Bacteriophages: what role may they play in life after spinal cord injury?

Bacterial infections are the leading cause of death in people with a spinal cord injury (SCI). Bacteriophages (phages) are viruses that solely infect and kill bacteria. The idea of using phages to treat bacterial infections, i.e., phage therapy, is very promising and potentially allows a more specific and personalized treatment of bacterial infections than antibiotics. While multi-drug resistant infections affect individuals from the general population, alternative therapeutic options are especially warranted in high-risk populations, such as individuals with SCI. However, more clinical data must be collected before phage therapy can be implemented in clinical practice, with numerous possible, subsequent applications

Short and oral antimicrobial therapy for diabetic foot infection: a narrative review of current knowledge

Diabetic foot infection is a frequent complication in long-standing diabetes mellitus. For antimicrobial therapy of this infection, both the optimal duration and the route of administration are often based more on expert opinion than on published evidence. We reviewed the scientific literature, specifically seeking prospective trials, and aimed at addressing two clinical issues: (1) shortening the currently recommended antibiotic duration and (2) using oral (rather than parenteral) therapy, especially after the patient has undergone debridement and revascularization. We also reviewed some older key articles that are critical to our understanding of the treatment of these infections, particularly with respect to diabetic foot osteomyelitis. Our conclusion is that the maximum duration of antibiotic therapy for osteomyelitis should be no more than to 4-6 weeks and might even be shorter in selected cases. In the future, in addition to conducting randomized trials and propagating national and international guidance, we should also explore innovative strategies, such as intraosseous antibiotic agents and bacteriophages

Indwelling catheter vs intermittent catheterization: is there a difference in UTI susceptibility?

BACKGROUND Patients with neurogenic lower urinary tract dysfunction (NLUTD) often rely on some type of catheterization for bladder emptying. Intermittent catheterization (IC) is considered the gold standard and is preferred over continuous catheterization, since it is considered to cause fewer urinary tract infections (UTIs) than indwelling catheterization. The main objective of our study was to describe UTI prevalence (at visit) and incidence (within the last 12 months) and urine culture characteristics between patients using an indwelling catheter versus (vs) those performing IC. METHODS In this cross-sectional study, we prospectively evaluated from 02/2020 to 01/2021 patients with NLUTD undergoing urine cultures for prophylactic reasons or due to UTI symptoms. At visit, all patients underwent a standardized interview on current UTI symptoms as well as UTI history and antibiotic consumption within the past year. Patients using an indwelling catheter (n = 206) or IC (n = 299) were included in the analysis. The main outcome was between-group differences regarding UTI characteristics. RESULTS Patients using an indwelling catheter were older (indwelling catheter vs IC: median 66 (Q1-Q3: 55-77) vs 55 (42-67) years of age) and showed a higher Charlson comorbidity index (indwelling catheter vs IC: median 4 (Q1-Q3: 2-6) vs 2 (1-4) (both p < 0·001). A total of 40 patients from both groups were diagnosed with a UTI at visit (indwelling catheters vs IC: 8% (16/206) vs 8% (24/299); p = 0·782), and the number of UTIs within the past 12 months was not significantly different between groups. Overall, Escherichia coli (21%), Enterococcus faecalis (17%), and Klebsiella spp. (12%) were the most frequently detected bacteria. CONCLUSIONS In this cohort of patients with NLUTD, we did not find relevant differences in UTI frequency between groups. These results suggest that UTI-related concerns should not be given undue emphasis when counseling patients for catheter-related bladder emptying methods

Engineered reporter phages for detection of Escherichia coli, Enterococcus, and Klebsiella in urine

The rapid detection and species-level differentiation of bacterial pathogens facilitates antibiotic stewardship and improves disease management. Here, we develop a rapid bacteriophage-based diagnostic assay to detect the most prevalent pathogens causing urinary tract infections: Escherichia coli, Enterococcus spp., and Klebsiella spp. For each uropathogen, two virulent phages were genetically engineered to express a nanoluciferase reporter gene upon host infection. Using 206 patient urine samples, reporter phage-induced bioluminescence was quantified to identify bacteriuria and the assay was benchmarked against conventional urinalysis. Overall, E. coli, Enterococcus spp., and Klebsiella spp. were each detected with high sensitivity (68%, 78%, 87%), specificity (99%, 99%, 99%), and accuracy (90%, 94%, 98%) at a resolution of ≥10$^{3}$ CFU/ml within 5 h. We further demonstrate how bioluminescence in urine can be used to predict phage antibacterial activity, demonstrating the future potential of reporter phages as companion diagnostics that guide patient-phage matching prior to therapeutic phage application

Silk Route to the Acceptance and Re-Implementation of Bacteriophage Therapy—Part II

This perspective paper follows up on earlier communications on bacteriophage therapy that we wrote as a multidisciplinary and intercontinental expert-panel when we first met at a bacteriophage conference hosted by the Eliava Institute in Tbilisi, Georgia in 2015. In the context of a society that is confronted with an ever-increasing number of antibiotic-resistant bacteria, we build on the previously made recommendations and specifically address how the Nagoya Protocol might impact the further development of bacteriophage therapy. By reviewing a number of recently conducted case studies with bacteriophages involving patients with bacterial infections that could no longer be successfully treated by regular antibiotic therapy, we again stress the urgency and significance of the development of international guidelines and frameworks that might facilitate the legal and effective application of bacteriophage therapy by physicians and the receiving patients. Additionally, we list and comment on several recently started and ongoing clinical studies, including highly desired double-blind placebo-controlled randomized clinical trials. We conclude with an outlook on how recently developed DNA editing technologies are expected to further control and enhance the efficient application of bacteriophages

ITN—VIROINF: understanding (harmful) virus-host interactions by linking virology and bioinformatics

Many recent studies highlight the fundamental importance of viruses. Besides their important role as human and animal pathogens, their beneficial, commensal or harmful functions are poorly understood. By developing and applying tailored bioinformatical tools in important virological models, the Marie Skłodowska-Curie Initiative International Training Network VIROINF will provide a better understanding of viruses and the interaction with their hosts. This will open the door to validate methods of improving viral growth, morphogenesis and development, as well as to control strategies against unwanted microorganisms. The key feature of VIROINF is its interdisciplinary nature, which brings together virologists and bioinformaticians to achieve common goals

The Rational Evaluation of Phage Therapy

Ten million people are projected to die in 2050 due to antibiotic résistance: that is more than the entire current population of Switzerland. Alarm was first voiced of the dangers of bacterial résistance shortly after their introduction into clinical practice, and the world is now up-in-arms about exactly what to do. The purpose of this doctoral study was to evaluate bacteriophage therapy as a potential alternative treatment to antibiotics, with a specific focus on determining the phage composition of commercially- available products and assessing phage susceptibility in vancomycin-resistant Staphylococcus aureus. This therapy, which harnesses the lytic cycle of naturally-occurring bacterial viruses (referred to as phages), has been used in Eastern European countries for clinical treatment for over 50 years. The renewed interest phage therapy has received since 2000 is presented in the first chapter to provide a meta-analysis of the accomplishments and short-comings of current efforts, as well as highlight certain factors that have deterred its broader application. Several reported case studies have used phage products from Georgia, where they are sold as over-the-counter medicines. A second focus of this work was to understand how these phage products are composed by using metagenomics to study the composition of ten products. This high-throughput technique identifïed which phage généra have been selected as therapeutic candidates against différent bacterial hosts, as well as characterized the genetic safety of this self-amplifying therapy. A closely-related group of Kayviruses was the sole phage component against S. aureus, except for one product, which included a P68-like phage that targets specific bacterial strains. Evaluating the in vitro activity of these products against S. aureus led to the discovery of increased phage insensitivity for strains also displaying intermediate levels of résistance to vancomycin (VISA), the last- resort antibiotic for S. aureus infections. This observation initiated a thorough investigation to identify the several, multifactorial molecular mechanisms and genetic mutations responsible for this correlated résistance. Phage infection of VISA strains is interrupted between ejection of phage DNA into the host and intracellular replication and is caused by mutations in genes involved with cell-wall composition, surface charge, metabolism, and protein synthesis. If phage therapy has the capacity to abate the antibiotic résistance crisis, then there is much to be learned from how it is currently used in countries such Russia, Georgia, and Poland. S. aureus is a frequently targeted pathogen for phage therapy and this study revealed that it may be more effective to use phage as a treatment option prior to the development of résistance to vancomycin. -- Les prévisions de santé publique suggèrent que la résistance bactérienne aux antibiotiques pourrait coûter dix millions de vies d'ici 2050 : un nombre de victimes supérieur à la population suisse. Les risques posés par l'émergence de bactéries résistantes ont été soulevés déjà très tôt après l'introduction de la pénicilline en pratique clinique, dès la fin des années 1940. Nous payons maintenant le résultat de l'utilisation démesurée de ces médicaments, qui est responsable de l'explosion actuelle de l'antibiorésistance. Le but de la présente thèse est l'étude d'une stratégie thérapeutique alternative contre les bactéries résistantes par l'utilisation des bactériophages, ou phagothérapie. Les bactériophages (phages) sont des virus prédateurs spécifiques des bactéries, dans lesquelles ils injectent leur matériel génétique et parasitent l'appareillage de synthèse pour se reproduire. A la fin de leur cycle reproductif, ils tuent l'hôte et le font éclater pour relâcher les nouveaux virions. La phagothérapie tire parti des propriétés bactéricides des phages pour traiter les infections. La phagothérapie a été utilisée depuis plus d'un demi-siècle, entre autre par les forces de l'Axe durant la seconde guerre mondiale, puis dans les pays de l'ex-URSS. Cependant, les critères de production des phages, le contenu des préparations et leur efficacité contre les bactéries résistantes ne sont en général pas bien déterminés. Le présent travail s'est intéressé à la faisabilité de la phagothérapie en terme de qualité et d'efficacité. Le premier chapitre revoit les fondements et les développements récents de cette stratégie antimicrobienne, pour laquelle un engouement nouveau existe dans les pays industrialisés depuis une décennie. Ce chapitre revoit la méthodologie et les résultats des essais cliniques récents, la plupart non contrôlés, et soulève les questions fondamentales qui doivent être abordées avant de pouvoir appliquer définitivement ce type de traitement dans les pays occidentaux. Le second chapitre décrit le développement et les résultats de techniques génomiques modernes, par la métagénomique, permettant d'analyser le contenu en phages de préparations vendues sans ordonnances médicales dans les pays de l'ex-URSS. Les résultats, originaux, permettent d'une part de décrire les phages utilisés au niveau génomique, d'autre part de connaître les contenus en phages de ces préparations, ainsi que l'évolution de ces contenus qui ne sont souvent pas parfaitement connus, et enfin de faire l'inventaire de gènes potentiellement dangereux que ces préparations pourraient contenir, tels que des gènes de résistance aux antibiotiques ou des gènes de virulence qui pourraient être transmis à la flore microbienne des patients par le traitement. Ce type de méthodologie deviendra certainement une étape obligatoire de la production de phages thérapeutiques dans les pays occidentaux. Le troisième chapitre s'intéresse à l'activité de phages anti-staphylococciques de ces préparations sur des collections de Staphylocoques dorés sensibles ou résistants aux antibiotiques disponibles en clinique, y compris à la vancomycine, considérée comme agent antimicrobien de dernier ressort. Les résultats montrent que lesdits phages sont en général efficaces contre toutes les souches antibio-sensibles, mais perdent leur efficacité contre la plupart des souches de sensibilité diminuée à la vancomycine, appelées « Vancomycin-Intermediate Slapbylococcus aureus » ou VISA. L'étude des mécanismes de résistance aux niveaux moléculaires et génétiques indique que cette perte d'efficacité résulte de l'addition de plusieurs dérèglements de la cellule, induits par la résistance à la vancomycine. Les altérations se situent aux niveaux (i) de la structure de la paroi cellulaire, au travers de laquelle les phages doivent injecter leur ADN, (ii) de la membrane plasmique, dont les phages utilisent le potentiel de membrane pour faire entrer l'ADN dans la cellule, et (iii) de l'appareil de transcription du RNA, que les phages utilisent pour transcrire leurs gènes. Parmi toutes ces altérations, aucune mutation unique ne semble pouvoir conférer la résistance aux phages. Deux au minimum sont nécessaires. Enfin, une étude complémentaire sur une grande collection de souches cliniques de France a confirmé le fait que les VISA étaient statistiquement plus souvent résistants aux phages que les staphylocoques sensibles, et que ceci devra être pris en compte pour les traitements futurs d'infections à Staphylocoques dorés par la phagothérapie. En conclusion, la phagothérapie est une stratégie antimicrobienne largement utilisée dans les pays de l'ex- URSS tels que la Russie, la Georgia, et la Pologne. Elle a un potentiel certain pour cibler les infections problématiques telles que celles dues à des bactéries résistantes. Mais elle doit être étudiée soigneusement, aussi bien au niveau de la production que de l'efficacité, comme le montre la résistance inattendue des VISA aux phages. La connaissance précise de ces nouveaux agents antimicrobiens et de leur interaction avec les agents pathogènes est un prérequis indispensable à leur utilisation future dans les pays occidentaux

Management of uncomplicated UTI in the post-antibiotic era (II): select non-antibiotic approaches

BACKGROUND Given the high frequency of patients presenting with urinary tract infections (UTIs) and the ensuing high degree of antibiotic prescription, UTI is a critical point of intervention for non-antibiotic treatments in order to curb the further development of antimicrobial resistance and provide risk-appropriate care for patients. OBJECTIVES To highlight several select non-antibiotic therapies for the treatment of uncomplicated UTI and relevant indications (prevention, complicated UTI) from recent literature. SOURCES Pubmed, Google Scholar, &clinicaltrials.gov were searched for clinical trials published in the English language corresponding to non-antibiotic treatments for UTI. CONTENT The focus of this narrative review centers on a limited number of non-antibiotic therapies for the treatment of UTI based on (1) herbal extracts or (2) antibacterial strategies (e.g. bacteriophage therapy, D-mannose). The experience of treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) is also used to fuel discussion on the risk of developing pyelonephritis without antibiotics - compared to the projected harms of continuing their widespread use. IMPLICATIONS Non-antibiotic treatment strategies for UTI have shown varying results in clinical trials, and the current evidence does not yet indicate a clear, better alternative to antibiotics. However, the collective experience with non-antibiotic treatments suggests there is a need to weigh the actual benefits/risks of unfettered, non-culture confirmed antibiotic use in uUTI. Given the different mechanisms of action of proposed alternatives, more in depth knowledge on microbiological and pathophysiological factors influencing UTI susceptibility and prognostic indicators are highly needed to stratify patients most likely to benefit. The feasibility of alternatives in clinical practice should also be considered

A systematic review of phage therapy applied to bone and joint infections: an analysis of success rates, treatment modalities and safety

Bone and joint infections are difficult to treat, and increasing antibiotic resistance has only made them more challenging. This has led to renewed interest in phage therapy (PT). The aim of this systematic review was to determine success rate, current treatment modalities and safety of PT in bone and joint infections.A systematic search of PubMed, EMBASE and Cochrane databases as well as the journal PHAGE for literature published between January 2000 and April 2021 was conducted according to PRISMA guidelines to identify all human studies assessing bacteriophages as therapy for bone and joint infections. All study designs and patient populations were eligible. The review's primary outcome was success rate.Twenty records describing a total of 51 patients and 52 treatment episodes were included. No randomized controlled studies were identified. The overall success rate was 71% (n = 37/52). Topical administration alone was the most frequent administration route (85%, n = 44/52). Antibiotics were administered concomitantly with PT in the majority of treatments (79%, n = 41/52), and surgery was performed for 87% (n = 45/52) of treatment episodes. Four minor adverse events related to PT were reported, representing 8% (n = 4/52) of treatment episodes.PT for bone and joint infections has not been evaluated in any randomized controlled clinical study, and current administration modalities are highly variable between case reports and case series. While publications included here show potential benefit and few adverse effects, clinical trials are warranted to assess the efficacy of PT for bone and joint infections and determine optimal treatment modalities