Infectious Complications After Battlefield Injuries: Epidemiology, Prevention, and Treatment

Abstract

Purpose of Review

Recent conflicts have resulted in an unprecedented proportion of survivors of complex battlefield injuries. These patients are predisposed to infectious complications with multidrug-resistant organisms (MDROs). The epidemiology, prevention, and treatment of these infections are described, with emphasis on recent literature.

Recent Findings

Data from the Trauma Infectious Disease Outcomes Study (TIDOS) cohort have revealed a 27% rate of infectious complications in those evacuated after traumatic injury; this increases to 50% in the intensive care unit. Acinetobacter baumannii-calcoaceticus was common in casualties injured in Iraq, but was replaced by other extended-spectrum beta-lactamase-producing Enterobacteriaceae as well as fungi in casualties from Afghanistan. Prevention of infections includes short courses of narrow-spectrum prophylactic antimicrobials and infection control; the mainstay of wound infection prevention is debridement and irrigation. Treatment of many infections is primarily surgical and antimicrobial therapy directed against expected and recovered pathogens.

Summary

Infections after combat trauma are common and complex, requiring a multidisciplinary approach to prevention and care.

Introduction

Infectious complications after battlefield injury are not a new phenomenon. The most ancient descriptions of war include attention to the resulting complications and treatments, some of which are still applicable today [1•]. In the pre-antibiotic era, these infections were frequently fatal, but appropriate modern treatment approaches have markedly reduced the risk of morbidity and long-term disability or death. However, as mechanisms of injury, theaters of operation, and medical care itself evolve, there is real-time change in the types and microbiology of infectious disease complications, necessitating important adjustments in care. Infectious complications after combat trauma can be disastrous, resulting in amputation, loss of function, or death. Particular attention to infection control is required to avoid preventable infections.

Epidemiology

Soon after combat began in Operations Iraqi Freedom and Enduring Freedom (OIF, OEF), military physicians noted an unusual number of multidrug-resistant (MDR) organisms causing infections in casualties. The most notable of these was Acinetobacter baumannii-calcoaceticus (ABC), but MDR Pseudomonas aeruginosa, Klebsiella pneumoniae, and methicillin-resistant Staphylococcus aureus were also being recovered from infected casualties. An early report of ABC infections primarily in servicemembers injured in Iraq described >100 bloodstream infections caused by the organism, clearly the tip of the iceberg [2]. Reports increased of MDR ABC causing wound, burn, skin and soft tissue, bone, and respiratory infections, including those in exposed healthcare workers and patients who had not been deployed but were treated alongside returning combat casualties [3,4,5].

The source of these infections was not immediately clear. ABC is a hardy environmental organism and, given the extensive contamination of most battlefield injuries, it was postulated that soil and debris in the wound might be the source for colonization and infection. Pre-injury colonization was also considered as a possibility, especially considering the likelihood of some changes to the skin and gut microbiomes of servicemembers in hot, austere conditions. Both of these possibilities were studied, with no evidence that either contributed to MDR ABC or any other MDR gram-negative rod (GNR) infection in combat casualties [6,7,8,9]. Instead, it became clear that nosocomial transmission within the chain of combat casualty care was the predominant mechanism for colonization and infection [10•, 12, 13]. Additionally, although these organisms were frequently found at the time of initial diagnosis of infection, they were predominantly replaced with Staphylococcus spp., especially S. aureus, by the time of relapsed or recurring infection [14, 15].

As the theater of combat operations shifted from Iraq to Afghanistan, the predominant organisms changed as well from ABC to other MDR GNR, especially extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli, Enterobacter spp., and K. pneumoniae. However, overall rates of colonization with any MDR GNR remained fairly stable at around 15% [16, 17]. In contrast to ABC, the role of other routes of transmission, especially the possibility of pre-injury colonization with these pathogens playing a role in later infection, is less clear. MDR GNRs were frequently isolated as community-acquired pathogens in local nationals admitted to deployed hospitals, similar to data seen with ABC in Iraq [11, 13]. However, there are also data to suggest that uninjured deployed personnel to that region are colonized with MDR E. coli at higher rates than US-based personnel; one evaluation revealed a 5.5-fold higher rate of colonization [18]. Severe, complex blast injuries in Afghanistan, particularly in the lushly vegetated southern Kandahar and Helmand provinces, were also found to be uniquely at risk for serious invasive fungal infections (IFI) with a wide variety of mold species [19•, 20]. Risk factors include dismounted blast injuries, above-the-knee amputations, and large-volume red cell transfusion requirements [21].

According to prospectively collected data from the TIDOS cohort enrolling trauma patients evacuated from combat theaters, 27% of casualties experience at least one infectious complication. This increases to 50% if only intensive care unit (ICU) patients are considered [22••]. The spectrum of these infections largely mirrors the anatomic distribution of combat injuries and the nosocomial infections common in trauma ICU populations. Wound/skin and soft tissue infections occurred in 18% of the TIDOS cohort, followed by osteomyelitis (9%), bloodstream infections (9%), and pneumonia (4%), with higher rates in ICU compared to those in ward patients for all sites of infection. The median number of days from injury to infection diagnosis was as short as 3 for pneumonia, 6 for bloodstream infections, 12 for wounds, and 15 for osteomyelitis. In patients with open extremity fractures, approximately 15% developed osteomyelitis; in Gustilo type III tibial plateau fractures, deep wound infection (including osteomyelitis) rates ranged from 22 to 77% [14, 15, 23, 24]. Bloodstream infections are typically secondary; one evaluation of central line-associated bloodstream infections at a deployed hospital in Iraq found substantial variability (0 to 29 per 1000 device-days), not apparently related to census or staff turnover periods [25]. The most common organism isolated was S. aureus. Catheter-associated urinary tract infections in the same study remained stable over the course of a year and comparable to rates seen in US trauma ICUs. Healthcare-associated pneumonia in evacuated casualties from the 2009–2010 TIDOS cohort has also been evaluated; 9% of all patients and 18% of ICU patients developed pneumonia, with the majority being ventilator associated. Although the majority of isolates were GNR, S. aureus was the single most common isolate recovered (11%) [26]. Thermal injury was relatively common in the first 5–6 years of the conflict in Iraq, sustained by approximately 5% of casualties; 12% of these developed at least one episode of bacteremia [27]. Every anatomical site of trauma has its own unique infectious complications, and while an extensive discussion of these is outside the scope of this review, the Journal of Trauma published guidelines and entire supplements in 2008 and 2011 dedicated to prevention of infections associated with combat injuries, excellent resources for further information [28••, 29••].

Infections after combat trauma are by no means trivial events, but lead to serious complications of their own. Longer times to fracture union and higher rates of both reoperation and amputation have been seen in patients with deep wound infections/osteomyelitis [30]. Infections after combat-related amputation can also result in conversion to a more proximal amputation, which carries significant additional morbidity and a decrease in functional outcomes. Additionally, compared to casualties without deep wound infections or osteomyelitis, those suffering these complications are less likely to return to duty, more likely to be rehospitalized, and fail limb salvage attempts [23, 30, 31]. Infection is the most common complication both before and after late amputation in limb salvage patients [32]. In those with invasive fungal infections, a crude mortality rate of 9% has been seen, along with high-level amputation (including hemipelvectomy and hip disarticulation) rates exceeding 20% [33]. In burn patients, death was more strongly associated with infection (most typically with K. pneumoniae, P. aeruginosa, or IFI) in combat casualties than it was in civilian patients in one autopsy study [34].

Prevention

First, it must be acknowledged that all infectious complications of medically attended trauma are by definition healthcare-associated infections, a reality which has been highlighted in recent conflicts by the clear evidence of nosocomial transmission of MDR organisms. The success of standardized, bundled approaches to infection prevention (IP) in the last decade, especially the reductions in central line-associated bloodstream infections and ventilator-associated pneumonias, has also underscored that such complications cannot be assumed to be inevitable or nonpreventable. Despite the challenges associated with IP in austere environments of care, simple measures have been proven effective in deployed hospitals. Hand hygiene adherence rates at Craig Joint Theater Hospital, Afghanistan, nearly tripled within 1 month of surveillance and increased access to alcohol-based hand rub [35]. Two- to fivefold reductions in ventilator-associated pneumonia (VAP) were seen there and at Balad Air Force Theater Hospital, Iraq, with promotion of hand hygiene, implementation of VAP bundles, antimicrobial stewardship, and attention to environmental disinfection [36•]. In Iraq, these measures also resulted in significant improvements in ABC susceptibilities to both amikacin and imipenem. In general, national guidelines to prevent specific infections and transmission of resistant infections should be followed throughout the course of combat casualty care. Guidelines for the prevention of infections associated with combat casualties, published in 2011, emphasize attention to established IP measures, command support, and deployed IP expertise [37•].

The mainstay of preventing combat wound infections and osteomyelitis after open fracture is early and thorough debridement and irrigation. Removal of foreign material, organic contamination, and devitalized tissue should be performed as early after injury as possible. Current guidelines recommend normal saline without additives, delivered at low pressure. Sterile or even potable water can also be used if necessary. The recently published FLOW study concluded that normal saline alone was preferable to the use of saline with castile soap, regardless of delivery pressure [38•]. Operative debridement is also recommended to be performed as early as possible and repeated until wounds are clean and free of necrosis. This may require serial operative debridement in the first few days after a grossly contaminated injury. However, the timing of initial operative debridement has been an unresolved issue in civilian trauma literature. While early debridement has long been seen as the primary intervention to reduce infection risk, recent studies with a range of times to first debridement have not demonstrated any consistent increase in risk with delayed surgery up to 24 h after injury [39, 40•]. External fixation is preferred initially by the USA, with open reduction and internal fixation typically delayed until evacuation and stabilization of the patient. The British military recommends casting, also with good outcomes, although this may not be scalable to larger numbers of casualties or with longer evacuation times [41]. Penetrating fragments can often be left in situ and observed, particularly if there is no evidence of infection or small entry/exit wounds, and they do not penetrate the peritoneum, pleura, bone, or vascular spaces. Obtaining routine cultures of uninfected appearing wounds is not recommended.

Adjunctive antimicrobials are thought to play an important role in prevention of infection after combat-related injuries, as in civilian trauma. Clinical practice guidelines published in 2011 were endorsed by the Infectious Disease Society of America and the Surgical Infection Society (SIS); these remain the most current guidelines focusing on antimicrobial use in battlefield injuries [28]. The choice of a prophylactic antibiotic has centered on the need to cover the staphylococcal and streptococcal species typically responsible for wound infections, and the need to limit antibiotic pressure driving resistance. High-dose cefazolin (2 g every 6 to 8 h) remains the agent of choice for most injury patterns, with metronidazole added in instances of hollow viscus injury or organic contamination of the brain or spinal cord (Table 1). As in the SIS civilian orthopedic trauma guidelines, neither extended-spectrum GNR coverage for high-risk open fractures nor penicillin for contaminated wounds is recommended [42]. A full discussion of the controversy surrounding the need for extended GNR coverage after open fracture is beyond the scope of this review. However, recent retrospective analysis of TIDOS data revealed additional risk of MDR isolate recovery with even cefazolin prophylaxis, with an OR of 3.5. This risk was increased further with the use of a fluoroquinolone (OR 5.4) [43]. The MDR ABC and ESBL-producing E. coli isolates seen in recent conflicts have typically been resistant to all agents but colistin and carbapenems, respectively; both of which are unattractive choices for prophylactic agents. This, together with the TIDOS data suggesting increased resistance with even fluoroquinolone use, provides additional reassurance that cefazolin alone is likely an appropriate strategy in this group. The duration of prophylaxis should be short (the maximum duration recommended for any extremity injury is 3 days) and not extended due to the presence of drains or fixators, or restarted after additional debridement. Point-of-injury antimicrobials should be administered on the battlefield if evacuation to surgical care is anticipated to be delayed, and evaluation of the need for tetanus vaccine and immunoglobulin must not be overlooked.

Table 1 Antimicrobial therapeutic agents and duration for prevention of infection in combat-related trauma

Since recognizing and characterizing the risk of IFI in a subset of combat-injured patients, in 2012, a DoD clinical practice guideline was published to address prevention and updated in 2015 [44, 45•]. These fungal pathogens originate in the environment of the injury and do not typically share the nosocomial route of transmission of the MDR GNR pathogens discussed above. In contrast to some natural disaster-related experiences with IFI, where only one species is described, these present with a wide variety of fungal species [19, 46]. These are often polymicrobial including Aspergillus, Fusarium, and Mucorales spp. While having any IFI delays wound closure, times to eventual wound closure in combat casualties have been seen to be longest with growth of Mucorales spp. compared to other genera [47]. Again, the primary method for prevention is aggressive debridement; this remains the primary therapy even for established infection. Dilute Dakin’s solution has an in vitro dose-related antifungal effect against multiple relevant species of molds, as well as limited toxicity in dilute concentrations [48]. These data have led to a recommendation for use in high-risk patients with battlefield injuries, even prior to the patient’s evacuation. Although in combat casualties this diagnosis has been context-specific to southern Afghanistan, similar infections have been seen after numerous natural disasters involving high-energy, heavily contaminated injuries in extensively vegetated environments [46, 49, 50]. It is possible that these could be diagnosed in future conflicts in such environments with much more regularity, given that the modern chain of combat casualty care involves evacuation to hospitals with fungal culture and histopathology within days of injury. It is likely that these infections require not only a similar environment of injury but also a host with high-energy injuries, further predisposed by super-massive requirements for blood product transfusion [51]. Understanding the role of blood product transfusions, and transfusion-transmitted infections like CMV, in immune modulation and predisposition to infection remains challenging. This is particularly relevant in combat casualty care, where the use of fresh whole blood (FWB) has been associated with CMV, and rarely HTLV-1 and hepatitis C transmission, and where practices continue to change to include use of frozen and low-titer O− blood in theater [52,53,54].

Other adjunctive strategies for infection prevention via combat wound care have been the subject of considerable recent research. Topical antimicrobial therapy has long been an attractive target for both prevention and treatment of wound infections, given the potential for high local concentrations to overcome biofilm activity and the absence of significant systemic absorption to drive major microbiome changes or toxicity. However, the literature has failed to conclusively demonstrate a clinical advantage to the use of antibiotic-impregnated beads or pouches, and recent efforts have not settled the question. The hypothetical advantages to topical therapy also prove to be limitations, since application methods that comprehensively and persistently cover irregular, complex wound surfaces are challenging, and penetration into tissue is limited. Appropriate injury management relies on keeping traumatic wounds free of blood and extravasated fluid, which clearly serve as growth media for bacteria, but in removing these fluids, any topical antimicrobials are also rapidly dispensed with. One recent evaluation of the use of a negative-pressure wound dressing (NWPD) along with antimicrobial-impregnated beads demonstrated that the wound dressing effectively obviated the effect of antimicrobial beads [55]. NWPD itself has been used increasingly, even in deployed hospitals and during aeromedical evacuation, and experience has demonstrated its feasibility in such settings. Its role in preventing infection is unclear, however. Some data suggest that there is an increased risk of S. aureus in the setting of NWPD, and others have raised concerns of local wound toxicity and effects on tissue appearance that make diagnosis of infection more challenging [56,57,58]. Finally, considerable efforts have gone into biomedical research investigating other novel therapies including gallium, blue and ultraviolet light, the development of biofilm-resistant surfaces for orthopedic hardware, and other materials used for dead space management and fracture stabilization [59,60,61,62]. Multiple federally funded translational studies remain underway.

Treatment

The treatment of infectious complications after combat trauma is specific to the host, the site of infection, and the microorganism(s) involved. Many infections are managed similarly to those seen after civilian trauma and should be treated according to relevant guidelines (e.g., catheter-associated bloodstream infections, ventilator-associated pneumonias). Wound infections and osteomyelitis constitute the majority of combat-related infections. The treatment of orthopedic infections has frequently been the most individualized and most challenging. This is a result of the heterogeneous nature of these injuries, the typical need for ongoing orthopedic hardware and fracture fixation, multiple operative takebacks, the frequent involvement of biofilm, and the challenges associated with often prolonged and repeated courses of antimicrobials.

Surgical treatment for infected wounds is paramount and relies upon debridement of overtly infected and devitalized tissue, draining abscesses or infected hematomas, removal of residual foreign bodies, and ensuring adequate vascular supply. When the underlying bone is involved, removal of orthopedic hardware is preferred, though not always possible. Diagnosis of the infected wound or bone relies on the surgeon’s direct visualization and obtaining diagnostic material. If there is suspicion for infection, adequate material for aerobic and anaerobic cultures should be obtained. In general, swabs should be avoided. Fluids should be aspirated into a syringe and capped, and multiple specimens of involved tissue should be obtained; yield increases with increasing number of specimens. While yeast will typically grow easily from standard bacterial cultures, mold will not. While occasionally a dressing change will reveal a wound visibly covered in mold, IFI should generally be suspected in high-risk patients in the setting of progressive, rapid wound necrosis. If IFI is suspected or proven, surgical debridement must be aggressive and frequent until wounds appear consistently healthy. Fungal cultures as well as histopathology to determine depth of invasion are essential to establish the diagnosis and optimize treatment. Mycobacteria have rarely been involved in combat-associated wound infections, and cultures for these organisms are indicated in chronic, nonhealing wounds [63].

Empiric therapy should be chosen based again upon the host, the site of infection, and the most likely pathogens involved. Accurate understanding of involved pathogens depends upon a current, context-specific antibiogram. The need for these has been highlighted even in the deployed environment, and given that predominant pathogens change over time and in different theaters of operation, it is impossible to give a standard regimen that will be appropriate in all future combat casualties. In recent casualties from Afghanistan, ESBL-producing Enterobacteriaceae have been predominant, necessitating empiric use of carbapenems for many serious infections. Newer combination agents including ceftazidime/avibactam and ceftolozane/tazobactam have been developed for treatment of MDR GNR infections and may have an increasing role for treating combat casualties in the future, although experience is currently limited with this population [64]. Initial treatment for suspected IFI requires broad antimold coverage, as many species have been involved, including some (e.g., Aspergillus terreus, Fusarium spp.) resistant to amphotericin. Given the predominance of Mucorales spp. and other resistant molds, echinocandins are not recommended for treatment. Clinical practice guidelines recommend the use of both amphotericin and voriconazole, and experience is also growing with posaconazole and newer broad-spectrum antifungals like isavuconazole in this context, though these are not recommended as monotherapy initially. When culture results are available, empiric therapy for both bacterial and fungal infections should be directed against organisms isolated from wounds and felt to be responsible for infection. This can be easier said than done, however, given the often polymicrobial involvement of wounds in the first few weeks after injury. Early GNR predominance gives way to primarily staphylococci in well-established, relapsing infections, especially with lower-virulence pathogens like ABC. S. aureus, beta-hemolytic streptococci, Enterobacteriaceae, and P. aeruginosa are considered to be pathogens when isolated from a wound. Anaerobes are occasionally isolated; though, even in established infection, they are often resistant to agents used for treatment without apparent differences in outcomes [65]. Candida spp., when isolated in wounds, are usually also part of a polymicrobial infection and do not appear to have an impact on mortality [66]. Enterococci as well as lower-virulence GNR (Stenotrophomonas maltophilia and non-aeruginosa Pseudomonas spp.) infrequently contribute to long-term infectious complications, although they are often found with other pathogens; Enterococcus in particular has been shown to be present in a majority of mangled extremities during the first few days after injury [67]. Coagulase-negative staphylococci are the single most frequently isolated organisms in the TIDOS cohort, and interpretation of their significance must take into account whether other organisms are also present, the size of the inoculum, whether they are repeatedly isolated, and perhaps most importantly, whether a device or hardware is involved.

Conclusions

Infectious complications after combat-related injury are common, affecting more than a quarter of all casualties, and are frequently caused by MDR pathogens transmitted within the chain of combat casualty care. These complications may cause delayed union of fractures, unplanned operative takebacks and rehospitalizations, failure of limb salvage, high-level amputations, prolonged ICU stays, and death. Prevention includes aggressive surgical management, judicious and brief use of antimicrobial prophylaxis, and systematic, command-supported efforts at IP. Treatment must take into account the overall clinical status of the patient, the anatomical site of infection, and the suspected and proven pathogens involved.

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Correspondence to Heather C. Yun.

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Yun, H.C., Blyth, D.M. & Murray, C.K. Infectious Complications After Battlefield Injuries: Epidemiology, Prevention, and Treatment. Curr Trauma Rep 3, 315–323 (2017). https://doi.org/10.1007/s40719-017-0102-2

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Keywords

  • Combat trauma
  • Military medicine
  • Trauma
  • Infection
  • Infection prevention
  • Drug-resistant organism