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The increase in antibiotic-resistant avian-pathogenic Escherichia coli (APEC), the causative agent of colibacillosis in poultry, warrants urgent research and the development of alternative therapies. This study describes the isolation and characterization of 19 genetically diverse, lytic coliphages, 8 of which were tested in combination for their efficacy in controlling in ovo APEC infections. Genome homology analysis revealed that the phages belong to nine different genera, one of them being a novel genus (Nouzillyvirus). One phage, REC, was derived from a recombination event between two Phapecoctavirus phages (ESCO5 and ESCO37) isolated in this study. Twenty-six of the 30 APEC strains tested were lysed by at least one phage. Phages exhibited varying infectious capacities, with narrow to broad host ranges. The broad host range of some phages could be partially explained by the presence of receptor-binding protein carrying a polysaccharidase domain. To demonstrate their therapeutic potential, a phage cocktail consisting of eight phages belonging to eight different genera was tested against BEN4358, an APEC O2 strain. In vitro, this phage cocktail fully inhibited the growth of BEN4358. In a chicken lethality embryo assay, the phage cocktail enabled 90% of phage-treated embryos to survive infection with BEN4358, compared with 0% of nontreated embryos, indicating that these novel phages are good candidates to successfully treat colibacillosis in poultry. IMPORTANCE Colibacillosis, the most common bacterial disease affecting poultry, is mainly treated by antibiotics. Due to the increased prevalence of multidrug-resistant avian-pathogenic Escherichia coli, there is an urgent need to assess the efficacy of alternatives to antibiotherapy, such as phage therapy. Here, we have isolated and characterized 19 coliphages that belong to nine phage genera. We showed that a combination of 8 of these phages was efficacious in vitro to control the growth of a clinical isolate of E. coli. Used in ovo, this phage combination allowed embryos to survive APEC infection. Thus, this phage combination represents a promising treatment for avian colibacillosis. ispartof: MICROBIOLOGY SPECTRUM vol:11 issue:3 ispartof: location:United States status: Published online

The rise in multi-drug resistant bacteria and the inability to develop novel antibacterial agents limits our arsenal against infectious diseases. Antibiotic resistance is a global issue requiring an immediate solution, including the development of new antibiotic molecules and other alternative modes of therapy. This article highlights the mechanism of bacteriophage treatment that makes it a real solution for multidrug-resistant infectious diseases. Several case reports identified phage therapy as a potential solution to the emerging challenge of multi-drug resistance. Bacteriophages, unlike antibiotics, have special features, such as host specificity and do not impact other commensals. A new outlook has also arisen with recent advancements in the understanding of phage immunobiology, where phages are repurposed against both bacterial and viral infections. Thus, the potential possibility of phages in COVID-19 patients with secondary bacterial infections has been briefly elucidated. However, significant obstacles that need to be addressed are to design better clinical studies that may contribute to the widespread use of bacteriophage therapy against multi-drug resistant pathogens. In conclusion, antibacterial agents can be used with bacteriophages, i.e. bacteriophage-antibiotic combination therapy, or they can be administered alone in cases when antibiotics are ineffective. Key points • AMR, a consequence of antibiotic generated menace globally, has led to the resurgence of phage therapy as an effective and sustainable solution without any side effects and high specificity against refractory MDR bacterial infections. • Bacteriophages have fewer adverse reactions and can thus be used as monotherapy as well as in conjunction with antibiotics. • In the context of the COVID-19 pandemic, phage therapy may be a viable option.

Introduction. At the same time, in the last decade, pediatricians have increased interest in the study of the therapeutic effect of bacteriophages in infectious diseases of rhinolaryngological organs.Objective. The analysis of results of the use of inhalation bacteriophage therapy in children with acute tonsillitis, on an outpatient basis.Materials and methods. Examined 212 children from 4 to 15 years old with acute tonsillitis. Conducted general clinical research, pharyngoscopy, bacteriological examination of a smear of tonsils. Bacteriophage therapy carried out using the Pyobacteriophage complex liquid (PCL).Results. In the course of an objective clinical analysis, on the day of seeking outpatient care, patients noted asthenovegetative disorders in all patients (100%), in the form of general weakness (96.8%), loss of appetite (94.8%), and headache (92.5%). During the examination, cervical lymphadenopathy (98.6%), tonsil hyperemia and hyperplasia (98.1%), and exudates (48.1%) noted. It revealed that the main causative agents of acute tonsillitis in children were the bacteria Streptococcus pyogenes, Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae, with different relative proportions (from 24.2% to 59%). Inhalation bacteriophage therapy carried out from the first days of the disease. Against the background of therapy, it was noted - a decrease in swelling in the tonsils by 2-3 days with a decrease in general intoxication signs. On the 6th day from the beginning of bacteriophage therapy, asthenovegetative disorders stopped 2.2 times faster in relation to patients who did not receive bacteriophage therapy, against the background of a decrease in the manifestation of objective clinical signs of the disease.Conclusion. The use of inhalation bacteriophage therapy as part of the conservative treatment of acute tonsillitis in children contributes 1.4 times to the fastest relief of the acute period and an improvement in the subjective assessment of well-being is 25% higher concerning the comparison group.

Antimicrobial resistance in pathogenic bacteria is increasing worldwide. One solution to this crisis is bacteriophage therapy, a treatment that harnesses naturally occurring bacterial viruses to in...

Although total hip arthroplasty (THA) is considered one of the most efficacious procedures for managing various hip conditions, failures due to different mechanisms are still being reported. Periprosthetic joint infection (PJI) is one of the devastating causes of failure and revision of THA. PJI carries a burden on the patient, the surgeon, and the health-care system. The diagnosis and management of PJIs carry many morbidities and increased treatment costs. The development of PJI is multifactorial, including issues related to the patient’s general condition, the surgeon’s efficiency, surgical technique, and the implants used. Recent advances in the area of diagnosis and predicting PJI as well as introducing new technologies and biomaterials update for the prevention and treatment of PJI. Local implant coatings, advancement in the bearing surfaces technologies, and new technologies such as immunotherapy and bacteriophage therapy were introduced and suggested as contemporary PJI eradication solutions. In this review, we aimed at discussing some of the newly introduced materials and technologies for the sake of PJI control.

Researchers have recently renewed interest in bacteriophages. Being valuable models for the study of eukaryotic viruses, and more importantly, natural killers of bacteria, bacteriophages are being tapped for their potential role in multiple applications. Bacteriophages are also being increasingly sought for bacteriophage therapy due to rising antimicrobial resistance among pathogens. Reports show that there is an increasing trend in therapeutic application of natural bacteriophages, genetically engineered bacteriophages, and bacteriophage-encoded products as antimicrobial agents. In view of these applications, the isolation and characterization of bacteriophages from the environment has caught attention. In this review, various methods for isolation of bacteriophages from environmental sources like water, soil, and air are comprehensively described. The review also draws attention towards a handful on-field bacteriophage isolation techniques and the need for their further rapid development.

Phage therapy is revolving to address the issues mainly dealing with antibiotic resistance in the pathogenic bacteria. Among the drug-resistant microbial populations, the bacterial species have been categorized as high-priority or critical-priority bacteria. This review summarizes the efficiency and development in phage therapy used against these drug-resistant bacteria in the past few years mainly belonging to the critical- and high-priority list. Phage therapy is more than just an alternative to antibiotics as it not only kills the target microbial population directly but also leads to the chemical and physical modifications in bacterial cell structures. These phage-mediated modifications in the bacterial cell may make them antibiotic sensitive. Application of phage therapy in antibiotic-resistant foodborne bacteria and possible modulation in gut microbes has also been explored. Further, the phage cocktail antibiotic formulation, containing more than one type of phage with antibiotics, has also been discussed.

Bacteriophages are bacterio-specific viruses that constitute the main portion of the environment. Bacteriophages inject their genome into the targeted bacterial cells and some of them can disrupt the metabolism of bacteria and cause bacterial cell disintegration. The application of bacteriophages to kill bacteria is known as bacteriophage therapy. Since bacteriophages target bacteria and are strain-specific, every bacteriophage/bacterial host pair is unique. They are believed to cause no harm to humans. An additional advantage of the strain-specific nature of bacteriophages is that they do not disrupt the beneficial natural flora in the body. Bacteriophage therapy in the West is not a recognized medicine at this time, and no products are registered. Some clinicians are turning to bacteriophage therapy for the treatment of antibiotic-resistant infections. Lack of adverse effects makes bacteriophage therapy ideal for use. Funding research, media attention, and the increased publication of articles helped in a widespread understanding of its therapeutic potential. The first prerequisite for the use of bacteriophage therapy is simply the availability of bacteriophages for treatment, which is often complicated at this stage of bacteriophage production. This includes providing access to all biologically active bacteriophages against the bacterial isolate of the patient and meeting regulatory criteria of purity, traceability, and characterization. A monophage preparation, which is a single bacteriophage, or a phage cocktail, which consists of a number of combined bacteriophages against one or more bacterial species may be used. Accordingly, the antibiotic resistance crisis brought back bacteriophage therapy as a potential complementary or alternative treatment. Bacteriophages are promising cheap antibacterials.

In connection with growing problem of antimicrobial resistance, the search for alternative treatments for infection is popular topic nowadays. This article represents an overview of published data on the therapeutic use of bacteriophages, specifically in urinary tract infections. The history of phage therapy of infectious diseases from the beginning of the 20th century to the present days is presented. The paper also discuss the mechanism of bacteriophages activity, differences between lytic and lysogenic phages, mechanisms of bacterial tolerance to phages and ways of its overcoming are. Authors present their own data on 30 years of clinical use of “bacteriophage cocktails” in the treatment and prevention of urological infection.

Background. Acne is one of the most common chronic dermatoses, which occurs in almost 8590% of the population. The disease manifests itself as polymorphic eruptions and is characterized by a recurrent and torpid course. Acne treatment is constantly improving, requires an integrated approach and long courses of therapy. Aims. To increase the effectiveness of acne therapy using new opportunities and promising methodological approaches using a combination of the therapeutic effects of platelet-rich plasma (PRP) and topical bacteriophage therapy. Materials and methods. The study included 30 patients with papulopustular acne of mild and moderate severity. Patients with mild acne were treated with PRP procedures as monotherapy. For moderate acne, PRP therapy was combined with regular applications of a staphylococcal bacteriophage (NPO Microgen, Nizhny Novgorod, Russia). The treatment was carried out on an outpatient basis: at least 3 procedures with an interval of 12 weeks (up to a maximum of 6 procedures within one year). The results were analyzed using descriptive statistics and the parametric Student's t-test. Data processing was carried out using the Biostat software. The value of the level of statistical significance of differences was taken as p 0.05. Results. Evaluation of the effectiveness of treatment was carried out on the basis of an analysis of the immediate outcomes of the disease, the dynamics of clinical symptoms and the severity of acne: regression of inflammatory elements of acne, a decrease in the phenomenon of seborrhea, improvement of the skin relief. As a result of the therapy, a transition to remission was noted in 16.6% of patients, an improvement in their condition 36.7%, a significant improvement 46.7%. Conclusions. An integrated approach combining PRP procedures and bacteriophage therapy can serve as a pathogenetically substantiated strategy for treating acne. A promising direction for further research is the development of new regimens and combinations of alternative therapeutic strategies using bacteriophages.

Kayviruses are polyvalent broad host range staphylococcal phages with a potential to combat staphylococcal infections. However, the implementation of rational phage therapy in medicine requires a thorough understanding of the interactions between bacteriophages and pathogens at omics level. To evaluate the effect of a phage used in therapy on its host bacterium, we performed differential transcriptomic analysis by RNA-Seq from bacteriophage K of genus Kayvirus infecting two Staphylococcus aureus strains, prophage-less strain SH1000 and quadruple lysogenic strain Newman. The temporal transcriptional profile of phage K was comparable in both strains except for a few loci encoding hypothetical proteins. Stranded sequencing revealed transcription of phage noncoding RNAs that may play a role in the regulation of phage and host gene expression. The transcriptional response of S. aureus to phage K infection resembles a general stress response with differential expression of genes involved in a DNA damage response. The host transcriptional changes involved upregulation of nucleotide, amino acid and energy synthesis and transporter genes and downregulation of host transcription factors. The interaction of phage K with variable genetic elements of the host showed slight upregulation of gene expression of prophage integrases and antirepressors. The virulence genes involved in adhesion and immune evasion were only marginally affected, making phage K suitable for therapy. Kayviruses are polyvalent broad host range staphylococcal phages with a potential to combat staphylococcal infections. However, the implementation of rational phage therapy in medicine requires a thorough understanding of the interactions between bacteriophages and pathogens at omics level. To evaluate the effect of a phage used in therapy on its host bacterium, we performed differential transcriptomic analysis by RNA-Seq from bacteriophage K of genus Kayvirus infecting two Staphylococcus aureus strains, prophage-less strain SH1000 and quadruple lysogenic strain Newman. The temporal transcriptional profile of phage K was comparable in both strains except for a few loci encoding hypothetical proteins. Stranded sequencing revealed transcription of phage noncoding RNAs that may play a role in the regulation of phage and host gene expression. The transcriptional response of S. aureus to phage K infection resembles a general stress response with differential expression of genes involved in a DNA damage response. The host transcriptional changes involved upregulation of nucleotide, amino acid and energy synthesis and transporter genes and downregulation of host transcription factors. The interaction of phage K with variable genetic elements of the host showed slight upregulation of gene expression of prophage integrases and antirepressors. The virulence genes involved in adhesion and immune evasion were only marginally affected, making phage K suitable for therapy.

A literature review dedicated to the problem of bacteriophage therapy for infectious and inflammatory diseases, including urological infections, is presented. Considering the growth of antibiotic resistance, the search for alternative treatments is relevant. Current data about bacteriophages and mechanism of their action, difference of virulent and temperate phages is given, as well as mechanisms of bacteria resistance to phages and ways of its overcoming. The history of phage therapy for infectious diseases from the beginning of the 20th century to the present days is presented. Pharmacokinetic studies of phages after oral administration are given. Moreover, we described our 30 years experience on of clinical use of bacteriophage cocktails in the treatment and prevention of urological infection. In addition, problems of phage therapy are discussed, including immunological issues and the advantages of bacteriophages over antibiotics.

Objective Data visualization software were used to display and analyze the research status, hotspot and development trend of the antibiotic-resistance of Acinetobacter baumannii objectively and comprehensively, so as to provide guidance and reference for the research of the antibiotic-resistant Acinetobacter baumannii. Materials and methods The data of relevant publications on antibiotic-resistant Acinetobacter baumanii from 1991 to 2019 were retrieved from Web of Science (WOS) Core database. VOSviewer and CiteSpace software were used to conduct co-citation visualization network rendering and cluster analysis on the publications' years, authors, countries, institutions, keywords and citations. Results A total of 3915 valid records on the study of antibiotic-resistant Acinetobacter baumanii were retrieved. The number of relevant publications was increasing year after year. The United States is the most influential country in the field, which works closely with other countries and publishes most of the papers. University of Sydney is the leading institution in this area. Bonomo Robert A publishes most of the papers. There are the highest number of publications in the research areas of antimicrobial agents and chemotherapy. "Nucleotide sequence" and "outbreak" were once the hotspots in this field, but recently "bacteriophage", "biofilm" and "colistin resistance" have become the research hotspots. Conclusion Since 1991, the number of publications on antibiotic-resistant Acinetobacter baumannii has grown rapidly, and various countries and institutions have paid close attention to the problem of antibiotic resistance. Countries, institutions and researchers, which have strong influential power, collaborate with each other closely. The future research direction of antibiotic-resistant Acinetobacter baumannii should lie in the further breakthrough of antibacterial peptides, bacteriophage therapy, CRISPR system and various combined therapies.

To investigate the potential role of bacteriophages in the treatment of surgical infections, we conducted a retrospective analysis of four surgical patients who have sought treatment at the Eliava Phage Therapy Center, Tbilisi, Georgia. Two patients had chronic osteomyelitis, one presented with a diabetic foot ulcer, and the fourth patient had developed a severe infectious complication after skin grafting surgery. Patients were treated with different combinations of bacteriophage preparations, based on the sensitivity of the isolated bacterial strain toward commercially available bacteriophages. The treatment lasted on average for 1 month, and positive results were obtained in all four cases: the wounds have healed, the general health status of the patients has improved. No allergic or adverse reactions have been observed throughout the treatment.

During the spread of bacterial infections with extensive drug resistance, the potential of existing antibacterial drugs is significantly reduced. The medical community is seeking opportunities for the rational use of antibacterial drugs, the development of new drugs, as well as the use of alternative treatments for these infections. Aim. The objective of this study was to evaluate the effectiveness of the use of a complex antibacterial and analgesic drug based on bacteriophages in gel form during various instrumental studies and diagnostic procedures in order to minimize the risk of the urinary system infections complications. Materials and methods. The study included 235 women aged 18 to 75 years who underwent treatment at the Moscow State Clinical Hospital named after Spasokukotsky and in the clinic of urology of Moscow State University of Medicine and Dentistry from September 2019 to January 2020. During the manipulation, all patients of the main group (n=120) used a developed preparation based on bacteriophages, and in the control group (n=115), a topical gel based on chlorhexidine dihydrochloride and lidocaine hydrochloride was used. All patients before the manipulation, as well as 10 days after the manipulation, underwent bacteriological analysis of urine. Efficiency assessment was carried out on the basis of laboratory data obtained, as well as according to the visual analogue scale of the pain syndrome severity. Results. None of the patients in the main group showed intolerance, side effects and allergic reactions of the developed drug based on bacteriophages. Bacteriological analysis of urine received before manipulation in both groups showed the absence of clinically significant titers of pathogenic bacteria, while 1 week after manipulation the number of titers of pathogenic bacteria (104) was significantly higher in the control group (p0.04). In patients of the main group, the incidence of dysuria was lower compared with the control group (p0.05). Conclusion. The study showed good tolerance of the developed drug and its clinical effectiveness in reducing the number of symptomatic bacteriuria; severity of pain after undergoing manipulation was relatively lower in the main group of patients. Conducting multicenter studies with the inclusion of a larger number of patients in the future will reduce the economic costs associated with treating patients by reducing the number of cases of nosocomial infections and reducing postoperative time spent by patients in the hospital.

Purpose of review Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. Recent findings Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. Summary The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.

Bacterial urinary tract infections (UTIs) are very frequent, especially in patients with neurogenic lower urinary tract dysfunction (NLUTD). The steady increase in antibiotic resistance among causative bacteria prompts the search for highly effective therapeutic alternatives with little or no side effects. Bacteriophages - obligate intracellular viruses that solely infect and kill bacteria - are promising tools for treating bacterial infections and have been used for this purpose for almost a century. Recent clinical studies using bacteriophage therapy for UTIs showed encouraging results. In particular, patients with recurrent UTIs, such as individuals with NLUTD who rely on assisted bladder emptying, might benefit from this treatment method. However, bacteriophages are not yet a panacea. More high-quality basic and clinical research on bacteriophage therapy is needed to answer questions on the use of this therapeutic option and its potential to provide a solution to the global threat of multidrug-resistant bacteria. PATIENT SUMMARY: Urinary tract infections are very common, especially in patients with neurogenic lower urinary tract dysfunction. In this review we discuss the potential of bacteriophage therapy as an alternative to antibiotics for treating patients with bladder infections.

Acinetobacter baumannii is a pathogenic bacterium commonly associated with multidrug resistance. In this issue of Antimicrobial Agents and Chemotherapy , a challenging case of ventilator-associated pneumonia is presented in which bacteriophage therapy was used as a last resort treatment in combination with systemic antibiotics. The data are promising, and several key areas are highlighted for future research.

Antibiotic resistance is one of the major challenges that humankind shall face in the short term. (Bacterio)phage therapy is a valuable therapeutic alternative to antibiotics and, although the concept is almost as old as the discovery of phages, its wide application was hindered in the West by the discovery and development of antibiotics in the mid-twentieth century. However, research on phage therapy is currently experiencing a renaissance due to the antimicrobial resistance problem. Some countries are already adopting new ad hoc regulations to favor the short-term implantation of phage therapy in clinical practice. In this regard, the Phage Therapy Work Group from FAGOMA (Spanish Network of Bacteriophages and Transducing Elements) recently contacted the Spanish Drugs and Medical Devices Agency (AEMPS) to promote the regulation of phage therapy in Spain. As a result, FAGOMA was asked to provide a general view on key issues regarding phage therapy legislation. This review comes as the culmination of the FAGOMA initiative and aims at appropriately informing the regulatory debate on phage therapy.

The aim — to assess the incidence of port site infection after laparoscopic cholecystectomy and laparoscopic cholecystectomy with bacteriophage therapy for acute destructive cholecystitis.Materials and methods. The analysis of the results of treatment of 96 patients with obesity of I — II stages at the age of 37 to 67 years carried out. All patients underwent laparoscopic cholecystectomy for acute destructive cholecystitis. The average body mass index was 35.04 ± 0.2 kg/m2. In the comparison group (n = 42), the subxiphoid trocar wound was sanitized with a 0.02 % decamethoxin solution in an isotonic sodium chloride solution (decasan solution) after gall bladder extraction. In the main group (n = 54), the subxiphoid trocar wound was irrigated with therapeutic and prophylactic bacteriophages (Sextaphag, Intesti‑bacteriophage, coli protein bacteriophage, and their combination). Treatment results were evaluated by the nature and frequency of infection of the trocar wound area.Results and discussion. Infiltrate and/or seromas of trocar wounds in the comparison group have observed in one (2.4 %) patient, in the main group — in 2 (3.7 %) patients. Suppuration of the trocar wound has observed only in the comparison group — 2 (4.8 %) cases. The nature of microbial bile flora and the exudate of the abdominal cavity, its amount, the sensitivity of microorganisms to antibiotics and bacteriophages were studied. In patients with gangrenous cholecystitis and local purulent peritonitis, microbial associations prevailed (65.9 %), Pseudomonas aeruginosa, Candida strains and anaerobic flora were detected. In patients with phlegmonous form of cholecystitis, the sensitivity of Escherichia coli, Staphylococci, Streptococci, Proteas and Klebsiella to Sextaphag was 76.9 — 100.0 %.Conclusions. The bacteriophage therapy after laparoscopic cholecystectomy for acute destructive cholecystitis contributed to a reduction of port site infection incidence in the postoperative period from 8.5 to 2.4 %., Цель работы — оценить частоту возникновения инфекции области троакарной раны после лапароскопической холецист­эктомии с терапией бактериофагами и без таковой по поводу острого деструктивного холецистита.Материалы и методы. Проведен анализ результатов лечения 96 пациентов с ожирением I — II степени в возрасте от 37 до 67 лет. Всем пациентам выполнили лапароскопическую холецистэктомию по поводу острого деструктивного холецистита. Индекс массы тела в среднем составлял (35,04 ± 0,2) кг/м2. В группе сравнения (n = 42) после удаления желчного пузыря санацию троакарной субксифоидальной раны осуществляли раствором 0,02 % декаметоксина в физиологическом растворе (раствор «Декасан»). В основной группе (n = 54) субксифоидальную рану орошали бактериофагами («Секстафаг», «Интест‑бактериофаг», колипротейный, а также их комбинация). Бактериофаги применяли в комплексе с антибактериальной терапией. Определяли качественный и количественный состав микробной флоры содержимого желчного пузыря и перитонеального экссудата, чувствительность микроорганизмов к антибиотикам и бактериофагам. Результаты лечения оценивали по характеру и частоте инфекции области троакарной раны.Результаты и обсуждение. Инфильтрат и/или серому троакарной раны в группе сравнения наблюдали у 1 (2,4 %) больного, в основной группе — у 2 (3, 7 %). Нагноение троакарной раны отмечено лишь в группе сравнения (2 (4,8 %) случая). Изучен характер микробной флоры желчи и экссудата брюшной полости, ее количество, чувствительность микроорганизмов к антибиотикам и бактериофагам. У больных с гангренозной формой холецистита и местным гнойным перитонитом преобладали микробные ассоциации (65,9 выявлены штаммы Pseudomonas aeruginosa, Candida, анаэробной флоры. У больных с флегмонозной формой холецистита чувствительность кишечной палочки, стафилококков, стрептококков, протея и клебсиеллы к «Секстафагу» представляла 76,9 — 100,0 %.Выводы. Применение терапии бактериофагами при лапароскопической холецистэктомии по поводу острого деструктивного холецистита способствовало снижению в послеоперационный период частоты возникновения инфекции области троакарной раны с 8,5 до 2,4 %., Мета роботи — оцінити частоту виникнення інфекції ділянки троакарної рани після лапароскопічної холецистектомії з терапією бактеріофагами та без такої з приводу гострого деструктивного холециститу у хворих з ожирінням I — II ступеня.Матеріали і методи. Проведено аналіз результатів лікування 96 пацієнтів з ожирінням I — II ступеня віком від 37 до 67 років. Усім пацієнтам виконано лапароскопічну холецистектомію з приводу гострого деструктивного холециститу. Індекс маси тіла в середньому становив (35,04 ± 0,2) кг/м2. У групі порівняння (n = 42) після вилучення жовчного міхура санацію троакарної субксифоїдальної рани здійснювали розчином 0,02 % декаметоксину у фізіологічному розчині (розчин «Декасану»). В основній групі (n = 54) субксифоїдальну рану зрошували бактеріофагами («Секстафаг», «Інтест‑бактеріофаг», коліпротейний, а також їх комбінація). Бактеріофаги застосовували в комплексі з антибактеріальною терапією. Визначали якісний та кількісний склад мікробної флори вмісту жовчного міхура і перитонеального ексудату, чутливість мікроорганізмів до антибіотиків та бактеріофагів. Результати лікування оцінювали за характером і частотою інфекції ділянки троакарної рани.Результати та обговорення. Інфільтрат і/або серому троакарної рани в групі порівняння спостерігали в 1 (2,4 %) хворого, в основній групі — у 2 (3,7 %). Нагноєння троакарної рани відзначено лише в групі порівняння (2 (4,8 %) випадки).Вивчено характер мікробної флори жовчі та ексудату черевної порожнини, її кількість, чутливість мікроорганізмів до антибіотиків і бактеріофагів. У хворих із гангренозною формою холециститу та місцевим гнійним перитонітом переважали мікробні асоціації (65,9 %), виявлено штами Pseudomonas aeruginosa, Candida, анаеробної флори. У хворих із флегмонозною формою холециститу чутливість кишкової палички, стафілококів, стрептококів, протею та клебсієли до «Секстафагу» становила 76,9 — 100,0 %.Висновки. Застосування терапії бактеріофагами при лапароскопічній холецистектомії з приводу гострого деструктивного холециститу сприяло зниженню в післяопераційний період частоти виникнення інфекції ділянки троакарної рани з 8,5 до 2,4 %.

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen that is found ubiquitously in the environment. It is also the cause of nosocomial infections, which affects patients with cystic fibrosis (CF) and cathether-related infections. Treatment and eradication of P. aeruginosa is an uphill task as it has already developed resistance to many commonly used antibiotics. Some of the resistance mechanisms that P. aeruginosa employ are having low cell wall permeability, developing efflux system to pump antibiotics out, producing enzymes to inactivate antibiotics, modifying antibiotic targets, forming biofilm as a protection layer against antibiotics, and turning into more pathogenic small colony variant form. In addition, P. aeruginosa uses a host of signaling mechanisms, such as secretion system and quorum sensing, to aid its virulence. With numerous resistance mechanisms developed against conventional antibiotics, new strategies to treat P. aeruginosa infection are required. Bacteriophages such as natural bacteria viruses and studies have suggested that they can be used as an alternative to antibiotics for treatment against P. aeruginosa infections. However, phage therapy also shares the same problem with that of antibiotics, i.e., the development and emergence of bacteria resistance by masking or altering surface recognition features, inhibiting phage DNA injection and employing abortive infection (Abi) system. Another alternative treatment strategy is to use antimicrobial peptides, which are small cationic peptides that are naturally found in most organisms’ immune system. These peptides disrupt cell membrane and key cellular processes, which requires major gene alteration if evasion is needed. Hence, lowering likelihood of resistance development. This paper aims to review our current understanding of the clinical implications of P. aeruginosa infections, the mechanisms of antibiotic resistance, phage-inspired and antimicrobial peptide approaches for treatment of P. aeruginosa infections.

Background and Objectives: Prevalence of extended spectrum β-lactamase (ESBL) leads to the development of antibiotic resistance and mortality in burn patients. One of the alternative strategies for controlling ESBL bacterial infections is clinical trials of bacteriophage therapy. The aim of this study was to isolate and characterize specific bacteriophages against ESBL-producing Klebsiella pneumoniae in patients with burn ulcers. Materials and Methods: Clinical samples were isolated from the hospitalized patient in burn medical centers, Iran. Biochemical screenings and 16S rRNA gene sequencing were determined. The phages were isolated from municipal sewerage treatment plants, Isfahan, Iran. TEM and FESEM, adsorption velocity, growth curve, host range, and the viability of the phage particles as well as proteomics and enzyme digestion patterns were examined. Results: The results showed that Klebsiella pneumoniae Iaufa_lad2 (GenBank accession number: MW836954) was confirmed as an ESBL-producing strain using combined disk method. This bacterium showed significant sensitivity to three phages including PɸBw-Kp1, PɸBw-Kp2, and PɸBw-Kp3. Morphological characterization demonstrated that the phage PɸBw-Kp3 to the Siphoviridae family (lambda-like phages) and both phages PɸBw-Kp1 and ɸBw-Kp2 to the Podoviridae family (T1-like phages). The isolated bacteriophages had a large burst size, thermal and pH viability and efficient adsorption rate to the host cells. Conclusion: In present study, the efficacy of bacteriophages against ESBL pathogenic bacterium promises a remarkable achievement for phage therapy. It seems that, these isolated bacteriophages, in the form of phage cocktails, had a strong antibacterial impacts and a broad-spectrum strategy against ESBL-producing Klebsiella pneumoniae isolated from burn ulcers.

The emergence of multidrug-resistant bacterial strains, especially in the clinical setting, has renewed interest in alternative treatment methods. The utilization of prokaryotic viruses in phage therapy has demonstrated potential as a novel treatment method against multidrug-resistant bacterial infections. As the post-antibiotic era quickly approaches, the development and standardization of phage therapy is critically relevant to public health. This review serves to highlight the development of phage therapy against methicillin-resistant Staphylococcus aureus (MRSA), an antibiotic-resistant bacterial strain responsible for severe clinical infections.

The prevalence of multidrug resistant bacterial diseases is a major global health risk. Multidrug resistant bacterial diseases are prevalent, and the need for novel methods of treatment is essential to the preservation of public health. Annually foodborne pathogens cause 1.35 million infections and 26,500 hospitalizations in the United States alone. Foodborne pathogens such as Salmonella spp. are a major threat to public health. Bacteriophages offer a unique method for the treatment of these multidrug resistant bacteria. We studied the infection dynamics of a potential mono-phage therapy of Salmonella typhimurium under various pathophysiological conditions. Furthermore, we determined the resistance dynamics of Salmonella typhimurium against P22 phage treatment. We also determined synergy with antibiotics such as ampicillin and kanamycin. This research helps to further define and show the versatility of bacteriophages as potential novel treatment methods.

Phage therapy as a promising alternative antimicrobial to treat multidrug resistant (MDR) bacteria related lung infections, has drawn significant attention in clinical trials and bench-scale study in the recent decade, and the therapeutic effect of local delivery of phage has been demonstrated by several clinical reports. This book chapter discusses the current clinical development of inhaled phage therapy followed by the advancement of phage formulation designs for respiratory delivery of phage using various inhalation devices and their in vivo efficacy. The development of combination therapy of phage and antibiotics to combat MDR bacteria associated lung infections is also covered to reflect the current clinical practice. Lastly, we also share our insights on the challenges of advancing inhaled phage therapy and potential directions for future research.

Phage therapy is a century-old technique employing viruses (phages) to treat bacterial infections, and in the clinic it is often used in combination with antibiotics. Antibiotics, however, interfere with critical bacterial metabolic activities that can be required by phages. Explicit testing of antibiotic antagonism of phage infection activities, though, is not a common feature of phage therapy studies. Here we use optical density-based ‘lysis-profile’ assays to assess the impact of two antibiotics, colistin and ciprofloxacin, on the bactericidal, bacteriolytic, and new-virion-production activities of three Pseudomonas aeruginosa phages. Though phages and antibiotics in combination are more potent in killing P. aeruginosa than either acting alone, colistin nevertheless substantially interferes with phage bacteriolytic and virion-production activities even at its minimum inhibitory concentration (1× MIC). Ciprofloxacin, by contrast, has little anti-phage impact at 1× or 3× MIC. We corroborate these results with more traditional measures, particularly colony-forming units, plaque-forming units, and one-step growth experiments. Our results suggest that ciprofloxacin could be useful as a concurrent phage therapy co-treatment especially when phage replication is required for treatment success. Lysis-profile assays also appear to be useful, fast, and high-throughput means of assessing antibiotic antagonism of phage infection activities.

Background and Objectives: Prevalence of extended spectrum β-lactamase (ESBL) leads to the development of antibi- otic resistance and mortality in burn patients. One of the alternative strategies for controlling ESBL bacterial infections is clinical trials of bacteriophage therapy. The aim of this study was to isolate and characterize specific bacteriophages against ESBL-producing Klebsiella pneumoniae in patients with burn ulcers. Materials and Methods: Clinical samples were isolated from the hospitalized patient in burn medical centers, Iran. Bio- chemical screenings and 16S rRNA gene sequencing were determined. The phages were isolated from municipal sewerage treatment plants, Isfahan, Iran. TEM and FESEM, adsorption velocity, growth curve, host range, and the viability of the phage particles as well as proteomics and enzyme digestion patterns were examined. Results: The results showed that Klebsiella pneumoniae Iaufa_lad2 (GenBank accession number: MW836954) was con- firmed as an ESBL-producing strain using combined disk method. This bacterium showed significant sensitivity to three phages including PɸBw-Kp1, PɸBw-Kp2, and PɸBw-Kp3. Morphological characterization demonstrated that the phage PɸBw-Kp3 to the Siphoviridae family (lambda-like phages) and both phages PɸBw-Kp1 and ɸBw-Kp2 to the Podoviridae family (T1-like phages). The isolated bacteriophages had a large burst size, thermal and pH viability and efficient adsorption rate to the host cells. Conclusion: In present study, the efficacy of bacteriophages against ESBL pathogenic bacterium promises a remarkable achievement for phage therapy. It seems that, these isolated bacteriophages, in the form of phage cocktails, had a strong an- tibacterial impacts and a broad-spectrum strategy against ESBL-producing Klebsiella pneumoniae isolated from burn ulcers.

In the present study, we evaluated the effect of spray-drying formulations and operating parameters of a laboratory-scale spray-dryer on the characteristics of spray-dried powders containing two Pseudomonas aeruginosa bacteriophages exhibiting different morphotypes: a podovirus (LUZ19) and a myovirus (14-1). We optimized the production process for bacteriophage-loaded powders, with an emphasis on long-term storage under ICH (international conference on harmonization) conditions. D-trehalose-/L-isoleucine-containing bacteriophage mixtures were spray-dried from aqueous solutions using a Büchi Mini Spray-dryer B-290 (Flawil, Switzerland). A response surface methodology was used for the optimization of the spray-drying process, with the following as-evaluated parameters: Inlet temperature, spray gas flow rate, and the D-trehalose/L-isoleucine ratio. The dried powders were characterized in terms of yield, residual moisture content, and bacteriophage lytic activity. L-isoleucine has demonstrated a positive impact on the activity of LUZ19, but a negative impact on 14-1. We observed a negligible impact of the inlet temperature and a positive correlation of the spray gas flow rate with bacteriophage activity. After optimization, we were able to obtain dry powder preparations of both bacteriophages, which were stable for a minimum of one year under different ICH storage conditions (up to and including 40 °C and 75% relative humidity).

The increase of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) causes a threat to human health. LA-MRSA can be transmitted from animals to animal caretakers, which may further spread MRSA to communities and health care facilities. The objective of this work was to study the efficacy of phage treatment in the eradication of LA-MRSA from healthy carrier pigs. A total of 19 MRSA -positive weanling pigs were assigned to a test (n = 10) and a control group (n = 9). A phage cocktail containing three Staphylococcus phages, or a control buffer was administered to the nares and skin of the pigs three times every two days, after which the phage and MRSA levels in nasal and skin swab samples were monitored for a three-week period. The sensitivity of the strains isolated during the follow-up period to the phage cocktail and each phage individually was analyzed and the pig sera were tested for antibodies against the phages used in the cocktail. The phage treatment did not cause any side effects to the pigs. Phages were found in the skin and nasal samples on the days following the phage applications, but there was no reduction in the MRSA levels in the sampled animals. Phage-resistant strains or phage-specific antibodies were not detected during the experiment. The MRSA load in these healthy carrier animals was only 10–100 CFU/swab or nasal sample, which was likely below the replication threshold of phages. The effectiveness of phage treatment to eradicate MRSA from the pigs could thus not be (reliably) determined.

A series of proof-of-concept studies were developed to determine whether a commercial bacteriophage cocktail could be utilized for the mitigation of Salmonella in bovine peripheral lymph nodes (LNs). The first objective sought to determine whether exogenous phage could be isolated from the LNs following administration. If isolation were successful, the second objective was to determine whether the phage in the LNs could effectively reduce Salmonella. Salmonella Montevideo was inoculated intradermally at multiple sites and multiple times, followed by delivery of the phage cocktail subcutaneously in two injections around each of the right and left prescapular and subiliac LNs. At the conclusion of each study, animals were euthanized, and the popliteal, prescapular, and subiliac LNs were examined. The inoculated phage was successfully isolated from the LNs; transmission electron microscopy revealed phages in the LNs of the treated cattle, and these phages were identical to those in the cocktail. Levels of phage were higher (P0.01) in the prescapular and subiliac LNs in the phage-treated than in the control cattle. In subsequent studies, the protocols were modified to increase Salmonella and phage levels within the LNs. Compared with the first study, overall Salmonella levels were increased in the LNs, and phage treatment decreased (P0.01) Salmonella in the some of the LNs. Phage levels were numerically but not significantly increased (P = 0.12) in the treated cattle. The final study was modified, hypothesizing that a 48-h postmortem period before LN removal would facilitate phage-Salmonella interaction; however, no differences (P0.10) in Salmonella levels were found among treatments. Salmonella-specific phages administered to live cattle can translocate to the LNs; however, these phages had limited to no effect on Salmonella in these LNs under these experimental conditions.

Study Group on Mechanisms of Action and Resistance to Antimicrobials (GEMARA) on behalf of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)., Klebsiella pneumoniae is an opportunistic Gram-negative pathogen that employs different strategies (resistance and persistence) to counteract antibiotic treatments. This study aimed to search for new means of combatting imipenem-resistant and persister strains of K. pneumoniae by repurposing the anticancer drug mitomycin C as an antimicrobial agent and by combining the drug and the conventional antibiotic imipenem with the lytic phage vB_KpnM-VAC13. Several clinical K. pneumoniae isolates were characterized, and an imipenem-resistant isolate (harboring OXA-245 β-lactamase) and a persister isolate were selected for study. The mitomycin C and imipenem MICs for both isolates were determined by the broth microdilution method. Time-kill curve data were obtained by optical density at 600 nm (OD600) measurement and CFU enumeration in the presence of each drug alone and with the phage. The frequency of occurrence of mutants resistant to each drug and the combinations was also calculated, and the efficacy of the combination treatments was evaluated using an in vivo infection model (Galleria mellonella). The lytic phage vB_KpnM-VAC13 and mitomycin C had synergistic effects on imipenem-resistant and persister isolates, both in vitro and in vivo. The phage-imipenem combination successfully killed the persisters but not the imipenem-resistant isolate harboring OXA-245 β-lactamase. Interestingly, the combinations decreased the emergence of in vitro resistant mutants of both isolates. Combinations of the lytic phage vB_KpnM-VAC13 with mitomycin C and imipenem were effective against the persister K. pneumoniae isolate. The lytic phage-mitomycin C combination was also effective against imipenem-resistant K. pneumoniae strains harboring OXA-245 β-lactamase., This study was funded by grants PI16/01163 and PI19/00878 awarded to M. Tomás within the State Plan for R+D+I 2013–2016 (National Plan for Scientific Research, Technological Development and Innovation 2008–2011) and cofinanced by the ISCIII-Deputy General Directorate for Evaluation and Promotion of Research–European Regional Development Fund and Instituto de Salud Carlos III FEDER, Spanish Network for the Research in Infectious Diseases (REIPI; RD16/0016/0001, RD16/0016/0006, and RD16/CIII/0004/0002) and by the Study Group on Mechanisms of Action and Resistance to Antimicrobials, GEMARA (SEIMC; http://www.seimc.org/). M. Tomás was financially supported by the Miguel Servet Research Program (SERGAS and ISCIII). I. Bleriot was financially supported by pFIS program (ISCIII, FI20/00302). O. Pacios and M. López were financially supported by grants IN606A-2020/035 and IN606B-2018/008, respectively (GAIN, Xunta de Galicia), and P. Domingo-Calap was financially supported by the ESCMID Research Grant 20200063.

The high specificity of bacteriophages is driven by their receptor-binding proteins (RBPs). Many Klebsiella bacteriophages target the capsular exopolysaccharide as the receptor and encode RBPs with depolymerase activity. The modular structure of these RBPs with an N-terminal structural module to attach the RBP to the phage tail, and a C-terminal specificity module for exopolysaccharide degradation, supports horizontal transfer as a major evolutionary driver for Klebsiella phage RBPs. We mimicked this natural evolutionary process by the construction of modular RBP chimeras, exchanging N-terminal structural modules and C-terminal specificity modules. All chimeras strictly follow the capsular serotype specificity of the C-terminal module. Transplanting chimeras with a K11 N-terminal structural RBP module in a Klebsiella phage K11 scaffold results in a capsular serotype switch and corresponding host range modification of the synthetic phages, demonstrating that horizontal transfer of C-terminal specificity modules offers Klebsiella phages an evolutionary highway for rapid adaptation to new capsular serotypes. IMPORTANCE The antimicrobial resistance crisis has rekindled interest in bacteriophage therapy. Phages have been studied over a century as therapeutics to treat bacterial infections, but one of the biggest challenges for the use of phages in therapeutic interventions remains their high specificity. In particular, many Klebsiella phages have a narrow spectrum constrained by the high diversity of exopolysaccharide capsules that shield access to the cells. In this work, we have elaborated how Klebsiella phages deal with this high diversity by exchanging building blocks of their receptor-binding proteins.

Acinetobacter baumannii has become a major concern for scientific attention due to extensive antimicrobial resistance. This resistance causes an increase in mortality rate because strains resistant to antimicrobial agents are a major challenge for physicians and healthcare workers regarding the eradication of either hospital or community-based infections. These strains with emerging resistance are a serious issue for patients in the intensive care unit (ICU). Antibiotic resistance has increased because of the acquirement of mobile genetic elements such as transposons, plasmids, and integrons and causes the prevalence of multidrug resistance strains (MDR). In addition, an increase in carbapenem resistance, which is used as last line antibiotic treatment to eliminate infections with multidrug-resistant Gram-negative bacteria, is a major concern. Carbapenems resistant A. baumannii (CR-Ab) is a worldwide problem. Because these strains are often resistant to all other commonly used antibiotics. Therefore, pathogenic multi-drug resistance A. baumannii (MDR-Ab) associated infections become hard to eradicate. Plasmid-mediated resistance causes outbreaks of extensive drug-resistant. A. baumannii (XDR-Ab). In addition, recent outbreaks relating to livestock and community settings illustrate the existence of large MDR-Ab strain reservoirs within and outside hospital settings. The purpose of this review, proper monitoring, prevention, and treatment are required to control (XDR-Ab) infections. Attachment, the formation of biofilms and the secretion of toxins, and low activation of inflammatory responses are mechanisms used by pathogenic A. baumannii strain. This review will discuss some aspects associated with antibiotics resistance in A. baumannii as well as cover briefly phage therapy as an alternative therapeutic treatment.

Family engagement in rounds has been recommended to improve communication, but its impact on patient outcomes is unknown. At the authors' institution, nurses encouraged family presence at rounds as part of a larger project to enhance communication during rounding. In the case reported here, family engagement resulted in a critical care patient's wife suggesting bacteriophage therapy, which led to her husband's survival. The wife's involvement provided unique insight into the patient's response to treatments and valuable suggestions regarding the treatment plan. Real-time communication among the nurse, family, and physician improved the accuracy and quality of shared information as well as the plan of care. This exemplar demonstrates how family engagement in rounds can not only optimize the outcomes of individual patients but also lead to medical and scientific advances. More research is needed to further elucidate the impact of families on treatment plans and outcomes.

The present study was planned to evaluate the efficacy of Pseudomonas aeruginosa specific phages in immunocompromised septicemia animal model as an alternative to antibiotics. Five different sets of experiments were performed: prophylactic administration of phage cocktail (3 lytic and unique) before and simultaneous with bacterial challenge; and therapeutic, that is, administration of phage cocktail 6, 12, and 24 hours after the bacterial challenge. No mortality was observed when simultaneous and late administration of phages was done with respect to the bacterial challenge. Contrary to this, administration of phage cocktail 100 µL (1012 PFU/mL) of volume after 6 hours of the infection resulted in a mortality rate of 60%. However, no mortality could be observed with reduced dose of cocktail, that is, 108, 109, and 1010 PFU administered 6 hours after bacterial challenge. Phage therapy in acute infections initiated with very small dosage under strict supervision may give better results. However, further studies to determine the quantity and frequency of dosage of phage cocktail for septicemia of various durations is strongly indicated.

Background: A chronic wound usually results due to halt in the inflammatory phase of wound healing. Bacterial infections and biofilm formation are considered to be the basic cause of it. Chronic wounds significantly impair the quality of life. Antibiotics are now failing due to biofilm formation emergence of drug-resistant bacteria. Objective: This study aims to see the effect of bacteriophage therapy in chronic nonhealing wound infected with the following bacteria: Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Subject: Patients with chronic nonhealing wound not responding to conventional local debridement and antibiotic therapy were included in the study. The age of patients ranged between 12 and 60 years. Method: A total of 20 patients selected and tissue biopsies and wound swabs were taken for isolation of the bacteria. After confirmation of organism, a cocktail of customized bacteriophages was topically applied over the wound on alternate days till the wound surface became microbiologically sterile. Mean bacterial count and clinical assessment were done and compared at the time of presentation and after 3 and 5 doses of application. Results: A significant improvement was observed in the wound healing, and there were no signs of infection clinically and microbiologically after 3 to 5 doses of topical bacteriophage therapy. Seven patients achieved complete healing on day21 during follow up while in others healthy margins and healthy granulation tissue were observed. Conclusion: Topical bacteriophage application may be quite effective therapy for the treatment of chronic nonhealing wounds.

To reduce the use of antibiotics in animal agriculture, a number of effective or commercially viable alternatives have been implemented by food animal producers or are under development. Perhaps the most well‐established strategies are flock and herd management practices to mitigate disease introduction and spread, and, subsequently, reduce the need for antibiotic use. While vaccines in food animal production have been used to prevent both bacterial and viral diseases, but historically, most vaccines have targeted viral diseases. Though vaccines against viral diseases can help reduce the need for antibiotic use by controlling the spread of secondary bacterial infections, more recent vaccines under development specifically target bacteria. New developments in selecting and potentially tailoring bacteriophages provide a promising avenue for controlling pathogenic bacteria without the need for traditional small‐molecule antibiotics. In this article we discuss these established and emerging strategies, which are anticipated to reduce the reliance on antibiotics in food animal production and should reduce the prevalence and transmission to humans of antimicrobial resistant bacteria from these systems.

Until a dangerous bacterial infection left her husband near death 3 years ago, scientist Steffanie Strathdee had never heard of bacteriophage therapy. After it ultimately saved his life, however, she not only has become a staunch advocate of the therapy, but also now serves as co-director of the newly established Center for Innovative Phage Applications and Therapeutics (IPATH) at the University of California San Diego (UCSD) ( Figure 1 ).

Bacteriophages, or phages, are viruses that infect bacteria. They were discovered around a century ago and have been used ever since for therapeutic purposes, particularly in former Soviet Union countries. Their use in Western countries was abandoned after the discovery and broad use of penicillin. The rising problem of antimicrobial resistance has revived interest in bacteriophage therapy. The aim of this article is to provide a comprehensive review of all aspects of natural phage therapy.

Bacteriophages (phages) are viruses that kill bacteria specifically but cannot infect other kinds of organisms. They have attracted new attention since the increasing antibiotic resistance developed into a global crisis. Phage therapy, a 100-year-old form of antibacterial treatment in medicine, is gaining momentum because phages represent a therapy concept without such negative side effects as toxicity; phages are the only therapeutic agent that regulates itself at the sites of infection and decays when the infectious bacteria have been killed. Nature is an almost infinite phage resource: New ones can be isolated for most kinds of problem bacteria as needed; bacteria and their phages constantly co-evolve. This is important as new pathogenic bacterial variants evolve and new challenging situations arise. In human therapy, “cocktails” of multiple phages may reduce the probability of selecting bacteria that developed resistance to a certain phage. Antibiotic agents can be applied together with phages in many circumstances; the two often function synergistically. Phages cannot be expected to replace antibiotic agents in our medical arsenal, but can be used where antibiotic agents fail. The selected phages, however, must be obligately virulent, well-characterized, and highly purified before application. Countless patients and their physicians are waiting for re-establishing phage therapy as a flexible, tailored medicine; infrastructures should be built in all countries urgently: The 2015 World Health Organization assembly resolution 68.7.3. called for national action plans by May 2017 to combat the antimicrobial drug resistance crisis. This article discusses the therapeutic potential of phages and describes challenges and recent developments.

The number of arthroplasties conducted annually continues to increase; however, approximately 1%–2% of all knee and hip arthroplasties will become infected. These prosthetic joint infections are costly, difficult to treat, and cause significant morbidity and mortality as a direct result of conventional surgical and medical managements. In this perspective, we discuss factors that make these infections arduous to treat as well as the potential use of adjuvant bacteriophage therapy with debridement, antibiotics, and implant retention surgery to cure these infections without removing the infected prosthesis. We also provide rationale as to why future clinical trials evaluating this novel therapeutic will need to be designed as noninferiority trials, and we compare this approach to 2-stage revision surgery. If bacteriophage therapy continues to show effectiveness, this could revolutionize the treatment of prosthetic joint infections and pioneer new treatments for similar infections.

Bacteriophages or phages, the viruses of bacteria, are abundant components of most ecosystems, including those where bacteria predominantly occupy biofilm niches. Understanding the phage impact on bacterial biofilms therefore can be crucial toward understanding both phage and bacterial ecology. Here, we take a critical look at the study of bacteriophage interactions with bacterial biofilms as carried out in vitro, since these studies serve as bases of our ecological and therapeutic understanding of phage impacts on biofilms. We suggest that phage-biofilm in vitro experiments often may be improved in terms of both design and interpretation. Specific issues discussed include (a) not distinguishing control of new biofilm growth from removal of existing biofilm, (b) inadequate descriptions of phage titers, (c) artificially small overlying fluid volumes, (d) limited explorations of treatment dosing and duration, (e) only end-point rather than kinetic analyses, (f) importance of distinguishing phage enzymatic from phage bacteriolytic anti-biofilm activities, (g) limitations of biofilm biomass determinations, (h) free-phage interference with viable-count determinations, and (i) importance of experimental conditions. Toward bettering understanding of the ecology of bacteriophage-biofilm interactions, and of phage-mediated biofilm disruption, we discuss here these various issues as well as provide tips toward improving experiments and their reporting.

Bacteriophages are the most abundant biological entities in the biosphere. Due to their host specificity and ability to kill bacteria rapidly, bacteriophages have many potential healthcare applications, including therapy against antibiotic-resistant bacteria. Infection by flagellotropic bacteriophages requires a properly rotating bacterial flagellar filament. The flagella-dependent phage χ (Chi) infects serovars of the pathogenic enterobacterium Salmonella enterica However, cell surface receptors and proteins involved in other stages of χ infection have not been discovered to date. We screened a multi-gene deletion library of S. enterica serovar Typhimurium by spotting mutants on soft agar plates seeded with bacteriophage χ and monitoring their ability to grow and form a swim ring, a characteristic of bacteriophage-resistant motile mutants. Those multi-gene deletion regions identified to be important for χ infectivity were further investigated by characterizing the phenotypes of corresponding single-gene deletion mutants. This way, we identified motile mutants with varying degrees of resistance to χ. Deletions in individual genes encoding the AcrABZ-TolC multi-drug efflux system drastically reduced infection by bacteriophage χ. Furthermore, an acrABtolC triple deletion strain was fully resistant to χ. Infection was severely reduced but not entirely blocked by the deletion of the gene tig encoding the molecular chaperone trigger factor. Finally, deletion in genes encoding enzymes involved in the synthesis of the antioxidants glutathione (GSH) and uric acid resulted in reduced infectivity. Our findings begin to elucidate poorly understood processes involved in later stages of flagellotropic bacteriophage infection and informs research aimed at the use of bacteriophages to combat antibiotic-resistant bacterial infections.IMPORTANCEAntimicrobial resistance is a large concern in the healthcare field. With more multi-drug resistant bacterial pathogens emerging, other techniques for eliminating bacterial infections are being explored. Among these is phage therapy, where combinations of specific phages are used to treat infections. Generally, phages utilize cell appendages and surface receptors for the initial attachment to their host. Phages that are flagellotropic are of particular interest because flagella are often important in bacterial virulence, making resistance to attachment of these phages harder to achieve without reducing virulence. This study discovered the importance of a multi-drug efflux pump for the infection of Salmonella enterica by a flagellotropic phage. In theory, if a bacterial pathogen develops phage resistance by altering expression of the efflux pump then the pathogen would simultaneously become more susceptible to the antibiotic substrates of the pump. Thus, co-administering antibiotics and flagellotropic phage may be a particularly potent antibacterial therapy.

Mycobacterium abscessus infections in cystic fibrosis patients are challenging to treat due to widespread antibiotic resistance. The therapeutic use of lytic bacteriophages presents a new potential strategy, but the great variation among clinical M. abscessus isolates demands determination of phage susceptibility prior to therapy., Mycobacterium abscessus is an opportunistic pathogen whose treatment is confounded by widespread multidrug resistance. The therapeutic use of bacteriophages against Mycobacterium abscessus infections offers a potential alternative approach, although the spectrum of phage susceptibilities among M. abscessus isolates is not known. We determined the phage infection profiles of 82 M. abscessus recent clinical isolates and find that colony morphotype—rough or smooth—is a key indicator of phage susceptibility. None of the smooth strains are efficiently killed by any phages, whereas 80% of rough strains are infected and efficiently killed by at least one phage. The repertoire of phages available for potential therapy of rough morphotype infections includes those with relatively broad host ranges, host range mutants of Mycobacterium smegmatis phages, and lytically propagated viruses derived from integrated prophages. The rough colony morphotype results from indels in the glycopeptidolipid synthesis genes mps1 and mps2, negating reversion to smooth as a common route to phage resistance. Resistance is thus rare, and although mutations in polyketide synthesis, uvrD2, and rpoZ can confer resistance, these likely also impair survival in vivo. The expanded therapeutic repertoire and the resistance profiles show that small cocktails or single phages could be suitable for controlling infections with rough strains.

23 p.-12 fig.-2 tab., Phage (endo)lysins are thought to be a viable alternative to usual antibiotic chemotherapy to fight resistant bacterial infections. However, a landscape view of lysins’ structure and properties regarding their function, with an applied focus, is somewhat lacking. Current literature suggests that specific features typical of lysins from phages infecting Gram-negative bacteria (G−) (higher net charge, amphipathic helices) are responsible for improved interaction with the G−envelope. Such antimicrobial peptide (AMP)-like elements are also of interest for antimicrobial molecules design. Thus, this study aims to provide an updated view on the primary structural landscape of phage lysins to clarify the evolutionary importance of several sequence-predicted properties, particularly for the interaction with the G−surface. A database of 2,182 lysin sequences was compiled, containing relevant information such as domain architectures, data on the phages’ host bacteria, and sequence -predicted physicochemical properties. Based on such classifiers, an investigation of the differential appearance of certain features was conducted. Such analyses revealed different lysin architectural variants that are preferably found in phages infecting certain bacterial hosts. Particularly, some physicochemical properties (higher net charge,hydrophobicity, hydrophobic moment, and aliphatic index) were associated with G−phage lysins, appearing specifically at their C-terminal end. Evidence on the remarkable genetic specialization of lysins regarding the features of the bacterial hosts has been provided, specifically supporting the nowadays common hypothesis that lysins from G− usually contain AMP-like regions., This study was funded by a grant from the Ministerio de Economía y Competitividad (MINECO-FEDER, SAF2017-88664-R). Additional funding was provided by the Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), an initiative of the Instituto de Salud Carlos III.

The use of engineered phages offers a unique opportunity to improve on wild-type (WT) phages to generate ever more successful therapeutics to combat bacterial infections. Here, we discuss how phage engineering could be used to overcome some of the technical challenges of phage therapy, and suggest some areas in which more research will be crucial to the development of further novel phage therapeutics.