Intravenous Cefazolin Achieves Sustained High Interstitial Concentrations in Open Lower Extremity Fractures.

BACKGROUND: Infection remains a serious clinical concern in patients with open fractures, despite timely antibiotic administration and surgical debridement. Soft tissue and periosteal stripping may alter local tissue homeostasis and antibiotic pharmacokinetics in the injured limb. The tissue (interstitial) concentration of intravenously administered antibiotics at an open fracture site has not been characterized using direct sampling techniques. QUESTION/PURPOSE: We performed this study to evaluate the concentration and pharmacokinetics of intravenously delivered cefazolin at an open fracture site after surgical debridement. METHODS: Twelve patients with an open fracture distal to the knee who presented at a regional Level I trauma center were approached for enrollment in this nonrandomized, observational study. Of the 12 patients, eight adults (one female, seven male) with a median age of 32 years (range 23 to 51 years) were enrolled and underwent successful sample collection for analysis. Three patients had incomplete datasets because of equipment malfunction and one elected not to participate. Seven patients had open tibia fractures, and one patient had an open fibula fracture associated with a closed tibia fracture. There were six Gustilo-Anderson Type II injuries and two Type IIIA injuries. Empiric antibiotics were administered in the prehospital setting or in the emergency department according to institutional protocol. When patients were taken to the operating room, a 2-g intravenous dose of cefazolin was administered. After surgical debridement, fracture stabilization, and wound closure, a microdialysis catheter was placed transdermally into the injury zone (within 5 cm of the fracture site) and a second catheter was placed in the contralateral uninjured (control) limb. Additional doses of cefazolin were administered every 8 hours postoperatively. Baseline and periodic interstitial fluid and whole blood (plasma) samples were collected in the operating room and at prespecified times for 24 hours postoperatively. Free cefazolin in the interstitial fluid and plasma samples were analyzed by ultra-high-performance liquid chromatography using C 18 column separation with quadrupole time-of-flight mass spectrometry detection. Data from the second postoperative dose of cefazolin were used to characterize pharmacokinetic parameters through a noncompartmental analysis using time-concentration curves of free cefazolin and assuming first-order elimination. For pharmacodynamic analyses, the modal cefazolin minimum inhibitory concentration (MIC) of Staphylococcus aureus (1 µg/mL) was used. RESULTS: With the samples available, no difference was observed in the median free cefazolin exposure over 24 hours ( f area under the curve [AUC] 0→24hrs ) between injured limbs (352 µg∙hr/mL [IQR 284 to 594 µg∙hr/mL]) and uninjured limbs (341 µg∙hr/mL [IQR 263 to 438 µg∙hr/mL]; p = 0.64). The median time to achieve the maximum concentration of free cefazolin ( f T max ) for injured limbs was delayed (2.7 hours [IQR 2.2 to 3.1 hours]) compared with control limbs (1.7 hours [IQR 1.2 to 2.0 hours]; p = 0.046). The time to the maximum concentration for plasma was not different from that of control limbs (p = 0.08). The time the cefazolin concentration was above the modal S. aureus MIC (T > MIC) in the injured and control limbs over 24 hours was 100% (IQR 100% to 100%) and 100% (IQR 97% to 100%), respectively. CONCLUSION: These preliminary findings suggest that current prophylactic cefazolin dosing regimens result in successful antibiotic delivery to the traumatized limb in moderately severe open fractures. Although cefazolin delivery to open-fracture wound beds was delayed compared with healthy tissues, the cefazolin concentration was sustained above the European Union Committee Antimicrobial Susceptibility Testing modal MIC for S. aureus , demonstrating a high likelihood of a prophylactic antimicrobial environment at an open fracture site with this empiric antimicrobial regimen. Importantly, patients in this analysis had Gustilo-Anderson Types II and IIIA injuries. Further research with a larger patient cohort is needed to determine whether antibiotic delivery to traumatized soft tissues in patients with higher-grade open fractures (Gustilo-Anderson Types IIIB and IIIC) demonstrates similar pharmacokinetic characteristics. LEVEL OF EVIDENCE: Level II, therapeutic study.

A Review of Omadacycline for Potential Utility in the Military Health System for the Treatment of Wound Infections.

INTRODUCTION: Combat-related wound infections complicate the recovery of wounded military personnel, contributing to overall morbidity and mortality. Wound infections in combat settings present unique challenges because of the size and depth of the wounds, the need to administer emergency care in the field, and the need for subsequent treatment in military facilities. Given the increase in multidrug-resistant pathogens, a novel, broad-spectrum antibiotic is desired across this continuum of care when the standard of care fails. Omadacycline was FDA-approved in 2018 for treatment of adults with acute bacterial skin and skin structure infections (ABSSSI), as well as community-acquired bacterial pneumonia (CABP). It is a broad-spectrum antibiotic with activity against gram-positive, gram-negative, and atypical bacterial pathogens, including multidrug-resistant species. Omadacycline can overcome commonly reported tetracycline resistance mechanisms, ribosomal protection proteins, and efflux pumps, and is available in once-daily intravenous or oral formulations. In this review, we discuss the potential role of omadacycline, which is included in the Department of Defense Formulary, in the context of combat wound infections. MATERIALS AND METHODS: A literature review was undertaken for manuscripts published before July 21, 2023. This included a series of publications found via PubMed and a bibliography made publicly available on the Paratek Pharmaceuticals, Inc. website. Publications presenting primary data published in English on omadacycline in relation to ESKAPEE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and Enterobacter species) pathogens and Clostridioides difficile, including in vitro, in vivo, and clinical data were included. RESULTS: Of 260 identified records, 66 were included for evidence review. Omadacycline has in vitro activity against almost all the ESKAPEE pathogens, apart from P. aeruginosa. Importantly, it has activity against the four most prevalent bacterial pathogens that cause wound infections in the military healthcare system: S. aureus, including methicillin-resistant S. aureus, A. baumannii, K. pneumoniae, and E. coli. In vivo studies in rats have shown that omadacycline is rapidly distributed in most tissues, with the highest tissue-to-blood concentration ratios in bone mineral. The clinical efficacy of omadacycline has been assessed in three separate Phase 3 studies in patients with ABSSSI (OASIS-1 and OASIS-2) and with CABP (OPTIC). Overall, omadacycline has an established safety profile in the treatment of both ABSSSI and CABP. CONCLUSIONS: Omadacycline has broad-spectrum activity, the option to be orally administered and an established safety profile, making it a potentially attractive replacement for moxifloxacin in the military individual first aid kit, especially when accounting for the increasing resistance to fluoroquinolones. Further studies and clinical evaluation are warranted to support broader use of omadacycline to treat combat wound infections in the military healthcare system.

DIAGNOSTIC VALUE OF MITOCHONDRIAL DNA AND PERIPHERAL BLOOD MONONUCLEAR CELL RESPIROMETRY FOR BURN-RELATED SEPSIS.

ABSTRACT: Background: Sepsis is the leading cause of mortality among burn patients that survive acute resuscitation. Clinical criteria have poor diagnostic value for burn-induced sepsis, making it difficult to diagnose. Protein biomarkers (e.g., procalcitonin) have been examined with limited success. We aimed to explore other biomarkers related to mitochondria (mitochondrial DNA [mtDNA]) and mitochondrial function of peripheral blood mononuclear cells (PBMCs) for sepsis diagnosis in burn patients. Methods: We conducted a follow-up analysis of a single center, prospective observational study of subjects (n = 10 healthy volunteers, n = 24 burn patients) to examine the diagnostic value of mtDNA and PBMC respirometry. Patients were enrolled regardless of sepsis status and followed longitudinally. Patient samples were classified as septic or not based on empiric clinical criteria. Isolated PBMCs were loaded into a high-resolution respirometer, and circulating mtDNA was measured with a PCR-based assay. Sequential Organ Failure Assessment (SOFA) criteria were also compared. Results: The SOFA criteria comparing septic versus before/nonseptic patients revealed significantly higher heart rate ( P = 0.012) and lower mean arterial pressure ( P = 0.039) in burn sepsis. MtDNA was significantly elevated in septic burn patients compared with healthy volunteers ( P < 0.0001) and nonseptic patients ( P < 0.0001), with no significant difference between healthy volunteers and nonseptic burn patients ( P = 0.187). The area under the ROC curve (AUC) for mtDNA was 0.685 (95% confidence interval = 0.50-0.86). For PBMC respirometry, burn patients exhibited increased routine and maximal respiration potential compared with healthy volunteers. However, no difference was found between nonseptic and septic patient samples. A subanalysis revealed a significant mortality difference in PBMC respirometry after sepsis diagnosis, wherein survivors had higher routine respiration ( P = 0.003) and maximal respiration ( P = 0.011) compared with nonsurvivors. Conclusion: Our findings reveal that mtDNA may have diagnostic value for burn sepsis, whereas PBMC respirometry is nonspecifically elevated in burns, but may have value in mortality prognosis. A larger, multisite study is warranted for further validity of the diagnostic value of mtDNA and PBMC respirometry as biomarkers for prognosis of sepsis and outcomes in burn patients.

Comparison of Piperacillin and Tazobactam Pharmacokinetics in Critically Ill Patients with Trauma or with Burn.

Critical illness caused by burn and sepsis is associated with pathophysiologic changes that may result in the alteration of pharmacokinetics (PK) of antibiotics. However, it is unclear if one mechanism of critical illness alters PK more significantly than another. We developed a population PK model for piperacillin and tazobactam (pip-tazo) using data from 19 critically ill patients (14 non-burn trauma and 5 burn) treated in the Military Health System. A two-compartment model best described pip-tazo data. There were no significant differences found in the volume of distribution or clearance of pip-tazo in burn and non-burn patients. Although exploratory in nature, our data suggest that after accounting for creatinine clearance (CrCl), doses would not need to be increased for burn patients compared to trauma patients on consideration of PK alone. However, there is a high reported incidence of augmented renal clearance (ARC) in burn patients and pharmacodynamic (PD) considerations may lead clinicians to choose higher doses. For critically ill patients with normal kidney function, continuous infusions of 13.5-18 g pip-tazo per day are preferable. If ARC is suspected or the most stringent PD targets are desired, then continuous infusions of 31.5 g pip-tazo or higher may be required. This approach may be reasonable provided that therapeutic drug monitoring is enacted to ensure pip-tazo levels are not supra-therapeutic.

Multidrug-Resistant and Virulent Organisms Trauma Infections: Trauma Infectious Disease Outcomes Study Initiative.

INTRODUCTION: During the wars in Iraq and Afghanistan, increased incidence of multidrug-resistant (MDR) organisms, as well as polymicrobial wounds and infections, complicated the management of combat trauma-related infections. Multidrug resistance and wound microbiology are a research focus of the Trauma Infectious Disease Outcomes Study (TIDOS), an Infectious Disease Clinical Research Program, Uniformed Services University, research protocol. To conduct comprehensive microbiological research with the goal of improving the understanding of the complicated etiology of wound infections, the TIDOS MDR and Virulent Organisms Trauma Infections Initiative (MDR/VO Initiative) was established as a collaborative effort with the Brooke Army Medical Center, Naval Medical Research Center, U.S. Army Institute of Surgical Research, and Walter Reed Army Institute of Research. We provide a review of the TIDOS MDR/VO Initiative and summarize published findings. METHODS: Antagonism and biofilm formation of commonly isolated wound bacteria (e.g., ESKAPE pathogens-Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), antimicrobial susceptibility patterns, and clinical outcomes are being examined. Isolates collected from admission surveillance swabs, as part of infection control policy, and clinical infection workups were retained in the TIDOS Microbiological Repository and associated clinical data in the TIDOS database. RESULTS: Over the TIDOS study period (June 2009 to December 2014), more than 8,300 colonizing and infecting isolates were collected from military personnel injured with nearly one-third of isolates classified as MDR. At admission to participating U.S. military hospitals, 12% of wounded warriors were colonized with MDR Gram-negative bacilli. Furthermore, 27% of 913 combat casualties with ≥1 infection during their trauma hospitalization had MDR Gram-negative bacterial infections. Among 335 confirmed combat-related extremity wound infections (2009-2012), 61% were polymicrobial and comprised various combinations of Gram-negative and Gram-positive bacteria, yeast, fungi, and anaerobes. Escherichia coli was the most common Gram-negative bacilli isolated from clinical workups, as well as the most common colonizing MDR secondary to extended-spectrum ß-lactamase resistance. Assessment of 479 E. coli isolates collected from wounded warriors found 188 pulsed-field types (PFTs) from colonizing isolates and 54 PFTs from infecting isolates without significant overlap across combat theaters, military hospitals, and study years. A minority of patients with colonizing E. coli isolates developed subsequent infections with the same E. coli strain. Enterococcus spp. were most commonly isolated from polymicrobial wound infections (53% of 204 polymicrobial cultures). Patients with Enterococcus infections were severely injured with a high proportion of lower extremity amputations and genitourinary injuries. Approximately 65% of polymicrobial Enterococcus infections had other ESKAPE organisms isolated. As biofilms have been suggested as a cause of delayed wound healing, wound infections with persistent recovery of bacteria (isolates of same organism collected ≥14 days apart) and nonrecurrent bacterial isolates were assessed. Biofilm production was significantly associated with recurrent bacteria isolation (97% vs. 59% with nonrecurrent isolates; P < 0.001); however, further analysis is needed to confirm biofilm formation as a predictor of persistent wound infections. CONCLUSIONS: The TIDOS MDR/VO Initiative provides comprehensive and detailed data of major microbial threats associated with combat-related wound infections to further the understanding of wound etiology and potentially identify infectious disease countermeasures, which may lead to improvements in combat casualty care.

Pharmacokinetics of piperacillin and tazobactam in critically Ill patients treated with continuous kidney replacement therapy: A mini-review and population pharmacokinetic analysis.

WHAT IS KNOWN AND OBJECTIVE: Timely and appropriate dosing of antibiotics is essential for the treatment of bacterial sepsis. Critically ill patients treated with continuous kidney replacement therapy (CKRT) often have physiologic derangements that affect pharmacokinetics (PK) of antibiotics and dosing may be challenging. We sought to aggregate previously published piperacillin and tazobactam (pip-tazo) pharmacokinetic data in critically ill patients undergoing CKRT to better understand pharmacokinetics of pip-tazo in this population and better inform dosing. METHODS: The National Library of Medicine Database was searched for original research containing piperacillin or tazobactam clearance (CL) or volume of distribution (V) estimates in patients treated with CKRT. The search yielded 77 articles, of which 26 reported suitable estimates of CL or V. Of the 26 articles, 10 for piperacillin and 8 for tazobactam had complete information suitable for population pharmacokinetic modelling. Also included in the analysis was piperacillin and tazobactam PK data from 4 critically ill patients treated with CKRT in the Military Health System, 2 with burn and 2 without burn. RESULTS AND DISCUSSION: Median and range of literature reported PK parameters for piperacillin (CL 2.76 L/hr, 1.4-7.92 L/hr, V 31.2 L, 16.77-42.27 L) and tazobactam (CL 2.34 L/hr, 0.72-5.2 L/hr, V 36.6 L, 26.2-58.87 L) were highly consistent with population estimates (piperacillin CL 2.7 L/hr, 95%CI 1.99-3.41 L/hr, V 25.83 22.07-29.59 L, tazobactam CL 2.49 L/hr, 95%CI 1.55-3.44, V 30.62 95%CI 23.7-37.54). The proportion of patients meeting pre-defined pharmacodynamic (PD) targets (median 88.7, range 71%-100%) was high despite significant mortality (median 44%, range 35%-60%). High mortality was predicted by baseline severity of illness (median APACHE II score 23, range 21-33.25). Choice of lenient or strict PD targets (ie 100%fT >MIC or 100%fT >4XMIC) had the largest impact on probability of target attainment (PTA), whereas presence or intensity of CKRT had minimal impact on PTA. WHAT IS NEW AND CONCLUSION: Pip-tazo overexposure may be associated with increased mortality, although this is confounded by baseline severity of illness. Achieving adequate pip-tazo exposure is essential; however, risk of harm from overexposure should be considered when choosing a PD target and dose. If lenient PD targets are desired, doses of 2250-3375 mg every 6 h are reasonable for most patients receiving CKRT. However, if a strict PD target is desired, continuous infusion (at least 9000-13500 mg per day) may be required. However, some critically ill CKRT populations may need higher or lower doses and dosing strategies should be tailored to individuals based on all available clinical data including the specific critical care setting.

A Prospective Observational Study Comparing Clinical Sepsis Criteria to Protein Biomarkers Reveals a Role for Vascular Dysfunction in Burn Sepsis.

OBJECTIVES: To compare the diagnostic value of clinical sepsis criteria to novel protein biomarkers in the burn patient. DESIGN: Prospective observational study. SETTING: American Burn Association verified Burn Center ICU. PATIENTS: Burn patients (n = 24) and healthy volunteers (n = 10). INTERVENTIONS: Enrolled burn patients (n = 24) were stratified based on whether or not they met a clinical definition of sepsis. Four separate clinical criteria for sepsis were analyzed for their diagnostic sensitivity and specificity, which were compared to a panel of protein biomarkers. The most significant protein biomarkers were further analyzed via the area under the receiver operating characteristic curves (AUROCs). MEASUREMENTS AND MAIN RESULTS: Of the clinical criteria, SEPSIS-2 criteria led to the highest AUROC (0.781; p < 0.001), followed by the quick Sequential Organ Failure Assessment score (AUROC = 0.670; p = 0.022). Multiplexing revealed a number of inflammatory proteins (complement C5) and matrix metalloproteinases (MMP1, MMP7) that were significantly elevated in septic samples compared with both healthy controls and nonseptic burn samples. Furthermore, three proteins associated with endothelial dysfunction and glycocalyx shedding revealed diagnostic potential. Specifically, syndecan-1, p-selectin, and galectin-1 were all significantly elevated in sepsis, and all resulted in an AUROC greater than 0.7; analyzing the sum of these three markers led to an AUROC of 0.808. CONCLUSIONS: These data reveal several potential biomarkers that may help with sepsis diagnosis in the burn patient. Furthermore, the role of endotheliopathy as a mechanistic etiology for sepsis after burns warrants further investigation.

Meropenem pharmacokinetics in critically ill patients with or without burn treated with or without continuous veno-venous haemofiltration.

INTRODUCTION: Severe burn injury involves widespread skin and tissue damage leading to systemic inflammation, hypermetabolism and multi-organ failure. The hypermetabolic phase of burn injury has been associated with increased systemic antibiotic clearance; however, critical illness in the absence of burn may also induce similar physiologic changes. Continuous renal replacement therapy (CRRT) is often implemented in critically ill patients and may also affect antibiotic clearance. Although the pharmacokinetics (PK) of meropenem has been described in both the burn and non-burn critically ill populations, direct comparative data is lacking. METHODS: For this study, we evaluated PK parameters of meropenem from 23 critically ill patients, burn or non-burn, treated with or without continuous veno-venous haemofiltration (CVVH) to determine the contribution of burn and CVVH to the variability of therapeutic meropenem levels. RESULTS: A two-compartment model best described the data and revealed creatinine clearance (CrCl) and total burn surface area (TBSA) as significant covariates on clearance (CL) and peripheral volume of distribution (Vp), respectively. Of interest, non-burn patients on CVVH displayed an overall lower inherent CL as compared to burn patients on CVVH (6.43 vs. 12.85 L/h). Probability of target attainment (PTA) simulations revealed augmented renal clearance (ARC) may necessitate dose adjustments, but TBSA and CVVH would not. CONCLUSIONS: We recommend a standard dose of 1000 mg every 8 hours; however, if ARC is suspected, or the severity of illness requires a more stringent therapeutic target, we recommend a loading dose of 1000-2000 mg infused over 30 minutes to 1 hour followed by continuous infusion (3000-6000 mg over 24 hours), or intermittent infusion of 2000 mg every 8 hours.

Analysis of Nonbattle Deaths Among U.S. Service Members in the Deployed Environment.

OBJECTIVE: Describe etiologies and trends in non-battle deaths (NBD) among deployed U.S. service members to identify areas for prevention. BACKGROUND: Injuries in combat are categorized as battle (result of hostile action) or nonbattle related. Previous work found that one-third of injured US military personnel in Iraq and Afghanistan had nonbattle injuries and emphasized prevention. NBD have not yet been characterized. METHODS: U.S. military casualty data for Iraq and Afghanistan from 2001 to 2014 were obtained from the Defense Casualty Analysis System (DCAS) and the Department of Defense Trauma Registry (DoDTR). Two databases were used because DoDTR does not capture prehospital deaths, while DCAS does not contain clinical details. Nonbattle injuries and NBD were identified, etiologies classified, and NBD trends were assessed using a weighted moving average and time-series analysis with autoregressive integrated moving average. Future NBD rates were forecast. RESULTS: DCAS recorded 59,799 casualties; 21.0% (n = 1431) of all deaths (n = 6745) were NBD. DoDTR recorded 29,958 casualties; 11.5% (n = 206) of all deaths (n = 1788) were NBD. After early fluctuations, NBD rates for both Iraq and Afghanistan stabilized at approximately 21%. Leading causes of NBD were gunshot wounds and vehicle accidents, accounting for 66%. Approximately 25% was self-inflicted. A 24% NBD rate was forecasted from 2015 through 2025. CONCLUSIONS: Approximately 1 in 5 deaths were NBD. The majority were potentially preventable, including a significant proportion of self-inflicted injuries. A single comprehensive data repository would facilitate future mortality monitoring and performance improvement. These data may assist military leaders with implementing targeted safety strategies.

Population Pharmacokinetic Modeling and Simulations of Imipenem in Burn Patients With and Without Continuous Venovenous Hemofiltration in the Military Health System.

Continuous venovenous hemofiltration (CVVH) is a life-sustaining procedure in patients with severe burns and acute kidney injury. Physiologic changes from burn injury and use of CVVH may alter imipenem pharmacokinetics (PK). We aimed to compare imipenem clearance (CL) in burn patients with and without CVVH, determine the effect of burn on imipenem volume of distribution (CVVH, n = 12; no CVVH, n = 11), in combination with previously published models. Model qualification was performed with standard diagnostics and comparing predicted PK parameters/time-concentration profiles with those in the existing literature. Monte Carlo simulations were conducted to evaluate the probability of target attainment. A 2-compartment model best described the data. Utilizing albumin as a covariate on volume parameters and leveraging the clearance model from prior literature, our model predicted imipenem central volume and CL within a 10% margin of error across healthy, renally impaired, and burn populations. We provide direct comparison of imipenem CL in burn patients with and without CVVH. Notably, there was no significant difference. Large imipenem Vd in patients with severe burns is likely explained by increased capillary permeability, for which serum albumin may be a reasonable surrogate. Dosing 500 mg every 6 hours is adequate for burn patients on renally dosed CVVH; however, suspicion of augmented renal clearance or patients placed on CVVH without renal impairment may necessitate dosing of 1000 mg every 6 hours.

Evidence for misleading decision support in characterizing differences in tolerance to reduced central blood volume using measurements of tissue oxygenation.

BACKGROUND: The physiological response to hemorrhage includes vasoconstriction in an effort to shunt blood to the heart and brain. Hemorrhaging patients can be classified as "good" compensators who demonstrate high tolerance (HT) or "poor" compensators who manifest low tolerance (LT) to central hypovolemia. Compensatory vasoconstriction is manifested by lower tissue oxygen saturation (StO2 ), which has propelled this measure as a possible early marker of shock. The compensatory reserve measurement (CRM) has also shown promise as an early indicator of decompensation. METHODS: Fifty-one healthy volunteers (37% LT) were subjected to progressive lower body negative pressure (LBNP) as a model of controlled hemorrhage designed to induce an onset of decompensation. During LBNP, CRM was determined by arterial waveform feature analysis. StO2 , muscle pH, and muscle H+ concentration were calculated from spectrum using near-infrared spectroscopy (NIRS) on the forearm. RESULTS: These values were statistically indistinguishable between HT and LT participants at baseline (p ≥ 0.25). HT participants exhibited lower (p = 0.01) StO2 at decompensation compared to LT participants. CONCLUSIONS: Lower StO2 measured in patients during low flow states associated with significant hemorrhage does not necessarily translate to a more compromised physiological state, but may reflect a greater resistance to the onset of shock. Only the CRM was able to distinguish between HT and LT participants early in the course of hemorrhage, supported by a significantly greater ROC AUC (0.90) compared with STO2 (0.68). These results support the notion that measures of StO2 could be misleading for triage and resuscitation decision support.

Duration of extremity tourniquet application profoundly impacts soft-tissue antibiotic exposure in a rat model of ischemia-reperfusion injury.

INTRODUCTION: Extremity tourniquet (TNK) application is an effective means of achieving compressible hemorrhage control in the emergency prehospital and clinical trauma setting. Modern United States military medical doctrine recommends TNK use to prevent lethal hemorrhage from extremity injury, followed by systemic prophylactic antibiotics to prevent wound infection. Because tissue pharmacokinetics of prophylactic antimicrobials during and after TNK-induced limb ischemia are largely unknown, this study was conducted to empirically determine the relationship between TNK application time and soft tissue antibiotic exposure in order to guide medical personnel in the management of extremity trauma. MATERIALS AND METHODS: Hind limbs of anesthetized male Sprague Dawley rats were exsanguinated, and ischemia maintained by a pneumatic cuff placed at the level of the mid femur on one limb; the non-ischemic contralateral limb served as comparison tissue. Systemic prophylactic antibiotics (cefazolin, moxifloxacin, or ertapenem) were administered intravenously before or after TNK release following 2 or 4 h of ischemia with subsequent re-dosing every 12 h for 3 days. Free antibiotic in the interstitial fluid (ISF) of the tibialis anterior muscle of both hind limbs was recovered via microdialysis during ischemia and over three periods during reperfusion: immediately following TNK release, at 24 h post TNK release, and at 72 h post TNK release. Plasma and ISF free drug concentrations were determined by high-performance liquid chromatography. RESULTS: Tourniquet application prevented delivery of prophylactic antibiotics into distal soft tissue for the duration of ischemia, and caused a profound reduction in skeletal muscle drug exposure for up to 72 h following TNK release. A progressive decline in tissue antibiotic exposure during reperfusion was observed as TNK times increased from 2 h to 4 h. The timing and severity of reduced drug distribution in post-ischemic skeletal muscle varied substantially among the three antibiotic classes evaluated. CONCLUSIONS: Prolonged tourniquet application can significantly reduce distribution of prophylactic antibiotics into soft tissue during and after ischemia, potentially impairing prophylaxis of extremity wound infection. Our findings support the examination of alternative approaches to wound infection prophylaxis under conditions of delayed casualty evacuation when occlusive hemorrhage control measures are utilized.

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.

Recurrent bacteremia: A 10-year retrospective study in combat-related burn casualties.

INTRODUCTION: Surviving the first episode of bacteremia predisposes burn casualties to its recurrence. Herein, we investigate the incidence, mortality, bacteriology, and source of infection of recurrent bacteremia in military burn casualties admitted to the U.S. Army Institute of Surgical Research Burn Center over a 10year period. METHODS: Bacteremia was defined as the growth of Gram-positive or Gram-negative organisms in a blood culture that excluded probable skin contaminants. Recurrent bacteremia was defined as a subsequent episode of bacteremia ≥7 days after the first episode. Polymicrobial bacteremia was the presence of more than one pathogen in the same blood culture. Bacteremia was attributed to UTI, pneumonia, or wound sepsis. All other bacteremias were considered non-attributable bloodstream infections. Univariate and multivariate analyses determined factors predictive of clinical outcome. RESULTS: Out of 952 combat-related burn casualties screened, 166 cases were identified; 63% (non-recurrent) and 37% (recurrent) with median time to recurrence of 20 days. Univariate and multivariate analysis showed that the mortality rate was two and nine-fold, respectively, higher with recurrent bacteremia. Univariate analysis found that except for urinary tract infection, large burn size (>20%), 3rd degree burns, increased injuiry severity, perineal burns, and mechanical ventilator days were independent factors predictive of recurrence of bacteremia as well as increased mortality in the recurrent bacteremia cohort. Acinetobacter baumannii complex (63%) was prevalent in the non-recurrent group, while Klebsiella pneumoniae (46% vs. 30%) and Pseudomonas aeruginosa (35% vs. 26%) were prevalent in recurrent bacteremia. Half of the recurrent bacteremia cases were polymicrobial, compared to 9% in non-recurrent bacteremia. Pneumonia was prevalent in non-recurrent bacteremia (38%) and a combination of pneumonia and wound sepsis (29%) in recurrent bacteremia casualties. CONCLUSIONS: Recurrent bacteremia increases mortality in military burn casualties. Additional research is needed to address and mitigate the underlying causes, thereby improving survival.

Differentiating compensatory mechanisms associated with low tolerance to central hypovolemia in women.

Women generally display lower tolerance to acute central hypovolemia than men. The measurement of compensatory reserve (CRM) is a novel metric that provides information about the sum total of all mechanisms that together work to compensate for the relative blood volume deficit. Hemodynamic decompensation occurs with depletion of the CRM (i.e., 0% CRM). In the present study, we hypothesized that the lower tolerance to progressive central hypovolemia reported in women can be explained by a faster reduction rate in CRM compared with men rather than sex differences in absolute integrated compensatory responses. Continuous, noninvasive measures of CRM were collected from 208 healthy volunteers (107 men and 85 women) who underwent progressive stepwise central hypovolemia induced by lower body negative pressure to the point of presyncope. Comparisons revealed shorter ( P < 0.01) times in female participants compared with male participants to reach 30% and 0% CRM. Similarly, the lower body negative pressure level, represented by the cumulative stress index, was less at 30% and 0% CRM in women compared with men ( P < 0.01). Changes in hemodynamic responses and frequency-domain data (oscillations in cerebral blood flow velocity and mean arterial blood pressure) were similar between men and women at 0% CRM ( P > 0.05). We conclude that compensatory responses to central hypovolemia in women were similar to men but were depleted at a faster rate compared with men. The earlier depletion of the compensatory reserve in women appears to be influenced by failure to maintain adequate cerebral oxygen delivery. NEW & NOTEWORTHY We compared hemodynamic and metabolic responses in men and women to experimentally controlled reductions in central blood volume at physiologically equivalent levels of compensatory reserve. We corroborated previous findings that females have lower tolerance to central hypovolemia than males but demonstrated for the first time that compensatory responses are similar. Our findings suggest lower tolerance to central hypovolemia in women results from reaching critical cerebral delivery of oxygen faster than men.

Rapid degradation and non-selectivity of Dakin's solution prevents effectiveness in contaminated musculoskeletal wound models.

BACKGROUND: Dakin's solution (buffered sodium hypochlorite) has been used as a topical adjunct for the treatment of invasive fungal infections in trauma patients. Prudent use of Dakin's solution (DS) for complex musculoskeletal wound management implies balancing antimicrobial efficacy and human tissue toxicity, but little empirical evidence exists to inform clinical practice. To identify potentially efficacious DS concentrations and application methods, we conducted two animal studies to evaluate the ability of DS to reduce bacterial burden in small and large animal models of contaminated musculoskeletal wounds. METHODS: An established rat (Rattus norvegicus) contaminated femoral defect model was employed to evaluate the antimicrobial efficacy of DS as a topical adjunctive treatment for Staphylococcus aureus infection. A range of clinically-relevant DS concentrations (0.00025%-0.125%) were tested, both with and without periodic replenishment during treatment. Next, an established goat (Capra hircus) musculoskeletal wound model, consisting of a Pseudomonas aeruginosa contaminated proximal tibia cortical defect, muscle crush, and thermal injury, was utilized to evaluate the antimicrobial efficacy of dilute DS (0.0025% and 0.025%) as a surgical irrigant solution. In situ reactive chlorine concentrations were monitored throughout each treatment using an automated iodometric titration approach. RESULTS: In a rat wound model, DS treatment did not significantly reduce S. aureus bioburden after 14 days as compared to saline control. Two treatment groups (0.01% single application and 0.025% multiple application) exhibited significantly higher bacterial burden than control. In a goat musculoskeletal wound model, neither 0.0025% nor 0.025% DS significantly altered P. aeruginosa bioburden immediately following treatment or at 48 h post-treatment. Overall, DS applied to exposed soft tissue exhibited rapid degradation, e.g., 0.125% DS degraded 32% after 5 s progressing to 86% degradation after 15 min following single application. CONCLUSIONS: We did not observe evidence of a therapeutic benefit following Dakin's solution treatment for any tested concentration or application method in two contaminated musculoskeletal wound models. Despite confirmation of robust bactericidal activity in vitro, our findings suggest DS at current clinically-used concentrations does not kill tissue surface-attached bacteria, nor does it necessarily cause host tissue toxicity that exacerbates infection in the setting of complex musculoskeletal injury.

Unrealized potential of the US military battlefield trauma system: DOW rate is higher in Iraq and Afghanistan than in Vietnam, but CFR and KIA rate are lower.

LEVEL OF EVIDENCE: Observational/retrospective/historic controls, level IV.

A 12-Year Analysis of Nonbattle Injury Among US Service Members Deployed to Iraq and Afghanistan.

Importance: Nonbattle injury (NBI) among deployed US service members increases the burden on medical systems and results in high rates of attrition, affecting the available force. The possible causes and trends of NBI in the Iraq and Afghanistan wars have, to date, not been comprehensively described. Objectives: To describe NBI among service members deployed to Iraq and Afghanistan, quantify absolute numbers of NBIs and proportion of NBIs within the Department of Defense Trauma Registry, and document the characteristics of this injury category. Design, Setting, and Participants: In this retrospective cohort study, data from the Department of Defense Trauma Registry on 29 958 service members injured in Iraq and Afghanistan from January 1, 2003, through December 31, 2014, were obtained. Injury incidence, patterns, and severity were characterized by battle injury and NBI. Trends in NBI were modeled using time series analysis with autoregressive integrated moving average and the weighted moving average method. Statistical analysis was performed from January 1, 2003, to December 31, 2014. Main Outcomes and Measures: Primary outcomes were proportion of NBIs and the changes in NBI over time. Results: Among 29 958 casualties (battle injury and NBI) analyzed, 29 003 were in men and 955 were in women; the median age at injury was 24 years (interquartile range, 21-29 years). Nonbattle injury caused 34.1% of total casualties (n = 10 203) and 11.5% of all deaths (206 of 1788). Rates of NBI were higher among women than among men (63.2% [604 of 955] vs 33.1% [9599 of 29 003]; P < .001) and in Operation New Dawn (71.0% [298 of 420]) and Operation Iraqi Freedom (36.3% [6655 of 18 334]) compared with Operation Enduring Freedom (29.0% [3250 of 11 204]) (P < .001). A higher proportion of NBIs occurred in members of the Air Force (66.3% [539 of 810]) and Navy (48.3% [394 of 815]) than in members of the Army (34.7% [7680 of 22 154]) and Marine Corps (25.7% [1584 of 6169]) (P < .001). Leading mechanisms of NBI included falls (2178 [21.3%]), motor vehicle crashes (1921 [18.8%]), machinery or equipment accidents (1283 [12.6%]), blunt objects (1107 [10.8%]), gunshot wounds (728 [7.1%]), and sports (697 [6.8%]), causing predominantly blunt trauma (7080 [69.4%]). The trend in proportion of NBIs did not decrease over time, remaining at approximately 35% (by weighted moving average) after 2006 and approximately 39% by autoregressive integrated moving average. Assuming stable battlefield conditions, the autoregressive integrated moving average model estimated that the proportion of NBIs from 2015 to 2022 would be approximately 41.0% (95% CI, 37.8%-44.3%). Conclusions and Relevance: In this study, approximately one-third of injuries during the Iraq and Afghanistan wars resulted from NBI, and the proportion of NBIs was steady for 12 years. Understanding the possible causes of NBI during military operations may be useful to target protective measures and safety interventions, thereby conserving fighting strength on the battlefield.

Thermal stability of mafenide and amphotericin B topical solution.

OBJECTIVE: Fungal infections remain a major cause of mortality in the burned population. Mafenide acetate/amphotericin B solution (SMAT) has been used topically for prophylaxis and treatment of these infections. Current manufacturer guidelines only guarantee the stability of mafenide solution and amphotericin B at room temperature. Additionally, the recommended maximum storage time for mafenide solution is 48h, leading to significant financial and material loss when unused solutions are discarded. The purpose of this study was to characterize the chemical stability, structure and bioactivity of SMAT stored at 2°C, 25°C, and 40°C for up to 90 days. METHODS: Stability analyses of SMAT solutions containing 2.5% or 5% mafenide plus 2µg/mL amphotericin B were performed using high performance liquid chromatography. Chemical structure was assessed using Fourier-transform infrared spectroscopy. Bioactivity against clinically relevant species was examined. RESULTS: The chemical structure and stability of mafenide did not change over 90days at all temperatures. Amphotericin B was undetectable in SMAT solutions after two days at high temperatures, which was slowed by refrigerated storage. Against Staphylococcus aureus, SMAT activity began to decrease generally between two and seven days. Against Pseudomonas aeruginosa, activity slowly tapered and was gone by day 90. SMAT retained high bioactivity against Candida albicans for over 40days and was not affected by temperature. CONCLUSIONS: The amphotericin B component of SMAT is degraded within 2days under warm storage. While mafenide was stable over 90 days, the bioactivity of SMAT solution may be lost within 2days as well.

Utility of the Nanosphere Verigene in the Identification of Bacteremia Isolates From the Burn Intensive Care Unit.

INTRODUCTION: The Nanosphere Verigene Blood Culture Nucleic Acid Tests allow pathogen and antimicrobial resistance marker identification within 2.5 hours of a positive blood culture. This study assessed the sensitivity of the Verigene among Burn Intensive Care Unit (BICU) isolates and acceleration to targeted antibiotic therapy. METHODS: Bacterial identifications from BICU patients with positive blood cultures over 8 months were compared using 2 different platforms, the Verigene Gram-positive and Gram-negative blood culture tests vs. the bioMerieux Vitek2 automated system. Turnaround times were compared, and Verigene sensitivity for identification and resistance marker detection was calculated. Antimicrobial stewardship was assessed by comparing date/time for empiric and targeted therapy to the Verigene result time. RESULTS: Forty-four isolates (29 target and 15 nontarget) from 17 patients were included. The Verigene correctly identified 15 of 17 Gram-negative (sensitivity 88.2%; 95% confidence interval [CI] [87.9, 88.9]) and 8 of 12 Gram-positive target organisms (sensitivity 66.7%; 95% CI [66.3, 67.5]). None of the nontarget isolates were identified. There were no discordant identifications. Resistance marker identification by the Verigene was 100% concordant with confirmatory testing. For 11 isolates with complete laboratory and clinical data, the median time between Verigene and final culture results was 59.3 hours (37.3, 102.2) and from Verigene results to targeted therapy was 62.2 hours (43.6, 66.2). DISCUSSION: Reasons for lower sensitivity than previously reported are unclear and, on the basis of this limited retrospective review, further study in the BICU population is needed. The Verigene appears useful for antimicrobial stewardship by accelerating the identification of blood isolates.