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According to the latest reports from WHO, the incidence of antibiotic-resistant bacterial infections is increasing worldwide, resulting in increased morbidity and mortality and a rising pressure on health-care systems. However, the development of new antibiotics is an expensive and time-consuming process, urging scientists to seek alternative antimicrobial strategies. Over the past few decades, the concept of therapeutic administration of bacteriophages (also known as phages) has gained popularity worldwide. Although conceptually promising, the widespread implementation of phage therapy in routine clinical practice is restricted by the scarcity of safety and efficacy data obtained according to the strict standards of the applicable clinical trial regulations. In this systematic review, we list clinical data published between Jan 1, 2000 and Aug 14, 2021 on the safety and efficacy of phage therapy for difficult-to-treat bacterial infections, and provide an overview of trials and case studies on the use of phage therapy in several medical disciplines.

Fracture-related infection is a major complication related to musculoskeletal injuries that not only has important clinical consequences, but also a substantial socioeconomic impact. Although fracture-related infection is one of the oldest disease entities known to mankind, it has only recently been defined and, therefore, its global burden is still largely unknown. In this Personal View, we describe the origin of the term fracture-related infection, present the available data on its global impact, and discuss important aspects regarding its prevention and management that could lead to improved outcomes in both high-resource and low-resource settings. We also highlight the need for health-care systems to be adequately compensated for the high cost of human resources (trained staff) and well-equipped facilities required to adequately care for these complex patients. Our aim is to increase awareness among clinicians and policy makers that fracture-related infection is a disease entity that deserves prioritisation in terms of research, with the goal to standardise treatment and improve patient outcomes on a global scale.

Fracture-related infection (FRI) remains a challenging complication that creates a heavy burden for orthopaedic trauma patients, their families and treating physicians, as well as for healthcare systems. Standardization of the diagnosis of FRI has been poor, which made the undertaking and comparison of studies difficult. Recently, a consensus definition based on diagnostic criteria for FRI was published. As a well-established diagnosis is the first step in the treatment process of FRI, such a definition should not only improve the quality of published reports but also daily clinical practice. The FRI consensus group recently developed guidelines to standardize treatment pathways and outcome measures. At the center of these recommendations was the implementation of a multidisciplinary team (MDT) approach. If such a team is not available, it is recommended to refer complex cases to specialized centers where a MDT is available and physicians are experienced with the treatment of FRI. This should lead to appropriate use of antimicrobials and standardization of surgical strategies. Furthermore, an MDT could play an important role in host optimization. Overall two main surgical concepts are considered, based on the fact that fracture fixation devices primarily target fracture consolidation and can be removed after healing, in contrast to periprosthetic joint infection were the implant is permanent. The first concept consists of implant retention and the second consists of implant removal (healed fracture) or implant exchange (unhealed fracture). In both cases, deep tissue sampling for microbiological examination is mandatory. Key aspects of the surgical management of FRI are a thorough debridement, irrigation with normal saline, fracture stability, dead space management and adequate soft tissue coverage. The use of local antimicrobials needs to be strongly considered. In case of FRI, empiric broad-spectrum antibiotic therapy should be started after tissue sampling. Thereafter, this needs to be adapted according to culture results as soon as possible. Finally, a minimum follow-up of 12 months after cessation of therapy is recommended. Standardized patient outcome measures purely focusing on FRI are currently not available but the patient-reported outcomes measurement information system (PROMIS) seems to be the preferred tool to assess the patients’ short and long-term outcome. This review summarizes the current general principles which should be considered during the whole treatment process of patients with FRI based on recommendations from the FRI Consensus Group.Level of evidence: Level V.

Bacteriophage therapy has recently attracted increased interest, particularly in difficult-to-treat infections. Although it is not a novel concept, standardized treatment guidelines are currently lacking. We present the first steps towards the establishment of a “multidisciplinary phage task force” (MPTF) and a standardized treatment pathway, based on our experience of four patients with severe musculoskeletal infections. After review of their medical history and current clinical status, a multidisciplinary team found four patients with musculoskeletal infections eligible for bacteriophage therapy within the scope of Article 37 of the Declaration of Helsinki. Treatment protocols were set up in collaboration with phage scientists and specialists. Based on the isolated pathogens, phage cocktails were selected and applied intraoperatively. A draining system allowed postoperative administration for a maximum of 10 days, 3 times per day. All patients received concomitant antibiotics and their clinical status was followed daily during phage therapy. No severe side-effects related to the phage application protocol were noted. After a single course of phage therapy with concomitant antibiotics, no recurrence of infection with the causative strains occurred, with follow-up periods ranging from 8 to 16 months. This study presents the successful outcome of bacteriophage therapy using a standardized treatment pathway for patients with severe musculoskeletal infection. A multidisciplinary team approach in the form of an MPTF is paramount in this process.

Purpose: Fracture-related infection (FRI) is an important complication related to orthopaedic trauma. Although the scientific interest with respect to the diagnosis and treatment of FRI is increasing, data on the microbiological epidemiology remains limited. Therefore, the primary aim of this study was to evaluate the microbiological epidemiology related to FRI, including the association with clinical symptoms and antimicrobial susceptibility data. The secondary aim was to analyze whether there was a relationship between the time to onset of infection and the microbiological etiology of FRI.Methods: FRI patients treated at the University Hospitals of Leuven, Belgium, between January 1st 2015 and November 24th 2019 were evaluated retrospectively. The microbiological etiology and antimicrobial susceptibility data were analyzed. Patients were classified as having an early (<2 weeks after implantation), delayed (2-10 weeks) or late-onset (> 10 weeks) FRI.Results: One hundred ninety-one patients with 194 FRIs, most frequently involving the tibia (23.7%) and femur (18.6%), were included. Staphylococcus aureus was the most frequently isolated pathogen, regardless of time to onset (n=61; 31.4%), followed by S. epidermidis (n=50; 25.8%) and non-epidermidis coagulase-negative staphylococci (n=35; 18.0%). Polymicrobial infections (n=49; 25.3%), mainly involving Gram negative bacilli (GNB) (n=32; 65.3%), were less common than monomicrobial infections (n=138; 71.1%). Virulent pathogens in monomicrobial FRIs were more likely to cause pus or purulent discharge (n=45;54.9%; p=0.002) and fistulas (n=21;25.6%; p=0.030). Susceptibility to piperacillin/tazobactam for GNB was 75.9%. Vancomycin covered 100% of Gram positive cocci.Conclusion: This study revealed that in early FRIs, polymicrobial infections and infections including Enterobacterales and enterococcal species were more frequent. A time-based FRI classification is not meaningful to estimate the microbiological epidemiology and cannot be used to guide empiric antibiotic therapy. Large multicenter prospective studies are necessary to gain more insight into the added value of (broad) empirical antibiotic therapy.

Hidradenitis suppurativa (HS) is a chronic skin disease in which the acute development of noduli, abscesses and in a later stage fistulas remains difficult to control, despite a wide range of recommended treatment options including immunomodulatory biologicals, surgical intervention and antibiotics. Besides being painful, associated lesions have an extensive impact on the quality of life. While HS is primarily an immune-mediated inflammatory disease, the skin microbiota plays a key role in its pathogenesis with pathogenic bacterial colonization of lesions observed. Bacteriophages, the viruses of bacteria, are used to treat a 52-year-old female HS patient with re-current colonization of lesions with Staphylococcus aureus . Phage therapy results in complete removal of lesions with a flare-free period of six months, along with a substantial improvement in the patient’s quality of life. The deployed experimental framework and the gained clinical experience will be valuable for future HS phage therapy research. In this work, authors present a personalized phage therapy regimen targeting Staphylococcus aureus , which led to complete lesion removal, a six-month flare-free period and improved quality-of-life in a Hidradenitis Suppurativa (HS) patient.

In times where only a few novel antibiotics are to be expected, antimicrobial resistance remains an expanding global health threat. In case of chronic infections caused by therapy-resistant pathogens, physicians have limited therapeutic options, which are often associated with detrimental consequences for the patient. This has resulted in a renewed interest in alternative strategies, such as bacteriophage (phage) therapy. However, there are still important hurdles that currently impede the more widespread implementation of phage therapy in clinical practice. First, the limited number of good-quality case series and clinical trials have failed to show the optimal application protocol in terms of route of administration, frequency of administration, treatment duration and phage titer. Second, there is limited information on the systemic effects of phage therapy. Finally, in the past, phage therapy has been applied intuitively in terms of the selection of phages and their combination as parts of phage cocktails. This has led to an enormous heterogeneity in previously published studies, resulting in a lack of reliable safety and efficacy data for phage therapy. We hereby present a study protocol that addresses these scientific hurdles using a multidisciplinary approach, bringing together the experience of clinical, pharmaceutical and molecular microbiology experts.

IntroductionRe-establishing anatomic rotational alignment of shaft fractures of the lower extremities remains challenging. Clinical evaluation in combination with radiological measurements is important in pre- and post-surgical assessment. Based on computed tomography (CT), a range of reference values for femoral torsion (FT) and tibial torsion (TT) have historically been reported, which require standardization to optimize the significant intra- and inter-observer variability. The aims of this study were (re-)evaluation of the reference FT and TT angles, determination of the normal intra-individual side-to-side torsional differences to aid the surgical decision-making process for reoperation, and development of a novel 3D measurement method for FT.Materials and methodsIn this retrospective study, we included 55 patients, without any known torsional deformities of the lower extremities. Two radiologists, independently, measured the rotational profile of the femora using the Hernandez and Weiner CT methods for FT, and the tibiae using the bimalleolar method for TT. The intra-individual side-to-side difference in paired femora and paired tibiae was determined. A 3D technique for FT assessment using InSpace was designed.ResultsFT and TT demographic values were lower than previously reported, with mean FT values of 5.1 8.8 and mean TT values of 25.5 27.7 . Maximal side-to-side differences were 12 13 for FT and 12 for TT. The Weiner method for FT was less variable than the Hernandez method. The new 3D method was equivocal to the conventional CT measurements.ConclusionThe results from this study showed that the maximal side-to-side tolerance in asymptomatic normal adult lower extremities is 12 13 for FT and 12 for TT, which could be a useful threshold for surgeons as indication for revision surgery (e.g., derotational osteotomy). We developed a new 3D CT method for FT measurement which is similar to 2D and could be used in the future for virtual 3D planning.

IntroductionRegional anaesthesia (RA) is often used in shoulder surgery because it provides adequate postoperative analgesia and may enhance the patient outcome. RA reduces overall opioid consumption and is frequently used in enhanced recovery programs to decrease hospital stay. However, there is very limited literature confirming these advantages in the surgical repair of proximal humerus fractures. This paper reviews the current literature on the use of RA in pain management after surgical repair of these fractures and evaluates the effect of RA on the functional outcome, length of stay in hospital, and health care expenditure.Materials and methodsThe PubMed, Embase, Web of Science, and Cochrane Library databases were searched up to March 1, 2018. Studies investigating the use of RA in the management of proximal humerus fractures were included.ResultsEleven studies (containing 1872 patients) were eligible for inclusion. The analgesic effect of RA was investigated in eight studies that confirmed its pain-relieving ability. Two studies measured functionality and length of hospitalization and suggested that RA improved function and shortened the stay in hospital. Nine papers mentioned side effects associated with RA while three articles claim that RA decreases the incidence of adverse events associated with general anaesthesia.ConclusionsThis systematic review suggests that RA is a good option for postoperative analgesia in patients undergoing surgical repair of a proximal humerus fracture and is associated with fewer adverse events, a shorter recovery time, and a better functional outcome than those achieved by general anaesthesia alone. However, given the limited amount of data available, conclusions need to be made with caution and prospective studies are needed in the future.