ORIGINAL INVESTIGATION. Reemergence of Gram-negative Health Care Associated Bloodstream Infections

Transcription

1 ORIGINAL INVESTIGATION Reemergence of Gram-negative Health Care Associated Bloodstream Infections Svenja J. Albrecht, MD; Neil O. Fishman, MD; Jennifer Kitchen, MD, PhD; Irving Nachamkin, DrPH, MPH; Warren B. Bilker, PhD; Cindy Hoegg, BSN, RN; Carol Samel, MS, MT; Stephanie Barbagallo, MBA, MT; Judy Arentzen, BS, MT; Ebbing Lautenbach, MD, MPH, MSCE Background: Primary health care associated bloodstream infections (PHA-BSIs) affect as many as patients in the United States annually. Whereas gramnegative organisms were the leading cause before the 1970s, gram-positive organisms have been the predominant microbial isolates since then. Methods: We identified all PHA-BSIs among adult inpatients in a 625-bed quaternary care hospital from January 1, 1996, through December 31, 2003, and evaluated trends in the microbial etiology, geographic distribution within the institution, and antimicrobial susceptibilities. Results: A total of 3662 PHA-BSIs caused by 4349 bacterial and fungal isolates were identified. From 1999 to 2003, the proportion of PHA-BSIs due to gram-negative organisms increased from 15.9% to 24.1% (P.001 for trend). This trend was not significantly different across various units of the hospital, and no specific gramnegative species contributed disproportionately to the increase. With few exceptions, there were no significant increases in antimicrobial resistance. The increase in gramnegative organisms was accompanied by a decline in the proportion of PHA-BSIs from coagulase-negative staphylococci (from 33.5% in 1999 to 29.9% in 2003, P=.007) and from Staphylococcus aureus (from 18.8% in 1999 to 11.8% in 2003, P=.004). The proportion of PHA-BSIs from Candida species almost doubled from 5.8% in 1999 to 11.3% in 2003 (P=.002). Conclusions: To our knowledge, this is the first US study to report a reemergence of gram-negative organisms as a cause of PHA-BSIs. This finding does not seem to be related to changes in specific gram-negative organisms or to antimicrobial resistance. If this trend continues, it will have important implications for the management of bloodstream infections. Arch Intern Med. 2006;166: Author Affiliations: Divisions of Infectious Diseases (Drs Albrecht, Fishman, and Lautenbach) and General Internal Medicine (Dr Kitchen), Department of Medicine, Department of Hospital Epidemiology and Infection Control (Drs Fishman and Lautenbach and Mss Hoegg, Samel, Barbagallo, and Arentzen), Department of Pathology and Laboratory Medicine (Dr Nachamkin), and Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, and Center for Education and Research on Therapeutics (Drs Bilker and Lautenbach), University of Pennsylvania School of Medicine, Philadelphia. HEALTH CARE ASSOCIATED infections annually affect approximately 2 million patients in the United States. 1 Primary bloodstream infections (BSIs) account for 15% to 20% of all health care acquired infections and afflict between and hospitalized patients in the United States every year. 2 Since the 1980s, the incidence of primary health care associated BSIs (PHA-BSIs) has been rising steadily, 3 and most are related to the use of intravascular devices, especially central venous catheters (CVCs). 2 These infections have a tremendous effect on patient outcome and hospital costs, resulting in increased hospital lengths of stay, additional costs up to $ per surviving patient, and an attributable mortality of approximately 35%. 4 Whereas gram-negative organisms were the leading cause of health care associated BSIs before the 1970s, 5 infections due to gram-positive organisms increased during the 1980s and have been the predominant microbial etiologies since then. During the 1980s, the National Nosocomial Infections Surveillance (NNIS) System found increasing rates of PHA-BSIs due to coagulase-negative staphylococci CME course available at (CNS), Staphylococcus aureus, enterococci, and Candida species, with no change in the frequency of gram-negative organisms. 6 During the 1990s, the NNIS System reported further increases in PHA- BSIs due to CNS in their combined medical-surgical intensive care units (ICUs) and among CVC-associated BSIs in medical ICUs. 2 Other studies in the United States and Europe during the last 2 decades have found similar increases in BSIs due to CNS, 3,7-9 S aureus, 3 enterococci 3,10 and Candida species. 3,7,

2 The microbial etiology of PHA-BSIs has important implications for empirical antimicrobial therapy, antimicrobial resistance, patient outcomes, and other patient care and infection control practices. Infection control surveillance data at our institution suggested an increase in gram-negative PHA-BSIs in recent years. Therefore, we chose to characterize the microbial etiology of PHA- BSIs among adult inpatients at our institution from 1996 to 2003, focusing specifically on the latter 5 years. METHODS STUDY DESIGN This study was conducted at the 625-bed quaternary care Hospital of the University of Pennsylvania. All bacterial and fungal isolates from adult inpatients from January 1, 1996, through December 31, 2003, that met the Centers for Disease Control and Prevention definition for nosocomial primary BSIs 12 were included in the study. Secondary BSIs (bloodstream infections related to infections at another site) and community-acquired BSIs (infections present or incubating at the time of admission) were not included in the analysis. Repeat isolates (same organism isolated from the same patient) were included only once unless the infection was considered a new episode. For polymicrobial BSIs, each organism was considered a separate isolate in the analysis. A central microbiology laboratory processes and cultures all clinical isolates from inpatients at the Hospital of the University of Pennsylvania. All organisms were classified broadly as gram-negative organisms, gram-positive organisms, or yeast. 13 Organisms not fitting any of these categories (eg, mycobacteria) were grouped as other organisms. The continuous monitoring Bactec 9240 System (Becton Dickinson Diagnostic Instrument Systems, Sparks, Md) was instituted in 1995, and there has been no change in the protocol since that time. Blood cultures were typically drawn by physicians or nurses, although a program using a dedicated blood culture drawing team was instituted on July 1, Antimicrobial susceptibility testing for all bacterial isolates was performed using the MicroScan Walkaway (Dade Behring, Sacramento, Calif) or the Vitek2 system (biomerieux, Inc, Durham, NC). Susceptible and resistant results were determined using the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards) break-point values. 14,15 All data were collected by infection control practitioners. Data collected on all BSIs included the following: (1) microbial etiology, (2) polymicrobial or monomicrobial status of the BSI episode, (3) location of the patient within the hospital at the onset of infection, (4) number of days from admission to the onset of infection, (5) central or peripheral catheter use at the onset of infection, (6) catheter types in place at the onset of infection, and (7) clinical or laboratory evidence of catheter infection. A PHA-BSI episode was considered catheter-related if a catheter tip grew more than 15 colony-forming units of the same organism that was isolated in blood culture or if there was evidence of local infection, such as purulent drainage at the catheter site. Bloodstream infections that occurred while a CVC was in place but that did not meet criteria for catheter-related infections were considered catheter-associated BSIs. Catheterassociated and catheter-related infections were combined as catheter-associated episodes in the final analysis. STATISTICAL ANALYSIS We first determined the annual incidence of PHA-BSIs, the annual percentage of polymicrobial BSIs, and the annual number of bacterial and fungal isolates. We then calculated the annual proportion of PHA-BSIs accounted for by each of the 10 most common bacterial and fungal organisms, as well as the annual proportion of PHA-BSIs accounted for by the following specific organisms or organism groups: S aureus, CNS, enterococci, gramnegative organisms, and Candida species. We evaluated trends in the annual proportion for these 5 organisms or groups using the Cochran-Armitage trend test ( 2 test for trend). 16 Preliminary data from the infection control practitioner surveillance indicated that there was a potential change in the microbial etiology of PHA-BSIs starting in 1999; therefore, we focused our analyses on 1999 to Because our initial analysis showed an increase in the proportion of PHA-BSIs due to gramnegative organisms, a Spearman rank correlation coefficient was calculated to evaluate the relationship between the yearly proportion of PHA-BSIs due to gram-negative organisms and the annual hospitalwide use of specific antibiotics or antibiotic classes. The hospitalwide use of the following specific agents or classes was documented: vancomycin, cefepime, quinolones, aminoglycosides, clindamycin, and metronidazole. Antibiotic use was described as defined daily doses per 1000 patient-days. To identify the effect of hospital location on temporal trends in the microbial etiology of BSIs, we used a logistic regression analysis with organism prevalence as the dependent variable and with calendar year and hospital location as the independent variable. Hospital floors and units were categorized as medical ICUs, surgical ICUs, oncology, and general medical or surgical floors. We evaluated the annual proportions and trends for the 4 most common gram-negative organisms (Klebsiella species, Escherichia coli, Pseudomonas species, and Enterobacter species), anaerobic gram-negative organisms, and all other gram-negative organisms combined. We used the Cochran-Armitage trend test for analysis. 16 To further elucidate our findings, we performed a subanalysis in which we repeated the aforementioned analyses but focused only on the subset of CVC-associated PHA-BSIs. In another subanalysis, we investigated the potential relationship between CVC type (specifically triple-lumen catheters and peripherally inserted central catheters [PICCs]) and trends in the microbial etiology of PHA-BSIs. In this subanalysis, we compared temporal trends in gram-negative PHA-BSIs among patients who had a triple-lumen catheter with those who did not have a triple-lumen catheter (ie, no central access or any other type of central access). Similarly, we compared temporal trends in gram-negative PHA-BSIs among patients who had a PICC with those who did not have a PICC. We subsequently evaluated whether the increasing trend in the prevalence of gram-negative PHA-BSIs was related to an increase in antimicrobial resistance among gram-negative organisms. We evaluated hospitalwide susceptibilities of the 4 most commonly isolated gram-negative organisms (Klebsiella pneumoniae, E coli, Pseudomonas aeruginosa, and Enterobacter cloacae) from 1999 to These data were obtained from the annual antibiogram of the microbiology laboratory and included susceptibility results for all inpatient bloodstream isolates (ie, including community-acquired and secondary BSI isolates). We evaluated the following organism-antibiotic combinations in our analysis: K pneumoniae: ampicillin-sulbactam, trimethoprimsulfamethoxazole, levofloxacin, gentamicin sulfate, and ceftazidime; E coli: trimethoprim-sulfamethoxazole, levofloxacin, gentamicin, and ceftazidime; P aeruginosa: ceftazidime, cefepime, levofloxacin, aztreonam, imipenem, gentamicin, tobramycin, and amikacin; and E cloacae: aztreonam, ceftazidime, cefepime, gentamicin, trimethoprim-sulfamethoxazole, and levofloxacin. We then assessed trends in susceptibility for PHA-BSI isolates of the same 4 gram-negative organisms during the same period. In this analysis, only the specific organisms from the 1290

3 % Organisms Among Total Isolates Gram-negative Organisms (P <.001) Staphylococcus aureus (P =.004) Coagulase-Negative Staphylococci (P =.007) Candida Species (P =.002) Enterococci (P =.91) Year Figure 1. Trends in the etiology of primary health care associated bloodstream infections. P values indicate P for trend from 1999 to list of PHA-BSI episodes were included. We evaluated the same organism-antibiotic combinations as in the hospitalwide analysis except for ceftazidime susceptibilities, which were not tested for most isolates, and for P aeruginosa susceptibilities to amikacin, which were tested in only a few isolates. We used the Cochran-Armitage trend test for both analyses. 16 A significance level of P=.05 (2-sided) was used for all statistical tests. Statistical analysis was performed using standard programs in STATA version 8.0 (StataCorp LP, College Station, Tex) and StatXact 4.0 (Cytel Software Corporation, Cambridge, Mass). This study was reviewed and approved by the Committee on Studies Involving Human Beings of the University of Pennsylvania School of Medicine. RESULTS From January 1, 1996, through December 31, 2003, a total of 3662 episodes of PHA-BSIs occurred in adults (2.42 BSIs per 1000 patient-days). The annual incidence of PHA- BSIs did not change significantly during the study period (range, BSIs per 1000 patient-days). Approximately 16% of all episodes were polymicrobial, resulting in 4349 bacterial and fungal isolates. The annual proportion of PHA-BSIs that was polymicrobial did not change significantly during the study period (mean, 15.7% [range, 11.6%-18.8%]). There was a mean±sd of 21.5±2.4 days from admission to the onset of PHA-BSIs, and this did not vary significantly during the study period (annual mean range, days [total range, days]). The annual proportion of PHA-BSIs accounted for by S aureus, CNS, gram-negative organisms, and Candida species changed markedly during the study period (Figure 1). From 1999 to 2003, the proportion of PHA- BSIs due to gram-negative organisms increased from 15.9% in 1999 to 24.1% in 2003 (P.001 for trend). During this same period, CNS decreased to 29.9% in 2003 from 33.5% in 1999 (P=.007). Similarly, S aureus decreased to 11.8% in 2003 from 18.8% in 1999 (P=.004). The proportion of PHA-BSIs due to Candida species almost doubled from 5.8% in 1999 to 11.3% in 2003 (P=.002). In 1999, gram-negative organisms ranked fourth after CNS, enterococci, and S aureus, but by 2003, % Gram-Negative Organisms Among Total Isolates Medical ICU (P =.05) Other Floors (P =.002) Oncology (P =.33) Surgical ICU (P =.37) Year Figure 2. Gram-negative primary health care associated bloodstream infection trends by hospital location. P values indicate P for trend from 1999 to 2003 (overall P=.38). ICU indicates intensive care unit. gram-negative organisms surpassed enterococci and S aureus to rank second only to CNS as a cause of PHA-BSIs. Furthermore, the proportion of PHA-BSIs in 2003 caused by Candida species (11.3%) approximately equals the proportion due to S aureus (11.9%). There were no significant trends for any of the others among the 10 most commonly isolated organisms (data not shown). Neither the rate of PHA-BSIs due to gram-negative organisms at any given time nor the trend over time differed significantly by hospital location (P=.38 for both) (Figure 2). There was a significant correlation of the annual proportion of PHA-BSIs due to gram-negative organisms with the annual hospitalwide use of levofloxacin (P.001) but not with the use of any other antibiotic assessed. The specific microbial etiology among gram-negative organisms did not change significantly during the study period, and no particular organism contributed disproportionately to the rise in PHA-BSIs from gram-negative organisms. For the study period, the following 4 species accounted for more than 70% of all PHA-BSIs due to gramnegative organisms: Klebsiella species (24.3%), E coli (19.0%), Pseudomonas species (14.8% [ 99% P aeruginosa]), and Enterobacter species (14.8%). There were no significant trends over time in the proportion of PHA- BSIs caused by these organisms (Figure 3). Between 85% and 92% of all PHA-BSIs each year were associated with the use of a CVC, and these proportions did not vary significantly across study years. When analyzing only CVC-associated infections, the results were not substantially different from those in the primary analysis (data not shown). Of 2898 PHA-BSIs from 1999 to 2003, a total of 2620 (90.4%) were associated with a CVC. Of these, 1119 (42.7%) involved a triple-lumen catheter, while 712 (27.2%) involved a PICC. Temporal trends in PHA-BSIs due to gram-negative organisms from 1999 to 2003 did not differ significantly when comparing patients who had and those who did not have a triplelumen catheter (P=.94) or when comparing patients who had and those who did not have a PICC (P=.78) Among hospitalwide inpatient bloodstream isolates of K pneumoniae, E coli, and P aeruginosa, there was no increase in resistance for any of the organism-antibiotic com- 1291

4 % Organisms Among GN Isolates Other GN Anaeorobic GN Pseudomonas Species Year binations studied from 1999 to For E cloacae, susceptibility rates declined from 1999 to 2003 for aztreonam (96% in 1999 to 67% in 2003, P=.005), ceftazidime (96% in 1999 to 63% in 2003, P=.003), and trimethoprimsulfamethoxazole (100% in 1999 to 74% in 2003, P=.05). Among the isolates in the PHA-BSI database, there were no significant increases in resistance from 1999 to 2003 for any of the organism-antibiotic combinations except for a decline in E cloacae susceptibilities to aztreonam (100% in 1999 to 64% in 2003, P.01) and levofloxacin (100% in 1999 to 80% in 2003, P=.04). COMMENT Klebsiella Species Enterobacter Species Escherichia coli Figure 3. Distribution of gram-negative primary health care associated bloodstream infections. GN indicates gram negative. We found a significant increase in the proportion of PHA- BSIs caused by gram-negative organisms from 1999 to By 2003, gram-negative organisms had surpassed enterococci and S aureus and ranked second only to CNS as a cause of PHA-BSIs. This increase in gram-negative organisms was observed across all hospital locations, and no particular species contributed disproportionately to the overall increase. With few exceptions, there was no increase in antimicrobial resistance among gramnegative organisms during the study period, and the increase in gram-negative organisms was seen in patients regardless of the use of specific types of CVCs. Finally, the annual incidence of PHA-BSIs did not change significantly during the study period. Before the onset of these trends in 1999, the frequency of gram-negative organisms as a cause of PHA-BSIs at our institution was similar to that among the NNIS System ICUs during the 1990s. 17,18 Comparing our data with those of the NNIS System needs to be done cautiously because the NNIS System during the 1990s was limited to ICUs, whereas our analysis is hospitalwide. Furthermore, the NNIS System summary does not report longitudinal trends in the proportion of infections caused by different groups of organisms (eg, gram negative). 19 Although other large prevalence and surveillance studies 11,20-27 have been performed in the last 10 years, all of them include secondary BSIs, and some include community-acquired BSIs. As such, E coli and other gram-negative organisms account for the higher proportions of BSIs in these studies. To our knowledge, ours is the first US study to report an increase in the proportion of PHA-BSIs due to gram-negative organisms in adults. Most other studies 3,6,9,18 have reported consistent increases in health care associated BSIs due to grampositive organisms, particularly CNS. The frequency of gram-negative organisms has been constant or declining in these investigations. 28 A study 29 in England and Wales from 1990 to 1998 reported significant annual increases for 7 organisms, 4 of which were gram-negative organisms (Acinetobacter species, Serratia species, Citrobacter species, and Enterobacter species). However, in addition to secondary BSIs, this study included communityacquired infections. The observed shift in the microbial etiology of PHA- BSIs at our institution suggests that selection of empirical therapy will become increasing complex given the recent increases in antibiotic resistance among gram-negative pathogens Our observed rise of gram-negative organisms as a cause of PHA-BSIs is particularly concerning given the lack of development of new antimicrobial agents. In addition to its effect on antimicrobial therapy and resistance, the shift in PHA-BSI organisms has important implications for patient outcomes. Mortality from BSIs varies significantly for different organisms and generally is highest for Candida species and is lowest for CNS. 11,19 Infections with gram-negative organisms are associated with worse outcomes. 8,11,37-40 In addition, patients with gramnegative infections frequently receive inadequate empirical therapy because of antimicrobial resistance, 41 which in turn is an important predictor of mortality. 42 We also evaluated the potential role of the use of triplelumen catheters in the microbial etiology of PHA-BSIs. Our institution introduced triple-lumen catheters that were coated with silver sulfadiazine chlorhexidine in Because these coated catheters are believed to more selectively inhibit growth of gram-positive organisms compared with gram-negative organisms and yeast, we hypothesized that this may have played a role in the changing microbial etiology of PHA-BSIs. The increase in the proportion of PHA-BSIs due to gram-negative organisms did not differ significantly among patients who had and those who did not have a triple-lumen catheter, and the substitution of the coated catheters in our institution is an unlikely explanation for the observed trends. Other possible explanations for the observed microbial trends include differences in patient populations over time and changes in CVC use other than the use of coated catheters. Differences in patient populations could not directly be evaluated but are unlikely to account for the observed trends because the changes were seen hospitalwide among all patient groups. Other potential changes in the practice of CVC use, such as line location or catheter type (other than triple-lumen catheters), were not formally examined. However, we do not have any reason to believe that line location practices or types of catheters (other than coated catheters) changed signifi- 1292

5 cantly during these 5 years. The observed trends were similar among patients who had and those who did not have a CVC. However, because most PHA-BSIs occurred in patients who had a CVC, differences among patients who had and those who did not have a CVC may have been difficult to detect given the few patients who did not have a CVC. We found a significant correlation between the annual hospitalwide use of levofloxacin therapy and the proportion of PHA-BSIs due to gram-negative organisms. However, the ecologic nature of these analyses limits the degree to which causal inferences can be made. In addition, we did not find significant increases in resistance as a possible explanation for increases in PHA-BSIs due to gram-negative organisms. Our study has several potential limitations. It is possible that a small percentage of BSI episodes each year were misclassified as to health care associated vs community acquired, primary vs secondary, or infection vs colonization or contaminant. However, it is unlikely that the number of misclassifications each year varied significantly over time because data were collected by the same infection control practitioner staff according to the same protocols and definitions. Therefore, any potential misclassifications should not have significantly affected the results of the study. Finally, the study was designed to specifically assess trends within our institution. Given differences in patient characteristics, antimicrobial use patterns, and other patient care and hospital factors (such as the use of CVCs, the frequency of invasive procedures, and the type of surgical procedures), our results may not be generalizable to other institutions. In summary, our study reports a reemergence of gramnegative organisms as a cause of PHA-BSIs among adults. Although the explanation for this finding remains unclear, it does not seem to be related to changes in specific gram-negative organisms, to antimicrobial resistance, or to the introduction of catheters coated with silver sulfadiazine chlorhexidine. This trend has important implications for the management of BSIs. Confirmation of these findings at other institutions would be valuable. Accepted for Publication: February 22, Correspondence: Ebbing Lautenbach, MD, MPH, MSCE, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 825 Blockley Hall, 423 Guardian Dr, Philadelphia, PA (elautenb@cceb.med.upenn.edu). Author Contributions: Dr Albrecht had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Financial Disclosure: None. Funding/Support: This study was supported by Public Health Service grant DK from the National Institutes of Health (Dr Lautenbach) and by Center for Education and Research on Therapeutics grant U18- HS10399 from the Agency for Healthcare Research and Quality. Previous Presentation: This study was presented in abstract form (Abstract 387) at the 14th Annual Meeting of the Society for Healthcare Epidemiology of America; April 19, 2004; Philadelphia. REFERENCES 1. Centers for Disease Control and Prevention. Public health focus: surveillance, prevention, and control of nosocomial infections. MMWR Morb Mortal Wkly Rep. 1992;41: Richards MJ, Edwards JR, Culver DH, Gaynes RP. Nosocomial infections in combined medical-surgical intensive care units in the United States. Infect Control Hosp Epidemiol. 2000;21: Pittet D, Wenzel RP. Nosocomial bloodstream infections: secular trends in rates, mortality, and contribution to total hospital deaths. Arch Intern Med. 1995; 155: Pittet D, Tarara D, Wenzel RP. Nosocomial bloodstream infection in critically ill patients: excess length of stay, extra costs, and attributable mortality. JAMA. 1994; 271: Maki DG. Nosocomial bacteremia: an epidemiologic overview. Am J Med. 1981; 70: Banerjee SN, Emori TG, Culver DH, et al. Secular trends in nosocomial primary bloodstream infections in the United States, : National Nosocomial Infections Surveillance System. AmJMed. 1991;91:86S-89S. 7. Weinstein MP, Towns ML, Quartey SM, et al. The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults. Clin Infect Dis. 1997;24: Hugonnet S, Harbarth S, Ferriere K, Ricou B, Suter P, Pittet D. Bacteremic sepsis in intensive care: temporal trends in incidence, organ dysfunction, and prognosis. Crit Care Med. 2003;31: Thylefors JD, Harbarth S, Pittet D. Increasing bacteremia due to coagulasenegative staphylococci: fiction or reality? Infect Control Hosp Epidemiol. 1998; 19: Edgeworth JD, Treacher DF, Eykyn SJ. A 25-year study of nosocomial bacteremia in an adult intensive care unit. Crit Care Med. 1999;27: Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study [published correction appears in Clin Infect Dis. 2004;39:1093]. Clin Infect Dis. 2004;39: Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report: August 9, MMWR Morb Mortal Wkly Rep. 2002;51: Murray PRBE, Jorgenson JH, Pfaller MA, Yolken RH. Manual of Clinical Microbiology. 8th ed. Washington, DC: American Society for Microbiology; National Committee for Clinical Laboratory Standards (NCCLS). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically.5th ed. Wayne, Pa: NCCLS; NCCLS-approved standard M7-A5, document National Committee for Clinical Laboratory Standards (NCCLS). Performance Standards for Antimicrobial Susceptibility Testing. Wayne, Pa: NCCLS; NCCLSapproved standard M100-S Armitage P. Test for linear trend in proportions and frequencies. Biometrics. 1955; 11: National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1990 May 1999, issued June Am J Infect Control. 1999; 27: Richards MJ, Edwards JR, Culver DH, Gaynes RP. Nosocomial infections in medical intensive care units in the United States: National Nosocomial Infections Surveillance System. Crit Care Med. 1999;27: National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October Am J Infect Control. 2004;32: Pfaller MA, Jones RN, Doern GV, Kugler K. Bacterial pathogens isolated from patients with bloodstream infection: frequencies of occurrence and antimicrobial susceptibility patterns from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 1997). Antimicrob Agents Chemother. 1998; 42: Vincent JL, Bihari DJ, Suter PM, et al; EPIC International Advisory Committee. The prevalence of nosocomial infection in intensive care units in Europe: results of the European Prevalence of Infection in Intensive Care (EPIC) Study. JAMA. 1995;274: Sader HS, Jones RN, Andrade-Baiocchi S, Biedenbach DJ; SENTRY Participants Group (Latin America). Four-year evaluation of frequency of occurrence and antimicrobial susceptibility patterns of bacteria from bloodstream infections in Latin American medical centers. Diagn Microbiol Infect Dis. 2002;44: Diekema DJ, Pfaller MA, Jones RN, et al; SENTRY Participants Group. Trends in antimicrobial susceptibility of bacterial pathogens isolated from patients with bloodstream infections in the USA, Canada and Latin America. Int J Antimicrob Agents. 2000;13: Diekema DJ, Pfaller MA, Jones RN, et al. Survey of bloodstream infections due 1293

6 to gram-negative bacilli: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, and Latin America for the SENTRY Antimicrobial Surveillance Program, Clin Infect Dis. 1999;29: Fluit AC, Jones ME, Schmitz FJ, Acar J, Gupta R, Verhoef J. Antimicrobial susceptibility and frequency of occurrence of clinical blood isolates in Europe from the SENTRY Antimicrobial Surveillance Program, 1997 and Clin Infect Dis. 2000;30: Fluit AC, Verhoef J, Schmitz FJ, European SP. Frequency of isolation and antimicrobial resistance of gram-negative and gram-positive bacteria from patients in intensive care units of 25 European university hospitals participating in the European arm of the SENTRY Antimicrobial Surveillance Program Eur J Clin Microbiol Infect Dis. 2001;20: Fluit AC, Schmitz FJ, Verhoef J; European SENTRY Participant Group. Frequency of isolation of pathogens from bloodstream, nosocomial pneumonia, skin and soft tissue, and urinary tract infections occurring in European patients. Eur J Clin Microbiol Infect Dis. 2001;20: Rosenthal EJ. Epidemiology of septicaemia pathogens [in German]. Dtsch Med Wochenschr. 2002;127: Reacher MH, Shah A, Livermore DM, et al. Bacteraemia and antibiotic resistance of its pathogens reported in England and Wales between 1990 and 1998: trend analysis. BMJ. 2000;320: Bell JM, Turnidge JD, Gales AC, Pfaller MA, Jones RN; SENTRY APAC Study Group. Prevalence of extended spectrum -lactamase (ESBL) producing clinical isolates in the Asia-Pacific region and South Africa: regional results from SENTRY Antimicrobial Surveillance Program ( ). Diagn Microbiol Infect Dis. 2002; 42: Lautenbach E, Patel JB, Bilker WB, Edelstein PH, Fishman NO. Extendedspectrum -lactamase producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes. Clin Infect Dis. 2001;32: NNIS System. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2003, issued August Am J Infect Control. 2003;31: Diekema DJ, BootsMiller BJ, Vaughn TE, et al. Antimicrobial resistance trends and outbreak frequency in United States hospitals. Clin Infect Dis. 2004;38: Fridkin SK, Steward CD, Edwards JR, et al; Project Intensive Care Antimicrobial Resistance Epidemiology (ICARE) Hospitals. Surveillance of antimicrobial use and antimicrobial resistance in United States hospitals: project ICARE phase 2. Clin Infect Dis. 1999;29: Karlowsky JA, Kelly LJ, Thornsberry C, et al. Susceptibility to fluoroquinolones among commonly isolated gram-negative bacilli in 2000: TRUST and TSN data for the United States: Tracking Resistance in the United States Today: The Surveillance Network. Int J Antimicrob Agents. 2002;19: Lautenbach E, Strom BL, Nachamkin I, et al. Longitudinal trends in fluoroquinolone resistance among Enterobacteriaceae isolates from inpatients and outpatients, : differences in the emergence and epidemiology of resistance across organisms. Clin Infect Dis. 2004;38: Weinstein MP, Reller LB, Murphy JR, Lichtenstein KA. The clinical significance of positive blood cultures: a comprehensive analysis of 500 episodes of bacteremia and fungemia in adults, I: laboratory and epidemiologic observations. Rev Infect Dis. 1983;5: Gatell JM, Trilla A, Latorre X, et al. Nosocomial bacteremia in a large Spanish teaching hospital: analysis of factors influencing prognosis. Rev Infect Dis. 1988; 10: Kreger BE, Craven DE, McCabe WR. Gram-negative bacteremia, IV: reevaluation of clinical features and treatment in 612 patients. Am J Med. 1980; 68: Raymond DP, Pelletier SJ, Crabtree TD, Evans HL, Pruett TL, Sawyer RG. Impact of antibiotic-resistant gram-negative bacilli infections on outcome in hospitalized patients. Crit Care Med. 2003;31: Zaragoza R, Artero A, Camarena JJ, Sancho S, Gonzalez R, Nogueira JM. The influence of inadequate empirical antimicrobial treatment on patients with bloodstream infections in an intensive care unit. Clin Microbiol Infect. 2003;9: Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118: Correction Error in Correspondence Address. In the Original Investigation by Vukanovic-Criley et al titled Competency in Cardiac Examination Skills in Medical Students, Trainees, Physicians, and Faculty: A Multicenter Study, published in the March 27 issue of the ARCHIVES (2006;166: ), an error occurred in the correspondence address. It should have appeared as follows: Jasminka M. Vukanovic-Criley, MD, 170 Alameda de las Pulgas, Redwood City, CA (jmcriley@gmail.com). 1294