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n engl j med 368;24 nejm.org june 13, 2013 2255 The new england journal of medicine esta\flished in 1812 june 1\b, 201\b vol. \b68 no. 24 Targeted versus Universal Decolonization to \frevent ICU Infection Susan S. Huang, M.D., M.P.H., Edward Sep\fimus, M.D., Ken K\beinman, Sc.D., Ju\bia Moody, M.S., Jason Hickok, M.B.A., R.N., Ta\biser R. Avery, M.S., Ju\bie Lankiewicz, M.P.H., Adrijana Gombosev, B.S., Leah Terps\fra, B.A., Fa\b\bon Har\fford, M.S., Mary K. Hayden, M.D., John A. Jernigan, M.D., Rober\f A. Weins\fein, M.D., Vic\foria J. Fraser, M.D., Ka\fherine Haffenreffer, B.S., Eric Cui, B.S., Rebecca E. Kaganov, B.A., Karen Lo\bans, B.S., Jona\fhan B. Per\bin, M.D., Ph.D., and Richard P\ba\f\f, M.D., for \fhe CDC Preven\fion Epicen\fers Program and \fhe AHRQ DECIDE Ne\fwork and Hea\b\fhcare-Associa\fe\pd Infec\fions Program* A B S T R A C T From \fhe Universi\fy of Ca\bifornia Irvine Schoo\b of Medicine, Orange (S.S.H., A.G., L.T., E.C.); Hospi\fa\b Corpora\fion of Amer - ica, Hous\fon (E.S.) and Nashvi\b\be ( J.M., J.H., J.B.P); Texas A&M Hea\b\fh Science Cen\fer, Hous\fon (E.S.); Harvard Medica\b Schoo\b and Harvard Pi\bgrim Hea\b\fh Care Ins\fi\fu\fe, Bos\fon (K.K., T.R.A., J.L., F.H., K.H., R.E.K., R.P.); Rush Medica\b Co\b\bege (M.K.H., K.L.) and John S\froger Hospi\fa\b of Cook Coun\fy (R.A.W.), Chicago; Cen\fers for Disease Con\fro\b and Preven\fion, A\f - \ban\fa ( J.A.J.); and Washing\fon Universi\fy in S\f. Louis, S\f. Louis ( V.J.F.). Address re - prin\f reques\fs \fo Dr. Huang a\f \fhe Divi - sion of Infec\fious Diseases and Hea\b\fh Po\bicy Research Ins\fi\fu\fe, Universi\fy of Ca\bifornia Irvine Schoo\b of Medicine, 101 Ci\fy Dr., Ci\fy Tower Sui\fe 400, ZC 4081, Or - ange, CA 92868, or a\f [email protected].

* Inves\figa\fors for \fhe Cen\fers for Dis - ease Con\fro\b and Preven\fion (CDC) Pre - ven\fion Epicen\fers Program and \fhe Agency for Hea\b\fhcare Research and Qua\bi\fy (AHRQ) Deve\boping Evidence \fo Inform Decisions abou\f Effec\fiveness (DECIDE) Ne\fwork and Hea\b\fhcare- Associa\fed Infec\fions Program are \bis\fed in \fhe Supp\bemen\far y Appendix, avai\b - ab\be a\f NEJM.org.

This ar \fic\be was pub\bished on May 29, 2013, and upda\fed on June 13, 2013, a\f NEJM.org.

N Engl J Med 2013;368:2255\f65.

DO\b: 10.1056/NEJMoa1207290 Copyright © 2013 Massach\fsetts Medical \bociety. BACKGROUND \both targeted decolonization and universal decolonization of patients in intensive care units (ICUs) are candidate strategies to prevent health care–associated infec - tions, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA).

METHODS We conducted a pragmatic, cluster-randomized trial. Hospitals were randomly as - signed to one of three strategies, with all adult ICUs in a given hospital assigned to the same strategy. Group 1 implemented MRSA screening and isolation; group 2, targeted decolonization (i.e., screening, isolation, and decolonization of MRSA carri - ers); and group 3, universal decolonization (i.e., no screening, and decolonization of all patients). \froportional-hazards models were used to assess differences in infec - tion reductions across the study groups, with clustering according to hospital.

RESULTS A total of 43 hospitals (including 74 ICUs and 74,256 patients during the interven - tion period) underwent randomization. In the intervention period versus the base - line period, modeled hazard ratios for MRSA clinical isolates were 0.92 for screen - ing and isolation (crude rate, 3.2 vs. 3.4 isolates per 1000 days), 0.75 for targeted decolonization (3.2 vs. 4.3 isolates per 1000 days), and 0.63 for universal decoloni - zation (2.1 vs. 3.4 isolates per 1000 days) (\f = 0.01 for test of all groups being equal).

In the intervention versus baseline periods, hazard ratios for bloodstream infection with any pathogen in the three groups were 0.99 (crude rate, 4.1 vs. 4.2 infections per 1000 days), 0.78 (3.7 vs. 4.8 infections per 1000 days), and 0.56 (3.6 vs. 6.1 infec - tions per 1000 days), respectively (\f<0.001 for test of all groups being equal). Univer - sal decolonization resulted in a signif icantly greater reduction in the rate of all bloodstream infections than either targeted decolonization or screening and isola - tion. One bloodstream infection was prevented per 54 patients who underwent de - colonization. The reductions in rates of MRSA bloodstream infection were similar to those of all bloodstream infections, but the difference was not signif icant. Adverse events, which occurred in 7 patients, were mild and related to chlorhexidine.

CONCLUSIONS In routine ICU practice, universal decolonization was more effective than targeted decolonization or screening and isolation in reducing rates of MRSA clinical iso - lates and bloodstream infection from any pathogen. (Funded by the Agency for Healthcare Research and the Centers for Disease Control and \frevention; REDUCE MRSA ClinicalTrials.gov number, NCT00980980.) T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 368;24 nejm.org june 13, 2013 2256 H ealth care–associated i\ffectio\f is a leading cause of preventable illness and death and often results from colo - nizing bacteria that overcome body defenses. 1-\b Among the pathogens causing health care–associ - ated infection, methicillin-resistant Staphylococcus aureus (MRSA) has been given priority as a target of reduction efforts because of its virulence and disease spectrum, multidrug-resistant prof ile, and increasing prevalence in health care settings, particularly among patients in the intensive care unit (ICU). Hospitals commonly screen patients in the ICU for nasal carriage of MRSA and use contact precautions with carriers. 2-6 Nine states mandate such screening. 7 Decolonization has been used to reduce trans - mission and prevent disease in S. aureus carriers, primarily carriers of methicillin-resistant strains but also carriers of methicillin-sensitive ones. 8,9 S. aureus, including both methicillin-resistant and methicillin-susceptible strains, accounts for more health care–associated infections than any oth - er pathogen. 4 It is the most common cause of ventilator-associated pneumonia and surgical-site infection and the second most common cause of central-catheter–associated bloodstream infec - tion. 4 Decolonization commonly involves a multi - day regimen of intranasal mupirocin and chlor - hexidine bathing. There is debate about whether decolonization should be used and, if so, whether to target high- risk pathogens or patient populations that are susceptible to infection from many pathogens. 10 In particular, the broad antimicrobial activity of chlorhexidine makes it attractive for preventing health care–associated infection from many pathogens. 11-14 Several studies have shown that daily chlorhexidine bathing of all patients in the ICU can reduce MRSA acquisition, the concen - tration of bacteria on the body surface, and bloodstream infection from all pathogens. 11-14 A comparative-effectiveness trial is needed to determine what type of decolonization strategy works best to reduce MRSA and other pathogens in ICUs. 1\b In addition, it is important to know whether decolonization can be effective in routine ICU care. We conducted a cluster-randomized, pragmatic, comparative-effectiveness trial in adult ICUs to compare targeted and universal decolo - nization with one another and with MRSA screen - ing and contact precautions alone. M E T H O D S STUDY DESIGN We designed the Randomized Evaluation of De - colonization versus Universal Clearance to Elimi - nate MRSA (REDUCE MRSA) trial, a three-group, cluster-randomized trial, to compare strategies for preventing MRSA clinical isolates and infec - tions in adult ICUs in Hospital Corporation of America (HCA) hospitals. The trial design has been described previously, 1\b and the protocols are available with the full text of this article at NEJM .org. The training materials are provided in the Supplementary Appendix, available at NEJM.org.

All the authors vouch for the accuracy of the re - ported data and the f idelity of the study to the protocol. There was a 12-month baseline period from Januar y 1 through December 31, 2009; a phase-in period from January 1 through April 7, 2010; and an 18-month intervention period from April 8, 2010, through September 30, 2011. The three strategy groups were def ined as follows. In group 1 (screening and isolation), bilateral screening of the nares for MRSA was performed on ICU admission, and contact pre - cautions were implemented for patients with a history of MRSA colonization or infection and for those who had any positive MRSA test. This was the previous standard of care in all hospitals.

The MRSA screening program for patients in the ICU, who are a group at high risk for infection, began in 2007 at HCA hospitals. 16 More than 90% of the patients admitted to the ICU under - went screening, and contact precautions were im - plemented for carriers of MRSA and other multi - drug-resistant pathogens. In group 2 (targeted decolonization), MRSA screening and contact precautions were similar to those in group 1. \fatients known to have MRSA colonization or infection under went a 5-day decolonization regimen consisting of twice- daily intranasal mupirocin and daily bathing with chlorhexidine-impregnated cloths. In group 3 (universal decolonization), there was no screening for MRSA on admission to the ICU. Contact precautions were similar to those in group 1. All patients received twice-daily intra - nasal mupirocin for 5 days, plus daily bathing with chlorhexidine-impregnated cloths for the entire ICU stay. All adult ICUs in a participating hospital were T a rge t ed v s . U\fi v er s a l De c ol o\fi z at io\f f or ICU I\ffe c t io\f n engl j med 368;24 nejm.org june 13, 2013 2257 assigned to the same study group. Contact- precaution policies, which were based on long - standing guidance from the Centers for Disease Control and \frevention (CDC), were identical and unchanged for all hospitals. \frecautions were initiated on the basis of current or historical MRSA cultures or other standard indications. 6 Results of cultures obtained on admission be - came available the next day. STUDY OUTCOMES The primary outcome was ICU-attributable, MRSA- positive clinical cultures. Screening tests were excluded from all analyses because hospitals im - plementing universal decolonization discontin - ued such cultures. Secondary outcomes included ICU-attributable bloodstream infection caused by MRSA and ICU-attributable bloodstream infec - tion caused by any pathogen. Clinical cultures were obtained at the clinician’s discretion.

RECRUITMENT AND ELIGIBILIT Y CRITERIA Recruitment occurred among the 160 HCA hospi - tals. Most were community hospitals with single- occupancy ICU rooms. Eligibility criteria includ - ed commitment by the hospital administration to have the hospital undergo randomization for the trial, less than 30% of patients in participating adult ICUs receiving either chlorhexidine bathing or intranasal mupirocin at baseline, stable use of infection-prevention initiatives and products dur - ing the baseline period, and agreement to refrain from adopting new initiatives that would conf lict with the trial. Throughout the study, corporate - wide campaigns were used to ensure compliance with national practice guidelines. 16-18 Each hospital obtained approval from an in - stitutional review board, with more than 90% of the hospitals delegating review to the Harvard \filgrim Health Care institutional review board.

\fatient notices about group-specif ic protocols were posted in each ICU room. The requirement for written informed consent was waived. 19 RANDOMI\fATION Randomization was stratif ied to optimize bal - ance in patient volume and baseline prevalence of MRSA carriage on the basis of clinical cultures and screening tests from July 2008 through June 2009. Hospitals were ranked according to ICU volume and were grouped into sets of six. Within each set, we ordered the hospitals according to the prevalence of MRSA carriage in the ICU. Each group of three consecutive hospitals was random - ly assigned, one to each strategy group, with the use of block randomization. Hospitals in states with legislative mandates for MRSA screening in the ICU were similarly and separately randomly assigned to group 1 or 2. IMPLEMENTATION On-site activities were implemented by hospital personnel responsible for quality-improvement initiatives, including ICU directors, infection pre - ventionists, and nurse educators. Standard com - munication channels were used, including group- specif ic, computer-based training modules and daily electronic documentation by nursing staff for all groups. On-site training in bathing with chlorhexidine-impregnated cloths was provided to hospitals assigned to a decolonization regimen (i.e., group 2 or 3). Nursing directors performed at least three quarterly observations of bathing, including questioning staff about protocol details. Investigators hosted group-specif ic coaching teleconferences at least monthly to discuss im - plementation, compliance, and any new, poten - tially conf licting initiatives. Compliance assess - ment involved verif ication on 1 day per week for each ICU. HCA leadership evaluated trial pro - cesses during routine hospital visits. Additional site visits were made at the request of the hospi - tal or if compliance was found to be low. Intranasal mupirocin ointment 2% (\bactro - ban, GlaxoSmithKline) and 2% chlorhexidine– impregnated cloths (Sage \froducts) were used for decolonization. All mupirocin and chlorhex - idine-impregnated cloths were purchased at their usual cost by the participating hospitals. In groups 2 and 3, bathing products and products used for wound prophylaxis that were incompatible with chlorhexidine were replaced with compatible products. Adverse events were managed by treat - ing physicians. DATA COLLEC TION AND OUTCOME ASSIGNMENT Census (i.e., the unit location of each patient for every hospitalization day), microbiologic, phar - macy, supply-chain, nursing-query, and adminis - trative data were obtained from corporate data warehouses, which undergo line-item validation until 99% accuracy is achieved. CDC criteria were T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 368;24 nejm.org june 13, 2013 2258 used for microbiologic outcomes (f irst outcome per patient). \fathogens were attributed to an ICU if the collection date occurred during the period from the third day after ICU admission through the second day after ICU discharge. For blood - stream infections to be attributed to skin-com - mensal organisms, the same organism had to be isolated from two or more blood cultures ob- tained within 2 calendar days of one another. 20 STATISTIC AL ANALYSIS We powered the trial on the basis of the rarest outcome, MRSA bloodstream infection. The study was designed to have 80% power to detect a 40% relative reduction in the rate of MRSA blood - stream infection in group 2, and a 60% relative reduction in the rate in group 3, as compared with group 1. The primary analyses were con - ducted according to the intention-to-treat prin - ciple (as-assigned analyses) and were unadjusted.

\froportional-hazards models with shared frail - ties accounted for clustering within hospitals (see the Supplementary Appendix). 21,22 The inter - vention effect was assessed on the basis of the interaction between group and study period, re - f lecting the difference in hazard between the base - line and intervention periods among the groups.

Data from the phase-in period were excluded from all analyses. When the null hypothesis of equal changes across the groups was rejected, we examined pairwise comparisons. Sensitivit y analyses included multivariable covariate-adjusted models, as-treated models, models that excluded hospitals in states mandat - ing MRSA screening in the ICU, models that accounted for assigned randomization strata, and models that excluded the small numbers of medical-only and surgical-only ICUs. Adjusted models accounted for age, sex, race, insurance type, coexisting conditions (def ined with the use of codes from the I\fter\fatio\fal Classif icatio\f of Diseases, \bth Revisio\f ), and surger y during the hospital stay. Analyses were performed with the use of SAS software, version 9.3 (SAS Institute). R E S U L T S STUDY PARTICIPANTS A total of 45 hospitals in 16 states underwent randomization (Fig. 1). A total of 43 (comprising 74 ICUs) implemented the assigned intervention; 2 hospitals that underwent randomization were excluded from all analyses because preexisting ex -clusion criteria were discovered before the interven - tion started. One hospital in group 2 (assigned to targeted decolonization) withdrew after the inter - vention started and was included in the as-assigned analyses but not in the as-treated analyses. \fatient characteristics were similar across groups and between the baseline and interven - tion periods (Table 1). There was excellent sepa - ration of interventions across groups. In group 1, less than 1.0% of patients (range for hospitals in group, 0 to 2.1%) received mupirocin or chlorhex - idine. In group 2, a total of 90.8% of MRSA carriers (range for hospitals in group, 56.5 to 100%) received mupirocin and 88.8% (range for hospitals in group, 54.2 to 98.4%) received chlorhexidine. In group 3, a total of 86.1% of patients (range for hospitals in group, 41.0 to 99.1%) received mupirocin and 80.8% (range for hospitals in group, 53.1 to 98.6%) received chlorhexidine. Reasons for noncompliance included dis - charge before scheduled bathing or mupirocin administration, discharge before MRSA-positive results were obtained, moribund state of the patient, length of ICU stay of less than 1 day, and patient’s decision to decline the intervention.

MRSA screening occurred in 97.5% of patients (hospital range, 90.6 to 100%) in group 1, in 98.6% (hospital range, 95.6 to 100%) in group 2, and in 0.7% (hospital range, 0 to 4.7%) in group 3. Of the 69 proposed practice changes that occurred at various hospitals during the trial, 36 conf licted with the trial protocol and were not implemented. OUTCOMES For the primary outcome of ICU-attributable, MRSA-positive clinical cultures in the as-assigned analysis, the relative hazards differed signif i - cantly among the groups in a comparison of the inter vention period with the baseline period (\f = 0.01) (Fig. 2). \fairwise analyses showed that universal decolonization resulted in a signif i - cantly greater reduction in the hazard of MRSA- positive clinical cultures than did screening and isolation (hazard ratio in group 3, 0.63; 95% con - f idence interval [CI], 0.52 to 0.75; hazard ratio in group 1, 0.92; 95% CI, 0.77 to 1.10; \f = 0.003 for test of all groups being equal). The effects of the strategies on ICU-attribut - able MRSA bloodstream infection were not sig - nif icantly different across the study groups (\f = 0.11 for test of all groups being equal), al - though the hazard reduction with universal de - T a rge t ed v s . U\fi v er s a l De c ol o\fi z at io\f f or ICU I\ffe c t io\f n engl j med 368;24 nejm.org june 13, 2013 2259 colonization was greater than the reductions with the other strategies (hazard ratio, 0.72 [95% CI, 0.48 to 1.08] vs. 1.23 [95% CI, 0.80 to 1.90] for screening and isolation and 1.23 [95% CI, 0.82 to 1.85] for targeted decolonization). For ICU- attributable bloodstream infection from any patho - gen, differences among the groups were signif i - cant (\f<0.001 for test of all groups being equal).

In pairwise comparisons, universal decolonization resulted in a signif icantly greater reduction in the hazard of infection (hazard ratio, 0.56; 95% CI, 0.49 to 0.65) than either screening and isolation (hazard ratio, 0.99; 95% CI, 0.84 to 1.16; \f<0.001) or targeted decolonization (hazard ratio, 0.78; 95% CI, 0.66 to 0.91; \f = 0.04). We found no sig - nificant difference in mortality across the groups, although the trial was inadequately powered to observe even relatively large effects on death. The effect of targeted decolonization was in - termediate between the effects of usual care 45 Hospitals (78 I\uCUs) u\fder\be\ft ra\fdomizatio\f 55 Hospitals (98 I\uCUs) \bere assessed for eligibility 10 Hospitals (20 IC\uUs) did\fot meet eligibility\u criteria States \bith ma\fdator\uy MRSA scree\fi\fg 6 Hospitals (14 ICU\us) ra\fdomly assig\fed\u to group 1 or 2 Group 1 16 Hospitals (23 IC\uUs a\fd 23,480 patie\fts) Group 3 13 Hospitals (29 IC\uUs a\fd 26,024 patie\fts) States \bithout ma\fda\utory MRSA scree\fi\fg 39 Hospitals (64 I\uCUs) ra\fdomly assig\u\fed to group 1, 2, or 3 1 Hospital (3 ICUs)\u reportedmeeti\fg exclusio\f crit\ueria a\fd \bas removed from \utrial 1 Hospital (1 ICU) r\ueported meeti\fg exclusio\f crit\ueria a\fd \bas removed from \utrial 5 Hospitals (11 ICUs\u) e\ftered trial 13 Hospitals 3 Hospitals 38 Hospitals (63 I\uCUs) e\ftered trial 1 Hospital (2 ICUs)\u \bithdre\b from the study Group 2 14 Hospitals (22 IC\uUs a\fd 24,752 patie\fts) 13 Hospitals (29 IC\uUs a\fd26,024 patie\fts) 13 Hospitals (20 IC\uUs a\fd22,105 patie\fts) 16 Hospitals (23 IC\uUs a\fd23,480 patie\fts) 2 Hospitals 12 Hospitals 13 Hospitals As-Assigned Analysis As-Treated Analysis Figure 1. Recruitment, Randomization, and \bnclusion in As\fAssigned and As\fTreated Analyses.

A \fo\fa\b of 45 hospi\fa\bs in 16 s\fa\fes were random\by assigned \fo a s\fudy group, wi\fh 43 (comprising 74 ICUs) beginning \fhe assigned in\fer - ven\fion; 2 hospi\fa\bs were exc\buded from a\b\b ana\byses because preexis\fing exc\busion cri\feria were discovered before \fhe in\ferven\fion s\far\fed.

One hospi\fa\b in group 2 (assigned \fo \farge\fed deco\boniza\fion) wi\fhdrew af\fer \fhe in\ferven\fion s\far\fed and was inc\buded in \fhe as-assigned ana\byses bu\f no\f \fhe as-\frea\fed ana\byses. The numbers of pa\fien\fs shown in each group are \fhe numbers from \fhe in\ferven\fion period. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 368;24 nejm.org june 13, 2013 2260 (i.e., screening and isolation) and universal de - colonization for ICU-attributable MRSA cultures and bloodstream infection from any pathogen.

Targeted decolonization resulted in signif icantly lower rates of bloodstream infection from any pathogen than did screening and isolation; other outcomes did not differ signif icantly between these two groups. Findings in all sensitivity analyses were similar to those in the as-assigned analysis (Table 2). Outcome events and their associated rates are shown in Table 3 and in the Supplementary Ap- pendix. There were no signif icant between-group differences at baseline (\f≥0.30 for all outcomes).

The baseline rate of MRSA-positive clinical cul - tures was higher in group 2 (4.3 per 1000 at - tributable days) than in the other strategy groups (3.4 per 1000 attributable days in each), but the difference was not signif icant. At baseline, the rate of bloodstream infections from any patho - Table 1. Characteristics of the \bntensive Care Unit (\bCU) Population, According to Study Period and Group.* Variable 12\fMo Baseline Period (N = 48,390) 18\fMo \bntervention Period (N = 74,256) Group 1 Group 2 Group 3 Group 1Group 2 Group 3 Admission wi\fh ICU s\fay (no.) 15,81615,21817,356 23,48024,75226,024 A\f\fribu\fab\be ICU pa\fien\f-days (no.) 63,13557,41869,668 88,22292,978101,603 ICU \fype (no.)† Medica\b 3 5 5 3 5 5 Surgica\b 1 2 6 1 2 6 Mixed medica\b and surgica\b 191418 191517 Hospi\fa\b s\fay (days) Median 7 7 8 7 7 7 In\ferquar\fi\be range 5–125–125–12 5–125–125–12 ICU s\fay (days) Median 3 3 3 3 3 3 In\ferquar\fi\be range 2–52–52–5 1–52–52–5 Age (yr) Median 656665 656665 In\ferquar\fi\be range 52–7753–7751–77 52–7753–7752–77 Fema\be sex (%)‡ 47.247.247.9 47.647.247.5 Nonwhi\fe race (%)§ 25.922.130.8 25.923.531.7 Coexis\fing condi\fion (%) Diabe\fes 31.333.0 30.7 31.832.731.5 Rena\b fai\bure 20.020.419.0 20.322.219.7 Cancer 10.410.814.1 9.9 10.8 13.0 Liver fai\bure 3.4 4.4 3.9 4.0 4.1 4.2 His\fory of MRSA infec\fion (%)¶ 10.211.510.6 9.7 11.1 3.9 Surgery during hospi\fa\biza\fion (%) 40.538.647.5 38.737.746.2 * Group 1 imp\bemen\fed me\fhici\b\bin-resis\fan\f\p \btaphylococc\fs a\fre\fs (MRSA) screening and iso\ba\fion; group 2, \farge\fed deco\boniza\fion (i.e., screening, iso\ba\fion, and deco\boniza\fion of MRSA carriers wi\fh ch\borhexidine and mupirocin); and group 3, universa\b deco\boniza\fion (i.e., no screening and a\b\b pa\fien\fs underwen\f deco\boniza\fion). A\f base\bine, \fhere were no significan\f be\fween-group differences. For addi\fiona\b de\fai\bs, see \fhe Supp\bemen\fary Appendix.

† Differences in \fhe number of ICUs in \fhe groups be\fween \fhe base\bine and in\ferven\fion periods ref\bec\f \fhe fac\f \fha\f one ICU in group 2 opened during \fhe \fria\b and one in group 3 c\bosed.

‡ Da\fa were missing for eigh\f pa\fien\fs.

§ Race was de\fermined from e\bec\fronic adminis\fra\five da\fa a\f each hospi\fa\b.

¶ A his\fory of MRSA infec\fion was iden\fified wi\fh \fhe use of a\b\b avai\bab\be screening and c\binica\b cu\b\fures, wi\fh \fhe his\fory defined as MRSA carriage documen\fed by \fhe Hospi\fa\b Corpora\fion of America during \fhe period from 1 year before admission \fo day 2 of \fhe ICU s\fay. Da\fa from group 3 during \fhe in\ferven\fion period are no\f comparab\be \fo da\fa from \fhe o\fher groups because universa\b deco\boniza\fion, wi\fhou\f screening, was performed for a\b\b pa\fien\fs in \fhis group. As \fhe in\ferven\fion progressed, pa\fien\fs who were readmi\f\fed \fo \fhe ICU were \bess \bike\by \fo be iden\fified as MRSA-posi\five. T a rge t ed v s . U\fi v er s a l De c ol o\fi z at io\f f or ICU I\ffe c t io\f n engl j med 368;24 nejm.org june 13, 2013 2261 gen was higher in group 3 (6.1 infections per 1000 attributable days) than in groups 2 and 3 (4.2 and 4.8 infections per 1000 attributable days, respectively), but the difference was not signif i - cant (\f = 0.87).

\by chance, group 3 contained three of the four hospitals that performed bone marrow and solid-organ transplantations. These three hospi - tals accounted for much of the excess risk in this group, including 72% of the baseline coagulase- negative staphylococcal bloodstream infections (baseline risk of 0.01 events per patient in these three hospitals). The baseline risk per patient in all other hospitals in group 3 (0.004 events) was similar to the baseline risks in all hospitals in groups 1 and 2 (0.003 events in each group).

During the intervention period, the risk declined in the three hospitals (0.002) and in all other hospitals implementing universal decolonization (0.0004), as compared with the baseline risks and as compared with the intervention risk for groups 1 and 2 (0.002 in each group). Analyses with adjustment for coexisting conditions such as cancer supported the f indings of the as-assigned analyses (Table 2).

ADVERSE EVENTS There were seven adverse events (two in group 2 and f ive in group 3) (see the Supplementary Ap- pendix). All involved mild pruritus or rash after chlorhexidine bathing and resolved on discon - tinuation of the use of chlorhexidine-impregnat - ed cloths. D I S C U S S I O N Universal decolonization of patients in the ICU was the most effective strategy, signif icantly re - ducing MRSA-positive clinical cultures by 37% and bloodstream infections from any pathogen by 44%.

This effect was observed under usual practice conditions in a wide array of hospitals, including community hospitals, that had already implement - ed national, evidence-based recommendations for preventing health care–associated MRSA infec - tion. A total of 181 patients would need to un - dergo decolonization to prevent one MRSA-posi - tive clinical culture, and 54 patients would need to undergo decolonization to prevent one blood - stream infection from any pathogen. Several factors may account for our observa - tion that universal decolonization had a greater preventive effect than the two other strategies. Hazard Ratio 1.50 2.00 1.00 0.50 0.00 1 2 3 Group B MRSA Bloodstr\fam In\b\f\sction A MRSA Clinical Cultu\sr\f P = 0.01 Hazard Ratio 2.00 1.50 1.00 0.50 0.00 1 2 3 Group P =0.11 C Bloodstr\fam In\b\fction \s\brom Any Pathog\fn Hazard Ratio 2.00 1.50 1.00 0.50 0.00 1 2 3 Group P<0.001 0.92 0.75 0.63 1.231.23 0.72 0.990.78 0.56 Figure 2. Effect of Trial \bnterventions on Outcomes.

Shown are group-specif ic hazard ra\fios and 95% conf idence in\ferva\bs (indi - ca\fed by ver\fica\b \bines) for ou\fcomes a\f\fribu\fab\be \fo \fhe in\fensive care uni\f.

Resu\b\fs are based on unadjus\fed propor\fiona\b-hazards mode\bs \fha\f accoun\f - ed for c\bus\fering wi\fhin hospi\fa\bs. Ana\byses were based on \fhe as-assigned s\fa\fus of hospi\fa\bs. Pane\b A shows hazard ra\fios for c\binica\b cu\b\fures \fha\f were posi\five for me\fhici\b\bin-resis\fan\f \btaphylococc\fs a\fre\fs (MRSA) infec- \fion, Pane\b B hazard ra\fios for MRSA b\boods\fream infec\fion, and Pane\b C hazard ra\fios for b\boods\fream infec\fion from any pa\fhogen. Bubb\be p\bo\fs of hazard ra\fios (predic\fed random effec\fs or exponen\fia\fed frai\b\fies) from in - dividua\b hospi\fa\bs re\ba\five \fo \fheir group effec\fs are shown. The size of \fhe bubb\be indica\fes \fhe re\ba\five number of pa\fien\fs con\fribu\fing da\fa \fo \fhe \fria\b. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 368;24 nejm.org june 13, 2013 2262 First, chlorhexidine reduces skin colonization by many pathogens, thus protecting patients in the ICU from their own microbiota during a period of heightened vulnerability to infection. 11-14 Sec - ond, universal decolonization reduces the environ - mental microbial burden, reducing opportunities for patient-to-patient transmission. 14,23 Third, universal decolonization began on the f irst ICU day, thus avoiding the delay in decolonization pending the results of screening tests.

Another potential benef it of universal decolo - nization is the elimination of MRSA surveillance tests and the associated reduction in contact pre - cautions, which can interfere with care. 24 These f indings have implications for legislative man - dates requiring MRSA screening in the ICU. 2\b Table 2. Hazard Ratios for Primary and Secondary Trial Outcomes.

Variable Hazard Ratio (95% C\b)Overall P Value Group 1 Group 2Group 3 MRSA C\binica\b cu\b\fureAs-assigned ana\bysisUnadjus\fed* 0.92 (0.77–1.10)0.75 (0.63–0.89)0.63 (0.52–0.75) 0.01 Adjus\fed 0.92 (0.77–1.10)0.74 (0.62–0.88)0.64 (0.53–0.77) 0.02 As-\frea\fed ana\bysis, unadjus\fed 0.93 (0.78–1.11)0.78 (0.65–0.94)0.63 (0.52–0.75) 0.01 Randomiza\fion \fo a\b\b \fhree groups, unadjus\fed ana\bysis† 0.93 (0.76–1.13) 0.74 (0.62–0.89)0.63 (0.52–0.75) 0.02 Randomiza\fion s\fra\fa accoun\fed for, unadjus\fed ana\bysis 0.93 (0.78–1.11) 0.75 (0.63–0.89)0.63 (0.52–0.75) 0.01 Mixed medica\b and surgica\b ICUs on\by, unadjus\fed ana\bysis 0.93 (0.76–1.12) 0.71 (0.59–0.86)0.57 (0.46–0.71) 0.004 B\boods\fream infec\fion As-assigned ana\bysisUnadjus\fed 1.23 (0.82–1.85)1.23 (0.80–1.90)0.72 (0.48–1.08) 0.11 Adjus\fed 1.20 (0.80–1.81)1.19 (0.77–1.84)0.74 (0.49–1.12) 0.18 As-\frea\fed ana\bysis, unadjus\fed 1.24 (0.82–1.86)1.34 (0.84–2.15)0.72 (0.48–1.08) 0.08 Randomiza\fion \fo a\b\b \fhree groups, unadjus\fed ana\bysis† 1.15 (0.74–1.79) 1.18 (0.74–1.89)0.72 (0.48–1.08) 0.19 Randomiza\fion s\fra\fa accoun\fed for, unadjus\fed ana\bysis 1.24 (0.83–1.86) 1.22 (0.79–1.88)0.73 (0.48–1.09) 0.12 Mixed medica\b and surgica\b ICUs on\by, unadjus\fed ana\bysis 1.15 (0.75–1.77) 1.20 (0.75–1.93)0.72 (0.44–1.20) 0.28 B\boods\fream infec\fion from any pa\fhogen As-assigned ana\bysisUnadjus\fed‡ 0.99 (0.84–1.16)0.78 (0.66–0.91)0.56 (0.49–0.65) <0.001 Adjus\fed 0.98 (0.84–1.15)0.77 (0.65–0.90)0.55 (0.48–0.64) <0.001 As-\frea\fed ana\bysis, unadjus\fed 0.99 (0.84–1.16)0.78 (0.66–0.92)0.56 (0.49–0.65) <0.001 Randomiza\fion \fo a\b\b \fhree groups, unadjus\fed ana\bysis† 0.93 (0.78–1.10) 0.77 (0.65–0.91)0.56 (0.49–0.65) <0.001 Randomiza\fion s\fra\fa accoun\fed for, unadjus\fed ana\bysis 0.99 (0.84–1.16) 0.78 (0.66–0.91)0.56 (0.49–0.65) <0.001 Mixed medica\b and surgica\b ICUs on\by, unadjus\fed ana\bysis 0.96 (0.81–1.13) 0.80 (0.67–0.96)0.59 (0.50–0.69) <0.001 * P va\bues in \fhe pairwise ana\bysis were as fo\b\bows: P = 0.09 for \fhe comparison of group 2 wi\fh group 1, P = 0.003 for \fhe comparison of group 3 wi\fh group 1, and P = 0.16 for \fhe comparison of group 3 wi\fh group 2.

† This ana\bysis exc\buded \fhe five hospi\fa\bs in s\fa\fes wi\fh \baws requiring MRSA screening in \fhe ICU.

‡ P va\bues in \fhe pairwise ana\bysis were as fo\b\bows: P = 0.04 for \fhe comparison of group 2 wi\fh group 1, P<0.001 for \fhe comparison of group 3 wi\fh group 1, and P = 0.003 for \fhe comparison of group 3 wi\fh group 2. T a rge t ed v s . U\fi v er s a l De c ol o\fi z at io\f f or ICU I\ffe c t io\f n engl j med 368;24 nejm.org june 13, 2013 226\b Nevertheless, there may be occasions when screening is warranted, such as periodic monitor - ing of resistance. Formal cost-effectiveness analy - sis is needed to understand whether the observed cessation of screening, reduced contact precau - tions, and reduced infections offset the product costs and the potential emergence of resistance.

It remains to be seen whether universal decolo - nization can obviate the need for all contact precautions for carriers of MRSA or other multi - drug-resistant organisms. The benef its attributable to universal decolo - nization are notable for several reasons. First, the large reductions in infections that we ob- served were achieved over and above the sub- stantial reductions in bloodstream infections due to MRSA and other pathogens that have oc - curred at HCA hospitals and other hospitals nationally within the past decade. 3,26,27 Our study included a direct comparison with high- compliance active surveillance and accompany - ing contact precautions, which have been associ - ated with decreased rates of MRSA transmission and MRSA bloodstream infection. 9,16,2\b,27,28 Hos - pitals that have not fully implemented a strategy of screening and isolation may derive additional benef it from this intervention. Second, universal decolonization was implemented as part of rou - tine practice with the use of the usual infra - structure of the hospital for practice change, without the need for on-site study personnel.

These results are thus likely to be generally achievable as part of regular practice. Third, the intervention was effective in community hospi - tals, which make up the majority of U.S. hospitals. The reduction in bloodstream infections from any pathogen occurred in the context of the relatively higher baseline rates of infection for all pathogen t ypes (gram-positive, gram-negative, and fungal) in group 3, as compared with the other groups. One explanation for these high rates is that this group included three of the four hospitals providing bone marrow and solid- organ transplantations. Such differences across groups are largely accounted for by comparing the outcome rate in each hospital with that hos - pital’s baseline rate, providing reassurance that the benef it is attributable to decolonization rather than to baseline variation in case mix or clinical practices across groups. In addition, group 3 did not have higher baseline rates of MRSA-positive clinical cultures than the other groups did, so regression to the mean would not explain the benef icial effect on that outcome. It is unknown whether a threshold level of compliance with universal decolonization is re - quired to achieve the observed benef it or wheth - er a compliance rate higher than the rate in our study (85%) would yield further improvement.

Although hospital staff members were aware of the assigned strategy, which could have resulted in unmeasured behavior that affected trial out - comes, 29 it is unclear what unmeasured behavior could effect a 44% improvement. Table 3. Frequency and Rates of Outcomes during the Baseline and \bntervention Periods, According to Study Group.* Outcome Group 1Group 2Group 3 Base\bine In\ferven\fion Base\bineIn\ferven\fion Base\bineIn\ferven\fion no. of events (cr\fde rate per 1000 patient-days) MRSA c\binica\b cu\b\fures 216 (3.4)279 (3.2) 245 (4.3)301 (3.2) 240 (3.4) 217 (2.1) B\boods\fream infec\fion MRSA 37 (0.6)63 (0.7) 31 (0.5)61 (0.6) 46 (0.6) 48 (0.5) Any pa\fhogen† 265 (4.2)360 (4.1) 273 (4.8)341 (3.7) 412 (6.1) 356 (3.6) Gram-posi\five organism 165 (2.6)228 (2.6) 159 (2.8)203 (2.2) 253 (3.7) 187 (1.9) Skin commensa\b organism 50 (0.8)55 (0.6) 49 (0.9)46 (0.5)120 (1.8) 38 (0.4) Noncommensa\b organism 115 (1.8)173 (2.0) 110 (1.9)157 (1.7) 133 (2.0) 149 (1.5) Gram-nega\five organism 62 (1.0)83 (0.9) 58 (1.0)75 (0.8)100 (1.5) 107 (1.1) Candida species 38 (0.6)49 (0.6) 56 (1.0)63 (0.7) 59 (0.9) 62 (0.6) * Provided ra\fes are crude ra\fes, defined as \fhe number of even\fs per 1000 ICU-a\f\fribu\fab\be pa\fien\f-days a\f risk for \fhe even\f. Pa\fien\f-days af\fer each even\f were exc\buded from \fhe ana\bysis; \fhus, denomina\fors are differen\f for each ce\b\b and are no\f inc\buded.

† The dis\fribu\fion of a\b\b b\boods\fream even\fs is based on \fhe firs\f e\bigib\be even\f from any pa\fhogen per pa\fien\f. For examp\be, a pa\fien\f wi\fh a firs\f ICU-associa\fed b\boods\fream infec\fion (due \fo a gram-posi\five organism) fo\b\bowed by a second ICU-associa\fed b\boods\fream infec\fion (due \fo a gram-nega\five organism) wou\bd be coun\fed on\by in \fhe \bis\fing for gram-posi\five organisms. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 368;24 nejm.org june 13, 2013 2264 This trial provides no information on the at - tributable benef it of mupirocin, either alone or in combination with chlorhexidine. On the basis of microbiologic activit y, any reduction in non– S. aureus bloodstream infections should be at - tributed to chlorhexidine. However, for S. aureus, the most common cause of health care–associ - ated infection, 4 clearance of the nasal reservoir in combination with body decolonization may be superior to either method alone. 30 Widespread use of chlorhexidine and mupiro - cin could possibly engender resistance. 9,31,32 Mu - pirocin resistance has been reported in some studies of MRSA decolonization, 9,30 but not all such studies. 8,32-3\b MRSA resistance to chlorhex - idine lacks a standard def inition, but recent re - ports suggest that resistant strains are rare in the United States.

36,37 A gene encoding a multi - drug eff lux pump that is active against chlorhex - idine has been reported in MRSA, 38 but its clinical signif icance is not understood. Reduced suscep- tibility to chlorhexidine has also been reported in gram-negative bacteria. 39 It will therefore be important for surveillance programs to monitor mupirocin and chlorhexidine resistance. 3,8 This trial was designed as a pragmatic, comparative-effectiveness trial implemented pri - marily through usual hospital processes. 1\b,19 We chose this design to obtain results that could be generalized to the broadest set of hospitals, to use processes potentially adoptable by many hos - pitals, and to conduct a study of suff icient size — all ICUs in dozens of hospitals — with the available resources. Randomization of entire hos - pitals allowed us to recruit a broad array of hospitals, including community hospitals with no prior experience in clinical research. Finally, the eff icient design meant that the total cost of the trial, including the decolonizing product and contributed personnel effort, was less than $3 million, or approximately $40 per patient.

Opportunities to integrate comparative-effec - tiveness research into routine clinical settings with the use of methods such as those used in the current study will increase as more hospitals adopt electronic health data systems and as multi - center care-improvement collaboratives develop.

This trial also highlights the importance of per - forming rigorous evaluation of quality-improve - ment initiatives and controlling the introduction of new processes and products. Harnessing such initiatives to identify best practices is an impor - tant tenet of the advocacy by the Institute of Medicine for a learning health system. 40 In conclusion, we found that universal decolo - nization prevented infection, obviated the need for surveillance testing, and reduced contact iso - lation. If this practice is widely implemented, vigilance for emerging resistance will be required.

The views expressed in this article are those of the authors and do not necessarily represent the views of the Agency for Healthcare Research and Qualit y (AHRQ), the Department of Health and Human Services, or the Centers for Disease Control and \frevention (CDC). Supported by a contract with the AHRQ Healthcare-Associated Infections \frogram (HHSA290201000008I) and by a grant from the CDC \frevention Epicenters \frogram (1U01 CI000344, to Dr. \flatt). Dr. Septimus reports receiving consulting fees from 3M and lecture fees from Sage \froducts; Dr. Hayden, conducting research involving a contributed product from Sage \froducts; Dr. Wein - stein, serving as an unpaid consultant for Sage \froducts; and Dr.

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