Classification of Trauma-Associated Invasive Fungal Infections to Support Wound Treatment Decisions.

To evaluate a classification system to support clinical decisions for treatment of contaminated deep wounds at risk for an invasive fungal infection (IFI), we studied 246 US service members (413 wounds) injured in Afghanistan (2009-2014) who had laboratory evidence of fungal infection. A total of 143 wounds with persistent necrosis and laboratory evidence were classified as IFI; 120 wounds not meeting IFI criteria were classified as high suspicion (patients had localized infection signs/symptoms and had received antifungal medication for >10 days), and 150 were classified as low suspicion (failed to meet these criteria). IFI patients received more blood than other patients and had more severe injuries than patients in the low-suspicion group. Fungi of the order Mucorales were more frequently isolated from IFI (39%) and high-suspicion (21%) wounds than from low-suspicion (9%) wounds. Wounds that did not require immediate antifungal therapy lacked necrosis and localized signs/symptoms of infection and contained fungi from orders other than Mucorales.

Molecular Detection of Filamentous Fungi in Formalin-Fixed Paraffin-Embedded Specimens in Invasive Fungal Wound Infections Is Feasible with High Specificity.

Trauma-related invasive fungal wound infections (IFIs) are associated with significant morbidity and mortality. Early identification and treatment are critical. Traditional identification methods (e.g., fungal cultures and histopathology) can be delayed and insensitive. We assessed a PCR-based sequencing assay for rapid identification of filamentous fungi in formalin-fixed paraffin-embedded (FFPE) specimens obtained from combat casualties injured in Afghanistan. Blinded FFPE specimens from cases (specimens positive on histopathology) and controls (specimens negative on histopathology) were submitted for evaluation with a panfungal PCR. The internal transcribed spacer 2 (ITS2) region of the fungal ribosomal repeat was amplified and sequenced. The PCR results were compared with findings from histopathology and/or culture. If injury sites contributed multiple specimens, findings for the site were collapsed to the site level. We included 64 case subjects (contributing 95 sites) and 102 controls (contributing 118 sites). Compared to histopathology, panfungal PCR was specific (99%), but not as sensitive (63%); however, sensitivity improved to 83% in specimens from sites with angioinvasion. Panfungal PCR identified fungi of the order Mucorales in 33 of 44 sites with angioinvasion (75%), whereas fungal culture was positive in 20 of 44 sites (45%). Saksenaea spp. were the dominant fungi identified by PCR in specimens from angioinvasion sites (57%). Panfungal PCR is specific, albeit with lower sensitivity, and performs better at identifying fungi of the order Mucorales than culture. DNA sequencing offers significant promise for the rapid identification of fungal infection in trauma-related injuries, leading to more timely and accurate diagnoses.

Environmental Factors Related to Fungal Wound Contamination after Combat Trauma in Afghanistan, 2009-2011.

During the recent war in Afghanistan (2001-2014), invasive fungal wound infections (IFIs) among US combat casualties were associated with risk factors related to the mechanism and pattern of injury. Although previous studies recognized that IFI patients primarily sustained injuries in southern Afghanistan, environmental data were not examined. We compared environmental conditions of this region with those of an area in eastern Afghanistan that was not associated with observed IFIs after injury. A larger proportion of personnel injured in the south (61%) grew mold from wound cultures than those injured in the east (20%). In a multivariable analysis, the southern location, characterized by lower elevation, warmer temperatures, and greater isothermality, was independently associated with mold contamination of wounds. These environmental characteristics, along with known risk factors related to injury characteristics, may be useful in modeling the risk for IFIs after traumatic injury in other regions.

Impact of Mucorales and Other Invasive Molds on Clinical Outcomes of Polymicrobial Traumatic Wound Infections.

Combat trauma wounds with invasive fungal infections (IFIs) are often polymicrobial with fungal and bacterial growth, but the impact of the wound microbiology on clinical outcomes is uncertain. Our objectives were to compare the microbiological features between IFI and non-IFI wounds and evaluate whether clinical outcomes differed among IFI wounds based upon mold type. Data from U.S. military personnel injured in Afghanistan with IFI wounds were examined. Controls were matched by the pattern/severity of injury, including blood transfusion requirements. Wound closure timing was compared between IFI and non-IFI control wounds (with/without bacterial infections). IFI wound closure was also assessed according to mold species isolation. Eighty-two IFI wounds and 136 non-IFI wounds (63 with skin and soft tissue infections [SSTIs] and 73 without) were examined. The time to wound closure was longer for the IFI wounds (median, 16 days) than for the non-IFI controls with/without SSTIs (medians, 12 and 9 days, respectively; P < 0.001). The growth of multidrug-resistant Gram-negative rods was reported among 35% and 41% of the IFI and non-IFI wounds with SSTIs, respectively. Among the IFI wounds, times to wound closure were significantly longer for wounds with Mucorales growth than for wounds with non-Mucorales growth (median, 17 days versus 13 days; P < 0.01). When wounds with Mucorales and Aspergillus spp. growth were compared, there was no significant difference in wound closure timing. Trauma wounds with SSTIs were often polymicrobial, yet the presence of invasive molds (predominant types: order Mucorales, Aspergillus spp., and Fusarium spp.) significantly prolonged the time to wound closure. Overall, the times to wound closure were longest for the IFI wounds with Mucorales growth.

A Seminested PCR Method for the Diagnosis of Invasive Fungal Infections in Combat Injured.

Background: Among combat injured, invasive fungal infections (IFIs) result in significant morbidity. Cultures and histopathology are the primary diagnostic methods for IFIs, but they have limitations. We previously evaluated a panfungal polymerase chain reaction assay, which was 83% sensitive and 99% specific for angioinvasive IFIs. Here, we evaluated 3 less resource-intensive seminested assays targeting clinically relevant fungi in the order Mucorales and genera Aspergillus and Fusarium. Methods: Formalin-fixed paraffin-embedded tissue specimens from a multicenter trauma IFI cohort (2009-2014) were used. Cases were US military personnel injured in Afghanistan with histopathologic IFI evidence. Controls were patients with similar injury patterns and no laboratory IFI evidence (negative culture and histopathology). Seminested assays specific to Mucorales (V4/V5 regions of 18S rDNA), Aspergillus (mitochondrial tRNA), and Fusarium (internal transcribed spacer [ITS]/28A regions of DNA) were compared with a panfungal assay amplifying the internal transcribed spacer 2 region of rDNA and to histopathology. Results: Specimens from 92 injury sites (62 subjects) were compared with control specimens from 117 injuries (101 subjects). We observed substantial agreement between the seminested and panfungal assays overall, especially for the order Mucorales. Moderate agreement was observed at the genus level for Aspergillus and Fusarium. When compared with histopathology, sensitivity and specificity of seminested assays were 67.4% and 96.6%, respectively (sensitivity increased to 91.7% when restricted to sites with angioinvasion). Conclusions: Prior studies of seminested molecular diagnostics have focused on culture-negative samples from immunocompromised patients. Our findings underscore the utility of the seminested approach in diagnosing soft-tissue IFIs using formalin-fixed paraffin-embedded tissue samples, especially with angioinvasion.

Seasonality of Microbiology of Combat-Related Wounds and Wound Infections in Afghanistan.

INTRODUCTION: Battlefield-related wound infections are a significant source of morbidity among combat casualties. Seasonality of these infections was demonstrated in previous conflicts (e.g., Korea) but has not been described with trauma-related health care-associated infections from the war in Afghanistan. METHODS: The study population included military personnel wounded in Afghanistan (2009-2014) medevac'd to Landstuhl Regional Medical Center and transitioned to participating military hospitals in the United States with clinical suspicion of wound infections and wound cultures collected ≤7 days post-injury. Analysis was limited to the first wound culture from individuals. Infecting isolates were collected from skin and soft-tissue infections, osteomyelitis, and burn soft-tissue infections. Data were analyzed by season (winter [ December 1-February 28/29], spring [March 1-May 31], summer [June 1-August 31], and fall [September 1-November 30]). RESULTS: Among 316 patients, 297 (94.0%) sustained blast injuries with a median injury severity score and days from injury to initial culture of 33 and 3.5, respectively. Although all patients had a clinical suspicion of a wound infection, a diagnosis was confirmed in 198 (63%) patients. Gram-negative bacilli (59.5% of 316) were more commonly isolated from wound cultures in summer (68.1%) and fall (67.1%) versus winter (43.9%) and spring (45.1%; P < .001). Multidrug-resistant (MDR) Gram-negative bacilli (21.8%) were more common in summer (21.8%) and fall (30.6%) versus winter (7.3%) and spring (19.7%; P = .028). Findings were similar for infecting Gram-negative bacilli (72.7% of 198)-summer (79.5%) and fall (83.6%; P = .001)-and infecting MDR Gram-negative bacilli (27.3% of 198)-summer (25.6%) and fall (41.8%; P = .015). Infecting anaerobes were more common in winter (40%) compared to fall (11%; P = .036). Gram-positive organisms were not significantly different by season. CONCLUSION: Gram-negative bacilli, including infecting MDR Gram-negative bacilli, were more commonly recovered in summer/fall months from service members injured in Afghanistan. This may have implications for empiric antibiotic coverage during these months.

Combat-Related Invasive Fungal Wound Infections.

INTRODUCTION: During Operation Enduring Freedom in Afghanistan, an outbreak of combat-related invasive fungal wound infections (IFIs) emerged among casualties with dismounted blast trauma and became a priority issue for the Military Health System. METHODS: In 2011, the Trauma Infectious Disease Outcomes Study (TIDOS) team led the Department of Defense IFI outbreak investigation to describe characteristics of IFIs among combat casualties and provide recommendations related to management of the disease. To support the outbreak investigation, existing IFI definitions and classifications utilized for immunocompromised patients were modified for use in epidemiologic research in a trauma population. Following the conclusion of the outbreak investigation, multiple retrospective analyses using a population of 77 IFI patients (injured during June 2009 to August 2011) were conducted to evaluate IFI epidemiology, wound microbiology, and diagnostics to support refinement of Joint Trauma System (JTS) clinical practice guidelines. Following cessation of combat operations in Afghanistan, the TIDOS database was comprehensively reviewed to identify patients with laboratory evidence of a fungal infection and refine the IFI classification scheme to incorporate timing of laboratory fungal evidence and include categories that denote a high or low level of suspicion for IFI. The refined IFI classification scheme was utilized in a large-scale epidemiologic assessment of casualties injured over a 5.5-year period. RESULTS: Among 720 combat casualties admitted to participating hospitals (2009-2014) who had histopathology and/or wound cultures collected, 94 (13%) met criteria for an IFI and 61 (8%) were classified as high suspicion of IFI. Risk factors for development of combat-related IFIs include sustaining a dismounted blast injury, experiencing a traumatic transfemoral amputation, and requiring resuscitation with large-volume (>20 units) blood transfusions. Moreover, TIDOS analyses demonstrated the adverse impact of IFIs on wound healing, particularly with order Mucorales. A polymerase chain reaction (PCR)-based assay to identify filamentous fungi and support earlier IFI diagnosis was also assessed using archived formalin-fixed, paraffin-embedded tissue specimens. Although the PCR-based assay had high specificity (99%), there was low sensitivity (63%); however, sensitivity improved to 83% in tissues collected from sites with angioinvasion. Data obtained from the initial IFI outbreak investigation (37 IFI patients) and subsequent TIDOS analyses (77 IFI patients) supported development and refinement of a JTS clinical practice guideline for the management of IFIs in war wounds. Furthermore, a local clinical practice guideline to screen for early tissue-based evidence of IFIs among blast casualties at the Landstuhl Regional Medical Center was critically evaluated through a TIDOS investigation, providing additional clinical practice support. Through a collaboration with the Uniformed Services University Surgical Critical Care Initiative, findings from TIDOS analyses were used to support development of a clinical decision support tool to facilitate early risk stratification. CONCLUSIONS: Combat-related IFIs are a highly morbid complication following severe blast trauma and remain a threat for future modern warfare. Our findings have supported JTS clinical recommendations, refined IFI classification, and confirmed the utility of PCR-based assays as a complement to histopathology and/or culture to promote early diagnosis. Analyses underway or planned will add to the knowledge base of IFI epidemiology, diagnostics, prevention, and management.

Anastomotic Outcomes in Military Exploratory Laparotomies in the Modern Combat Era.

BACKGROUND: Intestinal anastomoses in military settings are performed in severely injured patients who often undergo damage control laparotomy in austere environments. We describe anastomotic outcomes of patients from recent wars. METHODS: Military personnel with combat-related intra-abdominal injuries (June 2009-December 2014) requiring laparotomy with resection and anastomosis were analyzed. Patients were evacuated from Iraq or Afghanistan to Landstuhl Regional Medical Center (Germany) before being transferred to participating U.S. military hospitals. RESULTS: Among 341 patients who underwent 1053 laparotomies, 87 (25.5%) required ≥1 anastomosis. Stapled anastomosis only was performed in 57.5% of patients, while hand-sewn only was performed in 14.9%, and 9.2% had both stapled and hand-sewn techniques (type unknown for 18.4%). Anastomotic failure occurred in 15% of patients. Those with anastomotic failure required more anastomoses (median 2 anastomoses, interquartile range [IQR] 1-3 vs. 1 anastomosis, IQR 1-2, P = .03) and more total laparotomies (median 5 laparotomies, IQR 3-12 vs. 3, IQR 2-4, P = .01). There were no leaks in patients that had only hand-sewn anastomoses, though a significant difference was not seen with those who had stapled anastomoses. While there was an increasing trend regarding surgical site infections (SSIs) with anastomotic failure after excluding superficial SSIs, it was not significant. There was no difference in mortality. DISCUSSION: Military trauma patients have a similar anastomotic failure rate to civilian trauma patients. Patients with anastomotic failure were more likely to have had more anastomoses and more total laparotomies. No definitive conclusions can be drawn about anastomotic outcome differences between hand-sewn and stapled techniques.

Resistance patterns and clinical outcomes of Klebsiella pneumoniae and invasive Klebsiella variicola in trauma patients.

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.

Risk factors for abdominal surgical site infection after exploratory laparotomy among combat casualties.

BACKGROUND: Surgical site infections (SSIs) are well-recognized complications after exploratory laparotomy for abdominal trauma; however, little is known about SSI development after exploration for battlefield abdominal trauma. We examined SSI risk factors after exploratory laparotomy among combat casualties. METHODS: Military personnel with combat injuries sustained in Iraq and Afghanistan (June 2009 to May 2014) who underwent laparotomy and were evacuated to participating US military hospitals were included. Log-binominal regression was used to identify SSI risk factors. RESULTS: Of 4,304 combat casualties, 341 patients underwent a total of 1,053 laparotomies. Abdominal SSIs were diagnosed in 49 patients (14.4%): 8% with organ space SSI, 4% with deep incisional SSI, and 4% with superficial SSIs (4 patients had multiple SSIs). Patients with SSIs had more colorectal (p < 0.001), small bowel (p = 0.010), duodenum (p = 0.006), pancreas (p = 0.032), and abdominal vascular injuries (p = 0.040), as well as prolonged open abdomen (p = 0.004) and more infections diagnosed before the SSI (or final exploratory laparotomy) versus non-SSI patients (p < 0.001). Sustaining colorectal injuries (risk ratio [RR], 3.20; 95% confidence interval [CI], 1.58-6.45), duodenum injuries (RR, 6.71; 95% CI, 1.73-25.58), and being diagnosed with prior infections (RR, 10.34; 95% CI, 5.05-21.10) were independently associated with any SSI development. For either organ space or deep incisional SSIs, non-intra-abdominal infections, fecal diversion, and duodenum injuries were independently associated, while being injured via an improvised explosive device was associated with reduced likelihood compared with penetrating nonblast (e.g., gunshot wounds) injuries. Non-intra-abdominal infections and hypotension were independently associated with organ space SSIs development alone, while sustaining blast injuries were associated with reduced likelihood. CONCLUSION: Despite severity of injuries and the battlefield environment, the combat casualty laparotomy SSI rate is relatively low at 14%, with similar risk factors and rates reported following severe civilian trauma. LEVEL OF EVIDENCE: Epidemiological, level III.

1,3-Butadiene: II. Genotoxicity profile.

1,3-Butadiene’s (BD’s) major electrophilic metabolites 1,2-epoxy-3-butene (EB), 1,2-dihydroxy-3,4-epoxybutane (EBD), and 1,2,3,4-diepoxybutane (DEB) are responsible for both its mutagenicity and carcinogenicity. EB, EBD, and DEB are DNA reactive, forming a variety of adducts. All three metabolites are genotoxic in vitro and in vivo, with relative mutagenic potencies of DEB >> EB > EBD. DEB also effectively produces gene deletions and chromosome aberrations. BD’s greater mutagenicity and carcinogenicity in mice over rats as well as its failure to induce chromosome-level mutations in vivo in rats appear to be due to greater production of DEB in mice. Concentrations of EB and DEB in vivo in humans are even lower than in rats. Although most studies of BD-exposed humans have failed to find increases in gene mutations, one group has reported positive findings. Reasons for these discordant results are examined. BD-related chromosome aberrations have never been demonstrated in humans except for the possible production of micronuclei in lymphocytes of workers exposed to extremely high levels of BD in the workplace. The relative potencies of the BD metabolites, their relative abundance in the different species, and the kinds of mutations they can induce are major considerations in BD’s overall genotoxicity profile.

Human uptake of persistent chemicals from contaminated soil: PCDD/Fs and PCBs.

Trace amounts of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are ubiquitous in the environment. Because of industrial activity, other human activities, and accidents, higher concentrations of these chemicals may be present in soil, in residential and recreational areas. Human uptake of these chemicals from such soils has been assumed by regulators, and people contacting such soils may be concerned about potential adverse health effects. Accordingly, clean up levels have been set by state and federal agencies. Whether and to what extent humans actually take up these chemicals from soil is the focus of this review. Since humans are also exposed to PCDD/Fs and PCBs in food and air, their concentrations in these media are presented. We find that their presence in soils is unlikely to increase human body burdens.

Stenotrophomonas maltophilia infections: Clinical characteristics in a military trauma population.

Stenotrophomonas maltophilia is a pathogen with unique resistance patterns. We assessed 70 combat casualties with S. maltophilia clinical isolates to examine its role as a nosocomial pathogen in critically-ill trauma patients. Incidence density was 0.36 S. maltophilia infections per 100 patient-days (95% CI: 0.29-0.44). Patients predominantly had blast trauma (97%) and were critically injured (injury severity score [ISS] >25; 80%). Restricting to patients with ISS >15, 50 patients with S. maltophilia infections were compared to 441 patients with infections attributed to other gram-negative bacilli. Patients with S. maltophilia infections had significantly more operating room visits prior to isolation, traumatic or early surgical amputations, longer hospitalization (median 71 vs 47 days), and higher overall mortality (10% vs 2%; P = 0.01). Initial and serial (≥7 days between initial and subsequent isolation) S. maltophilia isolates had high susceptibility to trimethoprim-sulfamethoxazole and minocycline. Evaluation of newer agents awaiting CLSI breakpoints, including moxifloxacin, showed promising results.

Urinary Tract Infections after Combat-Related Genitourinary Trauma.

Background: We examined clinical outcomes among combat casualties with genitourinary injuries after blast trauma. Methods: Characteristics, clinical care, urologic complications, and infections for subjects enrolled in the Trauma Infectious Disease Outcomes Study (TIDOS) were collected from Department of Defense (DOD) and Department of Veterans Affairs (VA) sources. Logistic regression identified predictors for urinary tract infections (UTIs) after genitourinary trauma. Results: Among 530 TIDOS enrollees who entered VA care, 89 (17%) sustained genitourinary trauma. The majority of subjects (93%) were injured via a blast and 27% had a dismounted complex blast injury (DCBI). Sexual dysfunction was reported with 36% of subjects, whereas 14% had urinary retention/incontinence and 8% had urethral stricture. Urologic complications were comparable between patients with and without DCBIs. Nineteen (21%) subjects had one or more UTI with a total of 40 unique UTI events (25% during initial hospitalization and 75% during subsequent DOD or VA care). The UTI incidence rate was 0.89 per patient-year during initial hospitalization, 0.05 per patient-year during DOD follow-up, and 0.07 per patient-year during VA healthcare. Subjects with UTIs had a higher proportion of bladder injury (53% vs. 13%; p < 0.001), posterior urethral injury (26% vs. 1%; p = 0.001), pelvic fracture (47% vs. 4%; p < 0.001), soft-tissue infection of the pelvis/hip (37% vs. 4%; p = 0.001), urinary catheterization (47% vs. 11%; p < 0.001), urinary retention or incontinence (42% vs. 6%; p < 0.001), and stricture (26% vs. 3%; p = 0.004) compared with patients with genitourinary trauma and no UTI. Independent UTI risk factors were occurrence of a soft-tissue infection at the pelvis/hip, trauma to the urinary tract, and transtibial amputation. Conclusions: Among combat casualties with genitourinary trauma, UTIs are a common complication, particularly with severe blast injury and urologic sequelae. Episodes of UTIs typically occur early after the initial injury while in DOD care, however, recurrent infections may continue into long-term VA care.

Antimicrobial Prophylaxis with Combat-Related Open Soft-Tissue Injuries.

INTRODUCTION: All Department of Defense (DoD) guidance documents recommend cefazolin or clindamycin as post-trauma antibiotic prophylaxis for open soft-tissue injuries. Although not advocated, some patients with open soft-tissue injuries also received expanded Gram-negative coverage (EGN) prophylaxis based on the judgment of front-line trauma providers. During the study period, revised guidelines in 2011/2012 re-emphasized recommendations for using cefazolin or clindamycin, and stewardship efforts in the DoD trauma community aimed to reduce the practice of adding EGN to guideline-recommended antibiotic prophylaxis. Our objective was to examine antibiotic utilization among wounded military personnel with open extremity soft-tissue injuries over a 5-yr period and assess the impact on infectious outcomes in patients who received EGN prophylaxis versus guideline-directed prophylaxis. METHODS: The study population included military personnel with open extremity soft-tissue injuries sustained in Iraq and Afghanistan (2009-2014) who transferred to participating hospitals in the USA following medical evacuation. The analysis was restricted to patients who were hospitalized for at least seven days at a U.S. facility and excluded those who sustained open fractures. Post-trauma antibiotic prophylactic regimens were defined as narrow if they followed recommended guidance (e.g., IV cefazolin or clindamycin) or EGN coverage when the narrow regimen also included fluoroquinolones and/or aminoglycosides. Intravenous amoxicillin-clavulanate, which is commonly used at non-U.S. coalition theater hospitals, was also classified as narrow because it conformed to coalition antibiotic prophylaxis guidelines. This study was approved by the Infectious Disease Institutional Review Board of the Uniformed Services University of the Health Sciences. RESULTS: A total of 287 wounded personnel with open soft-tissue injuries were assessed, of which 212 (74%) received narrow prophylaxis and 75 (26%) received EGN coverage (p < 0.001). Among patients in the narrow prophylaxis group, 81% were given cefazolin and/or clindamycin, while 19% received amoxicillin-clavulanate. In the EGN group, 88% and 12% received a fluoroquinolone and aminoglycoside, respectively. Use of EGN coverage significantly declined during the study period from 39% in 2009-2010 to 11% in 2013-2014 (p < 0.001). Approximately 3% of patients who received a narrow regimen developed an extremity skin and soft-tissue infection, while there were no skin and soft-tissue infections among patients in the EGN coverage group. Nonetheless, this was not a significant difference (p = 0.345). In addition, the proportion of non-extremity infections was not significantly different between narrow and EGN regimen groups (11% and 15%, respectively). There were also no significant differences between the narrow and EGN regimen groups related to duration of hospitalization (median of 19 versus 20 d). CONCLUSION: Use of non-guideline directed EGN-based post-trauma antibiotic prophylaxis does not improve infectious outcomes nor does it shorten hospital stay.

Epidemiology of Trauma-Related Infections among a Combat Casualty Cohort after Initial Hospitalization: The Trauma Infectious Disease Outcomes Study.

BACKGROUND: The Trauma Infectious Disease Outcomes Study (TIDOS) cohort follows military personnel with deployment-related injuries in order to evaluate short- and long-term infectious complications. High rates of infectious complications have been observed in more than 30% of injured patients during initial hospitalization. We present data on infectious complications related to combat trauma after the initial period of hospitalization. PATIENTS AND METHODS: Data related to patient care for military personnel injured during combat operations between June 2009 and May 2012 were collected. Follow-up data were captured from interviews with enrolled participants and review of electronic medical records. RESULTS: Among 1,006 patients enrolled in the TIDOS cohort with follow-up data, 357 (35%) were diagnosed with one or more infection during their initial hospitalization, of whom 160 (45%) developed a trauma-related infection during follow-up (4.2 infections per 10,000 person-days). Patients with three or more infections during the initial hospitalization had a significantly higher rate of infections during the follow-up period compared with those with only one inpatient infection (incidence rate: 6.6 versus 3.1 per 10,000 days; p < 0.0001). There were 657 enrollees who did not have an infection during initial hospitalization, of whom 158 (24%) developed one during follow-up (incidence rate: 1.6 per 10,000 days). Overall, 318 (32%) enrolled patients developed an infection after hospital discharge (562 unique infections) with skin and soft-tissue infections being predominant (66%) followed by osteomyelitis (16%). Sustaining an amputation or open fracture, having an inpatient infection, and use of anti-pseudomonal penicillin (≥7 d) were independently associated with risk of an extremity wound infection during follow-up, whereas shorter hospitalization (15-30 d) was associated with a reduced risk. CONCLUSIONS: Combat-injured patients have a high burden of infectious complications that continue long after the initial period of hospitalization with soft-tissue and osteomyelitis being predominant. Further research on the long-term impact and outcomes of combat-associated infection is needed.

Variation in Postinjury Antibiotic Prophylaxis Patterns Over Five Years in a Combat Zone.

In 2008, a clinical practice guideline (CPG) was developed for the prevention of infections among combat casualties and was later revised in 2011. We evaluated utilization of antimicrobials within 48 hours following injury in the combat zone over a 5-year period (June 2009 through May 2014) with regard to number of regimens, type of antimicrobial, and adherence to the 2011 CPG. The study population consisted of 5,196 wounded military personnel. Open fractures and skin and soft-tissue injuries were the most frequent injuries. Closed injuries had the highest overall compliance (83%), whereas open fractures and maxillofacial injuries had significant improvement in compliance from 2009-2010 (34 and 50%, respectively) to 2013-2014 (73 and 76%, respectively; p < 0.05). Part of the improvement with open fractures was a significant reduction of expanded Gram-negative coverage (61% received it in 2009-2010 compared to 7% in 2013-2014; p < 0.001). Use of Gram-negative coverage with maxillofacial injuries also significantly declined (37-12%; p = 0.001). Being injured during 2011-2014 compared to 2009-2010 was associated with CPG compliance (p < 0.001), while high injury severity scores (≥10) and admission to the intensive care unit in Germany were associated with noncompliance (p < 0.001). Our analysis demonstrates an increasing trend toward CPG compliance with significant reduction of expanded Gram-negative coverage.

Early infectious outcomes after addition of fluoroquinolone or aminoglycoside to posttrauma antibiotic prophylaxis in combat-related open fracture injuries.

BACKGROUND: We examined combat-related open extremity fracture infections as a function of whether posttrauma antimicrobial prophylaxis included expanded Gram-negative (EGN) coverage. METHODS: Military personnel with open extremity fractures sustained in Iraq and Afghanistan (2009-2014) who transferred to participating hospitals in the United States were assessed. The analysis was restricted to patients with a U.S. hospitalization period of ≥7 days. Prophylaxis was classified as narrow (e.g., IV cefazolin, clindamycin, and/or amoxicillin-clavulanate) or EGN, if the prophylactic regimen included fluoroquinolones and/or aminoglycosides. RESULTS: The study population included 1,044 patients, of which 585 (56%) and 459 (44%) received narrow and EGN coverage, respectively (p < 0.001). Skin and soft-tissue infections (SSTIs) were more common among patients who received narrow prophylaxis compared to EGN coverage (28% vs. 22%; p = 0.029), whereas osteomyelitis rates were comparable between regimens (8%). Similar findings were noted when endpoints were measured at 2 and 4 weeks postinjury. There was no significant difference related to length of hospitalization between narrow and EGN regimens (median: 34 and 32 days, respectively) or operating room visits (median: 5 and 4). A higher proportion of EGN coverage patients had Gram-negative organisms isolated that were not susceptible to fluoroquinolones and/or aminoglycosides (49% vs. 40%; p < 0.001). In a Cox proportional model, narrow prophylaxis was independently associated with an increased risk of extremity SSTIs (hazard ratio: 1.41; 95% confidence interval: 1.09-1.83). DISCUSSION: Despite seeing a small benefit with EGN coverage related to a reduction of SSTIs, it does not decrease the risk of osteomyelitis, and there seems to be a cost of increased antibiotic resistance associated with use. Overall, our findings support the current post-combat trauma antibiotic prophylaxis guidelines, which recommend the use of cefazolin or clindamycin with open fractures. LEVEL OF EVIDENCE: Prognostic/Epidemiological, Level II; Therapy, level IV.

Impact of Operational Theater on Combat and Noncombat Trauma-Related Infections.

The Trauma Infectious Disease Outcomes Study began in June 2009 as combat operations were decreasing in Iraq and increasing in Afghanistan. Our analysis examines the rate of infections of wounded U.S. military personnel from operational theaters in Iraq and Afghanistan admitted to Landstuhl Regional Medical Center between June 2009 and December 2013 and transferred to a participating U.S. hospital. Infection risk factors were examined in a multivariate logistic regression analysis (expressed as odds ratios [OR]; 95% confidence intervals [CI]). The study population includes 524 wounded military personnel from Iraq and 4,766 from Afghanistan. The proportion of patients with at least one infection was 28% and 34% from the Iraq and Afghanistan theaters, respectively. The incidence density rate was 2.0 (per 100 person-days) for Iraq and 2.7 infections for Afghanistan. Independent risk factors included large-volume blood product transfusions (OR: 10.68; CI: 6.73-16.95), high Injury Severity Score (OR: 2.48; CI: 1.81-3.41), and improvised explosive device injury mechanism (OR: 1.84; CI: 1.35-2.49). Operational theater (OR: 1.32; CI: 0.87-1.99) was not a risk factor. The difference in infection rates between operational theaters is primarily a result of increased injury severity in Afghanistan from a higher proportion of blast-related trauma during the study period.

Compliance with antimalarial chemoprophylaxis recommendations for wounded United States military personnel admitted to a military treatment facility.

Malaria chemoprophylaxis is used as a preventive measure in military personnel deployed to malaria-endemic countries. However, limited information is available on compliance with chemoprophylaxis among trauma patients during hospitalization and after discharge. Therefore, we assessed antimalarial primary chemoprophylaxis and presumptive antirelapse therapy (primaquine) compliance among wounded United States military personnel after medical evacuation from Afghanistan (June 2009-August 2011) to Landstuhl Regional Medical Center in Landstuhl, Germany, and then to three U.S. military hospitals. Among admissions at Landstuhl Regional Medical Center, 74% of 2,540 patients were prescribed primary chemoprophylaxis and < 1% were prescribed primaquine. After transfer of 1,331 patients to U.S. hospitals, 93% received primary chemoprophylaxis and 33% received primaquine. Of 751 trauma patients with available post-admission data, 42% received primary chemoprophylaxis for four weeks, 33% received primaquine for 14 days, and 17% received both. These antimalarial chemoprophylaxis prescription rates suggest that improved protocols to continue malaria chemoprophylaxis in accordance with force protection guidelines are needed.