Measuring impact of antimicrobial resistance.

To the Editor: Staphylococcus aureus and Enterococcus faecium commonly cause healthcare-associated bloodstream infections (BSI) in the intensive care unit (ICU). Antimicrobial resistance is increasing in both organisms. The impact of antimicrobial resistance on dying of BSI has been studied extensively (1,2). Many studies have concluded that BSI caused by an antimicrobial-resistant organism results in higher death rates (1,3-8). However, as discussed in a recent report by Kaye et al., "outcome studies of antimicrobial drug resistance are notoriously hard to perform because of confounding variables related to coexisting conditions" (9). Indeed, almost all studies have shown that infections with antimicrobial-resistant organisms occur later in hospitalization than infections with antimicrobial-susceptible organisms, which suggests that differences in death rates may be, at least in part, caused by a difference in the patients' underlying illnesses and protracted hospital course. We report 2 additional methodologic issues that can affect estimates of the impact of antimicrobial resistance: combining different organisms and combining populations from different types of ICUs.

The original objective of our multicenter observational study was to quantify the clinical impact of antimicrobial resistance in S. aureus and E. faecium infections when these bacteria cause a specific type of infection: a monomicrobial, ICU-attributable, central vascular catheter-associated bloodstream infection (CVC-BSI). We studied 187 adult ICU patients with BSI caused by S. aureus and E. faecium at 3 tertiary care institutions from 1994 to 1999. The institutional review boards of each institution and the Centers for Disease Control and Prevention approved this study. Severity of illness was measured with an APACHE II score at ICU admission and on day 7 in the ICU (if applicable). The score would indicate the patient's risk of dying in the hospital before a BSI developed by using a measure validated for predicting in-hospital deaths in ICU patients (10).

The study population stratified by organism is shown in the Table. Fifty-eight percent of patients had CVC-BSI with S. aureus, and 42% had CVC-BSI with E. faecium. Overall, 58% of the organisms causing CVC-BSI were resistant to oxacillin if S. aureus or to vancomycin if E. faecium. However, patients with E. faecium CVC-BSI were more likely to be infected with antimicrobial-resistant bacteria (69% versus 50%, p<0.01), and had a higher mortality rate (54% versus 34%, p<0.01) than patients with S. aureus CVC-BSI. This finding indicates that the type of organism (E. faecium versus S. aureus) confounds the association between resistance and death. In addition, the distribution of ICU type by organism varies, which suggests that patient populations infected with these 2 different organisms were different in other ways. Thus, confounding factors for the association between resistance and death may differ for E. faecium and S. aureus, and analysis of the 2 organisms should be conducted separately. This is consistent with the results of Kaye et al. who showed that the effect of resistance was higher for S. aureus (odds ratio [OR] 3.4) than for E. faecium (OR 2.5) by using separate analyses to show death rates (9). Furthermore, these researchers found different confounding factors in the adjusted analysis of S. aureus than in the adjusted analysis of E. faecium. Because of the need to conduct separate analyses, which reduced our statistical power, our study was ultimately unable to show a difference in death rates if it existed.

In summary, future studies measuring the impact of antimicrobial resistance on death rates should be restricted to a specific type of infection cause by a single organism in a uniform setting using a validated system to predict mortality in that setting. As such, future studies should involve multiple study sites.

Table. Description of 187 adult patients with central vascular
catheter-associated bloodstream infections with Staphylococcus
aureus or Enterococcus faecium attributable to the intensive
care unit *

                                 S. aureus   E. faecium
Characteristics                  (n = 109)    (n = 78)    p value

Patient demographics
  Male (%)                          74           56        0.02
  Mean age, y (SD)                58 (17)     56 (16)      0.32
Type of ICU                                                <0.01
  Cardiac (%)                       20           10
  Cardiothoracic surgery (%)         6           6
  Medical (%)                       20           40
  Neurologic/neurosurgical (%)       6           0
  Surgical (%)                      20           37
  Trauma (%)                        28           6
Severity of illness
  Mean APACHE II score at ICU     19 (8)       21 (9)      0.12
    admission (SD)
  Mean APACHE II score within     17 (8)       20 (8)      0.05
    7 days of BSI (SD)
Resistant infections (%)            50           69        0.01
In-hospital death rate (%)          34           54        <0.01

* SD, standard deviation, ICU, intensive care unit.

This project was supported by cooperative agreements (U50/CCU316578-01 and UR8/CCU315092-03) from the Centers for Disease Control and Prevention. Mary-Claire Roghmann was supported by a VA Career Development Award during the time this work was performed.

References

(1.) Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis. 2003;36: 53-9.

(2.) Niederman MS. Impact of antibiotic resistance on clinical outcomes and the cost of care. Crit Care Med. 2001;29(Suppl 4):N114-20.

(3.) Selvey LA, Whitby M, Johnson B. Nosocomial methicillin-resistant Staphylococcus aureus bacteremia: Is it any worse than nosocomial methicillin-sensitive Staphylococcus aureus bacteremia? Infect Control Hosp Epidemiol. 2000;21:645-8.

(4.) Conterno LO, Wey SB, Castelo A. Risk factors for mortality in Staphylococcus aureus bacteremia. Infect Control Hosp Epidemiol. 1998;19:32-7.

(5.) McClelland RS, Fowler VG Jr, Sanders LL, Gottlieb G, Kong LK, Sexton DJ, et al. Staphylococcus aureus bacteremia among elderly vs younger adult patients: comparison of clinical features and mortality. Arch Intern Med. 1999;159:1244-7.

(6.) Bhavnani SM, Drake JA, Forrest A, Deinhart JA, Jones RN, Biedenbach DJ, et al. A nationwide, multicenter, case-control study comparing risk factors, treatment, and outcome for vancomycin-resistant and -susceptible enterococcal bacteremia. Diagn Microbiol Infect Dis. 2000;36: 145-58.

(7.) Stosor V, Peterson LR, Postelnick M, Noskin GA. Enterococcus faecium bacteremia: does vancomycin resistance make a difference? Arch Intern Med. 1998;158:522-7.

(8.) Vergis EN, Hayden MK, Chow JW, Snydman DR, Zervos MJ, Linden PK, et al. Determinants of vancomycin resistance and mortality rates in enterococcal bacteremia. A prospective multicenter study. Ann Intern Med. 2001;135:484-92.

(9.) Kaye KS, Engemann JJ, Mozaffari E, Carmeli Y. Reference group choice and antibiotic resistance outcomes. Emerg Infect Dis. 2004;10:1125-8.

(10.) Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818-29.

Mary-Claire Roghmann, * Douglas D. Bradham, ([dagger]) Min Zhan, * Scott K. Fridkin, ([double dagger]) and Trish M. Perl ([sections])

* University of Maryland School of Medicine, Baltimore, Maryland, USA: ([dagger]) VA Maryland Health Care System, Baltimore, Maryland, USA; ([double dagger]) Centers for Disease Control and Prevention, Atlanta, Georgia, USA; and ([sections]) Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

Address for correspondence: Mary-Claire Roghmann, VA Maryland Health Care System, 100 N. Greene St (lower level), Baltimore, MD 21201, USA; fax: [phone]; email: [e-mail]