the case of P. aeruginosa isolates, the susceptibility to ceftazidime increased from 78.9% to 88% and to cefepime increased from 68.4% to 84%. The susceptibility of P. aeruginosa to piperacillin/tazobactam and cefotaxime was nearly identical in 1997 and 2007, but decreased for gentamicin from 73.7% to 64%.

Antibiotic consumption

From 1997 to 2007 in the ICU, the consumption of cephalosporins showed a slight decrease: ceftazidime and cefuroxime decreased to 86% and 88%, respectively. The amount of cefotaxime used showed a decreasing trend from 1997 to 2006 and an unexpected increase up to 124% in 2007 (Table 4). Only the amount of ceftriaxone used increased ~2-fold. Cefepime usage was on the very low level for the whole period. Piperacillin/tazobactam consumption increased to 273%, and carbapenem consumption increased to 139%.


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  		Table 4. Antibiotic consumption in the ICU in the period 1997–2007 (g/year)

 
Similar trends in the consumption of antibiotics were observed in the whole hospital. The usage of cephalosporins decreased: ceftazidime to 80%, cefuroxime to 84% and cefotaxime to 77%. Cefepime was introduced into therapy in 2000 and its usage until 2007 decreased to 66%. The usage of ceftriaxone in the hospital showed a similar trend as in the ICU; it showed a 2-fold increase in contrast to the above-mentioned cephalosporins. The consumption of piperacillin/tazobactam in hospital increased 6-fold from 3247 to 20 655 g. During 1997–2007, the consumption of carbapenems increased 3-fold from 2364 to 6435 g. It is necessary to underline that meropenem was introduced for treatment in our hospital in 1997. Since then, usage of imipenem was partially replaced by meropenem.

The usage of ciprofloxacin in the whole hospital is very low. In the ICU, ciprofloxacin was used from 2000, and its consumption increased from a symbolic amount of 17 g in 2000 to 150 g in 2007, and in hospital it increased from 186 g in 1997 to 1396 g in 2007. Among aminoglycosides, amikacin and netilmicin were used in our hospital. During 1997–2007, the usage of amikacin in the ICU increased to 253% and netilmicin to 137%. In the hospital, the usage of amikacin increased from 1173 g in 1997 to 1637 g (143%) in 2007 and netilmicin from 799 to 1452 g (182%). In 2003 and 2004, netilmicin was not available and only amikacin was used. The usage of gentamicin in the ICU was very symbolic, about a few grams per year. Gentamicin and tobramycin were mainly used in eye drops.


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During the 11 year period, meropenem and imipenem demonstrated potent and consistent activity against Gram-negative bacteria isolated from the paediatric ICU, including ESBL- and AmpC-producing organisms. This finding is consistent with the results of other studies undertaken in Europe and the USA.8,9 In our earlier studies of the MYSTIC programme (1997–2000), the prevalence of β-lactamase producers was consistently higher and varied between 52.2% and 61.6%.10 It correlated with other MYSTIC data, which underlined a particularly high prevalence of ESBL- (28%) and AmpC-producing (47%) strains among Eastern European isolates in comparison to those data from the rest of Europe.11 In three UK centres participating in the MYSTIC programme, the incidence of β-lactamases was lower, but the increase in the prevalence of ESBL- and AmpC-producing Enterobacteriaceae from 4.8% to 7.4% and 11.3% to 16.7%, respectively, between 1997 and 2002 was found.12 Our MYSTIC data for the period 2001–05 showed a trend towards a decrease in the prevalence of ESBL- and AmpC-producing Enterobacteriaceae isolated from the ICU.13 The results of this study confirmed a decreasing trend of ESBL- and AmpC β-lactamase-producing isolates (prevalence of 21.8% and 5.7%, respectively) in 2007. The recent report on the MYSTIC 2006 results from 40 European centres showed that among Enterobacteriaceae, 8.0% of isolates produced ESBL and 4.5% produced AmpC β-lactamase.14

There is a possibility that the prevalence of ESBL-producing isolates among Enterobacteriaceae may be underestimated. In our earlier studies, Enterobacteriaceae were tested with cefotaxime, but not with cefotaxime plus clavulanic acid; therefore, CTX-M-type ESBLs could be missed. The frequent occurrence of CTX-M β-lactamases in the Enterobacteriaceae family is a rising problem. There are reports that they are spreading in Poland, as well as in the UK and Austria.15–17 The proportion of CTX-M producers among all ESBL producers in Austria increased from 0% in 1998 to 58% in 2004.17 Therefore, in our MYSTIC studies of 2006 and 2007, production of ESBL was examined by the synergy between three cephalosporins, ceftazidime, cefotaxime and cefepime, and clavulanic acid to detect CTX-M-type ESBLs also. The incidence of CTX-M-type β-lactamases among Enterobacteriaceae was 15 isolates in 2006 and 8 isolates in 2007.

Antibiotic consumption in the whole hospital and particularly in the ICU has influenced the trends in antibiotic susceptibility of isolated Gram-negative isolates. The changes in the usage of β-lactams had an effect on the percentage of ESBL- and AmpC β-lactamase-producing Enterobacteriaceae. The decrease in the prevalence of ESBL- and AmpC-producing Enterobacteriaceae observed in this study was connected with a better hospital antibiotic policy which stipulated a prudent usage of cephalosporins, a slight decrease in consumption from 1997 to 2007 and an increased usage of carbapenems and piperacillin/tazobactam.

High activity of ciprofloxacin against Gram-negative isolates over the 11 years of the MYSTIC study is a consequence of very low consumption of fluoroquinolones in this paediatric ICU. Therefore, even an increase in the consumption of ciprofloxacin in 2000–07 over 7-fold in the hospital and 9-fold in the ICU had no effect on the level of resistance to this antibiotic. Results obtained from centres participating in the US MYSTIC programme showed that a 2-fold increase in ciprofloxacin use, in 1999–2001, was accompanied by an 83.8% increase in resistance among Enterobacteriaceae.18 In general, the use of fluoroquinolones in paediatrics with the exception of cystic fibrosis and life-endangering infections should be limited.19 It is important to continue the policy of second-line use in children, only after failure of an earlier treatment and when other antibiotics approved for paediatric use cannot be used.20

The non-fermenting Gram-negative bacilli from this paediatric ICU were characterized by higher susceptibility to ciprofloxacin (90%) and lower susceptibility to meropenem (84.9%) and imipenem (78.4%). In contrast to our results, non-fermenters isolated from the three UK centres in the MYSTIC programme (1997–2002) were characterized by higher susceptibilities to meropenem (86–97%) and imipenem (87–94%) and lower susceptibility to ciprofloxacin (77%).12 Between 1997 and 2007, susceptibility of P. aeruginosa isolates to carbapenems decreased. Partially, it was connected with the occurrence of P. aeruginosa isolates resistant to imipenem and simultaneously susceptible to other antimicrobials. The clonally related imipenem-resistant P. aeruginosa of serotype O:11 showed only intermediate resistance to meropenem. Strains belonging to this genotype, as was shown by pulse-field gel electrophoresis, were found among P. aeruginosa isolates from the ICU in 2000–01.21 All MDR P. aeruginosa isolates were examined for the presence of metallo-β-lactamase (MBL). In 1998, the first P. aeruginosa strain which contained an unusual blaVIM-4 gene cassette was recovered from a child hospitalized in the general surgery ward of our hospital. In the next 3 years, 10 P. aeruginosa strains harbouring this MBL have been detected.22 Despite an intensive epidemiological search, the sources of these strains were not identified. During 2002–06, eight MDR P. aeruginosa strains producing MBL were found in this hospital. Among them, only one P. aeruginosa strain harbouring an unusual blaVIM-4 gene cassette was recovered from a child hospitalized in the ICU (J. A. Patzer and M. A. Teleman, unpublished results).

It was shown in this study that A. baumannii isolates from 1997 and 2007 characterized 100% susceptibility to carbapenems. Furthermore, in 2007, the susceptibility of A. baumannii to other antimicrobials increased in comparison to the results reported in 1997. Recent MYSTIC results for European isolates indicate a reduction in susceptibility of Acinetobacter spp. In 2006, the susceptibility to carbapenems decreased to 57–58% and all other comparators below 56%.14 It undoubtedly reflects the increasing number of MDR strains among Acinetobacter spp. isolated in Europe between 2002 and 2006. Fortunately, this type of strain has been very rarely isolated in our hospital. In general, infections due to the reported organisms were seen in the ICU on an ongoing basis rather than as discrete outbreaks.

The comparison of antibiotic susceptibility of Gram-negative isolates in 1997 and 2007 showed a trend of increase, and the number of β-lactamase producers among Enterobacteriaceae showed a trend of decrease. The MDR strains have not been a problem during the study period.

In this ICU, which actively prescribes meropenem, resistance has not increased during the 11 years. Meropenem is still retaining excellent activity against the majority of isolates studied.


   Funding
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This study had financial support from AstraZeneca in the frame of the MYSTIC Programme.


   Transparency declarations
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P. J. T. holds shares in AstraZeneca. J. A. P. and D. D. have none to declare.


   Acknowledgements
 
The excellent technical assistance of Malgorzata Walus is gratefully appreciated. We thank Anna Nowak from the hospital pharmacy for data on consumption of antibiotics.


   References
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 Results
 Discussion
 Funding
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1 . Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis (2002) 34:634–40.[CrossRef][Web of Science][Medline]

2 . Winokur PL, Canton RR, Casellas JM, et al. Variations in the prevalence of strains expressing an extended-spectrum β-lactamase phenotype and characterization of isolates from Europe, the Americas, and the Western Pacific region. Clin Infect Dis (2001) 32(Suppl. 2):S94–103.[CrossRef][Web of Science][Medline]

3 . Pfaller MA, Jones RN. Antimicrobial susceptibility of inducible AmpC β-lactamase-producing Enterobacteriaceae from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Programme, Europe 1997–2000. Int J Antimicrob Agents (2002) 19:383–8.[CrossRef][Web of Science][Medline]

4 . Turner PJ, Greenhalgh JM, Edwards JR, et al. The MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) Programme. Int J Antimicrob Agents (1999) 13:117–25.[CrossRef][Web of Science][Medline]

5 . Turner PJ. MYSTIC (Meropenem Yearly Susceptibility Test Information Collection): a global overview. J Antimicrob Chemother (2000) 46(Suppl. T2):9–23.[Abstract/Free Full Text]

6 . National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Sixth Edition: Approved Standard M7-A6 (2003) Wayne, PA, USA: NCCLS.

7 . National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing: Thirteenth Informational Supplement M100-S13 (2003) Wayne, PA, USA: NCCLS.

8 . Goossens H, Grabein B. Prevalence and antimicrobial susceptibility data for extended-spectrum β-lactamase- and AmpC-producing Enterobacteriaceae from the MYSTIC Program in Europe and the United States (1997–2004). Diagn Microbiol Infect Dis (2005) 53:257–64.[CrossRef][Web of Science][Medline]

9 . Jones RN, Mendes C, Turner PJ, et al. An overview of the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program: 1997–2004. Diagn Microbiol Infect Dis (2005) 53:247–57.[CrossRef][Web of Science][Medline]

10 . Patzer J, Dzierzanowska D, Turner P. Susceptibility patterns of Gram-negative bacteria from a Polish intensive care unit, 1997–2000. Int J Antimicrob Agents (2002) 19:431–4.[CrossRef][Web of Science][Medline]

11 . Goossens H. MYSTIC Program: summary of European data from 1997 to 2000. Diagn Microbiol Infect Dis (2001) 41:183–9.[CrossRef][Web of Science][Medline]

12 . Masterton RG, Turner PJ. Trends in antimicrobial susceptibility in UK centres: the MYSTIC Programme (1997–2002). Int J Antimicrob Agents (2006) 27:69–72.[CrossRef][Web of Science][Medline]

13 . Patzer JA, Dzierzanowska D, Pawinska A, et al. High activity of meropenem against Gram-negative bacteria from a paediatric intensive care unit, 2001–2005. Int J Antimicrob Agents (2007) 29:285–8.[CrossRef][Web of Science][Medline]

14 . Turner PJ. Meropenem activity against European isolates: report on the MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) 2006 results. Diagn Microbiol Infect Dis (2008) 60:185–92.[CrossRef][Web of Science][Medline]

15 . Baraniak A, Fiett J, Sulikowska A, et al. Countrywide spread of CTX-M-3 extended-spectrum β-lactamase-producing microorganisms of the family Enterobacteriaceae in Poland. Antimicrob Agents Chemother (2002) 46:151–9.[Abstract/Free Full Text]

16 . Livermore DM, Hawkey PM. CTX-M: changing the face of ESBLs in the UK. J Antimicrob Chemother (2005) 56:451–4.[Abstract/Free Full Text]

17 . Eisner A, Fagan EJ, Feierl G, et al. Emergence of Enterobacteriaceae isolates producing CTX-M extended-spectrum β-lactamase in Austria. Antimicrob Agents Chemother (2006) 50:785–7.[Abstract/Free Full Text]

18 . Mutnick AH, Rhomberg PR, Sader HS, et al. Antimicrobial usage and resistance trend relationships from the MYSTIC Programme in North America (1999–2001). J Antimicrob Chemother (2004) 53:290–6.[Abstract/Free Full Text]

19 . Leibovitz E. The use of fluoroquinolones in children. Curr Opin Pediatr (2006) 18:64–70.[Web of Science][Medline]

20 . Gendrel D, Chalumeau M, Moulin F, et al. Fluoroquinolones in paediatrics: a risk for the patient or for the community? Lancet Infect Dis (2003) 3:537–46.[CrossRef][Web of Science][Medline]

21 . Patzer JA, Dzierzanowska D. Increase of imipenem resistance among Pseudomonas aeruginosa isolates from a Polish paediatric hospital 1993–2002. Int J Antimicrob Agents (2007) 29:153–8.[CrossRef][Web of Science][Medline]

22 . Patzer J, Toleman MA, Lalitagauri MD, et al. Pseudomonas aeruginosa strains harbouring an unusual blaVIM-4 gene cassette isolated from hospitalized children in Poland (1998–2001). J Antimicrob Chemother (2004) 53:451–6.[Abstract/Free Full Text]


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