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An Outbreak in an Intensive Care Unit of a Strain of Methicillin-Resistant Staphylococcus aureus Sequence Type 239 Associated with an Increased Rate of Vascular Access Device—Related Bacteremia

  1. Jonathan D. Edgeworth1,3,
  2. Ghasem Yadegarfar5,
  3. Smriti Pathak3,
  4. Rahul Batra1,
  5. Joshua D. Cockfield4,
  6. Duncan Wyncoll2,
  7. Richard Beale2, and
  8. Jodi A. Lindsay4
  1. 1Department of Infection, London
  2. 2Intensive Care Unit, Guy's and St. Thomas' National Health Service Foundation Trust, London
  3. 3Department of Nephrology and Transplantation, King's College London School of Medicine at Guy's, King's College, and St. Thomas' Hospitals, Guy's Hospital, London
  4. 4Centre for Infection, Department of Cellular and Molecular Medicine, St. George's University of London, London
  5. 5Public Health Sciences and Medical Statistics Group, School of Medicine, Southampton University, Southampton, United Kingdom
  1. Reprints or correspondence: Dr. Jonathan D Edgeworth, Dept. of Infection, St. Thomas' Hospital, London, SE1 7EH, UK (Jonathan.Edgeworth{at}gstt.nhs.uk).
 
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Abstract

Background. Patients in intensive care units are at high risk of developing methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. We report an epidemiological and bacterial genomic analysis of a 2-year outbreak in an intensive care unit of a variant of MRSA sequence type 239 (hereafter designated TW).

Methods. A cohort study was conducted to compare risk factors for MRSA bacteremia in patients who acquired TW versus patients who acquired non-TW strains of MRSA. Genetic analysis of TW was performed using multilocus sequence typing and microarray analysis.

Results. Patients who acquired TW were more likely than patients who acquired non-TW strains of MRSA to have MRSA isolated from blood samples (47% vs. 13%; P < .001) and to have MRSA-positive vascular access device—sample cultures (59% vs. 26%; P < .001), but less likely to have MRSA isolated from screening swab samples (30% vs. 71%; P < .001). This increased rate of TW bacteremia was confined to the first week after acquisition of TW infection. Using Cox regression analysis, the adjusted hazard ratio for bacteremia with TW was 4.5 times that of non-TW strains of MRSA (95% confidence interval, 2.25–9.00; P < .001). Microarray analysis revealed that TW had accumulated all detectable mobile genetic elements that were variably expressed by other epidemic strains of MRSA sequence type 239 in the United Kingdom.

Conclusions. To our knowledge, this is the first report to provide direct evidence that strains of MRSA can differ in their ability to cause bacteremia. Further genetic and in vitro analysis of the TW strain may provide insight into the mechanism of vascular access device—related bacteremia in the intensive care unit environment.

Hospital-acquired strains of methicillin-resistant Staphylococcus aureus (MRSA) first appeared in the early 1960s; many countries are now areas of high endemicity [1, 2]. Multilocus sequence typing (MLST) has identified a limited number of dominant strains of MRSA with distinct, but often overlapping and evolving, geographical distribution [3, 4]. In the United Kingdom, sequence type (ST)–22 (epidemic MRSA [EMRSA]–15) and ST-36 (EMRSA-16) emerged in the early 1990s and spread rapidly [5, 6]. In contrast to previous strains, such as ST-239 (EMRSA-1, -4, -7 and -11) and ST-5 (EMRSA-3), these strains have not been controlled by infection-control measures and are now endemic in most hospitals [7]. Their emergence has led to a dramatic increase in invasive MRSA infection, with ∼40% of all S. aureus bacteremias caused by MRSA [7]—of which almost 95% are caused by these 2 strains [5, 7].

Despite this increase in incidence of MRSA bacteremia, there is no direct evidence that these—or indeed any—hospital-acquired strains are associated with an increased intrinsic ability to cause bacteremia. Strains emerge at different times and places, thereby preventing a comparison that accurately adjusts for other confounding factors. This is particularly relevant in the intensive care unit (ICU) environment, where rates of MRSA bacteremia are much higher than in general hospital wards [8, 9]—largely because of the frequent insertion of vascular access devices (VADs) [10–12]. We report an analysis of an outbreak in an ICU of infection with a variant of MRSA ST-239 (hereafter designated TW) that occurred at the same time as acquisition of other endemic strains (predominantly ST-22 and ST-36), demonstrating that TW has an increased ability to cause bacteremia.

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Methods

Clinical and infection control practice. Guy's and St. Thomas' Hospital (London, England) is a 1300-bed, dual-site teaching hospital. The general ICU has 2 wards containing 15 beds each (wards 1 and 2) that are located on adjacent floors. Four beds are located in side rooms. A total of 1200, 1130, and 1033 patients were admitted to the ICU in 2002, 2003, and 2004, respectively. Before the outbreak of TW, infection control interventions included daily infection control visits, audits and education, alcohol-gel dispensers at every bed space, and the use of gloves and gowns for patient examination. MRSA screening swabs (of the nose, groin, and axilla) were performed at the time of each patient's admission to the ICU and every Monday. MRSA-colonized patients were not isolated or cohorted. Other samples were obtained on the basis of clinical suspicion of infection at that site. Blood samples for culturing were obtained after skin was cleaned with a solution of 2% chlorhexidine and 70% alcohol, or they were obtained from a central VAD at time of insertion only. The VADs that were used were predominantly silver-impregnated, quadruple-lumen catheters (Vygon), chlorhexidine-silver sulphadiazine—impregnated Trialysis catheters (Abbott), and nonimpregnated arterial catheters (Vygon), all of which were inserted following skin disinfection with a solution of 2% chlorhexidine and 70% alcohol. The main additional interventions that were implemented were (1) increased education about and an audit of hand hygiene practices; (2) isolation or cohorting of MRSA-colonized patients; and (3) daily washing of MRSA-colonized patients with diluted chlorhexidine, twice-daily application of 1% chlorhexidine (Hibitane [Centrapharm]) to the anterior surface of the nares, and 1% chlorhexidine powder to skin folds, and treatment of noncolonized patients with nasal Hibitane and daily washes with diluted triclosan. Ward floors and surfaces were cleaned daily with detergent until May 2004, when 1 : 1000 hypochlorite solution was used—at first weekly, and then daily. Vancomycin was administered as a part of first-line empirical and targeted therapy for suspected or proven MRSA infection.

Environmental and staff screening. In each of 3 screens, 10 swabs each were collected from the edges of curtains, computer keyboards, bed frames, and the adjacent bed-space floor (a total of 40 swabs), including all areas occupied by MRSA-colonized patients. An anonymous nasal screening of staff members was performed in July 2004. Samples were requested on arrival to work from doctors, nurses, physiotherapists, radiographers, and pharmacists. A potential total of 223 staff members were identified as having MRSA colonization.

Laboratory detection of MRSA. MRSA was cultured from pooled screening swabs by direct plating on mannitol salt agar plates (Baird-Parker) until July 2004, when a selective mannitol broth method was introduced [13]. Isolates were confirmed to be MRSA by tube coagulase and disc diffusion testing methods, using methicillin discs. Clinical samples were processed according to standard laboratory techniques. VAD colonization was assessed using the semiquantitative method [14].

Data collection and definitions. The date of the first isolation of MRSA and the isolate's antibiotic resistance profile was recorded for every patient admitted to the ICU. A patient was defined as importing MRSA if MRSA was cultured from any sample obtained during the first 48 h of hospitalization or if MRSA had been previously isolated from that patient and an isolate with the same susceptibility pattern was obtained after admission. A patient was defined as having acquired MRSA infection if MRSA was isolated from any sample obtained after both a negative admission screen and 48 h in the ICU. The following data were collected from patients acquiring MRSA infection: age; sex; ICU ward (ward 1 or 2) placement; ICU speciality (whether the patient was admitted from a medical, surgical, or cardiothoracic team); daily APACHE II score; duration of ICU and hospital stay; ICU- and hospital-related mortality; dates of receipt of gentamicin or vancomycin therapy; dates of insertion and removal of VADs; dates of initiation of mechanical ventilation; tracheostomy or renal replacement; treatment with elective or emergency surgery either immediately before or during the ICU stay; and date of culture of MRSA from blood, VAD, screening swabs, respiratory tract samples, or wound swabs. A patient was defined as being MRSA colonized if MRSA was isolated from either screening swabs or any clinical sample. MRSA bacteremia was defined as the culture of MRSA from ≥1 blood culture samples. A VAD was identified as the focus of bacteremia if MRSA was cultured from a VAD that was removed at the time of bacteremia.

Typing and microarray analysis. Representative MRSA isolates from each antibiotic resistance profile were sent to the Health Protection Agency (London, England) for phage typing. MLST was performed on a TW isolate as described [3]. Sixteen TW isolates were analyzed using an S. aureus microarray containing 3623 PCR products representing every predicting open-reading frame from 7 S. aureus sequencing projects, using the ST-36 strain (MRSA-252) as a control [15, 16]. TW isolates were also compared with representatives of all UK EMRSA strains [6]. Microarray data were clustered using Spearman correlation for 728 core variable genes (GeneSpring, version 7.2; Silicon Genetics) [17]. Carriage of mobile genetic elements (MGEs) was assessed by comparison with composite genomes representing all 50 sequenced MGEs [17]. Fully annotated microarray data have been deposited in BµG@SBase (http://www.bugs.sgul.ac.uk; accession number E-BUGS-34), and also ArrayExpress (accession number E-BUGS-34).

Statistical analysis. Simple and multiple analyses were performed using Stata software, version 8 (StataCorp). Numerical data are presented as means ±; SD and medians, unless otherwise indicated. A χ2 test was used to compare categorical variables and a Student's t test or a Kruskal-Wallis test was used to compare numerical variables. Cumulative Kaplan-Meier plots were constructed for the first 50 days after acquisition of MRSA infection, with day of acquisition indicated as Day 0 and the first day of MRSA bacteremia or day of discharge from the ICU (censored) as the end point. Curves were compared using the log-rank test. The exposed group comprised patients who acquired TW infection, and unexposed cohort members were those patients who acquired non-TW MRSA infection. Patients who either had MRSA bacteremia or were discharged or died on Day 0 were excluded, resulting in a cohort of 53 patients with TW and 158 patients with non-TW MRSA infection. To identify predictors of bacteremia, a simple Cox regression proportional hazard model was performed. Factors were first included in a monovariate Cox regression analysis. Data were recorded from day of MRSA acquisition (except surgery and renal replacement, which were recorded from day of hospital admission) to bacteremia, discharge, or death (in nonbacteremic patients). The final multiple Cox regression model included MRSA strain type, surgery, renal replacement therapy, total duration of insertion of all arterial and central venous VADs, while known to be colonized with MRSA but without receiving treatment with gentamicin or vancomycin (if active against the acquired MRSA strain [CAA-MRSA days]), and mean daily APACHE II score. Suitable test and graphical approaches were applied to check the proportional hazard assumption.

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Results

Description of the outbreak. Prior to and during the outbreak, the ICU was a place of high endemicity for MRSA, with 117, 138, and 104 patients admitted who had MRSA and 115, 119, and 71 patients who acquired MRSA in 2002, 2003, and 2004, respectively. Overall, 20% of patients were colonized with MRSA at some time during their stay (a rate comparable with that of other ICUs in the United Kingdom [18]). From October 2002 to October 2004, there was an outbreak of a strain of MRSA, designated TW, that affected both ICU wards. This strain was initially identified by its distinctive and broad antibiotic-resistance profile (resistant to penicillin, methicillin, erythromycin, ciprofloxacin, gentamicin, neomycin, trimethoprim, and tetracycline, but susceptible to fucidic acid, rifampicin, linezolid, and vancomycin) (figure 1). Although the outbreak began in October 2002, the existence of TW was not recognized until January 2004. During the outbreak, phage typing indicated that non-TW MRSA strains were 95% EMRSA-15 or EMRSA-16 and 5% nontypable, consistent with local and national epidemiological statistics [5, 6]. The TW strain had a distinct phage pattern. During the first 6 months of the epidemic, there were only 5 acquisitions of TW; this number increased and persisted, despite introduction of heightened infection control measures, which had a significant impact on acquisition of non-TW strains of MRSA. Beginning in May 2004, when acquisitions of TW were increasing, an environmental and anonymous staff nasal screening program was instated. Three environmental screens cultured MRSA from only 1 floor sample collected on each occasion—none of which were TW. Nasal swabs were obtained from 167 out of a possible total of 223 staff. The majority of missing samples were the result of absences due to holidays, illness, or nonreturning agency staff. A total of 14 (8.4%) of 167 staff members were colonized with MRSA, which is similar to rates reported elsewhere [19], but none of the strains were TW. The conclusion was that ongoing TW transmission persisted, despite heightened infection-control measures, because of the transiently colonized hands of staff members. It was noted that TW was cultured from respiratory tract specimens collected from all 5 patients who were in the ICU at that time. This prompted treatment with a 5-day course of linezolid to attempt to eradicate TW from that site, a measure that was supported by results previously reported by Kollef et al. [20]. TW was cleared from the respiratory tracts of all 5 patients for the remainder of their stay in the ICU, and the outbreak was terminated.

Figure 1
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Figure 1

Epidemiological statistics of patients importing methicillin-resistant Staphylococcus aureus (MRSA), acquiring MRSA infection, and developing MRSA bacteremia during an outbreak in an intensive care unit in London. A, Monthly number of patients importing a variant of MRSA sequence type 239 (designated TW) and non-TW strains of MRSA; B, Monthly number of patients acquiring TW and non-TW strains of MRSA; C, Monthly number of cases of TW and non-TW MRSA bacteremia. aHand hygiene and education. bCohorting MRSA-colonized patients. cDecolonization strategies.

Characteristics of patients who acquire MRSA infection. During the outbreak, 34 (44%) of 77 patients who were admitted to the ICU with TW or who acquired TW developed bacteremia, compared with 33 (9%) of 380 patients who were admitted to the ICU with non-TW MRSA or who acquired non-TW MRSA. To address whether this increased rate of bacteremia was likely to be an intrinsic feature of TW, a detailed epidemiological analysis of patients who acquired TW and who acquired non-TW MRSA was performed. Clinical characteristics are shown in table 1. There were no statistically significant differences between the 2 groups, although there was a trend toward a longer duration of stay and exposure to VADs after acquisition of MRSA for patients who acquired the TW strain.

Figure 2
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Figure 2

Kaplan-Meier estimation of time to bacteremia from methicillin-resistant Staphylococcus aureus (MRSA) infection.

Figure 3
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Figure 3

Comparative genomic microarray analysis of mobile genetic element (MGE) carriage by a variant of methicillin-resistant Staphylococcus aureus (MRSA) sequence type (ST)–239 (designated TW), ST-239, and ST-240 strains of MRSA. A comparison of the distribution of genes carried on MGEs in TW (representative of 16 different patient isolates); 4 different epidemic MRSA (EMRSA) ST-239 strains in the United Kingdom: E1 (EMRSA-1), E4 (EMRSA-4), E7 (EMRSA-7), and E11 (EMRSA-11); and the ST-240 strain in the United Kingdom, E9 (EMRSA-9). All isolates are clustered into the same lineages using core variable genes (data not shown). The distribution of genes in these isolates is compared using color in GeneSpring 7.2 (Silicon Genetics) to indicate the presence or absence of genes. Red-orange indicates the gene is present in the isolate, and green-grey indicates that the isolate is missing. Data is shown for the aacA (gentamicin-resistance) region and qac (quarternary ammonium compound—resistance) regions of a plasmid identified in the Mu50 S. aureus strain genome sequence, plasmid pT181 (which includes tetracycline resistance derived from COL), the cadDX (cadmium-resistance) region of plasmid pN315, the seg (enterotoxin G) gene found on bacteriophage phi3 from MW2, and a fragment of 10 genes from the composite genome of bacteriophage ϕ1 from Mu50. Gene annotation numbers correspond to those found in GenBank (http://www.ncbi.nlm.nih.gov/genomes/static/eub.html; accessed August 2006) for the sequencing projects, with the prefix R referring to the MRSA-252 genome sequence, C to COL, V to Mu50, and N to N315.

Table 1
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Table 1

Clinical characteristics of patients acquiring a variant of MRSA sequence type (ST)–239 (designated TW) or non-TW strains of methicillin-resistant Staphylococcus aureus (MRSA).

In contrast, analysis of MRSA isolation sites demonstrated marked differences (table 2). Patients who acquired TW, compared with patients who acquired non-TW MRSA, were significantly more likely to have MRSA isolated from blood sample cultures (47% vs. 13%; P < .001) and VAD sample cultures (59% vs. 26%; P < .001). This implied that the increased rate of TW bacteremia is caused by colonization of VADs, which was supported by the observation that a greater proportion of TW bacteremia compared with non-TW MRSA bacteremia were directly attributable to VADs (19 [65%] of 29 vs. 9 [36%] of 23; P = .058). In contrast, patients who acquired non-TW MRSA, compared with patients who acquired TW were more likely to have MRSA isolated from screening swabs (71% vs. 30%, respectively; P < .001) (table 2). This higher rate of non-TW MRSA carriage was confined to the period before surface decolonization strategies were introduced; after this time period, the rate of carriage of non-TW MRSA was not significantly different from the rate of carriage of TW (data not shown). Decolonization strategies had no effect on the isolation of TW from carriage sites.

Table 2
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Table 2

Sites of isolation of methicillin-resistant Staphylococcus aureus (MRSA) from patients who acquired infection with a variant of MRSA sequence type (ST)–239 (designated TW) and non-TW strains.

An analysis was made of risk factors for MRSA bacteremia occurring between time of acquisition to bacteremia, discharge, or death, with a particular focus on exposure to VADs—the main risk factor for bacteremia in this environment [10–12]. First, the time of MRSA bacteremia after acquisition was assessed (table 3); a total of 9 (15%) of 62 patients who acquired TW and 7 (4%) of 171 patients who acquired non-TW MRSA had bacteremia either as the first indication of acquisition or on the same day as the first isolation of MRSA from other sites (Day 0). During the first week after acquisition (Days 1–7), the rate of bacteremia expressed either per 1000 bed days, per 1000 central VAD days, or per 1000 CAA-MRSA days was>4 times greater for patients who acquired TW compared with patients who acquired non-TW MRSA. After the first week of colonization (Day>7) the rates of bacteremia were the same for patients who acquired TW and for patients who acquired non-TW MRSA.

Table 3
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Table 3

Rates of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia from the time of detected acquisition.

Cumulative Kaplan-Meier plots of the probability of developing MRSA bacteremia were constructed (figure 2). The crude hazard ratio for TW bacteremia compared with non-TW MRSA bacteremia was 3.56 (95% CI, 1.83–6.93; P < .001). After adjustment for renal failure, surgery, mean APACHE II score, and exposure to VADs (CAA-MRSA days), the adjusted hazard ratio was 4.5 (95% CI, 2.25–8.99; P < .001) (table 4). It is of note that, in this model, exposure to VADs had a paradoxical protective effect against MRSA bacteremia—an effect also observed with central VAD days (data not shown).

Table 4
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Table 4

Adjusted hazard ratios of developing methicillin-resistant Staphylococcus aureus (MRSA) bacteremia.

Genetic characterisation of the TW strain. MLST of a single isolate identified TW as MRSA ST-239. Sixteen different TW isolates obtained throughout the 2-year outbreak period were analyzed using microarray [16, 18]. All isolates had the same profile of core variable genes that were indistinguishable from other strains of ST-239 and ST-240 (EMRSA-9) in the United Kingdom. All but 1 TW isolate carried the same complement of MGEs, implying that the TW outbreak was caused by a single clone. The 1 isolate had been stored at room temperature for>1 year before analysis and, as such, lost elements from plasmid N315 and Mu50—a frequent phenomenon when isolates are stored at room temperature (J.A.L., unpublished observation). A comparison of MGEs carried by TW and the other ST-239 and ST-240 strains noted that TW had accumulated all MGEs carrying virulence and antibiotic resistance genes that are only variably found in other strains (figure 3); however, we could not identify any genes in TW that were not also found in other strains and that might account for enhanced invasiveness. Importantly, TW did not carry the gene coding for Panton-Valentine leukocidin toxin that is associated with invasive, community-acquired MRSA [21].

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Discussion

To our knowledge, this report provides the first direct evidence that MRSA strains differ in their ability to cause bacteremia. Patients who acquired TW infection were>4 times more likely to develop bacteremia, compared with patients who acquired other strains of MRSA, after careful adjustment for VAD exposure and prescription of antibiotics active against the acquired strain. Approximately 30% of cases of TW and non-TW MRSA bacteremia occurred on the day of detected acquisition, often as the only indication of acquisition of MRSA. This occurred because screening and clinical sample gathering are not performed daily, and colonization can progress to bacteremia before detection, which has been noted previously [22]. For bacteremia occurring after the day of detected acquisition, the rates of both TW and non-TW MRSA bacteremia were higher in the first week; importantly, the increased bacteremic rate of TW was also confined to this first week. This reduced rate of both TW and non-TW MRSA bacteremia after the first week presumably explains the paradoxical protective effect of VAD exposure in the Cox regression model. It is not clear why both the higher rate of all MRSA bacteremia and the increased TW bacteremia phenotype should occur soon after acquisition, but this might partly be explained by a suppressive effect of decolonization protocols and by empiric treatment of sepsis with vancomycin.

The high rate of TW isolation from VAD cultures and the contrasting low rate from staphylococcal carriage sites suggest that the colonization capacity of TW is fundamentally different from other MRSA strains. The infrequent isolation of MRSA from carriage sites has been noted in a previous outbreak [23], but to our knowledge, the preferential colonization of VADs has not. Alternative explanations for preferential VAD colonization involving staff carriers or environmental reservoirs seem less likely, given that TW was not isolated from the environment or from staff screenings. Furthermore, the outbreak was rapidly terminated following the clearance of MRSA from patients' respiratory tracts [20], although any interpretation of the relative contribution of linezolid, compared with the cumulative effect of previously introduced infection-control measures, remains unclear.

MLST identified TW as ST-239, a widespread, international MRSA clone carrying staphylococcal chromosomal cassette mec type III [4, 24–27], which descended by recombination from 2 dominant lineages, ST-8 and ST-30 [28]. In the United Kingdom, ST-239 was first identified as EMRSA-1, and caused major outbreaks in the 1980s [29]. Other ST-239 variants with epidemic potential have been identified (EMRSA-4, -7 and -11), but none have been particularly associated with bacteremia, implying that TW has acquired MGEs conferring this phenotype. Although TW had accumulated all the detectable virulence and antibiotic and/or antiseptic resistance genes only variably carried by related strains, a depressingly common theme in the evolution of S. aureus [4, 30, 31], no unique TW genes were identified. This implies that genes responsible for TW bacteremia are not carried by the S. aureus strains used to construct this microarray. Genomic sequencing of a TW isolate is underway.

We believe that the highly bacteremic phenotype of the TW strain is unlikely to be unique. The rate of MRSA bacteremia in patients in the ICU varies from 5%–60% in published reports [11, 32–34], and it is possible that highly bacteremic strains contribute to the rates noted in some of these reports. Moreover, a recent laboratory study identified a variant Brazilian ST-239 strain (A1) that has an enhanced ability to produce biofilm and to adhere to and invade epithelial cells [35], which would provide a biologically plausible mechanism for bacteremia by TW. It also supports the proposal that this phenotype is acquired by horizontal transfer of MGEs into the ST-239 background. It will be interesting to explore whether A1 and TW share genotypic and phenotypic features.

In conclusion, we have identified a variant of MRSA ST-239 with an enhanced ability to cause bacteremia via colonization of VADs. The identification of TW-specific genes through genome sequencing should reveal insight into the mechanism of VAD-associated bacteremia and permit an assessment of the wider distribution of these genes in ST-239 and other lineages.

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Acknowledgments

We thank Craig Whiteley, Toby Gibb, and Christine Orezzi, for invaluable assistance with constructing the databases; the Bacterial Microarray Group at St. George's University of London (Jason Hinds, Kate Gould, Adam Witney, Lucy Brooks, and Philip Butcher), for supplying resources and their outstanding assistance with microarray experiments; the Health Protection Agency, for phage typing; and Jonathan Thomas and Mark Enright from University of Bath, for MLST typing.

Financial support. Guy's and St. Thomas' Charity (to J.D.E. and J.L.).

Potential Conflicts of interest. J.E., D.W., and J.L. have served as speakers at conferences supported by Pfizer. All other authors: no conflicts.

  • Received July 29, 2006.
  • Accepted September 27, 2006.
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  1. Clin Infect Dis. (2007) 44 (4): 493-501. doi: 10.1086/511034
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