Study Design

We designed the Randomized Evaluation of Decolonization versus Universal Clearance to Eliminate MRSA (REDUCE MRSA) trial, a three-group, cluster-randomized trial, to compare strategies for preventing MRSA clinical isolates and infections in adult ICUs in Hospital Corporation of America (HCA) hospitals. The trial design has been described previously,15 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 reported data and the fidelity of the study to the protocol. There was a 12-month baseline period from January 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 defined as follows. In group 1 (screening and isolation), bilateral screening of the nares for MRSA was performed on ICU admission, and contact precautions 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 underwent screening, and contact precautions were implemented for carriers of MRSA and other multidrug-resistant pathogens.

In group 2 (targeted decolonization), MRSA screening and contact precautions were similar to those in group 1. Patients known to have MRSA colonization or infection underwent 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 intranasal mupirocin for 5 days, plus daily bathing with chlorhexidine-impregnated cloths for the entire ICU stay.

All adult ICUs in a participating hospital were assigned to the same study group. Contact-precaution policies, which were based on longstanding guidance from the Centers for Disease Control and Prevention (CDC), were identical and unchanged for all hospitals. Precautions were initiated on the basis of current or historical MRSA cultures or other standard indications.6 Results of cultures obtained on admission became 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 implementing universal decolonization discontinued such cultures. Secondary outcomes included ICU-attributable bloodstream infection caused by MRSA and ICU-attributable bloodstream infection caused by any pathogen. Clinical cultures were obtained at the clinician's discretion.

Recruitment and Eligibility Criteria

Recruitment occurred among the 160 HCA hospitals. Most were community hospitals with single-occupancy ICU rooms. Eligibility criteria included 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 during the baseline period, and agreement to refrain from adopting new initiatives that would conflict with the trial. Throughout the study, corporatewide campaigns were used to ensure compliance with national practice guidelines.16-18

Each hospital obtained approval from an institutional review board, with more than 90% of the hospitals delegating review to the Harvard Pilgrim Health Care institutional review board. Patient notices about group-specific protocols were posted in each ICU room. The requirement for written informed consent was waived.19

Randomization

Randomization was stratified to optimize balance 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 randomly 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 preventionists, and nurse educators. Standard communication channels were used, including group-specific, 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-specific coaching teleconferences at least monthly to discuss implementation, compliance, and any new, potentially conflicting initiatives. Compliance assessment involved verification on 1 day per week for each ICU. HCA leadership evaluated trial processes during routine hospital visits. Additional site visits were made at the request of the hospital or if compliance was found to be low.

Intranasal mupirocin ointment 2% (Bactroban, GlaxoSmithKline) and 2% chlorhexidine–impregnated cloths (Sage Products) were used for decolonization. All mupirocin and chlorhexidine-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 treating physicians.

Data Collection and Outcome Assignment

Census (i.e., the unit location of each patient for every hospitalization day), microbiologic, pharmacy, supply-chain, nursing-query, and administrative data were obtained from corporate data warehouses, which undergo line-item validation until 99% accuracy is achieved. CDC criteria were used for microbiologic outcomes (first outcome per patient). Pathogens 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 bloodstream infections to be attributed to skin-commensal organisms, the same organism had to be isolated from two or more blood cultures obtained within 2 calendar days of one another.20

Statistical 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 bloodstream infection in group 2, and a 60% relative reduction in the rate in group 3, as compared with group 1. The primary analyses were conducted according to the intention-to-treat principle (as-assigned analyses) and were unadjusted. Proportional-hazards models with shared frailties accounted for clustering within hospitals (see the Supplementary Appendix).21,22 The intervention effect was assessed on the basis of the interaction between group and study period, reflecting the difference in hazard between the baseline 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.

Sensitivity analyses included multivariable covariate-adjusted models, as-treated models, models that excluded hospitals in states mandating 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 (defined with the use of codes from the International Classification of Diseases, 9th Revision), and surgery during the hospital stay. Analyses were performed with the use of SAS software, version 9.3 (SAS Institute).