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Replacement of HA-MRSA by CA-MRSA Infections at an Academic Medical Center in the Midwestern United States, 2004-5 to 2008

Replacement of HA-MRSA by CA-MRSA Infections at an Academic Medical Center in the Midwestern... We noted anecdotally that infections designated as health care-associated (HA-) MRSA by epidemiologic criteria seemed to be decreasing in incidence at the University of Chicago Medical Center (UCMC) after 2004. We compared MRSA patients seen at any site of clinical care at UCMC and the isolates that caused their infections in 2004-5 (n = 545) with those in 2008 (n = 135). The percent of patients with MRSA infections cultured . 2 days after hospital admission decreased from 19.5% in 2004-5 to 7.4% in 2008 (p = 0.001). The percent in 2004-5 compared with 2008 who had a hospitalization (49.1% to 26.7%, p = 0.001) or surgery (43.0% to 14.1%, p,0.001) in the previous year decreased. In 2008 a greater percent of patients was seen in the emergency department (23.1% vs. 39.3%) and a smaller percent both in intensive care units (15.6% vs. 6.7%) and in other inpatient units (40.7% vs. 32.6%) (p,0.001). The percent of patients with CA-MRSA infections by the CDC epidemiologic criteria increased from 36.5% in 2004-5 to 62.2% in 2008 (p,0.001). The percent of MRSA isolates sharing genetic characteristics of USA100 decreased from 27.9% (152/545) to 12.6% (17/135), while the percent with CA-MRSA (USA300) characteristics increased from 53.2% (290/545) to 66.7% (90/135). The percent of infections that were invasive did not change significantly. Our data suggest that HA-MRSA infections, both by epidemiologic and microbiologic criteria, relative to CA-MRSA, decreased between 2004-5 and 2008 at UCMC. Citation: David MZ, Cadilla A, Boyle-Vavra S, Daum RS (2014) Replacement of HA-MRSA by CA-MRSA Infections at an Academic Medical Center in the Midwestern United States, 2004-5 to 2008. PLoS ONE 9(4): e92760. doi:10.1371/journal.pone.0092760 Editor: Herminia de Lencastre, Rockefeller University, United States of America Received February 10, 2013; Accepted February 26, 2014; Published April 22, 2014 Copyright:  2014 David et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the National Institutes of Health (R01 A140481-01A1 and 2R56AI040481-08A1 to RSD and SBV; 1 U01 GM087729-01/ B270JA to RSD; and 1K23 AI095361-01 to MZD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: mdavid@medicine.bsd.uchicago.edu [9] has increased in the past decade. Second, USA300 has Introduction increasingly been the cause of nosocomial infections and infections The epidemiology of methicillin-resistant Staphylococcus aureus among people with healthcare exposure [10]. Third, there is (MRSA) changed dramatically in the first decade of the twenty- evidence that there were fewer invasive MRSA infections in the first century with the emergence of genotypically novel commu- U.S. among patients with recent health care exposure [11]. nity-associated (CA-) MRSA strains [1]. CA-MRSA strains were Fourth, during the past decade, among all MRSA infections in first noted in the late 1990s as causes of skin and soft tissue several U.S. populations, there has been an increase in the percent infections (SSTIs) as well as severe invasive syndromes in people that are classified epidemiologically as CA-MRSA [5,12–14]. with no known previous exposure to a health care setting. We noted anecdotally that infections designated as health care- Subsequently, a single genetic background, identified as USA300 associated (HA-) MRSA by epidemiologic criteria seemed to be by pulsed-field gel electrophoresis (PFGE), became the most decreasing in incidence at the University of Chicago Medical common cause of SSTIs in U.S. emergency departments (EDs) in Center (UCMC) after 2004. Previously, we assessed the clinical 2004 [2] and 2008 [3]. USA300 was the most common genetic and molecular epidemiology of MRSA infections at UCMC from background of MRSA causing bacteremia in 23 U.S. hospitals in July 1, 2004 to June 30, 2005 [15]. At that time, we found that 2009–2010 [4]. In surveillance at 12 laboratories in Minnesota, CA-MRSA infections, whether defined by epidemiologic or CA-MRSA infections defined by an epidemiologic criterion microbiologic criteria, were very common among inpatients and accounted for 33% of all MRSA infections in 2005, an increase outpatients in the clinic and the ED among both adults and from 11% in 2000 [5]. children. Here, we compare the results of that study with the USA300 has progressively increased as a proportion of MRSA clinical and microbiologic characteristics of MRSA patients and isolates causing infections cared for at large medical centers. As a their MRSA isolates at UCMC in 2008. Our hypothesis was that consequence, the overall number of MRSA infections has between 2004-5 and 2008, there was a major shift in the overall increased [6]. This has resulted from 4 epidemiologic trends. molecular epidemiology of MRSA infections at our center, with a First, the incidence of outpatient and ED MRSA SSTIs [7,8] and greater percent of infections caused by MRSA strains bearing the incidence of CA-MRSA infections resulting in hospitalization SCCmec type IV, a greater percent of isolates carrying the genes PLOS ONE | www.plosone.org 1 April 2014 | Volume 9 | Issue 4 | e92760 Replacement of HA-MRSA for the Panton-Valentine leukocidin (PVL), and a higher percent senting asymptomatic colonization were excluded from further analysis. Data collected for the 2008 subjects were identical to of strains having the ST8 multilocus sequence type (MLST), characteristics, when taken together, that identify USA300 [16]. those collected for the 2004-5 patient cohort previously described at UCMC [15] except that, in 2008, data on previous surgery were collected for the year prior to the MRSA infection. For the 2004-5 Methods data, history of surgery was assessed only for 6 months prior. Ethics Statement The study was approved by the University of Chicago Biological Microbiological Methods Sciences Division Institutional Review Board (IRB). The IRB For each MRSA isolate, antimicrobial susceptibilities to approved the following consent process. In-person consent was not erythromycin, ciprofloxacin, rifampin, gentamicin, trimethoprim- feasible because the study was performed without specific funding, sulfamethoxazole, and vancomyin were determined by Vitek and patients, in the majority of cases, were no longer inpatients at (Vitek 2, bioMe´rieux Vitek, Inc., Durham, NC). However, the D- our institution at the time of enrollment. Telephone consent was zone test was performed on all isolates found to be clindamycin obtained utilizing an IRB-approved text read to potential subjects; susceptible and erythromycin resistant on single-agent testing, for children ,7 years of age, consent was obtained from a parent according to NCCLS Guidelines [18]. or guardian. For children 8 to 18 years of age, in addition to consent from a parent or guardian, telephone assent was obtained Genotyping from the patient. Patients who refused consent were not enrolled. For each studied isolate, multilocus sequence typing (MLST) Consent was documented on a paper consent form for each was performed as described [19]. Detection of the Panton enrolled subject except in cases when the subject (or a parent or Valentine leukocidin (PVL) genes was performed by PCR as guardian for a child) could not be reached despite at least 5 described [20]. The SCCmec type in the isolates was determined by attempts. In cases when telephone consent could not be obtained, a panel of PCR assays that allowed for the determination of the a waiver of consent was granted by the IRB, and note was made of mec and ccr complex [21,22]. this in the study records. UCMC is comprised of pediatric and adult hospitals serving the Criteria for CA- and HA-MRSA population on the south side of Chicago as well as tertiary care Eight criteria commonly used to distinguish CA- from HA- patients from elsewhere in the midwestern United States, with MRSA infections were applied to each patient and his or her 26,288 admissions, 82,828 ED visits, and 388,277 outpatient visits MRSA isolate. Clinical criteria included the (1) the 48-hour in fiscal year 2008. UCMC follows the guidelines of the Health criterion, (2) CDC epidemiologic definitions for CA-MRSA and Care Infection Control Practices Advisory Committee of the HA-MRSA [11], and (3) SSTI as the clinical syndrome. (1) By the Centers for Disease Control and Prevention [17]. Also, in March 48-hour criterion, an infection was considered to be CA-MRSA if 2008 UCMC began a nasal screening for MRSA carriage, using a it was cultured as an outpatient or ,2 days after admission to the PCR-based test, of all patients admitted to an intensive care unit, hospital, and other infections were considered to be HA-MRSA. as mandated by Illinois state law. Carriers identified in this way (2) A MRSA infection was considered to be HA-MRSA by the were placed on contact precautions. CDC epidemiologic definitions if, in the year prior to culture, the subject had surgery, hospitalization, hemodialysis or a stay in a Bacterial Isolates long-term care facility, if an indwelling vascular catheter was in We began prospectively collecting and storing MRSA isolates place at the time of culture, or if the subject was an inpatient obtained by the UCMC Clinical Microbiology Laboratory on hospitalized for .2 days at the time of culture. Otherwise, the November 1, 2003. MRSA was isolated from 839 unique patients subject was considered to have a CA-MRSA infection [11]. The cultured as part of an evaluation for an infection in January 1 - CDC has a third category, the health-care-associated community- December 31, 2008. A random 20% sample of these patients and onset (HACO) group, and we include this in the group of HA- their isolates was selected (n = 168). The first MRSA isolate MRSA infections by the CDC criteria. Patients and their MRSA obtained from each selected subject was chosen for analysis except isolates were also separately classified as CA-MRSA by isolate when the first isolate represented asymptomatic colonization, in characteristics, including (4) the presence of the PVL genes, (5) the which case the first isolate from the patient’s clinical infection was presence of SCCmec type IV, (6) the ST8 MLST genotype, (7) used. clindamycin susceptibility, and (8) non-multidrug resistance [non- MDR, defined as resistance to $2 tested non-b-lactam antibiotic Medical Record Review drugs]), as done in our previous study [15]. Medical records were reviewed for each enrolled subject to assess age, gender, race, type of insurance, location of care when Statistical Analysis the MRSA culture was obtained, clinical MRSA syndrome, the For each clinical and microbial characteristic, subjects and their presence or absence of an indwelling vascular catheter, comorbid isolates in 2004-5 [15] were compared with those in 2008. Data medical conditions, and any previous MRSA infection or were compared by the chi-square, Fisher Exact, or t-test, as colonization. As in our previous study [15], each MRSA clinical appropriate (Stata 11, College Station, TX). The percent pairwise syndrome was assigned to a syndrome category (SSTI, osteomy- concordance for every possible pair of the 8 criteria for CA-MRSA elitis or septic arthritis, bacteremia and endocarditis, urinary tract was tabulated. infection [UTI], pneumonia or other). All infections were separately classified as invasive if the isolate was obtained from a Results normally sterile site, and all other infections were considered non- invasive. Invasive infections included pneumonia, bacteremia, Among 168 patient-isolates designated for study, 149 were endocarditis, sepsis, osteomyelitis, septic arthritis, pyomyositis, enrolled. Upon chart review, 135 (90.6%) were determined to peritonitis, necrotizing fasciitis and other deep-seated skin and soft have had an infection and 14 (9.4%) only had MRSA colonization. tissue infections, and cholecystitis. Subjects with isolates repre- Further analyses were limited to the 135 enrolled subjects with PLOS ONE | www.plosone.org 2 April 2014 | Volume 9 | Issue 4 | e92760 Replacement of HA-MRSA Table 1. Demographic and clinical characteristics of patients with methicillin-resistant Staphylococcus aureus infections at UCMC in 2004-5 and 2008. 2004-5, N = 545, (%) 2008, N = 135, (%) p-value Clinical syndrome 0.1 Bacteremia, endocarditis, or sepsis 63 (11.6) 15 (11.1) Osteomyelitis or septic arthritis 33 (6.1) 4 (3.0) Pneumonia 46 (8.4) 8 (5.9) Skin and soft tissue infection 354 (65.0) 103 (76.3) Urinary tract infection 22 (4.0) 1 (0.7) Other 27 (5.0) 4 (3.0) Age Group 0.3 Pediatric (,18.0 years) 200 (36.7) 56 (41.5) Adult 345 (63.3) 79 (58.5) Gender 0.9 Male 268 (49.2) 67 (49.6) Female 277 (50.8) 68 (50.4) Race 0.5 African American 406 (74.5) 96 (71.1) White 84 (15.4) 19 (14.1) Latino 11 (2.0) 4 (3.0) Native American 3 (0.6) 0 Unknown or other 41 (7.3) 16 (11.9) Type of insurance 0.001 Public assistance 378 (69.4) 76 (56.3) Private 132 (24.2) 42 (31.1) Uninsured 19 (3.5) 15 (11.1) Unknown 16 (2.9) 2 (1.5) Presence of risk factors for HA- MRSA Inpatient culture obtained .48 hrs after admission 106 (19.5) 10 (7.4) 0.001 Hospital stay, past year 225 (41.3) 36 (26.7) 0.002 Surgery, past 6 months 209 (38.4) 19 (14.1) ,0.001 Hemodialysis, past year 35 (6.4) 5 (3.7) 0.3 Indwelling catheter 69 (12.7) 8 (5.9) 0.03 Stay in long-term care facility, past year 16/290 (5.5) 8 (5.9) 0.9 Location of care ,0.001 Intensive care units 85 (15.6) 9 (6.7) Other inpatient units 220 (40.7) 44 (32.6) Emergency department 126 (23.1) 53 (39.3) Outpatient 112 (20.6) 29 (21.5) CDC Criteria for Infection Type ,0.001 CA 199 (36.5) 84 (62.2) HA 346 (63.5) 51 (37.8) Previous MRSA isolation UCMC laboratory report 58 (10.6) 21 (15.6) 0.1 The p-value was determined using the x-square or the Fisher exact test, as appropriate; for mutually exclusive categorical variables a single test was performed to compare the distribution of the data for 2004-5 with the data for 2008. Includes cholecystitis, conjunctivitis, peritonitis and upper respiratory infection. Denominators for HA-MRSA risk factors in 2004-5 exclude those interviewed patients who answered that that they did not know information requested of them and those patients about whom risk factor information could not be determined from chart review. Information regarding a stay in a long-term care facility for 2004-5 patients was determined only for those patients lacking another health-care risk factor for HA-MRSA infection. For 2008 patients, this was evaluated for all 135 enrolled. doi:10.1371/journal.pone.0092760.t001 clinical infections. Comparing patients with MRSA infections in or race, but the subjects differed significantly by distribution of 2004-5 and 2008, there was no significant difference in the types of insurance coverage, with the percent of uninsured and distribution of clinical syndromes, pediatric vs. adult age groups, privately insured higher in the 2008 patient cohort and the percent PLOS ONE | www.plosone.org 3 April 2014 | Volume 9 | Issue 4 | e92760 Replacement of HA-MRSA Figure 1. Percent of MRSA patients in 2004-5 and 2008 classified as CA-MRSA and HA-MRSA infections by the CDC epidemiologic definition. The percent that were HA-MRSA decreased from 63.5% (346/545) to 37.8% (51/135) (p,0.001), demonstrating a shift in the balance in the site of onset of MRSA infections from the healthcare setting to the community. doi:10.1371/journal.pone.0092760.g001 publicly insured lower (p = 0.001) (Table 1). Although this change had an SSTI diagnosis increased from 65.0% (354/545) in 2004-5 was statistically significant, the magnitude of the change was not to 76.3% (103/135) in 2008 (p = 0.01). great, and it is difficult to determine the importance of the finding. Genetic characteristics of isolates Clinical characteristics of patients In 2004-5 there were 12 MLSTs (10 defined STs and 2 single- The percent of MRSA patients with clinical characteristics of locus variants of defined STs) represented among the MRSA CA-MRSA infections increased in 2008 compared with the 2004- isolates studied, and in 2008, there were 14 types, demonstrating 5 cohort. The percent of patients with MRSA infections who were little evidence of changing diversity in the repertoire of genetic cultured . 2 days after hospital admission (i.e., the 48-hour MRSA backgrounds. However, the frequencies of different criterion) decreased from 19.5% in 2004-5 to 7.4% in 2008 MLSTs varied in 2004-5 and 2008 (p,0.001). (p = 0.001). The percent in 2008 compared with 2004-5 having By microbiological criteria, the percent of isolates that would be recorded exposures to the health care setting decreased signifi- categorized as CA-MRSA increased in 2008 compared with 2004- cantly. These included hospitalization (41.3% to 26.7%, p = 0.002) 5. The presence of the PVL genes (58.2% versus 76.3%, p,0.001) or surgery (38.4% to 14.1%, p,0.001) in the previous year. In and SCCmec type IV carriage (65.7% versus 79.4%, p = 0.006), 2004-5 compared with 2008, there was a lower prevalence of both markers of CA-MRSA strains in the U.S., increased in 2008 patients who had received hemodialysis in the past year and of compared with 2004-5. The percent of ST8 isolates (a marker for patients with an indwelling catheter at the time of culture, USA300 CA-MRSA isolates) increased from 58.9% to 71.1%, and although these differences were not significant. There was no the percent that were ST5 (a marker for USA100 HA-MRSA significant change in the percent of patients with a history of a stay isolates) decreased from 31.2% to 15.6%. The percent of isolates in a long-term care facility in the year prior to culture (p = 0.9). sharing the genetic characteristics of USA100 (ST5, SCCmec type The site of care at UCMC differed (p,0.001), with a greater II, PVL-negative) decreased from 27.9% (152/545) to 12.6% (17/ percent of patients in 2008, compared with 2004-5, receiving care 135). The percent of isolates with the CA-MRSA USA300 strain in the ED (23.1% versus 39.3%) and a smaller percent in intensive type’s characteristics (ST8, SCCmec type IV, PVL-positive) care units (15.6% versus 6.7%) and in other inpatient units (40.7% increased from 53.2% (290/545) to 66.7% (90/135). Interestingly, versus 32.6%) (Table 1), demonstrating a shift in the site of care for comparing isolates from 2004-5 and 2008, there was not a MRSA patients from inpatient to outpatient settings. significant change in susceptibility to most tested antimicrobial The percent of MRSA patients who would be classified as drug among those tested. The exception was clindamycin, for having CA-MRSA infections by the CDC definition increased which the susceptibility increased significantly in 2008 when from 36.5% in 2004-5 to 62.2% in 2008 (p,0.001). Thus, there compared with 2004-5 (Table 2). The percent that were MDR was a significant shift, even by this stringent criterion for CA- decreased from 34.7% (189/545) in 2004-5 to 21.5% (29/135) in MRSA infections, in the focus of MRSA epidemiology from 2008 (p = 0.003). people with previous exposure to the health care setting to those In 2004-5 there were 317/545 (58.2%) PVL-positive isolates, without such exposures (Figure 1). The percent of patients who which were ST8 (n = 290), ST1 (n = 19), ST5 (n = 5), ST8 single- locus variants (n = 2), and ST59 (n = 1). In 2008, there were 103/ PLOS ONE | www.plosone.org 4 April 2014 | Volume 9 | Issue 4 | e92760 Replacement of HA-MRSA Table 2. Genotypic and phenotypic characteristics of methicillin-resistant Staphylococcus aureus isolates at UCMC from 2004-5 and 2004-5 N = 545, (%) 2008 N = 135 (%) p-value Clonal Complex type/MLST type ,0.001 Clonal complex 1 1 21 (3.9) 1 (0.7) Clonal complex 5 5 170 (31.2) 21 (15.6) 5slv 1 (0.2) 0 105 3 (0.6) 2 (1.5) 231 14 (2.6) 2 (1.5) 1730 0 1 (0.7) 2113 0 1 (0.7) 2114 0 1 (0.7) Clonal complex 8 8 321 (58.9) 96 (71.1) 8slv 2 (0.4) 0 72 1 (0.2) 0 683 0 4 (3.0) 2511 0 1 (0.7) 2515 0 2 (1.5) 2516 0 1 (0.7) 2522 0 1 (0.7) Clonal complex 22 22 6 (1.1) 0 2512 0 1 (0.7) Clonal complex 30 30 0 0 36 3 (0.6) 0 Clonal complex 59 59 2 (0.4) 0 New ST 1 (0.2) 0 PVL gene carriage ,0.001 Positive 317 (58.2) 103 (76.3) Negative 228 (41.8) 32 (23.7) SCCmec type 0.003 II 180 (33.0) 27 (19.9) IV 358 (65.7) 108 (79.4) Other 7 (1.3) 0 Antibiotic resistance to Ciprofloxacin 230 (42.2) 48 (35.6) 0.2 Clindamycin (total) 220 (40.4) 36 (26.7) 0.003 Clindamycin, Vitek testing 176 (32.3) 34 (25.2) 0.1 Clindamycin, D-Test + 44 (12.4) 6 (4.4) 0.6 Erythromycin 500 (92) 122 (90.4) 0.6 Gentamicin 30 (5.5) 2 (1.5) 0.05 Trimethoprim/sulfamethoxazole 2/320 3 (2.2) 0.2 Rifampin 9 (1.7) 1 (0.7) 0.7 PLOS ONE | www.plosone.org 5 April 2014 | Volume 9 | Issue 4 | e92760 Replacement of HA-MRSA Table 2. Cont. 2004-5 N = 545, (%) 2008 N = 135 (%) p-value Vancomycin 0 0 N/A MLST clonal complex designations vary with time. The clonal cluster designations indicated here were accurate at the conclusion of 2008. slv, single locus variant with no assigned multilocus sequence type (MLST). 1-31-1-1-12-1-40 denote the allotypes of 7 genes (arcC, aroE, glpF, gmk, pta, tpi, and yqiL) that determine this undefined MLST type. 7 MRSA isolates from 2004-5 had multiple or no ccr genes and were thus considered nontypable. Includes intermediate susceptibility results as resistant. In some cases, isolates were not tested for clindamycin, ciprofloxacin, erythromycin susceptibility, and the number tested are indicated in the table as the denominator for each relevant category. doi:10.1371/journal.pone.0092760.t002 135 (76.3%) PVL-positive isolates, which were ST8 (n = 92), Among USA300-like strains obtained from patients who had ST683 (n = 4), ST2515 (n = 2), and a single isolate each of ST1, CA-MRSA infections by the CDC epidemiologic definition in ST5, ST2511, ST2516, and ST2522. In 2004-5 SCCmec type IV 2004-5, 4.1% (7/169) were invasive, and in 2008, 7.4% (5/68) was carried by 358/545 (69.7%) isolates, which were ST8 were invasive (p = 0.5), a change that was not significant. Similarly (n = 316), ST1 (n = 20), ST5 (n = 11), ST22 (n = 6), ST59 (n = 2), there was not a significant change among USA300-like strains ST8 single-locus variants (n = 2), and ST72 (n = 1). In 2008, causing invasive HA-MRSA infections by the CDC definition, SCCmec type IV was carried by 108/135 (79.4%) isolates, which with 24.8% (30/121) in 2004-5 and 22.7% (5/22) in 2008 being were ST8 (n = 93), ST683 (n = 4), ST5 (n = 3), ST2515 (n = 2), and invasive (p = 0.9). a single isolate each of ST1, ST2511, ST2512, ST2514, ST2516, ST2522. Concordance of criteria for CA-MRSA Even when limiting the analysis to HA-MRSA infections by the Tables 3 and 4 show the percent concordance of any CDC epidemiologic criteria, the percent that were caused by combination of 2 out of 8 studied epidemiologic and microbiologic USA100-like (i.e., ST5, SCCmec type II-bearing and PVL- criteria for CA-MRSA often used to distinguish CA- and HA- negative) and USA300-like (i.e., ST8, SCCmec type IV-bearing MRSA infections. The CDC definition for CA-MRSA had and PVL-positive) changed in the study period. In 2004-5 there approximately 50% concordance with other criteria often used were 41.4% (138/333) USA100-like and 36.3% (121/333) to identify CA-MRSA infections in 2004-5. The CDC definition in USA300-like isolates, and in 2008, these values changed to 2008 performed better in identifying patient-isolates that would be 27.5% (14/51) and 43.1% (22/51), respectively, suggesting a considered CA-MRSA infections. For example, in 2004-5 nearly significantly decreased role of USA100 (p = 0.06) among (Table 3), 67.3% of isolates had SCCmec type IV and were CA- epidemiologically defined HA-MRSA infections. Among CA- MRSA by the CDC definition or lacked SCCmec type IV and were MRSA infections defined by the CDC criteria, 6.6% (14/212) in HA-MRSA by the CDC definition; in 2008 (Table 4), this 2004-5 and 3.6% (3/84) in 2008 were caused by USA100-like percent increased to 71.9%. Similarly, the concordance between isolates. the CDC definition for CA-MRSA and the presence of PVL in an infecting isolate rose from 69.4% in 2004-5 to 78.5% in 2008. Characteristics of infections: Invasive and non-invasive This increase in concordance may be due to the greater The percent of infections that were invasive did not change prevalence of CA-MRSA among all MRSA infections in 2008 significantly. In 2004-5, 27.0% (147/545) of MRSA infections and the corresponding decrease in the percent that were HA- were classified as invasive compared with 23.7% (32/135) in 2008 MRSA infections. (p = 0.4). Invasive HA-MRSA infections (defined by the CDC criteria) increased, but not significantly, as a percent of all HA- Discussion MRSA infections in 2004-5 compared with 2008 from 39.9% (133/333) to 49.0% (25/51) (p = 0.2). The percent of invasive CA- Our data suggest that in 2008, the proportion of MRSA infections that were HA-MRSA, both by epidemiologic and MRSA infections among all CA-MRSA infections (by the CDC criteria) did not differ significantly in the two study periods, 6.6% microbiologic criteria, decreased compared with 2004-5 at (14/212) in 2004-5 and 5.7% (7/135) in 2008 (p = 0.6). UCMC. Most strikingly, there was a significant decrease in the Table 3. Percent concordance of 8 paired criteria for CA-MRSA, 2004-5. Criterion 48-hour Clindamycin susceptibility SCCmec IV Non-MDR PVL+ MLST 8 SSTI Clindamycin susceptibility 69.5 SCCmec IV 73.8 89.5 Non-MDR 74.5 93.2 93.8 PVL+ 69.5 88.3 92.5 90.2 ST8 (MLST) 69.9 89.4 90.1 90.3 89.4 SSTI 71.2 73.8 76.2 77.6 74.9 73.4 CDC definition 58.3 67.5 67.3 67.7 69.4 66.8 65.9 doi:10.1371/journal.pone.0092760.t003 PLOS ONE | www.plosone.org 6 April 2014 | Volume 9 | Issue 4 | e92760 Replacement of HA-MRSA Table 4. Percent concordance of 8 paired criteria for CA-MRSA, 2008. Criterion 48-hour Clindamycin susceptibility SCCmec IV Non-MDR PVL+ MLST 8 SSTI Clindamycin susceptibility 70.9 SCCmec IV 83.0 85.5 Non-MDR 80.0 95.5 91.1 PVL+ 79.2 89.0 94.1 93.3 ST8 (MLST) 73.3 80.0 86.0 82.9 88.2 SSTI 82.2 75.5 74.1 78.5 80.7 76.3 CDC definition 69.6 73.6 71.9 74.8 78.5 72.6 75.6 N = 110. doi:10.1371/journal.pone.0092760.t004 percent of MRSA infections cultured from inpatients more than 2 i.e., ST8 carrying the SCCmec type IV element and PVL+, caused days after admission, in the percent that had surgery or a hospital both CA- and HA-MRSA infections by the CDC epidemiologic stay in the previous year, and in isolates having the ST5 criteria, as noted in a few other U.S. centers [10,23]. Few CA- background, the most common background of U.S. HA-MRSA MRSA infections were caused by USA-100-like isolates. strains (USA100). We found that as USA300 has become an increasingly At the same time, the percent of all MRSA infections that were prevalent genetic background among MRSA infections, USA100 invasive did not change during the two periods studied. The shift became less so. In 2008, at our center less than one-quarter of HA- in molecular epidemiology of MRSA infections, with more MRSA infections defined epidemiologically were caused by USA300-like and fewer USA100-like isolates causing infection in USA100-like isolates. This trend has been shown in few previous 2008 compared with 2004-5, suggests that both of these genetic studies. While CDC Active Bacterial Core surveillance document- backgrounds are associated with invasive disease. This pattern, i.e., ed a decrease in invasive HA- and HACO-MRSA infections a shift in genetic backgrounds without a significant shift in the between 2005–2008, it did not report on non-invasive MRSA percent of infections that were invasive, also suggests that the infections [11], as we have done. development of an invasive infection may be more likely driven by A limitation to our study is our decision to use a 20% sample of patient characteristics and exposures than by characteristics of the all unique patients with a MRSA infection in 2008 at our medical bacteria causing infections although such patient characteristics center. It is possible that this number of patients is not an adequate were not assessed in our chart reviews. representation of all patients in 2008. However, our patient sample Patients with MRSA infections over time were increasingly seen was randomly selected, and with this sample, we demonstrated a in the ED and less often in the inpatient setting at our center. This significant change in the percent of infections caused by CA- shift in site of care for MRSA infections occurred with no compared with HA-MRSA infections at our medical center, no significant change in the overall distribution of the types of clinical matter which of the many criteria are used to distinguish them. syndromes caused by MRSA comparing 2004 with 2008. While As HA-MRSA strains become increasingly infrequent in the there was a non-significant increase in the percent of SSTIs among U.S., it is possible that we will enter an era in which USA300 is patients in the 2008 cohort compared with the 2004-5 cohort, the nearly the exclusive cause of MRSA infections in inpatient and percent that had bacteremia, endocarditis, or sepsis or other outpatient settings. This is concerning because isolates of this invasive infections was similar. This suggests that while the focus of background have been shown to be easily transmissible and onset of MRSA infections moved to the community in 2008, the virulent, potentially exacerbating infection control efforts. Further shift was not simply because of an increase in the percent of SSTIs surveillance is warranted for genotypic change and for changes in among MRSA infections. antimicrobial susceptibility among MRSA isolates causing clinical There were 2 dominant genetic backgrounds at UCMC in infections at U.S. medical centers. 2004-5 and 2008. Comparing these 2 time periods, there was a shift in their relative prevalence, with a lower percent of ST5 and a Author Contributions greater percent of ST8 isolates, i.e., from USA100 to USA300. The most common HA-MRSA genetic background, characteris- Conceived and designed the experiments: MZD AC SBV RSD. Performed tically ST5 with SCCmec II and lacking the PVL genes, decreased the experiments: MZD AC. Analyzed the data: MZD AC. Contributed from about one-third to less than one-sixth of all MRSA isolates reagents/materials/analysis tools: RSD SBV MZD. Wrote the paper: MZD RSD. that we sampled at our medical center. The USA300-like isolates, References 1. David MZ, Daum RS (2010) Community-associated methicillin-resistant 4. Tenover FC, Tickler IA, Goering RV, Kreiswirth BN, Mediavilla JR, et al. Staphylococcus aureus: epidemiology and clinical consequences of an emerging (2012) Characterization of nasal and blood culture isolates of methicillin- epidemic. Clin Microbiol Rev 23: 616–687. resistant Staphylococcus aureus from patients in United States Hospitals. Antimicrob 2. Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, McDougal LK, et al. Agents Chemother 56: 1324–1330. (2006) Methicillin-resistant S. aureus infections among patients in the emergency 5. Como-Sabetti K, Harriman KH, Buck JM, Glennen A, Boxrud DJ, et al. (2009) department. N Engl J Med 355: 666–674. Community-associated methicillin-resistant Staphylococcus aureus: trends in case 3. Talan DA, Krishnadasan A, Gorwitz RJ, Fosheim GE, Limbago B, et al. (2011) and isolate characteristics from six years of prospective surveillance. Public Comparison of Staphylococcus aureus from skin and soft-tissue infections in US Health Rep 124: 427–435. emergency department patients, 2004 and 2008. Clin Infect Dis 53: 144–149. PLOS ONE | www.plosone.org 7 April 2014 | Volume 9 | Issue 4 | e92760 Replacement of HA-MRSA 6. Ray GT, Suaya JA, Baxter R (2012) Trends and characteristics of culture- 15. David MZ, Glikman D, Crawford SE, Peng J, King KJ, et al. (2008) What is community-associated methicillin-resistant Staphylococcus aureus? J Infect Dis 197: confirmed Staphylococcus aureus infections in a large U.S. integrated health care 1235–1243. organization. J Clin Microbiol 50: 1950–1957. 16. David MZ, Rudolph KM, Hennessy TW, Zychowski DL, Asthi K, et al. (2012) 7. Hersh AL, Chambers HF, Maselli JH, Gonzales R (2008) National trends in MRSA USA300 at Alaska Native Medical Center, Anchorage, Alaska, USA, ambulatory visits and antibiotic prescribing for skin and soft-tissue infections. 2000-2006. Emerg Infect Dis 18: 105–108. Arch Intern Med 168: 1585–1591. 17. Siegel JD, Rhinehart E, Jackson M, Chiarello L, Health Care Infection Control 8. Qualls ML, Mooney MM, Camargo CA Jr, Zucconi T, Hooper DC, et al. Practices Advisory Committee (2007) Guideline for Isolation Precautions: (2012) Emergency department visit rates for abscess versus other skin infections Preventing Transmission of Infectious Agents in Health Care Settings. Am J during the emergence of community-associated methicillin-resistant Staphylococcus Infect Control. 2007 Dec;35(10 Suppl 2):S65–164. aureus, 1997-2007. Clin Infect Dis 55: 103–105. 18. National Committee for Clinical Laboratory Standards (NCCLS) 2004 (2004) 9. Farr AM, Aden B, Weiss D, Nash D, Marx MA (2012) Trends in hospitalization th Performance standards for antimicrobial disk susceptibility testing: 14 for community-associated methicillin-resistant Staphylococcus aureus in New York Informational Supplement, M100-S14. Villanova, PA: NCCLS. City, 1997-2006: data from New York State’s Statewide Planning and Research 19. Enright MC, Day NP, Davies CE, Peacock SJ, Spratt BG (2000) Multilocus Cooperative System. Infect Control Hosp Epidemiol 33: 725–731. sequence typing for characterization of methicillin-resistant and methicillin- 10. Seybold U, Kourbatova EV, Johnson JG, Halvosa SJ, Wang YF, et al. (2006) susceptible clones of Staphylococcus aureus. J Clin Microbiol 38: 1008–1015. Emergence of community-associated methicillin-resistant Staphylococcus aureus 20. Lina G, Pie´mont Y, Godail-Gamot F, Bes M, Peter MO, et al. (1999) USA300 genotype as a major cause of health care-associated blood stream Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in infections. Clin Infect Dis 42: 647–656. primary skin infections and pneumonia. Clin Infect Dis 29: 1128–1132. 11. Kallen AJ, Mu Y, Bulens S, Reingold A, Petit S, et al. (2010) Health care- 21. Boyle-Vavra S, Ereshefsky B, Wang CC, Daum RS (2005) Successful associated invasive MRSA infections, 2005-2008. JAMA 304: 641–648. multiresistant community-associated methicillin-resistant Staphylococcus aureus 12. Tracy LA, Furuno JP, Harris AD, Singer M, Langenberg P, et al. (2011) lineage from Taipei, Taiwan, that carries either the novel Staphylococcal Staphylococcus aureus infections in US veterans, Maryland, USA, 1999–2008. chromosome cassette mec (SCCmec) type VT or SCCmec type IV. J Clin Emerg Infect Dis 17: 441–448. Microbiol 43: 4719–4730. Erratum in: J Clin Microbiol 43: 6223. 13. Caffrey AR, LaPlante KL (2012) Changing epidemiology of methicillin-resistant 22. International Working Group on the Classification of Staphylococcal Cassette Staphylococcus aureus in the Veterans Affairs Healthcare System, 2002–2009. Chromosome Elements (IWG-SCC) (2009) Classification of staphylococcal Infection 40: 291–297. cassette chromosome mec (SCCmec): Guidelines for reporting novel SCCmec 14. Kennedy LA, Gill JA, Schmultz ME, Irmler M, Gordin FM (2010) Inside-Out: elements. Antimicrob Agents Chemother 53: 4961–4967. the changing epidemiology of methicillin-resistant Staphylococcus aureus. Infect 23. Chua T, Moore CL, Perri MB, Donabedian SM, Masch W, et al. (2008) Control Hosp Epidemiol 31: 983–985. Molecular epidemiology of methicillin-resistant Staphylococcus aureus bloodstream isolates in urban Detroit. J Clin Microbiol 46: 2345–2352. PLOS ONE | www.plosone.org 8 April 2014 | Volume 9 | Issue 4 | e92760 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png PLoS ONE Pubmed Central

Replacement of HA-MRSA by CA-MRSA Infections at an Academic Medical Center in the Midwestern United States, 2004-5 to 2008

PLoS ONE , Volume 9 (4) – Apr 22, 2014

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Abstract

We noted anecdotally that infections designated as health care-associated (HA-) MRSA by epidemiologic criteria seemed to be decreasing in incidence at the University of Chicago Medical Center (UCMC) after 2004. We compared MRSA patients seen at any site of clinical care at UCMC and the isolates that caused their infections in 2004-5 (n = 545) with those in 2008 (n = 135). The percent of patients with MRSA infections cultured . 2 days after hospital admission decreased from 19.5% in 2004-5 to 7.4% in 2008 (p = 0.001). The percent in 2004-5 compared with 2008 who had a hospitalization (49.1% to 26.7%, p = 0.001) or surgery (43.0% to 14.1%, p,0.001) in the previous year decreased. In 2008 a greater percent of patients was seen in the emergency department (23.1% vs. 39.3%) and a smaller percent both in intensive care units (15.6% vs. 6.7%) and in other inpatient units (40.7% vs. 32.6%) (p,0.001). The percent of patients with CA-MRSA infections by the CDC epidemiologic criteria increased from 36.5% in 2004-5 to 62.2% in 2008 (p,0.001). The percent of MRSA isolates sharing genetic characteristics of USA100 decreased from 27.9% (152/545) to 12.6% (17/135), while the percent with CA-MRSA (USA300) characteristics increased from 53.2% (290/545) to 66.7% (90/135). The percent of infections that were invasive did not change significantly. Our data suggest that HA-MRSA infections, both by epidemiologic and microbiologic criteria, relative to CA-MRSA, decreased between 2004-5 and 2008 at UCMC. Citation: David MZ, Cadilla A, Boyle-Vavra S, Daum RS (2014) Replacement of HA-MRSA by CA-MRSA Infections at an Academic Medical Center in the Midwestern United States, 2004-5 to 2008. PLoS ONE 9(4): e92760. doi:10.1371/journal.pone.0092760 Editor: Herminia de Lencastre, Rockefeller University, United States of America Received February 10, 2013; Accepted February 26, 2014; Published April 22, 2014 Copyright:  2014 David et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the National Institutes of Health (R01 A140481-01A1 and 2R56AI040481-08A1 to RSD and SBV; 1 U01 GM087729-01/ B270JA to RSD; and 1K23 AI095361-01 to MZD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: mdavid@medicine.bsd.uchicago.edu [9] has increased in the past decade. Second, USA300 has Introduction increasingly been the cause of nosocomial infections and infections The epidemiology of methicillin-resistant Staphylococcus aureus among people with healthcare exposure [10]. Third, there is (MRSA) changed dramatically in the first decade of the twenty- evidence that there were fewer invasive MRSA infections in the first century with the emergence of genotypically novel commu- U.S. among patients with recent health care exposure [11]. nity-associated (CA-) MRSA strains [1]. CA-MRSA strains were Fourth, during the past decade, among all MRSA infections in first noted in the late 1990s as causes of skin and soft tissue several U.S. populations, there has been an increase in the percent infections (SSTIs) as well as severe invasive syndromes in people that are classified epidemiologically as CA-MRSA [5,12–14]. with no known previous exposure to a health care setting. We noted anecdotally that infections designated as health care- Subsequently, a single genetic background, identified as USA300 associated (HA-) MRSA by epidemiologic criteria seemed to be by pulsed-field gel electrophoresis (PFGE), became the most decreasing in incidence at the University of Chicago Medical common cause of SSTIs in U.S. emergency departments (EDs) in Center (UCMC) after 2004. Previously, we assessed the clinical 2004 [2] and 2008 [3]. USA300 was the most common genetic and molecular epidemiology of MRSA infections at UCMC from background of MRSA causing bacteremia in 23 U.S. hospitals in July 1, 2004 to June 30, 2005 [15]. At that time, we found that 2009–2010 [4]. In surveillance at 12 laboratories in Minnesota, CA-MRSA infections, whether defined by epidemiologic or CA-MRSA infections defined by an epidemiologic criterion microbiologic criteria, were very common among inpatients and accounted for 33% of all MRSA infections in 2005, an increase outpatients in the clinic and the ED among both adults and from 11% in 2000 [5]. children. Here, we compare the results of that study with the USA300 has progressively increased as a proportion of MRSA clinical and microbiologic characteristics of MRSA patients and isolates causing infections cared for at large medical centers. As a their MRSA isolates at UCMC in 2008. Our hypothesis was that consequence, the overall number of MRSA infections has between 2004-5 and 2008, there was a major shift in the overall increased [6]. This has resulted from 4 epidemiologic trends. molecular epidemiology of MRSA infections at our center, with a First, the incidence of outpatient and ED MRSA SSTIs [7,8] and greater percent of infections caused by MRSA strains bearing the incidence of CA-MRSA infections resulting in hospitalization SCCmec type IV, a greater percent of isolates carrying the genes PLOS ONE | www.plosone.org 1 April 2014 | Volume 9 | Issue 4 | e92760 Replacement of HA-MRSA for the Panton-Valentine leukocidin (PVL), and a higher percent senting asymptomatic colonization were excluded from further analysis. Data collected for the 2008 subjects were identical to of strains having the ST8 multilocus sequence type (MLST), characteristics, when taken together, that identify USA300 [16]. those collected for the 2004-5 patient cohort previously described at UCMC [15] except that, in 2008, data on previous surgery were collected for the year prior to the MRSA infection. For the 2004-5 Methods data, history of surgery was assessed only for 6 months prior. Ethics Statement The study was approved by the University of Chicago Biological Microbiological Methods Sciences Division Institutional Review Board (IRB). The IRB For each MRSA isolate, antimicrobial susceptibilities to approved the following consent process. In-person consent was not erythromycin, ciprofloxacin, rifampin, gentamicin, trimethoprim- feasible because the study was performed without specific funding, sulfamethoxazole, and vancomyin were determined by Vitek and patients, in the majority of cases, were no longer inpatients at (Vitek 2, bioMe´rieux Vitek, Inc., Durham, NC). However, the D- our institution at the time of enrollment. Telephone consent was zone test was performed on all isolates found to be clindamycin obtained utilizing an IRB-approved text read to potential subjects; susceptible and erythromycin resistant on single-agent testing, for children ,7 years of age, consent was obtained from a parent according to NCCLS Guidelines [18]. or guardian. For children 8 to 18 years of age, in addition to consent from a parent or guardian, telephone assent was obtained Genotyping from the patient. Patients who refused consent were not enrolled. For each studied isolate, multilocus sequence typing (MLST) Consent was documented on a paper consent form for each was performed as described [19]. Detection of the Panton enrolled subject except in cases when the subject (or a parent or Valentine leukocidin (PVL) genes was performed by PCR as guardian for a child) could not be reached despite at least 5 described [20]. The SCCmec type in the isolates was determined by attempts. In cases when telephone consent could not be obtained, a panel of PCR assays that allowed for the determination of the a waiver of consent was granted by the IRB, and note was made of mec and ccr complex [21,22]. this in the study records. UCMC is comprised of pediatric and adult hospitals serving the Criteria for CA- and HA-MRSA population on the south side of Chicago as well as tertiary care Eight criteria commonly used to distinguish CA- from HA- patients from elsewhere in the midwestern United States, with MRSA infections were applied to each patient and his or her 26,288 admissions, 82,828 ED visits, and 388,277 outpatient visits MRSA isolate. Clinical criteria included the (1) the 48-hour in fiscal year 2008. UCMC follows the guidelines of the Health criterion, (2) CDC epidemiologic definitions for CA-MRSA and Care Infection Control Practices Advisory Committee of the HA-MRSA [11], and (3) SSTI as the clinical syndrome. (1) By the Centers for Disease Control and Prevention [17]. Also, in March 48-hour criterion, an infection was considered to be CA-MRSA if 2008 UCMC began a nasal screening for MRSA carriage, using a it was cultured as an outpatient or ,2 days after admission to the PCR-based test, of all patients admitted to an intensive care unit, hospital, and other infections were considered to be HA-MRSA. as mandated by Illinois state law. Carriers identified in this way (2) A MRSA infection was considered to be HA-MRSA by the were placed on contact precautions. CDC epidemiologic definitions if, in the year prior to culture, the subject had surgery, hospitalization, hemodialysis or a stay in a Bacterial Isolates long-term care facility, if an indwelling vascular catheter was in We began prospectively collecting and storing MRSA isolates place at the time of culture, or if the subject was an inpatient obtained by the UCMC Clinical Microbiology Laboratory on hospitalized for .2 days at the time of culture. Otherwise, the November 1, 2003. MRSA was isolated from 839 unique patients subject was considered to have a CA-MRSA infection [11]. The cultured as part of an evaluation for an infection in January 1 - CDC has a third category, the health-care-associated community- December 31, 2008. A random 20% sample of these patients and onset (HACO) group, and we include this in the group of HA- their isolates was selected (n = 168). The first MRSA isolate MRSA infections by the CDC criteria. Patients and their MRSA obtained from each selected subject was chosen for analysis except isolates were also separately classified as CA-MRSA by isolate when the first isolate represented asymptomatic colonization, in characteristics, including (4) the presence of the PVL genes, (5) the which case the first isolate from the patient’s clinical infection was presence of SCCmec type IV, (6) the ST8 MLST genotype, (7) used. clindamycin susceptibility, and (8) non-multidrug resistance [non- MDR, defined as resistance to $2 tested non-b-lactam antibiotic Medical Record Review drugs]), as done in our previous study [15]. Medical records were reviewed for each enrolled subject to assess age, gender, race, type of insurance, location of care when Statistical Analysis the MRSA culture was obtained, clinical MRSA syndrome, the For each clinical and microbial characteristic, subjects and their presence or absence of an indwelling vascular catheter, comorbid isolates in 2004-5 [15] were compared with those in 2008. Data medical conditions, and any previous MRSA infection or were compared by the chi-square, Fisher Exact, or t-test, as colonization. As in our previous study [15], each MRSA clinical appropriate (Stata 11, College Station, TX). The percent pairwise syndrome was assigned to a syndrome category (SSTI, osteomy- concordance for every possible pair of the 8 criteria for CA-MRSA elitis or septic arthritis, bacteremia and endocarditis, urinary tract was tabulated. infection [UTI], pneumonia or other). All infections were separately classified as invasive if the isolate was obtained from a Results normally sterile site, and all other infections were considered non- invasive. Invasive infections included pneumonia, bacteremia, Among 168 patient-isolates designated for study, 149 were endocarditis, sepsis, osteomyelitis, septic arthritis, pyomyositis, enrolled. Upon chart review, 135 (90.6%) were determined to peritonitis, necrotizing fasciitis and other deep-seated skin and soft have had an infection and 14 (9.4%) only had MRSA colonization. tissue infections, and cholecystitis. Subjects with isolates repre- Further analyses were limited to the 135 enrolled subjects with PLOS ONE | www.plosone.org 2 April 2014 | Volume 9 | Issue 4 | e92760 Replacement of HA-MRSA Table 1. Demographic and clinical characteristics of patients with methicillin-resistant Staphylococcus aureus infections at UCMC in 2004-5 and 2008. 2004-5, N = 545, (%) 2008, N = 135, (%) p-value Clinical syndrome 0.1 Bacteremia, endocarditis, or sepsis 63 (11.6) 15 (11.1) Osteomyelitis or septic arthritis 33 (6.1) 4 (3.0) Pneumonia 46 (8.4) 8 (5.9) Skin and soft tissue infection 354 (65.0) 103 (76.3) Urinary tract infection 22 (4.0) 1 (0.7) Other 27 (5.0) 4 (3.0) Age Group 0.3 Pediatric (,18.0 years) 200 (36.7) 56 (41.5) Adult 345 (63.3) 79 (58.5) Gender 0.9 Male 268 (49.2) 67 (49.6) Female 277 (50.8) 68 (50.4) Race 0.5 African American 406 (74.5) 96 (71.1) White 84 (15.4) 19 (14.1) Latino 11 (2.0) 4 (3.0) Native American 3 (0.6) 0 Unknown or other 41 (7.3) 16 (11.9) Type of insurance 0.001 Public assistance 378 (69.4) 76 (56.3) Private 132 (24.2) 42 (31.1) Uninsured 19 (3.5) 15 (11.1) Unknown 16 (2.9) 2 (1.5) Presence of risk factors for HA- MRSA Inpatient culture obtained .48 hrs after admission 106 (19.5) 10 (7.4) 0.001 Hospital stay, past year 225 (41.3) 36 (26.7) 0.002 Surgery, past 6 months 209 (38.4) 19 (14.1) ,0.001 Hemodialysis, past year 35 (6.4) 5 (3.7) 0.3 Indwelling catheter 69 (12.7) 8 (5.9) 0.03 Stay in long-term care facility, past year 16/290 (5.5) 8 (5.9) 0.9 Location of care ,0.001 Intensive care units 85 (15.6) 9 (6.7) Other inpatient units 220 (40.7) 44 (32.6) Emergency department 126 (23.1) 53 (39.3) Outpatient 112 (20.6) 29 (21.5) CDC Criteria for Infection Type ,0.001 CA 199 (36.5) 84 (62.2) HA 346 (63.5) 51 (37.8) Previous MRSA isolation UCMC laboratory report 58 (10.6) 21 (15.6) 0.1 The p-value was determined using the x-square or the Fisher exact test, as appropriate; for mutually exclusive categorical variables a single test was performed to compare the distribution of the data for 2004-5 with the data for 2008. Includes cholecystitis, conjunctivitis, peritonitis and upper respiratory infection. Denominators for HA-MRSA risk factors in 2004-5 exclude those interviewed patients who answered that that they did not know information requested of them and those patients about whom risk factor information could not be determined from chart review. Information regarding a stay in a long-term care facility for 2004-5 patients was determined only for those patients lacking another health-care risk factor for HA-MRSA infection. For 2008 patients, this was evaluated for all 135 enrolled. doi:10.1371/journal.pone.0092760.t001 clinical infections. Comparing patients with MRSA infections in or race, but the subjects differed significantly by distribution of 2004-5 and 2008, there was no significant difference in the types of insurance coverage, with the percent of uninsured and distribution of clinical syndromes, pediatric vs. adult age groups, privately insured higher in the 2008 patient cohort and the percent PLOS ONE | www.plosone.org 3 April 2014 | Volume 9 | Issue 4 | e92760 Replacement of HA-MRSA Figure 1. Percent of MRSA patients in 2004-5 and 2008 classified as CA-MRSA and HA-MRSA infections by the CDC epidemiologic definition. The percent that were HA-MRSA decreased from 63.5% (346/545) to 37.8% (51/135) (p,0.001), demonstrating a shift in the balance in the site of onset of MRSA infections from the healthcare setting to the community. doi:10.1371/journal.pone.0092760.g001 publicly insured lower (p = 0.001) (Table 1). Although this change had an SSTI diagnosis increased from 65.0% (354/545) in 2004-5 was statistically significant, the magnitude of the change was not to 76.3% (103/135) in 2008 (p = 0.01). great, and it is difficult to determine the importance of the finding. Genetic characteristics of isolates Clinical characteristics of patients In 2004-5 there were 12 MLSTs (10 defined STs and 2 single- The percent of MRSA patients with clinical characteristics of locus variants of defined STs) represented among the MRSA CA-MRSA infections increased in 2008 compared with the 2004- isolates studied, and in 2008, there were 14 types, demonstrating 5 cohort. The percent of patients with MRSA infections who were little evidence of changing diversity in the repertoire of genetic cultured . 2 days after hospital admission (i.e., the 48-hour MRSA backgrounds. However, the frequencies of different criterion) decreased from 19.5% in 2004-5 to 7.4% in 2008 MLSTs varied in 2004-5 and 2008 (p,0.001). (p = 0.001). The percent in 2008 compared with 2004-5 having By microbiological criteria, the percent of isolates that would be recorded exposures to the health care setting decreased signifi- categorized as CA-MRSA increased in 2008 compared with 2004- cantly. These included hospitalization (41.3% to 26.7%, p = 0.002) 5. The presence of the PVL genes (58.2% versus 76.3%, p,0.001) or surgery (38.4% to 14.1%, p,0.001) in the previous year. In and SCCmec type IV carriage (65.7% versus 79.4%, p = 0.006), 2004-5 compared with 2008, there was a lower prevalence of both markers of CA-MRSA strains in the U.S., increased in 2008 patients who had received hemodialysis in the past year and of compared with 2004-5. The percent of ST8 isolates (a marker for patients with an indwelling catheter at the time of culture, USA300 CA-MRSA isolates) increased from 58.9% to 71.1%, and although these differences were not significant. There was no the percent that were ST5 (a marker for USA100 HA-MRSA significant change in the percent of patients with a history of a stay isolates) decreased from 31.2% to 15.6%. The percent of isolates in a long-term care facility in the year prior to culture (p = 0.9). sharing the genetic characteristics of USA100 (ST5, SCCmec type The site of care at UCMC differed (p,0.001), with a greater II, PVL-negative) decreased from 27.9% (152/545) to 12.6% (17/ percent of patients in 2008, compared with 2004-5, receiving care 135). The percent of isolates with the CA-MRSA USA300 strain in the ED (23.1% versus 39.3%) and a smaller percent in intensive type’s characteristics (ST8, SCCmec type IV, PVL-positive) care units (15.6% versus 6.7%) and in other inpatient units (40.7% increased from 53.2% (290/545) to 66.7% (90/135). Interestingly, versus 32.6%) (Table 1), demonstrating a shift in the site of care for comparing isolates from 2004-5 and 2008, there was not a MRSA patients from inpatient to outpatient settings. significant change in susceptibility to most tested antimicrobial The percent of MRSA patients who would be classified as drug among those tested. The exception was clindamycin, for having CA-MRSA infections by the CDC definition increased which the susceptibility increased significantly in 2008 when from 36.5% in 2004-5 to 62.2% in 2008 (p,0.001). Thus, there compared with 2004-5 (Table 2). The percent that were MDR was a significant shift, even by this stringent criterion for CA- decreased from 34.7% (189/545) in 2004-5 to 21.5% (29/135) in MRSA infections, in the focus of MRSA epidemiology from 2008 (p = 0.003). people with previous exposure to the health care setting to those In 2004-5 there were 317/545 (58.2%) PVL-positive isolates, without such exposures (Figure 1). The percent of patients who which were ST8 (n = 290), ST1 (n = 19), ST5 (n = 5), ST8 single- locus variants (n = 2), and ST59 (n = 1). In 2008, there were 103/ PLOS ONE | www.plosone.org 4 April 2014 | Volume 9 | Issue 4 | e92760 Replacement of HA-MRSA Table 2. Genotypic and phenotypic characteristics of methicillin-resistant Staphylococcus aureus isolates at UCMC from 2004-5 and 2004-5 N = 545, (%) 2008 N = 135 (%) p-value Clonal Complex type/MLST type ,0.001 Clonal complex 1 1 21 (3.9) 1 (0.7) Clonal complex 5 5 170 (31.2) 21 (15.6) 5slv 1 (0.2) 0 105 3 (0.6) 2 (1.5) 231 14 (2.6) 2 (1.5) 1730 0 1 (0.7) 2113 0 1 (0.7) 2114 0 1 (0.7) Clonal complex 8 8 321 (58.9) 96 (71.1) 8slv 2 (0.4) 0 72 1 (0.2) 0 683 0 4 (3.0) 2511 0 1 (0.7) 2515 0 2 (1.5) 2516 0 1 (0.7) 2522 0 1 (0.7) Clonal complex 22 22 6 (1.1) 0 2512 0 1 (0.7) Clonal complex 30 30 0 0 36 3 (0.6) 0 Clonal complex 59 59 2 (0.4) 0 New ST 1 (0.2) 0 PVL gene carriage ,0.001 Positive 317 (58.2) 103 (76.3) Negative 228 (41.8) 32 (23.7) SCCmec type 0.003 II 180 (33.0) 27 (19.9) IV 358 (65.7) 108 (79.4) Other 7 (1.3) 0 Antibiotic resistance to Ciprofloxacin 230 (42.2) 48 (35.6) 0.2 Clindamycin (total) 220 (40.4) 36 (26.7) 0.003 Clindamycin, Vitek testing 176 (32.3) 34 (25.2) 0.1 Clindamycin, D-Test + 44 (12.4) 6 (4.4) 0.6 Erythromycin 500 (92) 122 (90.4) 0.6 Gentamicin 30 (5.5) 2 (1.5) 0.05 Trimethoprim/sulfamethoxazole 2/320 3 (2.2) 0.2 Rifampin 9 (1.7) 1 (0.7) 0.7 PLOS ONE | www.plosone.org 5 April 2014 | Volume 9 | Issue 4 | e92760 Replacement of HA-MRSA Table 2. Cont. 2004-5 N = 545, (%) 2008 N = 135 (%) p-value Vancomycin 0 0 N/A MLST clonal complex designations vary with time. The clonal cluster designations indicated here were accurate at the conclusion of 2008. slv, single locus variant with no assigned multilocus sequence type (MLST). 1-31-1-1-12-1-40 denote the allotypes of 7 genes (arcC, aroE, glpF, gmk, pta, tpi, and yqiL) that determine this undefined MLST type. 7 MRSA isolates from 2004-5 had multiple or no ccr genes and were thus considered nontypable. Includes intermediate susceptibility results as resistant. In some cases, isolates were not tested for clindamycin, ciprofloxacin, erythromycin susceptibility, and the number tested are indicated in the table as the denominator for each relevant category. doi:10.1371/journal.pone.0092760.t002 135 (76.3%) PVL-positive isolates, which were ST8 (n = 92), Among USA300-like strains obtained from patients who had ST683 (n = 4), ST2515 (n = 2), and a single isolate each of ST1, CA-MRSA infections by the CDC epidemiologic definition in ST5, ST2511, ST2516, and ST2522. In 2004-5 SCCmec type IV 2004-5, 4.1% (7/169) were invasive, and in 2008, 7.4% (5/68) was carried by 358/545 (69.7%) isolates, which were ST8 were invasive (p = 0.5), a change that was not significant. Similarly (n = 316), ST1 (n = 20), ST5 (n = 11), ST22 (n = 6), ST59 (n = 2), there was not a significant change among USA300-like strains ST8 single-locus variants (n = 2), and ST72 (n = 1). In 2008, causing invasive HA-MRSA infections by the CDC definition, SCCmec type IV was carried by 108/135 (79.4%) isolates, which with 24.8% (30/121) in 2004-5 and 22.7% (5/22) in 2008 being were ST8 (n = 93), ST683 (n = 4), ST5 (n = 3), ST2515 (n = 2), and invasive (p = 0.9). a single isolate each of ST1, ST2511, ST2512, ST2514, ST2516, ST2522. Concordance of criteria for CA-MRSA Even when limiting the analysis to HA-MRSA infections by the Tables 3 and 4 show the percent concordance of any CDC epidemiologic criteria, the percent that were caused by combination of 2 out of 8 studied epidemiologic and microbiologic USA100-like (i.e., ST5, SCCmec type II-bearing and PVL- criteria for CA-MRSA often used to distinguish CA- and HA- negative) and USA300-like (i.e., ST8, SCCmec type IV-bearing MRSA infections. The CDC definition for CA-MRSA had and PVL-positive) changed in the study period. In 2004-5 there approximately 50% concordance with other criteria often used were 41.4% (138/333) USA100-like and 36.3% (121/333) to identify CA-MRSA infections in 2004-5. The CDC definition in USA300-like isolates, and in 2008, these values changed to 2008 performed better in identifying patient-isolates that would be 27.5% (14/51) and 43.1% (22/51), respectively, suggesting a considered CA-MRSA infections. For example, in 2004-5 nearly significantly decreased role of USA100 (p = 0.06) among (Table 3), 67.3% of isolates had SCCmec type IV and were CA- epidemiologically defined HA-MRSA infections. Among CA- MRSA by the CDC definition or lacked SCCmec type IV and were MRSA infections defined by the CDC criteria, 6.6% (14/212) in HA-MRSA by the CDC definition; in 2008 (Table 4), this 2004-5 and 3.6% (3/84) in 2008 were caused by USA100-like percent increased to 71.9%. Similarly, the concordance between isolates. the CDC definition for CA-MRSA and the presence of PVL in an infecting isolate rose from 69.4% in 2004-5 to 78.5% in 2008. Characteristics of infections: Invasive and non-invasive This increase in concordance may be due to the greater The percent of infections that were invasive did not change prevalence of CA-MRSA among all MRSA infections in 2008 significantly. In 2004-5, 27.0% (147/545) of MRSA infections and the corresponding decrease in the percent that were HA- were classified as invasive compared with 23.7% (32/135) in 2008 MRSA infections. (p = 0.4). Invasive HA-MRSA infections (defined by the CDC criteria) increased, but not significantly, as a percent of all HA- Discussion MRSA infections in 2004-5 compared with 2008 from 39.9% (133/333) to 49.0% (25/51) (p = 0.2). The percent of invasive CA- Our data suggest that in 2008, the proportion of MRSA infections that were HA-MRSA, both by epidemiologic and MRSA infections among all CA-MRSA infections (by the CDC criteria) did not differ significantly in the two study periods, 6.6% microbiologic criteria, decreased compared with 2004-5 at (14/212) in 2004-5 and 5.7% (7/135) in 2008 (p = 0.6). UCMC. Most strikingly, there was a significant decrease in the Table 3. Percent concordance of 8 paired criteria for CA-MRSA, 2004-5. Criterion 48-hour Clindamycin susceptibility SCCmec IV Non-MDR PVL+ MLST 8 SSTI Clindamycin susceptibility 69.5 SCCmec IV 73.8 89.5 Non-MDR 74.5 93.2 93.8 PVL+ 69.5 88.3 92.5 90.2 ST8 (MLST) 69.9 89.4 90.1 90.3 89.4 SSTI 71.2 73.8 76.2 77.6 74.9 73.4 CDC definition 58.3 67.5 67.3 67.7 69.4 66.8 65.9 doi:10.1371/journal.pone.0092760.t003 PLOS ONE | www.plosone.org 6 April 2014 | Volume 9 | Issue 4 | e92760 Replacement of HA-MRSA Table 4. Percent concordance of 8 paired criteria for CA-MRSA, 2008. Criterion 48-hour Clindamycin susceptibility SCCmec IV Non-MDR PVL+ MLST 8 SSTI Clindamycin susceptibility 70.9 SCCmec IV 83.0 85.5 Non-MDR 80.0 95.5 91.1 PVL+ 79.2 89.0 94.1 93.3 ST8 (MLST) 73.3 80.0 86.0 82.9 88.2 SSTI 82.2 75.5 74.1 78.5 80.7 76.3 CDC definition 69.6 73.6 71.9 74.8 78.5 72.6 75.6 N = 110. doi:10.1371/journal.pone.0092760.t004 percent of MRSA infections cultured from inpatients more than 2 i.e., ST8 carrying the SCCmec type IV element and PVL+, caused days after admission, in the percent that had surgery or a hospital both CA- and HA-MRSA infections by the CDC epidemiologic stay in the previous year, and in isolates having the ST5 criteria, as noted in a few other U.S. centers [10,23]. Few CA- background, the most common background of U.S. HA-MRSA MRSA infections were caused by USA-100-like isolates. strains (USA100). We found that as USA300 has become an increasingly At the same time, the percent of all MRSA infections that were prevalent genetic background among MRSA infections, USA100 invasive did not change during the two periods studied. The shift became less so. In 2008, at our center less than one-quarter of HA- in molecular epidemiology of MRSA infections, with more MRSA infections defined epidemiologically were caused by USA300-like and fewer USA100-like isolates causing infection in USA100-like isolates. This trend has been shown in few previous 2008 compared with 2004-5, suggests that both of these genetic studies. While CDC Active Bacterial Core surveillance document- backgrounds are associated with invasive disease. This pattern, i.e., ed a decrease in invasive HA- and HACO-MRSA infections a shift in genetic backgrounds without a significant shift in the between 2005–2008, it did not report on non-invasive MRSA percent of infections that were invasive, also suggests that the infections [11], as we have done. development of an invasive infection may be more likely driven by A limitation to our study is our decision to use a 20% sample of patient characteristics and exposures than by characteristics of the all unique patients with a MRSA infection in 2008 at our medical bacteria causing infections although such patient characteristics center. It is possible that this number of patients is not an adequate were not assessed in our chart reviews. representation of all patients in 2008. However, our patient sample Patients with MRSA infections over time were increasingly seen was randomly selected, and with this sample, we demonstrated a in the ED and less often in the inpatient setting at our center. This significant change in the percent of infections caused by CA- shift in site of care for MRSA infections occurred with no compared with HA-MRSA infections at our medical center, no significant change in the overall distribution of the types of clinical matter which of the many criteria are used to distinguish them. syndromes caused by MRSA comparing 2004 with 2008. While As HA-MRSA strains become increasingly infrequent in the there was a non-significant increase in the percent of SSTIs among U.S., it is possible that we will enter an era in which USA300 is patients in the 2008 cohort compared with the 2004-5 cohort, the nearly the exclusive cause of MRSA infections in inpatient and percent that had bacteremia, endocarditis, or sepsis or other outpatient settings. This is concerning because isolates of this invasive infections was similar. This suggests that while the focus of background have been shown to be easily transmissible and onset of MRSA infections moved to the community in 2008, the virulent, potentially exacerbating infection control efforts. Further shift was not simply because of an increase in the percent of SSTIs surveillance is warranted for genotypic change and for changes in among MRSA infections. antimicrobial susceptibility among MRSA isolates causing clinical There were 2 dominant genetic backgrounds at UCMC in infections at U.S. medical centers. 2004-5 and 2008. Comparing these 2 time periods, there was a shift in their relative prevalence, with a lower percent of ST5 and a Author Contributions greater percent of ST8 isolates, i.e., from USA100 to USA300. The most common HA-MRSA genetic background, characteris- Conceived and designed the experiments: MZD AC SBV RSD. Performed tically ST5 with SCCmec II and lacking the PVL genes, decreased the experiments: MZD AC. Analyzed the data: MZD AC. Contributed from about one-third to less than one-sixth of all MRSA isolates reagents/materials/analysis tools: RSD SBV MZD. Wrote the paper: MZD RSD. that we sampled at our medical center. The USA300-like isolates, References 1. David MZ, Daum RS (2010) Community-associated methicillin-resistant 4. Tenover FC, Tickler IA, Goering RV, Kreiswirth BN, Mediavilla JR, et al. Staphylococcus aureus: epidemiology and clinical consequences of an emerging (2012) Characterization of nasal and blood culture isolates of methicillin- epidemic. Clin Microbiol Rev 23: 616–687. resistant Staphylococcus aureus from patients in United States Hospitals. Antimicrob 2. Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, McDougal LK, et al. Agents Chemother 56: 1324–1330. (2006) Methicillin-resistant S. aureus infections among patients in the emergency 5. Como-Sabetti K, Harriman KH, Buck JM, Glennen A, Boxrud DJ, et al. (2009) department. N Engl J Med 355: 666–674. 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(1999) USA300 genotype as a major cause of health care-associated blood stream Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in infections. Clin Infect Dis 42: 647–656. primary skin infections and pneumonia. Clin Infect Dis 29: 1128–1132. 11. Kallen AJ, Mu Y, Bulens S, Reingold A, Petit S, et al. (2010) Health care- 21. Boyle-Vavra S, Ereshefsky B, Wang CC, Daum RS (2005) Successful associated invasive MRSA infections, 2005-2008. JAMA 304: 641–648. multiresistant community-associated methicillin-resistant Staphylococcus aureus 12. Tracy LA, Furuno JP, Harris AD, Singer M, Langenberg P, et al. (2011) lineage from Taipei, Taiwan, that carries either the novel Staphylococcal Staphylococcus aureus infections in US veterans, Maryland, USA, 1999–2008. chromosome cassette mec (SCCmec) type VT or SCCmec type IV. J Clin Emerg Infect Dis 17: 441–448. Microbiol 43: 4719–4730. Erratum in: J Clin Microbiol 43: 6223. 13. Caffrey AR, LaPlante KL (2012) Changing epidemiology of methicillin-resistant 22. International Working Group on the Classification of Staphylococcal Cassette Staphylococcus aureus in the Veterans Affairs Healthcare System, 2002–2009. Chromosome Elements (IWG-SCC) (2009) Classification of staphylococcal Infection 40: 291–297. cassette chromosome mec (SCCmec): Guidelines for reporting novel SCCmec 14. Kennedy LA, Gill JA, Schmultz ME, Irmler M, Gordin FM (2010) Inside-Out: elements. Antimicrob Agents Chemother 53: 4961–4967. the changing epidemiology of methicillin-resistant Staphylococcus aureus. Infect 23. Chua T, Moore CL, Perri MB, Donabedian SM, Masch W, et al. (2008) Control Hosp Epidemiol 31: 983–985. Molecular epidemiology of methicillin-resistant Staphylococcus aureus bloodstream isolates in urban Detroit. J Clin Microbiol 46: 2345–2352. PLOS ONE | www.plosone.org 8 April 2014 | Volume 9 | Issue 4 | e92760

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Published: Apr 22, 2014

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