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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: In some US potable water supplies, 1,2,3-trichloropropane (TCP) has been present at ranges of non-detect to less than 100ppb, resulting from past uses. In subchronic oral studies, TCP produced toxicity in kidneys, liver, and other tissues. TCP administered by corn oil gavage in chronic studies produced tumors at multiple sites in rats and mice; however, interpretation of these studies was impeded by substantial premature mortality. Drinking water equivalent levels (DWELs) were estimated for a lifetime of consumption by applying biologically-based safety/risk assessment approaches, including Monte Carlo techniques, and with consideration of kinetics and modes of action, to possibly replace default assumptions. Internationally recognized Frameworks for human relevance of animal data were employed to interpret the findings. Calculated were a reference dose (=39μg/kgd) for non-cancer and Cancer Values (CV) (=10–14μg/kgd) based on non-linear dose–response relationships for mutagenicity as a precursor of cancer. Lifetime Average Daily Intakes (LADI) are 3130 and 790–1120μg/person-d for non-cancer and cancer, respectively. DWELs, estimated by applying a relative source contribution (RSC) of 50% to the LADIs, are 780 and 200–280μg/L for non-cancer and cancer, respectively. These DWELs may inform establishment of formal/informal guidelines and standards to protect public health. [Copyright &y& Elsevier]

Abstract: Water soluble compounds persistent in humans and the environment pose a challenge for estimating safe levels in tap water. A viable approach to estimate a drinking water equivalent level (DWEL) for perfluorooctanoic acid (PFOA) was applied to its extensive relevant information from human and laboratory animal studies. PFOA has been identified at 3.5μg/L (mean) in tap water in proximity to a manufacturing facility; however, in most supplies, the levels were below 7.5ng/L (usual limit of detection). PFOA has an average half-life in humans of 3.5years. From animal studies, PFOA is considered a possible hepatotoxicant and developmental toxicant for humans. Based on two chronic studies, PFOA was judged to be a possible human carcinogen, whose mode-of-action was likely to be related to receptor activation but not genotoxicity. The Benchmark Dose-Uncertainty Factor approach was selected for dose–response for noncancer and cancer. Based on internal dose of PFOA, the DWEL protective against cancer is 7.7μgPFOA/L tap water, and the noncancer DWELs range from 0.88 to 2.4μg/L. These DWELs can be considered a reliable, albeit conservative, basis to set a Maximum Concentration Level Goal under the US Safe Drinking Water Act. [Copyright &y& Elsevier]

Abstract: Disinfection by-products (DBP) are produced when water is treated with chemical disinfectants. Some toxicological and epidemiological studies suggest an association between DBP exposure and adverse reproductive and developmental effects. In a previous critical review, [Graves, C.G., Matanoski, G.M., Tardiff, R.G., 2001. Weight of evidence for an association between adverse reproductive and developmental effects and exposure to disinfection by-products: a critical review. Regul. Toxicol. Pharmacol. 34, (2) 103–124] evaluated the weight of evidence for this exposure and these effects. This investigation updates the previous evaluation and considers all toxicological and epidemiological evidence since the earlier review and reassesses the weight-of-evidence for all of the data on the various effects, outcome by outcome. The updated toxicity weight of evidence found little indication of previously unreported reproductive or developmental toxicity. In particular, the recently published findings of an exceptionally well conducted cohort study of broad scope found no impact of chlorination by-products on the highly controversial outcome of spontaneous abortion, unlike predecessor studies of more limited methodology, leading the authors to recommend no further epidemiologic pursuit for this hypothesis since the cohort was scrutinized very closely and dispelled any concern of such an association. The updated epidemiologic weight of evidence demonstrated that no association with DBP exposure exists for over a dozen outcomes including low and very low birth weight, preterm delivery, some specific congenital anomalies, and neonatal death. The analysis found inconsistent or very weak results for all congenital anomalies/birth defects, all central nervous system anomalies, neural tube defects, and spontaneous abortion. As in the previous article, the updated weight of evidence suggested a positive association with DBP exposure and some measure of growth retardation such as intrauterine growth retardation, small for gestational age, term low birth weight, and small body length or head circumference. Exposure assessment in most epidemiological studies remains inadequate to definitively demonstrate any association of small magnitude. [Copyright &y& Elsevier]

Abstract: In this laboratory study, the frequency of locomotor behaviors for two grass shrimp species, Palaemonetes pugio and Palaemonetes vulgaris, and the killifish Fundulus heteroclitus were determined. Additional behaviors, such as grouping of grass shrimp, and pursuit by killifish, the grass shrimp''s common predator, were also analyzed. The results show that mean behavioral frequencies for the two shrimp species were rarely significantly different statistically. Each shrimp species altered its behavior differently in the presence of the other shrimp species, but responded similarly to the presence of the predator. The results indicate that the response of each shrimp species to the predator was dependent upon the predator''s size and health. In situations involving the large health predator, both grass shrimp species significantly reduced swimming, but did not show a significant difference in walking. Behavioral frequencies of large and small healthy killifish were not significantly different from each other when alone, but were significantly different in the presence of prey, while the large unhealthy killifish''s behavior was significantly decreased in all situations compared to both the large and small health killifish. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [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: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: In recent years, invasive fungal infections (IFI) have complicated the clinical course of patients with combat-related injuries. Commonalities in injury patterns and characteristics among patients with IFI led to the development of a Joint Trauma System (JTS) clinical practice guideline (CPG) for IFI management. We performed a case-control study to confirm and further delineate risk factors associated with IFI development in combat casualties with the objective of generating data to refine the CPG and promote timelier initiation of treatment. Methods: Data were collected retrospectively for United States (U.S.) military personnel injured during deployment in Afghanistan from June 2009 through August 2011. Cases were identified as IFI based upon wound cultures with fungal growth and/or fungal elements seen on histology, in addition to the presence of recurrent wound necrosis. Controls were matched using date of injury (±3 mo) and injury severity score (±10). Risk factor parameters analyzed included injury circumstances, blood transfusion requirements, amputations after first operative intervention, and associated injuries. Data are expressed as multivariate odds ratios (OR; 95% confidence interval [CI]). Results: Seventy-six IFI cases were identified from 1,133 U.S. military personnel wounded in Afghanistan and matched to 150 controls. Parameters associated significantly with the development of IFI multivariate analysis were blast injuries (OR: 5.7; CI: 1.1-29.6), dismounted at time of injury (OR: 8.5; CI: 1.2-59.8); above the knee amputations (OR: 4.1; CI: 1.3-12.7), and large-volume packed red blood cell (PRBC; >20 U) transfusions within first 24 h (OR: 7.0; CI: 2.5-19.7). Conclusions: Our analysis indicates that dismounted blast injuries, resulting in above the knee amputations, and requirement of large volume PRBC transfusions are independent predictors of IFI development. These data confirm all the preliminary risk factors, except for genitalia/perineal injuries, utilized by JTS in their IFI CPG. Model validation is necessary for further risk factor specification. [ABSTRACT FROM AUTHOR]

Background: An outbreak of invasive fungal infections (IFI) began in 2009 among United States servicemen who sustained blast injuries in Afghanistan. In response, the military trauma community sought a uniform approach to early diagnosis and treatment. Toward this goal, a local clinical practice guideline (CPG) was implemented at Landstuhl Regional Medical Center (LRMC) in early 2011 to screen for IFI in high-risk patients using tissue histopathology and fungal cultures. Methods: We compared IFI cases identified after initiation of the CPG (February through August 2011) to cases from a pre-CPG period (June 2009 through January 2011). Results: Sixty-one patients were screened in the CPG period, among whom 30 IFI cases were identified and compared with 44 pre-CPG IFI cases. Demographics between the two study periods were similar, although significantly higher transfusion requirements (p<0.05) and non-significant trends in injury severity scores and early lower extremity amputation rates suggested more severe injuries in CPG-period cases. Pre-CPG IFI cases were more likely to be associated with angioinvasion on histopathology than CPG IFI cases (48% versus 17%; p<0.001). Time to IFI diagnosis (three versus nine days) and to initiation of antifungal therapy (seven versus 14 days) were significantly decreased in the CPG period (p<0.001). Additionally, more IFI patients received antifungal agent at LRMC during the CPG period (30%) versus pre-CPG period (5%; p=0.005). The CPG IFI cases were also prescribed more commonly dual antifungal therapy (73% versus 36%; p=0.002). There was no statistical difference in length of stay or mortality between pre-CPG and CPG IFI cases; although a non-significant reduction in crude mortality from 11.4% to 6.7% was observed. Conclusions: Angioinvasive IFI as a percentage of total IFI cases decreased during the CPG period. Earlier diagnosis and commencement of more timely treatment was achieved. Despite these improvements, no difference in clinical outcomes was observed compared with the pre-CPG period. [ABSTRACT FROM AUTHOR]

In 2008, a clinical practice guideline (CPG) was developed for the prevention of infections among military personnel with combat-related injuries. Our analysis expands on a prior 6-month evaluation and assesses CPG adherence with respect to antimicrobial prophylaxis for U.S. combat casualties medically evacuated to Landstuhl Regional Medical Center over a 1-year period (June 2009 through May 2010), with an eventual goal of continuously monitoring CPG adherence and measuring outcomes as a function of compliance. We classified adherence to the CPG as receipt of recommended antimicrobials within 48 hours of injury. A total of 1106 military personnel eligible for CPG assessment were identified and 74% received antimicrobial prophylaxis. Overall, CPG compliance within 48 hours of injury was 75%. Lack of antimicrobial prophylaxis contributed 2 to 22% to noncompliance varying by injury category, whereas receipt of antibiotics other than preferred was 11 to 30%. For extremity injuries, antimicrobial prophylaxis adherence was 60 to 83%, whereas it was 80% for closed injuries and 68% for penetrating abdominal injuries. Overall, the results of our analysis suggest an ongoing need to improve adherence, monitor CPG compliance, and assess effectiveness. [ABSTRACT FROM AUTHOR]

Abstract: Physiologically-based toxicokinetic (“pharmacokinetic”) (PBPK or PBTK) modeling can be used as a tool to compare internal doses of acrylamide (AA) and its metabolite glycidamide (GA) in humans and rats. An earlier PBTK model for AA and GA in rats was refined and extended to humans based on new data. With adjustments to the previous parameters, excellent fits to a majority of the data for male Fisher 344 rats were obtained. Kinetic parameters for the human model were estimated based on fit to available human data for urinary metabolites of AA, and levels of hemoglobin adducts of AA and GA measured in studies in which human volunteers ingested known doses of AA. The simulations conducted with the rat and human models predicted that rats and humans ingesting comparable levels of AA (in mg/kgday) would have similar levels of GA in blood and tissues. This finding stands in contrast to the default approach that assumes a 3.2-fold increase in human risk due to pharmacokinetic differences between rats and humans. This model was used in a companion paper to estimate safe levels of ingested AA. [Copyright &y& Elsevier]

Background Recent work has argued that genus Klebsiella is best divided into 3 clades: K. pneumoniae (Kp) , K. quasipneumoniae (Kq), and K. variicola (Kv). Kv has drawn attention from reports of higher mortality and virulence. We evaluated a previously defined group of military trauma patients with Klebsiella infections for the presence of Kv, described clinical and isolate characteristics, and compared Kv and Kp groups. Methods All initial and serial (≥7 days from prior isolate) infecting Kp isolates (identified by clinical laboratories without the ability to speciate Kq and Kv) were collected from the Trauma Infectious Disease Outcomes Study (6/09–12/14). Additionally, a previously defined group of colonizing isolates linked to the infecting isolates and a selection of random colonizers were included from groin swabs. DNA extraction and PCR targeting Kv per published methods was performed. Antimicrobial susceptibilities were determined using the BD Phoenix Automated Microbiology System and CLSI criteria. Multidrug resistance was defined as either resistance to ≥3 classes of aminoglycosides, β-lactams, carbapenems and/or fluoroquinolones or production of ESBL or KPC. Results Of 237 archived Kp isolates (from 122 patients), 10 (4%) were identified as Kv by PCR (from 8 [7%] patients). The Kv sources were 4 from blood (40%), 1 intra-abdominal (10%) and 5 from groin (50%). Six (3%) isolates were identified as Kq (4 from groin and 2 from respiratory specimens). The Kv and Kp patients were all males, with a median age of 25 (IQR 21–46) and 23 (IQR 21–28), length of hospital stay of 24 days (IQR: 5–106) and 53 days (IQR 36–74), and Injury Severity Score of 21 (IQR: 10–50) and 38 (IQR: 30–45), respectively. There were no deaths in the Kv group compared with 4 with Kp. Infecting Kv isolates were more likely to be from blood compared with Kp (80% vs. 17%, P = 0.04). No infecting Kv isolates were multidrug-resistant compared with 70% of infecting Kp isolates (P < 0.01). Conclusion Kv represented 4% of the previously identified Kp isolates in this population. Patient characteristics were similar in both groups. While Kv was less resistant than Kp, it was more likely to be associated with invasive disease in this group. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Biocides play an integral role in infection control. Paralleling concern about rising incidence of multidrug-resistant (MDR) organisms is a concern for resistance to biocides. In small studies, several genes involved in the production of efflux pump proteins have been identified as markers of biocide resistance in Klebsiella spp. namely cepA , qacA , qacE , qac∆E , and acrA. This study aimed to analyze the Klebsiella spp. isolates of a previously defined military trauma group with a high incidence of MDR organisms for the presence of these genes and their correlation with other resistance. Methods All infecting K. pneumoniae, K. variicola , and K. quasipneumoniae isolates archived by the Trauma Infectious Disease Outcomes Study (June 2009–December 2014) were selected. Additionally, all colonizing isolates linked with infecting isolates were included; the remainder to total 50 MDR and 46 non-MDR colonizing isolates were chosen randomly. Antimicrobial identification and susceptibilities were determined by CLSI criteria using the BD Phoenix Automated Microbiology System. PCR according to published methods for cepA , qacA , qacE , qac∆E , and acrA was accomplished in duplicate. MDR was defined as either resistance to ≥3 classes of aminoglycosides, β-lactams, carbapenems and/or fluoroquinolones or production of an ESBL or KPC. Results A total of 237 isolates (221 K. pneumoniae , 10 K. variicola , 6 K. quasipneumoniae) met inclusion criteria, of which 149 (63%) were MDR. All isolates had been exposed to antimicrobials prior to isolation. Of all isolates, 234 (98%) carried cepA : 218 (98%) K. pneumoniae carried cepA, 10 (100%) K. variicola carried cepA, and 6 (100%) of K. quasipneumoniae carried cepA. In addition, 148 (62%) isolates with cepA were MDR. One (10%) K. variicola isolate carried qacE along with cepA. This isolate was the only MDR K. variicola. None of the isolates carried qacA, qac∆E, or acrA. Conclusion We confirmed the near universal presence of the cepA biocide resistance gene in Klebsiella spp. isolated from trauma patients in Iraq and Afghanistan. In the largest evaluation of biocide resistance genes in Klebsiella spp. to our knowledge, the presence of qacA , qacE , qac∆E , and acrA was less common than has been reported elsewhere. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]