Biomarkers for the Early Diagnosis of Sepsis in Burns: Systematic Review and Meta-analysis.

OBJECTIVE: The aim of this study was to evaluate the diagnostic performance of all biomarkers studied to date for the early diagnosis of sepsis in hospitalized patients with burns. BACKGROUND: Early clinical diagnosis of sepsis in burns patients is notoriously difficult due to the hypermetabolic nature of thermal injury. A considerable variety of biomarkers have been proposed as potentially useful adjuncts to assist with making a timely and accurate diagnosis. METHODS: We searched Medline, Embase, Cochrane CENTRAL, Biosis Previews, Web of Science, and Medline In-Process to February 2020. We included diagnostic studies involving burns patients that assessed biomarkers against a reference sepsis definition of positive blood cultures or a combination of microbiologically proven infection with systemic inflammation and/or organ dysfunction. Pooled measures of diagnostic accuracy were derived for each biomarker using bivariate random-effects meta-analysis. RESULTS: We included 28 studies evaluating 57 different biomarkers and incorporating 1517 participants. Procalcitonin was moderately sensitive (73%) and specific (75%) for sepsis in patients with burns. C-reactive protein was highly sensitive (86%) but poorly specific (54%). White blood cell count had poor sensitivity (47%) and moderate specificity (65%). All other biomarkers had insufficient studies to include in a meta-analysis, however brain natriuretic peptide, stroke volume index, tumor necrosis factor (TNF)-alpha, and cell-free DNA (on day 14 post-injury) showed the most promise in single studies. There was moderate to significant heterogeneity reflecting different study populations, sepsis definitions and test thresholds. CONCLUSIONS: The most widely studied biomarkers are poorly predictive for sepsis in burns patients. Brain natriuretic peptide, stroke volume index, TNF-alpha, and cell-free DNA showed promise in single studies and should be further evaluated. A standardized approach to the evaluation of diagnostic markers (including time of sampling, cut-offs, and outcomes) would be useful.

Management of dengue in Australian travellers: a retrospective multicentre analysis.

OBJECTIVES: To describe the epidemiology, clinical and laboratory features and outcomes of dengue in returned Australian travellers, applying the revised WHO dengue classification (2009) to this population. DESIGN, SETTING AND PARTICIPANTS: Retrospective case series analysis of confirmed dengue cases hospitalised at one of four Australian tertiary hospitals, January 2012 - May 2015. MAIN OUTCOME MEASURES: Clinical features, laboratory findings and outcomes of patients with dengue; dengue classification according to 2009 WHO guidelines. RESULTS: 208 hospitalised patients (median age, 32 years; range, 4-76 years) were included in the study. Dengue was most frequently acquired in Indonesia (94 patients, 45%) and Thailand (40, 19%). The most common clinical features were fever (98% of patients) and headache (76%). 84 patients (40%) met the WHO criteria for dengue with warning signs, and one the criteria for severe dengue; the most common warning signs were mucosal bleeding (44 patients, 21%) and abdominal pain (43, 21%). Leukopenia (176 patients, 85%), thrombocytopenia (133, 64%), and elevated liver enzyme levels (154, 76%) were the most common laboratory findings. 46 patients (22%) had serological evidence of previous exposure to dengue virus. WHO guidelines were documented as a management benchmark in ten cases (5%); 46 patients (22%) received non-steroidal anti-inflammatory drugs (NSAIDs). CONCLUSIONS: A significant proportion of returning Australian travellers hospitalised for dengue have unrecognised warning signs of severe disease. Many received NSAIDs, which can increase the risk of haemorrhage in dengue. As travel to Asia from Australia continues to increase, it is vital for averting serious outcomes that clinicians can recognise and manage dengue.

Study protocol for ADAPT-TDM: A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring.

INTRODUCTION: Critically ill patients are at risk of suboptimal beta-lactam antibiotic (beta-lactam) exposure due to the impact of altered physiology on pharmacokinetics. Suboptimal concentrations can lead to treatment failure or toxicity. Therapeutic drug monitoring (TDM) involves adjusting doses based on measured plasma concentrations and individualising dosing to improve the likelihood of improving exposure. Despite its potential benefits, its adoption has been slow, and data on implementation, dose adaptation and safety are sparse. The aim of this trial is to assess the feasibility and fidelity of implementing beta-lactam TDM-guided dosing in the intensive care unit setting. METHODS AND ANALYSIS: A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring (ADAPT-TDM) is a single-centre, unblinded, feasibility randomised controlled trial aiming to enroll up to 60 critically ill adult participants (≥18 years). TDM and dose adjustment will be performed daily in the intervention group; the standard of care group will undergo plasma sampling, but no dose adjustment. The main outcomes include: (1) feasibility of recruitment, defined as the number of participants who are recruited from a pool of eligible participants, and (2) fidelity of TDM, defined as the degree to which TDM as a test is delivered as intended, from accurate sample collection, sample processing to result availability. Secondary outcomes include target attainment, uptake of TDM-guided dosing and incidence of neurotoxicity, hepatotoxicity and nephrotoxicity. ETHICS AND DISSEMINATION: This study has been approved by the Alfred Hospital human research ethics committee, Office of Ethics and Research Governance (reference: Project No. 565/22; date of approval: 22/11/2022). Prospective consent will be obtained and the study will be conducted in accordance with the Declaration of Helsinki. The finalised manuscript, including aggregate data, will be submitted for publication in a peer reviewed journal. ADAPT-TDM will determine whether beta-lactam TDM-guided dose adaptation is reproducible and feasible and provide important information required to implement this intervention in a phase III trial. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry, ACTRN12623000032651.

Risk of environmental and healthcare worker contamination with vancomycin-resistant enterococci during outpatient procedures and hemodialysis.

OBJECTIVE: To assess the risk of environmental and healthcare worker (HCW) contamination with vancomycin-resistant enterococci (VRE) during outpatient procedures performed on fecally continent patients currently colonized with VRE (cVRE) or previously colonized with VRE (pVRE). DESIGN: Observational study. SETTING: Outpatient consultation and radiology rooms and the hemodialysis unit in a university teaching hospital. PATIENTS: Fecally continent cVRE and pVRE patients. INTERVENTIONS: Both cVRE and pVRE patients attended standardized mock outpatient consultations and routine hemodialysis sessions in an area that had been thoroughly cleaned and microbiologically confirmed to be free of VRE contamination. After each session, the patient, environment, and participating HCW were tested for VRE contamination. RESULTS: Fourteen cVRE patients participated in 49 mock outpatient consultation sessions and radiology sessions or 26 actual hemodialysis sessions, and 7 pVRE patients participated in 28 outpatient consultation sessions. Sessions with cVRE patients had higher rates of contamination of the environment (chair cultures were positive for VRE in 36% of outpatient consultation sessions, 58% of hemodialysis sessions; couch cultures were positive in 48% of outpatient consultation sessions, 42% of radiology sessions, and 45% of hemodialysis sessions), contamination of HCW gowns (gown cultures were positive in 20% of outpatient consultation sessions, 4% of radiology sessions, and 30% of hemodialysis sessions), and contamination of patients' own hands (hand cultures were positive in 36% of outpatient consultation sessions, 25% of radiology sessions, and 54% of hemodialysis sessions). Overall, contamination rates associated with pVRE patients attendance at outpatient consultations were 12% of those noted for cVRE patients (odds ratio, 0.10; 95% confidence interval, 0.03-0.42; P = .001). CONCLUSIONS: Given the nature of the contamination risk posed by fecally continent cVRE patients undergoing outpatient procedures, infection control measures should focus on effective HCW and patient hand hygiene and chair and couch cleaning, to minimize transmission of VRE.

Secondary bacterial infection and empirical antibiotic use in toxic epidermal necrolysis patients.

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.

Microbiology of wildfire victims differs significantly from routine burns patients: data from an Australian wildfire disaster.

The catastrophic wildfires of February 2009 in Victoria, Australia killed 173 people and hospitalised 18 adults with burns. We conducted a case-control study of wildfire victims (WFVs) compared to routine burns patients to assess early differences in bacteriology. Demographic, outcome and bacteriology data (for the first 72 h) were prospectively collected on all 18 WFVs, and compared to those of 36 RBPs matched 2:1 for age, gender, burns severity (total body surface area ≥20%) and ICU admission. We found that WFVs had more positive cultures overall (10/18 [56%] vs 7/36 [19%], p=0.04), and we cultured more Gram negative bacteria from wounds (11/13 [85%] vs 3/12 [25%], p=0.005). Although WFVs were more likely to culture Enterobacteriaceae (5/18 vs 2/36) and Aeromonas spp. (3/18 vs 1/36), and less likely to culture Staphylococcus aureus (2/18 vs 6/36), these differences were not statistically significant. Given the predominance of Gram negative organisms cultured from WFVs, our routine burn wound prophylaxis (intravenous cephazolin) would have been inadequate in the WFV group. We suggest that an alternative regimen of oxacillin/nafcillin/flucloxacillin plus gentamicin (or a fluoroquinolone if renal impairment present) may be more appropriate for burn wound prophylaxis in this complex group of patients.

Candida in burns: risk factors and outcomes.

Sepsis due to Candida is an uncommon but a significant cause of death in burns patients. Colonization is common, but consensus guidelines for prophylaxis and empirical therapy do not specifically include this cohort. Our aim was to define predictive factors for candidaemia in a burns unit, to guide protocols for prevention and early treatment. We conducted a 10-year review (July 1998-December 2007) of patients admitted to the Victorian Adult Burns Service, Melbourne, Australia. Of 1929 patients admitted with acute burn injury, 143 had Candida isolated at any site, most commonly Candida albicans. There were 12 episodes of candidaemia. Prior colonization was an important risk factor for candidaemia, and the risk increased substantially with the number of colonized sites; indeed 43% of patients colonized at more than three sites (and not on antifungals) developed candidaemia. Other risk factors were higher total burn surface area, higher full-thickness surface area, prolonged admission, number and duration of intensive care unit admissions, number of visits to the operating theatre, alcohol as a contributing factor to burn, prior treatment with total parenteral nutrition, or certain antibiotics (ceftriaxone, vancomycin, amikacin, co-trimoxazole). The attributable mortality of candidaemia was 15% (n = 2). Initiation of antifungal therapy was often delayed. Our results support early empirical antifungal therapy in septic burns patients who are colonized, before the results of cultures become known. The role of prophylactic antifungals is less clear, but should be strongly considered for patients colonized at multiple sites.

Pseudomonas aeruginosa bacteraemia in burns patients: Risk factors and outcomes.

INTRODUCTION: We aimed to identify the risk factors for, and outcomes of Pseudomonas aeruginosa bacteraemia in adult burns patients. METHOD: All adult burns patients who developed a Gram-negative bacteraemia over a period of 7 years were included. Retrospective data analysed included patient demographics, organisms cultured, antibiotic susceptibility patterns, isolation of P. aeruginosa in non-blood isolates, treatment, length of stay and mortality. RESULTS: Forty-three patients developed a Gram-negative bacteraemia over the study period, 12 of whom had Pseudomonas bacteraemia during the course of their admission. In eight patients (18.6%) P. aeruginosa was the first Gram-negative isolated. The only factor predicting P. aeruginosa bacteraemia as a first episode (compared to another Gram-negative) was prior isolation of Pseudomonas at other sites (wound sites, urine or sputum). Overall length of stay was less in patients who developed P. aeruginosa as a first episode, mainly because of increased mortality in this group. Prior non-blood isolates of P. aeruginosa could have correctly predicted the sensitivity pattern of the strain of P. aeruginosa organism in 75% of patients who did not receive appropriate initial antibiotics. CONCLUSION: Prior colonisation with P. aeruginosa predicts P. aeruginosa in blood cultures, as opposed to other Gram-negative bacteria. Clinicians should have a high index of suspicion for P. aeruginosa bacteraemia where a septic burns patient has a prior history of non-blood P. aeruginosa cultures. Empirical antibiotic regimes based on the antibiotic-sensitivity patterns of previous non-blood P. aeruginosa isolates in each patient should be given at the time blood cultures are taken.

Consensus statement on the management of invasive candidiasis in Intensive Care Units in the Asia-Pacific Region.

Invasive candidiasis has emerged as an important nosocomial infection, especially in critically ill patients. The incidence of candidaemia in Intensive Care Units (ICUs) is 5- to 10-fold higher than in the entire hospital and the crude mortality rate of patients with candidaemia is between 35% and 60%. Candida albicans remains the predominant cause of invasive candidiasis in ICUs, followed by Candida tropicalis, Candida glabrata and Candida parapsilosis. Invasive isolates of Candida spp. remain highly susceptible to fluconazole (>90% susceptible), although among Asia-Pacific countries the susceptibility rate of C. glabrata to fluconazole varies widely from 22% to 72%. Early diagnosis and prompt initiation of antifungal therapy are crucial for the effective treatment of invasive candidiasis. However, invasive candidiasis is difficult to diagnose owing to its non-specific clinical features, and delayed therapy is a major contributor to poor outcomes. Combining clinical risk factors with Candida colonisation parameters appears promising for guiding early interventions. Because of considerable regional variability, local epidemiological knowledge is critical in the effective management of invasive candidiasis among ICU patients in Asia-Pacific.

Risk factors for new detection of vancomycin-resistant enterococci in acute-care hospitals that employ strict infection control procedures.

Accurate assessment of the risk factors for colonization with vancomycin-resistant enterococci (VRE) among high-risk patients is often confounded by nosocomial VRE transmission. We undertook a 15-month prospective cohort study of adults admitted to high-risk units (hematology, renal, transplant, and intensive care) in three teaching hospitals that used identical strict infection control and isolation procedures for VRE to minimize nosocomial spread. Rectal swab specimens for culture were regularly obtained, and the results were compared with patient demographic factors and antibiotic exposure data. Compliance with screening was defined as "optimal" (100% compliance) or "acceptable" (minor protocol violations were allowed, but a negative rectal swab specimen culture was required within 1 week of becoming colonized with VRE). Colonization with VRE was detected in 1.56% (66 of 4,215) of admissions (0.45% at admission and 0.83% after admission; the acquisition time was uncertain for 0.28%), representing 1.91% of patients. No patients developed infection with VRE. The subsequent rate of new acquisition of VRE was 1.4/1,000 patient days. Renal units had the highest rate (3.23/1,000 patient days; 95% confidence interval [CI], 1.54 to 6.77/1,000 patient days). vanB Enterococcus faecium was the most common species (71%), but other species included vanB Enterococcus faecalis (21%), vanA E. faecium (6%), and vanA E. faecalis (2%). The majority of isolates were nonclonal by pulsed-field gel electrophoresis analysis. Multivariate analysis of risk factors in patients with an acceptable screening suggested that being managed by a renal unit (hazard ratio [HR] compared to the results for patients managed in an intensive care unit, 4.6; 95% CI, 1.2 to 17.0 [P = 0.02]) and recent administration of either ticarcillin-clavulanic acid (HR, 3.6; 95% CI, 1.1 to 11.6 [P = 0.03]) or carbapenems (HR, 2.8; 95% CI, 1.0, 8.0 [P = 0.05]), but not vancomycin or broad-spectrum cephalosporins, were associated with acquisition of VRE. The relatively low rates of colonization with VRE, the polyclonal nature of most isolates, and the possible association with the use of broad-spectrum antibiotics are consistent with either the endogenous emergence of VRE or the amplification of previously undetectable colonization with VRE among high-risk patients managed under conditions in which the risk of nosocomial acquisition was minimized.