Wound infections impose significant health and financial burden on the military during wartime. Peacetime impact continues most evident during recruit training, where the risk of community-associated skin and soft-tissue infections (SSTIs) from Staphylococcus aureus is high. The management of these infections are further complicated by the increasing threat of multidrug-resistant strains, as well as the emergence of novel microbial threats, such as invasive filamentous fungi. Improving the prevention and clinical management of militarily-relevant wound infections continues to be a high priority of the Military Health System (MHS) research enterprise.
In January 2020, the Skin and Soft-tissue Infections and Trauma-Related Infections Research Areas merged to form the Wound Infections Research Area, which is focused primarily on the epidemiology, treatment, and prevention of wound infections impacting service members during training or deployment. The overall vision of the research area is to reduce the short- and long-term impact of wound infections among military personnel through improved evidence-based clinical practice guidance and the determination of effective strategies for prevention and treatment.
With regards to battlefield wound infections, one of the central protocols of the research area is the Trauma Infectious Disease Outcomes Study (TIDOS), which is led by Dr. David Tribble. From June 2009 through December 2014, TIDOS systematically collected information on the medical and surgical management, microbiology, and infectious outcomes from military personnel wounded during deployment. For patients who enrolled in the TIDOS cohort, information on trauma-related infections diagnosed after hospital discharge continues to be investigated. For cohort enrollees who left military service and entered Veterans Affairs (VA) health care, information was collected through our collaboration with the VA St. Louis Health Care System (led by Dr. Jay McDonald), which included mental and social health factors (e.g., depression, post-traumatic stress disorder, and opioid use).
The Department of Defense (DoD) Blast Injury Research Program Coordinating Office highlighted the TIDOS project and the impact for the DoD in the 2018 Annual Report to the DoD Executive Agent. Extremity trauma, often involving severe polytrauma due to blasts, is the most frequent type of battlefield injury and remains a focus of multiple analyses through the research area. TIDOS analyses are examining effectiveness of specific antimicrobial regimens related to the treatment of deep soft-tissue infections is nearing completion. These findings, coupled with literature review, will support future guidance on treatment.
Invasive fungal wounds infections (IFIs) are associated with substantial morbidity among blast casualties and effective management and improved clinical outcomes are dependent on early diagnosis. As a follow-on to the assessment of a polymerase chain reaction (PCR)-based diagnostic assay for IFI identification, led by Dr. Anuradha Ganesan, additional evaluation is underway to support applications of the PCR-based assay in future conflicts. Furthermore, comprehensive examination of patients with laboratory evidence of a fungus isolated from wounds led to the development of a refined IFI classification based on degree of certainty of diagnosis (i.e., IFI, High Suspicion of IFI, and Low Suspicion of IFI). This classification scheme provides a framework to support clinical decision making and reduce practice variation.
Although not as frequent as battlefield orthopedic injuries, non-extremity wound infections are also being assessed. One recent analysis examined risk factors for abdominal surgical site infections among trauma patients who underwent downrange exploratory laparotomy. Analyses to examine infectious complications following pelvic fractures and penetrating central nervous system injuries are in development.
Community-associated SSTIs impose a substantial healthcare and operational burden, and, as such, identifying effective strategies for the prevention and control of these infections in the military is crucial. A major accomplishment in 2019 was the completion of a Phase 2 trial of a S. aureus vaccine candidate (NDV-3A; NovaDigm Therapeutics, LLC), which was funded through the U.S. Army Medical Materiel Development Activity. Led by COL Jason Bennett (WRAIR), the safety, immunogenicity, and efficacy of the vaccine candidate against nasal acquisition of S. aureus was evaluated among U.S. Army Infantry trainees at Fort Benning, GA. Not only does this represent an advance for the first S. aureus vaccine candidate with a targeted indication for SSTI prevention, the success of the trial also demonstrated that investigational product trials can be conducted in the highly structured and regimented framework of the military training setting.
Another significant achievement over the past year was the successful leveraging of the vast number of isolates collected through observational studies at Fort Benning (led by Dr. Eugene Millar).These microbiological analyses have focused on the genomic characterization of S. aureus isolates, both methicillin-resistant (MRSA) and methicillin-susceptible (MSSA), and have greatly expanded our collaborative relationships. As one example, in collaboration with the Johns Hopkins Applied Physics Laboratory, whole genome sequencing of colonizing and infecting S. aureus isolates collected through the SSTI Epidemiology and the SSTI Prevention Trial indicated that intra-host reservoirs are common among those with recurrent SSTIs, suggesting that targeted decolonization after initial infections may be beneficial. Through collaboration with the Harvard T.H. Chan School of Public Health, whole genome sequencing was utilized to describe MRSA transmission dynamics and the relatedness of MRSA colonization and infection strains. As part of a collaboration with the Naval Medical Research Center (NMRC) Biological Defense Research Directorate, assessment of the genomics of MRSA isolates collected through the Epidemiology, Etiology, and Immunology of SSTI study indicated an epidemiologic link between MRSA colonization and purulent infections. Examination of the genomics of MSSA isolates (contributes ~40% of S. aureus SSTIs) is also underway in collaboration with the Walter Reed Army Institute of Research (WRAIR) Multidrug-Resistant Organism Repository and Surveillance Network.
The assessment of the human microbiome is another focus for community-associated SSTI research. Leveraging isolates collected through the SSTI Cohort Study, two analyses in collaboration with the USU Department of Microbiology are underway to evaluate the host microbiome among trainees with and without S. aureus SSTIs and examine host microbiome changes among individuals in a congregate setting. In collaboration with Johns Hopkins Applied Physics Laboratory, host microbiome changes following receipt of Bicillin as prophylaxis against Group A streptococcal disease among military trainees are being assessed.
During 2019, analyses also continued under the TIDOS Multidrug-Resistant and Virulent Organisms (MDR/VO) Trauma Infections initiative, which is led by Dr. Katrin Mende and involves a collaborative effort across multiple DoD laboratories (WRAIR, NMRC, U.S. Army Institute of Surgical Research, and Brooke Army Medical Center) to maximize the understanding of complex polymicrobial wounds using clinical data from TIDOS connected to isolates in the TIDOS Microbiological Specimen Repository. Ongoing analyses will further examine the interaction of common wound bacteria, as well as assess clinical outcomes with regards to wound microbiology and biofilm formation.
Military Impact
The research area’s aims and objectives continue to be responsive to priorities of the DoD Joint Trauma System and MHS. Analyses on battlefield wound infections provide essential information during inter-war periods to improve the understanding and best practices of infection-related issues following battlefield injury. In addition, investigations conducted through the research area have assessed community-associated SSTI epidemiology and evaluated strategies to prevent SSTIs in high-risk military populations. Overall, the strengths and opportunities presented by this research area present a robust platform to support development and refinement of evidence-based clinical practice guidelines for the management of militarily-relevant wound infections.
Highlights / Key Findings
- The Phase 2 S. aureus NDV-3A vaccine trial at Fort Benning, GA, vaccinated 382 U.S. Army Infantry trainees with 352 completing follow-up. Processing of specimens for microbiology and immunologic evaluation was completed. Future interventional trials in high-risk military training populations will benefit from the lessons learned in the successful execution of this trial.
- Genomic characterization of MRSA colonizing and infecting isolates collected from military trainees with purulent SSTIs indicated a high degree of strain relatedness. Limited intra-host diversity also suggests that persistent colonization may contribute to risk of recurrent infections.
- Collaboration with investigators in the USU Department of Microbiology and Immunology determined that S. aureus, as well as Staphylococcus epidermidis, were able to acquire resistance to antiseptics/biocides (e.g., chlorhexidine) via transfer of conjugate plasmids containing biocide-resistance genes (e.g., qacA).
- Among battlefield trauma patients who received vancomycin plus piperacillin-tazobactam combination therapy, 13% met criteria for acute kidney injury (relative risk: 1.73; 95% confidence interval: 1.03-2.77) compared to 9.7% among patients who received vancomycin plus other broad-spectrum beta-lactam antibiotics. Nevertheless, acute kidney injury severity was low, the duration was generally short-lived, and nearly all of the patients had a return to baseline renal function.
- Review of characteristics of patients who had fungi isolated from wounds resulted in a revised IFI classification scheme based on level of suspicion (IFI, High Suspicion, and Low Suspicion). Patients meeting criteria for an IFI classification were more likely to have pathogenic fungi from the order Mucorales isolated from their wounds (39%) compared to patients classified as High or Low Suspicion of IFI (22% and 9%, respectively). This IFI classification scheme provides a framework for clinical decision making with regards to initiation and withdrawal of antifungal therapy. In particular, when close follow-up can be ensured, wounds classified as Low Suspicion may be followed without immediate use of antifungal therapy.
- Patients with open upper extremity fractures characterized by substantial soft-tissue damage (i.e., extensive degloving) were 16 times more likely to develop osteomyelitis. Fracture severity was also an osteomyelitis risk factor as patients with upper extremity fractures needing soft-tissue coverage (Gustilo-Anderson grade IIIb) and those with vascular injury requiring repair (Gustilo-Anderson Grade IIIc and amputations) were 22 and 16 times more likely to develop osteomyelitis, respectively.
Wound Infection Research Area Presentations 2019 – present
Bozzay JD, Walker PF, Schechtman DW, Shaikh F, Stewart L, Tribble DR, Bradley MJ. Risk Factors for Abdominal Surgical Site Infection after Exploratory Laparotomy among Combat Casualties. 2020 American College of Surgeons Clinical Congress. 4-8 October 2020, Chicago, IL. [abstract accepted for presentation]
Stewart L, Shaikh F, Blyth DM, Campbell W, Tribble DR. Deployment-related Burn Epidemiology: Blast & Non-blast. DoD Blast Injury Research Program Coordinating Office State-of-the-Science Meeting on Mitigating The Impact of Blast-related Burn Injuries: From Prolonged Field Care to Rehabilitation and Resilience. 3-5 March 2020, Arlington, VA. [poster]
Bozzay JD, Walker PF, Schechtman DW, Shaikh F, Stewart L, Tribble DR, Bradley MJ. Outcomes of Exploratory Laparotomy and Abdominal Infections among Combat Casualties. 15th Annual Academic Surgical Congress. 4-6 February 2020, Orlando, FL. [oral presentation]
McCarthy S, Stewart L, Shaikh F, Carson ML, Merritt T, Whitman TJ, Petfield JL, Murray CK, Tribble DR, Blyth DM. Application of the Sequential Organ Failure Assessment Score to Combat-Injured Patients from OEF/OIF. 48th Critical Care Congress, 17-20 February 2019, San Diego, CA. [oral presentation]
Kiley JL, Mende K, Beckius M, Kaiser SJ, Carson ML, Lu D, Whitman TJ, Petfield JL, Tribble DR, Blyth DM. Clinical Characteristics and Outcomes of Klebsiella pneumoniae Infection in Service Members Who Sustained Trauma in Iraq and Afghanistan. 2019 Texas Infectious Diseases Society Annual Meeting. 7-9 June 2019, Lost Pines, TX. [oral presentation/poster]
Mende K, Mangum LC, Akers KS, Demons ST, Jones AR, Simons MP, Stewart L, Tyner SD, Tribble DR. The Multidrug-Resistant and other Virulent Organisms (MDR/VO) Trauma Infections Initiative: 2019 Update. 2019 Military Health System Research Symposium, 19-22 August 2019, Kissimmee, FL. [Poster #347]
Stanbro J, Hayes J, Reinhart A, Lipinski M, Roman J, Watters C, McLendon MK, Demons ST, Tyner SD, Mende K, Tribble DR, Simons MP. Antagonism of ESKAPE Pathogens by Enterococcus and Coagulase-negative Staphylococcus Isolates from the Multidrug-Resistant and Other Virulent Organisms (MDR/VO) Trauma Infections Initiative. 2019 Military Health System Research Symposium, 19-22 August 2019, Kissimmee, FL. [Poster #378]
Stewart L, Li P, Blyth DM, Petfield JL, Campbell W, Tribble DR. Epidemiology of Combat-Related Deep Soft-tissue Wound Infections. 2019 IDSA ID Week. 2-6 October 2019, Washington DC. [Poster #449].
Kiley JL, Mende K, Beckius M, Kaiser SJ, Carson ML, Lu D, Whitman TJ, Petfield JL, Tribble DR, Blyth DM. Klebsiella variicola Infections in Service Members who Sustained Trauma in Iraq and Afghanistan. 2019 IDSA ID Week. 2-6 October 2019, Washington DC. [Poster #502].
Kiley JL, Blyth DM, Beckius M, Kaiser SJ, Carson ML, Lu D, Whitman TJ, Petfield JL, Tribble DR, Mende K. Biocide Resistance Genes in Klebsiella spp. Infections from Trauma Patients in Iraq and Afghanistan. 2019 IDSA ID Week. 2-6 October 2019, Washington DC. [Poster #543].
Lee R, Millar EV, Callendrello A, English, C, Krasniewski A, Bennet J, Hanage W. Genomic Epidemiology of Methicillin-resistant Staphylococcus aureus in Two Cohorts of High-Risk Military Trainees. 2019 IDSA ID Week. 2-6 October 2019, Washington DC. [Poster #561].
Millar EV, McGann P, Ellis M, Tribble D, Jones A, Bennett J. Genomic Epidemiology of Methicillin-susceptible Staphylococcus aureus Colonization and Infection among US Army Trainees at Fort Benning, Georgia. 2019 IDSA ID Week. 2-6 October 2019, Washington DC. [oral presentation]
Barrall AL, Millar EV, Tribble DR, Ellis MW, Bennett JW. Clinical Characteristics of Recurrent Skin and Soft Tissue Infection among US Army Infantry Trainees at Fort Benning, GA. 2019 Military Health System Research Symposium, 19-22 August 2019, Kissimmee, FL. [Poster #369]
Wound Infection Research Area Publications 2019 – present
Yabes JM, Stewart L, Shaikh F, Robben PM, Petfield JL, Ganesan A, Campbell WR, Tribble DR, Blyth DM. Risk of Acute Kidney Injury in Combat-Injured Patients Associated with Concomitant Vancomycin and Extended-spectrum Beta-lactam Antibiotic Use. Journal of Intensive Care Medicine. Accepted for publication.
Tribble DR, Ganesan A, Rodriguez CJ. Combat Trauma-Related Invasive Fungal Wound Infections. Current Fungal Infection Reports. Accepted for publication. https://link.springer.com/article/10.1007/s12281-020-00385-4
Stewart L, Li P, Blyth DM, Campbell WR, Petfield JL, Krauss M, Greenberg L, Tribble DR. Antibiotic Practice Patterns for Extremity Wound Infections among Blast-injured Subjects. Military Medicine. 2020; 185(suppl 1): 628-36. https://academic.oup.com/milmed/article/185/Supplement_1/628/5740679
Patterson SB, Mende K, Li P, Lu D, Carson ML, Murray CK, Tribble DR, Blyth DM, and the IDCRP TIDOS Group. Stenotrophomonas maltophilia Infections: Clinical Characteristics in a Military Trauma Population. Diagnostic Microbiology and Infectious Diseases. 2020; 96(2): 114953. https://www.sciencedirect.com/science/article/abs/pii/S073288931930803X?via%3Dihub
Ganesan A, Wells J, Shaikh F, Peterson P, Bradley W, Carson ML, Petfield JL, Klassen-Fischer M, Akers KS, Downing K, Bialek R, Tribble DR, Wickes BL. Molecular Detection of Filamentous Fungi in Formalin-Fixed Paraffin-Embedded Specimens in Invasive Fungal Wound Infections is Feasible with High Specificity. Journal of Clinical Microbiology. 2020; 58(1): e01259-19. https://jcm.asm.org/content/58/1/e01259-19
Tribble DR, Murray CK, Lloyd BA, Ganesan A, Mende K, Blyth DM, Petfield JL, McDonald J. After the Battlefield: Infectious Complications among Wounded Warriors in the Trauma Infectious Disease Outcomes Study. Military Medicine. 2019; 184(suppl 2): 18-25. https://academic.oup.com/milmed/article-abstract/184/Supplement_2/18/5645093?redirectedFrom=fulltext
Liang SY, Jackson B, Kuhn J, Shaikh F, Blyth DM, Whitman TJ, Carson ML, Tribble DR, McDonald JR, and the IDCRP TIDOS Group. Urinary Tract Infections after Combat-Related Genitourinary Trauma. Surgical Infections. 2019; 20(8): 611-618. https://www.liebertpub.com/doi/10.1089/sur.2019.013
Ganesan A, Shaikh F, Bradley W, Blyth DM, Bennett D, Petfield JL, Carson ML, Wells JM, Tribble DR, and the IDCRP TIDOS Group. Classification of Trauma-Associated Invasive Fungal Infections to Support Wound Treatment Decisions. Emerging Infectious Diseases. 2019; 25(9): 1639-1647. https://wwwnc.cdc.gov/eid/article/25/9/19-0168_article
Mende K, Stewart L, Shaikh F, Bradley W, Lu D, Krauss M, Greenberg L, Yu Q, Blyth DM, Whitman TJ, Petfield JL, and Tribble DR. Microbiology of Combat-Related Extremity Wounds: Trauma Infectious Disease Outcomes Study. Diagnostic Microbiology and Infectious Disease. 2019; 94(2):173-179. https://www.sciencedirect.com/science/article/abs/pii/S073288931830806X?via%3Dihub
Stewart L, Shaikh F, Bradley W, Lu D, Blyth DM, Petfield JL, Whitman TJ, Krauss M, Greenberg L, Tribble DR. Combat-Related Extremity Wounds: Injury Factors Predicting Early Onset Infections. Military Medicine. 2019; 184(suppl 1): 83-91. https://academic.oup.com/milmed/article/184/Supplement_1/83/5418692
Potter BK, Forsberg JA, Silvius E, Wagner M, Khatri V, Schobel, S. A., Belard AJ, Weintrob AC, Tribble DR, and Elster EA. Combat-Related Invasive Fungal Infections: Development of a Clinically Applicable Clinical Decision Support System for Early Risk Stratification. Military Medicine. 2019; 184(1-2): e235-e242. https://academic.oup.com/milmed/article/184/1-2/e235/5074328
Lewandowski LR, Potter BK, Murray, CK, Petfield JL, Stinner DJ, Krauss M, Weintrob AC, Tribble DR and the Trauma Infectious Disease Outcomes Study Group. Osteomyelitis Risk Factors Related to Combat Trauma Open Femur Fractures: A Case-Control Analysis. Journal of Orthopaedic Trauma. 2019; 33(4): e110 e119. https://journals.lww.com/jorthotrauma/Abstract/2019/04000/Osteomyelitis_Risk_Factors_Related_to_Combat.9.aspx
Petfield JL, Tribble DR, Potter BK, Lewandowski LR, Weintrob AC, Krauss M, Murray CK, Stinner DJ, and the Trauma Infectious Disease Outcomes Study Group. Is Bone Loss or Devascularization Associated with Recurrence of Osteomyelitis in Wartime Open Tibia Fractures? Clinical Orthopaedics and Related Research. 2019; 477(4): 789-801. https://journals.lww.com/clinorthop/Fulltext/2019/04000/Is_Bone_Loss_or_Devascularization_Associated_With.25.aspx
Warkentien TE, Lewandowski LR, Potter BK, Petfield JL, Stinner DJ, Krauss M, Murray, CK, Tribble DR and the Trauma Infectious Disease Outcomes Study Group. Osteomyelitis Risk Factors Related to Combat Trauma Open Upper Extremity Fractures: A Case-Control Analysis. Journal of Orthopaedic Trauma. 2019; 33(12): e475-e483. https://journals.lww.com/jorthotrauma/Abstract/2019/12000/Osteomyelitis_Risk_Factors_Related_to_Combat.18.aspx
Millar EV, Schlett CD, Law NN, Whitman TJ, Ellis MW, Tribble DR, Bennett JW. Opportunities and Obstacles in the Prevention of Skin and Soft-Tissue Infections Among Military Personnel. Military Medicine. 2019; 184 (suppl 2): 35-43. https://academic.oup.com/milmed/article-abstract/184/Supplement_2/35/5645085?redirectedFrom=fulltext
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; 47(5): 729-737. https://link.springer.com/article/10.1007%2Fs15010-019-01282-w