ABSTRACT
Introduction
We examined antibiotic management of combat-related extremity wound infections (CEWI) among wounded U.S. military personnel (2009–2012).
Methods
Patients were included if they sustained blast injuries, resulting in ≥1 open extremity wound, were admitted to participating U.S. hospitals, developed a CEWI (osteomyelitis or deep soft-tissue infections) within 30 days post-injury, and received ≥3 days of relevant antibiotic (s) for treatment.
Results
Among 267 patients, 133 (50%) had only a CEWI, while 134 (50%) had a CEWI plus concomitant non-extremity infection. In the pre-diagnosis period (4–10 days prior to CEWI diagnosis), 95 (36%) patients started a new antibiotic with 28% of patients receiving ≥2 antibiotics. During CEWI diagnosis week (±3 days of diagnosis), 209 (78%) patients started a new antibiotic (71% with ≥2 antibiotics). In the week following diagnosis (4–10 days after CEWI diagnosis), 121 (45%) patients started a new antibiotic with 39% receiving ≥2 antibiotics. Restricting to ±7 days of CEWI diagnosis, patients commonly received two (35%) or three (27%) antibiotics with frequent combinations involving carbapenem, vancomycin, and fluoroquinolones.
Conclusions
Substantial variation in antibiotic prescribing patterns related to CEWIs warrants development of combat-related clinical practice guidelines beyond infection prevention, to include strategies to reduce the use of unnecessary antibiotics and improve stewardship.
INTRODUCTION
Blast-related trauma was common during the wars in Iraq and Afghanistan, resulting in a high proportion of combat casualties with extremity wounds to include amputations, open fractures, and soft-tissue injuries.1–4 These wounds were often complicated by infections, which frequently resulted in substantial morbidity.5–8 In particular, combat casualties with open Type III tibia fractures or leg-threatening injuries who required late amputations (i.e., >12 weeks post-injury) were more likely to have had a soft-tissue infection or osteomyelitis during their initial course of care.9,10 Infectious complications of open Type III tibia fractures were also associated with a decreased return-to-duty rate among wounded service members, as well as a higher proportion of disability.11
A review of civilian literature related to infectious complications of penetrating trauma advocated the use of antibiotic therapy directed toward the routinely identified pathogens for both skin and soft-tissue infections and osteomyelitis.12 Specifically, vancomycin, daptomycin, or linezolid were recommended for empiric Gram-positive coverage with skin and soft-tissue infections (vancomycin recommended for osteomyelitis with methicillin-resistant Staphylococcus aureus), while it was ceftazidime, cefepime, or meropenem for use with Gram-negative bacteria for both skin and soft-tissue infections and osteomyelitis. The duration of antimicrobial therapy, while unique to every setting, was generally recommended for a duration of 7–14 days for skin and soft-tissue infections and 4–6 weeks for osteomyelitis.12
Within the military health system, the Joint Trauma System (JTS) develops and disseminates clinical practice guidelines related to combat casualty care. Although JTS clinical practice guidelines provide recommendations related to post-trauma antibiotic prophylaxis, there is presently no clear guidance for the treatment of combat trauma-related infections. Battlefield injuries, particularly from blast-related trauma, are typically more complicated than the trauma that occurs in the civilian setting. In brief, combat casualties frequently sustain severe polytrauma characterized by open wounds, mangled extremities, open fractures, and/or amputations.1–3,13,14 Medical management for these patterns of injury includes post-trauma antibiotic prophylaxis (e.g., cefazolin and clindamycin), topical antibiotics, antibiotic beads, and various combinations of directed antibiotic therapy.5,15–18
Although practice patterns related to post-trauma antibiotic prophylaxis have been examined among combat casualties19–21; less information is available on antibiotic therapy for the treatment of combat-related extremity wound infections (CEWIs). We present data on the utilization of antibiotics for the management of CEWIs among casualties with blast trauma sustained over a 3-year period.
METHODS
Study Population and Data Sources
Data were collected through the Department of Defense (DoD)—Veterans Affairs Trauma Infectious Disease Outcomes Study (TIDOS), which is a observational, multicenter cohort study designed to examine infectious complications among wounded military personnel injured in support of operations in Iraq and Afghanistan.22 Patients were included in TIDOS if they were active-duty personnel or DoD beneficiaries, ≥18 years of age, and sustained an injury during deployment requiring medical evacuation to Landstuhl Regional Medical Center-Germany before transfer to a participating military hospital in the United States. The TIDOS-participating U.S. hospitals include Walter Reed National Military Medical Center in the National Capital Region (Walter Reed Army Medical Center and National Naval Medical Center prior to September 2011) and Brooke Army Medical Center in Texas. The study was approved by the Institutional Review Board of the Uniformed Services University of the Health Sciences (Protocol #351767).
Inclusion in this retrospective analysis herein required that patients sustained at least one blast-related open extremity wound (excluding shoulder and pelvic injuries, digit amputations/fractures, or distal to a more proximately surgical amputation prior to U.S. hospital admission) between June 2009 and May 2012 and were diagnosed with a CEWI within 30 days of injury. A further requirement was documented receipt of at least 3 days of antibiotics relevant for CEWI treatment (i.e., aminoglycosides, aminopenicillin, anti-pseudomonal penicillin, carbapenem, 3rd- or 4th-generation cephalosporin, clindamycin, fluoroquinolone, linezolid, polymyxin, vancomycin, and/or trimethoprim/sulfamethoxazole).
Patient demographics, injury characteristics, and surgical management through the initial hospitalization were collected from the DoD Trauma Registry (DoDTR).23 Information related to infections and antibiotic management was obtained from the supplemental TIDOS infectious disease module of the DoDTR.22
Infection Classification
For this analysis, CEWIs were defined as deep soft-tissue infections (DSTI) and/or osteomyelitis, which were identified based on clinical findings and laboratory test results through a review of medical charts. In addition, infections were classified using the standardized definitions of the National Healthcare Safety Network.22,24 Infections that did not meet the standardized a priori definitions were included in the analysis if there was a documented clinical diagnosis as well as directed antibiotic treatment (duration of ≥5 days for skin and soft-tissue infections and ≥21 days for osteomyelitis). Furthermore, infections were excluded if the medical record included documentation of an alternate diagnosis and antibiotic treatment was discontinued. For a skin and soft-tissue infection to be defined as a DSTI required at least one of the following criteria: purulent drainage from site, organisms isolated from deep wound/tissue culture, organisms isolated from purulent drainage, and the deep wound (or incision) spontaneously dehisces or is deliberately opened by a surgeon in the presence of fever or localized tenderness (unless the wound culture is negative, there is an abscess, or there is other evidence of infection).
Assessment of Antibiotic Utilization
Assessment of Antibiotic Use Prior to, During, and Following CEWI Diagnosis
The date of CEWI diagnosis was abstracted from electronic medical records, which has the potential of the diagnosis date being inexact. To account for potential imprecision regarding the diagnosis date, a 7-day period (±3 days of diagnosis) surrounding the diagnosis date from the electronic medical records was utilized for the evaluation of antibiotics. Two additional periods were incorporated to examine the use of antibiotics in the week prior to and after the diagnosis week with the total period of assessment spanning 21 days. The periods of assessment are as follows: pre-diagnosis week (4–10 days prior to CEWI diagnosis); week of diagnosis (±3 days of CEWI diagnosis date); and the week following diagnosis (4–10 days after CEWI diagnosis).
15-Day Period of Assessment and Infection Stratification
To provide a more focused evaluation of antibiotic use related to the CEWI, a 15-day period of assessment (±7 days surrounding the date of CEWI diagnosis) was utilized. Because of the high occurrence of polytrauma, patients frequently experience multiple infections post-injury. Patients were evaluated separately if they had only a CEWI (DSTI or osteomyelitis) or a CEWI along with a prior (diagnosed >7 days prior to CEWI diagnosis) or concurrent (diagnosed ±7 days of CEWI diagnosis) non-extremity infection. Antibiotic regimens were described for the following infection groups: 1) patients with only a DSTI; 2) only an osteomyelitis; 3) DSTI as the index CEWI plus a non-extremity infection prior to or concurrent with CEWI diagnosis date; and 4) an osteomyelitis as the index CEWI plus a non-extremity infection prior or concurrent with CEWI diagnosis date.
Statistical Analysis
Descriptive characteristics and antibiotic practice patterns of patients with only a CEWI and a CEWI plus non-extremity infections were assessed. Categorical variables were compared with Chi-squared and Fisher’s exact tests and continuous variables were assessed with non-parametric tests using SAS version 9.4 (SAS, Cary, NC). Statistical significance was defined as P < 0.05.
RESULTS
Study Population
Between 2009 and 2012, 1,858 combat casualties were admitted to participating U.S. hospitals, of which 267 (14%) met criteria for inclusion in the analysis. The patients were predominantly young (median age of 23 years; interquartile range: 21–27) men (99%) who were injured while serving in support of operations in Afghanistan (97%; Table I). Regarding the pattern of injury, 210 (79%) had an amputation (traumatic or early surgical) as their most severe injury, 48 (18%) had an open fracture, and nine (3%) had an open soft-tissue wound.
TABLE I.
Characteristics and Injury Circumstances, Number (%) of Military Personnel with CEWI
| Total Patients (N = 267) | Patients with Only CEWI (N = 133) | Patients with CEWI and Non-Extremity Infection (N = 134) | P-Value | |
|---|---|---|---|---|
| Male | 264 (98.9) | 130 (97.7) | 134 (100) | 0.122 |
| Age, median years (IQR) | 23 (21–27) | 23 (21–26) | 23 (21–27) | 0.992 |
| Operational theater | 0.722 | |||
| Afghanistan | 260 (97.4) | 129 (97.0) | 131 (97.8) | |
| Iraq | 7 (2.6) | 4 (3.0) | 3 (2.2) | |
| Branch of service | 1.000 | |||
| Air Force | 3 (1.1) | 1 (0.8) | 2 (1.5) | |
| Army | 120 (44.9) | 60 (45.1) | 60 (44.8) | |
| Marine | 137 (51.3) | 69 (51.9) | 68 (50.7) | |
| Navy | 7 (2.6) | 3 (2.3) | 4 (3.0) | |
| Type of Blast | 0.334 | |||
| IED | 258 (96.6) | 127 (95.5) | 131 (97.8) | |
| Non-IED | 9 (3.4) | 6 (4.5) | 3 (2.2) | |
| Injury severity score, median (IQR) | 33 (27–43) | 30 (21–35) | 38 (30–50) | <0.001 |
| 0–9 (minor) | 6 (2.3) | 6 (4.5) | 0 | <0.001 |
| 10–15 (moderate) | 11 (4.1) | 9 (6.8) | 2 (1.5) | |
| 16–24 (severe) | 44 (16.5) | 29 (21.8) | 15 (11.2) | |
| ≥25 (life-threatening) | 206 (77.2) | 89 (66.9) | 117 (87.3) | |
| Blood units within 24 hours post-injury, median (IQR) | 19 (12–31) | 15 (9–23) | 26 (15–40) | <0.001 |
| None/missing | 17 (6.4) | 16 (12.0) | 1 (0.7) | <0.001 |
| 1–9 | 45 (16.9) | 33 (24.8) | 12 (9.0) | |
| 10–20 | 84 (31.5) | 47 (35.3) | 37 (27.6) | |
| ≥21 | 121 (45.3) | 37 (27.8) | 84 (62.7) | |
| First documented shock index, median (IQR) | 1.08 (0.80–1.41) | 1.00 (0.74–1.29) | 1.26 (0.92–1.60) | <0.001 |
| <0.65 | 32 (12.0) | 19 (14.3) | 13 (9.7) | 0.064 |
| 0.65 to <0.80 | 34 (12.7) | 22 (16.5) | 12 (9.0) | |
| ≥0.80 | 201 (75.3) | 92 (69.2) | 109 (81.3) | |
| ICU admission | <0.001 | |||
| None | 40 (15.0) | 36 (27.1) | 4 (3.0) | |
| LRMC only | 39 (14.6) | 26 (19.5) | 13 (9.7) | |
| U.S. hospital ± LRMC | 188 (70.4) | 71 (53.4) | 117 (87.3) | |
| Most severe extremity injury | 0.084 | |||
| Amputation | 210 (78.7) | 98 (73.7) | 112 (83.6) | |
| Open fracture | 48 (18.0) | 28 (21.1) | 20 (14.9) | |
| Other soft-tissue wounda | 9 (3.4) | 7 (5.3) | 2 (1.5) | |
| Hospitalization, median days (IQR) | 51 (38–77) | 45 (33–60) | 61 (44–92) | <0.001 |
ICU: intensive care unit; IED: improvised explosive blast; IQR: interquartile range; LRMC: Landstuhl Regional Medical Center.
aOpen soft-tissue wounds include degloving injuries, lacerations, and penetrating wounds
Antibiotic Treatment
Among the 267 patients, 27 (10%) patients received only one antibiotic during their hospitalization, while 49 (18%) were prescribed two antibiotics, 67 (25%) prescribed three antibiotics, and 54 (20%) were prescribed four antibiotics. Seventy (26%) patients received at least five antibiotics during their hospitalization. The majority of patients received carbapenem or vancomycin (both 79% of 267) followed by fluoroquinolones (70%) and anti-pseudomonal penicillin (32%; Table II).
Table II.
Antibiotic Distribution and Duration of Use Relative to Timing of CEWI Diagnosis
| Antibiotic | Total Population (N = 267) | Period of Antibiotic Use Relative to CEWI Diagnosis a | |||||
|---|---|---|---|---|---|---|---|
| Pre-Diagnosis Week (N = 95) | Week of Diagnosis (N = 209) | Week Following Diagnosis (N = 121) | |||||
| N (%) | N (%) | Median Days (IQR) | N (%) | Median Days (IQR) | N (%) | Median Days (IQR) | |
| Carbapenem | 211 (79.0) | 22 (23.2) | 10 (4–14) | 147 (70.3) | 14 (8–19) | 26 (21.5) | 10 (4–15) |
| Vancomycin | 211 (79.0) | 29 (30.5) | 8 (7–13) | 137 (65.6) | 13 (7–20) | 45 (37.2) | 10 (4–14) |
| Fluoroquinolone | 187 (70.0) | 47 (49.5) | 4 (3–7) | 49 (23.4) | 5 (2–15) | 30 (24.8) | 9 (4–14) |
| Anti-pseudomonal penicillin | 86 (32.2) | 9 (9.5) | 3 (2–6) | 26 (12.4) | 5 (2–11) | 19 (15.7) | 6 (2–14) |
| Aminoglycoside | 71 (26.6) | 6 (6.3) | 4 (3–5) | 27 (12.9) | 3 (2–7) | 13 (10.7) | 5 (3–9) |
| Polymyxin | 42 (15.7) | 1 (1.1) | 4 (4–4) | 12 (5.7) | 8 (3–13) | 16 (13.2) | 17 (7–25) |
| Aminopenicillin | 33 (12.4) | 8 (8.4) | 4 (2–18) | 6 (2.9) | 10 (3–13) | 9 (7.4) | 13 (9–25) |
| Clindamycin | 31 (11.6) | 8 (8.4) | 3 (2–7) | 10 (4.8) | 4 (3–5) | 2 (1.7) | 5 (3–7) |
| TMP-SFX | 28 (10.5) | 1 (1.1) | 10 (10–10) | 3 (1.4) | 3 (3–8) | 14 (11.6) | 14 (8–16) |
| Fourth-generation cephalosporin | 19 (7.1) | 1 (1.1) | 8 (8–8) | 3 (1.4) | 5 (4–10) | 4 (3.3) | 13 (6–22) |
| Third-generation cephalosporin | 15 (5.6) | 0 | 0 | 3 (1.4) | 11 (6–32) | 4 (3.3) | 8 (6–11) |
| Linezolid | 8 (3.0) | 0 | 0 | 1 (0.5) | 2 (2–2) | 1 (0.8) | 13 (13–13) |
IQR: interquartile range; TMP-SMZ: trimethoprim-sulfamethoxazole.
aThe total for each of the three respective time periods includes patients who started an antibiotic during that period. Periods of assessment are mutually exclusive. Patients may receive more than one antibiotic during specific time periods so the numbers will sum to more than the total. The periods are as follows: Pre-Diagnosis Week is 4–10 days prior to CEWI diagnosis; Week of Diagnosis is ±3 days of CEWI diagnosis date; and Week Following Diagnosis is 4–10 days after CEWI diagnosis.
Assessment of Antibiotic Use Prior To, During, and Following CEWI Diagnosis
In CEWI pre-diagnosis week, 95 patients started an antibiotic with 68 (72%) patients receiving one antibiotic, 19 (20%) patients receiving two antibiotics, six (6%) patients receiving three antibiotics, and two (2%) patients receiving four antibiotics. Fluoroquinolones were received by 49% of the patients, while 31% and 23% were prescribed vancomycin and carbapenem, respectively (Table II). The median duration of use was 4 days for fluoroquinolone, 10 days for carbapenem, and 8 days for vancomycin when started during this period.
During the week of CEWI diagnosis, 209 patients started an antibiotic with 60 (29%) receiving one antibiotic, 97 (46%) receiving two antibiotics, 44 (21%) receiving three antibiotics, and eight (4%) receiving at least four antibiotics. Carbapenem was the most frequent antibiotic prescribed (70% of patients) followed by vancomycin (66%), fluoroquinolone (23%), and aminoglycosides (13%; Table II). Patients received carbapenem for a median of 14 days, while it was 13, 5, and 3 days for vancomycin, fluoroquinolones, and aminoglycosides, respectively.
In the week following CEWI diagnosis, 121 patients started an antibiotic with 74 (61%) patients receiving one antibiotic, 36 (30%) receiving two antibiotics, and 11 (9%) receiving at least three antibiotics. More than one-third of the patients received vancomycin, while 25%, 21%, and 16% received fluoroquinolone, carbapenem, and anti-pseudomonal penicillin, respectively (Table II). The median duration of use was 10 days for vancomycin and carbapenem, 9 days for fluoroquinolone, and 6 days for anti-pseudomonal penicillin.
15-Day Period of Assessment
In the 15-day period of assessment (±7 days of diagnosis date), most patients received either two (N = 93; 34.8%) or three antibiotics (N = 72; 27.0%). A total of 133 (50%) patients had only CEWIs (107 with DSTI and 26 with osteomyelitis as the index infection), while 134 (50%) had a non-extremity infection prior to and/or concurrent with the CEWI (115 with DSTI and 19 with osteomyelitis as the index infection; Supplementary Fig. S1). Both patients with only CEWIs and CEWIs plus other non-extremity infections largely were injured via an improvised explosive device (96% and 98%, respectively) and sustained amputations as their most severe injury (74% and 84%, respectively; Table I). Nevertheless, patients with only CEWIs had lower injury severity (median injury severity score of 30 vs 38; P < 0.001), lower initial shock index (median 1.00 vs 1.26; P < 0.001), had less admissions to the intensive care unit (73% vs 97%; P < 0.001), and required a lower number of units of blood within 24 hours of injury (median units of 15 vs 26; P < 0.001) compared to patients with CEWIs plus other non-extremity infections. In addition, patients with only a CEWI had a shorter duration of initial hospitalization (median of 45 days versus 61 days with CEWI patients with non-extremity infections; P < 0.001).
A total of 208 non-extremity infections were diagnosed in the period prior to and/or concurrent with the CEWI diagnosis: 175 infections among patients with DSTIs and 33 infections among patients with osteomyelitis as the index CEWI (Supplementary Table S1). Bloodstream infections were predominant, representing 30% to 52% of the non-extremity infections diagnosed among the patients with CEWIs (Supplementary Table S1). Pneumonia was also frequently diagnosed in the period prior to and/or concurrent with the DSTI diagnosis (24% and 28% of total non-extremity infection burden, respectively), as well as prior to the osteomyelitis diagnosis (33%).
Among the 107 patients with a DSTI as the index infection, 12 (11%) did not receive any new antibiotics within 7 days of the diagnosis date. Twenty-three (21%) patients received one antibiotic, 44 (41%) received two, 20 (19%) received three, and eight (8%) received at least four different antibiotics (Fig. 1). Fluoroquinolone and vancomycin were the most common antibiotics among patients who only received one antibiotic (seven patients each; 30% of 23). For the 44 patients who received two antibiotics, there were 15 different antibiotic combinations with the most frequent being vancomycin plus carbapenem (21 patients; 47%), while it was the combination of carbapenem plus vancomycin plus fluoroquinolone for patients who received three antibiotics (eight patients; 40% of 20). Three (38% of eight) patients in the group who received at least four antibiotics were prescribed the combination of carbapenem, fluoroquinolone, vancomycin, and aminoglycosides.
FIGURE 1.
Frequency of antibiotics prescribed ±7 days of CEWI diagnosis date and continued for three continuous days among patients with only DSTIs as index infection (N = 107).
Among 26 patients with osteomyelitis as the index infection, one (4%) patient did not receive any new antibiotics within 7 days of the diagnosis date. Eight patients (31% of 26) received only one antibiotic with 50% prescribed anti-pseudomonal penicillin (Fig. 2). Two antibiotics were received by 10 patients (38%) for a total of seven different antibiotic combinations with carbapenem plus vancomycin being the most frequent (four patients; 40%). Six patients received three antibiotics and the most common combination was anti-pseudomonal penicillin plus carbapenem plus fluoroquinolone (two patients; 33%). Lastly, one (4%) patient received aminopenicillin, fluoroquinolone, polymyxin, and vancomycin.
FIGURE 2.
Frequency of antibiotics prescribed ±7 days of CEWI diagnosis date and continued for three continuous days among patients with only osteomyelitis as index infection (N = 26).
Among the 115 patients with DSTIs and a non-extremity infection, five (4%) did not receive any new antibiotics within the 7-day window and 6 (5%) were prescribed only one antibiotic with carbapenem being most frequent (four patients; 67%; Fig. 3). Thirty-three (29%) patients received two antibiotics with 28 (85%) being prescribed the combination of vancomycin and carbapenem. The majority of patients were prescribed three antibiotics (43 patients; 37%) for a total of 13 different antibiotic combinations. Among those patients, the most frequent combination was carbapenem, vancomycin, and fluoroquinolone, which was prescribed to 15 (35%) patients. Twenty-eight (24%) patients were prescribed at least four antibiotics (22 different antibiotic combinations), of whom four (14%) received the combination of aminoglycoside, carbapenem, fluoroquinolone, and vancomycin.
FIGURE 3.
Frequency of antibiotics prescribed ±7 days of CEWI diagnosis date and continued for three continuous days among patients with DSTI plus a non-extremity infection prior to and/or current with DSTI (N = 115).
In the group of patients with osteomyelitis with a non-extremity infection (N = 19), one (5%) patient did not receive any new antibiotics within 7 days of the osteomyelitis diagnosis. Four (21%) patients received only one antibiotic with two (50%) patients being prescribed fluoroquinolones (Fig. 4). The majority of patients received two antibiotics (six patients; 32%) for a total of five different antibiotic combinations with carbapenem plus vancomycin the most common (two patients; 33%). Three (16%) patients received three antibiotics with the combination of carbapenem, vancomycin, and fluoroquinolone prescribed to two (67%) patients. Five patients received at least four antibiotics with each patient being prescribed a different combination.
FIGURE 4.
Frequency of antibiotics prescribed ±7 days of CEWI diagnosis date and continued for three continuous days among patients with osteomyelitis plus a non-extremity infection prior to and/or current with osteomyelitis (N = 19).
DISCUSSION
In the period surrounding a diagnosis of a CEWI (15- and 21-day window, respectively), there is substantial variation related to the number and type of antibiotics prescribed. Although the use of only one antibiotic was most common during the week prior to and after the week of CEWI diagnosis, 71% of patients who started a new antibiotic within 3 days of the CEWI diagnosis were prescribed at least two antibiotics. Combinations of two and three antibiotics were most common within 7 days of CEWI diagnosis with a carbapenem, vancomycin, and fluoroquinolones being the most frequently prescribed. Half of the patients with CEWIs also had a non-extremity wound infection prior to and/or current with the CEWI, resulting in more complicated antibiotic prescribing patterns. Among patients who had a DSTI and a non-extremity infection, 22 different antibiotic combinations containing at least four antibiotics were prescribed. These patients were also more severely injured than those who were diagnosed with only CEWIs and had a longer hospitalization period. With considerations for antibiotic stewardship, clinical practice guidelines are needed to reduce the use of unnecessary antibiotics for the treatment of CEWIs.
Variation for antibiotic prescribing patterns may be attributed to the provider and/or hospital-level factors, such as site-specific policies regulating antibiotic distribution. Clinical wound presentation, extensive polytrauma, and knowledge of other potential patient co-morbidities may have influenced a provider’s prescribing practices. In a prior multicenter, retrospective cohort study, purulence was an independent predictor of broad-spectrum Gram-negative activity or treatment for longer than 10 days for patients with acute bacterial skin and skin structure infections.25 Purulence was also associated with lower adherence to guidelines for the treatment of skin and soft-tissue infections in a single-center retrospective study. The study authors suggested that a potential reason for the reduced adherence is that purulence may have been viewed as a marker for severity and/or a polymicrobial wound infection.26
In 2017, the Global Alliance for Infections in Surgery Working Group, a task force of 234 experts from 83 countries, signed a declaration on the need for appropriate use of antibiotic/antifungal agents in hospitals related to surgical infections in response to the growing threat of antibiotic resistance.27 The declaration focused on antibiotic stewardship by improving prescribing behaviors to decreasing antibiotic misuse/overuse. In particular, locally developed customized antibiotic guidelines were suggested as a method to maintain the effectiveness of current and future antibiotics. For the treatment of surgical infections, it was recommended that empiric therapy should be initiated after an infection is recognized and broad-spectrum therapy should be narrowed once the pathogen is identified, typically performed over a period of days. In addition, empiric therapy should be selected based upon local epidemiology, the risk for multidrug resistance, clinical severity, and infection source. Furthermore, the declaration stressed daily evaluations to assess the ongoing need for and appropriateness of the antibiotic regimen.
Concerned with the rise in multidrug-resistant organisms, the Department of Defense Joint Trauma System convened a consensus panel of civilian and military authorities with expertise in infectious disease to review the knowledge base related to combat trauma-related infections and provide evidence-based recommendations to reduce the use of broad-spectrum antibiotics in the post-trauma antibiotic prophylaxis time frame.15,28 Following the publication of the JTS clinical practice guidelines in 2008 and 2011, post-trauma antibiotic prophylaxis practice patterns have been assessed and improvements in antibiotic stewardship are evident.19–21 In particular, the use of post-trauma expanded Gram-negative coverage with open fractures and maxillofacial injuries significantly declined between 2009 and 2014 (61–7% and 37–12%, respectively).19 However, the JTS guideline does not fully address strategies of empiric therapy recommendations for presumed active infection in combat-related trauma patients or directed therapy following availability of microbiology results. More work is needed to explore optimal management, balancing clinical outcome benefits with potential risk.
Our study does have limitations inherent with retrospective studies using data abstracted from electronic medical records. There is a potential for lack of precision with the date of the CEWI diagnosis; however, we accounted for it by utilizing a 7-day period (±3 days) around the diagnosis date. In addition, as described in the Methods section, we restricted our evaluation of antimicrobials to those used in the treatment of CEWIs.
In our analysis, carbapenem, and vancomycin were the most frequently prescribed antibiotics alone and utilized in multiple combinations with substantial variation in the antibiotics included. Recent studies in a combat casualty population have demonstrated that inclusion of an extended-spectrum antibiotic (i.e., fluoroquinolone or aminoglycoside) with a narrow-spectrum antibiotic (e.g., cefazolin) for post-trauma antibiotic prophylaxis with open fractures or soft-tissue injuries had little benefit.28,29 Specifically, there was no difference in the proportion of osteomyelitis among open fracture patients who received only the narrow-spectrum antibiotic and those who received a narrow-spectrum antibiotic plus an antibiotic with extended-spectrum Gram-negative coverage (8% in both groups). In addition, 49.5% of patients who received the combination of extended-spectrum Gram-negative coverage and a narrow-spectrum antibiotic had an unintended consequence of isolation of resistant Gram-negative organisms versus 40.5% in patients who only received a narrow-spectrum regimen (P < 0.001).29 Similar findings of an increase in resistant bacteria was observed in the study of open soft-tissue injuries (36% vs 19%, respectively; P = 0.001).30 Highly variable antibiotic practice patterns may promote selective resistance for frequently used and currently effective antibiotics. There is also a potential increase in adverse effects of receiving combination antibiotic therapy. In one example, a study found that inclusion of aminoglycoside to a cephalosporin post-trauma prophylaxis regimen with open fractures significantly increased the proportion of acute kidney injury in the patients (10% vs 4%).31 These findings relate to infection prevention; however, similar analyses are needed to assess benefits and harms in the application of empiric and directed antimicrobial therapy among CEWIs.
CONCLUSIONS
Various combinations of antibiotics are being used for the treatment of CEWIs and the long-term impact of these antibiotics is unknown. Clinical practice guidelines are needed to standardize antimicrobial management strategies and reduce the use of broad-spectrum antibiotics not only around the time of diagnosis but also in the periods prior to and following the infection diagnosis. Future analyses will further examine the appropriateness of and clinical outcomes with regards to different antibiotic regimens in order to determine the best clinical management of CEWIs.
Supplementary Material
ACKNOWLEDGMENTS
We are indebted to the Infectious Disease Clinical Research Program Trauma Infectious Disease Outcomes Study team of clinical coordinators, microbiology technicians, data managers, clinical site managers, and administrative support personnel for their tireless hours to ensure the success of this project.
Presented as an oral presentation (MHSRS-18-0908) at the 2018 Military Health System Research Symposium, 20-23 August 2018; Kissimmee, FL.
The views expressed are those of the authors and do not reflect the official views of the Uniformed Services University of the Health Sciences, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the National Institute of Health or the Department of Health and Human Services, Brooke Army Medical Center, Walter Reed National Military Medical Center, Landstuhl Regional Medical Center, the US Army Medical Department, the US Army Office of the Surgeon General, the Department of Defense, or the Departments of the Army, Navy or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the US Government
FUNDING
Support for this work (IDCRP-024) was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense program executed through the Uniformed Services University of the Health Sciences, Department of Preventive Medicine and Biostatistics. This project has been funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under Inter-Agency Agreement Y1-AI-5072, the Department of the Navy under the Wounded, Ill, and Injured Program, and the Defense Medical Research and Development Program.
REFERENCES
- 1. Ficke JR, Eastridge BJ, Butler F, et al. : Dismounted complex blast injury report of the Army Dismounted Complex Blast Injury Task Force. J Trauma Acute Care Surg; 2012; 73(6 Suppl 5): S520–34. [Google Scholar]
- 2. Belmont PJ, Owens BD, Schoenfeld AJ: Musculoskeletal injuries in Iraq and Afghanistan: Epidemiology and outcomes following a decade of war. J Am Acad Orthop Surg; 2016; 24(6): 341–8. [DOI] [PubMed] [Google Scholar]
- 3. Krueger CA, Wenke JC, Ficke JR: Ten years at war: comprehensive analysis of amputation trends. J Trauma Acute Care Surg; 2012; 73(6 Suppl 5): S438–44. [DOI] [PubMed] [Google Scholar]
- 4. Schoenfeld AJ, Dunn JC, Bader JO, Belmont PJ Jr: The nature and extent of war injuries sustained by combat specialty personnel killed and wounded in Afghanistan and Iraq, 2003-2011. J Trauma Acute Care Surg; 2013; 75(2): 287–91. [DOI] [PubMed] [Google Scholar]
- 5. Yun HC, Murray CK, Nelson KJ, Bosse MJ: Infection after orthopaedic trauma: prevention and treatment. J Orthop Trauma; 2016; 30(Suppl 3): S21–6. [DOI] [PubMed] [Google Scholar]
- 6. Brown KV, Murray CK, Clasper JC: Infectious complications of combat-related mangled extremity injuries in the British military. J Trauma; 2010; 69(Suppl 1): S109–15. [DOI] [PubMed] [Google Scholar]
- 7. Murray CK, Obremskey WT, Hsu JR, et al. : Prevention of infections associated with combat-related extremity injuries. J Trauma; 2011; 71(2 Suppl 2): S235–57. [DOI] [PubMed] [Google Scholar]
- 8. Yun HC, Branstetter JG, Murray CK: Osteomyelitis in military personnel wounded in Iraq and Afghanistan. J Trauma; 2008; 64(2 Suppl): S163–8. [DOI] [PubMed] [Google Scholar]
- 9. Huh J, Stinner DJ, Burns TC, Hsu JR: Late Amputation Study Team: infectious complications and soft tissue injury contribute to late amputation after severe lower extremity trauma. J Trauma; 2011; 71(1 Suppl): S47–51. [DOI] [PubMed] [Google Scholar]
- 10. Melcer T, Walker J, Bhatnagar V, Richard E, Sechriest VF 2nd, Galarneau M: A comparison of four-year health outcomes following combat amputation and limb salvage. PLoS One; 2017; 12(1): e0170569. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Napierala MA, Rivera JC, Burns TC, et al. : Infection reduces return-to-duty rates for soldiers with type III open tibia fractures. J Trauma Acute Care Surg; 2014; 77(3 Suppl 2): S194–7. [DOI] [PubMed] [Google Scholar]
- 12. Petersen K, Waterman P: Prophylaxis and treatment of infections associated with penetrating traumatic injury. Expert Rev Anti Infect Ther; 2011; 9(1): 81–96. [DOI] [PubMed] [Google Scholar]
- 13. Webster CE, Clasper J, Stinner DJ, Eliahoo J, Masouros SD: Characterization of lower extremity blast injury. J Mil Med 2018. doi: 10.1093/milmed/usx126 [DOI] [PubMed] [Google Scholar]
- 14. Godfrey BW, Martin A, Chestovich PJ, Lee GH, Ingalls NK, Saldanha V: Patients with multiple traumatic amputations: an analysis of Operation Enduring Freedom. Joint Theatre Trauma Registry data. Injury; 2017; 48(1): 75–9. [DOI] [PubMed] [Google Scholar]
- 15. Hospenthal DR, Murray CK, Andersen RC, et al. : Guidelines for the prevention of infections associated with combat-related injuries: 2011 update: endorsed by the Infectious Diseases Society of America and the Surgical Infection Society. J Trauma; 2011; 71(2 Suppl 2): S210–34. [DOI] [PubMed] [Google Scholar]
- 16. Schauer SG, Fisher AD, April MD, et al. : Prehospital administration of antibiotic prophylaxis for open combat wounds in Afghanistan: 2013-2014. J Spec Oper Med; 2018; 18(2): 53–6. [DOI] [PubMed] [Google Scholar]
- 17. Campbell WR, Li P, Whitman TJ, et al. : Multi-drug–resistant gram-negative infections in deployment-related trauma patients. Surg Infect; 2017; 18(3): 357–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Gordon WT, Petrides MG, Gunn PA, Howard M: Use of sterile pre-fabricated antibiotic beads in the combat hospital setting. J Mil Med 2013; 178(3): 330–3. [DOI] [PubMed] [Google Scholar]
- 19. Lloyd BA, Murray CK, Bradley W, et al. : Variation in postinjury antibiotic prophylaxis patterns over five years in a combat zone. J Mil Med; 2017; 182(S1): 346–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Tribble DR, Lloyd B, Weintrob A, et al. : Antimicrobial prescribing practices following publication of guidelines for the prevention of infections associated with combat-related injuries. J Trauma; 2011; 71(2 Suppl 2): S299–306. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Lloyd BA, Weintrob AC, Hinkle MK, et al. : Adherence to published antimicrobial prophylaxis guidelines for wounded service members in the ongoing conflicts in Southwest Asia. J Mil Med; 2014; 179(3): 324–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Tribble DR, Conger NG, Fraser S, et al. : Infection-associated clinical outcomes in hospitalized medical evacuees after traumatic injury: Trauma Infectious Disease outcome study. J Trauma; 2011; 71(1 Suppl): S33–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Eastridge BJ, Jenkins D, Flaherty S, Schiller H, Holcomb JB: Trauma system development in a theater of war: experiences from Operation Iraqi Freedom and Operation Enduring Freedom. J Trauma; 2006; 61(6): 1366–72. [DOI] [PubMed] [Google Scholar]
- 24. Centers for Disease Control and Prevention CDC/NHSN surveillance definitions for specific types of infections 2018. Available athttp://www.cdc.gov/nhsn/pdfs/pscmanual/17pscnosinfdef_current.pdf;accessed November 30, 2018.
- 25. Jenkins TC, Knepper BC, Moore SJ, et al. : Antibiotic prescribing practices in a multicenter cohort of patients hospitalized for acute bacterial skin and skin structure infection. Infect Control Hosp Epidemiol; 2014; 35(10): 1241–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Ezebuenyi MC, Brakta F, Onor IO, Sarpong DF, Bryant-Burks K, Figueroa JE 2nd: Evaluation of physician prescribing patterns for antibiotics in the treatment of nonnecrotizing skin and soft tissue infections. P&T; 2018; 43(5): 287–92. [PMC free article] [PubMed] [Google Scholar]
- 27. Global Alliance for Infections in Surgery Working Group : A global declaration on appropriate use of antimicrobial agents across the surgical pathway. Surg Infect (Larchmt); 2017; 18(8): 846–53. [DOI] [PubMed] [Google Scholar]
- 28. Hospenthal DR, Murray CK, Andersen RC, et al. : Guidelines for the prevention of infection after combat-related injuries. J Trauma; 2008; 64(3): S211–20. [DOI] [PubMed] [Google Scholar]
- 29. Lloyd BA, Murray CK, Shaikh F, et al. : Early infectious outcomes following addition of fluoroquinolone or aminoglycoside to post-trauma antibiotic prophylaxis in combat-related open fracture injuries. J Trauma Acute Care Surg; 2017; 83(5): 854–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Lloyd BA, Murray CK, Shaikh F, et al. : Antimicrobial prophylaxis with combat-related open soft-tissue injuries. J Mil Med; 2018; 183(9–10): e260–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Bankhead-Kendall B, Gutierrez T, Murry J, et al. : Antibiotics and open fractures of the lower extremity: less is more. Eur J Trauma Emerg Surg 2017. doi: 10.1007/s00068-017-0847-x. [DOI] [PubMed] [Google Scholar]
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