Epidemiology of Multidrug‐Resistant Bacteria in Patients With Long Hospital Stays
Objective. To determine rates of colonization with multidrug‐resistant (MDR) bacteria (ie, methicillin‐resistant Staphylococcus aureus [MRSA], vancomycin‐resistant Enterococcus [VRE], extended‐spectrum β‐lactamase [ESBL]‐producing Enterobacteriaceae, and Acinetobacter baumannii) after prolonged hospitalization and to assess the yield of surveillance cultures and variables associated with colonization with MDR bacteria.
Design. Prospective observational cohort study conducted from February 6 to May 26, 2006.
Methods. All patients who spent more than 30 days in our university hospital (Paris, France) were included. Rectal and nasal swab samples obtained during day 30 screening were examined for MRSA, VRE, ESBL‐producing Enterobacteriaceae, and A. baumannii.
Results. Of 470 eligible patients, 439 had surveillance culture samples available for analysis, including 51 patients (11.6%) with a history of colonization or infection due to 1 or more types of MDR bacteria (MRSA, recovered from 35 patients; ESBL‐producing Enterobacteriaceae, from 16 patients; A. baumannii, from 6 patients; and VRE, from 0 patients) and 37 patients (9.5% of the 388 patients not known to have any of the 4 MDR bacteria before day 30 screening) newly identified as colonized by 1 or more MDR bacteria (MRSA, recovered from 20 patients; ESBL‐producing Enterobacteriaceae, from 16 patients; A. baumannii, from 1 patient; and VRE, from 0 patients). A total of 87 (19.8%) of 439 patients were identified as colonized or infected with MDR bacteria at day 30. Factors that differed between patients with and without MRSA colonization included age, McCabe score, comorbidity score, receipt of surgery, and receipt of fluoroquinolone treatment. Patients with ESBL‐producing Enterobacteriaceae colonization were younger than patients with MRSA colonization.
Conclusions. Differences in the variables associated with MRSA colonization and ESBL‐producing Enterobacteriaceae colonization suggest differences in the epidemiology of these 2 organisms. Day 30 screening resulted in a 72.5% increase in the number of patients identified as colonized with at least 1 type of MDR bacteria.
Received April 11, 2007; accepted July 23, 2007; electronically published September 28, 2007.
The incidence of infection and colonization due to multidrug‐resistant (MDR) bacteria is increasing in hospitals worldwide. These organisms are now endemic in many hospitals, despite infection control measures and antibiotic management programs. The epidemiology of MDR bacteria varies across countries and institutions. Major trends include the rising incidence of infection and colonization due to methicillin‐resistant Staphylococcus aureus (MRSA) and vancomycin‐resistant Enterococcus (VRE)1 and the emergence of other MDR bacteria, such as extended‐spectrum β‐lactamase (ESBL)‐producing Enterobacteriaceae and strains of Acinetobacter baumannii that are intermediately susceptible or resistant to ticarcillin and/or ceftazidime.2,3
Little is known about the overall burden of MDR bacteria in hospitalized patients.4 Studies of infection and colonization with MRSA, VRE, and/or ESBL‐producing Enterobacteriaceae based on samples obtained at intensive care unit (ICU) admission5‐8 showed variable prevalences for each organism and low rates of cocolonization. However, a recent literature review suggests that the risk factors for nosocomial infection or colonization with these MDR bacteria may be quite common.9
Most studies involving surveillance cultures have focused on identifying colonization due to MDR bacteria at hospital admission so that colonized patients can be recognized, predictive rules for screening cultures can be developed, and contact precautions can be implemented appropriately.10,11 Few studies have determined the burden of MDR bacteria by obtaining surveillance specimens after hospital admission, and most studies have concentrated on ICU patients or on patients who were colonized and/or infected with MRSA.12‐14
An outbreak of infection and colonization due to VRE was successfully controlled in our hospital in the fall of 2005. MRSA is endemic in our hospital and in most other hospitals in France.15 Although the spread of ESBL‐producing Enterobacteriaceae was partly controlled in the early 1990s, the incidence of patients with clinical cultures positive for these organisms has increased over the last 2 years.16 We therefore decided to investigate the hospitalwide epidemiology of a broader spectrum of MDR bacteria, namely MRSA, ESBL‐producing Enterobacteriaceae, VRE, and A. baumannii, by screening patients who spent at least 30 consecutive days in our hospital. The main objectives were to maintain a high level of alert after the outbreak of VRE infection and to evaluate the burden of each of these 4 types of MDR bacteria in our hospital.
Methods
Setting
The Bichat‐Claude Bernard Teaching Hospital is a 900‐bed university hospital in the Paris area that serves as both a primary and tertiary care center. It has 27 wards, including 6 ICUs (which comprise 70 beds, including a 20‐bed medical ICU, a 12‐bed surgical ICU, and a 10‐bed intermediate ICU), wards for the main medical and surgical adult specialties, and a 60‐bed rehabilitation unit. Approximately 30,000 patients are admitted for stays longer than 24 hours each year, and the mean length of stay is 7.7 days.
A program for controlling ESBL‐producing Enterobacteriaceae and MRSA was instituted 15 years ago. As part of this program, patients in the ICUs and the intermediate care unit provided culture samples for surveillance of MRSA, A. baumannii, and ESBL‐producing Enterobacteriaceae at admission and then once a week during the study period.13 In addition, selective MRSA screening was performed when patients were admitted to several other units, chiefly the unit “downstream” of the emergency department, the dermatology unit, and the otolaryngology unit.17 If patients who had a history of infection or colonization with 1 of these 3 types of MDR bacteria were readmitted to the hospital, they were screened for the colonizing organism at readmission.18
Patients and Study Design
The study lasted 17 weeks, from February 6 to May 26, 2006. Consecutive patients who were hospitalized for 30 complete consecutive hospital‐days during the study period were eligible for inclusion. Within 3 days after day 30, a total of 2 perirectal specimens and a nasal specimen were obtained using premoistened swabs (Culturette EZ2; Becton Dickinson) (hereafter, this screening period is referred to as “D30 screening”). Because this screening was considered part of our infection control program, the requirement for informed consent was waived.
Study variables were collected prospectively by interviewing the patient and reviewing the patient's medical record and computerized microbiology log. The following variables were recorded on a standardized data collection form: demographic characteristics; unit of hospitalization; history of previous hospitalization; known history of carriage of any of the 4 types of MDR bacteria being studied, either before or during the first 30 hospital‐days; severity of underlying disease at admission, evaluated using the McCabe score19; Knaus score for chronic health status20; comorbidities, assessed using the Charlson index on day 3021; use of invasive devices or procedures and/or the receipt of antibiotics during the first 30 hospital‐days.
Microbiological Methods
Nasal swab samples were plated on Chapman agar (without oxacillin) and incubated for 48 hours at 37°C. The presence of S. aureus and the methicillin‐resistance status of the isolate were determined according to the recommendations of the French Society for Microbiology.17 One rectal swab sample was streaked on ESBL agar (AES Laboratory) to detect ESBL‐producing Enterobacteriaceae and A. baumannii. Enterobacteriaceae, including those that produced ESBL, and A. baumannii were identified using standard microbiological techniques.16,22 A. baumannii was classified as resistant if intermediate susceptibility or resistance to ticarcillin, gentamicin, amikacin, or ciprofloxacin was detected. The other rectal swab sample was streaked on bile esculin azide agar (D‐Coccosel agar; bioMérieux) supplemented with 10 mg/L of vancomycin, both directly and after 18 hours’ enrichment in bile esculin azide broth (Enterococcosel broth; Becton Dickinson) supplemented with 3 mg/L of vancomycin. Plates were incubated at 37°C for 48 hours. In addition, clinical specimens or other active surveillance culture samples were obtained at the discretion of the physician in charge of the patient.
Statistical Analysis
Continuous variables were expressed as means (±SD) and medians, and categorical variables were expressed as counts and percentages. Because we were looking for prevalence data, patients who had a history of previous colonization or infection with 1 of the 4 types of MDR bacteria and those with newly identified MDR bacteria colonization were collapsed into a single group. We evaluated associations between the study variables and colonization with either MRSA or ESBL‐producing Enterobacteriaceae by comparing carriers of each of the 4 types of MDR bacteria to patients who had a negative previous history of colonization and who provided specimens negative for that organism during D30 screening. Variables associated with carriage of MDR bacteria were compared using the χ2 test or the Fisher exact test, as appropriate, and continuous variables were compared by use of the nonparametric Wilcoxon rank sum test. Categories were defined for continuous variables, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. All tests were 2‐tailed. P values of less than .05 were considered significant.
Results
During the study period, 10,558 patients were admitted to our hospital, among whom 470 (4.5%) had hospital stays of 30 days or longer. Of these 470 patients, 17 were discharged or died within 3 days after day 30 of their stay; for 14 others, none of the 3 swab samples were obtained. Therefore, a total of 439 patients were included in the study. Patient characteristics are reported in Table 1. Patients' mean age (±SD) was 
years, and 232 (52.8%) of the patients were men. A previous hospitalization was recorded for 284 patients (64.7%). Most patients (407 [92.7%]) were admitted from their homes. Nearly half (204 [46.5%]) had an ultimately fatal underlying disease, and 81 (18.5%) had a rapidly fatal underlying disease. At the time culture samples were collected, 241 patients (54.9%) were in medical wards, 99 (22.5%) were in surgical wards, 60 (13.7%) were in the rehabilitation unit, and 39 (8.9%) were in the medical or surgical ICU. At the time of D30 screening, the mean Charlson comorbidity score (±SD) was 
, and chronic health status was poor for 214 patients (48.7%). During the first 30 hospital‐days, peripheral venous catheters were used for 361 (82.2%) patients, central venous catheters were used for 89 (20.3%), a total of 184 (41.9%) underwent surgery, urinary devices were used for 208 (47.4%), and 350 (79.7%) received 1 or more antibiotics.
One or more MDR bacteria were recovered from 51 patients during the first 30 hospital‐days (11.6%) (Table 2). MRSA was recovered from 35 (8.0%) of 439 patients, including 11 who were colonized and 24 with at least 1 MRSA‐positive clinical culture. ESBL‐producing Enterobacteriaceae were recovered from 16 patients (3.6%), including 6 who were colonized and 10 who had at least 1 ESBL‐producing Enterobacteriaceae–positive clinical culture. Of the 6 patients (1.4%) from whom A. baumannii was recovered, 1 was colonized, and 5 had at least 1 clinical culture positive for this organism. VRE was not recovered from any of the study patients. A total of 6 patients were cocolonized with 2 MDR bacteria. Of the 51 patients found to be colonized with MDR bacteria before D30 screening, 14 would not have been detected without active surveillance cultures.
At the time of D30 screening, 404 of the 439 patients had no known colonization or infection due to MRSA, including 399 who were tested for nasal carriage of this organism; culture results showed nasal carriage of MRSA in 20 patients (5.0%). At D30 screening, 423 patients had no known colonization or infection due to ESBL‐producing Enterobacteriaceae, including 412 tested for rectal carriage of this organism; culture results showed rectal carriage in 17 patients (4.1%). Rectal swab specimens collected during D30 screening identified an additional patient with gastrointestinal carriage of A. baumannii. No patients had cultures positive for VRE at D30 screening.
In total, D30 screening identified 38 new cases of MDR bacteria colonization in 37 (9.5%) of the 388 patients not known to be colonized with any of the 4 types of MDR bacteria before day 30. Of the 37 patients with newly detected MDR bacteria colonization, 7 had 1 or more clinical cultures positive for MDR bacteria later during the same hospital stay.
In total, the results of D30 screening showed that 87 (19.8%) of 439 patients were colonized or infected with at least 1 of the 4 types of MDR bacteria: MRSA was recovered from 55 (12.5%) patients, ESBL‐producing Enterobacteriaceae from 33 (7.5%), A. baumannii from 7 (1.6%), and VRE from 0 (Table 2). A single type of MDR bacteria was recovered from 80 patients, 2 types were recovered from 6 patients, and 3 types were recovered from 1 patient. The prevalence of patients who were infected or colonized with at least 1 type of MDR bacteria was 28.3% (17 of 60) in the rehabilitation unit, 28.2% (11 of 39) in the ICUs, 17.4% (42 of 241) in the medical units, and 17.1% (17 of 99) in the surgical units. Without performance of surveillance cultures before or on day 30, a total of 50 (57.5%) of the 87 cases of colonization or infection with MDR bacteria would have been missed.
We compared patients with and without colonization or infection due to MRSA or ESBL‐producing Enterobacteriaceae (Table 1). MRSA carriage at D30 screening was associated with age older than 69 years (OR, 2.11 [95% CI, 1.12‐3.97]), hospitalization in the rehabilitation unit (OR, 2.51 [95% CI, 1.20‐5.19]), rapidly or ultimately fatal disease at admission (OR, 2.10 [95% CI, 1.03‐4.37]), comorbidity score greater than 3 on day 30 (OR, 2.06 [95% CI, 1.10‐3.85]), no surgery during the first 30 hospital‐days (OR, 0.39 [95% CI, 0.19‐0.78]), and receipt of fluoroquinolone therapy during the first 30 hospital‐days (OR, 1.98 [95% CI, 1.04‐3.75]). The presence of a rapidly or ultimately fatal disease at admission was the only factor associated with the ESBL‐producing Enterobacteriaceae carriage identified by D30 screening (OR, 3.25 [95% CI, 1.16‐9.80]). Multivariate analysis was not performed, as this prevalence study could not determine whether MDR bacteria were present at admission or acquired during the hospital stay, and thus the meaning of significant independent associations with positive D30 screening results would be unclear. After excluding the 7 patients who were cocolonized with MRSA and ESBL‐producing Enterobacteriaceae, we compared the characteristics of patients colonized or infected with MRSA to those of patients colonized or infected with ESBL‐producing Enterobacteriaceae. The only statistically significant variable was age; patients with ESBL‐producing Enterobacteriaceae infection or colonization were younger than those infected or colonized with MRSA (
).
Discussion
MDR bacteria colonization or infection was present in one‐fifth of patients hospitalized for more than 30 days. D30 screening showed that prevalence rates for infection or colonization with MDR bacteria were highest in the rehabilitation unit and in the ICUs, and prevalences were higher for infection or colonization with MRSA or ESBL‐producing Enterobacteriaceae than for infection or colonization with A. baumannii or VRE. The prevalence and the infection‐to‐colonization ratio were similar for MRSA and ESBL‐producing Enterobacteriaceae. D30 screening resulted in a 75% increase in the number of patients identified as colonized or infected with at least 1 type of MDR bacteria. Overall, the active surveillance culture strategy more than doubled the number of patients known to be colonized or infected with at least 1 identified MDR bacteria. Cocolonization was uncommon.
We elected to screen patients within 3 days after day 30 of their stay for several reasons, of which the most important was the recent eradication of an outbreak of VRE infection in our hospital. The VRE colonization‐to‐infection ratio was high, indicating that the outbreak probably went undetected for several weeks. Therefore, we decided to maintain a high level of alert by screening potentially high‐risk patients, that is, patients who spent more than 30 days in the hospital. In addition, the fact that a prolonged hospital stay is a major risk factor for MDR bacteria carriage9 suggested that D30 screening might detect a high prevalence of colonization with MDR bacteria.
We found a high prevalence of patients carrying 1 or more of the 4 types of MDR bacteria at D30 screening. Because MDR bacteria carriage after a long stay may indicate either carriage at admission or acquisition during the stay, the performance of surveillance cultures during the stay may be useful, in addition to admission screening. The yield and cost‐effectiveness of performing screening cultures at different times after hospital admission remain to be determined and likely depend on the epidemiology of MDR bacteria in each country and hospital. We chose D30 screening on the basis of a previous study and on the acceptable workload for the bacteriology laboratory (4 to 5 screened patients per working day).
The higher prevalence of infection and/or colonization with MDR bacteria in the rehabilitation unit and the ICUs is consistent with known risk factors for MDR bacteria carriage. Admission to rehabilitation units usually occurs after a previous hospital stay. Risk factors in ICUs include a high prevalence of colonization or infection with MDR bacteria at ICU admission, high colonization pressure, high‐intensity care that creates opportunities for MDR bacteria transmission, and widespread use of antibiotics. However, the prevalence of infection or colonization with MDR bacteria was also high in other units, indicating that a long hospital stay was a risk factor for MDR bacteria carriage throughout the hospital.
MRSA was the type of MDR bacteria responsible for the highest prevalence of colonization or infection identified in D30 screening, in keeping with data from surveillance networks based on clinical isolates.15,23 However, infection or colonization with ESBL‐producing Enterobacteriaceae was nearly as prevalent as infection or colonization with MRSA in our study, in accordance with the growing incidence of infection or colonization with these pathogens in Europe and elsewhere.3,15 These 2 types of MDR bacteria shared a number of other characteristics: the colonization‐to‐infection ratios and the number of carriers identified by D30 screening, compared with the number of previously known carriers, were similar. The similarities between MRSA and ESBL‐producing Enterobacteriaceae may help infection control professionals to design strategies for active surveillance cultures and contact precautions.24 However, these 2 organisms differed with respect to several other factors. Patients identified as colonized or infected with MRSA during D30 screening were older, and larger proportions of them had comorbidities, underlying diseases, and had received treatment with fluoroquinolones during the first 30 days of their stay. Our results add to earlier data suggesting that fluoroquinolones may play a specific role in the epidemiology of MRSA.25,26 The ESBL‐producing Enterobacteriaceae carriage identified by D30 screening was associated only with severe underlying disease. The differences between factors associated with colonization or infection with MRSA or ESBL‐producing Enterobacteriaceae likely reflect differences in the epidemiology of these bacteria. Furthermore, the low rate of cocolonization with MRSA and ESBL‐producing Enterobacteriaceae observed in our study constitutes additional support for epidemiological differences between these organisms.27,28 Patients with MDR bacteria–positive clinical cultures constituted a small proportion of colonized patients. Our data indicated that screening approximately doubles the number of patients identified as having MRSA or ESBL‐producing Enterobacteriaceae carriage.
Our study has several limitations. First, our screening strategy may have failed to detect all carriers of MDR bacteria. Broth enrichment was used only for VRE. Therefore, patients with low counts of MRSA in nasal swab samples or low counts of ESBL‐producing Enterobacteriaceae in rectal swab samples may have escaped detection. In addition, we used only a rectal swab sample for A. baumannii detection. Although the sensitivity of this method was as high as 77%, a culture of a concurrently obtained pharyngeal sample further improved sensitivity.29 Second, our study was a cross‐sectional survey, and therefore we cannot determine whether carriers identified by D30 screening acquired the organism before admission or in the hospital. Therefore, factors associated with colonization or infection with MDR bacteria in our study may not be risk factors for MDR bacteria acquisition, although they help to define a population at risk for MDR bacteria carriage. On the other hand, screening for 4 types of MDR bacteria during D30 screening took into account the fact that a long hospital stay is the main major risk factor for colonization or infection with MDR bacteria, and it enabled us to compare the epidemiological characteristics of the 4 types of organisms. Finally, the data from our study in a single hospital may not apply to all hospitals. However, a multicenter study would have supplied information only on MDR bacteria epidemiology in France, which may not apply to other countries.
In conclusion, our study provides information on the overall epidemiology of the 4 main types of hand‐transmitted MDR bacteria in our hospital. Patients colonized with MRSA or ESBL‐producing Enterobacteriaceae shared similarities but also exhibited a number of differences, which argues in favor of different epidemiological mechanisms. Whether screening patients during their hospital stay is useful remains to be determined.
Acknowledgments
We are grateful to Mohamed Bouaita (Hospital Information System) for managing the administrative data and Antoinette Wolfe for editorial assistance.
Potential conflicts of interest. All authors report no conflicts of interest relevant to this article.
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