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Background: Severe cutaneous adverse reactions (SCAR) are a group of delayed presumed T-cell mediated hypersensitivities associated with significant morbidity and mortality. Despite their shared global healthcare burden and impact, the clinical phenotypes, genomic predisposition, drug causality, and treatment outcomes may vary. We describe the establishment and results from the first Australasian registry for SCAR (AUS-SCAR), that via a collaborative network advances strategies for the prevention, diagnosis and treatment of SCAR. Methods: Prospective multi-center registry of SCAR in Australian adult and adolescents, with planned regional expansion. The registry collects externally verified phenotypic data drug causality, therapeutics and long-term patient outcomes. In addition, biorepository specimens and DNA are collected at participating sites. Results: we report on the first 100 patients enrolled in the AUS-SCAR database. DRESS (50%) is the most predominant phenotype followed by SJS/TEN (39%) and AGEP (10%), with median age of 52 years old (IQR 37.5, 66) with 1:1 male-to-female ratio. The median latency for all implicated drugs is highly variable but similar for DRESS (median 15 days IQR 5,25) and SJS/TEN (median 21 days, IQR 7,27), while lowest for AGEP (median 2.5 days, IQR 1,8). Antibiotics (54.5%) are more commonly listed as primary implicated drug compare with non-antibiotics agent (45.5%). Mortality rate at 90 days was highest in SJS/TEN at 23.1%, followed by DRESS (4%) and AGEP (0%). Conclusion: In the first prospective national phenotypic and biorepository of SCAR in the southern hemisphere we demonstrate notable differences to other reported registries; including DRESS-predominant phenotype, varied antibiotic causality and low overall mortality rate. This study also highlights the lack of standardised preventative pharmacogenomic measures and in vitro/in vivo diagnostic strategies to ascertain drug causality. Trial registration: ANZCTR ACTRN1261900024113

Background The use of in vivo and ex vivo diagnostic tools for delayed immune-mediated adverse drug reactions is currently ill defined. Objective To determine whether the combination of skin testing and/or IFN-γ enzyme-linked immunoSpot assay (ELISpot) can aid diagnosis of these allergy phenotypes. Methods Patients with antibiotic-associated severe delayed immune-mediated adverse drug reaction hypersensitivity, including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, generalized bullous fixed drug eruption, and severe maculopapular exanthema, were prospectively recruited. In vivo testing was completed to the implicated drug(s), and ex vivo testing was performed with the patient's PBMCs stimulated with the relevant antibiotic concentrations for IFN-γ release ELISpot measurement. Results Eighty-one patients met the inclusion criteria, with DRESS (42; 51.9%) accounting for most cases. Among the 63 (78%) who had an ELISpot assay performed, 34 (54%) were positive to at least 1 implicated antibiotic (median spot-forming units/million cells, 99.5; interquartile range, 68-187), with glycopeptide being a strong predictor of positivity (adjusted odds ratio, 6.11; 95% CI, 1.74-21.42). In combination (in vivo and ex vivo), 51 (63%) of those tested were positive to an implicated antibiotic. For DRESS and severe maculopapular exanthema associated with penicillins and cephalosporins, this combination confirmed the culprit agent in 11 of the 12 cases and in 6 of 7 for DRESS associated with glycopeptides. Conclusions This study demonstrates that using in vivo in combination with ex vivo testing can enhance the diagnostic approach in these severe phenotypes by assisting with the identification of possible culprit antibiotics.

Several issues persist in clinical translation and application of cultured epithelial autografts during treatment of patients with massive burn injuries. The aim of this systematic review is to determine (1) current practice and trends in clinical application and (2) clinical efficacy of cultured epithelial autografts. A structured literature search was performed in Ovid MEDLINE from 1946 and Ovid EMBASE from 1974 until present. All published peer-reviewed randomized or non-randomized clinical studies, cohort studies, prospective, or retrospective series involving human application of cultured epithelial autografts in the setting of burn injury were included. From 7,267 studies initially identified, 77 studies were included in the analysis. In 96% (74/77) of these series, the sample size was less than 100 patients. In 76.6% (59/77) publications, average burn treated exceeded 40% total body surface area. Overall, cultured epithelial autograft take rates reported in the literature were inconsistent and varied significantly from 0 to 100%. There was a recent trend for co-application of cultured grafts with autologous skin grafts, achieving relatively high and consistent take rates of 73-96%. Results from cultured epithelial autograft application remained unpredictable. This technology remains an adjunct or biological dressing, and not an alternative to conventional split skin graft. However, it has contributed to wound closure and it has been life saving in selected circumstances. Skin tissue engineering should continue as the clinical need for skin replacement is foreseeable into the future.

Acinetobacter baumannii is a common causative agent of hospital-acquired infections and a leading cause of infection in burns patients. Carbapenem-resistant A. baumannii is considered a major public-health threat and has been identified by the World Health Organization as the top priority organism requiring new antimicrobials. The most common mechanism for carbapenem resistance in A. baumannii is via horizontal acquisition of carbapenemase genes. In this study, we sampled 20 A. baumannii isolates from a patient with extensive burns, and characterized the evolution of carbapenem resistance over a 45 day period via Illumina and Oxford Nanopore sequencing. All isolates were multidrug resistant, carrying two genomic islands that harboured several antibiotic-resistance genes. Most isolates were genetically identical and represented a single founder genotype. We identified three novel non-synonymous substitutions associated with meropenem resistance: F136L and G288S in AdeB (part of the AdeABC efflux pump) associated with an increase in meropenem MIC to ≥8 µg ml-1; and A515V in FtsI (PBP3, a penicillin-binding protein) associated with a further increase in MIC to 32 µg ml-1. Structural modelling of AdeB and FtsI showed that these mutations affected their drug-binding sites and revealed mechanisms for meropenem resistance. Notably, one of the adeB mutations arose prior to meropenem therapy but following ciprofloxacin therapy, suggesting exposure to one drug whose resistance is mediated by the efflux pump can induce collateral resistance to other drugs to which the bacterium has not yet been exposed.

BACKGROUND: Autologous split skin grafting is the gold standard in treating patients with massive burns. However, the limited availability of donor sites remains a problem. The aim of this study is to present our experience with the modified Meek technique of grafting, outcomes achieved and recommendations for optimized outcomes. METHODS: We retrospectively reviewed patient records from our tertiary referral burn centre and the Bi-National Burns Registry to identify all patients who had modified Meek grafting between 2010 and 2013. Patient records were reviewed individually and information regarding patient demographics, mechanism of injury and surgical management was recorded. Outcome measures including graft take rate, requirement for further surgery and complications were also recorded. RESULTS: Eleven patients had modified Meek grafting procedures. The average age of patients was 46 years old (range 23 - 64). The average total body surface area (TBSA) burnt was 56.75 % (range 20-80 %). On average, 87 % of the grafted areas healed well and did not require regrafting. In the regrafted areas, infection was the leading cause of graft failure. CONCLUSIONS: Modified Meek grafting is a useful method of skin expansion. Similar to any other grafting technique, infection needs to be sought and treated promptly. It is recommended for larger burns where donor sites are not adequate or where it is desirable to limit their extent.

The objective of this study was to determine rates of positive bacterial cultures in patients with extensive toxic epidermal necrolysis, the rate of bacteremia, whether empirical antibiotics had been commenced, and their effectiveness when commenced. The authors conducted a retrospective chart review of patients with extensive toxic epidermal necrolysis between January 2001 and December 2012 admitted to the Victorian Adult Burns Service, Melbourne, Australia, with respect to the amount of positive cultures, number and type of organisms identified, whether empirical antibiotics had been commenced, and whether antibiotics were effective against organisms cultured. A total of 27 patients were admitted over the study period of 11 years. Seventeen of these patients developed at least one positive bacterial culture. Patients who grew positive cultures had a longer length of stay in intensive care unit and in hospital overall compared with patients who did not grow positive cultures. Thirty-five positive cultures were collected overall, with empirical antibiotics commenced in 22 cases. In terms of sensitivity, antibiotics were appropriate in 19 cases. Four patients developed bacteremia, two of whom died. This study does not dispute the generally accepted practice of avoiding prophylactic antibiotics in toxic epidermal necrolysis patients, but in the context of a relatively low rate of bacteremia in this patient population, advises appropriate and targeted empirical antibiotic use where clinical infection is suspected.Copyright © 2014 by the American Burn Association.

Introduction: Our aim was to provide descriptive information to burn clinicians, who have extensive experience treating major burns and determining prognosis, as to whether significant differences in mortality exist between major burns injuries and the comparatively less common toxic epidermal necrolysis for a given age and total body surface area percentage. Method(s): Retrospective data was analyzed of all deceased patients admitted to the Victorian Adult Burns Service in Melbourne, Australia over a period of 10 years with greater than 30% total body surface area burned or greater than 30% total body surface area epidermal detachment in the case of toxic epidermal necrolysis. Retrospective data was also collected on all patients, survivors and deceased, with toxic epidermal necrolysis and these patients were matched with burns patients by age and % total body surface area burned. Comparisons in outcomes were performed with mortality being the primary variable of interest. Result(s): Toxic epidermal necrolysis patients that died were older (median: 68.5 vs 57 yrs; P = 0.04), had a longer length of hospital stay (36.5 vs 0.8 days; P = 0.001) and significantly longer periods of mechanical ventilation (1404 vs 14.5 h; P = 0.011) than major burns patients that died. When toxic epidermal necrolysis patients were matched to major burns patients by age and total body surface area burned, there were no significant differences between the two groups with respect to mortality. Conclusion(s): Palliative care approaches are more frequently administered at the time of presentation for major burns patients in comparison to toxic epidermal necrolysis patients. This may be due to a perception that if toxic epidermal necrolysis patients can survive their initial systemic injury, they are likely to survive, as opposed to major burns patients who often undergo extensive surgery and for whom other factors should be taken into account in the context of end-of-life decision making.Copyr

Background: Toxic epidermal necrolysis (TEN) is a rare but fatal condition characterised by cutaneous exfoliation of the dermoepidermal layer and mucosal surfaces. Extensive TEN with epidermal detachment >30% of the total body surface area has been associated with a high mortality. Objective(s): This study aims to evaluate factors associated with mortality in extensive TEN. In the absence of data to qualify scoring systems such as SCORTEN, this study also aims to evaluate the use of the auxiliary score as a tool for calculating expected mortality. Method(s): A retrospective chart review of all patients presenting to our burns service with extensive TEN was undertaken. Application and evaluation of the auxiliary score was also undertaken for this patient population. Result(s): In extensive TEN, age and delay in admission to a burns centre were factors associated with mortality. Applying the auxiliary score to our patient population, there were no significant differences between expected mortality and observed mortality. Conclusion(s): Mortality was associated with age and delay in definitive treatment in extensive TEN. Whilst SCORTEN is the gold standard prognostic tool for patients with TEN, in the absence of SCORTEN values, the auxiliary score provides an alternative scoring system to evaluate expected mortality.Copyright © 2013 S. Karger AG, Basel.

Tissue-engineered composite skin is a promising therapy for the treatment of chronic and acute wounds, including burns. Providing the wound bed with a dermal scaffold populated by autologous dermal and epidermal cellular components can further entice host cell infiltration and vascularization to achieve permanent wound closure in a single stage. However, the high porosity and the lack of a supportive basement membrane in most commercially available dermal scaffolds hinders organized keratinocyte proliferation and stratification in vitro and may delay re-epithelization in vivo. The objective of this study was to develop a method to enable the in vitro production of a human skin equivalent (HSE) that included a porous scaffold and dermal and epidermal cells expanded ex vivo, with the potential to be used for definitive treatment of skin defects in a single procedure. A collagen-glycosaminoglycan dermal scaffold (Integra(®)) was populated with adult fibroblasts. A near-normal skin architecture was achieved by the addition of coagulated human plasma to the fibroblast-populated scaffold before seeding cultured keratinocytes. This resulted in reducing scaffold pore size and improving contact surfaces. Skin architecture and basement membrane formation was further improved by the addition of aprotinin (a serine protease inhibitor) to the culture media to inhibit premature clot digestion. Histological assessment of the novel HSE revealed expression of keratin 14 and keratin 10 similar to native skin, with a multilayered neoepidermis morphologically comparable to human skin. Furthermore, deposition of collagen IV and laminin-511 were detected by immunofluorescence, indicating the formation of a continuous basement membrane at the dermal-epidermal junction. The proposed method was efficient in producing an in vitro near native HSE using the chosen off-the-shelf porous scaffold (Integra). The same principles and promising outcomes should be applicable to other biodegradable por

Background Toxic Epidermal Necrolysis (TEN) is characterized by an exfoliative rash resembling widespread burns. It is often considered on the same spectrum of disease as Stevens Johnson Syndrome but is distinguished by epidermal detachment of >30% of total body surface area (TBSA). Ocular involvement of TEN may result in complications requiring intensive topical, systemic or operative treatment. This study aimed to identify the current hospital management of, and factors associated with, ophthalmic involvement in adult TEN patients. Methods All adult TEN patients admitted to the Victorian Adult Burns Service over an 12-year period were included. Retrospective data analyzed included patient demographics, site of TEN involvement, % TBSA, complications, duration of ocular follow up and visual outcomes. Results TEN patients with and without ocular involvement were compared. Cutaneous involvement of the head and neck was found to be significantly associated with ocular involvement of TEN. Age, TBSA involvement, presence of a prodrome, and presence of comorbidities were not found to be significantly associated with ocular involvement. Management of ophthalmic involvement of TEN varied between patients. Conclusions Clinicians should have a high index of suspicion for ocular involvement when exfoliation of the head and neck is present and should seek ophthalmological advice early in the course of disease. © 2013 Elsevier Ltd and ISBI.