Optimization of bacteriophage therapy for difficult-to-treat musculoskeletal infections: a bench-to-bedside perspective.

Given the increasing threat of antimicrobial resistance, scientists are urgently seeking adjunct antimicrobial strategies, such as phage therapy (PT). However, despite promising results for the treatment of musculoskeletal infections in our center, crucial knowledge gaps remain. Therefore, a prospective observational study (PHAGEFORCE) and a multidisciplinary approach was set up to achieve and optimize standardized treatment guidelines. At our center, PT is strictly controlled and monitored by a multidisciplinary taskforce. Each phage treatment follows the same pathway to ensure standardization and data quality. Within the PHAGEFORCE framework, we established a testing platform to gain insight in the safety and efficacy of PT, biodistribution, phage kinetics and the molecular interaction between phages and bacteria. The draining fluid is collected to determine the phage titer and bacterial load. In addition, all bacterial isolates are fully characterized by genome sequencing to monitor the emergence of phage resistance. We hereby present a standardized bench-to-bedside protocol to gain more insight in the kinetics and dynamics of PT for musculoskeletal infections.

Evaluation of antibiofilm agents for treatment of cystic fibrosis-related chronic rhinosinusitis.

KEY POINTS: Treatment of cystic fibrosis-related chronic rhinosinusitis should target sinonasal biofilms. NaHCO3 salts with/without xylitol have limited antibiofilm properties, whereas rhDNAse has not. Phage effectivity varies and depends on the phage and the combination with antibiotics.

Evaluation of skin prick location on the forearm using a novel skin prick automated test device.

Background: The skin prick test (SPT) is the gold standard for identifying allergic sensitization in individuals suspected of having an inhalant allergy. Recently, it was demonstrated that SPT using a novel skin prick automated test (SPAT) device showed increased reproducibility and tolerability compared to the conventional SPT, among other benefits. Objective: This study aimed to evaluate prick location bias using the novel SPAT device. Methods: A total of 118 volunteers were enrolled in this study and underwent SPATs with histamine (nine pricks) and glycerol control (one prick) solutions on the volar side of their forearms. Imaging of the skin reactions was performed using the SPAT device, and the physician determined the longest wheal diameter by visually inspecting the images using a web interface. Prick location bias was assessed along the medial vs. lateral and proximal vs. distal axes of the forearm. Results: In total, 944 histamine pricks were analyzed. Four medial and four lateral histamine pricks were grouped, and wheal sizes were compared. The longest wheal diameters were not significantly different between the medial and lateral prick locations (p = 0.41). Furthermore, the pricks were grouped by two based on their position on the proximal-distal axis of the forearm. No significant difference was observed among the four groups of analyzed prick locations (p = 0.73). Conclusion: The prick location on the volar side of the forearm did not influence wheal size in SPAT-pricked individuals.

Stability of magistral phage preparations before therapeutic application in patients with chronic rhinosinusitis, sepsis, pulmonary, and musculoskeletal infections.

IMPORTANCE: As antimicrobial resistance becomes more prevalent, the application of (bacterio)phage therapy as an alternative treatment for difficult-to-treat infections is (re)gaining popularity. Over the past decade, numerous promising case reports and series have been published demonstrating the therapeutic potential of phage therapy. However, important questions remain regarding the optimal treatment protocol and, unlike for medicinal products, there are currently no predefined quality standards for the stability of phage preparations. Phage titers can be influenced by several factors which could lead to reduced titers after preparation and storage and, ultimately, subtherapeutic applications. Determining the stability of different phages in different recipients according to the route of administration is therefore one of the first important steps in establishing a standardized protocol for phage therapy.

Upper Airway Disease in Adults with Cystic Fibrosis in the Era of CFTR Modulators.

OBJECTIVES: Chronic rhinosinusitis (CRS) is prevalent in people with cystic fibrosis (PwCF) and is often refractory to treatments. Uncontrolled CRS might negatively impact the lower airways and the quality of life. The aim of this study is to evaluate the burden of cystic fibrosis (CF)-related CRS in the era of CF transmembrane conductance regulator (CFTR) modulators. METHODS: Adult PwCF were asked to fill in a questionnaire on sinonasal complaints, they underwent a nasal endoscopy, bacteriological sampling, and a CT scan. Afterwards, these outcome measures were compared between patients treated with and without modulators. RESULTS: In the 122 included patients, CRS was present in 83%. CFTR modulators were prescribed in 48% of the patients, with a median of 10 months since the start of the treatment. Subjectively, the median SNOT-22 score was 16/110. Objectively, a median Lund-Kennedy score of 6/12 and modified Lund-Mackay score of 10/24 were observed. No correlation could be found between SNOT-22 score and other outcome measures including endoscopy and radiology. Altogether, 21% of the patients had controlled disease. When comparing patients treated with and without modulators, significantly lower CT scores (p = 0.0018) and less bacterial colonization (p = 0.0082) were observed in patients receiving modulators. CONCLUSION: CF-CRS is highly prevalent in our cohort and only the minority of PwCF has a well-controlled disease. A multidisciplinary ENT-pneumology clinic would be beneficial, as there is a high discrepancy between patient-reported symptoms and the extent of the disease. CFTR modulators are promising, as lower CT scores and less bacterial colonization were observed in the modulator group. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 133:2898-2909, 2023.

Safety and efficacy of phage therapy in difficult-to-treat infections: a systematic review.

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.

Bacteriophage Therapy for Difficult-to-Treat Infections: The Implementation of a Multidisciplinary Phage Task Force (The PHAGEFORCE Study Protocol).

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.

The Potential Role of Bacteriophages in the Treatment of Recalcitrant Chronic Rhinosinusitis.

Chronic rhinosinusitis is a common condition affecting 5-12% of the general population worldwide. In a limited number of cases, the disease is recalcitrant to medical and surgical interventions, causing a major impact on physical, social and emotional well-being and increasing pressure on healthcare systems. Biofilm formation and dysbiosis caused by Staphylococcus aureus and Pseudomonas aeruginosa play a role in the pathogenesis of recalcitrant chronic rhinosinusitis. In these cases, a promising treatment alternative is the application of bacteriophages, which are viruses that infect and lyse bacteria. In this review, we appraise the evidence for the use of bacteriophages in the treatment of recalcitrant chronic rhinosinusitis. Additionally, (dis)advantages of bacteriophages and considerations for implementation of phage therapy in otorhinolaryngology practice will be discussed.

How to approach complications of acute rhinosinusitis in children?

Intraorbital and intracranial complications of acute rhinosinusitis (ARS) are uncommon, but potentially life threatening. Signs of progression of ARS should be recognized early to allow timely surgical treatment in order to avoid irreversible lesions such as vision loss and neurological deficits. In this case series, we provide an overview of 6 representative cases who presented at our tertiary center (2017-2018). The aim of this case series is (1) to draw new attention to the clinical manifestations and management of these complications, since even in highly-developed medical settings we still observe permanent sequellae due to delayed or inadequate treatment, (2) to give an updated analysis of the guidelines, stressing the low threshold for endoscopic sinus surgery, even in children, (3) to underline the benefits of a multidisciplinary approach in these young patients.

Perioperative Antibiotics in Clean-Contaminated Head and Neck Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: The optimal evidence-based prophylactic antibiotic regimen for surgical site infections following major head and neck surgery remains a matter of debate. METHODS: Medline, Cochrane, and Embase were searched for the current best evidence. Retrieved manuscripts were screened according to the PRISMA guidelines. Included studies dealt with patients over 18 years of age that underwent clean-contaminated head and neck surgery (P) and compared the effect of an intervention, perioperative administration of different antibiotic regimens for a variable duration (I), with control groups receiving placebo, another antibiotic regimen, or the same antibiotic for a different postoperative duration (C), on surgical site infection rate as primary outcome (O) (PICO model). A systematic review was performed, and a selected group of trials investigating a similar research question was subjected to a random-effects model meta-analysis. RESULTS: Thirty-nine studies were included in the systematic review. Compared with placebo, cefazolin, ampicillin-sulbactam, and amoxicillin-clavulanate were the most efficient agents. Benzylpenicillin and clindamycin were clearly less effective. Fifteen studies compared short- to long-term prophylaxis; treatment for more than 48 h did not further reduce wound infections. Meta-analysis of five clinical trials including 4336 patients, where clindamycin was compared with ampicillin-sulbactam, implied an increased infection rate for clindamycin-treated patients (OR = 2.73, 95% CI 1.50-4.97, p = 0.001). CONCLUSION: In clean-contaminated head and neck surgery, cefazolin, amoxicillin-clavulanate, and ampicillin-sulbactam for 24-48 h after surgery were associated with the highest prevention rate of surgical site infection.