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Cutaneous invasive fungal infections (IFI) occur in deep tissue wounds contaminated by environmental debris; such wounds are caused by agricultural accidents, tornadoes, and blast trauma (1-7). Among severely injured trauma [...]

Introduction: Extremity trauma is the most common battlefield injury, resulting in a high frequency of combat-related extremity wound infections (CEWIs). As these infections are associated with substantial morbidity and may impact wounded warriors long after initial hospitalization, CEWIs have been a focus of the Infectious Disease Clinical Research Program (IDCRP). Herein, we review findings of CEWI research conducted through the IDCRP and discuss future and ongoing analyses.Methods: Military personnel with deployment-related trauma sustained between 2009 and 2014 were examined in retrospective analyses through the observational Trauma Infectious Disease Outcomes Study (TIDOS). Characteristics of wounded warriors with ≥1 open extremity wound were assessed, focusing on injury patterns and infection risk factors. Through a separate trauma-associated osteomyelitis study, military personnel with combat-related open fractures of the long bones (tibia, femur, and upper extremity) sustained between 2003 and 2009 were examined to identify osteomyelitis risk factors.Results: Among 1,271 wounded warriors with ≥1 open extremity wound, 16% were diagnosed with a CEWI. When assessed by their most severe extremity injury (i.e., amputation, open fracture, or open soft-tissue wound), patients with amputations had the highest proportion of infections (47% of 212 patients with traumatic amputations). Factors related to injury pattern, mechanism, and severity were independent predictors of CEWIs during initial hospitalization. Having a non-extremity infection at least 4 days before CEWI diagnosis was associated with reduced likelihood of CEWI development. After hospital discharge, 28% of patients with extremity trauma had a new or recurrent CEWI during follow-up. Risk factors for the development of CEWIs during follow-up included injury pattern, having either a CEWI or other infection during initial hospitalization, and receipt of antipseudomonal penicillin for ≥7 days. A reduced likelihood for CEWIs during follow-up was associated with a hospitalization duration of 15-30 days. Under the retrospective osteomyelitis risk factor analysis, patients developing osteomyelitis had higher open fracture severity based on Gustilo-Anderson (GA) and the Orthopaedic Trauma Association classification schemes and more frequent traumatic amputations compared to open fracture patients without osteomyelitis. Recurrence of osteomyelitis was also common (28% of patients with open tibia fractures had a recurrent episode). Although osteomyelitis risk factors differed between the tibia, femur, and upper extremity groups, sustaining an amputation, use of antibiotic beads, and being injured in the earlier years of the study (before significant practice pattern changes) were consistent predictors. Other risk factors included GA fracture severity ≥IIIb, blast injuries, foreign body at fracture site (with/without orthopedic implant), moderate/severe muscle damage and/or necrosis, and moderate/severe skin/soft-tissue damage. For upper extremity open fractures, initial stabilization following evacuation from the combat zone was associated with a reduced likelihood of osteomyelitis.Conclusions: Forthcoming studies will examine the effectiveness of common antibiotic regimens for managing extremity deep soft-tissue infections to improve clinical outcomes of combat casualties and support development of clinical practice guidelines for CEWI treatment. The long-term impact of extremity trauma and resultant infections will be further investigated through both Department of Defense and Veterans Affairs follow-up, as well as examination of the impact on comorbidities and mental health/social factors. [ABSTRACT FROM AUTHOR]

Recent reclassification of the Klebsiella genus to include Klebsiella variicola, and its association with bacteremia and mortality, has raised concerns. We examined Klebsiella spp. infections among battlefield trauma patients, including occurrence of invasive K. variicola disease. Klebsiella isolates collected from 51 wounded military personnel (2009–2014) through the Trauma Infectious Disease Outcomes Study were examined using polymerase chain reaction (PCR) and pulsed-field gel electrophoresis. K. variicola isolates were evaluated for hypermucoviscosity phenotype by the string test. Patients were severely injured, largely from blast injuries, and all received antibiotics prior to Klebsiella isolation. Multidrug-resistant Klebsiella isolates were identified in 23 (45%) patients; however, there were no significant differences when patients with and without multidrug-resistant Klebsiella were compared. A total of 237 isolates initially identified as K. pneumoniae were analyzed, with 141 clinical isolates associated with infections (remaining were colonizing isolates collected through surveillance groin swabs). Using PCR sequencing, 221 (93%) isolates were confirmed as K. pneumoniae, 10 (4%) were K. variicola, and 6 (3%) were K. quasipneumoniae. Five K. variicola isolates were associated with infections. Compared to K. pneumoniae, infecting K. variicola isolates were more likely to be from blood (4/5 versus 24/134, p = 0.04), and less likely to be multidrug-resistant (0/5 versus 99/134, p<0.01). No K. variicola isolates demonstrated the hypermucoviscosity phenotype. Although K. variicola isolates were frequently isolated from bloodstream infections, they were less likely to be multidrug-resistant. Further work is needed to facilitate diagnosis of K. variicola and clarify its clinical significance in larger prospective studies. [ABSTRACT FROM AUTHOR]

Background: Multidrug-resistant infections complicating combat-related trauma necessitate the use of broad-spectrum antimicrobials. Recent literature posits an association between vancomycin (VANC) and piperacillin--tazobactam (VPT) combination therapy and acute kidney injury (AKI). We examined whether therapy with VPT was associated with an increased risk of AKI compared to VANC and other broad-spectrum b-lactam antibiotics (VBL) following combat-related injuries. Methods: Patients within the Trauma Infectious Disease Outcomes Study (TIDOS) who received ≥48 hours concomitant VPT or VBL started within 24 hours of each other were assessed. Exclusion criteria were receipt of renal replacement therapy and baseline creatinine >1.5 mg/dL. Acute kidney injury was defined by meeting any of the Risk, Injury, Failure, Loss, End Stage Renal Disease (RIFLE), AKIN, or VANC consensus guidelines criteria 3 to 7 days after therapy initiation. Variables significantly associated with AKI were used in inverse probability treatment weighting to perform univariate and subsequent logistic regression multivariate modeling to determine significant risk factors for AKI. Results: Sixty-one patients who received VPT and 207 who received VBL were included. Both groups had a median age of 24 years and initial median creatinine of 0.7 mg/dL. The VBL patients were more likely to have sustained blast injuries (P = .001) and received nephrotoxic agents (amphotericin [P = .002] and aminoglycosides [P < .001]). In the VBL group, AKI incidence was 9.7% compared to 13.1% in the VPT group (P = .438). Multivariate analysis identified a relative risk of 1.727 (95% CI: 1.027-2.765) for AKI associated with VPT exposure. Acute kidney injury severity generally met RIFLE Risk criteria and was 1 day in duration. Only 1 patient had persistent renal dysfunction 30 days after therapy completion. Conclusion: In this young and previously healthy, severely ill combat-injured population, VPT was associated with nearly twice the risk of AKI compared to VBL. Nevertheless, AKI was of low severity, short duration, and had high rates of renal recovery. [ABSTRACT FROM AUTHOR]

Background: During recent wars, 26% of combat casualties experienced open fractures and these injuries frequently are complicated by infections, including osteomyelitis. Risk factors for the development of osteomyelitis with combat-related open tibia fractures have been examined, but less information is known about recurrence of this infection, which may result in additional hospitalizations and surgical procedures.Questions/purposes: (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?Methods: A survey of US military personnel injured during deployment between March 2003 and December 2009 identified 215 patients with open tibia fractures, of whom 130 patients developed osteomyelitis and were examined in a retrospective analysis. No patients with bilateral osteomyelitis were included. Twenty-five patients meeting osteomyelitis diagnostic criteria were classified as definite/probable (positive bone culture, direct evidence of infection, or symptoms with culture and/or radiographic evidence) and 105 were classified as possible (bone contamination, organism growth in deep wound tissue, and evidence of local/systemic inflammation). Patients diagnosed with osteomyelitis were treated with débridement and irrigation as well as intravenous antibiotics. Fixation hardware was retained until fracture union, when possible. Osteomyelitis recurrence was defined as a subsequent osteomyelitis diagnosis at the original site ≥ 30 days after completion of initial treatment. This followup period was chosen based on the definition of recurrence so as to include as many patients as possible for analysis. Factors associated with osteomyelitis recurrence were assessed using univariate analysis in a subset of the population with ≥ 30 days of followup. Patients who had an amputation at or proximal to the knee after the initial osteomyelitis were not included in the recurrence assessment.Results: Of 112 patients meeting the criteria for assessment of recurrence, 31 (28%) developed an osteomyelitis recurrence, of whom seven of 25 (28%) had definite/probable and 24 of 87 (28%) had possible classifications for their initial osteomyelitis diagnosis. Risk of osteomyelitis recurrence was associated with missing or devascularized bone (recurrence, 14 of 31 [47%]; nonrecurrence, 22 of 81 [28%]; hazard ratio [HR], 3.94; 1.12-13.81; p = 0.032) and receipt of antibiotics for 22-56 days (recurrence, 20 of 31 [65%]; nonrecurrence: 37 of 81 [46%]; HR, 2.81; 1.05-7.49; p = 0.039). 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%]; risk ratio [RR], 1.95 [1.19-3.19]; p = 0.008) and less extensive skin and soft tissue injury at the time of trauma (9 of 22 [41%; three definite/probably patients missing data] versus 13 of 104 [13%; one possible patient missing data]; RR, 3.27 [1.60-6.69]; p = 0.001). Most osteomyelitis infections were polymicrobial (14 of 23 [61%; two patients with missing data] for definite/probable patients and 62 of 105 [59%] for possible patients; RR, 1.03 [0.72-1.48]; p = 0.870). More of the definite/probable patients received vancomycin (64%) compared with the possible patients (41%; p = 0.046), and the duration of polymyxin use was longer (median, 38 days versus 16 days, p = 0.018). Time to definitive fracture fixation was not different between the groups.Conclusions: Recurrent osteomyelitis after open tibia fractures is common. In a univariate model, patients with an intermediate amount of bone loss and those treated with antibiotics for 22 to 56 days were more likely to experience osteomyelitis recurrence. Because only univariate analysis was possible, these findings should be considered preliminary. Osteomyelitis recurrence rates were similar, regardless of initial osteomyelitis classification, indicating that diagnoses of possible osteomyelitis should be treated aggressively.Level Of Evidence: Level III, therapeutic study. [ABSTRACT FROM AUTHOR]

ABSTRACT Virtual stress testing (VST) provides a non-invasive estimate of the strength of a healing bone through a biomechanical analysis of a patient's computed tomography (CT) scan. We asked whether VST could improve management of patients who had a tibia fracture treated with external fixation. In a retrospective case-control study of 65 soldier-patients who had tibia fractures treated with an external fixator, we performed VST utilizing CT scans acquired prior to fixator removal. The strength of the healing bone and the amount of tissue damage after application of an overload were computed for various virtual loading cases. Logistic regression identified computed outcomes with the strongest association to clinical events related to nonunion within 2 months after fixator removal. Clinical events ( n = 9) were associated with a low tibial strength for compression loading ( p < 0.05, AUC = 0.74) or a low proportion of failed cortical bone tissue for torsional loading ( p < 0.005, AUC = 0.84). Using post-hoc thresholds of a compressive strength of four times body-weight and a proportional of failed cortical bone tissue of 5%, the test identified all nine patients who failed clinically (100% sensitivity; 40.9% positive predictive value) and over three fourths of those (43 of 56) who progressed to successful healing (76.8% specificity; 100% negative predictive value). In this study, VST identified all patients who progressed to full, uneventful union after fixator removal; thus, we conclude that this new test has the potential to provide a quantitative, objective means of identifying tibia-fracture patients who can safely resume weight bearing. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:805-811, 2017. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: During recent wars in Iraq and Afghanistan, improved survivability in severe trauma corresponded with a rise in the proportion of trauma-related infections, including those associated with multidrug-resistant organisms (MDROs). Significant morbidity was reported in association with the infections. There is also concern regarding potential long-term impacts of the trauma-related infectious complications. Therefore, to meet the critical need of prospective collection of standardized infection-related data to understand the disease burden and improve outcomes of wounded personnel, the Trauma Infectious Disease Outcomes Study (TIDOS) was developed. Herein, we review accomplishments and key peer-reviewed findings of TIDOS.Methods: The TIDOS project is a multicenter observational study of short- and long-term infectious complications following deployment-related trauma. Wounded military personnel medevac'd to Landstuhl Regional Medical Center (LRMC; Germany) before transfer to a participating US military hospital between June 2009 and December 2014 were eligible for inclusion. An infectious disease module to supplement the Department of Defense Trauma Registry by collecting infection-related data from all trauma patients admitted to participating hospitals was developed. Specimens from trauma patients were also collected and retained in a microbiological isolate repository. During the initial hospitalization, patients were given the opportunity to enroll in a prospective follow-up cohort study. Patients who received Department of Veterans Affairs (VA) care were also given the opportunity to consent to ongoing VA follow-up.Results: A total of 2,699 patients transferred to participating military hospitals in the USA, of which 1,359 (50%) patients enrolled in the TIDOS follow-up cohort. In addition, 638 enrolled in the TIDOS-VA cohort (52% of TIDOS enrollees who entered VA healthcare). More than 8,000 isolates were collected from infection control surveillance and diagnostic evaluations and retained in the TIDOS Microbiological Repository. Approximately 34% of the 2,699 patients at US hospitals developed a trauma-related infection during their initial hospitalization with skin and soft-tissue infections being predominant. After discharge from the US hospitals, approximately one-third of TIDOS cohort enrollees developed a new trauma-related infection during follow-up and extremity wound infections (skin and soft-tissue infections and osteomyelitis) continued to be the majority. Among TIDOS cohort enrollees who received VA healthcare, 38% developed a new trauma-related infection with the incident infection being diagnosed a median of 88 days (interquartile range: 19-351 days) following hospital discharge. Data from TIDOS have been used to support the development of Joint Trauma System clinical practice guidelines for the prevention of combat-related infections, as well as the management of invasive fungal wound infections. Lastly, due to the increasing proportion of infections associated with MDROs, TIDOS investigators have collaborated with investigators across military laboratories as part of the Multidrug-Resistant and Virulent Organisms Trauma Infections Initiative with the objective of improving the understanding of the complex wound microbiology in order to develop novel infectious disease countermeasures.Conclusions: The TIDOS project has focused research on four initiatives: (1) blast-related wound infection epidemiology and clinical management; (2) DoD-VA outcomes research; (3) Multidrug- Resistant and other Virulent Organisms Trauma Infections Initiative; and (4) Joint Trauma System clinical practice guidelines and antibiotic stewardship. There is a continuing need for longitudinal data platforms to support battlefield wound research and clinical practice guideline recommendation refinement, particularly to improve care for future conflicts. As such, maintaining a research platform, such as TIDOS, would negate the lengthy time needed to initiate data collection and analysis. [ABSTRACT FROM AUTHOR]

We examined risk factors for combat-related extremity wound infections (CEWI) among U.S. military patients injured in Iraq and Afghanistan (2009–2012). Patients with ≥1 combat-related, open extremity wound admitted to a participating U.S. hospital (≤7 days postinjury) were retrospectively assessed. The population was classified based upon most severe injury (amputation, open fracture without amputation, or open soft-tissue injury defined as non-fracture/non-amputation wounds). Among 1271 eligible patients, 395 (31%) patients had ≥1 amputation, 457 (36%) had open fractures, and 419 (33%) had open soft-tissue wounds as their most severe injury, respectively. Among patients with traumatic amputations, 100 (47%) developed a CEWI compared to 66 (14%) and 12 (3%) patients with open fractures and open soft-tissue wounds, respectively. In a Cox proportional hazard analysis restricted to CEWIs ≤30 days postinjury among the traumatic amputation and open fracture groups, sustaining an amputation (hazard ratio: 1.79; 95% confidence interval: 1.25–2.56), blood transfusion ≤24 hours postinjury, improvised explosive device blast, first documented shock index ≥0.80, and >4 injury sites were independently associated with CEWI risk. The presence of a non-extremity infection at least 4 days prior to a CEWI diagnosis was associated with lower CEWI risk, suggesting impact of recent exposure to directed antimicrobial therapy. Further assessment of early clinical management will help to elucidate risk factor contribution. The wound classification system provides a comprehensive approach in assessment of injury and clinical factors for the risk and outcomes of an extremity wound infection. [ABSTRACT FROM AUTHOR]

Introduction: Back pain related to spinal degenerative disease is one of the most common causes of missed duty days and medical separation for active service members. While the topic of operative versus non-operative treatment of degenerative spine conditions in active military personnel has received more and much needed attention in the last few years, there remains a paucity of data examining the expanded demographics and clinical findings of those undergoing spinal fusion in which validated outcome measures are used to assess post-operative results. The purpose of this study was to define the characteristics and outcomes of spinal fusion surgery at U.S. military medical treatment facilities.Materials and Methods: A cohort of 145 active military personnel undergoing spinal fusion at a single military medical center between 2008 and 2013 were examined in a retrospective fashion using data from primary source documentation recorded prospectively in the military electronic medical records and the image data repository for demographics, clinical/imaging findings and patient reported outcome scores at mean follow-up of 6 mo. Oswestery Disability Index (ODI) scores and the Visual Analog Scale (VAS) were used as patient reported outcome measures. Soldier rank, active duty status, and service-connected disability percentage were also analyzed as military specific outcome measures.Results: The typical solider undergoing spinal fusion was a Caucasian male serving in the U.S. Army. At last follow-up, there were statistically significant improvements in pre-operative to post-operative ODI and VAS scores. Younger age at the time of surgery was a negative predictor for post-operative VAS outcomes (p = 0.047). There were six reoperations in the cohort for neurologic symptoms and hardware migration. The majority of soldiers went on to medical retirement but a considerable number saw an increase in their rank prior to doing so. Those who ended their service in regular retirement and medical retirement went on to see 90.7% and 85% service-connected disability respectively.Discussion: This investigation reports on the largest cohort of active military personnel undergoing spinal fusion. A variety of demographic information are reviewed to clarify the picture of soldiers at risk for needing a spinal fusion. While younger age was an independent risk factors for worsened VAS scores, no independent variable portended a worse ODI score at last follow-up. Despite improvements in objective measures such as VAS, ODI, and increases in rank, soldiers going on to retirement collected a dramatic service-connected disability percentage.Level of Evidence: Level IV, Therapeutic. [ABSTRACT FROM AUTHOR]