Integrating Personal and Household Environmental Hygiene Measures to Prevent Methicillin-Resistant Staphylococcus Aureus Infection
Phase: PHASE4
Conditions: Skin and Subcutaneous Tissue Bacterial Infections, Staphylococcus Aureus, MRSA - Methicillin Resistant Staphylococcus Aureus Infection
Sponsor: Washington University School of Medicine

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Integrating Personal and Household Environmental Hygiene 
Measures to Prevent Methicillin-Resistant Staphylococcus 
aureus 
Principal Investigator: Stephanie A. Fritz, MD, MSCI 
Version Number:  1.0 
15 August 2015 
Last Reviewed 10 March 2025

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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
• 
ICH E6; 62 Federal Register 25691 (1997)  
• 
AHRQ Clinical Terms of Award 
 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 

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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Site Investigator:* 
Signed: 
 
Date:  
 
 
 
Name:  Stephanie A. Fritz 
Title:  Principal Investigator 
 
 
 

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TABLE OF CONTENTS 
 
Page 
Statement of Compliance ................................................................................................................ ii 
Signature Page ............................................................................................................................... iii 
Table of Contents ............................................................................................................................ iv 
List of Abbreviations ....................................................................................................................... vi 
Protocol Summary ........................................................................................................................ viii 
1 
Key Roles ............................................................................................................................... 1 
2 
Background Information and Scientific Rationale ................................................................. 2 
2.1 
Background Information ............................................................................................. 2 
2.2 
Rationale .................................................................................................................... 5 
2.3 
Potential Risks ........................................................................................................... 7 
2.3.1 
Potential Risks ............................................................................................... 7 
2.3.2 
Known Potential Benefits ............................................................................... 8 
3 
Objectives .............................................................................................................................. 9 
3.1 
Study Objectives ........................................................................................................ 9 
3.2 
Study Outcome Measures ......................................................................................... 9 
3.2.1 
Primary Outcome Measures .......................................................................... 9 
3.2.2 
Secondary Outcome Measures ..................................................................... 9 
4 
Study Design ........................................................................................................................ 11 
4.1 
Substudies (if applicable)......................................................................................... 14 
5 
Study Enrollment and Withdrawal ....................................................................................... 15 
5.1 
Subject Inclusion Criteria ......................................................................................... 15 
5.2 
Subject Exclusion Criteria ........................................................................................ 15 
5.2.1 
Randomization Procedures ......................................................................... 15 
5.2.2 
Masking Procedures .................................................................................... 15 
5.2.3 
Reasons for Withdrawal ............................................................................... 16 
5.2.4 
Handling of Withdrawals .............................................................................. 16 
5.2.5 
Termination of Study .................................................................................... 16 
6 
Study Intervention/Investigational Product .......................................................................... 17 
6.1 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product ..................................................................................................................... 17 
6.2 
Concomitant Medications/Treatments ..................................................................... 17 
7 
Study Schedule .................................................................................................................... 18 
7.1 
Screening ................................................................................................................. 18 
7.2 
Enrollment/Study visits ............................................................................................ 18 
8 
Study Procedures/Evaluation .............................................................................................. 21 
8.1 
Definitions ................................................................................................................ 21 

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8.2 
Laboratory Evaluations ............................................................................................ 22 
8.2.1 
Laboratory Evaluations ................................................................................ 22 
8.2.2 
Special Assays or Procedures ..................................................................... 22 
8.2.3 
Specimen Preparation, Handling, and Shipping. ........................................ 23 
9 
Assessment of Safety .......................................................................................................... 24 
9.1 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ............................................................................................................... 24 
9.1.1 
Adverse Events ............................................................................................ 24 
9.1.2 
Serious Adverse Events .............................................................................. 25 
9.2 
Reporting Procedures .............................................................................................. 25 
9.2.1 
Serious Adverse Events .............................................................................. 25 
9.2.2 
Reporting of Pregnancy ............................................................................... 25 
9.3 
Halting Rules ............................................................................................................ 25 
9.4 
Safety Oversight ...................................................................................................... 25 
10 
Statistical Considerations .................................................................................................... 27 
10.1 
Study Hypotheses .................................................................................................... 27 
10.2 
Sample Size Considerations ................................................................................... 27 
10.3 
Planned Interim Analyses ........................................................................................ 28 
10.4 
Final Analysis Plan ................................................................................................... 28 
11 
Source Documents and Access to Source Data/Documents ............................................. 30 
12 
Quality Control and Quality Assurance ............................................................................... 31 
13 
Ethics/Protection of Human Subjects .................................................................................. 32 
13.1 
Ethical Standard ....................................................................................................... 32 
13.2 
Institutional Review Board ....................................................................................... 32 
13.3 
Informed Consent Process ...................................................................................... 32 
13.3.1 Informed Consent/Assent Process .............................................................. 32 
13.4 
Subject Confidentiality ............................................................................................. 33 
13.5 
Study Discontinuation .............................................................................................. 33 
13.6 
Future Use of Stored Specimens ............................................................................ 33 
14 
Data Handling and Record Keeping .................................................................................... 34 
14.1 
Data Management Responsibilities ......................................................................... 34 
14.2 
Data Capture Methods ............................................................................................. 34 
14.3 
Types of Data ........................................................................................................... 35 
14.4 
Study Records Retention ......................................................................................... 35 
14.5 
Protocol Deviations .................................................................................................. 35 
15 
Publication Policy ................................................................................................................. 36 
16 
Literature References .......................................................................................................... 37 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
AHRQ 
Agency for Healthcare Research and Quality 
CA-MRSA 
Community-Associated Methicillin-Resistant Staphylococcus 
aureus 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CLSI 
Clinical Laboratory Standards Institute 
DSMP 
Data and Safety Monitoring Plan 
ED 
Emergency Department 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HA-MRSA 
Healthcare-Associated Methicillin-Resistant Staphylococcus 
aureus 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDSA 
Infectious Diseases Society of America 
IEC 
Independent or Institutional Ethics Committee 
IRB 
Institutional Review Board 
JAMA 
Journal of the American Medical Association 
MRSA 
Methicillin-Resistant Staphylococcus aureus 
MSSA 
Methicillin-Susceptible Staphylococcus aureus 
N 
Number (typically refers to subjects) 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PAWS 
Pediatric Acute Wound Service 
PHI 
Protected Health Information 
PI 
Principal Investigator 
QC 
Quality Control 
REDCap 
Research Electronic Data Capture 
repPCR 
repetitive-sequence polymerase chain reaction 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SCCmec 
Staphylococcal cassette chromosome mec 

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SLCH 
St. Louis Children’s Hospital 
SSTI 
Skin and Soft Tissue Infection 
TSB/TSA 
Trypticase Soy Broth/Trypticase Soy Agar 
US 
United States 
WU 
Washington University - St. Louis, MO 
WUCA 
Washington University Clinical Associates 
WU PAARC 
Washington University Pediatric & Adolescent Ambulatory 
Research Consortium 
 

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PROTOCOL SUMMARY 
Title: 
Phase: 
Population: 
Study Duration: 
Subject Participation 
Duration: 
Description of Agent 
or Intervention: 
Integrating Personal and Household Environmental Hygiene 
Measures to Prevent Methicillin-Resistant Staphylococcus aureus 
IV 
207 index patients (the pediatric patient presenting with a 
community-onset Staphylococcus aureus infection who is screened 
for study participation) aged birth to 21 years with documented S. 
aureus infections and their household members (an individual who 
sleeps in the home ≥4 nights per week).  
October 2015 through October 2020 (anticipated) 
Approximately 9 months 
Following a 5-day Baseline Personal Decolonization performed by all 
household participants, households will be allocated 1:1:1 to one of 
three treatment groups. The assigned intervention will be performed 
for 3 months, and participants will be followed for an additional 6 
months to track primary and secondary outcomes. The interventions 
are:  
Group 1: Periodic Personal Decolonization:  All household 
participants will perform chlorhexidine body washes (as described 
above) twice weekly for 3 months and apply mupirocin ointment to 
the anterior nares twice daily for five consecutive days each month 
for 3 months (Figures 2 and 3). Sufficient study materials for each 
assigned participant will be provided. A member of the study team 
will contact each household (via the family’s preferred method: 
phone call, text message, or e-mail) several days prior to their 
designated period for monthly mupirocin application.  
Group 2: Household Environmental Hygiene:  In addition to their 
usual cleaning, households assigned to Group 2 will be asked to 
perform targeted household hygiene focusing on sources known to 
harbor S. aureus and serve as reservoirs for transmission. Specific 
recommendations include:   
•
Launder all bed linens once a week.

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• 
Replace each kitchen and bathroom hand towel with a clean 
towel each day. Alternatively, rather than cloth towels, 
disposable paper towels (provided by the study team) may be 
used in the kitchen and bathroom.  
• 
Replace the kitchen sponge with a new sponge (provided by 
the study team) once a week. 
• 
Wipe the following surfaces with Clorox Disinfecting Wipes 
(provided by the study team) once a week, using 1 wipe per 
surface: 
o TV remote controls, telephones, computer keyboards 
and mouse  
o Bathrooms: Countertop, sink, and sink faucet handles; 
light switch; bathtub and faucet handles; toilet handle 
and seat 
o Kitchen: Refrigerator and freezer door handles; 
microwave door handle and key pad; oven door 
handle; sink and sink faucet handle; table top; counter 
tops 
At the enrollment visit, cleaning procedures will be demonstrated by 
study personnel, and printed instructions will be provided. 
Throughout the 3-month intervention period, to enhance adherence 
to the protocol, a member of the study team will contact each 
household weekly to remind them to perform targeted cleaning with 
the Clorox Disinfecting Wipes and to replace the kitchen sponge. 
Group 3:  Integrated Approach of Personal and Household 
Environmental Hygiene:  Participants in households randomized to 
Group 3 will perform the Periodic Personal Decolonization described 
for Group 1, plus the Household Environmental Hygiene described 
for Group 2. 
Objectives: 
 
 
To determine whether periodic personal decolonization performed by 
all household members (following baseline decolonization), weekly 
household environmental hygiene (following baseline decolonization) 
or a combination of the two for 3 months, results in a decreased 
incidence of S. aureus colonization and SSTI, both during and after 
the intervention period. 
Description of Study 
Design: 
This is a pragmatic comparative effectiveness trial evaluating several 
decolonization strategies in patients with S. aureus infection, their 

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household contacts, and household environmental surfaces.  
Estimated Time to 
Complete Enrollment: 
Forty-eight (48) months 

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Figure 1. Schematic of Study Design 
Figure 1. Schematic of Study Design 
 
 

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1 
KEY ROLES 
Individuals 
Principal Investigator:   
Stephanie A. Fritz, MD, MSCI 
Washington University School of Medicine 
Campus Box 8116 
660 South Euclid Ave 
St. Louis, MO 63110 
Phone: 314-454-4115 
e-mail: fritz.s@wustl.edu 
Fax: 314-286-1149 
 
Others 
 
Study Coordinators: 
 
Patrick Hogan, MPH 
Washington University School of Medicine 
Campus Box 8116 
660 South Euclid Ave 
St. Louis, MO 63110 
Phone: 314-747-6296 
e-mail: pghogan@wustl.edu 
 
Mary Boyle, RN, BSN, MSN 
Washington University School of Medicine 
Campus Box 8116 
660 South Euclid Ave 
St. Louis, MO 63110 
Phone: 314-286-1207 
e-mail: mboyle@wustl.edu 
 
Carol Muenks 
Washington University School of Medicine 
Campus Box 8116 
660 South Euclid Ave 
St. Louis, MO 63110 
Phone: 314-286-1208 
e-mail: muenks@wustl.edu 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
 
Description of the Proposed Clinical Trial. This study is a pragmatic comparative 
effectiveness trial evaluating several decolonization strategies in patients with Staphylococcus 
aureus infection, their household contacts, and household environmental surfaces. The central 
hypothesis of this proposal is that an integrated approach of periodic personal and household 
environmental hygiene will reduce S. aureus transmission in households and subsequently 
decrease the incidence of skin and soft tissue infections (SSTI). Patients with active or recent S. 
aureus SSTI will be recruited from St. Louis Children’s Hospital and community pediatric 
practices affiliated with our practice-based research network. All participants (index patients and 
their household contacts) will perform a baseline S. aureus decolonization protocol for 5 days 
consisting of enhanced hygiene measures, application of mupirocin antibiotic ointment to the 
anterior nares twice daily, and daily body washes with chlorhexidine antiseptic. Following the 5-
day baseline decolonization regimen, households will be randomized to one of three 
intervention groups: 1) Periodic personal decolonization performed by all household members, 
to include chlorhexidine body washes twice weekly for 3 months and application of intranasal 
mupirocin for 5 consecutive days each month for 3 months; 2) Household environmental 
hygiene, including targeted cleaning of household surfaces and laundering of bed linens, weekly 
for 3 months; and 3) Integrated periodic personal decolonization and household environmental 
hygiene for 3 months. Households will be followed prospectively (1-, 3-, 6-, and 9-months 
following randomization) to measure the prevalence of S. aureus colonization in the participants, 
household environmental surfaces, and pet dogs and cats and to document the incidence of 
recurrent SSTI. Molecular strain typing will be performed on all recovered S. aureus isolates to 
illuminate transmission dynamics and the effects of the decolonization measures on genetic 
epidemiology. Resistance to the prescribed topical antimicrobials will be assessed at baseline 
and longitudinal samplings.  
 
Summary of Relevant Studies. The Staphylococcus aureus epidemic poses a significant 
health and economic burden. The community has become an important and expanding 
reservoir for the spread of virulent Staphylococcus aureus strains into hospitals, likely increasing 
the severity of nosocomial S. aureus infections. Efforts are needed to lessen the spread of S. 
aureus in the community and decrease the burden of S. aureus infections. Households are 
significant reservoirs for S. aureus transmission and important targets for S. aureus eradication. 
Our prior study demonstrated that a one-time decolonization regimen performed by all 
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infection (SSTI) in index patients and household contacts. Given the widespread dissemination 
of S. aureus and risk for ongoing exposure, a periodic approach to personal decolonization may 
provide sustained protection against S. aureus reacquisition. Additionally, environmental 
surfaces in households of patients with S. aureus infection are frequently and persistently 
contaminated with S. aureus. These surfaces serve as vectors for the acquisition and spread of 
S. aureus among household members. Thus, decontamination of household surfaces may limit 
the acquisition and spread of S. aureus. 
 
Burden of S. aureus:  In its 2013 “Threat Report,” the Centers for Disease Control and 
Prevention classified methicillin-resistant S. aureus (MRSA) as having a threat level of “serious” 
46. In the U.S., annual deaths due to S. aureus infections exceed deaths due to influenza, viral 
hepatitis, and HIV/AIDS combined 47. The tremendous burden posed by CA-S. aureus in the 
U.S. is evidenced by its annual incidence of 2 million infections, resulting in an estimated $16 
billion in costs to third-party payers and society 48. Over the past decade, the incidence of 
invasive CA-S. aureus infections has risen substantially, with a case-fatality rate of 6% 39,49-51. 
The most common manifestation of CA-S. aureus infection is skin and soft tissue infection 
(SSTI). Although many SSTIs are superficial, they carry significant morbidity, including pain and 
subsequent scarring caused by drainage procedures, and time lost from school and work by 
patients and their families. Severe SSTI ranks among the top 10 reasons for pediatric hospital 
admissions 52. Importantly, up to 70% of patients with CA-S. aureus SSTI will experience 
recurrences, even after successful initial treatment 6,8,53-55, provoking frustration for both patients 
and clinicians. These recurrent infections also necessitate repeated courses of antibiotic 
therapy, further driving the pressure for development of antibiotic resistance 12,56. 
    
Determinants of S. aureus infection:  S. aureus colonizes the anterior nares, throat, and skin, 
including the axilla, inguinal area, perineum, and rectum 4,57-64. S. aureus carriage is a risk factor 
for the development of subsequent infections 2,57,65-69, and colonized individuals are also 
important sources for transmission 25. Behavioral and environmental factors also play an 
important role in the transmission and pathogenesis of CA-S. aureus infection 17,71,72. CA-S. 
aureus infections have been associated with use of contaminated fomites (e.g., shared personal 
hygiene items), poor hygiene, and close contact with infected individuals 17,73,74. Prior SSTI is 
also a risk factor for developing subsequent SSTI 2,75. CA-S. aureus disproportionately affects 
children, African Americans, and individuals of lower socioeconomic status 1-3,29,47,50,76-80. 
Importantly, the epidemiology of S. aureus infections differs between children and adults 50,81; as 
many preventive studies have focused mainly on adults, investigating optimal strategies to 
prevent S. aureus infections in children is of high priority. 
 
CA-S. aureus transmission:  Investigations of the evolution and spread of contemporary CA-
S. aureus strains have determined that households serve as major reservoirs of CA-S. aureus 
persistence and transmission, even more so than other institutional environments 12,25. S. 
aureus colonization and infections cluster among individuals within households 5,64,82-96. 
Transmission of S. aureus between pets and humans has been described, although the 

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directionality is unclear 97-103. Environmental surfaces serve as reservoirs for S. aureus 
transmission, and S. aureus strains persist within the household environment for prolonged 
periods of time, posing risk for the development of recurrent infections 17,32,75,90-92,96,104-108. In 
healthcare settings and schools, enhanced cleaning of heavily used fomites and contaminated 
surfaces has resulted in reduced environmental contamination and decreased incidence of 
infection 107-110. Yet, even in these settings, challenges persist 110. To date, there are no 
controlled studies evaluating the effect of household hygiene on interrupting S. aureus 
household transmission or preventing S. aureus infections. These data are essential to inform 
clinical guidelines to reduce the burden of S. aureus disease 111-113.  
 
 
Prevention of CA-S. aureus infections:  There is no available vaccine against S. aureus. 
Thus, other preventive measures, including decolonization (i.e., “the use of antimicrobial or 
antiseptic agents to suppress or eliminate S. aureus carriage” 111), have been used in an effort 
to prevent staphylococcal infections. Decolonization therapies include nasal mupirocin (a topical 
antibiotic with activity against S. aureus) and bathing with chlorhexidine (a topical antiseptic). 
While application of these therapies for a discrete period is effective in S. aureus eradication, 
maintenance of eradication diminishes over time 6,8,114-120. Decolonization measures traditionally 
employed in hospitals to combat S. aureus have been extrapolated to CA-S. aureus patients in 
community settings 18,111,113. However, the paucity of data available to guide the prevention of 
recurrent S. aureus SSTI in community settings has engendered inconsistency in treatment and 
decolonization practices 111,113. Several studies performed by our group and others in community 
settings have demonstrated that brief applications of topical antimicrobials effectively eradicate 
S. aureus carriage, yet patients continue to suffer a high burden of subsequent SSTI 6,8,72,119. 
These findings may reflect ongoing exposure to other sources of S. aureus, including other 
individuals and environmental reservoirs, and suggest that a periodic approach to 
decolonization may provide more effective, sustained protection. Of note, a recent trial of twice-
weekly bleach baths performed for 3 months did not result in a statistically significant reduction 
of medically-attended SSTI 63. As not all patients with recurrent SSTI seek medical attention 4, 
the effectiveness of this intervention may have been underestimated. Additionally, this trial did 
not utilize mupirocin, and thus, did not address intranasal staphylococcal carriage.  
 
An important consideration for S. aureus decolonization is the emergence of 
staphylococcal strains resistant to topical antimicrobial agents. The genes conferring resistance 
to mupirocin (most commonly mupA) and chlorhexidine (most commonly qacA/B) are carried on 
plasmids that can also harbor genes conferring resistance to other systemic antibiotics 121-128. 
Indiscriminate use of topical antimicrobials has been associated with increased prevalence of S. 
aureus strains resistant to these agents, which predicts failure of S. aureus decolonization 
efforts 9,121,124,128-134. In patients undergoing peritoneal dialysis, repeated topical prophylaxis with 
mupirocin was associated with subsequent carriage of mupirocin-resistant S. aureus strains 
135,136. However, targeted use of mupirocin in immunocompetent patients was effective in 
preventing recurrent SSTI and did not result in development of widespread resistance over time 
137. Currently, the prevalence of mupirocin and chlorhexidine resistance is low in our community 
9. However, topical antimicrobials are being utilized with increasing frequency for S. aureus 

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eradication to prevent recurrent SSTI, preoperative eradication to prevent postsurgical 
infections, and routine bathing of hospitalized patients 120,121,138. Thus, it is imperative to 
understand the epidemiology of mupirocin and chlorhexidine resistance, and to monitor the 
emergence of these resistant strains in healthcare and community settings.  
 
Importance of the Study. The proposed trial takes an integrated approach to eradicating 
carriage and interrupting transmission of contemporary CA-S. aureus. To date, the majority of S. 
aureus eradication studies have evaluated protocols employing brief applications of topical 
antimicrobials. The few trials which have employed a prolonged decolonization approach have 
employed only intranasal colonization or antimicrobial body washes not a comprehensive 
approach aimed at the many anatomic sites which may harbor S. aureus. In addition, the 
household environment as a key reservoir for S. aureus is a recent revelation, and at present, 
the effect of enhanced, targeted household hygiene on reducing S. aureus transmission, 
infection, and colonization has not been evaluated. In this pragmatic comparative effectiveness 
trial, we will take an integrated approach to S. aureus eradication, evaluating both periodic 
personal decolonization and household hygiene to prevent S. aureus infection and transmission. 
We will monitor for selection of S. aureus strains resistant to mupirocin and chlorhexidine when 
these topical antimicrobials are used repeatedly over time. In addition, the biological repositories 
established in this study will support future innovative investigations of how eradication efforts 
influence the human and environmental microbiota. 
 
2.2 
Rationale 
 
Study Population. We will recruit 207 index patients aged birth to 21 years with documented 
CA-S. aureus infections and their household members. Patients will be recruited from the St. 
Louis Children’s Hospital ED, inpatient units, Pediatric Acute Wound Service (PAWS), and the 
S. aureus clinic, a subspecialty outpatient clinic devoted to the care of patients with CA-S. 
aureus infections. Patients will also be referred from community pediatric practices affiliated with 
the Washington University Pediatric and Adolescent Ambulatory Research Consortium (WU 
PAARC), a practice-based research network in metropolitan St. Louis and through electronic 
reports of applicable diagnostic codes from WUCA (Washington University Clinical Associates) 
practices. Recruitment from SLCH and WUCA/WU PAARC-affiliated practices provides a 
diverse geographic and sociodemographic study population. Additionally, prior participants from 
our household transmission dynamics study will be contacted; those interested and eligible will 
be enrolled.  
The study team will recruit 207 households (~828 total participants) on a continuous 
basis over 48 months. Trial enrollment and randomization will take place in the homes of the 
study participants. Written informed consent will be obtained from all adult participants. A parent 
or legal guardian will provide consent for all minors. We will obtain written assent from minors of 
a developmentally appropriate age (typically ≥13 years).  

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Study Arms. Group 1: Periodic Personal Decolonization:  All household participants will 
perform chlorhexidine body washes twice weekly for 3 months and apply mupirocin ointment to 
the anterior nares twice daily for five consecutive days each month for 3 months (Figure 2). 
Sufficient study materials for each assigned participant will be provided. A member of the study 
team will contact each 
household (via the family’s 
preferred method: phone call, 
text message, or e-mail) several 
days prior to their designated 
period for monthly mupirocin 
application.  
 
Group 2: Household 
Environmental Hygiene:  In 
addition to their usual cleaning, 
households assigned to Group 2 
will be asked to perform targeted 
household hygiene (Figure 2) 
focusing on sources known to 
harbor S. aureus and serve as 
reservoirs for transmission. Specific recommendations include:   
• 
Launder all bed linens once a week. 
• 
Replace each kitchen and bathroom hand towel with a clean towel each day. 
Alternatively, rather than cloth towels, disposable paper towels (provided by the study 
team) may be used in the kitchen and bathroom.  
• 
Replace the kitchen sponge with a new sponge (provided by the study team) once a 
week. 
• 
Wipe the following surfaces with Clorox Disinfecting Wipes (provided by the study team) 
once a week, using 1 wipe per surface: 
o TV remote controls, telephones, computer keyboards and mouse  
o Bathrooms: Countertop, sink, and sink faucet handles; light switch; bathtub and 
faucet handles; toilet handle and seat 
o Kitchen: Refrigerator and freezer door handles; microwave door handle and key 
pad; oven door handle; sink and sink faucet handle; table top; counter tops 
At the enrollment visit, cleaning procedures will be demonstrated by study personnel, and 
printed instructions will be provided. Throughout the 3-month intervention period, to enhance 
adherence to the protocol, a member of the study team will contact each household weekly to 
remind them to perform targeted cleaning with the Clorox Disinfecting Wipes and to replace the 
kitchen sponge. 
 
Figure 2. Timeline of baseline decolonization and interventions. The first month of 
the intervention is depicted and will be repeated for two additional months. 

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Group 3:  Integrated Approach of Personal and Household Environmental Hygiene:  Participants 
in households randomized to Group 3 will perform the Periodic Personal Decolonization 
described for Group 1, plus the Household Environmental Hygiene described for Group 2 
(Figure 2). 
 
Hypothesis. There are two primary scientific hypotheses for this study. 
1. An integrated approach of periodic personal and household environmental hygiene will 
result in a lower incidence of SSTI at the household level 3 months following 
randomization compared to periodic personal decolonization or household 
environmental hygiene alone. 
 
2. An integrated approach of periodic personal and household environmental hygiene will 
reduce S. aureus colonization in participants and household environmental surfaces and 
S. aureus transmission within households. Following baseline decolonization for 5 days 
performed by all participants, periodic decolonization with mupirocin and chlorhexidine 
over 3 months (Groups 1 and 3) will not result in a significant increase in the prevalence 
of resistance to these agents among S. aureus strains recovered at longitudinal 
samplings compared to baseline decolonization alone (Group 2).  
2.3 
Potential Risks 
2.3.1 Potential Risks 
 
Participants may experience one or more of the risks indicated below during this study. In 
addition to these, there may be other unknown risks, or risks that we did not anticipate, 
associated with being in this study. Some questions the researchers ask might be 
uncomfortable. Obtaining swabs from the nostrils, underarms, and groin area might be 
uncomfortable. Dry skin may result from the use of chlorhexidine baths. The mupirocin ointment 
may cause diarrhea and/or irritation such as itching, burning, or stinging. Chlorhexidine baths 
may cause a mild rash, skin irritation, or sensitivity.  
 
All of these problems will go away if use of the mupirocin or chlorhexidine products is stopped. 
 
Chlorhexidine is for topical use only and should be applied from the neck down, avoiding the 
face. When using chlorhexidine, keep it out of mucus membranes. If contact with these areas 
does occur, rinse with cold water immediately. Do not routinely apply to open wounds. Avoid 
applying to genitals. Chlorhexidine is not readily absorbed through the skin. However, children 
under 2 months of age will not be assigned to use chlorhexidine. Women currently 
breastfeeding should avoid washing their breasts with chlorhexidine to ensure it is not ingested 
by their child.  
 

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There is a risk of loss of confidentiality but the study team will use best efforts to keep the 
information collected for this study secure.  
2.3.2 Known Potential Benefits 
 
This project may decrease the incidence of S. aureus infections, and thus reduce healthcare 
utilization for S. aureus treatment, potentially preventing additional spread of virulent S. aureus 
strains. The project findings may lead to therapeutic and/or preventive advances that will benefit 
a large number of patients and have a positive impact on healthcare utilization and 
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3 
OBJECTIVES 
3.1 
Study Objectives 
 
The overall objective is to identify best strategies for curtailing the incidence of CA-S. aureus 
infections, thus reducing healthcare utilization for CA-S. aureus treatment, potentially preventing 
additional migration of virulent CA-S. aureus strains into hospitals. Non-immunocompromised 
pediatric subjects and their household contacts will be enrolled into an open-label, randomized, 
pragmatic, comparative effectiveness trial. Households will be randomized to periodic personal 
decolonization, environmental hygiene, or an integrated approach to help interrupt the spread of 
CA-S. aureus and prevent CA-S. aureus infections. 
 
Primary null hypotheses: 
1. The incidence of SSTI at the household level 3 months after randomization will not differ 
between the three decolonization strategies (integrated, periodic personal, and 
environmental hygiene). 
 
Primary objective: 
1. To determine whether periodic personal decolonization performed by all household members 
(following baseline decolonization), weekly household environmental hygiene (following 
baseline decolonization), or a combination of the two for 3 months, results in a decreased 
incidence of S. aureus colonization and SSTI, both during and after the intervention period.  
3.2 
Study Outcome Measures 
3.2.1 Primary Outcome Measures 
 
Incidence of SSTI at the household level (i.e., occurring in any household member) 3 months 
after randomization. 
3.2.2 Secondary Outcome Measures 
 
1. Baseline and longitudinal prevalence of S. aureus colonization in index patients, 
household contacts, pet dogs and cats, and household surfaces, and the molecular 
characterization (i.e., strain type) and relatedness of these recovered strains. 
2. SSTI incidence at the household level 1, 6, and 9 months following randomization and at 
the individual level 1, 3, 6, and 9 months following randomization. 
3. Development of a confirmed S. aureus infection over 9 months at the household and 
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4. S. aureus transmission within households over 9 months as determined by molecular 
strain typing. 
5. Safety, tolerability, and adherence to study interventions. 
6. Mupirocin and chlorhexidine resistance in S. aureus strains recovered at serial 
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4 
STUDY DESIGN 
Study Description. This is a phase IV open label, randomized, pragmatic, comparative 
effectiveness trial. 
 
Study Population. Non-immunocompromised patients aged birth to 21 years with a culture 
confirmed S. aureus infection within the last two months will be eligible.  
 
Baseline Decolonization. All household participants will complete a 5-day baseline 
decolonization regimen (prior to randomization into the intervention arms) as this is considered 
standard-of-care for decolonization. Participants will apply mupirocin ointment to the anterior 
nares twice daily for five consecutive days and perform daily body washes with chlorhexidine 
gluconate (Hibiclens) in the bath or shower for five consecutive days. 
 
Study Groups and Treatment Arms.  
1. Group 1: Periodic Personal Decolonization:  All household participants will perform 
chlorhexidine body washes twice weekly for 3 months and apply mupirocin ointment to 
the anterior nares twice daily for five consecutive days each month for 3 months. 
Sufficient study materials for each assigned participant will be provided. A member of 
the study team will contact each household (via the family’s preferred method: phone 
call or e-mail) several days prior to their designated period for monthly mupirocin 
application.  
2. Group 2: Household Environmental Hygiene:  In addition to their usual cleaning, 
households assigned to Group 2 will be asked to perform targeted household hygiene 
focusing on sources known to harbor S. aureus and serve as reservoirs for transmission. 
Specific recommendations include:   
o Launder all bed linens once a week. 
o Replace each kitchen and bathroom hand towel with a clean towel each day. 
Alternatively, rather than cloth towels, disposable paper towels (provided by the 
study team) may be used in the kitchen and bathroom.  
o Replace the kitchen sponge with a new sponge (provided by the study team) 
once a week. 
o Wipe the following surfaces with Clorox Disinfecting Wipes (provided by the 
study team) once a week, using 1 wipe per surface: 
 
TV remote controls, telephones, computer keyboards and mouse  
 
Bathrooms: Countertop, sink, and sink faucet handles; light switch; 
bathtub and faucet handles; toilet handle and seat 
 
Kitchen: Refrigerator and freezer door handles; microwave door handle 
and key pad; oven door handle; sink and sink faucet handle; table top; 
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At the enrollment visit, cleaning procedures will be demonstrated by study personnel, 
and printed instructions will be provided. Throughout the 3-month intervention period, to 
enhance adherence to the protocol, a member of the study team will contact each 
household weekly to remind them to perform targeted cleaning with the Clorox 
Disinfecting Wipes and to replace the kitchen sponge. 
3. Group 3:  Integrated Approach of Personal and Household Environmental Hygiene:  
Participants in households randomized to Group 3 will perform the Periodic Personal 
Decolonization described for Group 1, plus the Household Environmental Hygiene 
described for Group 2. 
A total of 207 households (~828 subjects) will be enrolled, with 69 households in each of the 
three groups. The projected time to complete study enrollment is approximately 72 months.  
 
Subject Participation. The total duration of subject participation will be approximately 9 
months. The active treatment period is 3 months. Subjects will be evaluated at 5 study visits:   
1. the baseline visit (enrollment)  
2. 1 month follow up visit 
3. 3 month follow up visit (end of intervention visit) 
4. 6 month follow up visit 
5. 9 month follow up visit 
Subjects who fail to show for scheduled visits will be contacted by telephone or email (per 
consent) and, if necessary, by mail to request that a follow-up visit be rescheduled. The 
research team will inquire about the reason for the missed visit and will work with the subject to 
facilitate a follow-up visit. 
 
Study Drugs.  
 
Please refer to drug insert information. 
 
Data Collection. At study enrollment, detailed questionnaires will be administered to identify 
risk factors for CA-S. aureus colonization, infection, and transmission. Specifically, for each 
participant, we will collect data regarding past medical history, prior S. aureus infections, 
occupation, daycare or school location, activities, frequency and modes of bathing (showers vs. 
bath), washing of clothing (frequency and water temperature used), and sharing of personal 
hygiene and other household items (and which household members share specific items). To 
identify household factors contributing to CA-S. aureus transmission, a household questionnaire 
will be administered (one per household) and will ascertain current cleaning practices 
(frequency, surfaces cleaned, products used), layout of the home (number of rooms, square 
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information about the number, type, and health of pets in the home, and pet behaviors (e.g., 
where they sleep) will be obtained.  
Longitudinal study visits will be conducted in the participants’ homes 1, 3, 6, and 9 
months following randomization. At these visits, a questionnaire will be administered to each 
participant to document interval SSTI and any changes of occupation, daycare or school 
location, activities, frequency and modes of bathing (showers vs. bath), washing of clothing 
(frequency and water temperature used), and sharing of personal hygiene and other household 
items (and which household members share specific items). If a participant sought medical care 
for any infection, records from the hospital and/or provider’s office will be obtained for 
verification. The household questionnaire will also be administered at each follow-up visit to 
capture any changes to cleaning frequency, etc.  
  
Specimen Collection, Processing, and Culture Methods. Culture swab samples (BD ESwab; 
Becton Dickinson) will be obtained from each household member at the enrollment visit and at 
each follow-up visit. Three swabs will be used for each participant, to separately culture the 
anterior nares, axillae, and inguinal folds. At each study visit, standardized collection methods 7 
will be used to collect environmental cultures: sterile swabs (BD ESwab) and environmental 
sampling plates (Baird-Parker agar contact plate, Hardy Diagnostics) will be used to sample ~21 
household surfaces with frequent skin contact that will be targeted with the environmental 
cleaning intervention (the exact number will vary per household depending on the surfaces and 
objects present in the home). Items to be cultured include the bathroom sink/faucet handles, 
toilet handle/seat, bathtub, refrigerator and freezer door handle, microwave door handle and 
keypad, oven door handle, kitchen table, counter tops, kitchen sink/sink faucet handles, bed 
linens, primary television remote control, main telephone, and computer keyboard and mouse. 
Pet dogs or cats will also be cultured (nasal/oral and dorsal fur) at each study visit. 
Laboratory technicians will be blinded to participant randomization assignment. All 
culture swabs will be incubated overnight in tryptic soy broth (TSB) with 6.5% NaCl at 35°C. A 
sample of the broth will be plated to trypticase soy agar with 5% sheep blood (blood agar plate 
[BBL]; Becton Dickinson) and incubated for 24-48 hours. S. aureus identification and antibiotic 
susceptibility testing will be performed by established procedures 1,139,140. All isolates will be 
stored in TSB with glycerol at -80°C. For future microbiota studies, the eluate from the culture 
swabs will be frozen at -80°C immediately after the study visit. 
 
S. aureus Strain Characterization and Detection of Mupirocin and Chlorhexidine 
Resistance. Prior study data projects that we will amass ~5200 S.aureus isolates over the 
study period. To determine relatedness of isolates colonizing or infecting individuals in the same 
household, and those colonizing household pets and environmental surfaces, all recovered S. 
aureus isolates will be analyzed by genetic typing. Multiplex PCR will also be performed for 
staphylococcal cassette chromosome mec (SCCmec) characterization of all recovered S. 
aureus isolates using established methods 141. All S. aureus isolates will be interrogated for 
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diffusion; isolates phenotypically resistant to mupirocin will be genotyped using PCR to detect 
mupA 121,142.  
 
Interim Analyses. Interim analysis is discussed in Section 10.3. Safety monitoring and reviews 
and interim analyses for the study as a whole will be conducted by a Data and Safety Monitoring 
Plan (DSMP). 
 
Safety Oversight. Safety oversight will be provided by via safety monitoring plan. The monitors 
will meet a minimum of twice per year and will review interim and cumulative data for evidence 
of study-related adverse events and for quality, completeness, and timeliness.  
4.1 
Substudies (if applicable) 
Not applicable at the present time.  

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Projected enrollment is 207 households (~828 subjects). The total of 207 households includes a 
10% attrition rate among enrollees, a rate derived from our previous household study.  
5.1 
Subject Inclusion Criteria 
 
1) Inclusion Criteria:  Patients with confirmed (i.e., culture-positive) active or recent (within 
the past 2 months) S. aureus cutaneous infections who reside within 90 miles of SLCH 
will be screened. When possible, infecting isolates will be obtained for analysis; at 
minimum, antibiotic susceptibility reports will be obtained. There are no restrictions for 
household contacts. Only participants providing written, informed consent, or for whom 
consent is provided by a parent or legal guardian, will be included.  
5.2 
Subject Exclusion Criteria 
Subjects meeting any of the following criteria at baseline will not be eligible:  
1) Exclusion Criteria:  As the focus of this study is community-onset infections, we will 
exclude patients with nosocomial infections (i.e., >48 hours after hospitalization) and 
those with traditional risk factors for HA-S. aureus (e.g., immunodeficiency, indwelling 
catheter or percutaneous medical device, undergoing dialysis, presenting with a surgical 
site infection, or residing in a long-term care facility within the past year). Patients who 
are unable to give consent or for whom consent is not obtained, those refusing home 
Environmental cultures by the study team, and patients without a permanent home (e.g., 
living in a shelter or group home) will be excluded.  
 
5.2.1 Randomization Procedures 
 
Following Baseline Personal Decolonization performed by all household participants, 
households will be allocated 1:1:1 to one of the three treatment groups. Randomization 
assignments will be generated by the statistician with REDCap (Research Electronic Data 
Capture, a secure, web-based database application, http://www.biostat.wustl.edu/redcap). The 
assigned intervention will be performed for 3 months, and participants will be followed for an 
additional 6 months to track primary and secondary outcomes 
5.2.2 Masking Procedures 
Laboratory technicians will be blinded to participant randomization assignment. Research team 
members will be blinded to laboratory results to prevent bias during sampling. 

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5.2.3 Reasons for Withdrawal 
A study subject will be discontinued from participation in the study if: 
• 
Any clinical adverse event (AE), intercurrent illness, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
subject.  
• 
If the safety of the study team personnel is in danger while at the home of a participant 
Subjects are free to withdraw from participating in the study at any time upon request. The 
investigators may also withdraw a subject at any time for safety, behavioral, or administrative 
reasons.  
5.2.4 Handling of Withdrawals 
 
Participants will be instructed to call us immediately and discontinue the protocol if they 
experience skin or nasal burning, pain, rash, or other adverse effects. Participants who 
discontinue measures early will not be withdrawn from the study, and we will record the number 
of applications of each component of the protocol completed by the participant. Participants will 
be free to withdraw from study participation at any time, and the participants or their physicians 
may choose to stop the decolonization measures at any time.  
5.2.5 Termination of Study  
The study may be terminated early for the following reasons: 
• 
Safety concerns due to an excessive rate or number of serious adverse events 
• 
Study closure resulting from DSMP recommendation 
• 
Lack of efficacy of a treatment arm 
• 
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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
Mupirocin 2% ointment 
See package insert  
 
Chlorhexidine 4% (Hibiclens) 
See package insert  
6.1 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product  
 
All participants will be asked to complete a “Memory Aid” (tailored for each study group) to 
record their completion of the assigned personal and/or environmental hygiene measures; the 
Memory Aids will be collected by the study team at the 1- and 3-month longitudinal study visits. 
 
6.2 
Concomitant Medications/Treatments 
 
Concomitant medications will be recorded at baseline and all subsequent study visits. 
Concomitant medications and treatments are permitted unless it is medication that is 
contraindicated for administration with study medications. 
 

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7 
STUDY SCHEDULE 
7.1 
Screening/Recruitment 
Screening. Potential participants with active or recent S. aureus SSTI will be recruited from St. 
Louis Children’s Hospital and community pediatric practices affiliated with WU PAARC, a 
practice-based research network in metropolitan St. Louis. Additionally, prior participants from 
our household transmission dynamics study will be contacted; those interested and eligible will 
be enrolled. Informed consent will be collected prior to any study procedures being conducted. 
 
7.2 
Enrollment/Study visits 
At the enrollment visit, conducted in the study participant’s home, each household member will 
be consented for this study. A detailed questionnaire covering health history, hygiene, and 
activities to help identify potential risk factors for S. aureus will be conducted. A separate survey 
about the household (e.g., number of bedrooms and bathrooms, frequency of cleaning the 
kitchen and bathrooms, presence of pets, etc.) will also be completed. Swabs from the 
consented participants, indoor pet dogs and/or cats, and specific environmental surfaces will 
also be collected. Information regarding which treatment group the household was randomized 
to will be given to the participants as well as all supplies needed to complete the intervention. All 
study supplies and instructions will be provided at no cost to the research participants.  
All follow-up study visits will occur as stated in schedule of events (Figure 3).  
Randomization will occur at the enrollment visit and participants will begin the baseline 
decolonization protocol on the following day. 
Memory Aid Diary. Participants will be given a Memory Aid diary at the enrollment visit and 1 
month follow-up visit to record the completion of the assigned intervention measures. Memory 
Aids will be collected by the study team at the 1-month follow-up visit and 3-month follow-up 
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Figure 3. Schedule of Events 
 
 
 

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8 
STUDY PROCEDURES/EVALUATION 
8.1 
Definitions  
 
Informed consent. Informed consent is a process that is initiated prior to the individual’s 
agreeing to participate in the study and continuing throughout the individual’s study 
participation. Written informed consent will be obtained for all participating subjects.  
 
Index patient. The pediatric patient presenting with a CA-S. aureus infection who is screened 
for study participation.  
 
Household member. An individual who sleeps in the home ≥4 nights per week.  
 
Participant. Index patients and their household members consenting to study participation.  
 
Colonization. Carriage of S. aureus as determined by a positive culture from the nares, axillae, 
or inguinal folds.  
 
Infection. Symptomatic manifestation of disease (e.g., skin abscess, boil, or cellulitis, 
necrotizing pneumonia, musculoskeletal or bloodstream infection).  
 
Transmission. Colonization of an individual over the longitudinal period with a new strain type 
(i.e., not previously carried by that individual) that is identical to a strain type colonizing a 
household contact, environmental surface, or pet at a prior sampling.  
 
Concomitant Medications. Concomitant medications will be recorded and any changes to 
concomitant medications will be recorded at all subsequent study visits.  
 
Initial Wound Culture. A culture of the enrollment wound (the wound which qualified the patient 
for the present study) will be obtained when possible. Culture reports will be obtained for all 
index patients (the pediatric patient presenting with a CA-S. aureus infection who is screened 
for study participation).  
 
Randomization. Each household consented will be randomized to one of the three treatment 
protocols using the deterministic minimization method (see Section 5).  
 
Intervention Supplies. All households will be given study intervention supplies along with 
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Memory Aid. All participants will be asked to complete a “Memory Aid” (tailored for each study 
group) to record their completion of the assigned personal and/or environmental hygiene 
measures; this will be collected by the study team at the 1-month and 3-month longitudinal 
study visits. 
 
 
8.2 
Laboratory Evaluations 
8.2.1 Laboratory Evaluations 
 
Microbiological Studies. Culture swab samples (BD ESwab; Becton Dickinson) will be 
obtained from each household member at the enrollment visit and at each follow-up visit. Three 
swabs will be used for each participant, to separately culture the anterior nares, axillae, and 
inguinal folds. At each study visit, standardized collection methods 7 will be used to collect 
environmental cultures: sterile swabs (BD ESwab) and environmental sampling plates (Baird-
Parker agar contact plate, Hardy Diagnostics) will be used to sample ~21 household surfaces 
with frequent skin contact that will be targeted with the environmental cleaning intervention (the 
exact number will vary per household depending on the surfaces and objects present in the 
home). Items to be cultured include the bathroom sink/faucet handles, toilet handle/seat, 
bathtub, refrigerator and freezer door handle, microwave door handle and keypad, oven door 
handle, kitchen table, counter tops, kitchen sink/sink faucet handles, bed linens, primary 
television remote control, main telephone, sofa, and computer keyboard and mouse. Pet dogs 
or cats will also be cultured (nasal/oral and dorsal fur) at each study visit. Laboratory technicians 
will be blinded to participant randomization assignment. All culture swabs will be incubated 
overnight in tryptic soy broth (TSB) with 6.5% NaCl at 35°C. A sample of the broth will be plated 
to trypticase soy agar with 5% sheep blood (blood agar plate [BBL]; Becton Dickinson) and 
incubated for 24-48 hours. S. aureus identification and antibiotic susceptibility testing will be 
performed by established procedures 1,139,140. Any unusual isolates or isolates collected from 
pets will be identified by matrix-assisted laser desorption/ionization (MALDI). All isolates will be 
stored in TSB with glycerol at -80°C. For future microbiota studies, the eluate from the culture 
swabs will be frozen at -80°C immediately after the study visit. 
 
For more information on specific laboratory procedures, refer to the Laboratory Protocols binder. 
8.2.2 Special Assays or Procedures 
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8.2.3 Specimen Preparation, Handling, and Shipping. 
Clinical isolates of bacteria obtained from skin cultures will be handled and stored on-site in 
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9 
ASSESSMENT OF SAFETY 
9.1 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
9.1.1 Adverse Events 
Adverse events (AEs) will be classified, recorded, and reported in compliance with federal 
regulations (45 CFR 46.103(b)(5)) and policies and procedures of the Washington University 
School of Medicine Human Research Protection Office (HRPO) and the IRB. An adverse event 
(AE) is defined as any unfavorable or undesirable effect (sign, symptom, laboratory abnormality, 
or condition), regardless of causal relationship to study procedures or participation that occurs in 
a subject while enrolled in this clinical trial. Any medical condition that is present at the time that 
the subject is screened should be considered as baseline and not reported as an AE. The 
occurrence of an AE may come to the attention of study personnel during study visits and 
interviews of a study recipient presenting for medical care.  
 
All AEs including local and systemic reactions meeting the criteria for “serious adverse events” 
will be captured on the case report form. Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, relationship (related or unrelated) to study 
product assessed only by those with the training and authority to make a diagnosis, which would 
include MD, PA, or Nurse Practitioner, and time of resolution or stabilization of the event. All 
AEs occurring while on study will be documented. All AEs will be followed to adequate 
resolution or stabilization.  
 
Solicitation and Collection of Adverse Events. The PI will monitor adverse events on a 
continuous basis and is responsible for providing the DSMP members with new safety 
information relevant to the study. Adverse events will be collected over the entire period that 
subject is enrolled in the study or, in the case of a serious adverse event associated with study 
drug, until resolution of the outcome of that event.  
 
Occurrences of adverse events will be collected at all 4 follow-up study visits. Adverse events 
will be captured by open ended questions to address whether other events not specifically 
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9.1.2 Serious Adverse Events 
 
As required by the WU HRPO, the PI will report the following serious adverse events to the WU 
HRPO using methods specified by the WU HRPO: deaths will be reported immediately, life-
threatening events will be reported within 7 calendar days, and all other serious adverse events 
will be reported within 15 calendar days. 
9.2 
Reporting Procedures 
9.2.1 Serious Adverse Events 
 
The PI will monitor adverse events on a continuous basis and is responsible for providing the 
DSMP members with new safety information relevant to the study as required by the WU 
HRPO, the PI will report the following serious adverse events to the WU HRPO using methods 
specified by the WU HRPO: deaths will be reported immediately, life-threatening events will be 
reported within 7 calendar days, and all other serious adverse events will be reported within 15 
calendar days. 
9.2.2 Reporting of Pregnancy 
Women who become pregnant while enrolled will be followed per the schedule of events, for the 
duration of the protocol.  
9.3 
Halting Rules 
 
No formal halting rules are pre-specified.  
 
9.4 
Safety Oversight  
 
The DSMP members will review interim and cumulative data for evidence of study-related 
adverse events and for quality, completeness, and timeliness. The DSMP members will assess 
compliance with study goals for patient recruitment and retention, protocol adherence, and 
factors external to the study that may impact patient safety or the ethics of the study. Ad hoc 
meetings may occur at the request of the DSMP members or the WU HRPO. A safety and 
interim analysis report will be generated by the monitors twice annually. As required by the WU 
HRPO, the PI will report the following serious adverse events to the WU HRPO using methods 
specified by the WU HRPO: deaths will be reported immediately, life-threatening events will be 
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calendar days. The PI will monitor adverse events on a continuous basis and is responsible for 
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10 
STATISTICAL CONSIDERATIONS 
This trial will assess three decolonization strategies for the treatment of CA-S. aureus. Primary 
analyses will be comparisons across the three randomization groups for occurrence of SSTI at 
the household level at 3 months. Since Group 3 is of chief interest, the primary analysis will 
compare SSTI incidence in Group 3 to SSTI incidence in Groups 1 and 2 combined. As a 
secondary analysis, we will perform a chi-squared test across all 3 groups, and if significant, we 
will analyze the pairwise differences between the 3 groups as well. Since all analyses are pre-
specified, no adjustment for multiple comparisons is necessary. We will also perform the 
analyses at the household level for all time points to investigate potential time trends using 
repeated measures generalized estimating equation (GEE) models, adjusting for potential 
clinical and demographic covariates. 
 
Similarly, as secondary analyses, we will also use GEE models on the individual 
participant level, accounting for clustering of individuals within households and repeated 
measurements at 1, 3, 6, and 9 months to assess differences in colonization status, SSTI 
incidence, confirmed S. aureus infection, and transmission over 9 months between the 
randomization arms, adjusting for pertinent covariates. Adherence to study interventions will be 
described and compared between the 3 groups using GEE models, with appropriate link 
functions (e.g., log for number of chlorhexidine baths, applications of mupirocin ointment, or 
performance of environmental hygiene measures). Reported adverse reactions will also be 
characterized and compared between the 3 treatment groups. Additionally, we will evaluate 
mupirocin and chlorhexidine resistance in S. aureus isolates collected at baseline as predictors 
of decolonization failure (i.e., presence of colonization at 1 month). We will also compare the 
prevalence of mupirocin and chlorhexidine resistance in strains recovered at longitudinal 
samplings between Groups 1 and 3 combined (those performing baseline and periodic personal 
decolonization) and Group 2 (those performing only baseline personal decolonization). 
10.1 Study Hypotheses 
 
The primary null hypothesis is:  The three decolonization strategies (integrated, periodic 
personal, and environmental hygiene) will result in the same incidence of SSTI at the household 
level 3 months after randomization. 
10.2 Sample Size Considerations 
 
Primary Endpoint. The primary efficacy endpoint is occurrence of SSTI at the household level 
(i.e., in any household member) 3 months after randomization. 

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Study Populations 
 
1. The evaluable population for an analysis comprises all subjects for whom the endpoint is 
determined.  
2. The intent-to treat (ITT) population comprises all randomized subjects.  
 
Power Calculations. 
 
The primary outcome is incidence of SSTI at the household level (i.e., occurring in any 
household member) 3 months after randomization. The expected rate of SSTI in households 
randomized to Groups 1 and 2 is 40% based on our prior study 6. We expect the integrated 
personal and environmental approach (Group 3) will result in a 50% relative reduction, resulting 
in a household-level SSTI incidence of 20%. A sample of 189 households (63 per group; 
calculated using SAS 9.3) will have 80% power at α=0.05 to detect this difference. A total of 207 
households (~828 subjects) are planned to be randomized with 69 households in each of the 
three groups. 
 
The three groups are: 
1. Periodic Personal Decolonization 
2. Household Environmental Hygiene 
3. Integrated Approach of Personal and Household Environmental Hygiene 
 
The planned total of 207 households includes a 10% attrition from trial enrollment to the 3-
month follow-up visit, a rate based on our prior household studies.  
 
10.3 Planned Interim Analyses 
 
Interim Analyses. Annual reports will be generated according to the Data Safety and 
Monitoring Plan. These reports include information on any adverse events, updates on patient 
retention and recruitment, outcomes, and protocol violations. Additionally, progress reports for 
AHRQ are submitted annually.  
10.4 Final Analysis Plan 
 
Primary Analysis Plan. The primary outcome, occurrence of SSTI at the household level (i.e., 
in any household member) 3 months after randomization, will be determined for the 3 
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and 3) Integrated periodic personal decolonization and household environmental hygiene. A 
time point of 3 months was selected for the primary outcome as this is a reasonable interval for 
individuals to reacquire the organism and for a subsequent infection to develop. The analysis 
will be performed on the intention-to-treat population. At the household level, each household 
will be considered a unit of analysis and we will use a chi-square test to compare the incidence 
of SSTI between the 3 groups at 3 months. Since Group 3 is of chief interest, the primary 
analysis will compare SSTI incidence in Group 3 to SSTI incidence in Groups 1 and 2 
combined. We will also perform the analyses at the household level for all time points to 
investigate potential time trends using repeated measures generalized estimating equation 
(GEE) models, adjusting for potential clinical and demographic covariates. 
 
Secondary Analysis Plans. As a secondary analysis, we will perform a chi-squared test across 
all 3 groups, and if significant, we will analyze the pairwise differences between the 3 groups as 
well. Since all analyses are pre-specified, no adjustment for multiple comparisons is necessary 
Similarly, as secondary analyses, we will also use GEE models on the individual participant 
level, accounting for clustering of individuals within households and repeated measurements at 
1, 3, 6, and 9 months to assess differences in colonization status, SSTI incidence, confirmed S. 
aureus infection, and transmission over 9 months between the randomization arms, adjusting 
for pertinent covariates. Adherence to study interventions will be described and compared 
between the 3 groups using GEE models, with appropriate link functions (e.g., log for number of 
chlorhexidine baths, applications of mupirocin ointment, or performance of environmental 
hygiene measures). Reported adverse reactions will also be characterized and compared 
between the 3 treatment groups. Additionally, we will evaluate mupirocin and chlorhexidine 
resistance in S. aureus isolates collected at baseline as predictors of decolonization failure (i.e., 
presence of colonization at 1 month). We will also compare the prevalence of mupirocin and 
chlorhexidine resistance in strains recovered at longitudinal samplings between Groups 1 and 3 
combined (those performing baseline and periodic personal decolonization) and Group 2 (those 
performing only baseline personal decolonization).  

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11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Appropriate medical and research records will be kept for this trial, in compliance with ICH E6, 
Section 4.9 and regulatory and institutional requirements for the protection of confidentiality of 
subjects.  
 
 

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QUALITY CONTROL AND QUALITY ASSURANCE 
All data collected via interview questionnaires, intervention treatment adherence, serious 
adverse events, wound assessment, laboratory results, and clinical lab reports will be entered 
into the REDCap database by research team members. Research members will be assigned to 
one of two data groups so all data can be entered two independent times. Once all data is 
entered for a family, both copies on the database will be merged and reconciled by a research 
team member (not on either of the data teams). This double data entry process is utilized to 
avoid entry mistakes or mistypes.  
For more detailed information, refer to the Data Entry Protocol, Micro Data Entry Protocol, Good 
Data Practices powerpoint, and Laboratory QC protocols. 
 
 

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13 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
13.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the US National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46, 21CFR 
Parts 50 and 56, and/or the ICH E6; 62 Federal Regulations 25691 (1997).  
13.2 Institutional Review Board 
This study must provide the review and approval of this protocol and the associated informed 
consent documents and recruitment material by an appropriate independent ethics committee 
(IEC) or IRB registered with the OHRP. Any amendments to the protocol or consent materials 
must also be approved before they are placed into use. In the United States and in other 
countries, only institutions holding a current US Federal-wide Assurance issued by OHRP may 
participate. Refer to: http://www.hhs.gov/ohrp/assurances/. 
13.3 Informed Consent Process 
This protocol and the informed consent documents and any subsequent modifications will be 
reviewed and approved by the IRB or ethics committee responsible for oversight of the study. A 
signed consent form will be obtained from the subject (or parent, legal guardian, or person with 
power of attorney for subjects who cannot consent for themselves, such as those below the 
legal age). The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation. A signed copy of the consent form will be 
given to the subject, parent, or legal guardian, which will be documented on the consent 
checklist. 
13.3.1 Informed Consent/Assent Process 
Informed consent will be obtained from one parent or legal guardian for subjects under 18 years 
of age. Minors who are 0-6 years old are considered not old enough to provide verbal or written 
assent. Minors 6-12 years old will have the purpose of the study, the procedures to be followed, 
and the risks and benefits of participation explained to them in terms that are age appropriate 
and then asked if it is OK to continue.  After getting an age-appropriate description of the study 

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and its procedures, minors 13-17 years old will sign the consent document to assent to the 
study above where their parent/guardian signs to consent to the study. A signed copy of the 
consent form will be given to the subject, parent, or legal guardian, which will be documented on 
the consent checklist.  
13.4 Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover clinical information relating 
to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified by coded number only to maintain subject confidentiality. All records will be kept 
locked. All computer entry and networking programs will be done with coded numbers only. 
Clinical information will not be released without written permission of the subject, except as 
necessary for monitoring by IRB, the FDA, the NIAID, the OHRP, or the pharmaceutical 
supporters or the supporters’ designees. 
13.5 Study Discontinuation 
The study may be discontinued at any time by the PI, who holds primary responsibility for this 
decision, based on recommendations from the WU IRB, AHRQ, the FDA, DSMP, or other 
government agencies as part of their duties to ensure that research subjects are protected. 
13.6 Future Use of Stored Specimens 
Clinical isolates of S. aureus and other bacteria isolated from cultures will be stored in the PI’s 
laboratory space. These will be coded and delinked to personal identifying information.  

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14 
DATA HANDLING AND RECORD KEEPING 
14.1 Data Management Responsibilities 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data. Black or blue ink is required to ensure clarity 
of reproduced copies. When making a change or correction, the original entry should be 
crossed out with a single line, and the change should be initialed and dated. DO NOT ERASE, 
OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL.  
Data reported in the interview form should be consistent with the source documents or the 
discrepancies should be documented. Data collection is the responsibility of the clinical trial staff 
under the supervision of the PI. During the study, the investigator must maintain complete and 
accurate documentation for the study.  
Hard copy records will be transferred from homes to Washington University in a locked 
briefcase. The records will be stored in a locked filing cabinet in a locked office. Participant data 
will be collected, entered, and stored electronically. All data will be protected with a secure 
computer network and password access. Specifically, The Division of Biostatistics Informatics 
Core will be used as a central location for data processing and management. Washington 
University belongs to a consortium of institutional partners that work to maintain a software 
toolset and workflow methodology for electronic collection and management of research and 
clinical trial data. REDCap (Research Electronic Data Capture) data collection projects rely on a 
thorough study-specific data dictionary defined in an iterative self-documenting process by all 
members of the research team with planning assistance from the Division of Biostatistics 
Informatics Core. The iterative development and testing process results in a well-planned data 
collection strategy for individual studies. REDCap servers are securely housed in an on-site 
limited access data center managed by the Division of Biostatistics at Washington University. All 
web-based information transmission is encrypted. REDCap was developed specifically around 
HIPAA Security guidelines and is implemented and maintained according to Washington 
University guidelines. REDCap currently supports > 170 academic/non-profit consortium 
partners on six continents and 13,000 research end-users (www.project-redcap.org). 
14.2 Data Capture Methods 
Data will be collected prospectively and entered into a REDCap database built by the study 
team. 

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14.3 Types of Data 
Data for the study will be entered directly into the REDCap data entry system. Data for this 
study will include all information gathered via the interview questionnaires, intervention 
treatment adherence, serious adverse events, and wound assessment. 
14.4 Study Records Retention 
 
All research records, including signed consent forms, must be kept in their original form or a 
certified scanned electronic form for at least seven years beyond close of the study. Additional 
retention requirements may be required under State and Federal laws, the Covered 
Organization’s policies or at the request of the study sponsor. Protected Health Information 
must be stored in accordance with HIPAA and the Covered Organization’s HIPAA policies 
14.5 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice 
(GCP), or Manual of Procedures requirements. The noncompliance may be either on the part of 
the subject, the investigator, or the study site staff. As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly. Protocol deviations must be sent to 
the IRB per their guidelines. The site PI/study staff is responsible for knowing and adhering to 
their IRB/IEC requirements.  
  

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15 
PUBLICATION POLICY 
Following completion of the study, results of the research are planned for publication in a 
scientific journal. The policy of the International Committee on Medical Journal Editors (ICMJE) 
member journals, which that have adopted a trials-registration policy as a condition for 
publication, will be adhered to. This policy requires that all clinical trials be registered in a public 
trials registry such as ClinicalTrials.gov sponsored by the National Library of Medicine. It is the 
responsibility of the study team to register this trial in an acceptable registry. Any clinical trial 
starting enrollment after 01 July 2005 must be registered on or before subject enrollment.  
 
The Principal Investigator will formulate plans, organize data and prepare manuscript(s) for 
publication as appropriate. Authorship decisions will be made by the Principal Investigator with 
guidance from published guidelines from Cohen JJ and Siegel EK, Academic Medical Centers 
and Medical Research: The Challenges Ahead. JAMA.2005; 294: 1367-1372. 
 
Published guidelines will also be followed regarding the disclosure of relationships with 
government funding agencies such as the NIH and the CDC, foundations like the Grant Health 
Care foundation and corporate sponsors of related research. 
 
 

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16 
LITERATURE REFERENCES 
REFERENCES 
1. 
Fritz SA, Garbutt J, Elward A, Shannon W, Storch GA. Prevalence of and risk 
factors for community-acquired methicillin-resistant and methicillin-sensitive 
Staphylococcus aureus colonization in children seen in a practice-based research 
network. Pediatrics 2008;121:1090-8. 
2. 
Fritz SA, Epplin EK, Garbutt J, Storch GA. Skin infection in children colonized 
with community-associated methicillin-resistant Staphylococcus aureus. J Infect 
2009;59:394-401. 
3. 
Gorwitz RJ, Kruszon-Moran D, McAllister SK, et al. Changes in the prevalence of 
nasal colonization with Staphylococcus aureus in the United States, 2001-2004. J Infect 
Dis 2008;197:1226-34. 
4. 
Mertz D, Frei R, Jaussi B, et al. Throat swabs are necessary to reliably detect 
carriers of Staphylococcus aureus. Clin Infect Dis 2007;45:475-7. 
5. 
Rodriguez M, Hogan PG, Burnham CA, Fritz SA. Molecular epidemiology of 
Staphylococcus aureus in households of children with community-associated S aureus 
skin and soft tissue infections. J Pediatr 2014;164:105-11. 
6. 
Fritz SA, Hogan PG, Hayek G, et al. Household versus individual approaches to 
eradication of community-associated Staphylococcus aureus in children: a randomized 
trial. Clin Infect Dis 2012;54:743-51. 
7. 
Hogan PG, Singh LN, Al-Zubeidi D, et al. Evaluation of environmental sampling 
methods for detection of Staphylococcus aureus for epidemiologic studies.  IDWeek; 
2012; San Diego, CA: Infectious Diseases Society of America. 
8. 
Fritz SA, Camins BC, Eisenstein KA, et al. Effectiveness of measures to 
eradicate Staphylococcus aureus carriage in patients with community-associated skin 
and soft-tissue infections: a randomized trial. Infect Control Hosp Epidemiol 
2011;32:872-80. 
9. 
Fritz SA, Hogan PG, Camins BC, et al. Mupirocin and chlorhexidine resistance in 
Staphylococcus aureus in patients with community-onset skin and soft tissue infections. 
Antimicrob Agents Chemother 2013;57:559-68. 
10. 
Klevens RM, Morrison MA, Fridkin SK, et al. Community-associated methicillin-
resistant Staphylococcus aureus and healthcare risk factors. Emerg Infect Dis 
2006;12:1991-3. 
11. 
Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and 
health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 
2003;290:2976-84. 
12. 
Uhlemann AC, Dordel J, Knox JR, et al. Molecular tracing of the emergence, 
diversification, and transmission of S. aureus sequence type 8 in a New York 
community. Proc Natl Acad Sci U S A 2014;111:6738-43. 

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13. 
Kaplan SL, Hulten KG, Gonzalez BE, et al. Three-year surveillance of 
community-acquired Staphylococcus aureus infections in children. Clin Infect Dis 
2005;40:1785-91. 
14. 
Gonzalez BE, Hulten KG, Dishop MK, et al. Pulmonary manifestations in children 
with invasive community-acquired Staphylococcus aureus infection. Clin Infect Dis 
2005;41:583-90. 
15. 
Gonzalez BE, Martinez-Aguilar G, Hulten KG, et al. Severe Staphylococcal 
sepsis in adolescents in the era of community-acquired methicillin-resistant 
Staphylococcus aureus. Pediatrics 2005;115:642-8. 
16. 
Lina G, Piemont Y, Godail-Gamot F, et al. Involvement of Panton-Valentine 
leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia. 
Clin Infect Dis 1999;29:1128-32. 
17. 
Miller LG, Diep BA. Clinical practice: colonization, fomites, and virulence: 
rethinking the pathogenesis of community-associated methicillin-resistant 
Staphylococcus aureus infection. Clin Infect Dis 2008;46:752-60. 
18. 
Kaplan SL. Community-acquired methicillin-resistant Staphylococcus aureus 
infections in children. Semin Pediatr Infect Dis 2006;17:113-9. 
19. 
Tenover FC, McDougal LK, Goering RV, et al. Characterization of a strain of 
community-associated methicillin-resistant Staphylococcus aureus widely disseminated 
in the United States. J Clin Microbiol 2006;44:108-18. 
20. 
Diep BA, Gill SR, Chang RF, et al. Complete genome sequence of USA300, an 
epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus. 
Lancet 2006;367:731-9. 
21. 
Goering RV, McDougal LK, Fosheim GE, Bonnstetter KK, Wolter DJ, Tenover 
FC. Epidemiologic distribution of the arginine catabolic mobile element among selected 
methicillin-resistant and methicillin-susceptible Staphylococcus aureus isolates. J Clin 
Microbiol 2007;45:1981-4. 
22. 
DeLeo FR, Diep BA, Otto M. Host Defense and Pathogenesis in Staphylococcus 
aureus Infections. Infect Dis Clin North Am 2009;23:17-34. 
23. 
Loughman JA, Fritz SA, Storch GA, Hunstad DA. Virulence gene expression in 
human community-acquired Staphylococcus aureus infection. J Infect Dis 
2009;199:294-301. 
24. 
Baba T, Takeuchi F, Kuroda M, et al. Genome and virulence determinants of 
high virulence community-acquired S. AUREUS. Lancet 2002;359:1819-27. 
25. 
Macal CM, North MJ, Collier N, et al. Modeling the transmission of community-
associated methicillin-resistant Staphylococcus aureus: a dynamic agent-based 
simulation. Journal of translational medicine 2014;12:124. 
26. 
Ma XX, Ito T, Tiensasitorn C, et al. Novel type of staphylococcal cassette 
chromosome mec identified in community-acquired methicillin-resistant Staphylococcus 
aureus strains. Antimicrob Agents Chemother 2002;46:1147-52. 
27. 
Ito T, Ma XX, Takeuchi F, Okuma K, Yuzawa H, Hiramatsu K. Novel type V 
staphylococcal cassette chromosome mec driven by a novel cassette chromosome 
recombinase, ccrC. Antimicrob Agents Chemother 2004;48:2637-51. 

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39 
28. 
Popovich KJ, Weinstein RA, Hota B. Are community-associated methicillin-
resistant Staphylococcus aureus (S. AUREUS) strains replacing traditional nosocomial 
S. AUREUS strains? Clin Infect Dis 2008;46:787-94. 
29. 
Liu C, Graber CJ, Karr M, et al. A population-based study of the incidence and 
molecular epidemiology of methicillin-resistant Staphylococcus aureus disease in San 
Francisco, 2004-2005. Clin Infect Dis 2008;46:1637-46. 
30. 
Saiman L, O'Keefe M, Graham PL, 3rd, et al. Hospital transmission of 
community-acquired methicillin-resistant Staphylococcus aureus among postpartum 
women. Clin Infect Dis 2003;37:1313-9. 
31. 
Community-associated methicillin-resistant Staphylococcus aureus infection 
among healthy newborns--Chicago and Los Angeles County, 2004. MMWR Morb Mortal 
Wkly Rep 2006;55:329-32. 
32. 
Hulten KG, Kaplan SL, Lamberth LB, et al. Hospital-acquired Staphylococcus 
aureus infections at Texas Children's Hospital, 2001-2007. Infect Control Hosp 
Epidemiol 2010;31:183-90. 
33. 
Gonzalez BE, Rueda AM, Shelburne SA, 3rd, Musher DM, Hamill RJ, Hulten KG. 
Community-associated strains of methicillin-resistant Staphylococccus aureus as the 
cause of healthcare-associated infection. Infect Control Hosp Epidemiol 2006;27:1051-
6. 
34. 
Healy CM, Hulten KG, Palazzi DL, Campbell JR, Baker CJ. Emergence of new 
strains of methicillin-resistant Staphylococcus aureus in a neonatal intensive care unit. 
Clin Infect Dis 2004;39:1460-6. 
35. 
Boyce JM. Community-associated methicillin-resistant Staphylococcus aureus as 
a cause of health care-associated infection. Clin Infect Dis 2008;46:795-8. 
36. 
D'Agata EM, Webb GF, Horn MA, Moellering RC, Jr., Ruan S. Modeling the 
invasion of community-acquired methicillin-resistant Staphylococcus aureus into 
hospitals. Clin Infect Dis 2009;48:274-84. 
37. 
Diekema DJ, Richter SS, Heilmann KP, et al. Continued emergence of USA300 
methicillin-resistant Staphylococcus aureus in the United States: results from a 
nationwide surveillance study. Infect Control Hosp Epidemiol 2014;35:285-92. 
38. 
Otter JA, French GL. Nosocomial transmission of community-associated 
methicillin-resistant Staphylococcus aureus: an emerging threat. Lancet Infect Dis 
2006;6:753-5. 
39. 
Gerber JS, Coffin SE, Smathers SA, Zaoutis TE. Trends in the incidence of 
methicillin-resistant Staphylococcus aureus infection in children's hospitals in the United 
States. Clin Infect Dis 2009;49:65-71. 
40. 
Prager M, Wallace MA, Bommarito K, Olsen MA, Burnham CA, Warren DK. 
Prevalence of qacA/B among methicillin-resistant Staphylococcus aureus (S. AUREUS) 
isolates recovered from active surveillance cultures of the anterior nares in the setting of 
chlorhexidine bathing.  ID Week; 2014; Philadelphia, PA. 
41. 
Klein E, Smith DL, Laxminarayan R. Hospitalizations and deaths caused by 
methicillin-resistant Staphylococcus aureus, United States, 1999-2005. Emerg Infect Dis 
2007;13:1840-6. 

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42. 
Boyle-Vavra S, Ereshefsky B, Wang CC, Daum RS. Successful multiresistant 
community-associated methicillin-resistant Staphylococcus aureus lineage from Taipei, 
Taiwan, that carries either the novel Staphylococcal chromosome cassette mec 
(SCCmec) type VT or SCCmec type IV. J Clin Microbiol 2005;43:4719-30. 
43. 
Diep BA, Chambers HF, Graber CJ, et al. Emergence of multidrug-resistant, 
community-associated, methicillin-resistant Staphylococcus aureus clone USA300 in 
men who have sex with men. Ann Intern Med 2008;148:249-57. 
44. 
Han LL, McDougal LK, Gorwitz RJ, et al. High frequencies of clindamycin and 
tetracycline resistance in methicillin-resistant Staphylococcus aureus pulsed-field type 
USA300 isolates collected at a Boston ambulatory health center. J Clin Microbiol 
2007;45:1350-2. 
45. 
McDougal LK, Fosheim GE, Nicholson A, et al. Emergence of resistance among 
USA300 methicillin-resistant Staphylococcus aureus isolates causing invasive disease 
in the United States. Antimicrob Agents Chemother 2010;54:3804-11. 
46. 
Threat Report 2013. (Accessed 10/08/2013, at 
http://www.cdc.gov/drugresistance/threat-report-2013/.) 
47. 
Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant 
Staphylococcus aureus infections in the United States. JAMA 2007;298:1763-71. 
48. 
Lee BY, Singh A, David MZ, et al. The economic burden of community-
associated methicillin-resistant Staphylococcus aureus (CA-S. AUREUS). Clin Microbiol 
Infect 2013;19:528-36. 
49. 
Kallen AJ, Mu Y, Bulens S, et al. Health care-associated invasive S. AUREUS 
infections, 2005-2008. Jama 2010;304:641-8. 
50. 
Iwamoto M, Mu Y, Lynfield R, et al. Trends in invasive methicillin-resistant 
Staphylococcus aureus infections. Pediatrics 2013;132:e817-24. 
51. 
Herigon JC, Hersh AL, Gerber JS, Zaoutis TE, Newland JG. Antibiotic 
management of Staphylococcus aureus infections in US children's hospitals, 1999-
2008. Pediatrics 2010;125:e1294-300. 
52. 
Overview of Hospital Stays for Children in the United States, 2012. 2014. 
(Accessed January 29, 2015, at http://www.hcup-us.ahrq.gov/reports/statbriefs/sb187-
Hospital-Stays-Children-2012.jsp.) 
53. 
Chen AE, Cantey JB, Carroll KC, Ross T, Speser S, Siberry GK. Discordance 
between Staphylococcus aureus nasal colonization and skin infections in children. 
Pediatr Infect Dis J 2009;28:244-6. 
54. 
Duong M, Markwell S, Peter J, Barenkamp S. Randomized, controlled trial of 
antibiotics in the management of community-acquired skin abscesses in the pediatric 
patient. Ann Emerg Med 2010;55:401-7. 
55. 
Miller LG, Quan C, Shay A, et al. A prospective investigation of outcomes after 
hospital discharge for endemic, community-acquired methicillin-resistant and -
susceptible Staphylococcus aureus skin infection. Clin Infect Dis 2007;44:483-92. 
56. 
Tacconelli E. Antimicrobial use: risk driver of multidrug resistant microorganisms 
in healthcare settings. Curr Opin Infect Dis 2009;22:352-8. 

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57. 
Kluytmans J, van Belkum A, Verbrugh H. Nasal carriage of Staphylococcus 
aureus: epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev 
1997;10:505-20. 
58. 
Eveillard M, de Lassence A, Lancien E, Barnaud G, Ricard JD, Joly-Guillou ML. 
Evaluation of a strategy of screening multiple anatomical sites for methicillin-resistant 
Staphylococcus aureus at admission to a teaching hospital. Infect Control Hosp 
Epidemiol 2006;27:181-4. 
59. 
Buehlmann M, Frei R, Fenner L, Dangel M, Fluckiger U, Widmer AF. Highly 
effective regimen for decolonization of methicillin-resistant Staphylococcus aureus 
carriers. Infect Control Hosp Epidemiol 2008;29:510-6. 
60. 
Nilsson P, Ripa T. Staphylococcus aureus throat colonization is more frequent 
than colonization in the anterior nares. J Clin Microbiol 2006;44:3334-9. 
61. 
Faden H, Lesse AJ, Trask J, et al. Importance of colonization site in the current 
epidemic of staphylococcal skin abscesses. Pediatrics 2010;125:e618-24. 
62. 
Peters PJ, Brooks JT, Limbago B, et al. Methicillin-resistant Staphylococcus 
aureus colonization in HIV-infected outpatients is common and detection is enhanced 
by groin culture. Epidemiol Infect 2011;139:998-1008. 
63. 
Kaplan SL, Forbes A, Hammerman WA, et al. Randomized trial of "bleach baths" 
plus routine hygienic measures vs. routine hygienic measures alone for prevention of 
recurrent infections. Clin Infect Dis 2014;58:679-82. 
64. 
Fritz SA, Hogan PG, Hayek G, et al. Staphylococcus aureus colonization in 
children with community-associated Staphylococcus aureus skin infections and their 
household contacts. Arch Pediatr Adolesc Med 2012;166:551-7. 
65. 
von Eiff C, Becker K, Machka K, Stammer H, Peters G. Nasal carriage as a 
source of Staphylococcus aureus bacteremia. N Engl J Med 2001;344:11-6. 
66. 
Wertheim HF, Melles DC, Vos MC, et al. The role of nasal carriage in 
Staphylococcus aureus infections. Lancet Infect Dis 2005;5:751-62. 
67. 
Toshkova K, Annemuller C, Akineden O, Lammler C. The significance of nasal 
carriage of Staphylococcus aureus as risk factor for human skin infections. FEMS 
Microbiol Lett 2001;202:17-24. 
68. 
Davis KA, Stewart JJ, Crouch HK, Florez CE, Hospenthal DR. Methicillin-
resistant Staphylococcus aureus (S. AUREUS) nares colonization at hospital admission 
and its effect on subsequent S. AUREUS infection. Clin Infect Dis 2004;39:776-82. 
69. 
Ellis MW, Hospenthal DR, Dooley DP, Gray PJ, Murray CK. Natural history of 
community-acquired methicillin-resistant Staphylococcus aureus colonization and 
infection in soldiers. Clin Infect Dis 2004;39:971-9. 
70. 
Creech CB, 2nd, Kernodle DS, Alsentzer A, Wilson C, Edwards KM. Increasing 
rates of nasal carriage of methicillin-resistant Staphylococcus aureus in healthy 
children. Pediatr Infect Dis J 2005;24:617-21. 
71. 
Frazee BW, Lynn J, Charlebois ED, Lambert L, Lowery D, Perdreau-Remington 
F. High prevalence of methicillin-resistant Staphylococcus aureus in emergency 
department skin and soft tissue infections. Ann Emerg Med 2005;45:311-20. 

SHINE Trial  
Version 2.0 
HRPO # 201508155                                                                                                                                   1 August 2018 
_____________________________________________________________________________________________ 
 
 
 
42 
72. 
Whitman TJ, Herlihy RK, Schlett CD, et al. Chlorhexidine-impregnated cloths to 
prevent skin and soft-tissue infection in Marine recruits: a cluster-randomized, double-
blind, controlled effectiveness trial. Infect Control Hosp Epidemiol 2010;31:1207-15. 
73. 
Begier EM, Frenette K, Barrett NL, et al. A high-morbidity outbreak of methicillin-
resistant Staphylococcus aureus among players on a college football team, facilitated 
by cosmetic body shaving and turf burns. Clin Infect Dis 2004;39:1446-53. 
74. 
Turabelidze G, Lin M, Wolkoff B, Dodson D, Gladbach S, Zhu BP. Personal 
hygiene and methicillin-resistant Staphylococcus aureus infection. Emerg Infect Dis 
2006;12:422-7. 
75. 
Miller LG, Eells SJ, David MZ, et al. Staphylococcus aureus Skin Infection 
Recurrences Among Household Members: An Examination of Host, Behavioral, and 
Pathogen-Level Predictors. Clin Infect Dis 2014. 
76. 
Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant Staphylococcus 
aureus disease in three communities. N Engl J Med 2005;352:1436-44. 
77. 
King MD, Humphrey BJ, Wang YF, Kourbatova EV, Ray SM, Blumberg HM. 
Emergence of community-acquired methicillin-resistant Staphylococcus aureus USA 
300 clone as the predominant cause of skin and soft-tissue infections. Ann Intern Med 
2006;144:309-17. 
78. 
Bagger JP, Zindrou D, Taylor KM. Postoperative infection with meticillin-resistant 
Staphylococcus aureus and socioeconomic background. Lancet 2004;363:706-8. 
79. 
Eady EA, Cove JH. Staphylococcal resistance revisited: community-acquired 
methicillin resistant Staphylococcus aureus--an emerging problem for the management 
of skin and soft tissue infections. Curr Opin Infect Dis 2003;16:103-24. 
80. 
Charlebois ED, Bangsberg DR, Moss NJ, et al. Population-based community 
prevalence of methicillin-resistant Staphylococcus aureus in the urban poor of San 
Francisco. Clin Infect Dis 2002;34:425-33. 
81. 
Hudson LO, Murphy CR, Spratt BG, et al. Differences in methicillin-resistant 
Staphylococcus aureus strains isolated from pediatric and adult patients from hospitals 
in a large county in California. J Clin Microbiol 2012;50:573-9. 
82. 
Osterlund A, Kahlmeter G, Bieber L, Runehagen A, Breider JM. Intrafamilial 
spread of highly virulent Staphylococcus aureus strains carrying the gene for Panton-
Valentine leukocidin. Scandinavian Journal of Infectious Diseases 2002;34:763-4. 
83. 
Jones TF, Creech CB, Erwin P, Baird SG, Woron AM, Schaffner W. Family 
outbreaks of invasive community-associated methicillin-resistant Staphylococcus 
aureus infection. Clin Infect Dis 2006;42:e76-8. 
84. 
L'Heriteau F, Lucet JC, Scanvic A, Bouvet E. Community-acquired methicillin-
resistant Staphylococcus aureus and familial transmission. Jama 1999;282:1038-9. 
85. 
Dietrich DW, Auld DB, Mermel LA. Community-acquired methicillin-resistant 
Staphylococcus aureus in southern New England children. Pediatrics 2004;113:e347-
52. 
86. 
Hollis RJ, Barr JL, Doebbeling BN, Pfaller MA, Wenzel RP. Familial carriage of 
methicillin-resistant Staphylococcus aureus and subsequent infection in a premature 
neonate. Clin Infect Dis 1995;21:328-32. 

SHINE Trial  
Version 2.0 
HRPO # 201508155                                                                                                                                   1 August 2018 
_____________________________________________________________________________________________ 
 
 
 
43 
87. 
Huijsdens XW, van Santen-Verheuvel MG, Spalburg E, et al. Multiple cases of 
familial transmission of community-acquired methicillin-resistant Staphylococcus 
aureus. J Clin Microbiol 2006;44:2994-6. 
88. 
Nerby JM, Gorwitz R, Lesher L, et al. Risk Factors for Household Transmission 
of Community-associated Methicillin-resistant Staphylococcus aureus. Pediatr Infect Dis 
J 2011. 
89. 
Mollema FP, Richardus JH, Behrendt M, et al. Transmission of methicillin-
resistant Staphylococcus aureus to household contacts. J Clin Microbiol 2010;48:202-7. 
90. 
Fritz SA, Hogan PG, Singh LN, et al. Contamination of environmental surfaces 
with Staphylococcus aureus in households with children infected with methicillin-
resistant S aureus. JAMA pediatrics 2014;168:1030-8. 
91. 
Uhlemann AC, Knox J, Miller M, et al. The environment as an unrecognized 
reservoir for community-associated methicillin resistant Staphylococcus aureus 
USA300: a case-control study. PLoS ONE 2011;6:e22407. 
92. 
Knox J, Uhlemann AC, Miller M, et al. Environmental contamination as a risk 
factor for intra-household Staphylococcus aureus transmission. PLoS ONE 
2012;7:e49900. 
93. 
Davis MF, Iverson SA, Baron P, et al. Household transmission of meticillin-
resistant Staphylococcus aureus and other staphylococci. Lancet Infect Dis 
2012;12:703-16. 
94. 
Johansson PJ, Gustafsson EB, Ringberg H. High prevalence of S. AUREUS in 
household contacts. Scand J Infect Dis 2007;39:764-8. 
95. 
Huang YC, Ho CF, Chen CJ, Su LH, Lin TY. Nasal carriage of methicillin-
resistant Staphylococcus aureus in household contacts of children with community-
acquired diseases in Taiwan. Pediatr Infect Dis J 2007;26:1066-8. 
96. 
Eells SJ, David MZ, Taylor A, et al. Persistent environmental contamination with 
USA300 methicillin-resistant Staphylococcus aureus and other pathogenic strain types 
in households with S. aureus skin infections. Infect Control Hosp Epidemiol 
2014;35:1373-82. 
97. 
Hanselman BA, Kruth SA, Rousseau J, et al. Methicillin-resistant Staphylococcus 
aureus colonization in veterinary personnel. Emerg Infect Dis 2006;12:1933-8. 
98. 
Weese JS, Dick H, Willey BM, et al. Suspected transmission of methicillin-
resistant Staphylococcus aureus between domestic pets and humans in veterinary 
clinics and in the household. Vet Microbiol 2006;115:148-55. 
99. 
Rutland BE, Weese JS, Bolin C, Au J, Malani AN. Human-to-dog transmission of 
methicillin-resistant Staphylococcus aureus. Emerg Infect Dis 2009;15:1328-30. 
100. Manian FA. Asymptomatic nasal carriage of mupirocin-resistant, methicillin-
resistant Staphylococcus aureus (S. AUREUS) in a pet dog associated with S. 
AUREUS infection in household contacts. Clin Infect Dis 2003;36:e26-8. 
101. van Duijkeren E, Wolfhagen MJ, Box AT, Heck ME, Wannet WJ, Fluit AC. 
Human-to-dog transmission of methicillin-resistant Staphylococcus aureus. Emerg 
Infect Dis 2004;10:2235-7. 

SHINE Trial  
Version 2.0 
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_____________________________________________________________________________________________ 
 
 
 
44 
102. van Duijkeren E, Wolfhagen MJ, Heck ME, Wannet WJ. Transmission of a 
Panton-Valentine leucocidin-positive, methicillin-resistant Staphylococcus aureus strain 
between humans and a dog. J Clin Microbiol 2005;43:6209-11. 
103. Boost MV, O'Donoghue MM, James A. Prevalence of Staphylococcus aureus 
carriage among dogs and their owners. Epidemiol Infect 2008;136:953-64. 
104. Scott E, Duty S, McCue K. A critical evaluation of methicillin-resistant 
Staphylococcus aureus and other bacteria of medical interest on commonly touched 
household surfaces in relation to household demographics. Am J Infect Control 
2009;37:447-53. 
105. Hardy KJ, Oppenheim BA, Gossain S, Gao F, Hawkey PM. A study of the 
relationship between environmental contamination with methicillin-resistant 
Staphylococcus aureus (S. AUREUS) and patients' acquisition of S. AUREUS. Infect 
Control Hosp Epidemiol 2006;27:127-32. 
106. Milstone AM. Uncovering reservoirs of methicillin-resistant Staphylococcus 
aureus: children contaminating households or households contaminating children? 
JAMA pediatrics 2014;168:994-5. 
107. Weber DJ, Rutala WA. Understanding and preventing transmission of 
healthcare-associated pathogens due to the contaminated hospital environment. Infect 
Control Hosp Epidemiol 2013;34:449-52. 
108. Boyce JM. Environmental contamination makes an important contribution to 
hospital infection. J Hosp Infect 2007;65 Suppl 2:50-4. 
109. Bright KR, Boone SA, Gerba CP. Occurrence of bacteria and viruses on 
elementary classroom surfaces and the potential role of classroom hygiene in the 
spread of infectious diseases. J Sch Nurs 2010;26:33-41. 
110. Carling PC, Huang SS. Improving healthcare environmental cleaning and 
disinfection: current and evolving issues. Infect Control Hosp Epidemiol 2013;34:507-
13. 
111. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious 
diseases society of america for the treatment of methicillin-resistant Staphylococcus 
aureus infections in adults and children. Clin Infect Dis 2011;52:e18-55. 
112. Gorwitz RJ, Jernigan DB, Powers JH, Jernigan JA, Participants in the CDC-
Convened Experts' Meeting on Management of S. AUREUS in the Community. 
Strategies for clinical management of S. AUREUS in the community: Summary of an 
experts' meeting convened by the Centers for Disease Control and Prevention. 2006. 
113. Creech CB, Beekmann SE, Chen Y, Polgreen PM. Variability among pediatric 
infectious diseases specialists in the treatment and prevention of methicillin-resistant 
Staphylococcus aureus skin and soft tissue infections. Pediatr Infect Dis J 2008;27:270-
2. 
114. Laupland KB, Conly JM. Treatment of Staphylococcus aureus colonization and 
prophylaxis for infection with topical intranasal mupirocin: an evidence-based review. 
Clin Infect Dis 2003;37:933-8. 
115. Perl TM, Cullen JJ, Wenzel RP, et al. Intranasal mupirocin to prevent 
postoperative Staphylococcus aureus infections. N Engl J Med 2002;346:1871-7. 

SHINE Trial  
Version 2.0 
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_____________________________________________________________________________________________ 
 
 
 
45 
116. Chen SF. Staphylococcus aureus decolonization. Pediatr Infect Dis J 
2005;24:79-80. 
117. Sandri AM, Dalarosa MG, Ruschel de Alcantara L, da Silva Elias L, Zavascki AP. 
Reduction in incidence of nosocomial methicillin-resistant Staphylococcus aureus (S. 
AUREUS) infection in an intensive care unit: role of treatment with mupirocin ointment 
and chlorhexidine baths for nasal carriers of S. AUREUS. Infect Control Hosp Epidemiol 
2006;27:185-7. 
118. Tacconelli E, Carmeli Y, Aizer A, Ferreira G, Foreman MG, D'Agata EM. 
Mupirocin prophylaxis to prevent Staphylococcus aureus infection in patients 
undergoing dialysis: a meta-analysis. Clin Infect Dis 2003;37:1629-38. 
119. Ellis MW, Griffith ME, Dooley DP, et al. Targeted intranasal mupirocin to prevent 
colonization and infection by community-associated methicillin-resistant Staphylococcus 
aureus strains in soldiers: a cluster randomized controlled trial. Antimicrob Agents 
Chemother 2007;51:3591-8. 
120. Climo MW, Yokoe DS, Warren DK, et al. Effect of daily chlorhexidine bathing on 
hospital-acquired infection. N Engl J Med 2013;368:533-42. 
121. Patel JB, Gorwitz RJ, Jernigan JA. Mupirocin resistance. Clin Infect Dis 
2009;49:935-41. 
122. McDonnell G, Russell AD. Antiseptics and disinfectants: activity, action, and 
resistance. Clin Microbiol Rev 1999;12:147-79. 
123. Mayer S, Boos M, Beyer A, Fluit AC, Schmitz FJ. Distribution of the antiseptic 
resistance genes qacA, qacB and qacC in 497 methicillin-resistant and -susceptible 
European isolates of Staphylococcus aureus. J Antimicrob Chemother 2001;47:896-7. 
124. Lee AS, Macedo-Vinas M, Francois P, et al. Impact of combined low-level 
mupirocin and genotypic chlorhexidine resistance on persistent methicillin-resistant 
Staphylococcus aureus carriage after decolonization therapy: a case-control study. Clin 
Infect Dis 2011;52:1422-30. 
125. McNeil JC, Hulten KG, Kaplan SL, Mason EO. Mupirocin resistance in 
Staphylococcus aureus causing recurrent skin and soft tissue infections in children. 
Antimicrob Agents Chemother 2011;55:2431-3. 
126. Cadilla A, David MZ, Daum RS, Boyle-Vavra S. Association of high-level 
mupirocin resistance and multidrug-resistant methicillin-resistant Staphylococcus 
aureus at an academic center in the midwestern United States. J Clin Microbiol 
2011;49:95-100. 
127. Sheng WH, Wang JT, Lauderdale TL, Weng CM, Chen D, Chang SC. 
Epidemiology and susceptibilities of methicillin-resistant Staphylococcus aureus in 
Taiwan: emphasis on chlorhexidine susceptibility. Diagn Microbiol Infect Dis 
2009;63:309-13. 
128. McNeil JC, Hulten KG, Kaplan SL, Mason EO. Decreased susceptibilities to 
Retapamulin, Mupirocin, and Chlorhexidine among Staphylococcus aureus isolates 
causing skin and soft tissue infections in otherwise healthy children. Antimicrob Agents 
Chemother 2014;58:2878-83. 

SHINE Trial  
Version 2.0 
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_____________________________________________________________________________________________ 
 
 
 
46 
129. Robicsek A, Beaumont JL, Thomson RB, Jr., Govindarajan G, Peterson LR. 
Topical therapy for methicillin-resistant Staphylococcus aureus colonization: impact on 
infection risk. Infect Control Hosp Epidemiol 2009;30:623-32. 
130. Simor AE, Phillips E, McGeer A, et al. Randomized controlled trial of 
chlorhexidine gluconate for washing, intranasal mupirocin, and rifampin and doxycycline 
versus no treatment for the eradication of methicillin-resistant Staphylococcus aureus 
colonization. Clin Infect Dis 2007;44:178-85. 
131. Upton A, Lang S, Heffernan H. Mupirocin and Staphylococcus aureus: a recent 
paradigm of emerging antibiotic resistance. J Antimicrob Chemother 2003;51:613-7. 
132. Conly JM, Johnston BL. Mupirocin - Are we in danger of losing it? Can J Infect 
Dis 2002;13:157-9. 
133. Miller MA, Dascal A, Portnoy J, Mendelson J. Development of mupirocin 
resistance among methicillin-resistant Staphylococcus aureus after widespread use of 
nasal mupirocin ointment. Infect Control Hosp Epidemiol 1996;17:811-3. 
134. Vasquez JE, Walker ES, Franzus BW, Overbay BK, Reagan DR, Sarubbi FA. 
The epidemiology of mupirocin resistance among methicillin-resistant Staphylococcus 
aureus at a Veterans' Affairs hospital. Infect Control Hosp Epidemiol 2000;21:459-64. 
135. Annigeri R, Conly J, Vas S, et al. Emergence of mupirocin-resistant 
Staphylococcus aureus in chronic peritoneal dialysis patients using mupirocin 
prophylaxis to prevent exit-site infection. Perit Dial Int 2001;21:554-9. 
136. Perez-Fontan M, Rosales M, Rodriguez-Carmona A, Falcon TG, Valdes F. 
Mupirocin resistance after long-term use for Staphylococcus aureus colonization in 
patients undergoing chronic peritoneal dialysis. American journal of kidney diseases : 
the official journal of the National Kidney Foundation 2002;39:337-41. 
137. Raz R, Miron D, Colodner R, Staler Z, Samara Z, Keness Y. A 1-year trial of 
nasal mupirocin in the prevention of recurrent staphylococcal nasal colonization and 
skin infection. Arch Intern Med 1996;156:1109-12. 
138. Milstone AM, Elward A, Song X, et al. Daily chlorhexidine bathing to reduce 
bacteraemia in critically ill children: a multicentre, cluster-randomised, crossover trial. 
Lancet 2013;381:1099-106. 
139. Clinical and Laboratory Standards Institute. Performance Standards for 
Antimicrobial Susceptibility Testing; Twenty-Second Informational Supplement. 2012; 
Wayne, PA: Clinical and Laboratory Standards Institute. 
140. Lewis JS, 2nd, Jorgensen JH. Inducible clindamycin resistance in Staphylococci: 
should clinicians and microbiologists be concerned? Clin Infect Dis 2005;40:280-5. 
141. Boye K, Bartels MD, Andersen IS, Moller JA, Westh H. A new multiplex PCR for 
easy screening of methicillin-resistant Staphylococcus aureus SCCmec types I-V. Clin 
Microbiol Infect 2007;13:725-7. 
142. Zhang K, Sparling J, Chow BL, et al. New quadriplex PCR assay for detection of 
methicillin and mupirocin resistance and simultaneous discrimination of Staphylococcus 
aureus from coagulase-negative staphylococci. J Clin Microbiol 2004;42:4947-55.