RESEARCH Response to Emerging Infection Leading to Outbreak of Linezolid- Resistant Enterococci Marion A. Kainer,* Rose A. Devasia,*† Timothy F. Jones,* Bryan P. Simmons,‡ Kelley Melton,‡ Susan Chow,‡ Joyce Broyles,‡ Kelly L. Moore,* Allen S. Craig,* and William Schaffner§ Linezolid was approved in 2000 for treatment of gram- Linezolid, 1 of the oxazolidinone class of antimicro- positive coccal infections. We performed a case–control bial drugs, inhibits bacterial protein synthesis by binding to study during a hospital outbreak of linezolid-resistant en- the 50S subunit of 23S rRNA. In April 2000, linezolid was terococci (LRE) infections, comparing cases of LRE infec- approved in the United States and has been heavily mar- tion (cases) with linezolid-sensitive enterococci infections keted to treat methicillin-resistant Staphylococcus aureus (controls). Nasal and perirectal swab samples were ob- (MRSA) and vancomycin-resistant enterococci (VRE) in- tained from all patients in a 1-day point-prevalence survey. We examined antimicrobial drug use and calculated the fections (4,5). Although more expensive than vancomycin, defi ned daily dose of linezolid per 1,000 patient-days. Fif- linezolid does not require testing for adequate serum drug teen LRE cases were identifi ed (13 Enterococcus faecalis concentrations or dosing adjustment for renal or hepatic and 2 E. faecium); 7 were vancomycin-resistant. Compared insuffi ciency (6), and it has been regarded by some health- with controls, case-patients had increased in-hospital mor- care providers as more effective than vancomycin in treat- tality rates and lengths of stay. Multivariate analysis identi- ing nosocomial pneumonia and MRSA skin and soft tissue fi ed independent predictors of LRE infection: prior cultures infections (7–9). Most reports of linezolid-resistant entero- positive for methicillin-resistant Staphylococcus aureus (ad- cocci (LRE) have been individual cases or small case series justed odds ratio [AOR] 27), hospitalization duration before (10–20) or have specifi cally described linezolid-resistant index culture (AOR 1.1 per day), and duration of preceding and vancomycin-resistant E. faecium (LRVRE) (17–22). linezolid therapy (AOR 1.1 per day). Linezolid exposure and We describe a large hospital outbreak of LRE infections. patient-to-patient transmission appear to be responsible for LRE infections, an important emerging hospital problem. Hospital A is an urban, 500-bed, adult inpatient, teach- ing facility with surgical, transplant, and medical ICUs in a city of ≈850,000 persons. Community-associated MRSA nterococci are common inhabitants of the human gas- is an important emerging pathogen in that city (23,24). At Etrointestinal tract. Although >40 enterococcus species hospital A in 2004, 154 MRSA and 29 VRE blood cul- exist, nosocomial infections are primarily caused by En- ture isolates were identifi ed; compared with results for terococcus faecalis and E. faecium (1). Enterococcal in- 1997, these are increases of 428% and 725%, respectively fections are the third most common cause of nosocomial (Figure 1). Linezolid became available in hospital A infection in intensive care units (ICUs), and multidrug-re- in April 2000, but it was restricted for use by infectious sistant enterococcal infections have been associated with disease and critical care physicians only, some of whom higher hospitalization costs and a higher number of related believed it provided an advantage over vancomycin for deaths (2,3). treatment of MRSA, especially pulmonary MRSA (8,9). In February 2005, hospital A’s infection-control staff contact- *Tennessee Department of Health, Nashville, Tennessee, USA; ed the Tennessee Department of Health after isolating LRE †Centers for Disease Control and Prevention, Atlanta, Georgia, in the blood culture of a ventilated patient. Within a week, USA; ‡Methodist University Hospital, Memphis, Tennessee, USA; surveillance cultures identifi ed a second patient with LRE and §Vanderbilt University School of Medicine, Nashville, Tennes- in the same unit. We undertook an investigation to charac- see, USA terize the epidemiology of LRE, to determine risk factors 1024 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 13, No. 7, July 2007 Linezolid-Resistant Enterococci tive holding area (overfl ow ICU), coronary care unit, and ventilator rehabilitation unit. Specimen information for clinical isolates of E. fae- cium, E. faecalis, S. aureus, and S. epidermidis was ob- tained for the index hospitalization and for the preceding 12 months. Isolates from surveillance cultures (not illness- associated) were not included. Invasive clinical isolates were defi ned as isolates from any of the following sources: blood; bone; cerebrospinal, joint, pericardial, peritoneal, or pleural fl uid; surgical specimen or aspirate; or any other Figure 1. No. nonduplicate blood-culture isolates of methicillin- normally sterile site. Noninvasive isolates included isolates resistant Staphylococcus aureus (MRSA), methicillin-sensitive S. from sputum, urine, or wounds. We performed a subset aureus (MSSA), and vancomycin-resistant Enterococcus faecalis analysis comparing linezolid-sensitive and vancomycin- and E. faecium (VRE) per year, hospital A, Tennessee, 1990– 2004. resistant enterococci (LSVRE) and LRVRE infections (case–control study II). After the initial random selection of controls with LSE infections, we selected additional con- for emergence of linezolid resistance in enterococci among trols with LSVRE to obtain a 1:4 ratio of LRVRE-infected patients previously infected or colonized with linezolid- case-patients to LSVRE controls. sensitive enterococci (LSE), and to determine outcomes associated with LRE infection. This investigation was ap- Point-Prevalence Survey proved by the institutional review board of hospital A. A 1-day point-prevalence culture survey for E. faeca- lis, E. faecium, and S. aureus was performed in hospital Methods A. On March 28, 2005, all patients hospitalized in hospital A were asked if they would give informed consent for the Epidemiology collection and culture of nasal and perirectal swab speci- Cases were identifi ed by manually reviewing hospital mens; specimens were obtained from all patients who gave A’s microbiology susceptibility testing reports related to consent. Identifi cation and antimicrobial drug susceptibili- all E. faecium and E. faecalis isolates for January 2004 ties of nasal and perirectal swab specimen cultures were through February 2005. Patients for whom a clinical iso- performed in hospital A’s microbiology laboratory. late of LRE had been identifi ed during the study period were selected for the study. For each case, 4 randomly se- Laboratory Studies lected hospitalized control subjects with LSE were identi- Hospital A used the Dade Microscan Walkaway 96 fi ed by using hospital microbiology reports; no matching (Diamond Diagnostics, Holliston, MA, USA) SI Pos Com- was performed. The index hospitalization was defi ned bo 21 for all species identifi cation and susceptibility testing as the hospital admission during which LRE or LSE had of gram-positive clinical isolates (25). Linezolid resistance been identifi ed. Trained staff performed chart reviews by was confi rmed at the Centers for Disease Control and Pre- using standard questionnaires to determine demographics, vention (CDC, Atlanta, GA, USA) by use of the broth-dilu- hospital course, immunocompromising conditions, instru- tion method; the MIC was >16 μg/mL for all isolates tested. mentation during the index hospitalization, and history of For the point-prevalence survey, hospital A microbiology hospitalization and inpatient antimicrobial drug exposure staff plated nasal swabs specimens onto mannitol-salt agar during the 12 months preceding the index isolate. Instru- plates; linezolid (30 μg) and oxacillin (1 μg) disks were mentation was defi ned as receipt of Foley catheteriza- placed in the fi rst quadrant to screen for LRSA and MRSA, tion, chest tube, Swan-Ganz catheterization, mechanical respectively. Perirectal swabs samples were plated directly ventilation, dialysis catheter, central line, arterial line, onto 2 bile-esculin plates, 1 of which contained 6 μg vanco- peripherally inserted central catheter, permanent central mycin/mL to screen for VRE. A linezolid disk was placed venous catheter, balloon pump, or intraabdominal or other on the heavy inoculum on the plate without vancomycin to surgery. Immunocompromising conditions were defi ned screen for LRE. as the presence of leukemia or nonskin cancer, chronic Pulsed-fi eld gel electrophoresis (PFGE) subtyping was renal failure, requiring dialysis, diabetes, HIV infection, performed at the Tennessee Department of Health labora- pancreatitis, steroid use of >10 mg for >5 days, or solid tory on available LRE isolates (clinical [3], surveillance organ or stem cell transplantation. Mortality was defi ned [3], and environmental [3]) from hospital A. The PulseNet as patient death during the index hospitalization. Critical (CDC) standardized protocol for Listeria monocytogenes care areas were defi ned as the ICUs, extended postopera- (26) was used for DNA preparation. Specifi c conditions Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 13, No. 7, July 2007 1025 RESEARCH adapted for this application included separate 5-h digestions with 100 U SmaI and 100 U ApaI restriction endonucleases and 18-h electrophoresis, using a CHEF Mapper (Bio-Rad Laboratories, Hercules, CA, USA) programmed for a mo- lecular weight range of 25–350 kb, an initial