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.

Phenotypic and genotypic changes over time and across facilities of serial colonizing and infecting Escherichia coli isolates recovered from injured service members.

Escherichia coli is the most common colonizing and infecting organism isolated from U.S. service members injured during deployment. Our objective was to evaluate the phenotypic and genotypic changes of infecting and colonizing E. coli organisms over time and across facilities to better understand their transmission patterns. E. coli isolates were collected via surveillance cultures and infection workups from U.S. military personnel injured during deployment (June 2009 to May 2011). The isolates underwent antimicrobial susceptibility testing, pulsed-field gel electrophoresis, and multiplex PCR for phylotyping to determine their resistance profiles and clonality. A total of 343 colonizing and 136 infecting E. coli isolates were analyzed, of which 197 (57%) and 109 (80%) isolates, respectively, produced extended-spectrum ß-lactamases (ESBL). Phylogroup A was predominant among both colonizing (38%) and infecting isolates (43%). Although 188 unique pulsed-field types (PFTs) were identified from the colonizing isolates, and 54 PFTs were identified from the infecting isolates, there was a lack of PFT overlap between study years, combat zones, and military treatment facilities. On a per-subject basis, 26% and 32% of the patients with serial colonizing isolates and 10% and 21% with serial infecting isolates acquired changes in their phylogroup and PFT profiles, respectively, over time. The production of ESBL remained high over time and across facilities, with no substantial changes in antimicrobial susceptibilities. Overall, our results demonstrated an array of genotypic and phenotypic differences for the isolates without large clonal clusters; however, the same PFTs were occasionally observed in the colonizing and infecting isolates, suggesting that the source of infections may be endogenous host organisms.

After the Battlefield: Infectious Complications among Wounded Warriors in the Trauma Infectious Disease Outcomes Study.

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.

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.

Early Infections Complicating the Care of Combat Casualties from Iraq and Afghanistan.

BACKGROUND: During the conflicts in Iraq and Afghanistan, more than 52,000 U.S. military members were wounded in action. The battlefield mortality rate was lower than in past conflicts, however, those surviving often had complex soft tissue and bone injuries requiring multiple surgeries. This report describes the rates, types, and risks of infections complicating the care of combat casualties. PATIENTS AND METHODS: Infection and microbiology data obtained from the Trauma Infectious Disease Outcomes Study (TIDOS), a prospective observational study of infections complicating deployment-related injuries, were used to determine the proportion of infection, types, and associated organisms. Injury and surgical information were collected from the Department of Defense Trauma Registry. Multivariable Cox proportional hazards and logistic regression models were used to evaluate potential factors associated with infection. RESULTS: From 2009-2012, 1,807 combat casualties were evacuated to U.S. TIDOS-participating hospitals. Among the 1,807 patients, the proportion of overall infections from time of injury through initial U.S. hospitalization was 34% with half being skin, soft tissue, or bone infections. Infected wounds most commonly grew Enterococcus faecium, Pseudomonas aeruginosa, Acinetobacter spp. or Escherichia coli. In the multivariable model, amputation, blood transfusions, intensive care unit admission, injury severity scores, mechanical ventilation, and mechanism of injury were associated with risk of infection. CONCLUSIONS: One-third of combat casualties from Iraq and Afghanistan develop infections during their initial hospitalization. Amputations, blood transfusions, and overall injury severity are associated with risk of infection, whereas more easily modifiable factors such as early operative intervention or antibiotic administration are not.

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.

Early Complications and Outcomes in Combat Injury-Related Invasive Fungal Wound Infections: A Case-Control Analysis.

OBJECTIVE: Clinicians have anecdotally noted that combat-related invasive fungal wound infections (IFIs) lead to residual limb shortening, additional days and operative procedures before initial wound closure, and high early complication rates. We evaluated the validity of these observations and identified risk factors that may impact time to initial wound closure. DESIGN: Retrospective review and case-control analysis. SETTING: Military hospitals. PATIENTS/PARTICIPANTS: US military personnel injured during combat operations (2009-2011). The IFI cases were identified based on the presence of recurrent, necrotic extremity wounds with mold growth in culture, and/or histopathologic fungal evidence. Non-IFI controls were matched on injury pattern and severity. In a supplemental matching analysis, non-IFI controls were also matched by blood volume transfused within 24 hours of injury. INTERVENTION: None. MAIN OUTCOME MEASUREMENTS: Amputation revision rate and loss of functional levels. RESULTS: Seventy-one IFI cases (112 fungal-infected extremity wounds) were identified and matched to 160 control patients (315 non-IFI extremity wounds). The IFI wounds resulted in significantly more changes in amputation level (P < 0.001). Additionally, significantly (P < 0.001) higher number of operative procedures and longer duration to initial wound closure were associated with IFI. A shorter duration to initial wound closure was significantly associated with wounds lacking IFIs (Hazard ratio: 1.53; 95% confidence interval, 1.17-2.01). The supplemental matching analysis found similar results. CONCLUSIONS: Our analysis indicates that IFIs adversely impact wound healing and patient recovery, requiring more frequent proximal amputation revisions and leading to higher early complication rates. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

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.

Adherence to published antimicrobial prophylaxis guidelines for wounded service members in the ongoing conflicts in Southwest Asia.

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.

Risk factors associated with invasive fungal infections in combat trauma.

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.

Mycobacterium tuberculosis infection of a presumed Charcot joint.

A 65-year-old male with peripheral neuropathy and small lymphocytic lymphoma presented with erythema and edema of the left foot. A Charcot midfoot was diagnosed and treated with a total contact cast and restricted weight bearing. However, subsequent analysis of bone and synovial fluid months later revealed Mycobacterium tuberculosis infection.