Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, controlled, double-blind phase 1/2 trial.

BACKGROUND: Wound infections are the main cause of sepsis in patients with burns and increase burn-related morbidity and mortality. Bacteriophages, natural bacterial viruses, are being considered as an alternative therapy to treat infections caused by multidrug-resistant bacteria. We aimed to compare the efficacy and tolerability of a cocktail of lytic anti-Pseudomonas aeruginosa bacteriophages with standard of care for patients with burns. METHODS: In this randomised phase 1/2 trial, patients with a confirmed burn wound infection were recruited from nine burn centres in hospitals in France and Belgium. Patients were eligible if they were aged 18 years or older and had a burn wound clinically infected with P aeruginosa. Eligible participants were randomly assigned (1:1) by use of an interactive web response system to a cocktail of 12 natural lytic anti-P aeruginosa bacteriophages (PP1131; 1 × 106 plaque-forming units [PFU] per mL) or standard of care (1% sulfadiazine silver emulsion cream), both given as a daily topical treatment for 7 days, with 14 days of follow-up. Masking of treatment from clinicians was not possible because of the appearance of the two treatments (standard of care a thick cream, PP1131 a clear liquid applied via a dressing), but assignments were masked from microbiologists who analysed the samples and patients (treatment applied while patients were under general anaesthetic). The primary endpoint was median time to sustained reduction in bacterial burden by at least two quadrants via a four-quadrant method, assessed by use of daily swabs in all participants with a microbiologically documented infection at day 0 who were given at least one sulfadiazine silver or phage dressing (modified intention-to-treat population). Safety was assessed in all participants who received at least one dressing according to protocol. Ancillary studies were done in the per-protocol population (all PP1131 participants who completed 7 days of treatment) to assess the reasons for success or failure of phage therapy. This trial is registered with the European Clinical Trials database, number 2014-000714-65, and ClinicalTrials.gov, number NCT02116010, and is now closed. FINDINGS: Between July 22, 2015, and Jan 2, 2017, across two recruitment periods spanning 13 months, 27 patients were recruited and randomly assigned to receive phage therapy (n=13) or standard of care (n=14). One patient in the standard of care group was not exposed to treatment, giving a safety population of 26 patients (PP1131 n=13, standard of care n=13), and one patient in the PP1131 group did not have an infection at day 0, giving an efficacy population of 25 patients (PP1131 n=12, standard of care n=13). The trial was stopped on Jan 2, 2017, because of the insufficient efficacy of PP1131. The primary endpoint was reached in a median of 144 h (95% CI 48-not reached) in the PP1131 group versus a median of 47 h (23-122) in the standard of care group (hazard ratio 0·29, 95% CI 0·10-0·79; p=0·018). In the PP1131 group, six (50%) of 12 analysable participants had a maximal bacterial burden versus two (15%) of 13 in the standard of care group. PP1131 titre decreased after manufacturing and participants were given a lower concentration of phages than expected (1 × 102 PFU/mL per daily dose). In the PP1131 group, three (23%) of 13 analysable participants had adverse events versus seven (54%) of 13 in the standard of care group. One participant in each group died after follow-up and the deaths were determined to not be related to treatment. The ancillary study showed that the bacteria isolated from patients with failed PP1131 treatment were resistant to low phage doses. INTERPRETATION: At very low concentrations, PP1131 decreased bacterial burden in burn wounds at a slower pace than standard of care. Further studies using increased phage concentrations and phagograms in a larger sample of participants are warranted. FUNDING: European Commission: Framework Programme 7.

Tourniquet Training Program Assessed by a New Performance Score.

IntroductionApplication of a tourniquet is the cornerstone in management of combat-related extremity hemorrhages. Continuous and appropriate training is required to use tourniquets correctly.HypothesisThe aim of this study was to analyze the impact of a refresher training session, conducted directly in the theater of military operations, on the performance of tourniquet use. METHODS: During their deployment (October 2015-April 2016) in the Central African Republic, a first simulation session evaluated soldiers from two combats platoons for the application of the SOFFT (Special Operation Forces Tactical Tourniquet; Tactical Medical Solutions; Anderson, South California USA) tourniquet. After randomization, a R (+) group underwent a refresher training session, while a R (-) group did not. Two months later, a second simulation session was conducted for both groups: R (+) and R (-). A dedicated score (one to seven points), including delay and effectiveness, evaluated the soldiers' performance for tourniquet application. RESULTS: Twenty-six subjects were included in the R (+) group and 24 in the R (-) group. Between the two assessments, the score improved for 61.5% of subjects of the R (+) group and 37.5% subjects of the R (-) group (P=.09). More particularly, the performance score increased from 4.2 (SD=1.4) to 5.5 (SD=0.9; P=.002) in subjects of the R (+) group whose last training for tourniquet application was over six months prior. CONCLUSION: A refresher tourniquet training session, conducted directly in a combat zone, is especially effective for soldiers whose last training session was over six months prior. A dedicated score can assess appropriately the performance of tourniquet training. MartinezT, DuronS, SchaalJV, BaudoinY, BarbierO, DabanJL, BoutonnetM, AussetS, PasquierP. Tourniquet training program assessed by a new performance score. Prehosp Disaster Med. 2018;33(5):519-525.

Outbreak of Invasive Wound Mucormycosis in a Burn Unit Due to Multiple Strains of Mucor circinelloides f. circinelloides Resolved by Whole-Genome Sequencing.

Mucorales are ubiquitous environmental molds responsible for mucormycosis in diabetic, immunocompromised, and severely burned patients. Small outbreaks of invasive wound mucormycosis (IWM) have already been reported in burn units without extensive microbiological investigations. We faced an outbreak of IWM in our center and investigated the clinical isolates with whole-genome sequencing (WGS) analysis. We analyzed M. circinelloides isolates from patients in our burn unit (BU1, Hôpital Saint-Louis, Paris, France) together with nonoutbreak isolates from Burn Unit 2 (BU2, Paris area) and from France over a 2-year period (2013 to 2015). A total of 21 isolates, including 14 isolates from six BU1 patients, were analyzed by whole-genome sequencing (WGS). Phylogenetic classification based on de novo assembly and assembly free approaches showed that the clinical isolates clustered in four highly divergent clades. Clade 1 contained at least one of the strains from the six epidemiologically linked BU1 patients. The clinical isolates were specific to each patient. Two patients were infected with more than two strains from different clades, suggesting that an environmental reservoir of clonally unrelated isolates was the source of contamination. Only two patients from BU1 shared one strain, which could correspond to direct transmission or contamination with the same environmental source. In conclusion, WGS of several isolates per patients coupled with precise epidemiological data revealed a complex situation combining potential cross-transmission between patients and multiple contaminations with a heterogeneous pool of strains from a cryptic environmental reservoir.IMPORTANCE Invasive wound mucormycosis (IWM) is a severe infection due to environmental molds belonging to the order Mucorales. Severely burned patients are particularly at risk for IWM. Here, we used whole-genome sequencing (WGS) analysis to resolve an outbreak of IWM due to Mucor circinelloides that occurred in our hospital (BU1). We sequenced 21 clinical isolates, including 14 from BU1 and 7 unrelated isolates, and compared them to the reference genome (1006PhL). This analysis revealed that the outbreak was mainly due to multiple strains that seemed patient specific, suggesting that the patients were more likely infected from a pool of diverse strains from the environment rather than from direct transmission among them. This study revealed the complexity of a Mucorales outbreak in the settings of IWM in burn patients, which has been highlighted based on WGS combined with careful sampling.

Bispectral Index Measurements Are Not Degraded During Aeromedical Evacuations.

For a decade, depth of anesthesia monitoring has become a reality in the operating room. It provides valuable help for managing anesthesia, especially for unstable patients. This might be particularly relevant during aeromedical evacuation. In this study, we aimed to assess the validity of the bispectral index (BIS) during long-range patient transportation aboard fixed-wing aircraft. BIS was recorded in 30 patients, 25 under anesthesia and 5 awake, during aeromedical evacuations performed by the French Air Force. BIS index was available and analyzable (signal quality index above 50%) more than 90% of time. Despite potential pitfalls related to mechanical or electrical interference, BIS monitor can be reliably used to monitor depth of anesthesia during individual strategic aeromedical evacuations.