Nosocomial Bloodstream Infections: Organisms, Risk Factors, and Implications

S139 Nosocomial Bloodstream Infections: Organisms, Risk Factors, and Implications Adolf W. Karchmer Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts In the last 30 years, the frequency, etiology, and epidemiology of bloodstream infections (BSIs) have changed with the evolution of medical care, particularly among the increasing number of hospitalized patients who require intensive care. Although gram-negative bacilli were the predominant nosocomial pathogens in the 1970s, gram-positive cocci have emerged as a more frequent cause of nosocomial BSIs during the 1980s and 1990s. Many gram-positive cocci associated with nosocomial BSIs are now resistant to commonly used antibiotics. Currently, the 3 most common causes of nosocomial BSIs in the United States are coagulasenegative staphylococci, Staphylococcus aureus, and enterococci. The emergence of vancomycin-resistant staphylococcal infections is of particular concern. In addition, the incidence of methicillin-resistant S. aureus (MRSA) infections appears to be increasing; however, the effect of MRSA infection on mortality in hospitalized patients remains unclear. Therefore, newer, more effective antimicrobial therapies are needed to treat BSIs caused by gram-positive cocci are needed. Bloodstream infections (BSIs), which represent the failure of the immune system to contain infection at a focal site and consequent disseminated disease, are a major cause of morbidity and mortality. The frequency of these infections, their epidemiology, and the invading organisms have changed in parallel with the evolution of medical care, particularly with the emergence of an increasingly ill and immunocompromised population of hospitalized patients who are often heavily dependent on medical support and indwelling devices. Currently, slightly more than 50% of BSIs are hospital acquired [1, 2]. It is estimated that hospitalized patients in the United States have 250,000 episodes of nosocomial BSIs annually, and when these infections occur in patients in intensive care units, they are associated with an attributable mortality rate of 35%, 24 additional hospital days, and excess hospital costs of $40,000 per survivor [3]. Trends in the Etiology of BSIs With the development of potent antistaphylococcal b-lactam agents, Staphylococcus aureus gave way to gram-negative bacilli, often Enterobacteriaceae, as the predominant nosocomial pathogens in the 1970s. Nearly 75% of nosocomial infections were caused by gram-negative bacilli. However, by the early 1980s, a change in the spectrum of nosocomial pathogens was apparent, and gram-positive cocci began to reemerge as predominant nosocomial pathogens. The resurgence of gram-positive cocci as Reprints or correspondence: Dr. Adolf W. Karchmer, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Kennedy-6, Boston, MA 02215 (akarchme @caregroup.harvard.edu). Clinical Infectious Diseases 2000;31(Suppl 4):S139 43 2000 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2000/310S4-0004$03.00 causes of nosocomial infections is illustrated by the frequency of nosocomial BSIs caused by gram-positive cocci at the University of Iowa Hospital and Clinic from 1981 through 1992 (table 1). From 1981 through 1983, gram-negative bacilli were recovered in 52% of the episodes of nosocomial BSIs and gram-positive cocci were recovered in 42%; however, from 1990 through 1992, gram-positive cocci accounted for 54% of these episodes and gram-negative rods accounted only for 29% [4]. The greater role of gram-positive cocci as causes of nosocomial BSIs continues and is a nationwide phenomenon as illustrated by data from 49 hospitals across the United States that participate in the Surveillance and Control of Pathogens of Epidemiologic Importance Project (SCOPE) [5]. From April 1995 through April 1998, the three most common causes of nosocomial BSIs in these institutions (in descending order) were coagulase-negative staphylococci, S. aureus, and enterococci. Gram-positive cocci were isolated in 64% of 10,617 episodes of nosocomial bacteremia, whereas gram-negative bacilli were isolated in 27%. BSIs Caused by Gram-Positive Cocci: A Closer Look It is interesting to take a more detailed look at the epidemiology and clinical significance of BSIs caused by gram-positive cocci. The time to onset of bacteremia varies depending on the infecting organism. Nosocomial bacteremia caused by viridans streptococci and S. aureus occurs earlier during hospitalization than does bacteremia caused by gram-negative bacilli, Candida, and enterococci. The average time to onset of bacteremia caused by streptococci and S. aureus is 2 weeks after the start of hospitalization. Gram-negative bacilli, Candida, and enterococci are encountered in blood cultures on average a week or so longer after the start of hospitalization. The mean time to

S140 Karchmer CID 2000;31 (Suppl 4) Table 1. Trends in nosocomial bloodstream infections from 1981 through 1992 at the University of Iowa Hospital and Clinic. Organisms No. (%) of organisms isolated 1981 1983 1984 1986 1987 1989 1990 1992 Gram-positive cocci 276 (42) 448 (44) 586 (55) 700 (54) Coagulase-negative staphylococci 79 (12) 175 (17) 254 (24) 391 (30) Staphylococcus aureus 115 (17) 120 (12) 150 (14) 167 (13) Streptococci 39 (6) 69 (6.8) 68 (6.4) 41 (3.2) Enterococci 7 (1) 37 (3.6) 61 (5.7) 48 (3.7) Gram-negative rods 342 (52) 458 (45) 370 (35) 376 (29) Candida species 17 (2.5) 68 (6.7) 74 (6.9) 92 (7.1) Total no. of pathogens 663 (100) 1018 (100) 1066 (100) 1291 (100) Total no. of episodes 593 861 903 1107 NOTE. Data are from [4]. onset of bacteremia caused by coagulase-negative staphylococci is 19 days after the start of hospitalization [5]. Organisms causing nosocomial BSIs vary depending on the location of patients within the institution. Coagulase-negative staphylococci are more likely to be isolated from cultures of blood specimens from patients in intensive care settings, whereas viridans streptococci and S. aureus are more commonly isolated from ward patients. Enterococci are isolated with similar frequency from patients in both settings. BSIs caused by viridans streptococci are associated with neutropenia and are commonly observed in patients on the hematology and oncology services. Crude mortality rates among patients with BSIs caused by these gram-positive cocci range from 17% to 32%; the lowest mortality rates are associated with coagulase-negative staphylococci, and the highest mortality rates have been noted among patients with enterococcal bacteremia [5, 6]. Resistance to many of the antibiotics used to treat infections caused by gram-positive cocci is now commonplace in the isolates associated with nosocomial BSIs. In the SCOPE study [5], 80% of 3908 coagulase-negative staphylococci causing BSIs were resistant to methicillin and other b-lactam antibiotics, as were 29% of 1928 S. aureus isolates. Resistance to vancomycin was noted in 18% of all enterococci. Within the enterococci, resistance was notably segregated to Enterococcus faecium; among this species, the frequency of resistance to vancomycin was 50%, and that of resistance to ampicillin was 80%. Enterococci. The evolution of serious infections caused by enterococci can be observed by comparing the site or source of infection in 2 periods (table 2). The major changes observed between the cases encountered from 1970 through 1983 and those encountered more recently (through 1992) are an increase in catheter-related and primary bacteremia and a decrease in intra-abdominal infections in the more recent period [7, 8]. Although enterococcal infections were more commonly nosocomial during the earlier period than during the later period (77% vs. 61%, respectively), mortality rates were higher during the later period (16% vs. 23%, respectively). Of 478 enterococci causing nosocomial BSIs in SCOPE hospitals during 1995 and 1996, 288 (60%) were Enterococcus faecalis, 96 (20%) were E. Table 2. The clinical site or source of serious enterococcal infections in 2 different periods. Site or source of infection 1970 1983 a (n p 153) No. (%) of infections 1992 b (n p 110) Catheter-related bacteremia 24 (16) 31 (28) Primary bacteremia 18 (12) 20 (18) Endocarditis 14 (9) 7 (6) Phlebitis 1 (1) Intra-abdominal 43 (28) 14 (13) Genitourinary 25 (16) 14 (13) Other 29 (19) 23 (21) a Data are from [7]. b Data are from [8]. faecium, 79 (16%) were not identified to the species level, and the remaining 15 (3%) were distributed among uncommonly encountered species (Enterococcus raffinosus, Enterococcus durans, Enterococcus avium, Enterococcus gallinarum, and Enterococcus casseliflavus) [9]. A comparison of the experience of the SCOPE hospitals from 1995 through 1998 [5] with the reports from the Centers for Disease Control and Prevention from the late 1980s and early 1990s suggests that the distribution within hospitals of those patients with infections caused by vancomycin-resistant enterococci has shifted. Although vancomycin resistance was noted more frequently in enterococci isolated from patients in intensive care settings during the earlier period, the SCOPE data indicate that vancomycin-resistant enterococci caused bacteremia more often in ward patients than in those in intensive care units. Of enterococci isolated from blood cultures, vancomycin-resistant enterococci were recovered more frequently from patients on wards than from patients in intensive care units in 1996 and 1997 (19.6% vs. 15.9% and 24.9% vs. 18.4%, respectively) [5]. A number of risk factors have been associated with nosocomial infections and BSIs caused by vancomycin-resistant enterococci (table 3) [10]. A recent study, however, illustrates how the choice of a control group can alter the apparent significance of potential risk factors [11]; in a meta-analysis, the elimination of confounding factors, including length of stay and selection of controls (sources of heterogeneity in the analysis), rendered the relationship between vancomycin exposure and subsequent infection or colonization with vancomycin-resistant enterococci small and not statistically significant. Increased resistance in enterococci adversely impacts the choices of antimicrobial therapy available for enterococcal infections. Sahm et al. [12] studied ampicillin and vancomycin susceptibilities in enterococci collected from 118 hospital microbiology laboratories in the United States. They reported that of 2125 E. faecalis isolates from blood cultures 95% were susceptible to both ampicillin and vancomycin, 4% were susceptible to vancomycin only, 1.3% were susceptible to ampicillin only, and 0.1% were resistant to both ampicillin and vancomycin. In contrast, of 715 E. faecium isolates, only 25% were susceptible to both ampicillin and vancomycin, 31% were sus-

CID 2000;31 (Suppl 4) Nosocomial Bloodstream Infections S141 Table 3. Risk factors associated with infection and bacteremia caused by vancomycin-resistant enterococci. Demographic factors (length of hospitalization and location in hospital) Antibiotic exposure (cephalosporins, vancomycin and metronidazole) Severity of illness Iatrogenic noninvasive interventions (immunosuppression) Iatrogenic invasive interventions (surgery and solid organ transplantation) ceptible to vancomycin only, 0.3% were susceptible to ampicillin only, and 44% were resistant to both ampicillin and vancomycin. In addition to the limitations of cell wall active bacteriostatic agents for the treatment of infections caused by E. faecium, the ability to achieve bactericidal synergy against E. faecium and E. faecalis is restricted by extensive distribution of genes that mediate high-level resistance to gentamicin and streptomycin [9]. Of E. faecalis and E. faecium isolates from the SCOPE program in 1995 1996, 25% and 33% and 52% and 58%, respectively, had high-level resistance to gentamicin and streptomycin. Isolates commonly have high-level resistance to both aminoglycosides, which precludes synergistic therapy. Although antibiotic resistance clearly limits therapeutic options for treating enterococcal infections, it is not clear whether resistance to vancomycin in infecting enterococci is associated with increased mortality. This lack of effect on mortality could be because vancomycin-resistant enterococci have intrinsically low virulence or because of the presence of more outcomedefining comorbid conditions in patients who develop infections with the resistant organisms. In 7 studies, comparisons of mortality rates among patients with BSIs caused by vancomycin-susceptible and vancomycin-resistant enterococci revealed higher rates among those infected with vancomycinresistant organisms [10]. The differences in mortality rates between the 2 groups ranged from 2% to 44%. These differences, however, may be less a consequence of the differences between the organisms themselves than differences among the patients who are infected or among the site-specific infections caused by resistant and susceptible organisms. A comparison of outcomes for patients with BSIs caused by enterococci with and without high-level resistance to aminoglycosides reveals only marginal increases in mortality rates among patients with infections caused by organisms highly resistant to aminoglycosides [13, 14]. On the other hand, in patients with endocarditis, a disease for which bactericidal therapy is required for cure, antibiotic therapy commonly fails to eradicate enterococci when the strain is highly resistant to aminoglycosides and synergistic bactericidal therapy is not possible. However, bacteriologic eradication is achieved in at least 85% of cases for which synergistic therapy is possible. Staphylococci. As noted earlier, resistance to methicillin has become relatively commonplace in staphylococci causing BSI. The rate of resistance to vancomycin, as evidenced by the percent of strains for which MICs are 4 mg/ml, has increased from 1.8% among coagulase-negative staphylococci isolated in 1995 to 4.1% and 5.0% among isolates recovered in 1996 and 1997, respectively [12]. Resistance to vancomycin in Staphylococcus haemolyticus has been noted, and both intermediate resistance and full resistance to teicoplanin have been reported in coagulase-negative staphylococci, most of which were Staphylococcus epidermidis [15, 16]. Significant resistance to vancomycin had not been encountered in S. aureus until recently, when vancomycin intermediate strains were reported in Japan and the United States [17, 18]. Although coagulase-negative staphylococci are the most common isolates associated with nosocomial BSIs in recent years, their role as a cause of morbidity and mortality is difficult to ascertain. Because these organisms commonly contaminate blood cultures, identifying patients with true bacteremia may be difficult. By using relatively stringent criteria for coagulase-negative staphylococcal BSIs, the rate of mortality attributable to the bacteremia that is, the residual rate after subtracting the mortality rate among a matched nonbacteremic cohort has been 13% [19] and 18% [20]. Nevertheless, in a multivariate analysis of factors influencing mortality after nosocomial BSIs, infection caused by coagulase-negative staphylococci was associated with a trend toward reduced mortality, although this difference was not statistically significant [6]. A comparison of cases of S. aureus BSI encountered from 1980 through 1983 with those observed from 1990 through 1993 illustrates some changes in the epidemiology of this infection (table 4). During the later 3-year period, rates of communityacquired bacteremia and nosocomial bacteremia increased, the rate of intravascular device associated nosocomial bacteremia increased, and catheter-related community-acquired (onset) bacteremia was first noted. During the later period, methicillin resistance was noted more frequently in staphylococci, causing both nosocomial bacteremia and community-acquired S. aureus bacteremia. Of note, methicillin-resistant S. aureus (MRSA) causing community-acquired BSI was encountered predominantly in patients who resided in nursing homes or had extensive previous contact with hospitals [21]. More recently, however, reports have suggested that MRSA is being encountered as a true community-acquired pathogen [22, 23]. The increased frequency of the methicillin-resistant phenotype among S. aureus that causes nosocomial BSIs is confirmed by the findings of the SCOPE program, which found that 29% of S. aureus isolates recovered from 1995 through 1998 were methicillin resistant [5]. The risk factors associated with BSIs caused by MRSA include extensive prior antibiotic therapy, prolonged hospitalization, presence of indwelling central venous catheters, severe comorbid diseases, and nasal colonization with MRSA. The relative morbidity of BSIs caused by MRSA compared with BSIs caused by methicillin-susceptible S. aureus remains an issue of controversy. Although methicillin resistance in S. aureus strains that cause infection significantly limits the antimicrobials available for treatment, it is not clear whether these organisms are associated with increased morbidity and mor-

S142 Karchmer CID 2000;31 (Suppl 4) Table 4. Atlanta. The changing epidemiology of Staphylococcus aureus bacteremia in Finding 1980 1983 1990 1993 No. of community-acquired cases, per 1000 discharges 0.84 2.43 No. of nosocomial cases, per 1000 discharges 0.75 2.80 No. of intravascular device associated cases/total no. of cases (%) Nosocomial 16/65 (25) 128/230 (56) Community-acquired 0/74 43/200 (22) a No. of cases caused by methicillin-resistant S. aureus/total no. of cases (%) Nosocomial 1/65 (2) 73/230 (32) Community-acquired 1/74 (1) 37/200 (19) b NOTE. Data are from [21]. a Observed in patients with renal failure, AIDS, sickle-cell disease, and cancer. b Increased contact with hospitals and nursing homes. tality relative to comparable infections caused by susceptible S. aureus. Romero-Vivas et al. [24] compared outcomes of S. aureus bacteremia for 100 patients infected with methicillinsusceptible organisms with those for 84 patients infected with methicillin-resistant isolates. Patients infected with methicillinresistant organisms had inferior outcomes compared with those infected with susceptible S. aureus as measured by the overall mortality rate (58% vs. 32%, respectively), the rate of mortality attributed to S. aureus infection (42% vs. 22%, respectively), and the mortality rate among patients receiving adequate antimicrobial therapy (18 [29%] of 62 vs. 11 [13%] of 83, respectively). In a multivariate analysis that used stepwise logistic regression to adjust for confounding variables, infection with methicillin-resistant organisms was associated with a higher mortality rate. Of note, however, patients with MRSA bacteremia had been hospitalized nearly twice as long before they developed bacteremia (mean, 31.9 vs. 14.5 days, respectively), had longer hospitalizations (mean, 63 vs. 39 days, respectively), and were older (mean, 69 vs. 54 years, respectively) than those with bacteremia caused by methicillin-susceptible staphylococci findings that may belie significant intrinsic differences in the 2 patient populations that may have affected outcome. Harbarth et al. [25] performed a matched case-control study of patients with bacteremia caused by MRSA and patients with bacteremia caused by methicillin-susceptible S. aureus. Analysis of the total bacteremic population from which the cases were derived showed that patients with BSIs caused by methicillinresistant organisms had longer hospitalizations before they developed bacteremia ( 32 34 vs. 8 15 days, respectively), had nosocomial bacteremia more frequently (74% vs. 52%, respectively), had longer total mean hospitalizations (73 vs. 27 days, respectively), and had higher crude mortality rates (36% vs. 28%, respectively) than did patients with BSIs caused by methicillinsusceptible organisms. However, when the 38 patients with MRSA bacteremia were compared with a rigorously matched group with bacteremia caused by methicillin-susceptible organisms, the outcomes were similar (table 5). Viridans streptococci. Examination of the antimicrobial susceptibility patterns of viridans streptococci that were isolated in the SCOPE hospitals from 1994 through 1996 reveals significant antibiotic resistance in these organisms [26]. MICs for 150 isolates were as follows: 14 mg of penicillin/ml, 9%; 18 mg of ceftriaxone/ml, 10%; and 10.25 mg of erythromycin/ml, 44%. Similarly, Doern et al. [27] have reported increasing antibiotic resistance in recent bloodstream isolates of viridans streptococci. Of 352 isolates from 43 U.S. medical centers, 13% had high-level penicillin resistance (MIC, 4.0 mg/ml), and 43% had intermediate penicillin resistance (MIC, 10.25 to 2.0 mg/ml); ceftriaxone resistance (MIC, 12 mg/ml) was noted in 17% of isolates. Table 5. Comparison of outcomes of bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) and to methicillin-susceptible S. aureus (MSSA): matched case-control analysis for 38 patients. Finding MRSA bacteremia MSSA bacteremia No. of positive blood cultures 4.8 4.7 No. (%) of patients with complications 8 (21) 15 (39) No. (%) of patients receiving adequate therapy 35 (92) 37 (97) Total no. (%) of deaths (hospital) 13 (34) 13 (34) No. (%) of deaths caused by S. aureus infection 7 (18) 9 (24) No. of deaths caused by bacteremia/total no. of cases (%) Community-acquired 2/9 (22) 2/14 (14) Nosocomial 11/29 (38) 11/24 (46) NOTE. Data are from [25].

CID 2000;31 (Suppl 4) Nosocomial Bloodstream Infections S143 Summary It seems that the past decade has seen the reemergence of gram-positive cocci as the predominant cause of nosocomial BSIs in the United States. In addition, in each of the genera of gram-positive cocci causing these BSIs, notable antimicrobial resistance is present. It is difficult to distinguish whether the morbidity and mortality rates in patients that are associated with infection caused by antibiotic-resistant species (as compared with their antibiotic-susceptible equivalents) relate to features that are intrinsic to the resistant strains and available therapy or to characteristics that are unique to the patients infected with each strain. Nevertheless, it seems obvious that options for effective antimicrobial therapy are becoming increasingly limited. Furthermore, in time, the absence of effective therapy will cause morbidity and mortality to increase. In addition, although the data presented here are derived from the United States, the concerns are global. Data from the SENTRY Antimicrobial Surveillance Program [28] confirm the importance of gram-positive cocci as causes of BSIs and the notable antibiotic resistance present in staphylococci, streptococci, and enterococci in both North America and Latin America. Thus, there are mandates to develop new effective antimicrobial therapies for infections caused by gram-positive cocci, to intensify efforts to limit the spread of resistance in these organisms, and to reduce the nosocomial transmission of and infection with these organisms. References 1. 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;24:584 602. 2. Bryan CS, Hornung CA, Reynolds KL, Brenner ER. 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