Decolonization Strategies to Prevent Staphylococcal Infections

Staphylococcal infections among hospitalized patients, due to both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus strains, are a substantial problem in the US. S aureus was the leading causative pathogen among health care–associated infections (HAIs) identified during the Centers for Disease Control and Prevention’s (CDC) 2015 national HAI prevalence survey (excluding Clostridioides difficile), accounting for 23% of all health care–associated bloodstream infections.¹ Despite an overall 74% decline in the incidence of hospital-onset MRSA bloodstream infections from 2005 to 2016, these rates did not significantly change between 2013 and 2016.² More sobering, strides made in the past 15 years in reducing HAIs in acute care settings, including those due to S aureus, markedly receded during the COVID-19 pandemic.³

Multiple interventions are recommended to prevent the spread of S aureus in health care settings, best detailed in the multispecialty guideline “A Compendium of Strategies to Prevent Healthcare-Associated Infections in Acute Care Hospitals.”⁴ Focused on MRSA, the compendium outlines strategies including hand hygiene, environmental cleaning, and consideration for transmission-based precautions as key S aureus transmission prevention measures. S aureus resides as part of the normal flora of many persons, with a particular niche in the anterior nares. Over the past 2 decades, studies have examined whether acutely reducing a person’s S aureus burden (ie, decolonization) and the resultant reduction in environmental S aureus contamination leads to a reduced risk of development of health care–associated S aureus infections.⁵

Early HAI prevention decolonization studies focused on the use of chlorhexidine gluconate (CHG) daily bathing, which has had an effective impact on a variety of populations and outcomes, most notably health care–associated bloodstream infections among patients in the intensive care unit (ICU). A second decolonization intervention, intranasal application of an antiseptic or antibiotic agent, targets the anterior nares niche for S aureus and is often added to CHG bathing. In the pragmatic cluster-randomized REDUCE MRSA clinical trial, universal decolonization of ICU patients with CHG and nasal mupirocin regimen was more effective than targeted decolonization or screening and isolation in reducing rates of MRSA clinical isolates and bloodstream infections from any pathogen.⁶ This landmark study led to recommendations for use of this combination intervention, such as CDC guidelines from 2019 that outlined core and supplemental strategies to prevent S aureus infections in acute care settings.⁷ Core strategies include the use of CHG bathing with an intranasal antistaphylococcal antibiotic/antiseptic in all ICU patients, regardless of institutional S aureus rates. For those facilities with higher rates of S aureus transmission in the setting of core practice use, the CDC recommends a similar decolonization strategy for patients outside of the ICU who have a vascular catheter in place.

Nasal decolonization products include the antibiotic mupirocin, iodophor antiseptics, alcohol-based products, and photodynamic therapy,⁸ with mupirocin and the iodophors having the strongest evidence base. Decolonization has been used as a preprocedure intervention to reduce the risk of surgical site infections and as a routine intervention to prevent HAIs in ICU patients; however, the uptake of CHG bathing alone is wider than use of nasal decolonization. In 2021, while 63% of US hospitals had implemented CHG bathing as an infection prevention strategy, only 37% reported also using a nasal decolonization agent.⁹ The concern for and reports of mupirocin resistance and associated clinical decolonization failures have led some to shy away from use of the antibiotic in favor of antiseptic decolonization agents (or to avoid intranasal decolonization entirely). Whether the use of nonmupirocin nasal decolonization agents provides the same benefits noted in studies such as REDUCE MRSA is an increasing question as infection prevention programs work to reduce health care–associated S aureus infections.

Now there is a new large-scale, pragmatic study, the Mupirocin-Iodophor ICU Decolonization Swap Out Trial, to help assess and clarify decolonization practice issues for ICU patients. Huang et al¹⁰ used their successful REDUCE MRSA trial partnership with HCA Healthcare to conduct a study that has wide-reaching implications on infection prevention practices across adult ICUs in the US. In this study,¹⁰ the authors presented an exceptionally well-designed, implemented, and analyzed pragmatic cluster-randomized clinical trial to understand which nasal decolonization agent when combined with routine CHG bathing is preferred to reduce ICU-attributable staphylococcal (MRSA and methicillin-sensitive S aureus) infections. Performed among 137 hospitals across the US and including 233 ICUs and more than 3.3 million patient-days, their noninferiority study revealed a surprising finding: in the setting of a well-established mupirocin-CHG ICU decolonization program, a switch to an iodophor nasal agent resulted in a significant 18% higher hazard ratio for ICU-attributable staphylococcal clinical cultures. The failure of iodophor to meet criteria for noninferiority was maintained in multiple subanalyses.

The adherence to the iodophor-CHG regimen was lower than with the mupirocin-CHG strategy across the study period, namely in relation to the intranasal agent. This raises an interesting question: if the iodophor adherence had matched that of mupirocin, would the differences in study outcomes between the 2 groups remain? It may be that there are unique aspects of the iodophor intervention that led to lower adherence compared with mupirocin. In a survey of frontline health care personnel to assess barriers to use of an iodophor nasal decolonization protocol, Stern et al¹¹ noted several critical issues that may have limited adherence. These included concerns about the size of the product swab, patient perceptions of brown nasal discoloration with the iodophor, and issues with product use tracking.¹¹ Specifically, while mupirocin, an antibiotic, would require a clinician order and its administration would be recorded on a medication administration record, a topical antiseptic like an iodophor at many institutions is not considered a medication and would not be tracked on the medication administration record to guide adherence. It is unclear if these were factors at the study sites for the Mupirocin-Iodophor Swap Out Trial.

In the as-treated analysis, the increased hazard ratio with the use of the iodophor remained when the analysis was restricted to patients who received at least 2 doses of the nasal product; however, this threshold reflects only 20% of the recommended decolonization course. More insight into the product adherence, such as details on the median number of doses completed in each group and the proportion of patients who completed the full 10-dose course, would help interpret the differences between the 2 study groups.

Nonetheless, it is possible that lower adherence alone does not account fully for the differences in the 2 products’ effects. As the authors noted, the presence of mupirocin resistance in these populations (7.5% in the REDUCE MRSA cohort) ought to have negatively impacted mupirocin’s effect. Perhaps the difference in the compounds, from differences in their antibacterial mechanisms to product formulation (ie, does the aqueous nature of the iodophor vs the ointment-based mupirocin have differing stability and persistence on the nasal mucosa), could also account for the findings.

After the implementation of the mupirocin-CHG regimen in HCA’s system of community hospitals since the REDUCE MRSA trial completion, the authors could examine whether use of this decolonization protocol waned over time, suggesting a population-level increase in mupirocin resistance. Reassuringly, the mupirocin-CHG decolonization effects remained stable when comparing the current study period with the previous REDUCE MRSA study period, suggesting that resistance to mupirocin, if present to an appreciable amount, has not led to a reduced impact of the interventions over time.

There are many strengths to this study, including the very large and geographically diverse population of study sites, the long baseline and intervention periods, and the pairing of hospitals based on important underlying criteria. For implementation, the investigators again used the local hospital personnel responsible for infection prevention project implementation, which more closely reflects the use of these strategies in the real world vs use of dedicated study personnel who would not usually be present to aid implementation in most hospitals.

The Mupirocin-Iodophor Swap Out Trial provides another important piece of evidence to guide S aureus infection prevention programs and important insights into nasal decolonization. The sustained effectiveness of mupirocin-CHG over 7 years of use, even in the setting of reports of rising and high rates of mupirocin resistance, is also reassuring, and the results of this study may have moved mupirocin ahead of other nasal decolonization agents. The study also highlighted a larger concern regarding uptake of decolonization in any form at many US hospitals. The juxtaposition of the rise in and burden of S aureus in health care with the powerful data demonstrating a positive impact of decolonization on ICU patients underscores that the underuse of even CHG bathing alone in this population is likely unacceptable. Restricting decolonization to settings with “unacceptably high” S aureus rates (vs use as a core practice) is too lenient and may lead to decolonization as an optional aspect of institutional infection prevention bundles. While a study of CHG alone compared with a dual decolonization regimen is still needed, it is becoming harder to argue that the use of a combination decolonization regimen should not be the standard of care for ICU patients.

Corresponding Author: Thomas R. Talbot, MD, MPH, Vanderbilt University School of Medicine, 1161 21st Ave S, A2200 Medical Center North, Nashville, TN 37232 ([email protected]).

Published Online: October 20, 2023. doi:10.1001/jama.2023.4852

Conflict of Interest Disclosures: Dr Talbot reported serving on the board of directors for OmniSolve.