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The activity of meropenem and comparators against Acinetobacter strains isolated from European hospitals, 1997–2000

2003; Elsevier BV; Volume: 9; Issue: 6 Linguagem: Inglês

10.1046/j.1469-0691.2003.00591.x

1469-0691

Philip J. Turner, Jeannette Greenhalgh,

Infections and bacterial resistance

In vitro susceptibilities to meropenem and comparators of Acinetobacter strains isolated from serious infections in 37 European hospital centers participating in the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program (1997–2000) were tested. There were 635 Acinetobacter strains collected: 490 A. baumannii; 51 A. calcoaceticus var. lwooffii; and 94 other Acinetobacter strains. Overall, meropenem and imipenem were the most effective agents tested. Resistance to the antimicrobials was: 14%, meropenem; 16%, imipenem; 39%, piperacillin–tazobactam; 41%, tobramycin; 45%, ceftazidime; and 53%, ciprofloxacin. Thus, the carbapenems have useful activity against Acinetobacter spp. and represent a viable choice for treating infections caused by these organisms. In vitro susceptibilities to meropenem and comparators of Acinetobacter strains isolated from serious infections in 37 European hospital centers participating in the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program (1997–2000) were tested. There were 635 Acinetobacter strains collected: 490 A. baumannii; 51 A. calcoaceticus var. lwooffii; and 94 other Acinetobacter strains. Overall, meropenem and imipenem were the most effective agents tested. Resistance to the antimicrobials was: 14%, meropenem; 16%, imipenem; 39%, piperacillin–tazobactam; 41%, tobramycin; 45%, ceftazidime; and 53%, ciprofloxacin. Thus, the carbapenems have useful activity against Acinetobacter spp. and represent a viable choice for treating infections caused by these organisms. Acinetobacter spp. are opportunistic pathogens with increasing relevance in nosocomial infections [1Bergogne-Berezin E Towner KJ The increasing role of Acinetobacter species as nosocomial pathogens.Curr Infect Dis Rep. 2001; 3: 440-444Crossref PubMed Google Scholar]. Members of the genus are implicated in a wide spectrum of infections, including nosocomial pneumonia, skin and soft tissue infections, urinary tract infections, and bacteremias. Antimicrobial treatment of these infections, particularly those caused by A. baumannii, may be compromised by multiresistance to the aminoglycosides, fluoroquinolones, ureidopenicillins, and cephalosporins [2Seifert H Baginski R Schulze A Pulverer G Antimicrobial susceptibility of Acinetobacter species.Antimicrob Agents Chemother. 1993; 37: 750-753Crossref PubMed Scopus (153) Google Scholar,3Go ES Urban C Burns J et al.Clinical and molecular epidemiology of Acinetobacter infections sensitive only to polymyxin and sulbactam.Lancet. 1994; 344: 1329-1332Abstract PubMed Scopus (312) Google Scholar]. MYSTIC (Meropenem Yearly Susceptibility Test Information Collection), a global antimicrobial resistance surveillance program, monitors the activity of meropenem and certain other broad-spectrum antimicrobials against bacterial isolates causing serious infections in centers actively prescribing meropenem [4Pfaller MA Jones RN MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) results from the Americas: resistance implications in the treatment of serious infections.J Antimicrob Chemother. 2000; 46: 25-37Crossref Google Scholar,2Seifert H Baginski R Schulze A Pulverer G Antimicrobial susceptibility of Acinetobacter species.Antimicrob Agents Chemother. 1993; 37: 750-753Crossref PubMed Scopus (153) Google Scholar]. No data are available on the susceptibility of Acinetobacter spp. to some commonly used antimicrobials such as ampicillin–sulbactam or rifampicin, as these were not included in the MYSTIC protocol. The antimicrobial susceptibility of 635 Acinetobacter strains collected across Europe from 1997 to 2000 is reported here. Thirty-seven centers collected Acinetobacter isolates: Turkey (nine centers); Belgium (seven centers); the UK (seven centers); Germany (six centers); Italy (two centers); Bulgaria (one center); the Czech Republic (one center); Poland (one center); Russia (one center); Sweden (one center); and Switzerland (one center). The intensive care unit was surveyed in the majority of these hospitals (n = 28). The study design and in vitro susceptibility testing methods used in the MYSTIC Program are described by Turner [5Turner PJ MYSTIC (Meropenem Yearly Susceptibility Test Information Collection): a global overview.J Antimicrob Chemother. 2000; 46: 9-23Crossref Scopus (75) Google Scholar]. In brief, each center tested aerobic Gram-positive and Gram-negative isolates from serious infections in hospitalized patients. Organisms were speciated by the participating centers using the identification method routinely employed in their clinical microbiology laboratory. A minority of isolates were referred to AstraZeneca and were identified using API 20NE test strips. Minimum inhibitory concentrations (MICs) were determined in each center using the methodology described in National Committee for Clinical Laboratory Standards (NCCLS) documents [6National Committee for Clinical Laboratory Standards Methods for dilution antimicrobial tests for bacteria that grow aerobically. Approved standard M7-A5. NCCLS, Wayne, PA2000Google Scholar]. Interpretive criteria were those recommended by the NCCLS [7National Committee for Clinical Laboratory Standards Performance standards for antimicrobial susceptibility testing. M100-S12. NCCLS, Wayne, PA2002Google Scholar]. Breakpoints used were as follows: susceptible ≤4 mg/L, resistant ≥16 mg/L, for mer-openem and imipenem; susceptible ≤ 4 mg/L, resistant ≥8 mg/L, for tobramycin; susceptible ≤8 mg/L, resistant ≥32 mg/L, for ceftazidime; susceptible ≤ 16 mg/L, resistant ≥128 mg/L, for piperacillin–tazobactam; and susceptible ≤1 mg/L, resistant ≥4 mg/L, for ciprofloxacin. The control strains used throughout the MYSTIC Program were Staphylococcus aureus ATCC 29213, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853. A. baumannii was the commonest Acinetobacter species isolated (490 isolates, 77.2%), followed by A. calcoaceticus var. lwoffii (51 isolates, 8.0%), and other Acinetobacter spp. (94 isolates, 14.8%). The last group comprised: 14 A. calcoaceticus isolates, 10 A. calcoaceticus var. anitratus isolates, 11 A. junii isolates, five A. hemolyticus isolates, and 54 Acinetobacter isolates not further identified. Among the 490 isolates of A. baumannii, the two carbapenems showed the greatest clinically useful activity (Table 1). Considerable resistance to piperacillin–tazobactam, ceftazidime, tobramycin and ciprofloxacin was seen (Table 1).Table 1Antimicrobial activity against Acinetobacter spp.Species/antimicrobial agentMIC50 (mg/L)MIC90 (mg/L)MIC range (mg/L)Resistant (%)aDetermined using NCCLS susceptibility and resistance breakpoints [7].Susceptible (%)aDetermined using NCCLS susceptibility and resistance breakpoints [7].A. baumanniiMeropenem1320.008 to >1281182Imipenem0.5320.016 to >1281184Ceftazidime16>1280.25 to w1283342Piperacillin–tazobactam64>1280.008 to >1282834Ciprofloxacin41280.008 to >1284940Tobramycin21280.06 to >1283360A. calcoaceticus var. lwoffiiMeropenem0.520.03–64494Imipenem0.5320.008–641288Ceftazidime8>1280.03 to >1283459Piperacillin–tazobactam16>1280.008 to >1281663Ciprofloxacin0.25640.016 to >1282965Tobramycin1320.03 to >1281780Other Acinetobacter spp.Meropenem0.5320.03–642268Imipenem0.5320.06–643168Ceftazidime16>1280.25 to >1283548Piperacillin–tazobactam16>1280.008 to >1283454Ciprofloxacin2640.016 to >1284046Tobramycin16>1280.008 to >1285337a Determined using NCCLS susceptibility and resistance breakpoints [7National Committee for Clinical Laboratory Standards Performance standards for antimicrobial susceptibility testing. M100-S12. NCCLS, Wayne, PA2002Google Scholar]. Open table in a new tab The susceptibilities of A. baumannii in the different countries are given in Table 2. Susceptibilities to meropenem were very high (97–100%) in all countries except Italy (70%), Turkey (66%), and the UK (77%). A similar pattern was seen for imipenem (93–100%, except for Italy (78%), Turkey (62%), and the UK (78%)). In general, considerably lower susceptibilities to the other antimicrobials tested were seen across all countries (Table 2), with the exception of Sweden (all three A. baumannii isolates from this country were susceptible to all agents tested). Susceptibilities to the non-carbapenem antimicrobials were all below 50% in Bulgaria, Turkey, and the UK.Table 2Percentage susceptibilities* of Acinetobader spp. by countryCountrySpecies/antimicrobial agentBelgiumBulgariaCzech RepublicGermanyItalyPolandRussiaSwedenSwitzerlandTurkeyUKA. baumannii (n)328334127294714318076Meropenem97100100100701001001001006677Imipenem941001009878100100931006278Ceftazidime75384890527957931001228Piperacillin–tazobactam8125679377234571001114Ciprofloxacin81252171487932931002037TobramycinNTNT70935693621001004944A. calcoaceticus var. lwoffii (n)6001323102213Meropenem100––100100100100100–87100Imipenem100––100100100100100–73100Ceftazidime67––1006710067100–4162Piperacillin–tazobactam83––1003350670–6854Ciprofloxacin83––1006710067100–5562TobramycinNT––10010010067100–7778Other Acinetobacter spp. (n)1101148110003712Meropenem91–10010088100100––2792Imipenem91–1009388100100––27100Ceftazidime73–1001005010070––567Piperacillin–tazobactam91–1001008810070––867Ciprofloxacin73–100913810070––1950TobramycinNT–10093010030––1657NT, not tested; –, none collected.a Determined using NCCLS susceptibility and resistance breakpoints [7National Committee for Clinical Laboratory Standards Performance standards for antimicrobial susceptibility testing. M100-S12. NCCLS, Wayne, PA2002Google Scholar]. Open table in a new tab NT, not tested; –, none collected. a Determined using NCCLS susceptibility and resistance breakpoints [7National Committee for Clinical Laboratory Standards Performance standards for antimicrobial susceptibility testing. M100-S12. NCCLS, Wayne, PA2002Google Scholar]. The 51 isolates of A. calcoaceticus var. lwoffii were more susceptible than A. baumannii, with meropenem being the most active compound, followed by imipenem, tobramycin, ciprofloxacin, piperacillin–tazobactam, and ceftazidime (Table 1). The low numbers of strains of this species isolated makes cross-country comparisons less valuable (Table 2). However, the patterns generally reflect those seen with A. baumannii. Susceptibilities of A. calcoaceticus var. lwoffii to meropenem and imipenem were 100% in all countries except Turkey, where there was 87% susceptibility to meropenem, and 73% susceptibility to imipenem (Table 2). The 94 isolates of other Acinetobacter spp. showed a similar susceptibility pattern; the carbapenems were the most active compounds (Table 1). The rank order of susceptibility of the other agents was: piperacillin–tazobactam > ceftazidime > ciprofloxacin > tobramycin (Table 1). Some countries did not isolate organisms from this group, thus limiting any between-country comparisons (Table 2). High (91–100%) susceptibilities to meropenem and imipenem were seen in all countries that obtained isolates from this group, except Italy (88%) and Turkey (27%) (Table 2). Approximately 4.9% (635) of 12 995 infections due to Gram-negative organisms in hospitalized patients in the MYSTIC Program (Europe) between 1997 and 2000 were due to Acinetobacter spp. These data are consistent with a survey of European intensive care units by Hanberger et al (2–10% of Gram-negative isolates) [8Hanberger H Garcia-Rodriguez JA Gobernado M Goossens H Nilsson LE Struelens MJ Antibiotic susceptibility among aerobic gram-negative bacilli in intensive care units in 5 European countries. French and Portuguese ICU Study Groups.JAMA. 1999; 281: 67-71Crossref PubMed Scopus (281) Google Scholar]. In the present study, the overall resistance rank order (% resistant) against Acinetobacter (635 strains) was ciprofloxacin (53%) > ceftazidime (45%) > tobramycin (41%) > piperacillin–tazobactam (39%) > imipenem (16%) > meropenem (14%). This suggests that the carbapenems, unlike the other broad-spectrum antimicrobials tested, have useful activity against these organisms. This finding is supported by previous studies [9Wisplinghoff H Edmond MB Pfaller MA et al.Nosocomial bloodstream infections caused by Acinetobacter species in United States hospitals: clinical features, molecular epidemiology and antimicrobial susceptibility.Clin Infect Dis. 2000; 31: 690-697Crossref PubMed Scopus (183) Google Scholar, 10Chang SC Fang CT Chen YC Hsueh PR Luh KT Hsieh WC In vitro activity of meropenem against common pathogenic bacteria isolated in Taiwan.Diagn Microbiol Infect Dis. 1998; 32: 273-279Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 11Gales AC Jones RN Forward KR Liñares J Sader HS Verhoef J Emerging importance of multidrug-resistant Acinetobacter species and Stenotrophomonas maltophilia as pathogens in seriously ill patients: geographic patterns, epidemiological features, and trends in the SENTRY antimicrobial surveillance program (1997–1999).Clin Infect Dis. 2001; 32: 104-113Crossref Scopus (374) Google Scholar]. Acinetobacter spp., especially A. baumannii, have become increasingly important as nosocomial pathogens, especially in intensive care units [1Bergogne-Berezin E Towner KJ The increasing role of Acinetobacter species as nosocomial pathogens.Curr Infect Dis Rep. 2001; 3: 440-444Crossref PubMed Google Scholar]. The incidence varies between countries, with outbreaks often associated with the spread of a unique strain [12Hartstein AI Rashad AL Liebler JM et al.Multiple intensive care unit outbreak of Acinetobacter calcoaceticus subspecies anitratus respiratory infection and colonization associated with contaminated, reusable ventilator circuits and resuscitation bags.Am J Med. 1988; 85: 624-631Abstract Full Text PDF PubMed Google Scholar, 13Patterson JE Vecchio J Pantelick EL et al.Association of contaminated gloves with transmission of Acinetobacter calocaceticus var anitratus in an intensive care unit.Am J Med. 1991; 91: 479-483Abstract Full Text PDF PubMed Scopus (97) Google Scholar, 14Jawad A Seifert H Snelling AM et al.Survival of Acinetobacter baumannii on dry surfaces: comparison of outbreak and sporadic isolates.J Clin Microbiol. 1998; 36: 1938-1941PubMed Google Scholar]. In this study, as in others [11Gales AC Jones RN Forward KR Liñares J Sader HS Verhoef J Emerging importance of multidrug-resistant Acinetobacter species and Stenotrophomonas maltophilia as pathogens in seriously ill patients: geographic patterns, epidemiological features, and trends in the SENTRY antimicrobial surveillance program (1997–1999).Clin Infect Dis. 2001; 32: 104-113Crossref Scopus (374) Google Scholar,2Seifert H Baginski R Schulze A Pulverer G Antimicrobial susceptibility of Acinetobacter species.Antimicrob Agents Chemother. 1993; 37: 750-753Crossref PubMed Scopus (153) Google Scholar,16Chu YW Afzal-Shah M Houang E et al.IMP-4, a novel metallo-beta-lactamase from nosocomial Acinetobacter spp. collected in Hong Kong between 1994 and 1998.Antimicrob Agents Chemother. 2001; 45: 710-714Crossref PubMed Scopus (213) Google Scholar], A. baumannii was the most commonly isolated species (77.2%). Here, meropenem and imipenem, in that order, were found to be the most active agents of those tested. In most of the European countries investigated, a large proportion (93–100%) of A. baumannii isolates were susceptible to the carbapenems. However, it is worrying that in Italy and the UK only 70–78% of A. baumannii isolates were susceptible to the carbapenems, and in Turkey only 62–66% were susceptible. Similarly, Gunseren et al found that 70% of Acinetobacter isolates from Turkey were susceptible to imipenem [15Gunseren F Mamikoglu L Ozturk S et al.A surveillance study of antimicrobial resistance of Gram-negative bacteria isolated from intensive care units in eight hospitals in Turkey.J Antimicrob Chemother. 1999; 43: 373-378Crossref PubMed Scopus (78) Google Scholar]. Higher carbapenem susceptibility (73–87%) was seen in A. calcoaceticus var. lwoffii in Turkey. However, only 27% of isolates from the other Acinetobacter spp. group were susceptible to either meropenem or imipenem in this country. These types of strains, which include carbapenem resistance in their antibiograms, have been previously reported in a number of countries [16Chu YW Afzal-Shah M Houang E et al.IMP-4, a novel metallo-beta-lactamase from nosocomial Acinetobacter spp. collected in Hong Kong between 1994 and 1998.Antimicrob Agents Chemother. 2001; 45: 710-714Crossref PubMed Scopus (213) Google Scholar, 17Afzal-Shah M Villar HE Livermore DM Biochemical characteristics of a carbapenemase from an Acinetobacter baumannii isolate collected in Buenos Aires, Argentina.J Antimicrob Chemother. 1999; 43: 127-131Crossref PubMed Scopus (31) Google Scholar, 18Afzal-Shah M Woodford N Livermore DM Characterization of OXA-25, OXA-26 and OXA-27, molecular Class D beta-lactamases associated with carbapenem resistance in clinical isolates of Acinetobacter baumannii.Antimicrob Agents Chemother. 2001; 45: 583-588Crossref PubMed Scopus (270) Google Scholar], and though in the minority, emphasize the need for future surveillance. As part of the MYSTIC Program, this study has documented the antimicrobial susceptibilities of Acinetobacter spp. in European hospitals. The results confirm that the carbapenems have useful in vitro activity against these organisms. Therefore, meropenem and imipenem are viable first-line choices for the treatment of infections caused by Acinetobacter spp. The members of the MYSTIC Study Group (Europe) involved in this study were as follows. Turkey: Professor H. Kurt (Ankara University), Professor H. Eraksoy (Istanbul), Professor R. Ozturk (Istanbul), Ass. Professor A. Basustaoglu (Ankara), Professor V. Korten (Istanbul), Professor S. Unal (Ankara), Ass. Professor S. Ulusoy (Izmir), Professor A. Yuce (Izmir), and Ass. Professor Y. Taoova (Adana). Belgium: Professor J. Verhaegen (Leuven), Professor G. Verschraegen (Gent), Professor P. de Mol (Liege), Dr G. Glupczynski (Godinne), Professor M. Delmee (Brussels), Professor S. Lauwers (Brussels), and Professor M. Struelens (Brussels). UK: Dr R. Masterton (Edinburgh), Dr J. Hood (Glasgow), Dr A. Bint (Newcastle upon Tyne), Dr P. Chadwick (Salford), Dr R. Holliman (London), Dr U. Riley (London), and Dr R. A. Swann (Leicester). Germany: Dr E. Pritzbuer (Bremen), Professor R. Thomssen (Gottingen), Professor A. Rodloff (Leipzig), Professor J. Heesemann (Munich), Professor H. Hahn (Berlin), and Professor K.-P. Schaal (Bonn). Italy: Dr E. Giacobone (Pavia) and Professor R. Fontana (Verona). Bulgaria: Professor B. Markova (Sofia). The Czech Republic: Dr E. Chemelerova (Ostrava). Poland: Professor D. Dzierzanowska (Warsaw). Russia: Dr S. V. Resvan (Moscow). Sweden: Dr P. Larsson (Gothenborg). Switzerland: Professor J. Bille (Lausanne).