Extremity wounds are predominant among combat casualties and, although soft tissue injuries represent the majority, open fractures have been reported to contribute 26% of the cumulative burden of injury [2, 4, 10, 28-30]. Extremity wound treatment begins in the combat zone with hemorrhage control, wound débridement, provisional fracture stabilization, and antibiotic prophylaxis. Patient outcomes have improved through these early and aggressive interventions [8, 9, 21]. However, despite these interventions, infections are a common complication that may occur long after the injury [4, 14, 20-23, 29, 33, 35]. In fact, in a recent review of open tibia fractures sustained by UK military personnel, a deep infection rate of 23% was reported .
The highest rate of infection (deep soft tissue infections and osteomyelitis) is associated with severe open tibia fractures (Gustilo-Anderson [GA] Type III) [11, 24, 32, 36]. In an analysis of 101 wounded military personnel with an osteomyelitis diagnosis, 28% were hospitalized for a recurrence with a median duration of 128 days to relapse. Injury severity was not different between the patients with and without recurrence. Implantation of orthopaedic devices was associated with recurrent osteomyelitis infections; however, site of infection, pathogen, and antibiotics were not different . Another analysis examined data from 129 civilian patients with osteomyelitis, of which 89% were the result of fractures. Thirty patients (23%) had an osteomyelitis recurrence; 23 were caused by the initial offending microorganism and seven were reinfections with a different organism. Recurrent osteomyelitis was associated with advanced age, involvement of a long bone, inadequate antibiotic treatment, and with treatment solely by an orthopaedic surgeon rather than in conjunction with an infectious disease physician . Furthermore, a review of 67 infected long bone nonunions in a civilian population found 9% developed a recurrent infection with an association with the use of internal fixation .
Although a previous analysis of US military personnel sustaining severe wartime tibia injury identified the risk factors related to the development of osteomyelitis, which include increasing fracture severity, blast injury mechanism, muscle damage, traumatic transtibial amputation, presence of a foreign body near the injury (fragment and/or hardware), and the use of antibiotic beads , less information is known about characteristics of and risk for subsequent osteomyelitis diagnoses (new or recurrent infections) after resolution of the initial infection. Therefore, we asked: (1) What is the risk of osteomyelitis recurrence after wartime open tibia fractures and how does the microbiology compare with initial infections? (2) What factors are associated with osteomyelitis recurrence among patients with open tibia fractures? (3) What clinical characteristics and management approaches are associated with definite/probable osteomyelitis as opposed to possible osteomyelitis and what was the microbiology of these infections?
Patients and Methods
Study Design and Population
Data were retrospectively collected from US service members with deployment-related open tibia fractures sustained between March 19, 2003, and December 31, 2009. Patients were medically evacuated from the theater of combat operations to Landstuhl Regional Medical Center in Germany and subsequently transferred to a military hospital in the United States: Walter Reed Army Medical Center (Washington, DC, USA), the National Naval Medical Center (Bethesda, MD, USA), or Brooke Army Medical Center (San Antonio, TX, USA).
We reviewed records from the Military Health System Data Repository to identify patients with open tibia fractures as potential patients for this retrospective analysis using International Classification of Diseases, 9th Revision codes. Information was also obtained from the Department of Defense Trauma Registry and the Military Health System pharmacy, laboratory, and radiology databases. Patients were included if they met standardized criteria for an osteomyelitis diagnosis and were verified by independent medical record review by an infectious disease clinician and orthopaedic surgeon.
We classified patients with osteomyelitis in accordance with published diagnostic grading (definite, probable, and possible ) and characteristics among the groups were compared to evaluate the validity of the classifications. To examine the burden of and risk factors for osteomyelitis recurrence, we compared characteristics of patients with a minimum of 30 days of followup after resolution of the initial infection. This followup period was chosen based on the definition of recurrence so as to include as many patients as possible for analysis. Patients who had a surgical transfemoral or knee disarticulation amputation after their initial osteomyelitis diagnosis were excluded from the analysis of osteomyelitis recurrence. Use of Military Health System databases and standardized injury codes as well as independent reviews of medical charts limited the potential of bias related to study population selection/classification.
In accordance with published diagnostic grading of the Centers for Disease Control and Prevention, National Healthcare Safety Network , definite osteomyelitis was classified as having either a positive bone culture or evidence of bone infection on direct examination during a surgical procedure or histopathologic examination. Patients in the probable osteomyelitis category had to have at least two of the following signs/symptoms: > 38° C temperature, localized swelling, localized heat, localized tenderness, or drainage at the site along with either blood culture or radiographic evidence of infection. Possible osteomyelitis was defined by patients having environmental contamination at the time of injury, growth of any organisms in deep wound tissue, and evidence of either local or systemic inflammation. Patients with a fracture nonunion on followup examination, in addition to evidence of systemic inflammation, were also classified as having possible osteomyelitis.
A modified version of the GA classification system was used to characterize injuries with open fractures (at the discretion of the orthopaedic surgeon) into four established types: GA-I, GA-II, GA-III  as well as using an additional category for transtibial amputation to adjust for the large number of traumatic and early surgical transtibial amputations in the study population. Fractures were also classified using the Orthopaedic Trauma Association (OTA) Open Fracture Classification (OFC) [19, 27] for skin, muscle, arterial, bone loss, and contamination variables. An osteomyelitis recurrence was defined as the diagnosis and treatment of osteomyelitis at the original wound site ≥ 30 days after completion of the original course of treatment. Infection resolution was defined as the absence of any original findings of infection after the discontinuation of antibiotics and continued progression toward fracture union.
Management of Patients With Osteomyelitis
Patients sustaining an open tibia injury in the combat theatre were initially treated with external fixation and a series of débridement and irrigation procedures as the patient was evacuated from the theater to Landstuhl Regional Medical Center and then subsequently transitioned to a gaining facility in the United States. Care principles followed the clinical practice guidelines on extremity injury, war wounds, and infection prevention published by the Department of Defense Joint Trauma System . Open wounds were typically treated with negative pressure wound therapy. Definitive fixation and wound coverage, if indicated, was performed at hospitals in the United States when the wounds appeared free of necrosis, foreign debris, and any sign of infection. Patients were followed closely to assess for fracture healing and development of complications, including osteomyelitis. Concern for deep infection or osteomyelitis was treated with return to the operating room for débridement and irrigation, where cultures were obtained. The patient was started on intravenous antibiotics with antibiotic therapy managed by an infectious disease consultant. Internal fixation implants were retained when possible. Retention versus conversion to alternative fixation methods, to include external fixation, as well as use of local antibiotic therapy [13, 37], occurred at the discretion of the managing orthopaedic surgeon. Cases of recurrent osteomyelitis were treated in a similar fashion after diagnosis.
Accounting for All Patients
Per the methods described previously, a survey of combat casualties injured between 2003 and 2009 identified 215 patients with open tibia fractures. Among these patients, 130 had an osteomyelitis diagnosis, of whom 12 were classified as definite, 13 as probable, and 105 were possible (Table 1). As a result of their low numbers, patients with the definite and probable classification were combined (N = 25) to facilitate comparison to patients with possible osteomyelitis. Patients were predominantly young (median age, 24 years) men (96%) injured via a blast mechanism (82%) between 2003 and 2006 (62%). Regarding injury severity, 24% experienced a transtibial amputation, 25% had high Injury Severity Scores (ISS ≥ 16, indicating severe to life-threatening injuries), and 24% required large-volume (≥ 10 units) blood transfusions within 24 hours after injury. After excluding seven possible patients who did not have at least 30 days of followup and 11 possible patients who had an amputation at or proximal to the knee after the incident osteomyelitis, a total of 112 patients (25 definite/probable and 87 possible) were assessed for recurrence of osteomyelitis.
Patient characteristics were compared using Fisher’s exact test for categorical variables and the Mann-Whitney U test for continuous variables. Risk ratios (RRs) were calculated to compare characteristics between patients with definite/probable osteomyelitis and those with possible osteomyelitis. Potential risk factors for recurrence of osteomyelitis were examined through Cox proportional hazard models. Covariates with a p value ≤ 0.2 in the univariable model were assessed for inclusion in the multivariable model using stepwise, backward, and forward selection. Kaplan-Meier plots were used to examine time to osteomyelitis recurrence. Probability values of < 0.05 were considered statistically significant. Analysis was conducted with SAS version 9.4 (SAS Institute Inc, Cary, NC, USA).
Osteomyelitis Recurrence and Microbiology
Of 112 patients, 31 (28%) developed an osteomyelitis recurrence; seven of 25 (28%) were classified as definite/probable osteomyelitis and 24 of 87 (28%) were classified as possible for their initial osteomyelitis diagnosis (Table 2). The initial osteomyelitis was diagnosed a median of 8 days after injury (interquartile range [IQR], 6–21 days) for patients with a recurrence and 9 days after injury (IQR, 6–18 days) for patients without a recurrence (p = 0.971). Patients with a recurrence had a median of 1176 days of followup (IQR,724–1873), whereas those who did not were followed for a median of 902 days (IQR, 412–1496; p = 0.046). No patients died during followup. The time from the end of treatment for the initial infections to osteomyelitis recurrence was a median of 188 days (IQR, 114–302). Twenty-eight patients with an osteomyelitis recurrence had isolates recovered from cultures, of which 18 (64%) had polymicrobial infections (Table 3). Eight of 28 patients (29%) had Gram-negative organisms recovered that were consistent with their initial osteomyelitis. No Acinetobacter spp associated with the initial infections were recovered from the recurrent osteomyelitis episodes. Seven of 28 patients (25%) also had a Gram-positive organism recovered that was consistent with the initial infection. Fifteen patients had Staphylococcus aureus isolated from a recurrent infection; however, only two also had S aureus recovered from the initial infection. No Enterococcus spp were isolated from recurrent episodes. No mold species isolated from cultures collected from the initial infection were recovered from the recurrence.
Factors Associated With Osteomyelitis Recurrence
Risk of osteomyelitis recurrence was associated with missing or devascularized bone (recurrence, 14 of 31 [47%]; nonrecurrence, 22 of 81 [28%]; hazards ratio [HR], 3.94; 1.12–13.81; p = 0.032) and receipt of antibiotics for 22-56 days (recurrence, 20 of 31 [64%]; nonrecurrence, 37 of 81 [46%]; HR, 2.81; 1.05–7.49; p = 0.039; Table 2). Other factors (osteomyelitis classification, age, tobacco history, blast injury mechanism, ISS, fracture grade, external fixation, foreign body at bone site, use of antibiotic beads, change in antibiotics after diagnosis, time from injury to osteomyelitis diagnosis, and Acinetobacter spp being the etiologic agent) were not associated with recurrence of osteomyelitis. Assessment with a Kaplan-Meier survival plot found no association with bone loss (Fig. 1).
Clinical Factors, Microbiology, and Management Approaches Associated With Definite/Probable Osteomyelitis
Compared with possible osteomyelitis, definite/probable osteomyelitis was associated with localized swelling at the bone site (13 of 25 [52%] versus 28 of 105 [27%]; RR, 1.95 [1.19-3.19]; p = 0.008; Table 4) and less extensive skin and soft tissue injury at the time of trauma (9 of 22 [41%; three definite/probable patients missing data] versus 13 of 104 [13%; one possible patient missing data]; RR, 3.27 [1.60-6.69]; p = 0.001; Table 5).
Nonetheless, there were no differences with the numbers available related to temperature, localized tenderness, heat, drainage, purulent drainage/necrotic soft tissue, spontaneous dehiscing, and abscesses (Table 4). There were also no differences in GA fracture classification or the OTA OFC muscle, arterial, bone loss, and contamination variables between definite/probable osteomyelitis and possible osteomyelitis (Table 5). Most osteomyelitis infections were polymicrobial (14 of 23 [61%; two patients with missing information] for the definite/probable groups and 62 of 105 [59%] for the possible group; RR, 1.03 [0.72-1.48]; p = 870). The predominant organisms in osteomyelitis infections were Gram-negative bacteria, which were identified in cultures from 19 of 25 (76%) definite/probable patients and 86 of 105 (82%) possible patients (p = 0.573). Nearly half of definite/probable and possible patients (11 of 23 [44%; two patients with missing information] and 59 of 105 [56%], respectively) had infections that involved Acinetobacter spp (with/without other organisms). Gram-positive bacteria were isolated in cultures from 15 of 25 (60%) definite/probable patients and 54 of 105 (51%) possible patients (p = 0.508). A low proportion of mold was also recovered (one definite/probable and five possible patients; p = 1.00).
More of the definite/probable patients received vancomycin (16 of 25 [64%]) compared with the patients in the possible group (43 of 105 [41%]; p = 0.046), and their duration of polymyxin use was longer (median 38 days [IQR, 18-44] versus median 16 days [IQR, 14-18]; p = 0.018; Table 6). After diagnosis, 20 of 25 patients with definite/probable osteomyelitis (80%) and 64 of 105 of those with possible osteomyelitis (62%) had a change in their antibiotic regimens (p = 0.103). The duration of all antibiotic regimens used for treatment was not different between the definite/probable (median, 41 days; IQR, 18–58 days) and possible patients (median, 35 days; IQR, 18–52 days; p = 0.636). When restricted to patients with amputations or amputation revisions after an infection diagnosis, the duration of antibiotic treatment was a median of 60 days (IQR, 25–67) for definite/probable patients and 34 days (IQR, 19–52) for possible patients (p = 0.125). Both groups predominantly received antibiotics from at least four different antibiotic classes during their treatment (nine of 25 [36%] for definite/probable and 39 of 104 [38%; one patient with missing information] for possible patients; Table 6). When restricted to the first 24 days after diagnosis, most definite/probable patients received antibiotics from two different antibiotic classes (nine of 24 [38%; one patient with missing information]); patients in the possible group received antibiotics from four classes (29 of 98 [30%; seven patients with missing information]; p = 0.363). The time from injury to initial osteomyelitis diagnosis was not different between the definite/probable and possible patients (median, 12 [IQR, 6-87] versus 8 [IQR, 6-13] days; p = 0.062; Table 6). Sixty-eight percent of patients (88 of 130) had more than one surgery at the infection site after diagnosis; most were amputation revisions, placement/removal of external hardware, skin graft, and negative-pressure wound therapy. Among the 58 patients who had a surgical amputation or amputation revision (52 after infection diagnosis), 47 (81%) had a transtibial amputation, whereas 11 (19%) required a through-knee or above-knee amputation. For 16 of 58 patients (28%), their amputation or amputation revision was attributed to an infection with no statistical difference between the definite/probable and possible groups (p = 1.00).
Open tibia fractures sustained during war are a common occurrence and frequently result in severe infections such as osteomyelitis. The development of infection has been shown to decrease the likelihood of a service member returning to duty and to increase the disability rate . Care of these patients is further complicated by osteomyelitis recurrence after the initial infection was resolved, resulting in additional hospitalizations, surgical procedures, and antibiotic treatment. We found that recurrence is quite common, occurring in 28% of patients. Cultures from patients with recurrent diagnoses are commonly polymicrobial. Univariate analysis demonstrates that patients sustaining injuries with devascularized bone or requiring antibiotic treatment of 22 to 56 days are associated with osteomyelitis recurrence. Patients diagnosed with osteomyelitis classified less stringently as possible osteomyelitis demonstrated similar recurrence rates, despite being treated with vancomycin less frequently.
Our study has several limitations. Our minimum followup time requirement of 30 days is a short period in comparison to many fracture studies. This interval was chosen to include all possible patients based on our definition of osteomyelitis recurrence that required recurrent symptoms to occur > 30 days after the initial treatment regimen. Despite this short minimum followup for inclusion, the average length of followup for patients with recurrences was 1176 days. An additional pertinent limitation is the low number of patients with osteomyelitis recurrences, precluding multivariate analysis. As such, our findings must be considered exploratory. Additional limitations include the fact that the exact timing of initial débridement and antibiotic administration is unknown, and antibiotic timing represents an important treatment variable, because prior studies have demonstrated that delayed antibiotic administration after open fracture increases the risk of subsequent deep infection [17, 26]. Nevertheless, all patients were treated similarly following established Department of Defense Joint Trauma System treatment guidelines. Furthermore, antibiotic susceptibility information was missing for 21 patients. Nonetheless, most patients received carbapenem or vancomycin as their initial treatment, which should have provided adequate coverage as a result of their broad-spectrum nature. In addition, 54% of patients received at least three different antibiotic classes during their treatment regimen. Future investigations addressing these limitations might explore timing to débridement, use of antibiotic beads or negative-pressure wound dressings, timing to definitive fixation as well as antibiotic susceptibility and capacity to form biofilms with regard to infectious outcomes. In addition, further exploration of the microbiology of recurrent episodes, particularly with S aureus, may be warranted.
Twenty-eight percent of the patients in this cohort developed an osteomyelitis recurrence after resolution of the initial infection with a median time to recurrence of 188 days. Compared with 67% of initial osteomyelitis infections, 64% of recurrent infections were polymicrobial; 50% of these had one or more organisms in common with the initial infection. The rate of recurrence is higher than the approximately 20% relapse rate found in the civilian population . It is similar to the recurrence rate found by Yun and colleagues in military trauma patients, despite our study’s patient group demonstrating higher rates of recurrent polymicrobial infection .
In a case-control analysis of the same patient population with severe wartime tibia injury used in this study, we identified several independent risk factors for the development of osteomyelitis. These factors include a blast injury mechanism, muscle loss, GA fracture type, foreign body near the fracture site (fragment and/or hardware), and use of antibiotic beads. Patients sustaining a transtibial amputation were at highest risk for osteomyelitis . Smoking status and degree of bone loss have also been identified as osteomyelitis risk factors [5, 16, 31]. Regarding antibiotic duration, one analysis of military patients treated for osteomyelitis did not find length of therapy to be associated with recurrence risk , whereas an analysis of civilian patients observed an increased risk with antibiotic regimens shorter than 4 weeks . In our assessment, devascularized or missing bone was a factor associated with osteomyelitis recurrence. Although antibiotic duration was associated with recurrence in our study, it is likely that the duration was chosen in response to intraoperative findings denoting a more severe injury. Interestingly, there was no difference in the proportion of recurrent infections when comparing patients with traumatic amputations with those with open tibia fractures. It is important to note that there was no difference in the likelihood of recurrence whether the initial infection was classified as definite/probable or possible. All patients with an initial diagnosis of osteomyelitis after a severe tibia injury should, therefore, be considered at risk for potential recurrence.
Although not different from definite/probable patients, possible patients did have a shorter time from injury to osteomyelitis diagnoses, likely the result of the less stringent classification definition. Possible patients did not require a positive bone culture, evidence of bone infection on direct examination, or radiographic evidence of infection. Injury severity and characteristics were comparable between the groups except for a lower proportion of less severe soft tissue injury among possible patients. Consistent with a prior analysis , Acinetobacter spp was the predominant etiologic agent. Patients with definite/probable osteomyelitis were more likely to receive vancomycin. Otherwise, these patients were treated in a similar fashion in regard to surgical and antibiotic treatment, including time to definitive fixation. Our findings corroborate the high morbidity associated with an initial diagnosis of osteomyelitis, either definite/probable or possible, because 68% of these patients required at least two surgical procedures after diagnosis; the most common type involved skin grafts, amputation revisions, wound vacuum-assisted closure, and placement of external fixation. Based on this high morbidity, we recommend all patients meeting diagnostic criteria for possible osteomyelitis should be treated definitively.
Overall, our analysis demonstrates that recurrent tibial osteomyelitis is common after combat injury, occurring in 28% of patients. Devascularized bone and antibiotic regimen duration are associated with recurrence among combat casualties. Patients with a probable diagnosis of osteomyelitis have a similar recurrence rate despite receiving vancomycin less frequently. Further investigation of these exploratory findings, with a more detailed focus on their surgical treatment, is merited to better characterize and prevent infection recurrence.
The Trauma Infectious Disease Outcomes Study Group includes Anuradha Ganesan MD, Tyler Warkentien MD, Joseph R. Hsu MD, Jamie Fraser MPH, Denise Bennett MS, Adriana McClung BS, William Bradley MS, Lauren Greenberg MPH, and Jiahong Xu MS, MPH. We are indebted to our 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. We also wish to thank M. Leigh Carson for her assistance in preparing the manuscript.
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