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Antimicrobial activity against strains of Escherichia coli and Klebsiella spp. with resistance phenotypes consistent with an extended-spectrum β-lactamase in Europe

2003; Elsevier BV; Volume: 9; Issue: 7 Linguagem: Inglês

10.1046/j.1469-0691.2003.00555.x

1469-0691

Ronald N. Jones, Michael A. Pfaller,

Pneumonia and Respiratory Infections

Extended-spectrum β-lactamases (ESBLs) have continued to evolve after their initial detection in Europe nearly two decades ago. The summary results from the MYSTIC Program (31 medical centers) were utilized to assess the extent of ESBL occurrence in Europe from 1997 to 2000. ESBL phenotype rates in Klebsiella spp. (32.8%) and Escherichia coli (14.4%) were generally stable, but extensive hospital-to-hospital and unit-to-unit variations were noted. The highest ESBL rates were found in eastern Europe (including Turkey) and in intensive care unit patient populations. Carbapenems remained active against the ESBL-producing strains (meropenem MIC90,0.25–1 mg/L), while some other agents, such as aminoglycosides, fluoroquinolones, and piperacillin–tazobactam, were significantly less effective. International surveillance initiatives should be maintained to monitor future progression of this important resistance. Extended-spectrum β-lactamases (ESBLs) have continued to evolve after their initial detection in Europe nearly two decades ago. The summary results from the MYSTIC Program (31 medical centers) were utilized to assess the extent of ESBL occurrence in Europe from 1997 to 2000. ESBL phenotype rates in Klebsiella spp. (32.8%) and Escherichia coli (14.4%) were generally stable, but extensive hospital-to-hospital and unit-to-unit variations were noted. The highest ESBL rates were found in eastern Europe (including Turkey) and in intensive care unit patient populations. Carbapenems remained active against the ESBL-producing strains (meropenem MIC90,0.25–1 mg/L), while some other agents, such as aminoglycosides, fluoroquinolones, and piperacillin–tazobactam, were significantly less effective. International surveillance initiatives should be maintained to monitor future progression of this important resistance. Surveillance studies are valuable tools for assessing the changes in patterns of resistance of clinical isolates to antimicrobial agents [1Monnet DL Toward multinational antimicrobial resistance surveillance systems in Europe.Int J Antimicrob Agents. 2000; 15: 91-101Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program is an international, multicenter, longitudinal surveillance study of antimicrobial activity [2Turner PJ Greenhalgh JM Edwards JR McKellar J The MYSTIC (meropenem yearly susceptibility test information collection) programme.Int J Antimicrob Agents. 1999; 13: 117-125Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. The data generated by these surveillance systems are essential for good healthcare resource planning and the use of antimicrobial agents in infection control or therapy, and may avert emerging resistance by predicting antimicrobial agents at risk of selective pressure [3Masterton RG Surveillance studies: how can they help the management of infection?.J Antimicrob Chemother. 2000; 46: 53-58Crossref Scopus (80) Google Scholar]. The MYSTIC Program began in Europe in 1997 and is expected to continue beyond six years. It is estimated that, by the end of 2002, clinical isolates will have been collected from approximately 120 sentinel hospital units across six continents, all of which prescribe the widely used carbapenem meropenem. Units participating in the MYSTIC Program include intensive care, cystic fibrosis, neutropenia (hematology/oncology) and general wards treating patients with serious infections [2Turner PJ Greenhalgh JM Edwards JR McKellar J The MYSTIC (meropenem yearly susceptibility test information collection) programme.Int J Antimicrob Agents. 1999; 13: 117-125Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. The global nature of the MYSTIC Program means that resistance patterns and antimicrobial potency can be compared between different nations as well as between diverse types of center [4Jones RN Detection of emerging resistance patterns within longitudinal surveillance systems: data sensitivity and microbial susceptibility. MYSTIC Advisory Board. Meropenem Yearly Susceptibility Test Information Collection.J Antimicrob Chemother. 2000; 46: 1-8Crossref Google Scholar]. The trend towards increased antimicrobial resistance shown by many of the Gram-negative bacteria is worrying, and has developed as a consequence of widespread and/or inappropriate use of various agents [5Waterer GW Wunderink RG Increasing threat of Gram-negative bacteria.Crit Care Med. 2001; 29: N75-N81Crossref PubMed Scopus (83) Google Scholar]. Bacterial resistance to β-lactam antimicrobial agents among Gram-negative bacteria occurs principally via β-lactamases, a large number of which have been described in recent years [6Medeiros AA Evolution and dissemination of beta-lactamases accelerated by generations of beta-lactam antibiotics.Clin Infect Dis. 1997; 24: S19-S45Crossref PubMed Google Scholar]. Strains of primarily Escherichia coli and Klebsiella spp. are known to harbor the extended-spectrum β-lactamases (ESBLs), resulting in their broad resistance to the ‘third-generation’ cephalosporins and monobactams [7Jones RN Kehrberg EN Erwin ME Anderson SC Prevalence of important pathogens and antimicrobial activity of parenteral drugs at numerous medical centers in the United States, I. Study on the threat of emerging resistances: real or perceived? Fluoroquinolone Resistance Surveillance Group.Diagn Microbiol Infect Dis. 1994; 19: 203-215Abstract Full Text PDF PubMed Scopus (140) Google Scholar]. Since 1997, it has been apparent from the MYSTIC Program results that the incidence of plasmid-mediated ESBL-producing isolates is high in some geographic regions or medical centers [8Turner PJ MYSTIC (Meropenem Yearly Susceptibility Test Information Collection): a global overview.J Antimicrob Chemother. 2000; 46: 9-23Crossref Scopus (75) Google Scholar]. These have been generally underestimated in the past, because they have not been routinely tested for. Reduced activity of specific cephalosporins, penicillins, monobactams and β-lactamase inhibitor combinations against the enteric bacilli that harbor these inactivating enzymes has been shown [8Turner PJ MYSTIC (Meropenem Yearly Susceptibility Test Information Collection): a global overview.J Antimicrob Chemother. 2000; 46: 9-23Crossref Scopus (75) Google Scholar]. This brief report assesses the European data from 1997 to 2000 from the MYSTIC Program in order to examine the diversity, trends and geographic occurrence of ESBL-producing strains in Europe, and to estimate the extent of the problem across the continent. Data were collected from 31 centers in Europe, located in three MYSTIC Program defined regions: north—Belgium (eight centers), UK (seven centers), Germany (six centers), Sweden (one center); south—Italy (three centers), Switzerland (one center); and east—Turkey (two centers), Czech Republic (one center), Poland (one center), and Russia (one center). The centers sampled consisted of 18 intensive care units (ICUs), four neutropenia units, three cystic fibrosis patient units, and six general hospital wards. For patients from the general wards, isolates predominantly originated from intra-abdominal and/or lower respiratory tract infections. Each center tested 100 Gram-negative isolates. Only the E. coli and Klebsiella spp. were tabulated, those species having screening criteria published by the National Committee for Clinical Laboratory Standards (NCCLS) [9National Committee for Clinical Laboratory Standards Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. M7-A5. NCCLS, Wayne, PA2000Google Scholar, 10National Committee for Clinical Laboratory Standards Performance standards for antimicrobial susceptibility testing. M100-S11. NCCLS, Wayne, PA2001Google Scholar]. The MYSTIC Program broad-spectrum core antimicrobial agents tested (per protocol) were: meropenem, imipenem, cefepime, piperacillin–tazobactam, ciprofloxacin, gentamicin, tobramycin, and amikacin. Tobramycin and amikacin were not routinely tested within the European arm of the MYSTIC Program, but some sites used these agents, so data were considered if they were tested in sufficient numbers. In addition, cefepime was included in the standard set of comparators in the first year, but thereafter, resistance levels were only surveyed by some centers. Minimum inhibitory concentration (MIC) values were determined with agar dilution methods recommended by the NCCLS [9National Committee for Clinical Laboratory Standards Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. M7-A5. NCCLS, Wayne, PA2000Google Scholar]. Percentage susceptibilities to the antimicrobial agents were determined at the NCCLS susceptibility breakpoint concentrations of ≤1 mg/L for ciprofloxacin, ≤4 mg/L for meropenem, imipenem, gentamicin and tobramycin, ≤8 mg/L for cefepime, and ≤16 mg/L for piperacillin–tazobactam and amikacin. Percentage resistance to antimicrobial agents was determined at concentrations of ≥4 mg/L for ciprofloxacin, ≥8 mg/L for gentamicin and tobramycin, ≥16 mg/L for meropenem and imipenem, ≥32 mg/L for amikacin and cefepime, and ≥128 mg/L for piperacillin–tazobactam [10National Committee for Clinical Laboratory Standards Performance standards for antimicrobial susceptibility testing. M100-S11. NCCLS, Wayne, PA2001Google Scholar]. Isolates of E. coli and Klebsiella spp. were screened for the presence of the ESBL phenotype by NCCLS criteria as defined by a ceftazidime MIC of ≥2 mg/L, confirmed by in vitro synergy between ceftazidime and clavulanic acid (4 mg/L); criteria for other species have not been reported [10National Committee for Clinical Laboratory Standards Performance standards for antimicrobial susceptibility testing. M100-S11. NCCLS, Wayne, PA2001Google Scholar]. The overall rate of the ESBL phenotype in E. coli and Klebsiella spp. in Europe was (22.1%). ESBLs were most prevalent among Klebsiella spp. (n = 306, 32.8%), and comparatively low among E. coli (n = 189, 14.4%). Potency and spectrum data for tested antimicrobial agents against ESBL-producing strains and all strains are shown in Table 1. Potency is expressed as MIC90, and spectrum as the percentage of resistant strains. These data showed high levels of resistance spanning several antimicrobial classes, including cephalosporins, β-lactamase inhibitor combinations, aminoglycosides and fluoroquinolones. ESBL-producing strains were generally more resistant than all strains to the antimicrobial agents tested. ESBL producers were resistant to the other classes of antimicrobial agents, but susceptible to carbapenems (meropenem and imipenem). Gentamicin, tobramycin and ciprofloxacin susceptibilities were particularly compromised in ESBL isolates, especially among Klebsiella spp. strains.Table 1Potency and spectrum of antimicrobial agents against ESBL phenotypes and all strains in European regions (1997–2000)MIC90 (mg/L)% resistantaResistance as defined by NCCLS [10].Organism (number tested (ESBL/All))Antimicrobial agentESBL producersAll strainsESBL producersAll strainsE. coli (189/1310)Meropenem0.250.120.00.0Imipenem211.10.4Cefepime811.80.4Piperacillin–tazobactam64165.81.8Gentamicin128831.78.8Tobramycin128833.18.3Ciprofloxacin16823.312.7Klebsiella spp. (306/934)Meropenem10.120.30.2Imipenem220.70.2Cefepime321617.86.9Piperacillin–tazobactam>1286423.99.7Gentamicin>1286449.723.2Tobramycin1286460.227.7Ciprofloxacin16424.210.7a Resistance as defined by NCCLS [10National Committee for Clinical Laboratory Standards Performance standards for antimicrobial susceptibility testing. M100-S11. NCCLS, Wayne, PA2001Google Scholar]. Open table in a new tab ESBL phenotypes were more commonly found in the eastern European countries (231 isolates; 29.9% of the two species tested) than in the northern and southern European regions. Great differences existed between nations, with the majority (57%) of ESBL isolates in eastern Europe coming from Turkish ICU patients. In southern Europe, all ESBL cases emerged in Italy among all four groups of monitored patients, and were especially frequent in ICUs and in neutropenic patients. For the northern European sites, ESBL-producing strains were most prevalent in Germany (36% of all cases), Belgium (30%), and the UK (30%), in ICU clinical settings. Data on susceptibilities and resistances of ESBL phenotypes in Klebsiella spp. and E. coli by region are shown in Table 2. The MICs for the two carbapenems meropenem and imipenem were low for both the strains of E. coli (MIC90 0.25–2 mg/L) and Klebsiella spp. (MIC90 1–2 mg/L) that produced ESBLs in all regions of Europe. In contrast, the two aminoglycosides gentamicin and tobramycin showed consistently high resistance rates and MIC values, especially in eastern Europe for E. coli and in northern and eastern regions for Klebsiella spp. A similar pattern was observed for piperacillin–tazobactam; high MIC90 values (E. coli, 64 mg/L; Klebsiella spp., >128 mg/L) were recorded in northern and eastern Europe for this agent. In contrast, the highest MIC90 results shown by cefepime for Klebsiella spp. were noted in southern Europe (64 mg/L). The MIC50 values for ciprofloxacin were high for Klebsiella spp. in southern Europe, and the ciprofloxacin MIC90 was in the resistant range in all regions. The highest ciprofloxacin resistance rates in Europe were recorded for E. coli (29%) in northern Europe and for Klebsiella spp. (49%) in southern Europe. No trend towards greater ESBL occurrence was noted in Europe overall, but individual unit variations were identified (data not shown).Table 2Activity and potency of antimicrobial agents against ESBL phenotypes in European regions (1997–2000)Antimicrobial agentMIC50/90 (mg/L)% S/RaPercentage by NCCLS [10] category for susceptible (S) and resistant (R)MIC50/90 (mg/L)% S/RMIC50/90 (mg/L)% S/RMIC50/90% S/RE. coliNorth (n = 59)bFour nations: Belgium, Germany, Sweden, and the UK.South (n = 64)cTwo nations: Italy and Switzerland.East (n = 66)dFour nations: Czech Republic, Poland, Russia, and Turkey.All (n = 189)Meropenem0.06/0.5100/00.12/0.5100/00.03/0.12100/00.03/0.25100/0Imipenem0.25/297/00.5/2100/00.12/0.597/30.25/298/1Cefepime0.5/891/22/897/02/1687/42/892/2Piperacillin–tazobactam8/6475/84/3288/032/6447/98/6469/6Amikacin2/892/0NTeNT, not tested in sufficient numbers (<25.0% of strains detected) to determine spectrum.NTeNT, not tested in sufficient numbers (<25.0% of strains detected) to determine spectrum.NTeNT, not tested in sufficient numbers (<25.0% of strains detected) to determine spectrum.NTeNT, not tested in sufficient numbers (<25.0% of strains detected) to determine spectrum.NTeNT, not tested in sufficient numbers (<25.0% of strains detected) to determine spectrum.NTeNT, not tested in sufficient numbers ( 12833/592/12864/32Tobramycin2/1676/122/1686/1132/>12830/674/12862/33Ciprofloxacin0.12/1671/290.5/3272/170.016/6473/240.25/1672/23Klebsiella spp.North (n = 80)bFour nations: Belgium, Germany, Sweden, and the UK.South (n = 61)cTwo nations: Italy and Switzerland.East (n = 165)dFour nations: Czech Republic, Poland, Russia, and Turkey.All (n = 306)Meropenem0.06/0.599/00.25/1100/00.06/0.2598/<10.06/199/<1Imipenem0.25/498/01/2100/00.25/198/<10.25/298/ 12846/208/3277/364/>12829/3332/>12843/24Amikacin8/3267/4NTNTeNT, not tested in sufficient numbers (<25.0% of strains detected) to determine spectrum.NTeNT, not tested in sufficient numbers (<25.0% of strains detected) to determine spectrum.NTeNT, not tested in sufficient numbers (<25.0% of strains detected) to determine spectrum.NTeNT, not tested in sufficient numbers (<25.0% of strains detected) to determine spectrum.NTeNT, not tested in sufficient numbers ( 12858/394/3269/2516/>12823/648/>12841/50Tobramycin2/12856/404/3251/3832/>12819/7416/12832/60Ciprofloxacin0.25/3275/212/3249/490.12/477/160.25/1671/24a Percentage by NCCLS [10National Committee for Clinical Laboratory Standards Performance standards for antimicrobial susceptibility testing. M100-S11. NCCLS, Wayne, PA2001Google Scholar] category for susceptible (S) and resistant (R)b Four nations: Belgium, Germany, Sweden, and the UK.c Two nations: Italy and Switzerland.d Four nations: Czech Republic, Poland, Russia, and Turkey.e NT, not tested in sufficient numbers (<25.0% of strains detected) to determine spectrum. Open table in a new tab In summary, European data from the MYSTIC Program between 1997 and 2000 showed that ESBLs were more prevalent in Klebsiella spp. than in E. coli. Geographic differences were observed, with a higher prevalence of ESBL phenotypes in eastern Europe (231 strains), especially Turkey, compared to the remainder of the continent (264 strains), although prevalence was generally high throughout Europe. Meropenem and imipenem both exhibited excellent activity against E. coli and Klebsiella spp., and, of the range of antimicrobial agents tested, were shown to have the highest susceptibility rates. This study therefore showed that the carbapenems are valuable options in the treatment of infections caused by Enterobacteriaceae, even those involving ESBL-producing organisms. The prevalence of ESBLs presented here, especially in Klebsiella spp., agrees with previously reported observations in Europe [11Babini GS Livermore DM Antimicrobial resistance amongst Klebsiella spp. collected from intensive care units in Southern and Western Europe in 1997–1998.J Antimicrob Chemother. 2000; 45: 183-189Crossref PubMed Scopus (154) Google Scholar, 12Babini GS Livermore DM Are SHV beta-lactamases universal in Klebsiella pneumoniae?.Antimicrob Agents Chemother. 2000; 44: 2230Crossref PubMed Scopus (69) Google Scholar], and is high enough to warrant consideration when selecting initial therapy if both the organism and its susceptibility are unknown and where ESBL-producing phenotypes have been encountered. Control of these problematic ESBL strains of E. coli and Klebsiella spp. in Europe will require comprehensive programs of infection control and formulary management, supplemented by quality surveillance systems at the local level and by global systems such as the MYSTIC Program. The participating MYSTIC investigators in Europe were as follows. UK: Dr Masterton (Edinburgh), Dr Bint (Newcastle), Dr Hood (Glasgow), Dr Chadwick (Salford), Dr Gaya (London), Dr Holliman (London), and Dr Riley (London). Belgium: Professor Goossens (Antwerp), Professor Verschraegen (Ghent), Professor Lauwers (Brussels), Professor Verhaegen (Leuven), Professor Struelens (Brussels), Professor Delmee (Louvain), Dr Glupczynski (Godinne), and Professor De Mol (Liege). Germany: Dr Pritzbuer (Bremen), Professor Bauernfeind (Munich), Professor Thomssen (Göttingen), Professor Rodloff (Leipzig), Professor Heesemson (Munich), and Professor Hahn (Berlin). Turkey: Professor Kurt (Ankara) and Professor Eraksoy (Istanbul). Czech Republic: Dr Chmelarova (Ostrava). Russia: Dr Resvan (Moscow). Poland: Professor Dzierzanowska (Warsaw). Sweden: Dr Larsson (Gothenburg). Switzerland: Professor Bille (Lausanne). Italy: Dr Giacobone (Pavia), Professor Fontana (Verona), and Professor Fraschini (Milan). The MYSTIC Program is supported by an educational/research grant from AstraZeneca.