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Eur J Clin Microbiol Infect Dis (2006) 25:815–817DOI 10.1007/s10096-006-0211-2 Multicentre study of antimicrobial resistanceand antibiotic consumption among 6,780 patientswith bloodstream infections U. Frank & E. M. Kleissle & F. D. Daschner &L. Leibovici & M. Paul & S. Andreassen &H. C. Schonheyder & R. Cauda & E. Tacconelli Several lines of evidence suggest there is a causal antimicrobial agents and the prevalence of drug resistance association between the use of antimicrobial agents and the prevalence of antimicrobial resistance in hospital- The participating hospitals were partners in the TREAT acquired bacterial pathogens However, recently project, financed by the European Community (EC, 5th published works have indicated the magnitude of the Framework, 1999) and focusing on the application of an association may be lower than that previously observed electronic decision support system to reduce antimicrobial and that many other variables, such as patient factors may resistance in hospitalised patients This multicentre study be responsible for the development of antimicrobial was conducted at Freiburg University Hospital, Freiburg, resistance [, ]. The specific goals of this study were (1) Germany; Rabin Medical Center, Tel Aviv (Petah Tiqva), to estimate antimicrobial resistance rates for four epidemi- Israel; Aalborg Hospital, Aalborg, Denmark; and Catholic ologically important pathogens causing bloodstream infec- tions (BSI), (2) to compare the antimicrobial resistance Data on consumption of antibiotics (from 1998 to 2001) rates with the hospital’s antibiotic consumption data, and were supplied by the hospital pharmacies and expressed in (3) to determine a possible relationship between the use of daily defined doses (DDD) per 1,000 bed-days, as outlinedby the World Health Organisation. Data on consumption ofthe following drugs were provided (if included in the local formulary): clindamycin, trimethoprim-sulfamethoxazole, U. Frank E. M. Kleissle F. D. DaschnerInstitute of Environmental Medicine and Hospital Epidemiology, imipenem, ampicillin, ceftazidime, cefepime, piperacillin, piperacillin-tazobactam, and gentamicin. We prospectively included, from 1998 to 2001, all consecutive non-repeatblood isolates of patients with nosocomial BSI according to L. Leibovici : M. PaulDepartment of Medicine, Rabin Medical Center, the definition given by the Centers for Disease Control and Prevention (Atlanta, GA, USA). Mixed cultures wereexcluded. Selected isolates from patients with bacteraemia included Staphylococcus aureus, Escherichia coli, Klebsi- Center for Model-Based Medical Decision Support,Aalborg University, ella pneumoniae and Pseudomonas aeruginosa. Micro- organisms were identified using standard methods. Trendsin resistance and the possible correlation between resistance and consumption were analysed using the logit regression Department of Clinical Microbiology, Aalborg Hospital,Aalborg, Denmark Antimicrobial consumption patterns varied widely at the four sites. The most frequently prescribed drugs (>40 DDD Department of Infectious Diseases, Catholic University Hospital, per 1,000 bed-days) were ampicillin and gentamicin in Rome, Italye-mail: [email protected] Denmark and Israel and ceftazidime in Germany and Italy.
Eur J Clin Microbiol Infect Dis (2006) 25:815–817 A significant increase in antibiotic consumption (>25% resistance in K. pneumoniae and E. coli were reported in over the study period) was observed for ampicillin, Israel only. A significant correlation between consumption gentamicin, clindamycin, piperacillin, and ceftazidime in of ampicillin and resistance in E. coli was found in Germany; for clindamycin, piperacillin, and ceftazidime in Germany and Italy (p=0.02 and p<0.001, respectively), Denmark; and for piperacillin in Italy.
whereas for gentamicin resistance in K. pneumoniae, a Isolates causing bacteraemia (n = 6,780) included significant correlation was noted in Italy only (p=0.002). In S. aureus (n=2,112), E. coli (n=2,983), K. pneumoniae Germany, a positive correlation was found between the con- (n=876) and P. aeruginosa (n=809). An increase in the sumption of piperacillin and resistance in E. coli (p=0.002).
prevalence of nosocomial BSI caused by antibiotic-resistant For piperacillin, data on consumption and resistance in bacteria was observed at all four sites. Table shows the K. pneumoniae could be correlated in Italy (p<0.001) and differing percentages of antimicrobial resistance for the for piperacillin/tazobactam in Israel (p=0.02). For cef- selected microorganisms. BSI caused by piperacillin-resis- epime, a positive correlation between consumption and tant K. pneumoniae was increasingly reported in all resistance in P. aeruginosa was found in Italy (p=0.03).
countries. In particular, all strains of K. pneumoniae Our study included more than 6,000 patients with BSI in isolated in Italy in 2001 were resistant to piperacillin. The four countries and documented an association between prevalence of BSI due to gentamicin-resistant K. pneumo- increasing usage for some antibiotics, expressed as DDD, niae increased in Germany, Italy, and Israel. Statistically and rising resistance rates. The increasing resistance of significant increases were observed for cefepime-resistant E. coli to ampicillin observed in our study confirms the and gentamicin-resistant P. aeruginosa in Italy (p<0.01); findings of other recent surveillance studies. Livermore et for piperacillin-resistant K. pneumoniae in Italy and Den- al. [] reported an upward trend in the proportion of E. coli mark (p<0.01); for clindamycin-resistant S. aureus in Italy isolates resistant to ampicillin, trimethoprim–sulfamethox- (p<0.01) and Israel (p=0.03); and for piperacillin-tazobac- azole and gentamicin as well as ciprofloxacin in isolates tam-resistant K. pneumoniae in Israel (p=0.01). Imipenem from patients with bacteraemia or meningitis between 1991 Table 1 Rates of resistance (%) to select antibiotics among 6,780 non-repeat blood culture isolates in Germany, Denmark, Israel, and Italy NA, data not available for drugs not included in local formulary or not testeda Prevalence in 2000 since the use of the drug was abandoned in 2001b Sporadic cases of microorganism resistant to the drug were isolated during 1999–2000 Eur J Clin Microbiol Infect Dis (2006) 25:815–817 and 1997. We also demonstrated a statistically significant piperacillin and piperacillin-tazobactam and the develop- correlation between hospital consumption of ampicillin and ment of resistance in E. coli and K. pneumoniae. Therefore, the development of resistance in E. coli BSI in Germany.
periodic surveillance of antimicrobial susceptibility patterns These data confirm the results from a recent case-control and hospital antibiotic usage remain essential for the study that documented that exposure to penicillin antibiotics detection of antimicrobial resistance emergence, especially as a class and to ampicillin and ampicillin-sulbactam for blood culture isolates, which tend to represent the most individually were the only significant, independent risk clinically relevant pathogenic microorganisms causing factors associated with the isolation of ampicillin-sulbactam- nosocomial infections. Large prospective multicenter trials resistant E. coli, but they were not associated with the to examine the impact of selective antibiotic restriction isolation of ampicillin-sulbactam-susceptible E. coli [].
From 1997 to 1998, the SENTRY project reported that P. aeruginosa blood culture isolates had a high level ofsusceptibility to ceftazidime and cefepime In our studywe noted an increase in the number of ceftazidime- and cefepime-resistant P. aeruginosa isolates and a significantassociation between cefepime consumption in hospitals and 1. Seppala H, Klaukka T, Vuopio-Varkila J et al (1997) The effect of changes in the consumption of macrolide antibiotics on erythro- the resistance rate in Italy. In the same centre Tacconelli et mycin resistance in group A streptococci in Finland. Finnish study al. [] observed that advanced age, HIV infection, intravenous group for antimicrobial resistance. N Engl J Med 337:441–446 drug abuse, and previous therapy with quinolones were in- 2. Tacconelli E, Venkataraman L, De Girolami PC et al (2004) dependent risk factors for multidrug-resistant P. aeruginosa Methicillin-resistant Staphylococcus aureus bacteraemia diag-nosed at hospital admission: distinguishing between community- acquired versus healthcare-associated strains. J Antimicrob The impressive decrease in susceptibility to piperacillin in K. pneumoniae (no susceptible isolates in Italy in 2001) 3. Bolon MK, Wright SB, Gold HS et al (2004) The magnitude of is especially worrisome because only a limited number of the association between fluoroquinolone use and quinolone-resistant Escherichia coli and Klebsiella pneumoniae may be antibiotic agents are available to treat these infections. To lower than previously reported. Antimicrob Agents Chemother the best of our knowledge, this study is the first to identify a significant correlation between the consumption of 4. Priest P, Yudkin P, McNulty C et al (2001) Antibacterial piperacillin and piperacillin-tazobactam and the develop- prescribing and antibacterial resistance in English general prac-tice: cross sectional study. BMJ 323:1037–1041 ment of resistance in E. coli and K. pneumoniae.
5. Paul M, Andreassen S, Nielsen AD et al (2006) TREAT study The literature on the relationship between the use of group. prediction of bacteremia using TREAT, a computerized aminoglycosides and the development of resistance is rather decision-support system. Clin Infect Dis 42:1274–1282 controversial and complex. Although a previous study was 6. Livermore DM, Threlfall EJ, Reacher MH et al (2000) Are routine sensitivity test data suitable for the surveillance of resistance? not successful in revealing such a relationship ], we Resistance rates amongst Escherichia coli from blood and CSF were able to demonstrate a positive correlation between from 1991–1997, as assessed by routine and centralized testing.
gentamicin consumption and resistance in K. pneumoniae in Italy. Our results are in accordance with those of other 7. Kaye KS, Harris AD, Gold H et al (2000) Risk factors for recovery of ampicillin–sulbactam-resistant Escherichia coli in investigators who reported increased aminoglycoside resis- hospitalized patients. Antimicrob Agents Chemother 44:1004– tance following unrestricted use of this substance class over 8. Fluit AC, Jones ME, Schmitz FJ et al (2000) Antimicrobial It must be pointed out that this research has two major susceptibility and frequency of occurrence of clinical bloodisolates in Europe from the SENTRY antimicrobial surveillance limitations related to the difficulty of retrospectively program, 1997 and 1998. Clin Infect Dis 30:454–460 collecting patients’ clinical data: (1) it lacks an analysis of 9. Tacconelli E, Tumbarello M, Bertagnolio S et al (2002) confounders, such as different case-mixes of hospitalised Multidrug-resistant Pseudomonas aeruginosa bloodstream infec- patients, inappropriate dosages, different infection control tions: analysis of trends in prevalence and epidemiology. EmergInfect Dis 8:220–221 systems or prevalence of cross-transmission; and (2) it lacks 10. Harbarth S, Rohner P, Safran E et al (1998) Resistance to an analysis of reasons for changing antibiotic policies in amikacin and gentamicin among gram-negative bloodstream isolates in a university hospital between 1989 and 1994. Clin The results of this study confirm that the development of 11. Mebis J, Goossens H, Bruyneel P et al (1998) Decreasing antimicrobial resistance is probably linked to the consump- antibiotic resistance of Enterobacteriaceae by introducing a new tion of antimicrobial agents and document, for the first antibiotic combination therapy for neutropenic fever patients.
time, a significant correlation between the consumption of

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