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Emerging resistance among bacterial pathogens in the intensive care unit – a European and North American Surveillance study (2000–2002)

Emerging resistance among bacterial pathogens in the intensive care unit – a European and North... Background: Globally ICUs are encountering emergence and spread of antibiotic-resistant pathogens and for some pathogens there are few therapeutic options available. Methods: Antibiotic in vitro susceptibility data of predominant ICU pathogens during 2000–2 were analyzed using data from The Surveillance Network (TSN) Databases in Europe (France, Germany and Italy), Canada, and the United States (US). Results: Oxacillin resistance rates among Staphylococcus aureus isolates ranged from 19.7% to 59.4%. Penicillin resistance rates among Streptococcus pneumoniae varied from 2.0% in Germany to as high as 20.2% in the US; however, ceftriaxone resistance rates were comparably lower, ranging from 0% in Germany to 3.4% in Italy. Vancomycin resistance rates among Enterococcus faecalis were ≤ 4.5%; however, among Enterococcus faecium vancomycin resistance rates were more frequent ranging from 0.8% in France to 76.3% in the United States. Putative rates of extended-spectrum β-lactamase (ESBL) production among Enterobacteriaceae were low, <6% among Escherichia coli in the five countries studied. Ceftriaxone resistance rates were generally lower than or similar to piperacillin-tazobactam for most of the Enterobacteriaceae species examined. Fluoroquinolone resistance rates were generally higher for E. coli (6.5% – 13.9%), Proteus mirabilis (0–34.7%), and Morganella morganii (1.6– 20.7%) than other Enterobacteriaceae spp (1.5–21.3%). P. aeruginosa demonstrated marked variation in β-lactam resistance rates among countries. Imipenem was the most active compound tested against Acinetobacter spp., based on resistance rates. Conclusion: There was a wide distribution in resistance patterns among the five countries. Compared with other countries, Italy showed the highest resistance rates to all the organisms with the exception of Enterococcus spp., which were highest in the US. This data highlights the differences in resistance encountered in intensive care units in Europe and North America and the need to determine current local resistance patterns by which to guide empiric antimicrobial therapy for intensive care infections. Page 1 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 each country. These surveillance programs help to main- Background Antimicrobial resistance has emerged as an important fac- tain current knowledge of susceptibilities and relevant tor in predicting outcomes and overall resource use after treatment options. infections in intensive care units (ICU) [1]. Globally ICUs are encountering emergence and spread of antibiotic- Methods resistant pathogens. For some pathogens there are few TSN Database – United States and Europe therapeutic options available, e.g., vancomycin-resistant TSN is a queriable, real-time database that electronically Enterococcus faecium. Awareness of these problems has assimilates daily antimicrobial susceptibility testing and been underscored with data from a number of surveil- patient demographic data from a network of geographi- lance studies aimed at improving the use of empiric ther- cally dispersed laboratories in the United States (283 hos- apy. In the United States there have been several national pital sites), France (63 hospital sites), Germany (169 programs, which have focused on both the etiology of hospital sites), Italy (48 hospital sites) and Canada (87 infections and resistance patterns of nosocomial or ICU hospital sites) [12]. infections including the National Nosocomial Infections Surveillance (NNIS) [2] and more recently an ICU-specific Laboratories included in TSN include those servicing uni- study examining the epidemiology of antimicrobial resist- versity, community, and private hospitals with bed sizes ance, Project ICARE [3,4]. Stephen et al. collected strains ranging from 100 to >1000 beds. Routine diagnostic sus- from 28 ICUs from across the United States as part of the ceptibility testing results are collected daily from each par- SENTRY Antimicrobial Surveillance Program in 2001 [5]. ticipating laboratory. The methods used by these laboratories include VITEK (bioMérieux, St. Louis, MO), European data on the antimicrobial resistance of ICU MicroScan (Dade-Microscan, Sacramento, CA), Sceptor pathogens has also been collected in several recent surveil- and Pasco MIC/ID (Becton Dickinson, Sparks, MD) and lance studies. A large prevalence survey of nosocomial Etest (AB Biodisk, Solna, Sweden), as well as manual infections in ICUs in 17 countries was published in 1995 broth microdilution MIC, disk diffusion and agar dilu- [6], and more recently a number of nation-specific surveys tion. TSN reflects current testing in participant laborato- were reported [7-9]. Several key points emerge: first, anti- ries and represents the data reported to physicians from microbial resistance among ICU pathogens is generally the respective laboratories [13]. increasing, but variations do exist among different coun- tries, probably due to individual antimicrobial use pat- Although some European countries have alternate break- terns; second, when new medical practices and alternative points, all data forwarded to TSN Databases are derived antimicrobials are introduced changes in the dominant from hospitals that utilized NCCLS standards and defini- microbial etiologies may emerge prompting novel tions (United States, Canada, Italy, and Germany) [14] or empiric selections; and third, the standards of hygiene the Comité de L'Antibiogramme de La Societé Français de and infection control also vary across countries. Finally, Microbiologie (France) [15] thus standardizing datasets. appropriate therapy of ICU infections directed by local Results were interpreted as susceptible, intermediate (if resistance data can have significant consequences for both available), or resistant in TSN, based upon the NCCLS patient and the healthcare system. It is against this back- interpretative guidelines in place during 2001 [16]. In ground that local resistance surveillance programs are of addition, a series of quality-control filters (i.e., critical rule most value in developing appropriate therapeutic guide- sets) were used in TSN to screen susceptibility test results lines for specific infections and patient types. For exam- for patterns indicative of testing error and suspect results ple, the recent modification to the American Thoracic were removed from analysis for laboratory confirmation. Society guidelines for the treatment of hospital-acquired In TSN, any result from the same patient with the same pneumonia [10] considered contemporary resistance organism identification and the same susceptibility pat- data. Local surveillance data can be applied to other infec- tern received within five days was considered a repeat cul- tions to assist in local formulary policy such as those gov- ture and was counted only once in the database. erning treatment of nosocomial urinary tract infections Bacterial species and antimicrobials tested [11]. For this study, data from TSN results for each individual This study using TSN program reports the antimicrobial database from January 1, 2000 through to December 31, resistance profiles of bacterial isolates from ICU patients 2002 were included in the analysis to determine the pro- in five countries during the period 2000–2002. The rele- portion of species and their susceptibility to antimicrobial vance of these recent nation-specific data will be discussed agents commonly tested in clinical laboratories through- on a country-by-country basis, as part of improving and out the participating regions. Only isolates derived from updating empiric therapeutic approaches to specific path- patients located in hospital ICUs were considered in the ogens causing infections in the ICU setting according to analysis. Gram-positive species included in the analysis Page 2 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 1: Incidence of pathogens isolated from ICU patients by country (%) United States Canada Italy Germany France Organism Incidence (%) Organism Incidence (%) Organism Incidence (%) Organism Incidence (%) Organism Incidence (%) a a 1 S. aureus 20.2 S. aureus 17.4 P. aeruginosa 22.3 CNS 16.4 S. aureus 17.2 b a CNS 15.9 CNS 16.1 CNS 18.7 S. aureus 13.6 CNS 16.7 P. aeruginosa 13.1 E. coli 12.6 S. aureus 18.1 E. coli 12.3 E. coli 15.5 E. coli 9.2 P. aeruginosa 11.3 E. coli 7.7 P. aeruginosa 10.8 P. aeruginosa 13.8 K. pneumoniae 5.8 Enterococcus spp 7.6 E. faecalis 3.9 Enterococcus spp 7.4 S. pneumoniae 3.3 Enterococcus spp 5.4 K. pneumoniae 5.5 K. pneumoniae 3.5 K. pneumoniae 5.4 E. cloacae 3.3 E. cloacae 4.3 E. cloacae 4.2 Enterococcus spp 3.3 E. cloacae 4.7 E. faecalis 3.0 E. faecalis 3.7 S. marcenscens 2.5 E. cloacae 2.6 E. faecalis 4.3 K. pneumoniae 2.7 S. marcescens 2.7 H. influenzae 2.1 S. marcescens 2.2 P. mirabilis 2.6 P. mirabilis 2.5 A. baumanii 2.6 E. faecalis 2.1 P. mirabilis 1.9 K. oxytoca 2.4 Enterococcus spp 2.3 Enterobacteriaceae 29.5 Enterobacteriaceae 33.0 Enterobacteriaceae 30.2 Enterobacteriaceae 36.0 Enterobacteriaceae 32.1 (all species (all species (all species (all species (all species combined) combined) combined) combined) combined) Total (n) 26,624 Total (n) 54,445 Total (n) 34,609 Total (n) 48,385 Total (n) 62,459 a b Proportion of S. aureus testing as MRSA was USA (52.3%), Canada (19.7%), Italy (59.4%), Germany (21.0%), and France (40.6%) CNS = Coagulase-negative staphylococci Enterobacteriaceae includes all species of genera occurring at >0.1% were comprised of S. aureus, coagulase negative staphylo- Tables 2,3,4,5 show the antimicrobial susceptibility pro- cocci, Enterococcus faecalis,Enterococcus faecium, Streptococ- files of various Gram-positive and Gram-negative patho- cus pyogenes, Streptococcus pneumoniae and viridans group gens isolated from ICU patients against a range of relevant streptococci. Gram-negative species studied comprised antimicrobials. the predominantly encountered enteric species (Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Specifically notable susceptibility patterns include the Proteus mirabilis, Morganella morganii and Serratia vancomycin susceptibility of all strains of staphylococci. marcescens), and Pseudomonas aeruginosa and Acinetobacter Generally, there was a low proportion of vancomycin spp. resistant E. faecalis <5%, whereas vancomycin-resistant E. faecium was more prevalent ranging from 0.8% in France The antibiotics studied are listed in Tables 2,3,4,5. Among to 76.3% in the United States, with a wide inter-country E. coli, putative ESBL production was defined as those iso- variation (Table 2). Penicillin resistance rates varied lates that were intermediate or resistant (non-susceptible) among S. pneumoniae, from 2.0% in Germany to 20.2% in to ceftazidime [17]. Given the large number of isolate the US with concurrent ceftriaxone resistance rates of 0% results included in the majority of analyses in this study, in Germany to 3.4% in Italy (Table 3). statistical analysis was not performed, as even subtle dif- ferences in percent resistance (<1%) to an antimicrobial β-lactam activity was assessed by comparing four different agent for any time period or demographic parameters cephalosporins and a β-lactam/β-lactamase inhibitor would be reported as highly significant (P <0.001). combination, piperacillin-tazobactam. Overall, the puta- tive production of ESBLs among E. coli was low, <6%, but Results ceftazidime resistance was reported at higher rates in K. In vitro susceptibility data from over 220,000 isolates pneumoniae and S. marcescens, with the highest rates seen from ICUs in five countries over the period 2000–2002 in M. morganii, from 16.0% in Germany to 26.4% in the were assimilated. The most frequent species isolated from United States (Table 4). Among the gram-negative organ- infections in the ICU was S. aureus, being most common isms tested, ceftriaxone resistance rates were usually lower in three of the five countries (Table 1). The oxacillin resist- than ceftazidime, with the exception among P. aeruginosa ance rates among S. aureus varied markedly across coun- and Acinetobacter spp. Cefepime, a fourth generation tries from 19.7% in Canada to 59.5% in Italy. E. coli cephalosporin with anti-pseudomonal activity was also (7.7%–15.5%) and P. aeruginosa (10.8%–22.3%) were more active than ceftazidime (Table 5). Against the Entero- the most frequent Gram-negative organisms encountered. bacteriaceae, the β-lactam combination agent piperacillin- The Gram-positive genus Enterococcus, either as E. faecalis, tazobactam was generally less active than ceftriaxone. E. faecium or non-speciated isolates accounted for <10% These species showed a wide variation in fluoroquinolone of isolates in most countries with E. faecalis being the most susceptibility among both species and countries. Gen- common species <4.3%. Community-acquired respira- tamicin resistance rates among the Enterobacteriaceae var- tory pathogens such as Streptococcus pneumoniae and Hae- ied from 1.2% among K. oxytoca from Germany to 37.2% mophilus influenzae were relatively uncommon in all five in P. mirabilis from Italy. Ciprofloxacin resistance rates countries. among E. coli ranged from 6.5% in France to 12.7% in Page 3 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 2: S. aureus, Coagulase-negative staphylococci, E. faecalis, and E. faecium isolated from ICU patients during 2000–2002 United States Canada Italy Germany France Organism Agent Total n %S %R Total n %S %R Total n %S %R Total n %S %R Total n %S %R Staphylococcus Ampicillin 19,703 6.7 93.3 3,792 12.6 87.4 1,665 5.6 94.4 2,867 16.2 83.8 15 6.7 93.3 aureus b c> Cefepime 1,260 52.9 46.9 NT NT NT 304 15.8 84.2 483 80.5 17.0 <10 NA NA Cefotaxime 6,898 50.2 49.7 220 55.5 44.5 671 36.4 63.6 729 92.0 8.0 490 63.9 36.1 Ceftriaxone 5,914 45.6 54.3 153 69.3 30.7 1,048 28.1 71.8 220 88.6 11.4 23 73.9 26.1 Ciprofloxacin 24,350 47.4 51.0 5,958 74.5 24.1 4,600 39.7 58.6 5,243 73.4 26.1 316 57.0 40.5 Gentamicin 35,034 85.6 13.7 6,641 89.4 10.3 5,531 40.9 58.0 5,735 90.0 9.7 10,100 90.4 9.4 Oxacillin 44,939 47.7 52.3 10,105 80.3 19.7 6,147 40.6 59.4 6,475 79.0 21.0 10,512 59.4 40.6 Teicoplanin NT NT NT NT NT NT 5,868 100 0 4,632 99.8 0.2 8,232 100 0 Vancomycin 43,245 100 0 7,882 100 0 5,937 100 0 5,276 100 0 9,453 100 0 Staphylococcus aureus OSSA Ampicillin 9,047 14.5 85.5 3,055 15.7 84.3 741 12.6 87.4 2,414 19.3 80.7 10 0 100 Cefepime 672 99.1 0.4 NT NT NT 49 98.0 2.0 387 99.5 0.3 NT NT NT Cefotaxime 3,451 99.7 0.2 122 100 0 244 100 0 653 100 0 312 100 0 Ceftriaxone 2,707 99.5 0.2 106 100 0 295 99.0 0.3 194 100 0 16 100 0 Ciprofloxacin 11,827 91.2 6.5 4,692 93.5 4.8 1,902 91.4 4.9 4,171 91.4 8.0 188 90.4 6.4 Gentamicin 16,951 98.3 1.4 5,384 98.1 1.8 2,223 95.1 4.5 4,527 98.4 1.5 5,958 99.4 0.5 Oxacillin 21,416 100 0 8,110 100 0 2,495 100 0 5,115 100 0 6,244 100 0 Teicoplanin NT NT NT NT NT NT 2,402 100 0 3,593 99.9 0.1 5,018 100 0 Vancomycin 20,110 100 0 6,046 100 0 2,430 100 0 4,002 100 0 5,580 100 0 Staphylococcus aureus ORSA Ampicillin 10,656 0 100 737 0 100 924 0 100 453 0 100 <10 NA NA Cefepime 588 0 100 NT NT NT 255 0 100 96 4.2 84.4 <10 NA NA Cefotaxime 3,447 0.6 99.3 98 0 100 427 0 100 76 23.7 76.3 178 0.6 99.4 Ceftriaxone 3,207 0 100 47 0 100 753 0.3 99.7 26 3.8 96.2 <10 NA NA Ciprofloxacin 12,523 6.1 93.1 1,266 3.9 95.5 2,698 3.3 96.4 1,072 3.3 96.6 128 7.8 90.6 Gentamicin 18,083 73.7 25.2 1,257 52.0 46.8 3,308 4.5 94.0 1,208 58.7 40.5 4,142 77.5 22.2 Oxacillin 23,523 0 100 1,995 0.2 99.8 3,652 0 100 1,360 0 100 4,268 0 100 Teicoplanin NT NT NT NT NT NT 3,466 100 0 1,039 99.7 0.3 3,214 100 0 Vancomycin 23,135 100 0 1,836 100 0 3,507 100 0 1,274 100 0 3,873 100 0 Staphylcoccus species, coagulase- negative Ampicillin 16,288 5.7 94.3 3,533 6.3 93.7 2,142 10.6 89.4 4,075 8.1 91.9 <10 NA NA Cefepime 991 11.8 88.1 <10 NA NA 116 0 100 625 11.0 73.1 <10 NA NA Cefotaxime 5,538 17.7 82.3 240 17.9 82.1 335 16.7 83.3 625 37.4 62.4 174 28.7 69.0 Ceftriaxone 3,471 14.8 84.8 116 22.4 77.6 512 11.7 88.3 412 25.0 74.8 <10 NA NA Ciprofloxacin 18,829 40.2 58.3 5,366 44.4 54.7 5,102 42.7 54.0 6,197 29.5 67.6 198 44.4 53.0 Gentamicin 27,248 51.5 38.1 5,571 40.6 47.3 5,241 33.8 60.7 6,848 41.5 51.7 9,422 46.8 51.5 Oxacillin 35,135 15.8 84.2 9,172 20.6 79.4 5,961 15.2 84.8 7,442 18.6 81.4 9,884 30.1 69.9 Teicoplanin NT NT NT NT NT NT 5,797 93.7 2.4 5,096 95.6 0.7 7,670 84.6 3.1 Vancomycin 34,424 100 0 8,239 100 0 5,937 100 0 6,953 100 0 8,300 100 0 Staphylcoccus species, coagulase- negative Oxacillin Ampicillin 2,582 35.7 64.3 638 34.6 65.4 437 51.7 48.3 824 39.6 60.4 <10 NA NA susceptible Cefepime 117 100 0 NT NT NT NT NT NT <10 NA NA NT NT NT Cefotaxime 978 99.5 0.2 42 100 0 56 100 0 128 100 0 54 92.6 0 Ceftriaxone 523 98.3 0.4 26 100 0 59 100 0 103 100 0 <10 NA NA Ciprofloxacin 2,844 82.4 16.6 988 91.8 7.6 779 87.7 10.1 1,103 89.5 9.2 78 83.3 14.1 Gentamicin 4,424 93.5 4.2 1,068 91.9 5.3 698 94.3 5.3 1,263 96.5 2.7 2,822 93.9 5.4 Oxacillin 5,565 100 0 1,886 99.9 0.1 904 100 0 1,383 100 0 2,980 100 0 Teicoplanin NT NT NT NT NT NT 890 99.1 0.3 691 98.4 0.3 2,454 95.8 0.2 Vancomycin 5,240 100 0 1,587 100 0 897 100 0 981 100 0 2,467 100 0 Staphylcoccus species, coagulase- negative Oxacillin resistant Ampicillin 13,706 0.1 99.9 2,895 0 100 1,705 0 100 3,251 0.2 99.8 <10 NA NA Cefepime 874 0 99.9 <10 NA NA 116 0 100 624 10.9 73.2 <10 NA NA Page 4 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 2: S. aureus, Coagulase-negative staphylococci, E. faecalis, and E. faecium isolated from ICU patients during 2000–2002 (Continued) Cefotaxime 4,560 0.1 99.9 198 0.5 99.5 279 0 100 497 21.3 78.5 120 0 100 Ceftriaxone 2,948 0 99.8 90 0 100 453 0.2 99.8 309 0.0 99.7 <10 NA NA Ciprofloxacin 15,985 32.7 65.8 4,378 33.7 65.3 4,323 34.7 61.9 5,094 16.5 80.2 120 19.2 78.3 Gentamicin 22,824 43.3 44.7 4,503 28.5 57.3 4,543 24.5 69.2 5,585 29.1 62.8 6,600 26.6 71.3 Oxacillin 29,570 0 100 7,286 0 100 5,057 0 100 6,059 0 100 6,904 0 100 Teicoplanin NT NT NT NT NT NT 4,907 92.7 2.8 4,405 95.1 0.8 5,216 79.3 4.5 Vancomycin 29,184 100 0 6,652 100 0 5,040 100 0 5,972 100 0 5,833 100 0 Enterococcus faecalis Ampicillin 7,865 98.8 1.2 1,000 99.4 0.6 1,289 95.3 4.7 1,902 99.6 0.4 1,183 99.5 0.2 Ciprofloxacin 3,311 56.9 38.7 625 45.3 50.4 1,159 64.0 31.1 2,012 39.7 39.5 559 78.5 17.0 Gentamicin 5,503 65.1 34.8 706 63.0 36.8 1,156 62.9 37.1 965 64.8 35.2 1,563 63.6 13.4 (HL Testing) Teicoplanin NT NT NT <10 NA NA 1,248 97.1 2.4 1,294 99.7 0.2 1,747 99.9 0.1 Vancomycin 7,656 95.1 4.5 1,005 98.3 0.9 1,303 96.7 2.8 1,636 99.4 0.3 1,811 99.7 0.2 Enterococcus faecium Ampicillin 3,896 9.7 90.3 383 17.2 82.8 260 21.5 78.5 481 12.3 87.7 151 41.7 49.7 Ciprofloxacin 1,846 5.3 92.5 221 10.9 85.5 234 10.3 77.4 591 6.9 73.9 66 21.2 39.4 Gentamicin 2,512 57.5 42.5 291 59.5 40.5 223 67.7 32.3 349 60.2 39.8 263 65.4 12.2 (HL Testing) Teicoplanin 23 8.7 87.0 <10 NA NA 234 86.3 13.7 517 97.9 2.1 266 99.6 0.4 Vancomycin 4,066 23.2 76.3 415 85.1 14.5 264 75.4 24.2 628 93.9 4.8 247 98.4 0.8 a b c NCCLS breakpoints were used for all countries, except (CA-SFM) Not tested Not applicable if <10 isolates were tested Italy. Variable fluoroquinolone resistance rates among S. cefepime were the most active agents, based on suscepti- marcescens were also demonstrated, with a range of resist- bility, against P. aeruginosa in Germany. Conversely, ceftri- ance from 4.5% in Italy to 12.4% in Germany. axone and imipenem were the most active agents, based on susceptibility, against Klebsiella spp., which account for almost 8% of ICU isolates. Discussion Data derived from international surveillance studies, such as those presented here, can provide a unique contempo- Staphylococcal species from French ICU isolates showed a rary perspective on the susceptibility of commonly high proportion of oxacillin resistance, 40.6% and 69. 9% encountered organisms to commonly used antibiotics. of S. aureus and coagulase-negative staphylococci spp., Such surveillance systems play a crucial role in detecting respectively. S. pneumoniae showed penicillin resistance of emerging trends in resistance. Comparisons of these with 17.9%, higher than the other four countries, although the data of other recent surveillance programs show the wide activity of third-generation cephalosporins, ceftriaxone variations in susceptibility profiles and the need for ongo- and cefotaxime, showed only 0.6% and 0.8% resistance, ing unit-specific surveys. respectively. Despite a lower ceftazidime susceptibility breakpoint compared to NCCLS standards (MIC 4 µg/ml In Germany the prevalence of resistance among gram-pos- instead of 8 µg/ml) putative ESBL expression were slightly itive organisms remained comparatively low with an inci- lower in France than in Germany in 2000–2002. Ceftazi- dence of 21% MRSA. In 2000, Frank et al. reported that dime non-susceptibility rates among E. coli, K. oxytoca, 96% of German isolates of S. marcescens and M. morganii and P. mirabilis were ≤ 2.2%; however, ceftazidime non- were susceptible to ceftazidime, yet in this study we found susceptibility rates among K. pneumoniae, M. morganii and 89.7% and 84.0%, respectively [9]. A similar decrease in S. marcescens were 7.5%, 21.4%, and 5.3%, respectively. activity was noted with E. coli and ciprofloxacin between Imipenem was active against all Enterobacteriaceae. Against the two studies, 91% in 1996–1997 compared with P. aeruginosa and Acinetobacter spp., imipenem resistance 86.7% in this study. Marked decreases in susceptibility of rates were 21.4% and 3.8%, respectively. Previously, a P. aeruginosa in Germany were also evident, with no agent lower imipenem resistance of 24% among French isolates showing >85.8% susceptibility (piperacillin-tazobactam) of P. aeruginosa was reported [7]. compared with most agents having 85%–94% susceptibil- ity in 1996–1997. Changes of 15–20% have been Among the Italian isolates of staphylococci, oxacillin reported with ceftazidime, imipenem, ciprofloxacin and resistance occurred in 59.4% of S. aureus and 84.8% of meropenem, while piperacillin-tazobactam has shown coagulase-negative isolates. This MRSA rate was similar to the smallest decrease in susceptibility with <6% over the that reported by Frank et al. from bacteremic isolates in 4-year period. Piperacillin plus or minus tazobactam and Italy; however, they reported an increase in MRSA from Page 5 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 3: S. pneumoniae, S. pyogenes, S. agalactiae, and Viridans group streptococci isolated from ICU patients during 2000–2002 United States Canada Italy Germany France Organism Agent Total n %S %R Total n %S %R Total n %S %R Total n %S %R Total n %S %R Streptococcus Amoxicillin 120 91.7 2.5 31 100 0 60 93.3 6.7 17 100 0 1,328 71.2 2.3 pneumoniae b c Cefepime 22 90.9 4.5 25 60.0 12.0 66 90.9 7.6 NT NT NT <10 NA NA Cefotaxime 1,571 82.2 6.3 145 93.8 0.7 108 93.5 4.6 63 100 0 1,181 77.1 0.8 Ceftriaxone 2,373 88.3 3.2 145 91.7 0.7 145 91.7 3.4 29 100 0 544 80.1 0.6 Clarithromycin 184 71.7 25.5 56 69.6 30.4 90 64.4 31.1 <10 NA NA NT NT NT Erythromycin 3,029 67.9 30.5 539 78.5 20.8 313 69.6 28.1 405 88.6 9.4 1,567 59.0 38.8 Levofloxacin 2,133 99.1 0.4 356 98.6 1.1 174 98.3 0.6 340 99.4 0.3 62 98.4 1.6 Penicillin 3,096 51.5 20.2 325 59.1 7.1 198 77.3 7.6 102 96.1 2.0 1,387 45.5 17.9 Vancomycin 2,865 100 - 271 100 - 231 100 - 190 100 - 1,479 100 - Streptococcus pyogenes Amoxicillin NT NT NT NT NT NT NT NT NT NT NT NT 58 100 0 Cefepime <10 NA NA NT NTNT NT NTNT NT NTNT NT NTNT Cefotaxime 32 100 - 29 100 - <10 NA NA 11 100 - 30 100 - Ceftriaxone 75 100 - <10 NA NA <10 NA NA <10 NA NA <10 NA NA Clarithromycin 19 84.2 5.3 <10 NA NA 17 88.2 11.8 NT NT NT NT NT NT Erythromycin 118 92.4 6.8 102 81.4 11.8 59 74.6 23.7 63 84.1 11.1 170 82.9 14.7 Levofloxacin 71 97.2 1.4 <10 NA NA <10 NA NA 61 77.0 4.9 NT NT NT Penicillin 140 100 - 97 100 - 58 100 - 64 100 - 139 100 - Vancomycin 121 100 - 42 100 - 12 100 - 34 100 - 162 100 - Streptococcus agalactiae Amoxicillin NT NT NT NT NT NT NT NT NT NT NT NT 165 100 0 Cefepime 28 100 - NT NT NT <10 NA NA NT NT NT NT NT NT Cefotaxime 71 100 - 17 100 - 24 100 - 50 100 - 50 100 - Ceftriaxone 184 100 - <10 NA NA 38 100 - 37 100 - <10 NA NA Clarithromycin 21 81.0 9.5 <10 NA NA 21 71.4 28.6 NT NT NT <10 NA NA Erythromycin 489 76.3 21.7 222 82.9 14.9 121 77.7 18.2 192 83.9 10.9 588 79.9 16.2 Levofloxacin 333 97.9 1.2 <10 NA NA 51 98.0 0 180 91.1 1.7 173 99.4 0 Penicillin 518 100 - 226 100 - 145 100 - 184 100 - 369 100 - Vancomycin 463 100 - 179 100 - 143 100 - 65 100 - 526 100 - Streptococcus viridans group Amoxicillin NT NT NT NT NT NT NT NT NT NT NT NT 268 92.9 0.7 Cefepime 23 95.7 4.3 NT NT NT 12 66.7 33.3 NT NT NT NT NT NT Cefotaxime 434 83.6 11.1 101 92.1 4.0 31 90.3 9.7 75 97.3 2.7 56 94.6 0 Ceftriaxone 678 87.3 7.7 130 89.2 3.8 99 81.8 18.2 40 97.5 2.5 <10 NA NA Clarithromycin 34 52.9 38.2 21 76.2 19.0 21 71.4 23.8 <10 NA NA NT NT NT Erythromycin 959 57.2 37.7 289 71.6 23.2 192 64.6 32.8 796 88.1 9.2 626 59.9 31.6 Levofloxacin 331 96.1 2.7 <10 NA NA 16 87.5 0 93 89.2 4.3 <10 NA NA Penicillin 1,047 63.7 6.2 303 79.2 0 61 78.7 8.2 <10 NA NA 452 69.0 3.1 Vancomycin 1,095 100 - 276 100 - 180 100 - 277 100 - 580 100 - a b c NCCLS breakpoints were used for all countries, except France (CA-SFM) Not tested Breakpoints do not currently exist to interpret as S (susceptible) or R (resistant) 25% to 55% over the period 1997 to 2001 [18]. Vancomy- cillin susceptibility have less effect on the activity of third- cin resistance rates of 2.8% for E. faecalis and 24.2% for E. generation cephalosporins such as ceftriaxone with 3.4% faecium are some of the highest rates recorded in Europe, and cefotaxime with 4.6% resistance, respectively. S. pyo- although still modest compared to rates experienced in genes was fully susceptible to penicillin; however, 11.8% the United States; however, teicoplanin was more active of isolates were resistant to clarithromycin and 23.7% with 2.4% and 13.7% of strains being resistant, respec- were resistant to erythromycin. tively. Pneumococcal resistance to penicillin and erythro- mycin was 7.6% and 28.1%, respectively. The impact of The proportion of ESBLs was slightly higher in Italy with alterations in penicillin-binding protein that reduce peni- E. coli showing ceftazidime non-susceptibility of 5.3%, Page 6 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 4: Enterobacteriaceae isolated from ICU patients during 2000–2002 United States Canada Italy Germany France Organism Agent Total n %S %R Total n %S %R Total n %S %R Total n %S %R Total n %S %R Escherichia coli Cefepime 10,356 98.1 1.5 207 98.1 1.9 1,426 98.1 1.4 2,830 98.6 1.2 4,358 98.9 0.6 Cefotaxime 9,086 96.5 2.2 3,231 96.3 2.5 1,748 94.5 3.8 5,828 97.8 1.8 9,362 98.8 0.6 Ceftazidime 14,574 95.3 3.0 4,438 97.7 1.6 2,548 94.7 3.7 3,924 97.9 1.6 9,164 97.8 1.2 Ceftriaxone 15,897 97.4 1.7 3,829 96.8 2.2 1,423 94.4 4.2 534 99.8 0.2 834 98.6 1.0 Ciprofloxacin 17,294 89.0 10.7 5,028 90.3 9.5 2,616 87.0 12.7 4,615 86.7 12.4 8,577 93.1 6.5 Gentamicin 20,581 92.4 6.5 6,654 92.8 5.3 2,650 92.2 6.6 4,825 94.3 5.2 9,442 95.4 4.2 Imipenem 15,353 100 0 3,386 100 0 2,254 100 0 5,172 100 0 8,994 100 0 Levofloxacin 14,920 88.2 11.6 776 85.1 13.9 496 86.5 13.3 3,137 88.2 11.0 NT NT NT Piperacillin- 13,573 93.1 3.6 4,305 95.1 2.4 1,879 95.8 2.4 5,637 93.6 3.4 7,255 95.4 1.1 tazobactam Trimethoprim- 20,296 79.2 20.7 6,737 84.6 15.3 2,440 75.0 24.9 5,598 73.1 26.6 9,028 78.2 21.1 sulfamethoxazole Klebsiella oxytoca Cefepime 1,476 96.2 3.3 19 100 0 255 99.6 0 566 96.8 2.7 478 97.1 0.4 Cefotaxime 1,324 92.7 4.7 486 94.2 4.5 230 96.5 1.7 1,117 93.8 4.4 865 96.3 0.8 Ceftazidime 1,909 91.7 7.0 661 94.9 4.1 361 83.4 15.2 749 95.3 4.5 870 98.3 0.5 Ceftriaxone 2,035 89.9 6.6 536 93.8 2.8 197 81.7 2.0 83 97.6 0 79 87.3 2.5 Ciprofloxacin 2,226 92.5 5.9 745 96.0 3.0 368 96.7 3.0 905 90.1 7.8 815 94.5 4.8 Gentamicin 2,569 89.9 8.3 857 95.0 4.9 366 89.6 3.0 1,016 98.2 1.2 865 97.1 2.4 Imipenem 2,061 100 0 516 100 0 337 100 0 1,062 100 0 845 100 0 Levofloxacin 1,754 93.3 3.4 159 96.9 1.3 133 97.0 3.0 560 94.6 3.2 NT NT NT Piperacillin- 1,801 82.7 13.9 624 91.2 7.1 313 81.8 11.2 1,113 78.9 18.1 742 88.3 10.4 tazobactam Trimethoprim- 2,467 92.5 7.5 863 96.3 3.6 308 95.1 4.9 1,084 93.7 6.3 802 94.1 5.7 sulfamethoxazole Klebsiella pneumoniae Cefepime 7,276 95.8 3.4 98 100 0 552 93.5 5.6 1,068 95.7 3.5 840 95.6 3.0 Cefotaxime 6,243 91.0 6.1 1,411 97.9 1.5 850 76.7 16.4 2,414 93.1 6.0 1,553 94.4 1.9 Ceftazidime 9,597 88.5 10.1 2,238 97.5 2.2 1,142 69.8 28.5 1,665 90.0 8.2 1,591 92.5 5.2 Ceftriaxone 10,337 92.7 4.7 1,736 97.9 1.1 816 75.2 15.0 166 98.8 0.6 112 86.6 5.4 Ciprofloxacin 11,089 89.9 8.4 2,484 91.8 7.2 1,190 88.2 9.9 2,128 85.4 9.4 1,473 89.5 8.7 Gentamicin 13,012 91.6 7.0 2,906 96.7 2.9 1,211 81.4 14.5 2,065 91.6 6.1 1,553 97.1 2.7 Imipenem 10,263 100 0 1,766 100 0 1,066 100 0 2,351 100 0 1,567 100 0 Levofloxacin 9,626 91.0 6.4 485 93.4 3.7 287 78.4 21.3 1,228 92.6 4.4 NT NT NT Piperacillin- 9,359 85.9 7.4 2,160 91.5 2.7 746 82.2 14.6 2,408 84.9 8.3 1,286 89.4 5.1 tazobactam Trimethoprim- 12,641 88.6 11.1 2,924 92.8 7.1 1,103 82.0 18.0 2,324 82.2 17.2 1,443 88.2 10.9 sulfamethoxazole Morganella morganii Cefepime 566 95.9 2.3 <10 NA NA 121 97.5 2.5 262 94.7 5.0 412 96.1 0.2 Cefotaxime 499 78.8 8.4 156 91.0 3.8 144 74.3 6.3 437 86.7 3.9 678 81.1 5.9 Ceftazidime 715 73.6 17.3 256 79.7 10.9 213 75.6 15.0 313 84.0 7.7 673 78.6 8.0 Ceftriaxone 806 91.1 2.2 219 96.3 1.4 125 91.2 3.2 22 86.4 0 57 84.2 5.3 Ciprofloxacin 841 78.1 20.7 292 94.2 4.5 220 87.3 9.5 344 97.7 2.0 634 88.6 8.5 Gentamicin 967 84.0 14.1 329 94.5 4.6 222 90.1 8.6 378 96.8 2.1 679 95.6 3.4 Imipenem 784 100 0 196 100 0 206 100 0 402 100 0 649 99.8 0 Levofloxacin 725 78.1 19.3 42 95.2 4.8 55 90.9 9.1 251 98.0 1.6 NT NT NT Piperacillin- 725 91.2 5.1 254 97.2 1.6 150 94.0 3.3 430 94.2 3.5 564 91.0 4.6 tazobactam Trimethoprim- 936 75.1 24.7 329 91.8 8.2 193 79.8 20.2 435 93.1 6.9 627 83.9 14.2 sulfamethoxazole Proteus mirabilis Cefepime 1,964 98.2 1.0 20 100 0 395 87.6 11.4 599 99.2 0.8 736 99.0 0.1 Cefotaxime 1,794 99.1 0.5 295 99.7 0 441 69.4 23.4 1,209 98.8 0.7 1,503 99.5 0.1 Ceftazidime 2,684 98.0 1.1 463 99.4 0.2 630 86.0 9.4 821 98.5 1.0 1,505 99.3 0.2 Ceftriaxone 3,034 99.4 0.3 392 99.5 0 385 80.5 13.8 77 98.7 0 72 100 0 Ciprofloxacin 3,169 85.2 12.7 504 95.2 4.6 657 70.6 22.7 980 92.9 5.1 1,424 90.9 6.8 Gentamicin 3,796 91.5 7.7 698 92.6 7.2 670 61.6 37.2 992 92.9 5.9 1,509 91.3 7.9 Imipenem 2,850 100 0 367 100 0 580 100 0 1,020 100 0 1,319 100 0 Levofloxacin 2,825 87.8 10.5 94 100 0 202 61.9 34.7 688 96.5 2.3 <10 NA NA Page 7 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 4: Enterobacteriaceae isolated from ICU patients during 2000–2002 (Continued) Piperacillin- 2,715 97.7 0.8 449 98.2 0.2 465 95.7 2.8 1,201 98.6 0.8 1,231 99.3 0.2 tazobactam Trimethoprim- 3,706 85.2 14.7 708 89.4 10.6 615 61.6 38.0 1,159 80.8 19.1 1,411 79.7 18.6 sulfamethoxazole Serratia marcescens Cefepime 3,653 96.7 2.3 52 96.2 1.9 497 96.8 2.2 546 94.1 3.5 509 98.6 0.2 Cefotaxime 3,134 87.0 5.7 670 92.8 2.7 470 79.6 9.8 951 84.0 7.5 809 81.5 3.3 Ceftazidime 4,718 89.7 7.9 1,113 95.2 3.0 738 81.4 13.3 851 89.7 7.5 812 94.7 3.0 Ceftriaxone 4,710 90.5 4.6 846 95.4 1.7 444 86.7 6.3 160 45.6 0 115 77.4 4.3 Ciprofloxacin 5,006 91.0 6.7 1,292 85.0 11.7 757 83.5 4.5 978 72.6 12.4 787 78.9 10.5 Gentamicin 5,905 92.9 5.9 1,313 94.6 5.2 758 97.4 2.1 665 92.9 6.3 808 91.6 6.6 Imipenem 4,960 100 0 880 100 0 727 100 0 1,018 100 0 805 100 0 Levofloxacin 4,356 94.3 4.2 264 92.4 4.2 266 95.5 1.5 595 87.6 6.6 <10 NA NA Piperacillin- 4,337 88.1 5.1 1,155 91.6 3.3 547 92.7 3.8 1,053 77.6 3.1 749 82.6 2.4 tazobactam Trimethoprim- 5,697 95.9 3.9 1,325 94.9 5.1 646 81.4 18.6 908 88.1 10.9 699 84.1 13.6 sulfamethoxazole a b c NCCLS breakpoints were used for all countries, except France (CA-SFM) Not tested Not applicable if <10 isolates were tested whereas K. pneumoniae and K. oxytoca demonstrated Overall the susceptibility rates for Gram-negative isolates 30.2% and 16.6% ceftazidime non-susceptibility, respec- from Canadian ICUs were higher than those in the other tively. Fluoroquinolone resistance rates among the Entero- four countries examined. A low rate of ESBLs was bacteriaceae, using ciprofloxacin as a marker, varied from reported, but there was variable activity of piperacillin- 3.0% for K. oxytoca to 22.7% for P. mirabilis, and 12.7% for tazobactam which showed >9% resistance among Kleb- E. coli. Thus, among Enterobacteriaceae, ciprofloxacin was siella spp. and S. marcescens tested. The rate of fluoroqui- generally less active than the third-generation nolone resistance was similar to those of other countries cephalosporin, ceftriaxone. P. aeruginosa and Acinetobacter with E. coli showing 13.9% levofloxacin resistance. spp. strains from Italian ICUs demonstrated significant Among Enterobacteriaceae, <10% of most species were resistance rates. Isolates of P. aeruginosa showed resistance resistant to third-generation cephalosporins tested with rates of >28% for all agents tested except piperacillin-tazo- the exception of ceftazidime and M. morganii. Resistance bactam. Thus empiric therapy for possible pseudomonal among P. aeruginosa and Acinetobacter spp. was generally infections will require combination therapy. Acinetobacter lower than in other countries apart from Germany. Only spp. showed a similar lack of susceptibility except to imi- piperacillin-tazobactam showed reliable activity against P. penem and meropenem (19.0% and 13.6% resistant). An aeruginosa (9% resistant), while resistance to all other increase in fluoroquinolone resistance in E. coli and K. agents was >19%. Acinetobacter spp. remained susceptible pneumoniae in bacteremic isolates from Italy was observed to only the carbapenems, imipenem and meropenem. during 1997–2001, with rates of 26.7% and 24%, respec- tively [9]. An increase in ureidopenicillin resistance was Comparison of the data from Canadian isolates with noted in P. aeruginosa isolates in Italy from 30% to 37% in those from the United States shows some significant dif- a 4-year period [9]. This study showed 22.0% piperacillin- ferences. This demonstrates the limitations of pooling tazobactam and 36.7% piperacillin resistance among ICU Canadian and United States data since the differences P. aeruginosa isolates. between the two regions, such as the rate of MRSA, may have some impact on empiric therapy. Data from the In Canada oxacillin-resistance among S. aureus was noted NNIS system has previously reported an increasing trend in 19.7% and coagulase-negative staphylococci in 79.4%. towards resistance within ICUs in the United States [19]. Vancomycin resistance was reported among 0.9% and Oxacillin resistance among staphylococci from ICUs in 14.5% of E. faecalis and E. faecium, respectively. The low- the United States was 52.3% and 84.2% for S. aureus and est rate of penicillin resistance in S. pneumoniae in this coagulase-negative species, respectively. study was noted from Canada at 7.1%; however, clarithro- mycin resistance was 30.4%. Ceftriaxone showed 0.7% This value is identical to that of S. aureus and very similar resistance whereas cefepime exhibited 12.0% resistance to the CNS data reported by the 1999 NNIS system. The among pneumococci from the ICU. NNIS highlighted a 37% increase in MRSA over the period Page 8 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 5: P. aeruginosa and Acinetobacter spp isolated from ICU patients during 2000–2002 United States Canada Italy Germany France Organism Agent Total n %S %R Total n %S %R Total n %S %R Total n %S %R Total n %S %R Acinetobacter Cefepime 5,162 43.8 40.2 97 67.0 23.7 475 17.9 73.7 623 74.2 10.8 857 28.0 40.3 species Cefotaxime 3,830 23.3 49.9 705 36.7 34.9 555 11.0 78.7 1,254 34.9 24.6 671 15.4 38.7 Ceftazidime 5,954 42.2 40.8 1,162 70.8 22.9 692 25.6 68.5 988 66.7 14.5 1,106 34.9 35.5 Ceftriaxone 4,709 16.3 55.9 874 32.4 28.7 452 8.8 72.6 104 42.3 11.5 81 9.9 51.9 Ciprofloxacin 5,808 39.7 58.0 1,156 72.1 25.9 686 21.1 76.7 1,126 74.8 22.9 1,038 37.7 61.2 Gentamicin 6,618 47.2 47.2 1,185 72.8 22.8 768 23.3 72.4 979 82.0 14.1 936 49.3 43.5 Imipenem 6,006 87.0 7.5 918 95.8 1.9 569 77.9 19.0 1,253 96.2 3.4 1,088 93.8 3.8 Levofloxacin 5,099 43.8 52.2 489 61.1 25.6 295 13.9 75.3 840 82.0 10.5 NT NT NT Meropenem 2,154 66.3 26.5 348 93.7 4.9 455 74.5 13.6 1,024 96.0 3.4 147 68.0 28.6 Piperacillin 4,658 35.4 45.9 959 66.5 19.5 635 19.5 69.9 1,171 59.7 12.9 805 35.0 50.3 Piperacillin- 3,429 53.6 28.5 903 70.7 23.1 425 35.1 46.4 1,225 81.8 7.5 878 74.5 10.5 tazobactam Trimethoprim- 5,697 51.4 48.4 1,155 74.8 25.2 750 44.1 55.7 1,234 83.6 15.6 93 45.2 52.7 sulfamethoxazole Pseudomonas aeruginosa Cefepime 20,220 72.5 12.4 371 73.3 12.4 5,056 58.9 28.9 3,483 80.3 7.8 7,967 52.6 16.2 Cefotaxime 11,283 9.2 50.4 1,836 13.3 47.5 4,181 6.0 70.7 2,689 7.7 52.2 NT NT NT Ceftazidime 26,353 71.2 17.4 6,036 73.7 13.4 7,640 56.7 31.3 5,141 76.2 14.9 8,547 70.2 14.9 Ceftriaxone 14,066 12.1 56.4 2,847 11.3 59.7 3,383 8.4 70.4 154 26.6 7.8 NT NT NT Ciprofloxacin 26,700 62.8 33.1 5,924 67.2 30.2 7,388 58.4 38.8 4,746 68.6 24.4 8,560 55.3 40.6 Gentamicin 29,268 69.4 21.5 5,951 72.2 15.9 7,522 52.2 41.7 3,913 74.0 14.3 7,327 44.0 46.1 Imipenem 26,076 73.5 22.1 3,775 77.9 18.2 7,057 59.7 27.8 4,412 70.5 19.0 8,575 69.5 21.4 Levofloxacin 21,059 62.7 31.7 713 56.8 33.5 2,427 44.9 51.0 2,953 68.0 23.9 NT NT NT Meropenem 7,540 76.0 18.2 1,266 80.3 14.5 4,082 57.3 32.7 4,351 77.8 13.8 1,818 81.1 6.4 Piperacillin 22,855 77.7 22.2 5,520 80.9 18.8 7,004 63.1 36.7 4,554 81.7 14.1 8,454 64.1 24.1 Piperacillin- 21,848 85.5 14.4 4,190 91.0 9.0 5,252 77.7 22.0 4,746 85.8 10.7 8,256 69.6 15.9 tazobactam Trimethoprim- 15,618 3.6 96.4 4,283 4.0 96.0 7,054 4.1 95.8 3,375 4.2 95.8 NT NT NT sulfamethoxazole a b NCCLS breakpoints were used for all countries, except France (CA-SFM) NT = not tested 1994–98 to 1999, but only a 2% increase among CNS non-susceptibility was higher in K. oxytoca 8.3%,K. pneu- strains [4]. Vancomycin resistance in the United States moniae 11.5%,S. marcescens 10.3% and M. morganii was observed in 4.5% of E. faecalis; however, over 76% E. 26.4%. These data are consistent with other recent reports faecium were vancomycin non-susceptible. [21]. Fluoroquinolone resistance was observed in all Enterobacteriaceae tested, in the US for example, resistance Although streptococci are uncommon ICU pathogens rates were as follows, using ciprofloxacin as a marker: E. they can be rapidly invasive and possibly fatal unless ade- coli 10.7%, K. oxytoca 5.9%, K. pneumoniae 8.4%, M. mor- quate therapeutic approaches are adopted. S. pneumoniae ganii 20.7%, P. mirabilis 12.7% and S. marcescens 6.7%. in the United States has acquired a range of resistance These data show increased fluoroquinolone resistance mechanisms with resistance to penicillin and the mac- compared with recent reports [21]. Jones et al. previously rolides, clarithromycin and erythromycin, being com- reported susceptibility data on ICU pathogens isolated mon, 20.2% and 25.5%–30.5% respectively. The newer over the period 1998–2001 [22]. generation cephalosporins, ceftriaxone, cefotaxime and cefepime showed good activity against pneumococci, Specifically, enteric bacteria showed changes over this 3.2%, 6.3% and 4.5% resistant, respectively. Less than time. Fluoroquinolone resistance doubled among E. coli 1.0% of isolates were resistant to levofloxacin. These data isolates from 3.3–5.5% to 10.8–11.4% [22]. This study are similar to other recent reports [20]. showed a generally higher level of activity among third- generation cephalosporins than other reports [23], with For Enterobacteriaceae which account for approximately ceftriaxone showing <10% resistance rates against most 30% of all isolates from ICU infections, the incidence of species tested. Piperacillin-tazobactam showed less con- putative ESBLs was low in E. coli, 4.7% but ceftazidime sistent activity with some species being >14% resistant, Page 9 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 e.g. Klebsiella spp.,P. aeruginosa, and Acinetobacter spp. such as ceftriaxone with vancomycin may be appropriate present significant therapeutic challenges in ICUs in the for bloodstream infections based upon the NNIS etiology United States. With the exception of cefepime, all other data from 1992–1999. tested antimicrobials demonstrated >12% resistance to P. aeruginosa, many considerably higher. Piperacillin-tazo- Conclusions bactam showed the next lowest resistance rate, 14.4%, The current study confirmed the emergence of fluoroqui- with all other agents having rates of 17% or higher. Non- nolone resistance among various Gram-negative species susceptibility to ciprofloxacin among P. aeruginosa was and staphylococci, which may be increasing due to the 37.2%, higher than in the Neuberger report. Sahm et al. heightened use of these drugs; however the reported ESBL reported a 10% increase in fluoroquinolone resistance rates among Enterobacteriaceae was lower than noted in among P. aeruginosa in the United States, whereas resist- other studies and appeared to be stable. The prevalence of ance emerged more slowly with the other classes of anti- MRSA, perhaps the most significant resistant hospital microbials tested [12]. Acinetobacter infections continue to pathogen, varied among the five countries and appeared present significant therapeutic challenges due to the to be increasing. Parenteral cephalosporins such as ceftri- extensive resistance mechanisms demonstrated by the axone and cefotaxime remained quite active against >25% resistance shown in Table 5. Only imipenem has Enterobacteriaceae. Up-to-date susceptibility data should any reliable activity against Acinetobacter spp. with an 87% be made available as rapidly as possible to physicians so susceptibility rate. that appropriate targeted empirical therapy can be insti- tuted, this approach can assist in maintaining the activity There are several implications of these data. It is essential of the current antimicrobials. While local surveillance that local surveillance programs be maintained in each studies remain crucial, national surveillance studies such country's ICU setting. The local data are vital to the formu- as this can provide an invaluable data source to provide lary committees as they select appropriate agents to treat guidance in formulary decision-making. infections. There are clear differences among the five countries studied in this report. Although the predomi- Authors Contributions nant pathogens are similar, ongoing surveillance is essen- MJ conceived the study, provided data interpretation and drafted the manuscript. DD analyzed the study data; JK tial to detect the emergence of resistant species. It is clear that certain classes of compounds are losing activity and DS provided expert microbiological analysis and against the ICU pathogens tested. For example, the fluor- interpretation of study data; RW provided clinical exper- oquinolones have reduced susceptibility among many tise in interpretation of data and drafting manuscript. All Gram-negative species as well as staphylococci; however, authors read and approved the final manuscript. the newer class members have enhanced activity against pneumococci. Advanced-generation cephalosporins have Acknowledgments We thank F. Hoffmann-La Roche Ltd., Basel, Switzerland for financial sup- variable activity, with ceftriaxone showing consistently port of this study. Additionally, we thank the many clinical microbiology lab- good activity against the Enterobacteriaceae and some sta- oratories around the world that contribute data to TSN Databases, phylococci. Ceftazidime has lost potency due to the emer- without whom such studies would not be possible. gence of ESBL enzymes and also has diminished activity against P. aeruginosa. Piperacillin-tazobactam is generally References active against P. aeruginosa in ICUs. The aminoglycoside, 1. Kollef MH, Fraser VJ: Antibiotic resistance in the Intensive Care gentamicin has shown continued activity against most Unit. Ann Intern Med 2001, 134:298-314. 2. CDC NNIS system: National nosocomial infections surveil- Enterobacteriaceae in all five countries, and modest activity lance (NNIS) system report, data summary from January against S. aureus but not against CNS strains. The gen- 1992-April issued August 2001. Amer J Infect Contr 2001, 29:400-421. Correction 2002, 30:74 tamicin susceptibility of P. aeruginosa ranged from 44.0% 3. NNIS system report Intensive Care Antimicrobial Resist- in France to 74.0% in Germany, whereas Acinetobacter spp ance Epidemiology (ICARE) Surveillance report, data sum- . showed more variable gentamicin susceptibility varying mary from January 1996 through December 1997. Amer J Infect Contr 1999, 27:279-284. from 23.3% in Italy to 82.0% in Germany. These local 4. Fridkin SK, Steward CD, Edwards JR, Pryor ER, McGowan JE, data should be considered when treating infections in the Archibald LK, Gaynes RP, Tenover FC: Surveillance of antimicro- ICU. bial use and antimicrobial resistance in United States hospi- tals: Project ICARE Phase 2. Project Intensive Care Antimicrobial Resistance Epidemiology (ICARE) Hospitals. Use of agents with anti-pseudomonal activity such as Clin Infec Dis 1999, 29:245-252. 5. Stephen J, Mutnick A, Jones RN: Assessment of pathogens and cefepime, piperacillin-tazobactam or the carbapenems resistance (R) patterns among intensive care unit (ICU) in should preferably be reserved for patient types or infec- North America (NA): initial report from the SENTRY anti- tions where this pathogen is present or risk factors exist, as microbial surveillance program (2001). Presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San per the ATS Community acquired-pneumonia guidelines Diego, CA 2002. Abstract C2-297 [24]. A combination of a third-generation cephalosporin Page 10 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 6. Vincent JL, Bihari DJ, Suter PM, Bruining HA, White J, Nicloas-Chaoin Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA MH, Wolff M, Spencer RC, Hemmer M: The prevalence of noso- 2002. Abstract C2-313 comial infection in intensive care units in Europe. Results of 24. Guidelines for the Management of Adults with Community- the European Prevalence of Infection in Intensive Care acquired Pneumonia. Am J Respir Crit Care Med 2001, (EPIC) Study. EPIC International Advisory Committee. J Amer Med Assoc 163:1730-1754. 1995, 274:639-644. 7. Hanberger H, Garcia-Rodriguez JA, Gobernado M, the French and Portuguese ICU Study Groups, et al.: Antibiotic susceptibility among aerobic Gram-negative bacilli in Intensive Care Units in 5 European countries. JAMA 1999, 281:67-71. 8. Garcia-Rodriguez JA, Jones RN, the MYSTIC study group: Antimi- crobial resistance in gram-negative isolates from European intensive care units: data from the Meropenem Yearly Sus- ceptibility Test Information Collection (MYSTIC) programme. J Chem 2002, 14:25-32. 9. Frank U, Jonas D, Lupke T, Ribeiro-Ayeh B, Schmidt-Eisenlohr E, Ruden H, Daschner FD, National Reference Centre Study Group on Antimicrobial Resistance: Antimicrobial susceptibility among nosocomial pathogens isolated in intensive care units in Germany. Eur J Clin Microbiol Infect Dis 2000, 19:888-891. 10. Fiel S: Guidelines and critical pathways for severe hospital- acquired pneumonia. Chest 2001, 119:412-418S. 11. Laupland KB, Zygun DA, Davies HD, Church DL, Louie TJ, Doig CJ: Incidence and risk factors for acquiring nosocomial urinary tract infection in the critically ill. J Crit Care 2002, 17:50-57. 12. Sahm DF, Draghi DC, Master RN, Thonsberry C, Jones ME, Kar- lowsky JA, Critchley IA: Pseudomonas aeruginosa antimicrobial resistance update: US resistance trends from 1998 to 2001. Presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA 2002. Abstract C2-305 13. Sahm DF, Marsilio MK, Piazza G: Antimicrobial resistance in key bloodstream bacterial isolates: electronic surveillance with the surveillance network database – USA. Clin Infect Dis 1999, 29:259-263. 14. National Committee for Clinical Laboratory Standards: Methods for dilution antimicrobial tests for bacteria that grow aerobi- cally; M7-A5. National Committee for Clinical Laboratory Standards, Wayne PA 52000. 15. Société Française de Microbiologie, Institut Pasteur: Comité de L' Antibiogramme De La Societé Française de Microbiologie Communiqué 2000-2001 (edition Janvier 2001). Société Française de Microbiologie, Institut Pasteur, 28, rue du Dr Roux, F 75724 Paris Cedex 15, France 2001. 16. National Committee for Clinical Laboratory Standards: Perform- ance standards for antimicrobial susceptibility testing; Elev- enth Informational Supplement, M100-S11. National Committee for Clinical Laboratory Standards, Wayne PA, USA 2001. 17. Hadziyannis E, Tuohy M, Thomas L, Procop GW, Washington JA, Hal GS: Screening and confirmatory testing for extended spec- trum β-lactamases (ESBL) in E. coli, Klebsiella pneumoniae and Klebsiella oxytoca clinical isolates. Diagn Microbiol Infect Dis 2000, 36:113-117. 18. Frank UK, Daschner FD, Leibovici L: Antimicrobial susceptibility patterns of bacteremic isolates from university hospitals in Denmark, Germany, Italy and Israel. Presented at the 42nd Inter- science Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA 2002. Abstract C2-301 19. Fridkin SK: Increasing prevalence of antimicrobial resistance in intensive care units. Crit Care Med 2001, 29:64-68. 20. Jones ME, Blosser-Middleton RS, Critchley IA, Thornsberry C, Kar- lowsky JA, Sahm DF: The activity of levofloxacin and compara- Publish with Bio Med Central and every tor agents against clinical isolates of Streptococcus scientist can read your work free of charge pneumoniae during 1999–2000. Chemotherapy 2002, 48:232-237. 21. Neuberger MM, Weinstein RA, Rydman R, Danzinger LH, Quinn JP: "BioMed Central will be the most significant development for Antibiotic resistance among Gram-negative bacilli in US disseminating the results of biomedical researc h in our lifetime." intensive care units. Implications for fluoroquinolone use. J Sir Paul Nurse, Cancer Research UK Amer Medical Assoc 2003, 289:885-888. 22. Jones ME, Draghi DC, Master RN, Thornsberry C, Karlowsky JA, Your research papers will be: Critchley IA, Sahm DF: Trends in resistance among Enterobac- available free of charge to the entire biomedical community teriaceae (isolated from in-patients and intensive-care unit patients in the US from 1998 to 2001. Presented at the 42nd Inter- peer reviewed and published immediately upon acceptance science Conference on Antimicrobial Agents and Chemotherapy, San Diego, cited in PubMed and archived on PubMed Central CA 2002. Abstract C2-311 23. Friedland I, Stinson L, Ikaiddi M, Harm S, Woods G: Resistance in yours — you keep the copyright Enterobacteriaceae: results of a multicenter US ICU surveil- BioMedcentral lance study (ISS), 1995-2000. Presented at the 42nd Interscience Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 11 of 11 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Clinical Microbiology and Antimicrobials Springer Journals

Emerging resistance among bacterial pathogens in the intensive care unit – a European and North American Surveillance study (2000–2002)

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Springer Journals
Copyright
Copyright © 2004 by Jones et al; licensee BioMed Central Ltd.
Subject
Biomedicine; Medical Microbiology; Infectious Diseases
eISSN
1476-0711
DOI
10.1186/1476-0711-3-14
pmid
15283864
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Abstract

Background: Globally ICUs are encountering emergence and spread of antibiotic-resistant pathogens and for some pathogens there are few therapeutic options available. Methods: Antibiotic in vitro susceptibility data of predominant ICU pathogens during 2000–2 were analyzed using data from The Surveillance Network (TSN) Databases in Europe (France, Germany and Italy), Canada, and the United States (US). Results: Oxacillin resistance rates among Staphylococcus aureus isolates ranged from 19.7% to 59.4%. Penicillin resistance rates among Streptococcus pneumoniae varied from 2.0% in Germany to as high as 20.2% in the US; however, ceftriaxone resistance rates were comparably lower, ranging from 0% in Germany to 3.4% in Italy. Vancomycin resistance rates among Enterococcus faecalis were ≤ 4.5%; however, among Enterococcus faecium vancomycin resistance rates were more frequent ranging from 0.8% in France to 76.3% in the United States. Putative rates of extended-spectrum β-lactamase (ESBL) production among Enterobacteriaceae were low, <6% among Escherichia coli in the five countries studied. Ceftriaxone resistance rates were generally lower than or similar to piperacillin-tazobactam for most of the Enterobacteriaceae species examined. Fluoroquinolone resistance rates were generally higher for E. coli (6.5% – 13.9%), Proteus mirabilis (0–34.7%), and Morganella morganii (1.6– 20.7%) than other Enterobacteriaceae spp (1.5–21.3%). P. aeruginosa demonstrated marked variation in β-lactam resistance rates among countries. Imipenem was the most active compound tested against Acinetobacter spp., based on resistance rates. Conclusion: There was a wide distribution in resistance patterns among the five countries. Compared with other countries, Italy showed the highest resistance rates to all the organisms with the exception of Enterococcus spp., which were highest in the US. This data highlights the differences in resistance encountered in intensive care units in Europe and North America and the need to determine current local resistance patterns by which to guide empiric antimicrobial therapy for intensive care infections. Page 1 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 each country. These surveillance programs help to main- Background Antimicrobial resistance has emerged as an important fac- tain current knowledge of susceptibilities and relevant tor in predicting outcomes and overall resource use after treatment options. infections in intensive care units (ICU) [1]. Globally ICUs are encountering emergence and spread of antibiotic- Methods resistant pathogens. For some pathogens there are few TSN Database – United States and Europe therapeutic options available, e.g., vancomycin-resistant TSN is a queriable, real-time database that electronically Enterococcus faecium. Awareness of these problems has assimilates daily antimicrobial susceptibility testing and been underscored with data from a number of surveil- patient demographic data from a network of geographi- lance studies aimed at improving the use of empiric ther- cally dispersed laboratories in the United States (283 hos- apy. In the United States there have been several national pital sites), France (63 hospital sites), Germany (169 programs, which have focused on both the etiology of hospital sites), Italy (48 hospital sites) and Canada (87 infections and resistance patterns of nosocomial or ICU hospital sites) [12]. infections including the National Nosocomial Infections Surveillance (NNIS) [2] and more recently an ICU-specific Laboratories included in TSN include those servicing uni- study examining the epidemiology of antimicrobial resist- versity, community, and private hospitals with bed sizes ance, Project ICARE [3,4]. Stephen et al. collected strains ranging from 100 to >1000 beds. Routine diagnostic sus- from 28 ICUs from across the United States as part of the ceptibility testing results are collected daily from each par- SENTRY Antimicrobial Surveillance Program in 2001 [5]. ticipating laboratory. The methods used by these laboratories include VITEK (bioMérieux, St. Louis, MO), European data on the antimicrobial resistance of ICU MicroScan (Dade-Microscan, Sacramento, CA), Sceptor pathogens has also been collected in several recent surveil- and Pasco MIC/ID (Becton Dickinson, Sparks, MD) and lance studies. A large prevalence survey of nosocomial Etest (AB Biodisk, Solna, Sweden), as well as manual infections in ICUs in 17 countries was published in 1995 broth microdilution MIC, disk diffusion and agar dilu- [6], and more recently a number of nation-specific surveys tion. TSN reflects current testing in participant laborato- were reported [7-9]. Several key points emerge: first, anti- ries and represents the data reported to physicians from microbial resistance among ICU pathogens is generally the respective laboratories [13]. increasing, but variations do exist among different coun- tries, probably due to individual antimicrobial use pat- Although some European countries have alternate break- terns; second, when new medical practices and alternative points, all data forwarded to TSN Databases are derived antimicrobials are introduced changes in the dominant from hospitals that utilized NCCLS standards and defini- microbial etiologies may emerge prompting novel tions (United States, Canada, Italy, and Germany) [14] or empiric selections; and third, the standards of hygiene the Comité de L'Antibiogramme de La Societé Français de and infection control also vary across countries. Finally, Microbiologie (France) [15] thus standardizing datasets. appropriate therapy of ICU infections directed by local Results were interpreted as susceptible, intermediate (if resistance data can have significant consequences for both available), or resistant in TSN, based upon the NCCLS patient and the healthcare system. It is against this back- interpretative guidelines in place during 2001 [16]. In ground that local resistance surveillance programs are of addition, a series of quality-control filters (i.e., critical rule most value in developing appropriate therapeutic guide- sets) were used in TSN to screen susceptibility test results lines for specific infections and patient types. For exam- for patterns indicative of testing error and suspect results ple, the recent modification to the American Thoracic were removed from analysis for laboratory confirmation. Society guidelines for the treatment of hospital-acquired In TSN, any result from the same patient with the same pneumonia [10] considered contemporary resistance organism identification and the same susceptibility pat- data. Local surveillance data can be applied to other infec- tern received within five days was considered a repeat cul- tions to assist in local formulary policy such as those gov- ture and was counted only once in the database. erning treatment of nosocomial urinary tract infections Bacterial species and antimicrobials tested [11]. For this study, data from TSN results for each individual This study using TSN program reports the antimicrobial database from January 1, 2000 through to December 31, resistance profiles of bacterial isolates from ICU patients 2002 were included in the analysis to determine the pro- in five countries during the period 2000–2002. The rele- portion of species and their susceptibility to antimicrobial vance of these recent nation-specific data will be discussed agents commonly tested in clinical laboratories through- on a country-by-country basis, as part of improving and out the participating regions. Only isolates derived from updating empiric therapeutic approaches to specific path- patients located in hospital ICUs were considered in the ogens causing infections in the ICU setting according to analysis. Gram-positive species included in the analysis Page 2 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 1: Incidence of pathogens isolated from ICU patients by country (%) United States Canada Italy Germany France Organism Incidence (%) Organism Incidence (%) Organism Incidence (%) Organism Incidence (%) Organism Incidence (%) a a 1 S. aureus 20.2 S. aureus 17.4 P. aeruginosa 22.3 CNS 16.4 S. aureus 17.2 b a CNS 15.9 CNS 16.1 CNS 18.7 S. aureus 13.6 CNS 16.7 P. aeruginosa 13.1 E. coli 12.6 S. aureus 18.1 E. coli 12.3 E. coli 15.5 E. coli 9.2 P. aeruginosa 11.3 E. coli 7.7 P. aeruginosa 10.8 P. aeruginosa 13.8 K. pneumoniae 5.8 Enterococcus spp 7.6 E. faecalis 3.9 Enterococcus spp 7.4 S. pneumoniae 3.3 Enterococcus spp 5.4 K. pneumoniae 5.5 K. pneumoniae 3.5 K. pneumoniae 5.4 E. cloacae 3.3 E. cloacae 4.3 E. cloacae 4.2 Enterococcus spp 3.3 E. cloacae 4.7 E. faecalis 3.0 E. faecalis 3.7 S. marcenscens 2.5 E. cloacae 2.6 E. faecalis 4.3 K. pneumoniae 2.7 S. marcescens 2.7 H. influenzae 2.1 S. marcescens 2.2 P. mirabilis 2.6 P. mirabilis 2.5 A. baumanii 2.6 E. faecalis 2.1 P. mirabilis 1.9 K. oxytoca 2.4 Enterococcus spp 2.3 Enterobacteriaceae 29.5 Enterobacteriaceae 33.0 Enterobacteriaceae 30.2 Enterobacteriaceae 36.0 Enterobacteriaceae 32.1 (all species (all species (all species (all species (all species combined) combined) combined) combined) combined) Total (n) 26,624 Total (n) 54,445 Total (n) 34,609 Total (n) 48,385 Total (n) 62,459 a b Proportion of S. aureus testing as MRSA was USA (52.3%), Canada (19.7%), Italy (59.4%), Germany (21.0%), and France (40.6%) CNS = Coagulase-negative staphylococci Enterobacteriaceae includes all species of genera occurring at >0.1% were comprised of S. aureus, coagulase negative staphylo- Tables 2,3,4,5 show the antimicrobial susceptibility pro- cocci, Enterococcus faecalis,Enterococcus faecium, Streptococ- files of various Gram-positive and Gram-negative patho- cus pyogenes, Streptococcus pneumoniae and viridans group gens isolated from ICU patients against a range of relevant streptococci. Gram-negative species studied comprised antimicrobials. the predominantly encountered enteric species (Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Specifically notable susceptibility patterns include the Proteus mirabilis, Morganella morganii and Serratia vancomycin susceptibility of all strains of staphylococci. marcescens), and Pseudomonas aeruginosa and Acinetobacter Generally, there was a low proportion of vancomycin spp. resistant E. faecalis <5%, whereas vancomycin-resistant E. faecium was more prevalent ranging from 0.8% in France The antibiotics studied are listed in Tables 2,3,4,5. Among to 76.3% in the United States, with a wide inter-country E. coli, putative ESBL production was defined as those iso- variation (Table 2). Penicillin resistance rates varied lates that were intermediate or resistant (non-susceptible) among S. pneumoniae, from 2.0% in Germany to 20.2% in to ceftazidime [17]. Given the large number of isolate the US with concurrent ceftriaxone resistance rates of 0% results included in the majority of analyses in this study, in Germany to 3.4% in Italy (Table 3). statistical analysis was not performed, as even subtle dif- ferences in percent resistance (<1%) to an antimicrobial β-lactam activity was assessed by comparing four different agent for any time period or demographic parameters cephalosporins and a β-lactam/β-lactamase inhibitor would be reported as highly significant (P <0.001). combination, piperacillin-tazobactam. Overall, the puta- tive production of ESBLs among E. coli was low, <6%, but Results ceftazidime resistance was reported at higher rates in K. In vitro susceptibility data from over 220,000 isolates pneumoniae and S. marcescens, with the highest rates seen from ICUs in five countries over the period 2000–2002 in M. morganii, from 16.0% in Germany to 26.4% in the were assimilated. The most frequent species isolated from United States (Table 4). Among the gram-negative organ- infections in the ICU was S. aureus, being most common isms tested, ceftriaxone resistance rates were usually lower in three of the five countries (Table 1). The oxacillin resist- than ceftazidime, with the exception among P. aeruginosa ance rates among S. aureus varied markedly across coun- and Acinetobacter spp. Cefepime, a fourth generation tries from 19.7% in Canada to 59.5% in Italy. E. coli cephalosporin with anti-pseudomonal activity was also (7.7%–15.5%) and P. aeruginosa (10.8%–22.3%) were more active than ceftazidime (Table 5). Against the Entero- the most frequent Gram-negative organisms encountered. bacteriaceae, the β-lactam combination agent piperacillin- The Gram-positive genus Enterococcus, either as E. faecalis, tazobactam was generally less active than ceftriaxone. E. faecium or non-speciated isolates accounted for <10% These species showed a wide variation in fluoroquinolone of isolates in most countries with E. faecalis being the most susceptibility among both species and countries. Gen- common species <4.3%. Community-acquired respira- tamicin resistance rates among the Enterobacteriaceae var- tory pathogens such as Streptococcus pneumoniae and Hae- ied from 1.2% among K. oxytoca from Germany to 37.2% mophilus influenzae were relatively uncommon in all five in P. mirabilis from Italy. Ciprofloxacin resistance rates countries. among E. coli ranged from 6.5% in France to 12.7% in Page 3 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 2: S. aureus, Coagulase-negative staphylococci, E. faecalis, and E. faecium isolated from ICU patients during 2000–2002 United States Canada Italy Germany France Organism Agent Total n %S %R Total n %S %R Total n %S %R Total n %S %R Total n %S %R Staphylococcus Ampicillin 19,703 6.7 93.3 3,792 12.6 87.4 1,665 5.6 94.4 2,867 16.2 83.8 15 6.7 93.3 aureus b c> Cefepime 1,260 52.9 46.9 NT NT NT 304 15.8 84.2 483 80.5 17.0 <10 NA NA Cefotaxime 6,898 50.2 49.7 220 55.5 44.5 671 36.4 63.6 729 92.0 8.0 490 63.9 36.1 Ceftriaxone 5,914 45.6 54.3 153 69.3 30.7 1,048 28.1 71.8 220 88.6 11.4 23 73.9 26.1 Ciprofloxacin 24,350 47.4 51.0 5,958 74.5 24.1 4,600 39.7 58.6 5,243 73.4 26.1 316 57.0 40.5 Gentamicin 35,034 85.6 13.7 6,641 89.4 10.3 5,531 40.9 58.0 5,735 90.0 9.7 10,100 90.4 9.4 Oxacillin 44,939 47.7 52.3 10,105 80.3 19.7 6,147 40.6 59.4 6,475 79.0 21.0 10,512 59.4 40.6 Teicoplanin NT NT NT NT NT NT 5,868 100 0 4,632 99.8 0.2 8,232 100 0 Vancomycin 43,245 100 0 7,882 100 0 5,937 100 0 5,276 100 0 9,453 100 0 Staphylococcus aureus OSSA Ampicillin 9,047 14.5 85.5 3,055 15.7 84.3 741 12.6 87.4 2,414 19.3 80.7 10 0 100 Cefepime 672 99.1 0.4 NT NT NT 49 98.0 2.0 387 99.5 0.3 NT NT NT Cefotaxime 3,451 99.7 0.2 122 100 0 244 100 0 653 100 0 312 100 0 Ceftriaxone 2,707 99.5 0.2 106 100 0 295 99.0 0.3 194 100 0 16 100 0 Ciprofloxacin 11,827 91.2 6.5 4,692 93.5 4.8 1,902 91.4 4.9 4,171 91.4 8.0 188 90.4 6.4 Gentamicin 16,951 98.3 1.4 5,384 98.1 1.8 2,223 95.1 4.5 4,527 98.4 1.5 5,958 99.4 0.5 Oxacillin 21,416 100 0 8,110 100 0 2,495 100 0 5,115 100 0 6,244 100 0 Teicoplanin NT NT NT NT NT NT 2,402 100 0 3,593 99.9 0.1 5,018 100 0 Vancomycin 20,110 100 0 6,046 100 0 2,430 100 0 4,002 100 0 5,580 100 0 Staphylococcus aureus ORSA Ampicillin 10,656 0 100 737 0 100 924 0 100 453 0 100 <10 NA NA Cefepime 588 0 100 NT NT NT 255 0 100 96 4.2 84.4 <10 NA NA Cefotaxime 3,447 0.6 99.3 98 0 100 427 0 100 76 23.7 76.3 178 0.6 99.4 Ceftriaxone 3,207 0 100 47 0 100 753 0.3 99.7 26 3.8 96.2 <10 NA NA Ciprofloxacin 12,523 6.1 93.1 1,266 3.9 95.5 2,698 3.3 96.4 1,072 3.3 96.6 128 7.8 90.6 Gentamicin 18,083 73.7 25.2 1,257 52.0 46.8 3,308 4.5 94.0 1,208 58.7 40.5 4,142 77.5 22.2 Oxacillin 23,523 0 100 1,995 0.2 99.8 3,652 0 100 1,360 0 100 4,268 0 100 Teicoplanin NT NT NT NT NT NT 3,466 100 0 1,039 99.7 0.3 3,214 100 0 Vancomycin 23,135 100 0 1,836 100 0 3,507 100 0 1,274 100 0 3,873 100 0 Staphylcoccus species, coagulase- negative Ampicillin 16,288 5.7 94.3 3,533 6.3 93.7 2,142 10.6 89.4 4,075 8.1 91.9 <10 NA NA Cefepime 991 11.8 88.1 <10 NA NA 116 0 100 625 11.0 73.1 <10 NA NA Cefotaxime 5,538 17.7 82.3 240 17.9 82.1 335 16.7 83.3 625 37.4 62.4 174 28.7 69.0 Ceftriaxone 3,471 14.8 84.8 116 22.4 77.6 512 11.7 88.3 412 25.0 74.8 <10 NA NA Ciprofloxacin 18,829 40.2 58.3 5,366 44.4 54.7 5,102 42.7 54.0 6,197 29.5 67.6 198 44.4 53.0 Gentamicin 27,248 51.5 38.1 5,571 40.6 47.3 5,241 33.8 60.7 6,848 41.5 51.7 9,422 46.8 51.5 Oxacillin 35,135 15.8 84.2 9,172 20.6 79.4 5,961 15.2 84.8 7,442 18.6 81.4 9,884 30.1 69.9 Teicoplanin NT NT NT NT NT NT 5,797 93.7 2.4 5,096 95.6 0.7 7,670 84.6 3.1 Vancomycin 34,424 100 0 8,239 100 0 5,937 100 0 6,953 100 0 8,300 100 0 Staphylcoccus species, coagulase- negative Oxacillin Ampicillin 2,582 35.7 64.3 638 34.6 65.4 437 51.7 48.3 824 39.6 60.4 <10 NA NA susceptible Cefepime 117 100 0 NT NT NT NT NT NT <10 NA NA NT NT NT Cefotaxime 978 99.5 0.2 42 100 0 56 100 0 128 100 0 54 92.6 0 Ceftriaxone 523 98.3 0.4 26 100 0 59 100 0 103 100 0 <10 NA NA Ciprofloxacin 2,844 82.4 16.6 988 91.8 7.6 779 87.7 10.1 1,103 89.5 9.2 78 83.3 14.1 Gentamicin 4,424 93.5 4.2 1,068 91.9 5.3 698 94.3 5.3 1,263 96.5 2.7 2,822 93.9 5.4 Oxacillin 5,565 100 0 1,886 99.9 0.1 904 100 0 1,383 100 0 2,980 100 0 Teicoplanin NT NT NT NT NT NT 890 99.1 0.3 691 98.4 0.3 2,454 95.8 0.2 Vancomycin 5,240 100 0 1,587 100 0 897 100 0 981 100 0 2,467 100 0 Staphylcoccus species, coagulase- negative Oxacillin resistant Ampicillin 13,706 0.1 99.9 2,895 0 100 1,705 0 100 3,251 0.2 99.8 <10 NA NA Cefepime 874 0 99.9 <10 NA NA 116 0 100 624 10.9 73.2 <10 NA NA Page 4 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 2: S. aureus, Coagulase-negative staphylococci, E. faecalis, and E. faecium isolated from ICU patients during 2000–2002 (Continued) Cefotaxime 4,560 0.1 99.9 198 0.5 99.5 279 0 100 497 21.3 78.5 120 0 100 Ceftriaxone 2,948 0 99.8 90 0 100 453 0.2 99.8 309 0.0 99.7 <10 NA NA Ciprofloxacin 15,985 32.7 65.8 4,378 33.7 65.3 4,323 34.7 61.9 5,094 16.5 80.2 120 19.2 78.3 Gentamicin 22,824 43.3 44.7 4,503 28.5 57.3 4,543 24.5 69.2 5,585 29.1 62.8 6,600 26.6 71.3 Oxacillin 29,570 0 100 7,286 0 100 5,057 0 100 6,059 0 100 6,904 0 100 Teicoplanin NT NT NT NT NT NT 4,907 92.7 2.8 4,405 95.1 0.8 5,216 79.3 4.5 Vancomycin 29,184 100 0 6,652 100 0 5,040 100 0 5,972 100 0 5,833 100 0 Enterococcus faecalis Ampicillin 7,865 98.8 1.2 1,000 99.4 0.6 1,289 95.3 4.7 1,902 99.6 0.4 1,183 99.5 0.2 Ciprofloxacin 3,311 56.9 38.7 625 45.3 50.4 1,159 64.0 31.1 2,012 39.7 39.5 559 78.5 17.0 Gentamicin 5,503 65.1 34.8 706 63.0 36.8 1,156 62.9 37.1 965 64.8 35.2 1,563 63.6 13.4 (HL Testing) Teicoplanin NT NT NT <10 NA NA 1,248 97.1 2.4 1,294 99.7 0.2 1,747 99.9 0.1 Vancomycin 7,656 95.1 4.5 1,005 98.3 0.9 1,303 96.7 2.8 1,636 99.4 0.3 1,811 99.7 0.2 Enterococcus faecium Ampicillin 3,896 9.7 90.3 383 17.2 82.8 260 21.5 78.5 481 12.3 87.7 151 41.7 49.7 Ciprofloxacin 1,846 5.3 92.5 221 10.9 85.5 234 10.3 77.4 591 6.9 73.9 66 21.2 39.4 Gentamicin 2,512 57.5 42.5 291 59.5 40.5 223 67.7 32.3 349 60.2 39.8 263 65.4 12.2 (HL Testing) Teicoplanin 23 8.7 87.0 <10 NA NA 234 86.3 13.7 517 97.9 2.1 266 99.6 0.4 Vancomycin 4,066 23.2 76.3 415 85.1 14.5 264 75.4 24.2 628 93.9 4.8 247 98.4 0.8 a b c NCCLS breakpoints were used for all countries, except (CA-SFM) Not tested Not applicable if <10 isolates were tested Italy. Variable fluoroquinolone resistance rates among S. cefepime were the most active agents, based on suscepti- marcescens were also demonstrated, with a range of resist- bility, against P. aeruginosa in Germany. Conversely, ceftri- ance from 4.5% in Italy to 12.4% in Germany. axone and imipenem were the most active agents, based on susceptibility, against Klebsiella spp., which account for almost 8% of ICU isolates. Discussion Data derived from international surveillance studies, such as those presented here, can provide a unique contempo- Staphylococcal species from French ICU isolates showed a rary perspective on the susceptibility of commonly high proportion of oxacillin resistance, 40.6% and 69. 9% encountered organisms to commonly used antibiotics. of S. aureus and coagulase-negative staphylococci spp., Such surveillance systems play a crucial role in detecting respectively. S. pneumoniae showed penicillin resistance of emerging trends in resistance. Comparisons of these with 17.9%, higher than the other four countries, although the data of other recent surveillance programs show the wide activity of third-generation cephalosporins, ceftriaxone variations in susceptibility profiles and the need for ongo- and cefotaxime, showed only 0.6% and 0.8% resistance, ing unit-specific surveys. respectively. Despite a lower ceftazidime susceptibility breakpoint compared to NCCLS standards (MIC 4 µg/ml In Germany the prevalence of resistance among gram-pos- instead of 8 µg/ml) putative ESBL expression were slightly itive organisms remained comparatively low with an inci- lower in France than in Germany in 2000–2002. Ceftazi- dence of 21% MRSA. In 2000, Frank et al. reported that dime non-susceptibility rates among E. coli, K. oxytoca, 96% of German isolates of S. marcescens and M. morganii and P. mirabilis were ≤ 2.2%; however, ceftazidime non- were susceptible to ceftazidime, yet in this study we found susceptibility rates among K. pneumoniae, M. morganii and 89.7% and 84.0%, respectively [9]. A similar decrease in S. marcescens were 7.5%, 21.4%, and 5.3%, respectively. activity was noted with E. coli and ciprofloxacin between Imipenem was active against all Enterobacteriaceae. Against the two studies, 91% in 1996–1997 compared with P. aeruginosa and Acinetobacter spp., imipenem resistance 86.7% in this study. Marked decreases in susceptibility of rates were 21.4% and 3.8%, respectively. Previously, a P. aeruginosa in Germany were also evident, with no agent lower imipenem resistance of 24% among French isolates showing >85.8% susceptibility (piperacillin-tazobactam) of P. aeruginosa was reported [7]. compared with most agents having 85%–94% susceptibil- ity in 1996–1997. Changes of 15–20% have been Among the Italian isolates of staphylococci, oxacillin reported with ceftazidime, imipenem, ciprofloxacin and resistance occurred in 59.4% of S. aureus and 84.8% of meropenem, while piperacillin-tazobactam has shown coagulase-negative isolates. This MRSA rate was similar to the smallest decrease in susceptibility with <6% over the that reported by Frank et al. from bacteremic isolates in 4-year period. Piperacillin plus or minus tazobactam and Italy; however, they reported an increase in MRSA from Page 5 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 3: S. pneumoniae, S. pyogenes, S. agalactiae, and Viridans group streptococci isolated from ICU patients during 2000–2002 United States Canada Italy Germany France Organism Agent Total n %S %R Total n %S %R Total n %S %R Total n %S %R Total n %S %R Streptococcus Amoxicillin 120 91.7 2.5 31 100 0 60 93.3 6.7 17 100 0 1,328 71.2 2.3 pneumoniae b c Cefepime 22 90.9 4.5 25 60.0 12.0 66 90.9 7.6 NT NT NT <10 NA NA Cefotaxime 1,571 82.2 6.3 145 93.8 0.7 108 93.5 4.6 63 100 0 1,181 77.1 0.8 Ceftriaxone 2,373 88.3 3.2 145 91.7 0.7 145 91.7 3.4 29 100 0 544 80.1 0.6 Clarithromycin 184 71.7 25.5 56 69.6 30.4 90 64.4 31.1 <10 NA NA NT NT NT Erythromycin 3,029 67.9 30.5 539 78.5 20.8 313 69.6 28.1 405 88.6 9.4 1,567 59.0 38.8 Levofloxacin 2,133 99.1 0.4 356 98.6 1.1 174 98.3 0.6 340 99.4 0.3 62 98.4 1.6 Penicillin 3,096 51.5 20.2 325 59.1 7.1 198 77.3 7.6 102 96.1 2.0 1,387 45.5 17.9 Vancomycin 2,865 100 - 271 100 - 231 100 - 190 100 - 1,479 100 - Streptococcus pyogenes Amoxicillin NT NT NT NT NT NT NT NT NT NT NT NT 58 100 0 Cefepime <10 NA NA NT NTNT NT NTNT NT NTNT NT NTNT Cefotaxime 32 100 - 29 100 - <10 NA NA 11 100 - 30 100 - Ceftriaxone 75 100 - <10 NA NA <10 NA NA <10 NA NA <10 NA NA Clarithromycin 19 84.2 5.3 <10 NA NA 17 88.2 11.8 NT NT NT NT NT NT Erythromycin 118 92.4 6.8 102 81.4 11.8 59 74.6 23.7 63 84.1 11.1 170 82.9 14.7 Levofloxacin 71 97.2 1.4 <10 NA NA <10 NA NA 61 77.0 4.9 NT NT NT Penicillin 140 100 - 97 100 - 58 100 - 64 100 - 139 100 - Vancomycin 121 100 - 42 100 - 12 100 - 34 100 - 162 100 - Streptococcus agalactiae Amoxicillin NT NT NT NT NT NT NT NT NT NT NT NT 165 100 0 Cefepime 28 100 - NT NT NT <10 NA NA NT NT NT NT NT NT Cefotaxime 71 100 - 17 100 - 24 100 - 50 100 - 50 100 - Ceftriaxone 184 100 - <10 NA NA 38 100 - 37 100 - <10 NA NA Clarithromycin 21 81.0 9.5 <10 NA NA 21 71.4 28.6 NT NT NT <10 NA NA Erythromycin 489 76.3 21.7 222 82.9 14.9 121 77.7 18.2 192 83.9 10.9 588 79.9 16.2 Levofloxacin 333 97.9 1.2 <10 NA NA 51 98.0 0 180 91.1 1.7 173 99.4 0 Penicillin 518 100 - 226 100 - 145 100 - 184 100 - 369 100 - Vancomycin 463 100 - 179 100 - 143 100 - 65 100 - 526 100 - Streptococcus viridans group Amoxicillin NT NT NT NT NT NT NT NT NT NT NT NT 268 92.9 0.7 Cefepime 23 95.7 4.3 NT NT NT 12 66.7 33.3 NT NT NT NT NT NT Cefotaxime 434 83.6 11.1 101 92.1 4.0 31 90.3 9.7 75 97.3 2.7 56 94.6 0 Ceftriaxone 678 87.3 7.7 130 89.2 3.8 99 81.8 18.2 40 97.5 2.5 <10 NA NA Clarithromycin 34 52.9 38.2 21 76.2 19.0 21 71.4 23.8 <10 NA NA NT NT NT Erythromycin 959 57.2 37.7 289 71.6 23.2 192 64.6 32.8 796 88.1 9.2 626 59.9 31.6 Levofloxacin 331 96.1 2.7 <10 NA NA 16 87.5 0 93 89.2 4.3 <10 NA NA Penicillin 1,047 63.7 6.2 303 79.2 0 61 78.7 8.2 <10 NA NA 452 69.0 3.1 Vancomycin 1,095 100 - 276 100 - 180 100 - 277 100 - 580 100 - a b c NCCLS breakpoints were used for all countries, except France (CA-SFM) Not tested Breakpoints do not currently exist to interpret as S (susceptible) or R (resistant) 25% to 55% over the period 1997 to 2001 [18]. Vancomy- cillin susceptibility have less effect on the activity of third- cin resistance rates of 2.8% for E. faecalis and 24.2% for E. generation cephalosporins such as ceftriaxone with 3.4% faecium are some of the highest rates recorded in Europe, and cefotaxime with 4.6% resistance, respectively. S. pyo- although still modest compared to rates experienced in genes was fully susceptible to penicillin; however, 11.8% the United States; however, teicoplanin was more active of isolates were resistant to clarithromycin and 23.7% with 2.4% and 13.7% of strains being resistant, respec- were resistant to erythromycin. tively. Pneumococcal resistance to penicillin and erythro- mycin was 7.6% and 28.1%, respectively. The impact of The proportion of ESBLs was slightly higher in Italy with alterations in penicillin-binding protein that reduce peni- E. coli showing ceftazidime non-susceptibility of 5.3%, Page 6 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 4: Enterobacteriaceae isolated from ICU patients during 2000–2002 United States Canada Italy Germany France Organism Agent Total n %S %R Total n %S %R Total n %S %R Total n %S %R Total n %S %R Escherichia coli Cefepime 10,356 98.1 1.5 207 98.1 1.9 1,426 98.1 1.4 2,830 98.6 1.2 4,358 98.9 0.6 Cefotaxime 9,086 96.5 2.2 3,231 96.3 2.5 1,748 94.5 3.8 5,828 97.8 1.8 9,362 98.8 0.6 Ceftazidime 14,574 95.3 3.0 4,438 97.7 1.6 2,548 94.7 3.7 3,924 97.9 1.6 9,164 97.8 1.2 Ceftriaxone 15,897 97.4 1.7 3,829 96.8 2.2 1,423 94.4 4.2 534 99.8 0.2 834 98.6 1.0 Ciprofloxacin 17,294 89.0 10.7 5,028 90.3 9.5 2,616 87.0 12.7 4,615 86.7 12.4 8,577 93.1 6.5 Gentamicin 20,581 92.4 6.5 6,654 92.8 5.3 2,650 92.2 6.6 4,825 94.3 5.2 9,442 95.4 4.2 Imipenem 15,353 100 0 3,386 100 0 2,254 100 0 5,172 100 0 8,994 100 0 Levofloxacin 14,920 88.2 11.6 776 85.1 13.9 496 86.5 13.3 3,137 88.2 11.0 NT NT NT Piperacillin- 13,573 93.1 3.6 4,305 95.1 2.4 1,879 95.8 2.4 5,637 93.6 3.4 7,255 95.4 1.1 tazobactam Trimethoprim- 20,296 79.2 20.7 6,737 84.6 15.3 2,440 75.0 24.9 5,598 73.1 26.6 9,028 78.2 21.1 sulfamethoxazole Klebsiella oxytoca Cefepime 1,476 96.2 3.3 19 100 0 255 99.6 0 566 96.8 2.7 478 97.1 0.4 Cefotaxime 1,324 92.7 4.7 486 94.2 4.5 230 96.5 1.7 1,117 93.8 4.4 865 96.3 0.8 Ceftazidime 1,909 91.7 7.0 661 94.9 4.1 361 83.4 15.2 749 95.3 4.5 870 98.3 0.5 Ceftriaxone 2,035 89.9 6.6 536 93.8 2.8 197 81.7 2.0 83 97.6 0 79 87.3 2.5 Ciprofloxacin 2,226 92.5 5.9 745 96.0 3.0 368 96.7 3.0 905 90.1 7.8 815 94.5 4.8 Gentamicin 2,569 89.9 8.3 857 95.0 4.9 366 89.6 3.0 1,016 98.2 1.2 865 97.1 2.4 Imipenem 2,061 100 0 516 100 0 337 100 0 1,062 100 0 845 100 0 Levofloxacin 1,754 93.3 3.4 159 96.9 1.3 133 97.0 3.0 560 94.6 3.2 NT NT NT Piperacillin- 1,801 82.7 13.9 624 91.2 7.1 313 81.8 11.2 1,113 78.9 18.1 742 88.3 10.4 tazobactam Trimethoprim- 2,467 92.5 7.5 863 96.3 3.6 308 95.1 4.9 1,084 93.7 6.3 802 94.1 5.7 sulfamethoxazole Klebsiella pneumoniae Cefepime 7,276 95.8 3.4 98 100 0 552 93.5 5.6 1,068 95.7 3.5 840 95.6 3.0 Cefotaxime 6,243 91.0 6.1 1,411 97.9 1.5 850 76.7 16.4 2,414 93.1 6.0 1,553 94.4 1.9 Ceftazidime 9,597 88.5 10.1 2,238 97.5 2.2 1,142 69.8 28.5 1,665 90.0 8.2 1,591 92.5 5.2 Ceftriaxone 10,337 92.7 4.7 1,736 97.9 1.1 816 75.2 15.0 166 98.8 0.6 112 86.6 5.4 Ciprofloxacin 11,089 89.9 8.4 2,484 91.8 7.2 1,190 88.2 9.9 2,128 85.4 9.4 1,473 89.5 8.7 Gentamicin 13,012 91.6 7.0 2,906 96.7 2.9 1,211 81.4 14.5 2,065 91.6 6.1 1,553 97.1 2.7 Imipenem 10,263 100 0 1,766 100 0 1,066 100 0 2,351 100 0 1,567 100 0 Levofloxacin 9,626 91.0 6.4 485 93.4 3.7 287 78.4 21.3 1,228 92.6 4.4 NT NT NT Piperacillin- 9,359 85.9 7.4 2,160 91.5 2.7 746 82.2 14.6 2,408 84.9 8.3 1,286 89.4 5.1 tazobactam Trimethoprim- 12,641 88.6 11.1 2,924 92.8 7.1 1,103 82.0 18.0 2,324 82.2 17.2 1,443 88.2 10.9 sulfamethoxazole Morganella morganii Cefepime 566 95.9 2.3 <10 NA NA 121 97.5 2.5 262 94.7 5.0 412 96.1 0.2 Cefotaxime 499 78.8 8.4 156 91.0 3.8 144 74.3 6.3 437 86.7 3.9 678 81.1 5.9 Ceftazidime 715 73.6 17.3 256 79.7 10.9 213 75.6 15.0 313 84.0 7.7 673 78.6 8.0 Ceftriaxone 806 91.1 2.2 219 96.3 1.4 125 91.2 3.2 22 86.4 0 57 84.2 5.3 Ciprofloxacin 841 78.1 20.7 292 94.2 4.5 220 87.3 9.5 344 97.7 2.0 634 88.6 8.5 Gentamicin 967 84.0 14.1 329 94.5 4.6 222 90.1 8.6 378 96.8 2.1 679 95.6 3.4 Imipenem 784 100 0 196 100 0 206 100 0 402 100 0 649 99.8 0 Levofloxacin 725 78.1 19.3 42 95.2 4.8 55 90.9 9.1 251 98.0 1.6 NT NT NT Piperacillin- 725 91.2 5.1 254 97.2 1.6 150 94.0 3.3 430 94.2 3.5 564 91.0 4.6 tazobactam Trimethoprim- 936 75.1 24.7 329 91.8 8.2 193 79.8 20.2 435 93.1 6.9 627 83.9 14.2 sulfamethoxazole Proteus mirabilis Cefepime 1,964 98.2 1.0 20 100 0 395 87.6 11.4 599 99.2 0.8 736 99.0 0.1 Cefotaxime 1,794 99.1 0.5 295 99.7 0 441 69.4 23.4 1,209 98.8 0.7 1,503 99.5 0.1 Ceftazidime 2,684 98.0 1.1 463 99.4 0.2 630 86.0 9.4 821 98.5 1.0 1,505 99.3 0.2 Ceftriaxone 3,034 99.4 0.3 392 99.5 0 385 80.5 13.8 77 98.7 0 72 100 0 Ciprofloxacin 3,169 85.2 12.7 504 95.2 4.6 657 70.6 22.7 980 92.9 5.1 1,424 90.9 6.8 Gentamicin 3,796 91.5 7.7 698 92.6 7.2 670 61.6 37.2 992 92.9 5.9 1,509 91.3 7.9 Imipenem 2,850 100 0 367 100 0 580 100 0 1,020 100 0 1,319 100 0 Levofloxacin 2,825 87.8 10.5 94 100 0 202 61.9 34.7 688 96.5 2.3 <10 NA NA Page 7 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 4: Enterobacteriaceae isolated from ICU patients during 2000–2002 (Continued) Piperacillin- 2,715 97.7 0.8 449 98.2 0.2 465 95.7 2.8 1,201 98.6 0.8 1,231 99.3 0.2 tazobactam Trimethoprim- 3,706 85.2 14.7 708 89.4 10.6 615 61.6 38.0 1,159 80.8 19.1 1,411 79.7 18.6 sulfamethoxazole Serratia marcescens Cefepime 3,653 96.7 2.3 52 96.2 1.9 497 96.8 2.2 546 94.1 3.5 509 98.6 0.2 Cefotaxime 3,134 87.0 5.7 670 92.8 2.7 470 79.6 9.8 951 84.0 7.5 809 81.5 3.3 Ceftazidime 4,718 89.7 7.9 1,113 95.2 3.0 738 81.4 13.3 851 89.7 7.5 812 94.7 3.0 Ceftriaxone 4,710 90.5 4.6 846 95.4 1.7 444 86.7 6.3 160 45.6 0 115 77.4 4.3 Ciprofloxacin 5,006 91.0 6.7 1,292 85.0 11.7 757 83.5 4.5 978 72.6 12.4 787 78.9 10.5 Gentamicin 5,905 92.9 5.9 1,313 94.6 5.2 758 97.4 2.1 665 92.9 6.3 808 91.6 6.6 Imipenem 4,960 100 0 880 100 0 727 100 0 1,018 100 0 805 100 0 Levofloxacin 4,356 94.3 4.2 264 92.4 4.2 266 95.5 1.5 595 87.6 6.6 <10 NA NA Piperacillin- 4,337 88.1 5.1 1,155 91.6 3.3 547 92.7 3.8 1,053 77.6 3.1 749 82.6 2.4 tazobactam Trimethoprim- 5,697 95.9 3.9 1,325 94.9 5.1 646 81.4 18.6 908 88.1 10.9 699 84.1 13.6 sulfamethoxazole a b c NCCLS breakpoints were used for all countries, except France (CA-SFM) Not tested Not applicable if <10 isolates were tested whereas K. pneumoniae and K. oxytoca demonstrated Overall the susceptibility rates for Gram-negative isolates 30.2% and 16.6% ceftazidime non-susceptibility, respec- from Canadian ICUs were higher than those in the other tively. Fluoroquinolone resistance rates among the Entero- four countries examined. A low rate of ESBLs was bacteriaceae, using ciprofloxacin as a marker, varied from reported, but there was variable activity of piperacillin- 3.0% for K. oxytoca to 22.7% for P. mirabilis, and 12.7% for tazobactam which showed >9% resistance among Kleb- E. coli. Thus, among Enterobacteriaceae, ciprofloxacin was siella spp. and S. marcescens tested. The rate of fluoroqui- generally less active than the third-generation nolone resistance was similar to those of other countries cephalosporin, ceftriaxone. P. aeruginosa and Acinetobacter with E. coli showing 13.9% levofloxacin resistance. spp. strains from Italian ICUs demonstrated significant Among Enterobacteriaceae, <10% of most species were resistance rates. Isolates of P. aeruginosa showed resistance resistant to third-generation cephalosporins tested with rates of >28% for all agents tested except piperacillin-tazo- the exception of ceftazidime and M. morganii. Resistance bactam. Thus empiric therapy for possible pseudomonal among P. aeruginosa and Acinetobacter spp. was generally infections will require combination therapy. Acinetobacter lower than in other countries apart from Germany. Only spp. showed a similar lack of susceptibility except to imi- piperacillin-tazobactam showed reliable activity against P. penem and meropenem (19.0% and 13.6% resistant). An aeruginosa (9% resistant), while resistance to all other increase in fluoroquinolone resistance in E. coli and K. agents was >19%. Acinetobacter spp. remained susceptible pneumoniae in bacteremic isolates from Italy was observed to only the carbapenems, imipenem and meropenem. during 1997–2001, with rates of 26.7% and 24%, respec- tively [9]. An increase in ureidopenicillin resistance was Comparison of the data from Canadian isolates with noted in P. aeruginosa isolates in Italy from 30% to 37% in those from the United States shows some significant dif- a 4-year period [9]. This study showed 22.0% piperacillin- ferences. This demonstrates the limitations of pooling tazobactam and 36.7% piperacillin resistance among ICU Canadian and United States data since the differences P. aeruginosa isolates. between the two regions, such as the rate of MRSA, may have some impact on empiric therapy. Data from the In Canada oxacillin-resistance among S. aureus was noted NNIS system has previously reported an increasing trend in 19.7% and coagulase-negative staphylococci in 79.4%. towards resistance within ICUs in the United States [19]. Vancomycin resistance was reported among 0.9% and Oxacillin resistance among staphylococci from ICUs in 14.5% of E. faecalis and E. faecium, respectively. The low- the United States was 52.3% and 84.2% for S. aureus and est rate of penicillin resistance in S. pneumoniae in this coagulase-negative species, respectively. study was noted from Canada at 7.1%; however, clarithro- mycin resistance was 30.4%. Ceftriaxone showed 0.7% This value is identical to that of S. aureus and very similar resistance whereas cefepime exhibited 12.0% resistance to the CNS data reported by the 1999 NNIS system. The among pneumococci from the ICU. NNIS highlighted a 37% increase in MRSA over the period Page 8 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 Table 5: P. aeruginosa and Acinetobacter spp isolated from ICU patients during 2000–2002 United States Canada Italy Germany France Organism Agent Total n %S %R Total n %S %R Total n %S %R Total n %S %R Total n %S %R Acinetobacter Cefepime 5,162 43.8 40.2 97 67.0 23.7 475 17.9 73.7 623 74.2 10.8 857 28.0 40.3 species Cefotaxime 3,830 23.3 49.9 705 36.7 34.9 555 11.0 78.7 1,254 34.9 24.6 671 15.4 38.7 Ceftazidime 5,954 42.2 40.8 1,162 70.8 22.9 692 25.6 68.5 988 66.7 14.5 1,106 34.9 35.5 Ceftriaxone 4,709 16.3 55.9 874 32.4 28.7 452 8.8 72.6 104 42.3 11.5 81 9.9 51.9 Ciprofloxacin 5,808 39.7 58.0 1,156 72.1 25.9 686 21.1 76.7 1,126 74.8 22.9 1,038 37.7 61.2 Gentamicin 6,618 47.2 47.2 1,185 72.8 22.8 768 23.3 72.4 979 82.0 14.1 936 49.3 43.5 Imipenem 6,006 87.0 7.5 918 95.8 1.9 569 77.9 19.0 1,253 96.2 3.4 1,088 93.8 3.8 Levofloxacin 5,099 43.8 52.2 489 61.1 25.6 295 13.9 75.3 840 82.0 10.5 NT NT NT Meropenem 2,154 66.3 26.5 348 93.7 4.9 455 74.5 13.6 1,024 96.0 3.4 147 68.0 28.6 Piperacillin 4,658 35.4 45.9 959 66.5 19.5 635 19.5 69.9 1,171 59.7 12.9 805 35.0 50.3 Piperacillin- 3,429 53.6 28.5 903 70.7 23.1 425 35.1 46.4 1,225 81.8 7.5 878 74.5 10.5 tazobactam Trimethoprim- 5,697 51.4 48.4 1,155 74.8 25.2 750 44.1 55.7 1,234 83.6 15.6 93 45.2 52.7 sulfamethoxazole Pseudomonas aeruginosa Cefepime 20,220 72.5 12.4 371 73.3 12.4 5,056 58.9 28.9 3,483 80.3 7.8 7,967 52.6 16.2 Cefotaxime 11,283 9.2 50.4 1,836 13.3 47.5 4,181 6.0 70.7 2,689 7.7 52.2 NT NT NT Ceftazidime 26,353 71.2 17.4 6,036 73.7 13.4 7,640 56.7 31.3 5,141 76.2 14.9 8,547 70.2 14.9 Ceftriaxone 14,066 12.1 56.4 2,847 11.3 59.7 3,383 8.4 70.4 154 26.6 7.8 NT NT NT Ciprofloxacin 26,700 62.8 33.1 5,924 67.2 30.2 7,388 58.4 38.8 4,746 68.6 24.4 8,560 55.3 40.6 Gentamicin 29,268 69.4 21.5 5,951 72.2 15.9 7,522 52.2 41.7 3,913 74.0 14.3 7,327 44.0 46.1 Imipenem 26,076 73.5 22.1 3,775 77.9 18.2 7,057 59.7 27.8 4,412 70.5 19.0 8,575 69.5 21.4 Levofloxacin 21,059 62.7 31.7 713 56.8 33.5 2,427 44.9 51.0 2,953 68.0 23.9 NT NT NT Meropenem 7,540 76.0 18.2 1,266 80.3 14.5 4,082 57.3 32.7 4,351 77.8 13.8 1,818 81.1 6.4 Piperacillin 22,855 77.7 22.2 5,520 80.9 18.8 7,004 63.1 36.7 4,554 81.7 14.1 8,454 64.1 24.1 Piperacillin- 21,848 85.5 14.4 4,190 91.0 9.0 5,252 77.7 22.0 4,746 85.8 10.7 8,256 69.6 15.9 tazobactam Trimethoprim- 15,618 3.6 96.4 4,283 4.0 96.0 7,054 4.1 95.8 3,375 4.2 95.8 NT NT NT sulfamethoxazole a b NCCLS breakpoints were used for all countries, except France (CA-SFM) NT = not tested 1994–98 to 1999, but only a 2% increase among CNS non-susceptibility was higher in K. oxytoca 8.3%,K. pneu- strains [4]. Vancomycin resistance in the United States moniae 11.5%,S. marcescens 10.3% and M. morganii was observed in 4.5% of E. faecalis; however, over 76% E. 26.4%. These data are consistent with other recent reports faecium were vancomycin non-susceptible. [21]. Fluoroquinolone resistance was observed in all Enterobacteriaceae tested, in the US for example, resistance Although streptococci are uncommon ICU pathogens rates were as follows, using ciprofloxacin as a marker: E. they can be rapidly invasive and possibly fatal unless ade- coli 10.7%, K. oxytoca 5.9%, K. pneumoniae 8.4%, M. mor- quate therapeutic approaches are adopted. S. pneumoniae ganii 20.7%, P. mirabilis 12.7% and S. marcescens 6.7%. in the United States has acquired a range of resistance These data show increased fluoroquinolone resistance mechanisms with resistance to penicillin and the mac- compared with recent reports [21]. Jones et al. previously rolides, clarithromycin and erythromycin, being com- reported susceptibility data on ICU pathogens isolated mon, 20.2% and 25.5%–30.5% respectively. The newer over the period 1998–2001 [22]. generation cephalosporins, ceftriaxone, cefotaxime and cefepime showed good activity against pneumococci, Specifically, enteric bacteria showed changes over this 3.2%, 6.3% and 4.5% resistant, respectively. Less than time. Fluoroquinolone resistance doubled among E. coli 1.0% of isolates were resistant to levofloxacin. These data isolates from 3.3–5.5% to 10.8–11.4% [22]. This study are similar to other recent reports [20]. showed a generally higher level of activity among third- generation cephalosporins than other reports [23], with For Enterobacteriaceae which account for approximately ceftriaxone showing <10% resistance rates against most 30% of all isolates from ICU infections, the incidence of species tested. Piperacillin-tazobactam showed less con- putative ESBLs was low in E. coli, 4.7% but ceftazidime sistent activity with some species being >14% resistant, Page 9 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 e.g. Klebsiella spp.,P. aeruginosa, and Acinetobacter spp. such as ceftriaxone with vancomycin may be appropriate present significant therapeutic challenges in ICUs in the for bloodstream infections based upon the NNIS etiology United States. With the exception of cefepime, all other data from 1992–1999. tested antimicrobials demonstrated >12% resistance to P. aeruginosa, many considerably higher. Piperacillin-tazo- Conclusions bactam showed the next lowest resistance rate, 14.4%, The current study confirmed the emergence of fluoroqui- with all other agents having rates of 17% or higher. Non- nolone resistance among various Gram-negative species susceptibility to ciprofloxacin among P. aeruginosa was and staphylococci, which may be increasing due to the 37.2%, higher than in the Neuberger report. Sahm et al. heightened use of these drugs; however the reported ESBL reported a 10% increase in fluoroquinolone resistance rates among Enterobacteriaceae was lower than noted in among P. aeruginosa in the United States, whereas resist- other studies and appeared to be stable. The prevalence of ance emerged more slowly with the other classes of anti- MRSA, perhaps the most significant resistant hospital microbials tested [12]. Acinetobacter infections continue to pathogen, varied among the five countries and appeared present significant therapeutic challenges due to the to be increasing. Parenteral cephalosporins such as ceftri- extensive resistance mechanisms demonstrated by the axone and cefotaxime remained quite active against >25% resistance shown in Table 5. Only imipenem has Enterobacteriaceae. Up-to-date susceptibility data should any reliable activity against Acinetobacter spp. with an 87% be made available as rapidly as possible to physicians so susceptibility rate. that appropriate targeted empirical therapy can be insti- tuted, this approach can assist in maintaining the activity There are several implications of these data. It is essential of the current antimicrobials. While local surveillance that local surveillance programs be maintained in each studies remain crucial, national surveillance studies such country's ICU setting. The local data are vital to the formu- as this can provide an invaluable data source to provide lary committees as they select appropriate agents to treat guidance in formulary decision-making. infections. There are clear differences among the five countries studied in this report. Although the predomi- Authors Contributions nant pathogens are similar, ongoing surveillance is essen- MJ conceived the study, provided data interpretation and drafted the manuscript. DD analyzed the study data; JK tial to detect the emergence of resistant species. It is clear that certain classes of compounds are losing activity and DS provided expert microbiological analysis and against the ICU pathogens tested. For example, the fluor- interpretation of study data; RW provided clinical exper- oquinolones have reduced susceptibility among many tise in interpretation of data and drafting manuscript. All Gram-negative species as well as staphylococci; however, authors read and approved the final manuscript. the newer class members have enhanced activity against pneumococci. Advanced-generation cephalosporins have Acknowledgments We thank F. Hoffmann-La Roche Ltd., Basel, Switzerland for financial sup- variable activity, with ceftriaxone showing consistently port of this study. Additionally, we thank the many clinical microbiology lab- good activity against the Enterobacteriaceae and some sta- oratories around the world that contribute data to TSN Databases, phylococci. Ceftazidime has lost potency due to the emer- without whom such studies would not be possible. gence of ESBL enzymes and also has diminished activity against P. aeruginosa. Piperacillin-tazobactam is generally References active against P. aeruginosa in ICUs. The aminoglycoside, 1. Kollef MH, Fraser VJ: Antibiotic resistance in the Intensive Care gentamicin has shown continued activity against most Unit. Ann Intern Med 2001, 134:298-314. 2. CDC NNIS system: National nosocomial infections surveil- Enterobacteriaceae in all five countries, and modest activity lance (NNIS) system report, data summary from January against S. aureus but not against CNS strains. The gen- 1992-April issued August 2001. Amer J Infect Contr 2001, 29:400-421. 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Stephen J, Mutnick A, Jones RN: Assessment of pathogens and cefepime, piperacillin-tazobactam or the carbapenems resistance (R) patterns among intensive care unit (ICU) in should preferably be reserved for patient types or infec- North America (NA): initial report from the SENTRY anti- tions where this pathogen is present or risk factors exist, as microbial surveillance program (2001). Presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San per the ATS Community acquired-pneumonia guidelines Diego, CA 2002. Abstract C2-297 [24]. A combination of a third-generation cephalosporin Page 10 of 11 (page number not for citation purposes) Annals of Clinical Microbiology and Antimicrobials 2004, 3:14 http://www.ann-clinmicrob.com/content/3/1/14 6. Vincent JL, Bihari DJ, Suter PM, Bruining HA, White J, Nicloas-Chaoin Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA MH, Wolff M, Spencer RC, Hemmer M: The prevalence of noso- 2002. 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Chemotherapy 2002, 48:232-237. 21. Neuberger MM, Weinstein RA, Rydman R, Danzinger LH, Quinn JP: "BioMed Central will be the most significant development for Antibiotic resistance among Gram-negative bacilli in US disseminating the results of biomedical researc h in our lifetime." intensive care units. Implications for fluoroquinolone use. J Sir Paul Nurse, Cancer Research UK Amer Medical Assoc 2003, 289:885-888. 22. Jones ME, Draghi DC, Master RN, Thornsberry C, Karlowsky JA, Your research papers will be: Critchley IA, Sahm DF: Trends in resistance among Enterobac- available free of charge to the entire biomedical community teriaceae (isolated from in-patients and intensive-care unit patients in the US from 1998 to 2001. Presented at the 42nd Inter- peer reviewed and published immediately upon acceptance science Conference on Antimicrobial Agents and Chemotherapy, San Diego, cited in PubMed and archived on PubMed Central CA 2002. Abstract C2-311 23. Friedland I, Stinson L, Ikaiddi M, Harm S, Woods G: Resistance in yours — you keep the copyright Enterobacteriaceae: results of a multicenter US ICU surveil- BioMedcentral lance study (ISS), 1995-2000. Presented at the 42nd Interscience Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 11 of 11 (page number not for citation purposes)

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Annals of Clinical Microbiology and AntimicrobialsSpringer Journals

Published: Jul 29, 2004

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