Biofilms and Wound Infection Research in the US Military

  • Kevin S. AkersEmail author
  • Joseph C. Wenke
  • Clinton K. Murray


Recent US military conflicts have involved severe extremity injuries frequently requiring implantation of orthopedic stabilizing devices. Simultaneously, bacterial wound contamination, including by multidrug-resistant organisms, has presented a significant clinical challenge due to reduced antimicrobial treatment options, with an unclear but likely contribution from biofilm formation on implanted devices. In this chapter, we detail investigations conducted by the US military medical research community into wound infections occurring in casualties from conflicts in Iraq and Afghanistan.


Military Conflicts Wound Biofilm Antimicrobial Research 



The opinions or assertions contained herein are the private views of the author and not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.


  1. 1.
    Jackman, R. P. (2013). Immunomodulation in transfused trauma patients. Current Opinion in Anaesthesiology, 26(2), 196–203.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ake, J., et al. (2011). Gram-negative multidrug-resistant organism colonization in a US military healthcare facility in Iraq. Infection Control and Hospital Epidemiology, 32(6), 545–552.CrossRefGoogle Scholar
  3. 3.
    Landrum, M. L., & Murray, C. K. (2008). Ventilator associated pneumonia in a military deployed setting: The impact of an aggressive infection control program. The Journal of Trauma, 64(2 Suppl), S123–S127; discussion S127–8.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Scott, P., et al. (2007). An outbreak of multidrug-resistant Acinetobacter baumannii-calcoaceticus complex infection in the US military health care system associated with military operations in Iraq. Clinical Infectious Diseases, 44(12), 1577–1584.CrossRefGoogle Scholar
  5. 5.
    Akers, K. S., et al. (2014). Biofilms and persistent wound infections in United States military trauma patients: A case-control analysis. BMC Infectious Diseases, 14, 190.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Owens, B. D., et al. (2007). Characterization of extremity wounds in Operation Iraqi Freedom and Operation Enduring Freedom. Journal of Orthopaedic Trauma, 21(4), 254–257.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Brown, K. V., Murray, C. K., & Clasper, J. C. (2010). Infectious complications of combat-related mangled extremity injuries in the British military. The Journal of Trauma, 69(Suppl 1), S109–S115.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Murray, C. K., et al. (2011). Prevention of infections associated with combat-related extremity injuries. The Journal of Trauma, 71(2 Suppl 2), S235–S257.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Masini, B. D., et al. (2011). Rehospitalization after combat injury. The Journal of Trauma, 71(1 Suppl), S98–S102.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Cross, J. D., et al. (2012). Return to duty after type III open tibia fracture. Journal of Orthopaedic Trauma, 26(1), 43–47.CrossRefGoogle Scholar
  11. 11.
    Stinner, D. J., et al. (2010). Return to duty rate of amputee soldiers in the current conflicts in Afghanistan and Iraq. The Journal of Trauma, 68(6), 1476–1479.CrossRefGoogle Scholar
  12. 12.
    Napierala, M. A., et al. (2014). Infection reduces return-to-duty rates for soldiers with Type III open tibia fractures. Journal of Trauma and Acute Care Surgery, 77(3 Suppl 2), S194–S197.CrossRefGoogle Scholar
  13. 13.
    Huh, J., et al. (2011). Infectious complications and soft tissue injury contribute to late amputation after severe lower extremity trauma. The Journal of Trauma, 71(1 Suppl), S47–S51.CrossRefGoogle Scholar
  14. 14.
    Tribble, D. R., et al. (2011). Infection-associated clinical outcomes in hospitalized medical evacuees after traumatic injury: Trauma Infectious Disease Outcome Study. The Journal of Trauma, 71(1 Suppl), S33–S42.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Weintrob, A. C., et al. (2018). Early infections complicating the care of combat casualties from Iraq and Afghanistan. Surgical Infections, 19(3), 286–297.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Johnson, E. N., et al. (2007). Infectious complications of open type III tibial fractures among combat casualties. Clinical Infectious Diseases, 45(4), 409–415.CrossRefGoogle Scholar
  17. 17.
    Yun, H. C., Branstetter, J. G., & Murray, C. K. (2008). Osteomyelitis in military personnel wounded in Iraq and Afghanistan. The Journal of Trauma, 64(2 Suppl), S163–S168; discussion S168.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Eastridge, B. J., et al. (2009). Impact of joint theater trauma system initiatives on battlefield injury outcomes. American Journal of Surgery, 198(6), 852–857.CrossRefGoogle Scholar
  19. 19.
    Tribble, D. R., et al. (2018). Osteomyelitis risk factors related to combat trauma open tibia fractures: A case-control analysis. Journal of Orthopaedic Trauma, 32, e344.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    McDonald, J. R., et al. (2018). Infectious complications after deployment trauma: Following wounded United States military personnel into veterans affairs care. Clinical Infectious Diseases, 67, 1205.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Keeling, J. J., et al. (2008). Short-term outcomes of severe open wartime tibial fractures treated with ring external fixation. The Journal of Bone and Joint Surgery. American Volume, 90(12), 2643–2651.CrossRefGoogle Scholar
  22. 22.
    Costerton, J. W., Montanaro, L., & Arciola, C. R. (2005). Biofilm in implant infections: Its production and regulation. The International Journal of Artificial Organs, 28(11), 1062–1068.CrossRefGoogle Scholar
  23. 23.
    Costerton, J. W. (2005). Biofilm theory can guide the treatment of device-related orthopaedic infections. Clinical Orthopaedics and Related Research, (437), 7–11.Google Scholar
  24. 24.
    Forsberg, J. A., et al. (2008). Correlation of procalcitonin and cytokine expression with dehiscence of wartime extremity wounds. The Journal of Bone and Joint Surgery. American Volume, 90(3), 580–588.CrossRefGoogle Scholar
  25. 25.
    Hawksworth, J. S., et al. (2009). Inflammatory biomarkers in combat wound healing. Annals of Surgery, 250(6), 1002–1007.CrossRefGoogle Scholar
  26. 26.
    Utz, E. R., et al. (2010). Metalloproteinase expression is associated with traumatic wound failure. The Journal of Surgical Research, 159(2), 633–639.CrossRefGoogle Scholar
  27. 27.
    Brown, T. S., et al. (2011). Inflammatory response is associated with critical colonization in combat wounds. Surgical Infections, 12(5), 351–357.CrossRefGoogle Scholar
  28. 28.
    Evans, K. N., et al. (2012). Inflammatory cytokine and chemokine expression is associated with heterotopic ossification in high-energy penetrating war injuries. Journal of Orthopaedic Trauma, 26(11), e204–e213.CrossRefGoogle Scholar
  29. 29.
    Sanchez, C. J., Jr., et al. (2013). Biofilm formation by clinical isolates and the implications in chronic infections. BMC Infectious Diseases, 13, 47.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Heitkamp, R. A., et al. (2018). Association of enterococcus spp. with severe combat extremity injury, intensive care, and polymicrobial wound infection. Surgical Infections, 19(1), 95–103.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Cardile, A. P., et al. (2014). Human plasma enhances the expression of Staphylococcal microbial surface components recognizing adhesive matrix molecules promoting biofilm formation and increases antimicrobial tolerance In Vitro. BMC Research Notes, 7, 457.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Akers, K. S., et al. (2015). Biofilm formation by clinical isolates and its relevance to clinical infections. Advances in Experimental Medicine and Biology, 830, 1–28.CrossRefGoogle Scholar
  33. 33.
    Penn-Barwell, J. G., Murray, C. K., & Wenke, J. C. (2012). Comparison of the antimicrobial effect of chlorhexidine and saline for irrigating a contaminated open fracture model. Journal of Orthopaedic Trauma, 26(12), 728–732.CrossRefGoogle Scholar
  34. 34.
    Svoboda, S. J., et al. (2006). Comparison of bulb syringe and pulsed lavage irrigation with use of a bioluminescent musculoskeletal wound model. The Journal of Bone and Joint Surgery. American Volume, 88(10), 2167–2174.PubMedGoogle Scholar
  35. 35.
    Owens, B. D., White, D. W., & Wenke, J. C. (2009). Comparison of irrigation solutions and devices in a contaminated musculoskeletal wound survival model. The Journal of Bone and Joint Surgery. American Volume, 91(1), 92–98.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Barsoumian, A., et al. (2013). In vitro toxicity and activity of Dakin’s solution, mafenide acetate, and amphotericin B on filamentous fungi and human cells. Journal of Orthopaedic Trauma, 27(8), 428–436.CrossRefGoogle Scholar
  37. 37.
    Homeyer, D. C., et al. (2015). In vitro activity of Melaleuca alternifolia (tea tree) oil on filamentous fungi and toxicity to human cells. Medical Mycology, 53(3), 285–294.CrossRefGoogle Scholar
  38. 38.
    Yabes, J. M., et al. (2017). In Vitro activity of Manuka Honey and polyhexamethylene biguanide on filamentous fungi and toxicity to human cell lines. Medical Mycology, 55(3), 334–343.PubMedGoogle Scholar
  39. 39.
    Molinari, R. W., Khera, O. A., & Molinari, W. J., 3rd. (2012). Prophylactic intraoperative powdered vancomycin and postoperative deep spinal wound infection: 1,512 consecutive surgical cases over a 6-year period. European Spine Journal, 21 Suppl 4, S476–S482.CrossRefGoogle Scholar
  40. 40.
    Pahys, J. M., et al. (2013). Methods to decrease postoperative infections following posterior cervical spine surgery. The Journal of Bone and Joint Surgery. American Volume, 95(6), 549–554.CrossRefGoogle Scholar
  41. 41.
    Sweet, F. A., Roh, M., & Sliva, C. (2011). Intrawound application of vancomycin for prophylaxis in instrumented thoracolumbar fusions: Efficacy, drug levels, and patient outcomes. Spine (Phila Pa 1976), 36(24), 2084–2088.CrossRefGoogle Scholar
  42. 42.
    Tennent, D. J., et al. (2016). Time-dependent effectiveness of locally applied vancomycin powder in a contaminated traumatic orthopaedic wound model. Journal of Orthopaedic Trauma, 30(10), 531–537.CrossRefGoogle Scholar
  43. 43.
    Owens, B. D., & Wenke, J. C. (2007). Early wound irrigation improves the ability to remove bacteria. The Journal of Bone and Joint Surgery. American Volume, 89(8), 1723–1726.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lack, W. D., et al. (2015). Type III open tibia fractures: Immediate antibiotic prophylaxis minimizes infection. Journal of Orthopaedic Trauma, 29(1), 1–6.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Zheng, Z., & Stewart, P. S. (2002). Penetration of rifampin through Staphylococcus epidermidis biofilms. Antimicrobial Agents and Chemotherapy, 46(3), 900–903.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Liu, C., et al. (2011). Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: Executive summary. Clinical Infectious Diseases, 52(3), 285–292.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Shiels, S. M., et al. (2017). Determining potential of PMMA as a depot for rifampin to treat recalcitrant orthopaedic infections. Injury, 48(10), 2095–2100.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Shiels, S. M., Tennent, D. J., & Wenke, J. C. (2018). Topical rifampin powder for orthopaedic trauma part I: Rifampin powder reduces recalcitrant infection in a delayed treatment musculoskeletal trauma model. Journal of Orthopaedic Research, 36, 3136.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Rathbone, C. R., et al. (2011). Effect of various concentrations of antibiotics on osteogenic cell viability and activity. Journal of Orthopaedic Research, 29(7), 1070–1074.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Shiels, S. M., et al. (2018). Topical rifampin powder for orthopaedic trauma part II: Therapeutic levels of topical rifampin allows for spontaneous bone healing in both sterile and contaminated wounds. Journal of Orthopaedic Research, 36, 3142–3150.CrossRefGoogle Scholar
  51. 51.
    Bhattacharjee, A., Nusca, T. D., & Hochbaum, A. I. (2016). Rhamnolipids mediate an interspecies biofilm dispersal signaling pathway. ACS Chemical Biology, 11(11), 3068–3076.CrossRefGoogle Scholar
  52. 52.
    Kumar Shukla, S., & Rao, T. S. (2013). Dispersal of Bap-mediated Staphylococcus aureus biofilm by proteinase K. Journal of Antibiotics (Tokyo), 66(2), 55–60.CrossRefGoogle Scholar
  53. 53.
    Roizman, D., et al. (2017). In vitro evaluation of biofilm dispersal as a therapeutic strategy to restore antimicrobial efficacy. Antimicrobial Agents and Chemotherapy, 61(10).Google Scholar
  54. 54.
    Cardile, A. P., et al. (2017). Activity of norspermidine on bacterial biofilms of multidrug-resistant clinical isolates associated with persistent extremity wound infections. Advances in Experimental Medicine and Biology, 973, 53–70.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Sanchez, C. J., Jr., et al. (2014). D-amino acids enhance the activity of antimicrobials against biofilms of clinical wound isolates of Staphylococcus aureus and Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy, 58(8), 4353–4361.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Sanchez, C. J., Jr., et al. (2013). Effects of local delivery of D-amino acids from biofilm-dispersive scaffolds on infection in contaminated rat segmental defects. Biomaterials, 34(30), 7533–7543.CrossRefGoogle Scholar
  57. 57.
    Be, N. A., et al. (2014). Microbial profiling of combat wound infection through detection microarray and next-generation sequencing. Journal of Clinical Microbiology, 52(7), 2583–2594.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Regeimbal, J. M., et al. (2016). Personalized therapeutic cocktail of wild environmental phages rescues mice from Acinetobacter baumannii wound infections. Antimicrobial Agents and Chemotherapy, 60(10), 5806–5816.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Schooley, R. T., et al. (2017). Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrobial Agents and Chemotherapy, 61(10).Google Scholar
  60. 60.
    Sambanthamoorthy, K., et al. (2014). Antimicrobial and antibiofilm potential of biosurfactants isolated from lactobacilli against multi-drug-resistant pathogens. BMC Microbiology, 14, 197.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Sambanthamoorthy, K., et al. (2014). Identification of small molecules inhibiting diguanylate cyclases to control bacterial biofilm development. Biofouling, 30(1), 17–28.CrossRefGoogle Scholar
  62. 62.
    Sambanthamoorthy, K., et al. (2015). Modulating Acinetobacter baumannii biofilm development with molecules containing 3,4,5-trimethoxy-N,N′,N′-trimethylbenzohydrazide moiety. Bioorganic & Medicinal Chemistry Letters, 25(10), 2238–2242.CrossRefGoogle Scholar
  63. 63.
    Feng, X., et al. (2013). The human antimicrobial peptide LL-37 and its fragments possess both antimicrobial and antibiofilm activities against multidrug-resistant Acinetobacter baumannii. Peptides, 49, 131–137.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Kevin S. Akers
    • 1
    • 2
    Email author
  • Joseph C. Wenke
    • 1
  • Clinton K. Murray
    • 2
    • 3
  1. 1.United States Army Institute of Surgical ResearchFort Sam HoustonUSA
  2. 2.Uniformed Services University of the Health SciencesBethesdaUSA
  3. 3.1st Area Medical Laboratory, Aberdeen Proving GroundAberdeenUSA

Personalised recommendations