Skin and Soft Tissue Infections

Military personnel, particularly trainees and deployed service members, are at increased risk for developing skin and soft-tissue infections (SSTIs), which are most frequently caused by Staphylococcus aureus. As these infections impose a substantial operational and healthcare utilization burden, SSTIs are a top concern of the Military Health System.

Research Area Description 

Due to the high infectious disease burden associated with SSTIs, the overall objective of the research area is to determine effective strategies for the prevention and control of SSTIs in military populations. Among congregate populations, such as military trainees and deployed populations, SSTIs are largely caused by Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), and, as such, IDCRP prevention strategies and associated epidemiologic studies primarily focus on this pathogen.

In January 2018, we initiated a Phase 2 trial of a S. aureus vaccine candidate (NDV-3A; NovaDigm Therapeutics, LLC), led by LTC Jason Bennett (USU), among U.S. Army Infantry trainees at Fort Benning, GA, to evaluate the safety, immunogenicity, and efficacy of vaccination against nasal acquisition of S. aureus. Funded through the U.S. Army Medical Materiel Development Activity, this study is a significant achievement as it is the first S. aureus vaccine trial to be conducted in a high-risk population of military trainees. Use of a vaccine to inhibit S. aureus colonization would be momentous in furthering the development of strategies related to the prevention of SSTIs in military populations.

In addition to the vaccine trial, the SSTI Research Area, led by Dr. Eugene Millar, has a broad portfolio of observational research studies (led by LTC Bennett and Dr. Millar), which strengthen the evidence base of SSTI and S. aureus epidemiology, risk factors, clinical characteristics, immunology, and microbial genomics. In 2018, the Submarine MRSA Studyfound a moderate level of S. aureus colonization among U.S. Navy submariners at Kings Bay, GA; however, the prevalence of MRSA was low and no cases of SSTIs occurred during the deployment period. This negative study was important to allay Command concerns regarding this pathogen.

The genomic epidemiology of S. aureus infection and colonization  is also a focus of multiple studies. As part of the SSTI Cohort Study at Fort Benning, longitudinal data on the transmission, acquisition, and natural history of SSTIs, including MRSA SSTIs, were collected from military trainees. Through a collaboration with the Harvard School of Public Health, whole genome sequencing is being applied to examine the dynamics of MRSA transmission in the study population. Genomic methods are also being applied in the analysis of specimens from the Epidemiology, Etiology, and Immunology of SSTI study. In particular, MRSA colonization isolates were assessed in collaboration with the Naval Medical Research Center (NMRC) Biological Defense Research Directorate and methicillin-susceptible S. aureus infection isolates are being examined by Walter Reed Army Institute of Research (WRAIR) Multidrug-Resistant Organism Repository and Surveillance Network (MRSN). Furthermore, through a new collaboration with the Johns Hopkins Applied Physics Laboratory, whole genome sequencing of S. aureus isolates from individuals with recurrent S. aureus SSTIs was conducted, using specimens from the SSTI Epidemiology study and the SSTI Prevention Trial. Finally, investigators in the Department of Microbiology and Immunology at USU are examining characteristics of the host microbiome, namely longitudinal changes in microbiome and its association with infection risk.

Enrollment and follow-up activities for the Phase 2 S. aureus vaccine trial at Fort Benning will be completed by June 2019. The processing of immunology and microbiome specimens collected from the prior cohort studies is nearing completion and analyses are planned for the upcoming year. New initiatives related to the genomic and proteomic characterization of S. aureus clinical and colonizing isolates are also underway.

Key Studies

IDCRP-001: Chlorhexidine Impregnated Cloths to Prevent Skin and Soft Tissue Infections in Marine Officer Candidates: A Randomized, Double-Blind, Placebo-Controlled Trial

IDCRP-035:  Evaluate the safety and immunogenicity of Staphylococcus aureus toxoid (rAT and rLuKS-PVL)

IDCRP-055: Evaluating strategies to prevent methicillin-resistant Staphylococcus aureus skin and soft tissue infections in military trainees at Fort Benning, Georgia

IDCRP-066: The disease and cost burden of SSTIs and MRSA-associated SSTIs in the U.S. Army Active Duty Training Population

IDCRP-068: Evaluation of the Prevalence of Staphylococcus aureus Colonization and Risk Factors for Infection among Naval Personnel in a Deployment Setting: a pilot study

IDCRP-074: Skin and soft-tissue infection in military trainees: epidemiology and economic burden of disease

IDCRP-090: Natural history of Staphylococcus aureus colonization, infection, and immune response in military trainees

IDCRP-104: A phase 2 double-blind placebo-controlled study to evaluate the safety, immunogenicity and efficacy of NDV-3A vaccine in preventing S. aureus colonization

Military Impact

Substantial operational, healthcare, and economic costs are associated with the burden of SSTI in military populations.  Efforts under this research area support the development of preventive efforts by (1) generating epidemiological, clinical, immunological, microbiological, and genomic data related to SSTIs associated with S. aureus and other etiologic agents; (2) detailing the epidemiological and economic burden of SSTI in military training setting; (3) assessing the effectiveness of personal hygiene-based efforts  on other common communicable diseases, such as acute respiratory infections; (4) examining transmission dynamics of MRSA in SSTI clusters among trainees; and (5) securing funding to conduct S. aureus vaccine trial among military trainees.

Highlights / Key Findings

  • In a Phase 2 S. aureus vaccine trial at Fort Benning, GA, more than 50% of the target population of U.S. Army Infantry trainees were enrolled.. Future interventional trials in the high-risk military training population will benefit from the successful execution of this current trial.

  • Among U.S. Navy submariners, 25% were nasally colonized with S. aureus prior to deployment and 13% were colonized at a post-deployment visit. Prevalence of MRSA was <1% and no SSTIs were identified.

  • Molecular genomics studies found that intrahost reservoirs are common among individuals with recurrent S. aureus SSTIs, which indicate that host decolonization strategies after the initial infection may be necessary to reduce the risk of recurrence.

  • Methicillin-susceptible S. aureus (MSSA) contributes ~40% of S. aureus-associated SSTIs and the majority of colonizing isolates. Genomic characterization of MSSA isolates will advance our understanding of the epidemiology and pathogenesis of these infections.

Partners and Collaborators

IDCRP efforts in the field of SSTI have addressed numerous aspects of SSTI, especially MRSA SSTI, ranging from epidemiology to prevention studies. These research efforts have led to collaborations with Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), the Global Emerging Infections Surveillance (GEIS), Nabi Biopharmaceuticals, Naval Medical Research Center (NMRC), USUHS (Microbiology), Fort Benning (Martin Army Community Hospital), and on submarines.

Publications  2019

Millar EV, Rice GK, Schlett CD, Elassal EM, Cer RZ, Frey KG, Hamilton T, Ellis MW, Tribble DR, Bishop-Lilly KA, Bennett JW. Genomic epidemiology of MRSA infection and colonization isolates among military trainees with skin and soft
tissue infection
. Infection. 2019 Feb 22.

Publications  2018

LaBreck PT, Rice GK, Paskey AC, Elassal EM, Cer RZ, Law NN, Schlett CD, Bennett JW, Millar EV, Ellis MW, Hamilton T, Bishop-Lilly KA, Merrell DS. Conjugative Transfer of a Novel Staphylococcal Plasmid Encoding the Biocide Resistance Gene, qacA. Front Microbiol. 2018 Nov 19;9:2664.

Millar EV, St Clair KJ, Schlett CD, Bennett JW, Virgilio GR, Kronmann KC, Lalani T. Brief report: Pre- and post-deployment prevalence of Staphylococcus aureus colonization among U.S. Navy submariners. MSMR. 2018 Aug;25(8):5-7.

Publications  2017

Millar EV, Rice GK, Elassal EM, et al. Genomic Characterization of USA300 MRSA to Evaluate Intraclass Transmission and Recurrence of SSTI among High Risk Military Trainees. Clinical Infectious Diseases. 2017;65(3):461-468.

Presentations 2017 

Military Health System Research Symposium, August 27-30, Kissimmee, FL

Oral Presentation: Millar EV, Rice GK, Elassal EM, Schlett CD, Bennett JW, Redden CL, Mor D, Law NN, Tribble DR, Hamilton T, Ellis MW, Bishop-Lilly KA. Genomic Characterization of USA300 MRSA to Evaluate Intraclass Transmission and Recurrence of SSTI among High Risk Military Trainees.

ID Week, October 3-7, San Diego, CA

Poster #265:  Schlett CD, Millar EV, Elassal EM, Law NN, Lyles DT, Hadley A, Dowlen S, Hardge D, Ellis MW, Bennett JW. Dynamics of S. aureus acquisition and colonization in a military training environment.

Publications  2016

Johnson RC, Ellis MW, Schlett CD, et al. Bacterial Etiology and Risk Factors Associated with Cellulitis and Purulent Skin Abscesses in Military Trainees. PLoS One. 2016 Oct 25;11(10):e0165491.

Singh J, Johnson RC, Schlett CD, et al. Multi-Body-Site Microbiome and Culture Profiling of Military Trainees Suffering from Skin and Soft Tissue Infections at Fort Benning, Georgia. mSphere. 2016 Oct 5;1(5):e00232.

Publications 2014

Ellis MW, Schlett CD, Millar EV, et al. Prevalence of nasal colonization and strain concordance in patients with community-associated Staphylococcus aureus skin and soft-tissue infectionsInfection Control and Hospital Epidemiology. 2014; 35(10):1251-1256. 

Schlett CD, Millar EV, Crawford KB, et al. Prevalence of chlorhexidine-resistant methicillin-resistant Staphylococcus aureus following prolonged exposureAntimicrobial Agents and Chemotherapy. 2014; 58(8):4404-4410. 

Ellis MW, Schlett CD, Millar EV, et al. Hygiene strategies to prevent methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: A cluster-randomized controlled trial among high-risk military traineesClinical Infectious Diseases. 2014; 51(11):1540-1548.

Ellis MW, Johnson R, Crawford KB, et al. Molecular characterization of a catalase-negative methicillin-susceptible Staphylococcus aureus subsp. aureus strain collected from a patient with cutaneous abscess. Journal of Clinical Microbiology. 2014; 52(1):344-346.

Johnson R, Ellis MW, Lanier JB, et al.  Correlation between nasal microbiome composition and remote purulent skin and soft tissue infectionsInfection and Immunity. 2015; 83(2):802-811.

D’Onofrio MJ, Schlett CD, Millar EV, et al. Reduction in acute gastroenteritis among military trainees: Secondary effects of a hygiene-based cluster-randomized trial for skin and soft tissue infection prevention. Infection Control and Hospital Epidemiology. In Press. doi: 10.1017/ice.2014.65.

Millar EV, Chen W, Schlett CD, et al.  Frequent use of chlorhexidine-based body wash associated with a reduction in methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization among military trainees. Clinical Infectious Diseases. In Press. doi: 10.1128/AAC.03993-14.

Heaton SM, Weintrob AC, Downing K, Keenan B, Aggarwal D, Shaikh F, Tribble DR, Wells J, and the IDCRP TIDOS Group. Histopathological Techniques for the Diagnosis of Combat-Related Invasive Fungal Wound Infections. BMC Clinical Pathology. 2016; 16:11.

Presentations 2014

Ellis MW, Schlett CD, Cui T, et al. Epidemiology of skin and soft-tissue infections in US Army trainees at Fort Benning. ID Week, A Joint Meeting of IDSA, SHEA, HIVMA, and PIDS, 8-12 October 2014, Philadelphia, PA.

Ellis MW, Chen W, Millar EV, et al. Routine use of chlorhexidine-based body wash associated with a reduction in methicillin-resistant Staphylococcus aureus nasal colonization among military trainees.  ID Week, A Joint Meeting of IDSA, SHEA, HIVMA, and PIDS, 8-12 October 2014, Philadelphia, PA.

D’Onofrio MJ, Schlett CD, Millar EV, et al. Reduction in acute gastrointestinal infection among military trainees: Secondary effects of a hygiene-based cluster-randomized trial for SSTI prevention.  ID Week, A Joint Meeting of IDSA, SHEA, HIVMA, and PIDS, 8-12 October 2014, Philadelphia, PA.

Ellis MW, Lanier JB, Schlett CD, et al. Combating Staphylococcal skin and soft-tissue infections in trainees at Fort Benning.  Military Health System Research Symposium, 18-21 August 2014, Fort Lauderdale, FL.

Ellis MW, Schlett CD, Millar EV, et al. Epidemiology of skin and soft-tissue infections in trainees at Fort Benning.  Military Health System Research Symposium, 18-21 August 2014, Fort Lauderdale, FL.

Johnson R, Lanier JB, Schlett CD, et al.  Impact of the nasal microbiome on the development of Staphylococcal skin and soft-tissue infections at Fort Benning.  114th General Meeting of the American Society for Microbiology, 17-20 May 2014, Boston, MA; and Military Health System Research Symposium, 18-21 August 2014, Fort Lauderdale, FL.

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