Opinion
EDITORIAL
Decolonization Strategies to Prevent Staphylococcal Infections
Mupirocin by a Nose
Thomas R. Talbot, MD, MPH
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 caus-
ative pathogen among health care–associated infections
(HAIs) identified during the Centers for Disease Control and
Prevention’s (CDC) 2015 national HAI prevalence survey (ex-
cluding 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, mark-
edly 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 contamina-
tion 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 popula-
tions 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 pa-
tients with CHG and nasal mupirocin regimen was more
effective than targeted decolonization or screening and iso-
lation in reducing rates of MRSA clinical isolates and blood-
stream infections from any pathogen.6 This landmark study
led to recommendations for use of this combination inter-
vention, such as CDC guidelines from 2019 that outlined
core and supplemental strategies to prevent S aureus infec-
tions in acute care settings.7 Core strategies include the use
jama.com
© 2023 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ Mexico | Access Provided by JAMA by Fidelio Peralta López on 10/20/2023
of CHG bathing with an intranasal antistaphylococcal
antibiotic/antiseptic in all ICU patients, regardless of institu-
tional 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 iodo-
phors 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 decoloniza-
tion. 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 con-
cern 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 decoloniza-
tion 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 pre-
vention 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 prac-
tices 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 com-
bined 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 main-
tained in multiple subanalyses.
(Reprinted) JAMA Published online October 20, 2023 E1
 Opinion Editorial

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 discolor-
ation 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 topi-
cal 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 re-
stricted to patients who received at least 2 doses of the nasal
product; however, this threshold reflects only 20% of the rec-
ommended decolonization course. More insight into the prod-
uct 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 dif-
ferences in their antibacterial mechanisms to product for-
mulation (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. Reassur-
ingly, the mupirocin-CHG decolonization effects remained
stable when comparing the current study period with the pre-
vious REDUCE MRSA study period, suggesting that resis-
tance 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 proj-
ect 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 imple-
mentation in most hospitals.
The Mupirocin-Iodophor Swap Out Trial provides
another important piece of evidence to guide S aureus infec-
tion 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 ris-
ing 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 decoloniza-
tion 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 decoloniza-
tion 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 insti-
tutional 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 com-
bination decolonization regimen should not be the standard
of care for ICU patients.

ARTICLE INFORMATION
Author Affiliation: Vanderbilt University School of
Medicine, Nashville, Tennessee.
Corresponding Author: Thomas R. Talbot, MD,
MPH, Vanderbilt University School of Medicine, 1161
21st Ave S, A2200 Medical Center North, Nashville,
TN 37232 (tom.talbot@vumc.org).
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.
REFERENCES
1. Magill SS, O’Leary E, Janelle SJ, et al; Emerging
Infections Program Hospital Prevalence Survey
Team. Changes in prevalence of health
care-associated infections in US hospitals. N Engl J
Med. 2018;379(18):1732-1744. doi:10.1056/
NEJMoa1801550
2. Kourtis AP, Hatfield K, Baggs J, et al; Emerging
Infections Program MRSA author group. Vital signs:
epidemiology and recent trends in
methicillin-resistant and in methicillin-susceptible
Staphylococcus aureus bloodstream
infections—United States. MMWR Morb Mortal Wkly
Rep. 2019;68(9):214-219. doi:10.15585/mmwr.
mm6809e1
3. Lastinger LM, Alvarez CR, Kofman A, et al.
Continued increases in the incidence of
healthcare-associated infection (HAI) during the
second year of the coronavirus disease 2019
(COVID-19) pandemic. Infect Control Hosp Epidemiol.
2022;44(6):997-1001. doi:10.1017/ice.2022.116
4. Popovich KJ, Aureden K, Ham DC, et al.
SHEA/IDSA/APIC practice recommendation:
strategies to prevent methicillin-resistant
Staphylococcus aureus transmission and infection in
acute-care hospitals: 2022 update. Infect Control
Hosp Epidemiol. 2023;44(7):1-29. doi:10.1017/ice.
2023.102
5. Sharara SL, Maragakis LL, Cosgrove SE.
Decolonization of Staphylococcus aureus. Infect Dis
Clin North Am. 2021;35(1):107-133. doi:10.1016/j.idc.
2020.10.010
6. Huang SS, Septimus E, Kleinman K, et al; CDC
Prevention Epicenters Program; AHRQ DECIDE
Network and Healthcare-Associated Infections
Program. Targeted versus universal decolonization

E2 JAMA Published online October 20, 2023 (Reprinted) jama.com

© 2023 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ Mexico | Access Provided by JAMA by Fidelio Peralta López on 10/20/2023
 Editorial Opinion

to prevent ICU infection. N Engl J Med. 2013;368
(24):2255-2265. doi:10.1056/NEJMoa1207290
7. Centers for Disease Control and Prevention.
Strategies to prevent hospital-onset Staphylococcus
aureus bloodstream infections in acute care
facilities. Accessed March 25, 2023. https://www.
cdc.gov/hai/prevent/staph-prevention-strategies.
html
8. Septimus EJ. Nasal decolonization: what
antimicrobials are most effective prior to surgery?
Am J Infect Control. 2019;47S:A53-A57. doi:10.1016/
j.ajic.2019.02.028
9. Ham C. Gram positives: Staphylococcus aureus
and vancomycin-resistant Enterococci. Presented
at the Drug Development Considerations for the
Prevention of Healthcare-Associated Infections
Virtual Public Workshop. August 30, 2022.
Accessed March 25, 2023. https://6498387.fs1.
hubspotusercontent-na1.net/hubfs/6498387/10_
Session%201_F_Cal%20Ham.pdf
10. Huang SS, Septimus EJ, Kleinman K, et al. Nasal
iodophor antiseptic vs nasal mupirocin antibiotic in
the setting of chlorhexidine bathing to prevent
infections in adult ICUs: a randomized clinical trial.
JAMA. 2023;330(14):1337-1347. doi:10.1001/jama.
2023.17219
11. Stern RA, Harris BD, DeVault M, Talbot TR.
Identifying barriers to compliance with a universal
inpatient protocol for Staphylococcus aureus nasal
decolonization with povidone-iodine. Infect Control
Hosp Epidemiol. 2022;44(7):1-4.

jama.com (Reprinted) JAMA Published online October 20, 2023 E3

© 2023 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ Mexico | Access Provided by JAMA by Fidelio Peralta López on 10/20/2023