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A literature review of the practical application of bacteriophage research
Abstract
Bacteriophage is a live micro-organism, a natural enemy of bacteria. Canadian microbiologist Felix d'Herelle proposed that bacteriophage might be applied to the control of bacterial diseases, however in the West this idea was not explored with the same enthusiasm as in the former Soviet Union and was eventually discarded with the arrival of antibiotics. Phage therapy is successfully used for the treatment of a wide spectrum of bacterial infections. Such experience has now become extremely important with the rapidly-increasing spread of antibiotic-resistant bacterial infections which are almost impossible to overcome these days. Phage therapy has been considered as an alternative to antibiotic-therapy and it is now attracting global interest. Most of the scientific works in phage therapy were published in Russian and are thus not easily available in the West. This fact inspired the authors to write a book based on the historical publications found in the library of the Eliava Institute.
... Rapid emergence of antibiotic resistance has generated global interest in phage therapy [5]. Phages have been successfully applied in surgery, wound treatment, gynaecological infections and opthalmology in the past [6]. The wide range of applications along with no adverse effects, phage therapy holds huge potentials to treat infectious diseases [6]. ...
... Phages have been successfully applied in surgery, wound treatment, gynaecological infections and opthalmology in the past [6]. The wide range of applications along with no adverse effects, phage therapy holds huge potentials to treat infectious diseases [6]. Phages are widely available where their host bacterium is present. ...
... actions to reduce the burden of infections [12]. Bacteriophages are being used in clinical medicine since 1940s in Georgia, Ukraine and Russia for treating various types of ailments [6]. They have wide range of applications including sectors like agriculture, food, healthcare, aquaculture and poultry [6]. ...
... Additionally, Shigella flexneri and Shi-have remained low [22]; epidemics suspected to target gay and bisexual men (MSM) [19]. Transmission across Europe has been observed [23] gella sonnei phages have been utilized in clinical phage therapy [25,107] ...
... In the beginnings of phage therapy, Felix d'Herelle, one of the discoverers of bacteriophages, utilized phages to treat dysentery. Since that time, S. flexneri and S. sonnei treatments and prophylaxis have been occurring with bacteriophages throughout Eastern Europe and the former Soviet Union [25,107]. The current studies of phage application in the treatment of vaginal infections with bacterial agents [25,132] provide support that with appropriate phages, the topical application process may provide successful results that are transferrable to BSTI treatment. ...
... The lack of bacteriophage research into these four hosts is either that they are a rarer BSTI or that they do not pose a significant enough antibiotic-resistant threat. Despite this, in 1947, Zaeva reports the use of anaerobic bacteriophages against Clostridium species in animal models [107]. It would suggest that regardless of a bacterium's challenging growth conditions, successful isolation and therapy may be possible, thus providing hope for future phage therapy on many of the fastidious BSTIs. ...
Bacterial sexually transmitted infections (BSTIs) are becoming increasingly significant with the approach of a post-antibiotic era. While treatment options dwindle, the transmission of many notable BSTIs, including Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum, continues to increase. Bacteriophage therapy has been utilized in Poland, Russia and Georgia in the treatment of bacterial illnesses, but not in the treatment of bacterial sexually transmitted infections. With the ever-increasing likelihood of antibiotic resistance prevailing and the continuous transmission of BSTIs, alternative treatments must be explored. This paper discusses the potentiality and practicality of phage therapy to treat BSTIs, including Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, Streptococcus agalactiae, Haemophilus ducreyi, Calymmatobacterium granulomatis, Mycoplasma genitalium, Ureaplasma parvum, Ureaplasma urealyticum, Shigella flexneri and Shigella sonnei. The challenges associated with the potential for phage in treatments vary for each bacterial sexually transmitted infection. Phage availability, bacterial structure and bacterial growth may impact the potential success of future phage treatments. Additional research is needed before BSTIs can be successfully clinically treated with phage therapy or phage-derived enzymes.
... Phages were first described to be active in the treatment of bacterial pathogens in 1917 by Felix d'Herelle. Since that time, phages were studied extensively for their bioactivity application in the treatment of different human infections (2). However, attention on the therapeutic potential of phages subsided dramatically after the wide use of antibiotics in the1940s; however, many phages worker in the former Soviet Union continued paying their attention to the application of phages alone in the treatment of human bacterial pathogens (2). ...
... Since that time, phages were studied extensively for their bioactivity application in the treatment of different human infections (2). However, attention on the therapeutic potential of phages subsided dramatically after the wide use of antibiotics in the1940s; however, many phages worker in the former Soviet Union continued paying their attention to the application of phages alone in the treatment of human bacterial pathogens (2). Nowadays, bacteriophage therapy took great attention from the global scientific society and scientific research and became one of the most fast-developed areas of scientific research and interest owing to the surging demand to dissolve common problems of drug resistance of bacterial pathogens towards various human infections, including UTIs (3). ...
Escherichia coli (E. coli) is a major bacterial pathogen associated with many cases of serious infections, such as urinary tract infections (UTI) and meningitis intestinal. The rapid emergence of antimicrobial multidrug-resistant bacteria occurring worldwide has been attributed to the overuse of antibiotics. Alternative strategies must be developed to overcome antibiotic resistance. A promising alternative for the treatment of infections is the use of phages as antibacterial agents. A total of 90 female albino mice were randomly divided into three groups (n=30) and used for the induction of UTI. The animals were acclimatized in their cages for 24 h before inoculation and allowed to access chow and water freely. For UTI induction, the peri-urethral area was sterilized with 70% ethanol, and bacterial inoculation was then injected into the bladder through the urethra using a 24-gauge sterile Teflon catheter with an outer diameter of 0.7 mm and length of 19 mm. A single phage and a phage cocktail preparation have been evaluated for their therapeutic activity in the mouse model of chronic UTI induced by transurethral injection of two isolates of the uropathogenic E. coli 8 and E. coli 302. The results of the transurethral and intra-peritoneal injection of phage(s) that prepared on day 10 after the establishment of the mouse chronic model showed no effect of a single phage PEC80 in the treatment of UTI, whereas both administration routes of the phage cocktail preparation resulted in the clearance of bacteria from mice urine and homogenates of the urinary bladders and kidneys of the sacrificed mice after 24 h following the administration of phage cocktail dose. The high activity of the phage cocktail in the treatment of mouse chronic model of UTI is attributed to the broader host range of the phage cocktail, compared to the very narrow host range of the phage PEC80. It is concluded that the phage therapy by using phage preparations as the 25 phages cocktail evaluated in this study is a highly promising and potential alternative therapy for human UTIs.
... In 2012, a book was published in English that comprehensively reviews the publications on phage therapy that were found in the library of the Eliava Institute. [9] Although the design and quality of old Soviet clinical trials and scientific publications do not conform with current international standards, they often contain valuable information that should not be neglected by current phage therapy stakeholders. One of the largest and most imaginative studies was conducted in Tbilisi, Georgia, during 1963 and 1964. ...
... Additionally, unrealistically high or uninformed expectations for phage treatment are widespread, leading patients to seek to use phages incorrectly against a nondiagnosed bacterial infection, or even attempting to treat another kind of infection (e.g., fungal or viral). 9. Limited expertise: the selection and preparation of therapeutic phages and cocktails requires skilled personnel with significant knowledge and experience, specific laboratories, and existing phage collections. ...
Phage therapy refers to the use of bacteriophages (phages - bacterial viruses) as therapeutic agents against infectious bacterial diseases. This therapeutic approach emerged in the beginning of the 20th century but was progressively replaced by the use of antibiotics in most parts of the world after the second world war. More recently however, the alarming rise of multidrug-resistant bacteria and the consequent need for antibiotic alternatives has renewed interest in phages as antimicrobial agents. Several scientific, technological and regulatory advances have supported the credibility of a second revolution in phage therapy. Nevertheless, phage therapy still faces many challenges that include: i) the need to increase phage collections from reference phage banks; ii) the development of efficient phage screening methods for the fast identification of the therapeutic phage(s); iii) the establishment of efficient phage therapy strategies to tackle infectious biofilms; iv) the validation of feasible phage production protocols that assure quality and safety of phage preparations; and (v) the guarantee of stability of phage preparations during manufacturing, storage and transport. Moreover, current maladapted regulatory structures represent a significant hurdle for potential commercialization of phage therapeutics. This article describes the past and current status of phage therapy and presents the most recent advances in this domain.
... Fourth, especially early development of the practice of phage therapy was a time during which substantial clinical experimentation was permissible, for example, Abedon (2015dAbedon ( , 2018a, but also Chanishvili (2012a). When alternative treatments are lacking, and especially when a patient's survival is under threat, then principles of compassionate care can be applied including as emergency investigational new drugs Kutter et al. 2015;Fish et al. 2016;Schooley et al. 2017;Chan et al. 2018). ...
... As noted, a key reason for why phage therapy has tended to be developed without an accompanying robust pharmacological tradition is the relative safety of phages as antibacterials, which includes, historically, the phage therapy of fairly large numbers of people in Europe and the former Soviet Union Kutter et al. 2010;Chanishvili 2012a;Kutter et al. 2014); see also (Abedon 2015d). This safety is the result of a number of factors stemming from a combination of inherent phage properties and well-informed phage choice. ...
... In Ovid these terms were followed by the suffix '.mp.' and they were searched as topics on the Web of Science platform. This systematic strategy was supplemented by hand searching of sources not widely available or indexed online [31][32][33], reports cited in review articles [34][35][36][37] or relevant papers that became available after the systematic search date [38]. A protocol was not published prior to this study. ...
... Systematic searching yielded 9983 records published between 1929 and 2019. Eleven additional records were identified from other sources; three from a review article [34], seven from grey literature sources known to the authors not to be indexed or available online [31][32][33] and another published after the search date but included for completeness [38]. Figure 1 illustrates the screening process. ...
Superficial bacterial infections, such as dermatological, burn wound and chronic wound/ulcer infections, place great human and financial burdens on health systems globally and are often complicated by antibiotic resistance. Bacteriophage (phage) therapy is a promising alternative antimicrobial strategy with a 100-year history of successful application. Here, we report a systematic review of the safety and efficacy of phage therapy for the treatment of superficial bacterial infections. Three electronic databases were systematically searched for articles that reported primary data about human phage therapy for dermatological, burn wound or chronic wound/ulcer infections secondary to commonly causative bacteria. Two authors independently assessed study eligibility and performed data extraction. Of the 27 eligible reports, eight contained data on burn wound infection (n = 156), 12 on chronic wound/ulcer infection (n = 327) and 10 on dermatological infections (n = 1096). Cautionary pooled efficacy estimates from the studies that clearly reported efficacy data showed clinical resolution or improvement in 77.5% (n = 111) of burn wound infections, 86.1% (n = 310) of chronic wound/ulcer infections and 94.14% (n = 734) of dermatological infections. Over half of the reports that commented on safety (n = 8/15), all published in or after 2002, did not express safety concerns. Seven early reports (1929–1987), described adverse effects consistent with the administration of raw phage lysate and co-administered bacterial debris or broth. This review strongly suggests that the use of purified phage to treat superficial bacterial infections can be highly effective and, by various routes of administration, is safe and without adverse effects.
... 9 Decades of extensive use of phage in surgical wounds have been well documented in Georgian and Russian literature. 18 Conventional treatment, including antibiotics, is crucial in the treatment of wound infections, but the problem of antibiotic resistance has created a need for alternatives, such as bacteriophage. In the following sections, we present four cases, which indicate the successful use of bacteriophages in the surgical practice at the EPTC. ...
... 19 Tsulukidze has reported that during a 5-6-day treatment, the improvement was usually seen after the first 2 days of phage application. 18 In the former Soviet Union, phages were used for multiple purposes: treatment of purulent wounds, management of postoperative infections, and prevention of wound infections. 20 The route of phage administration varied from oral to intravenous to topical, and the highest success rates were reported in cases of staphylococcal and streptococcal infections. ...
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.
... Lately, the use of bacteriophages as a target therapy against bacterial pathogens has gained a renewed interest. Reviews involving reports of successfully applied bacteriophage therapies for different medical speciali sations have been published, 8,9 and the role of bacteriophages as a possible treatment for several types of bacterial infection has been recognised. [8][9][10][11] However, there has been criticism of the related studies for not meeting current standards of evidence-based medicine. ...
... Reviews involving reports of successfully applied bacteriophage therapies for different medical speciali sations have been published, 8,9 and the role of bacteriophages as a possible treatment for several types of bacterial infection has been recognised. [8][9][10][11] However, there has been criticism of the related studies for not meeting current standards of evidence-based medicine. [11][12][13][14][15] The role of bacteriophages in infections in the lower urinary tract is becoming increasingly interesting for various fields of research. ...
Background:
Urinary tract infections (UTIs) are among the most prevalent microbial diseases and their financial burden on society is substantial. In the context of increasing antibiotic resistance, finding alternative treatments for UTIs is a top priority. We aimed to determine whether intravesical bacteriophage therapy with a commercial bacteriophage cocktail is effective in treating UTI.
Methods:
We did a randomised, placebo-controlled, clinical trial, at the Alexander Tsulukidze National Centre of Urology, Tbilisi, Georgia. Men older than 18 years of age, who were scheduled for transurethral resection of the prostate (TURP), with complicated UTI or recurrent uncomplicated UTI but no signs of systemic infection, were allocated by block randomisation in a 1:1:1 ratio to receive intravesical Pyo bacteriophage (Pyophage; 20 mL) or intravesical placebo solution (20 mL) in a double-blind manner twice daily for 7 days, or systemically applied antibiotics (according to sensitivities) as an open-label standard-of-care comparator. Urine culture was taken via urinary catheter at the end of treatment (ie, day 7) or at withdrawal from the trial. The primary outcome was microbiological treatment response after 7 days of treatment, measured by urine culture; secondary outcomes included clinical and safety parameters during the treatment period. Analyses were done in a modified intention-to-treat population of patients having received at least one dose of the allocated treatment regimen. This trial is registered with ClinicalTrials.gov, NCT03140085.
Findings:
Between June 2, 2017, and Dec 14, 2018, 474 patients were screened for eligibility and 113 (24%) patients were randomly assigned to treatment (37 to Pyophage, 38 to placebo, and 38 to antibiotic treatment). 97 patients (28 Pyophage, 32 placebo, 37 antibiotics) received at least one dose of their allocated treatment and were included in the primary analysis. Treatment success rates did not differ between groups. Normalisation of urine culture was achieved in five (18%) of 28 patients in the Pyophage group compared with nine (28%) of 32 patients in the placebo group (odds ratio [OR] 1·60 [95% CI 0·45-5·71]; p=0·47) and 13 (35%) of 37 patients in the antibiotic group (2·66 [0·79-8·82]; p=0·11). Adverse events occurred in six (21%) of 28 patients in the Pyophage group compared with 13 (41%) of 32 patients in the placebo group (OR 0·36 [95% CI 0·11-1·17]; p=0·089) and 11 (30%) of 37 patients in the antibiotic group (0·66 [0·21-2·07]; p=0·47).
Interpretation:
Intravesical bacteriophage therapy was non-inferior to standard-of-care antibiotic treatment, but was not superior to placebo bladder irrigation, in terms of efficacy or safety in treating UTIs in patients undergoing TURP. Moreover, the bacteriophage safety profile seems to be favourable. Although bacteriophages are not yet a recognised or approved treatment option for UTIs, this trial provides new insight to optimise the design of further large-scale clinical studies to define the role of bacteriophages in UTI treatment.
Funding:
Swiss Continence Foundation, the Swiss National Science Foundation, and the Swiss Agency for Development and Cooperation.
Translations:
For the Georgian and German translations of the abstract see Supplementary Materials section.
... Lately, the use of bacteriophages as a target therapy against bacterial pathogens has gained a renewed interest. Reviews involving reports of successfully applied bacteriophage therapies for different medical speciali sations have been published, 8,9 and the role of bacteriophages as a possible treatment for several types of bacterial infection has been recognised. [8][9][10][11] However, there has been criticism of the related studies for not meeting current standards of evidence-based medicine. ...
... Reviews involving reports of successfully applied bacteriophage therapies for different medical speciali sations have been published, 8,9 and the role of bacteriophages as a possible treatment for several types of bacterial infection has been recognised. [8][9][10][11] However, there has been criticism of the related studies for not meeting current standards of evidence-based medicine. [11][12][13][14][15] The role of bacteriophages in infections in the lower urinary tract is becoming increasingly interesting for various fields of research. ...
... Lately, the use of bacteriophages as a target therapy against bacterial pathogens has gained a renewed interest. Reviews involving reports of successfully applied bacteriophage therapies for different medical speciali sations have been published, 8,9 and the role of bacteriophages as a possible treatment for several types of bacterial infection has been recognised. [8][9][10][11] However, there has been criticism of the related studies for not meeting current standards of evidence-based medicine. ...
... Reviews involving reports of successfully applied bacteriophage therapies for different medical speciali sations have been published, 8,9 and the role of bacteriophages as a possible treatment for several types of bacterial infection has been recognised. [8][9][10][11] However, there has been criticism of the related studies for not meeting current standards of evidence-based medicine. [11][12][13][14][15] The role of bacteriophages in infections in the lower urinary tract is becoming increasingly interesting for various fields of research. ...
... И поскольку это совпало с открытием пенициллина и сульфонамидных антибиотиков, а позднее многих других антибиотиков, энтузиазм в отношении фаготерапии быстро угас. Работы по выделению и использованию фагов в лечении ряда заболеваний продолжали проводиться лишь в СССР, Грузии, Польше [6][7][8]. ...
... Препараты, содержащие несколько фагов с различным кругом хозяев и разной специфичностью к рецепторам бактерий, известные под названием «фаговые коктейли», создаются с целью расширения спектра их активности и предотвращения появления фагоустойчивых вариантов бактерий. В ряде работ показано, что лечение биопленочных инфекций с помощью таких препаратов приводит к уменьшению бактериальной биомассы в уже сформированных биопленках, в других случаях -к предотвращению образования биопленок [8,[44][45][46][47][48]. ...
... Lately, the use of bacteriophages as a target therapy against bacterial pathogens has gained a renewed interest. Reviews involving reports of successfully applied bacteriophage therapies for different medical speciali sations have been published, 8,9 and the role of bacteriophages as a possible treatment for several types of bacterial infection has been recognised. [8][9][10][11] However, there has been criticism of the related studies for not meeting current standards of evidence-based medicine. ...
... Reviews involving reports of successfully applied bacteriophage therapies for different medical speciali sations have been published, 8,9 and the role of bacteriophages as a possible treatment for several types of bacterial infection has been recognised. [8][9][10][11] However, there has been criticism of the related studies for not meeting current standards of evidence-based medicine. [11][12][13][14][15] The role of bacteriophages in infections in the lower urinary tract is becoming increasingly interesting for various fields of research. ...
... In 2009, Chanishvili et al. reported several cases of patients treated with phages at the G. Eliava Institute in Georgia [58]. One cannot not conclude on the efficacy of phages due to the disparity in methods used and the range of treated infections. ...
Growing antibiotic resistance and the broken antibiotic market have renewed interest in the use of phages, a century-old therapy that fell into oblivion in the West after two decades of promising results. This literature review with a particular focus on French literature aims to complement current scientific databases with medical and non-medical publications on the clinical use of phages. While several cases of successful treatment with phages have been reported, prospective randomized clinical trials are needed to confirm the efficacy of this therapy.
... Owing to the increasing occurrence of antibiotic-resistant bacterial infections, bacteriophages and their potential use in PT have gained tremendous interest [90]. PT is currently making a comeback as an antibiotic-free alternative, but only Georgia and Russia have commercialised it [91][92][93]. Therefore, several initiatives have been formulated and implemented to expedite the development of PT. ...
Melioidosis, also known as Whitmore’s disease, is a potentially fatal infection caused by the Gram-negative bacteria Burkholderia pseudomallei with a mortality rate of 10–50%. The condition is a “glanders-like” illness prevalent in Southeast Asian and Northern Australian regions and can affect humans, animals, and sometimes plants. Melioidosis received the epithet “the great mimicker” owing to its vast spectrum of non-specific clinical manifestations, such as localised abscesses, septicaemia, pneumonia, septic arthritis, osteomyelitis, and encephalomyelitis, which often lead to misdiagnosis and ineffective treatment. To date, antibiotics remain the backbone of melioidosis treatment, which includes intravenous therapy with ceftazidime or meropenem, followed by oral therapy with TMP-SMX or amoxicillin/clavulanic acid and supported by adjunctive treatment. However, bacteria have developed resistance to a series of antibiotics, including clinically significant ones, during treatment. Therefore, phage therapy has gained unprecedented interest and has been proposed as an alternative treatment. Although no effective phage therapy has been published, the findings of experimental phage therapies suggest that the concept could be feasible. This article reviews the benefits and limitations of antibiotics and phage therapy in terms of established regimens, bacterial resistance, host specificity, and biofilm degradation.
... Even though all PT randomized controlled trials that have been performed to date evaluated defined phage products as stand-alone therapies 20 , PAS is increasingly being reported in the literature 21 , where it is linked to the enhanced bacterial killing, increased penetration into biofilms, and decreased selection of antibiotic-or phage-resistant clones. We investigated the possible in vitro PAS between phage PNM and sub-optimal concentrations of colistin (0.5 mg/L), aztreonam (8 mg/L), and gentamycin (2 mg/L), which were administered in combination with PT (Fig. 1). ...
Post-operative bacterial infections are a leading cause of mortality and morbidity after ongoing liver transplantation. Bacteria causing these infections in the hospital setting can exhibit high degrees of resistance to multiple types of antibiotics, which leads to major therapeutic hurdles. Alternate ways of treating these antibiotic-resistant infections are thus urgently needed. Phage therapy is one of them and consists in using selected bacteriophage viruses – viruses who specifically prey on bacteria, naturally found in various environmental samples – as bactericidal agents in replacement or in combination with antibiotics. The use of phage therapy raises various research questions to further characterize what determines therapeutic success or failure. In this work, we report the story of a toddler who suffered from extensively drug-resistant Pseudomonas aeruginosa sepsis after liver transplantation. He was treated by a bacteriophage-antibiotic intravenous combination therapy for 86 days. This salvage therapy was well tolerated, without antibody-mediated phage neutralization. It was associated with objective clinical and microbiological improvement, eventually allowing for liver retransplantation and complete resolution of all infections. Clear in vitro phage-antibiotic synergies were observed. The occurrence of bacterial phage resistance did not result in therapeutic failure, possibly due to phage-induced virulence tradeoffs, which we investigated in different experimental models.
... After the discovery of penicillin, interest in phage therapy quickly disappeared, although it continued to be described and studied in eastern Europe 5 and the former Soviet Union. 6 During the past decade, phages have regained popularity, mainly because of an increase in antimicrobial resistance, a greater awareness of the importance of infectious diseases, and the need for sustainable antimicrobials. However, the widespread implementation of phage therapy in routine clinical practice is impeded by the scarcity of clinical data from formal clinical trials, such as randomised controlled trials (RCTs), conducted according to current regulatory standards and requirements. ...
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.
... Bacteriophages are considered a promising alternative means for control of fish microbial diseases. Phage therapy in medicine has a long successful history in Eastern Europe and FSU countries, including Georgia [38]. The results of the experimental studies with marine animal models demonstrated the efficacy of phage therapy against different infectious diseases [39][40][41]. ...
Phage therapy can be an effective alternative to standard antimicrobial chemotherapy for control of Aeromonas hydrophila infections in aquaculture. Aeromonas hydrophila-specific phages AhMtk13a and AhMtk13b were studied for basic biological properties and genome characteristics. Phage AhMtk13a (Myovirus, 163,879 bp genome, 41.21% CG content) was selected based on broad lytic spectrum and physiologic parameters indicating its lytic nature. The therapeutic potential of phage AhMtk13a was evaluated in experimental studies in zebrafish challenged with A. hydrophila GW3-10 via intraperitoneal injection and passive immersion in aquaria water. In experimental series 1 with single introduction of AhMtk13a phage to aquaria water at phage–bacteria ratio 10:1, cumulative mortality 44% and 62% was registered in fish exposed to phage immediately and in 4 h after bacterial challenge, correspondingly, compared to 78% mortality in the group with no added phage. In experimental series 2 with triple application of AhMtk13a phage at ratio 100:1, the mortality comprised 15% in phage-treated group compared to the 55% in the control group. Aeromonas hydrophila GW3-10 was not detectable in aquaria water from day 9 but still present in fish at low concentration. AhMtk13a phage was maintained in fish and water throughout the experiment at the higher concentration in infected fish.
... Phage therapy was already being used in the USSR during the Soviet-Finnish War and during World War II. These historical data are not considered in this review but are given elsewhere [32], [33]. The declining enthusiasm for bacteriophages especially in the Western World started with the discovery of penicillin in 1928. ...
Background: In recent years, resistance to antibiotics has become a global threat, and alternatives to antibiotics have become an area of research. The main alternative methods are briefly described in this review. However, the main focus is bacteriophage-related therapy.
Bacteriophages are viruses which, due to the production of the enzyme endolysin, are able to kill bacterial host cells. Bacteriophage therapies have a long tradition. Their potential to function as antibiotics lies in their bactericidal activity and specificity in killing bacteria without infecting or affecting eukaryotic cells.
Objective: To systematically review the outcomes of bacteriophage therapy in patients with bacterial infections.
Methods: The MEDLINE, EMBASE, Web of Science and CENTRAL databases were searched electronically using search terms referring to bacteriophages, endolysins and antimicrobial resistance. After the literature was screened for their titles and abstracts, full-text reviews considering inclusion/exclusion criteria were performed.
Data concerning patients with bacterial infections, treatment with either bacteriophages or its enzyme endolysin and their outcomes were extracted and analysed.
Results: Thirteen publications were identified that met all inclusion criteria. Data extraction shows that bacteriophages or endolysins have the potential to combat bacterial infections and significantly reduce inflammatory mediators. However, 3 out of 4 randomized controlled trials revealed that there was no significant difference between phage/endolysin treated patients and control group. Significant clinical improvements were seen in cohort and case studies. A few minor side effects were reported.
Conclusions: Although there are countries in which bacteriophages are prescribed as an alternative to established antibiotics, this valuable experience has yet to be examined sufficiently in clinical trials conducted to modern standards. Despite improvements in symptoms shown in the reviewed clinical trials, the infection and the bacteria themselves were rarely completely eradicated. Therefore, no definite answer can be given as to effectiveness, and further clinical trials are necessary.
... Transport of phage particles through soil, i.e. the upper part of the Critical Zone, however remains largely unknown, yet may play a major role in regulating soil microbial life (Wilhartitz et al., 2013) and controlling groundwater quality (Keswick and Gerba, 1980). Being of nano-particulate size, phages have been described as tracers for ground-and surface water flows (Flynn et al., 2004a(Flynn et al., , 2004bFlynn et al., 2015;Flynn and Sinreich, 2010;Goldscheider et al., 2007;Mallén et al., 2005;Rossi et al., 1998) or the presence of pathogens (Chanishvili, 2012;Masciopinto et al., 2008;Morales et al., 2014), but not yet described as tracers for soil transport processes. To reflect soil transport processes, good tracers should be non-pathogenic, non-toxic, non-multiplying and absent in the natural background (Rossi et al., 1998). ...
Marine phages have been applied to trace ground- and surface water flows. Yet, information on their transport in soil and related particle intactness is limited. Here we compared the breakthrough of two lytic marine tracer phages (Pseudoalteromonas phages PSA-HM1 and PSA-HS2) with the commonly used Escherichia virus T4 in soil- and sand-filled laboratory percolation columns. All three phages showed high mass recoveries in the effluents and a higher transport velocity than non-reactive tracer Br⁻. Comparison of effluent gene copy numbers (CN) to physically-determined phage particle counts or infectious phage counts showed that PSA-HM1 and PSA-HS2 retained high phage particle intactness (Ip > 81%), in contrast to T4 (Ip < 36%). Our data suggest that marine phages may be applied in soil to mimic the transport of (bio-) colloids or anthropogenic nanoparticles of similar traits. Quantitative PCR (qPCR) thereby allows for highly sensitive quantification and thus for the detection of even highly diluted marine tracer phages in environmental samples.
... For over 100 years, whole phages have been successfully applied to treat various bacterial infections [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47]. This includes infections caused by pathogens belonging to infamous ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) [48], whose members literally have escaped from currently available antibacterial therapies [49]. ...
Over the past few decades, we have witnessed a surge around the world in the emergence of antibiotic-resistant bacteria. This global health threat arose mainly due to the overuse and misuse of antibiotics as well as a relative lack of new drug classes in development pipelines. Innovative antibacterial therapeutics and strategies are, therefore, in grave need. For the last twenty years, antimicrobial enzymes encoded by bacteriophages, viruses that can lyse and kill bacteria, have gained tremendous interest. There are two classes of these phage-derived enzymes, referred to also as enzybiotics: peptidoglycan hydrolases (lysins), which degrade the bacterial peptidoglycan layer, and polysaccharide depolymerases, which target extracellular or surface polysaccharides, i.e., bacterial capsules, slime layers, biofilm matrix, or lipopolysaccharides. Their features include distinctive modes of action, high efficiency, pathogen specificity, diversity in structure and activity, low possibility of bacterial resistance development, and no observed cross-resistance with currently used antibiotics. Additionally, and unlike antibiotics, enzybiotics can target metabolically inactive persister cells. These phage-derived enzymes have been tested in various animal models to combat both Gram-positive and Gram-negative bacteria, and in recent years peptidoglycan hydrolases have entered clinical trials. Here, we review the testing and clinical use of these enzymes.
... Antibiotics, for example, are known to be potentially antagonistic to phage infection activities [47]. One common aspect of both pre-clinical [34,42,47,102,114,[116][117][118][119][120][121][122] and clinical phage therapy treatments [26,, however, is concurrent combination of phages with antibiotics. Here we have assessed the potential of two different antibiotics, colistin (polymyxin) and ciprofloxacin (fluoroquinolone), to interfere with the infection activities of P. aeruginosa phage PEV2, LUZ19, and ΦKMV at bacterial growth-inhibiting antibiotic concentrations (greater than or equal to MIC). ...
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.
... Notwithstanding their opinion that phage therapy in some cases could demonstrably contribute to the curing of bacterial infections, the Eaton and Bayne-Jones [16][17][18] report nevertheless contributed, likely along with the widespread introduction of antibiotics in the 1940s, to a substantial decline in the practice of phage therapy by many European, and especially North American practitioners [11,13,19]. This decline did not, however, occur in the former Soviet Union, where phage therapy continued to be researched and developed [2,11,20]. In response to concerns over the diminishing utility of many antibiotics in treating bacterial infections, the Eastern Bloc experience-particularly as centered in former-Soviet Georgia, as well as in Poland [21]-served to inspire a worldwide revival of phage use to treat bacterial infections. ...
Many bacteriophages are obligate killers of bacteria. That this property could be medically useful was first recognized over one hundred years ago, with 2021 being the 100-year anniversary of the first clinical phage therapy publication. Here we consider modern use of phages in clinical settings. Our aim is to answer one question: do phages serve as effective anti-bacterial infection agents when used clinically? An important emphasis of our analyses is on whether phage therapy-associated anti-bacterial infection efficacy can be reasonably distinguished from that associated with often coadministered antibiotics. We find that about half of 70 human phage treatment reports—published in English thus far in the 2000s—are suggestive of phage-mediated anti-bacterial infection efficacy. Two of these are randomized, double-blinded, infection-treatment studies while 14 of those studies, in our opinion, provide superior evidence of a phage role in observed treatment successes. Roughly three-quarters of these potentially phage-mediated outcomes are based on microbiological as well as clinical results, with the rest based on clinical success. Since many of these phage treatments are of infections for which antibiotic therapy had not been successful, their collective effectiveness is suggestive of a valid utility in employing phages to treat otherwise difficult-to-cure bacterial infections.
... Bacteriophages are defined as bacterial viruses that target and kill their specific bacteria. It was used clinically for the first time in 1919 by Felix D'Herelle in France [6]. Bacteriophages, which were thought to be used as antibacterial material, were used in the treatment of many diseases such as upper respiratory tract infections, abscesses, burns and inflamed wounds in a few countries such as Georgia, Poland, former Russia and the USA until the 1940s. ...
Objective: The decrease in the efficacy of antimicrobials in the treatment of Klebsiella-related infections necessitated the search for alternative treatment strategies. This study aims to provide isolation of lytic bacteriophage specific to Klebsiella species and to investigate its potential for use as alternative antimicrobial agent. Material and Method: One Extended spectrum beta lactamase (ESBL) producer Klebsiella strain was used as host bacteria and water samples were collected from river in Ankara for bacteriophage isolation. Spot test method was applied to determine the possible presence of bacteriophage after phage enrichment. To confirm the presence of the lytic bacteriophage, double layer agar method was applied to spot test positive samples. The susceptibility of the bacteriophage was determined using in vitro spot test. 38 clinical ESBL positive Klebsiella spp. strains were used for this analysis. Result and Discussion: In the initial screening, the vB_K1 bacteriophage producing visible plaques with a diameter of 1.00 mm was isolated in the petri dish. The susceptibility of ESBL positive Klebsiella spp. strains to this bacteriophage was determined as 73.7%. It was proved that vB_K1 bacteriophage is very effective to Klebsiella spp. strains. However, in vitro bacteriophage susceptibility of characterized bacteriophage is encouraging development.
... In real-life farming systems, the effect of introduced mucosal phages might even be stronger as the bacterial numbers initiating the infection are likely to be lower than in the experimental infection used here. Pre-colonisation of vertebrate hosts with phages has been shown to be efficient also in preventing Vibrio cholerae infections in mice [37], and the approach has been used also in humans in the former Soviet Union [38]. ...
Viruses of bacteria, bacteriophages, specifically infect their bacterial hosts with minimal effects on the surrounding microbiota. They have the potential to be used in the prevention and treatment of bacterial infections, including in the field of food production. In aquaculture settings, disease-causing bacteria are often transmitted through the water body, providing several applications for phage-based targeting of pathogens, in the rearing environment, and in the fish. We tested delivery of phages by different methods (via baths, in phage-coated material, and via oral delivery in feed) to prevent and treat Flavobacterium columnare infections in rainbow trout fry using three phages (FCOV-S1, FCOV-F2, and FCL-2) and their hosts (FCO-S1, FCO-F2, and B185, respectively). Bath treatments given before bacterial infection and at the onset of the disease symptoms were the most efficient way to prevent F. columnare infections in rainbow trout, possibly due to the external nature of the disease. In a flow-through system, the presence of phage-coated plastic sheets delayed the onset of the disease. The oral administration of phages first increased disease progression, although total mortality was lower at the end of the experiment. When analysed for shelf-life, phage titers remained highest when maintained in bacterial culture media and in sterile lake water. Our results show that successful phage therapy treatment in the aquaculture setting requires optimisation of phage delivery methods in vivo.
... In post-Soviet Union countries, phage preparations have a long history of application for treatment and prophylaxis against dysenterial diseases, such as shigellosis, escherichiosis, and salmonellosis. These preparations have been successfully used for prophylaxis of salmonellosis among civilian population as well as in Red Army units [4][5][6]. In Western countries phage applications are used for biocontrol in foods [3]. ...
Bacteriophages that lyse Salmonella enterica are potential tools to target and control Salmonella infections. Investigating the host range of Salmonella phages is a key to understand their impact on bacterial ecology, coevolution and inform their use in intervention strategies. Virus–host infection networks have been used to characterize the “predator–prey” interactions between phages and bacteria and provide insights into host range and specificity. Here, we characterize the target-range and infection profiles of 13 Salmonella phage clones against a diverse set of 141 Salmonella strains. The environmental source and taxonomy contributed to the observed infection profiles, and genetically proximal phages shared similar infection profiles. Using in vitro infection data, we analyzed the structure of the Salmonella phage–bacteria infection network. The network has a non-random nested organization and weak modularity suggesting a gradient of target-range from generalist to specialist species with nested subsets, which are also observed within and across the different phage infection profile groups. Our results have implications for our understanding of the coevolutionary mechanisms shaping the ecological interactions between Salmonella phages and their bacterial hosts and can inform strategies for targeting Salmonella enterica with specific phage preparations.
... We compared the solutions over prolonged storage at 4 • C with four different phages with high therapeutic potential [42,43] against three different bacterial species and belonging to two phage morphologies (three Myoviruses and one Podovirus). As an empirical rule, the therapeutic titer of the phages should be in the range of 6-9 log pfu/mL [3,[44][45][46]. Therefore, we decided to test two different concentrations within this range. ...
In Belgium, the incorporation of phages into magistral preparations for human application has been permitted since 2018. The stability of such preparations is of high importance to guarantee quality and efficacy throughout treatments. We evaluated the ability to preserve infectivity of four different phages active against three different bacterial species in five different buffer and infusion solutions commonly used in medicine and biotechnological manufacturing processes, at two different concentrations (9 and 7 log pfu/mL), stored at 4 °C. DPBS without Ca2+ and Mg2+ was found to be the best option, compared to the other solutions. Suspensions with phage concentrations of 7 log pfu/mL were unsuited as their activity dropped below the effective therapeutic dose (6–9 log pfu/mL), even after one week of storage at 4 °C. Strong variability between phages was observed, with Acinetobacter baumannii phage Acibel004 being stable in four out of five different solutions. We also studied the long term storage of lyophilized staphylococcal phage ISP, and found that the titer could be preserved during a period of almost 8 years when sucrose and trehalose were used as stabilizers. After rehydration of the lyophilized ISP phage in saline, the phage solutions remained stable at 4 °C during a period of 126 days.
... Ten additional records were identified from other sources. Five were reports that described the use of phage therapy for a wide variety of conditions and therefore the titles and abstracts of these records did not contain the specific search terms used [18][19][20][21][22]; three were from grey literature sources known to the authors not to be indexed or available online [23][24][25]31]; and the authors became aware of two further relevant records published after the systematic search date but that were included for completeness [26,27]. ...
Bacterial resistance to antibiotics has catalysed interest in alternative antimicrobial strategies. Bacteriophages (phages) are viruses of bacteria with a long history of successful therapeutic use. Phage therapy is a promising antibacterial strategy for infections with a biofilm component, including recalcitrant bone and joint infections, which have significant social, financial and human impacts. Here, we report a systematic review of the safety and efficacy of phage therapy for the treatment of bone and joint infections. Three electronic databases were systematically searched for articles that reported primary data about human phage therapy for bone and joint infections. Two authors independently assessed study eligibility and performed data extraction. Seventeen reports were eligible for inclusion in this review, representing the treatment of 277 patients. A cautionary, crude, efficacy estimate revealed that 93.1% (n = 258/277) achieved clinical resolution, 3.3% (n = 9/277) had improvement and 3.6% (n = 10/277) showed no improvement. Seven of the nine reports that directly commented on the safety of phage therapy did not express safety concerns. The adverse effects reported in the remaining two were not severe and were linked to the presence of contaminating endotoxins and pre-existing liver pathology in a patient treated with high-titre intravenous phage therapy. Three other reports, from 1940–1987, offered general comments on the safety of phage therapy and documented adverse effects consistent with endotoxin co-administration concomitant with the use of raw phage lysates. Together, the reports identified by this review suggest that appropriately purified phages represent a safe and highly efficacious treatment option for complex and intractable bone and joint infections.
... Widely distributed phage therapy medications are made available through pharmacies in Russia and Georgia. These products are approved following regulatory processes that typically apply to ready-made preparations produced at a commercial scale (Chanishvili and Sharp, 2009). However, phage therapy may be regulated differently. ...
... Despite the early success of bacteriophages as antimicrobials, their use as a treatment, and even phage research, declined dramatically with the discovery of antibiotics, penicillin in particular. Only some Eastern European nations, such as Poland, Georgia, and Russia, continued the research in this field and the treatment of infectious diseases with phage therapy [14,22,23]. Unfortunately, despite the demonstrated potential for phage treatment of phytopathogenic bacteria, some researchers remained skeptical and questioned the efficacy of phage therapy in this field [24]. ...
Agriculture, together with aquaculture, supplies most of the foodstuffs required by the world human population to survive. Hence, bacterial diseases affecting either agricultural crops, fish, or shellfish not only cause large economic losses to producers but can even create food shortages, resulting in malnutrition, or even famine, in vulnerable populations. Years of antibiotic use in the prevention and the treatment of these infections have greatly contributed to the emergence and the proliferation of multidrug-resistant bacteria. This review addresses the urgent need for alternative strategies for the use of antibiotics, focusing on the use of bacteriophages (phages) as biocontrol agents. Phages are viruses that specifically infect bacteria; they are highly host-specific and represent an environmentally-friendly alternative to antibiotics to control and kill pathogenic bacteria. The information evaluated here highlights the effectiveness of phages in the control of numerous major pathogens that affect both agriculture and aquaculture, with special emphasis on scientific and technological aspects still requiring further development to establish phagotherapy as a real universal alternative to antibiotic treatment.
... However, still, there are no authorized instructions for using phages on humans in the western countries, and current methods are only approved in some countries like Russia and Georgia. 132,133 Noteworthy, the clinical trials phase I was approved by the Food and Drug Administration (FDA), and no safety concerns were found. 132,134 So, a comprehensive guideline is needed to be available to all researchers to reduce phage therapy restriction. ...
Wound infection kills a large number of patients worldwide each year. Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the most important colonizing pathogens of wounds that, with various virulence factors and impaired immune system, causes extensive tissue damage and nonhealing wounds. Furthermore, the septicemia caused by these pathogens increases the mortality rate due to wound infections. Because of the prevalence of antibiotic resistance in recent years, the use of antibiotics to inhibit these pathogens has been restricted, and the topical application of antibiotics in wound infections increases antibiotic resistance. Therefore, finding a new therapeutic strategy against wound infections is so essential since these infections have a destructive effect on the patient's mental health and high medical costs. In this review, we discussed the use of phages for the prevention of multidrug-resistant (MDR) bacteria, causing wound infection and their role in wound healing in animal models and clinical trials. The results showed that phages have a high ability to inhibit different wound infections caused by MDR bacteria, heal the wound faster, have lower side effects and toxicity, destroy bacterial biofilm, and they are useful in controlling immune responses. Many studies have used animal models to evaluate the function of phages, and this study appears to have a positive impact on the use of phages in clinical practice and the development of a new therapeutic approach to control wound infections, although there are still many limitations.
... Indeed, a standard concern outside of the phage therapy community seems to be that phages simply will be inactivated by the body's immune system prior to the achievement of efficacy. This potential, however, is inconsistent with numerous examples of seeming phage therapy efficacy found throughout the phage therapy literature (Chanishvili, 2012;Abedon, 2015c;2018a;Morozova et al., 2018b;Abedon, 2019b;El Haddad et al., 2019;Melo et al., 2020), and indeed would constitute an argument against the use of nonhuman protein-based drugs generally. In addition, and importantly, there are conceptual as well as empirical arguments against the relevance of these concerns regarding phage therapy. ...
Pharmacology can be differentiated into two key aspects, pharmacodynamics and pharmacokinetics. Pharmacodynamics describes a drug's impact on the body while pharmacokinetics describes the body's impact on a drug. Another way of understanding these terms is that pharmacodynamics is a description of both the positive and negative consequences of drugs attaining certain concentrations in the body while pharmacokinetics is concerned with our ability to reach and then sustain those concentrations. Unlike the drugs for which these concepts were developed, including antibiotics, the bacteriophages (or 'phages') that we consider here are not chemotherapeutics but instead are the viruses of bacteria. Here we review the pharmacology of these viruses, particularly as they can be employed to combat bacterial infections (phage therapy). Overall, an improved pharmacological understanding of phage therapy should allow for more informed development of phages as antibacterial 'drugs', allow for more rational post hoc debugging of phage therapy experiments, and encourage improved design of phage therapy protocols. Contrasting with antibiotics, however, phages as viruses impact individual bacterial cells as single virions rather than as swarms of molecules, and while they are killing bacteria, bacteriophages also can amplify phage numbers, in situ. Explorations of phage therapy pharmacology consequently can often be informed as well by basic principles of the ecological interactions between phages and bacteria as by study of the pharmacology of drugs. Bacteriophages in phage therapy thus can display somewhat unique as well as more traditional pharmacological aspects.
... Indeed, a standard concern outside of the phage therapy community seems to be that phages simply will be inactivated by the body's immune system prior to the achievement of efficacy. This potential, however, is inconsistent with numerous examples of seeming phage therapy efficacy found throughout the phage therapy literature (Chanishvili, 2012;Abedon, 2015c;Morozova et al., 2018b;Abedon, 2019b;El Haddad et al., 2019;Melo et al., 2020), and indeed would constitute an argument against the use of nonhuman protein-based drugs generally. In addition, and importantly, there are conceptual as well as empirical arguments against the relevance of these concerns regarding phage therapy. ...
... Various reviews have been written summarizing the early potential of phage preparations for the treatment of skin infections, surgical, and purulent wounds as well as acquired postsurgical infections caused by E. coli, P. aeruginosa, S. aureus, and other well-established and prevalent pathogens to this date. [56][57][58] More recently, Morozova et al reported on serial case reports published in the Russian literature. 59 These reviews comprehensively highlight the widespread use of phage therapy prior and even after the discovery of antibiotics, including during World War II, with reports of clinical success ranging from 50% to 69% depending on the target pathogen. ...
Wound infections associated with multidrug-resistant (MDR) bacteria are one of the important threats to public health. Bacteriophage (phage) therapy is a promising alternative or supplementary therapeutic approach to conventional antibiotics for combating MDR bacterial infections. In recent years, significant effort has been put into the development of phage formulations and delivery methods for topical applications, along with preclinical and clinical uses of phages for the treatment of acute and chronic wound infections. This paper reviews the application of phages for wound infections, with focuses on the current status of phage formulations (including liquid, semi-solid and liposome-encapsulated formulations, phage-immobilized wound dressings), safety and efficacy assessment in clinical settings and major challenges to overcome.
... Furthermore, massive human trials based on preventive phage therapy (called "prophylactic phaging") were performed in the past by the former Soviet Union. Phage pretreatment reduced disease occurrence, and phage persistence for days in the human body was recorded (25). Although the exact mechanism of phage retention was not studied, it is possible that the success of prophylactic use of phages, under experimental conditions and in human trials, is mediated at least in part by phage subdiffusion on mucosal surfaces. ...
The mucosal surfaces of animals are habitat for microbes, including viruses. Bacteriophages—viruses that infect bacteria—were shown to be able to bind to mucus. This may result in a symbiotic relationship in which phages find bacterial hosts to infect, protecting the mucus-producing animal from bacterial infections in the process. Here, we studied phage binding on mucus and the effect of mucin on phage-bacterium interactions. The significance of our research is in showing that phage adhesion to mucus results in preventive protection against bacterial infections, which will serve as basis for the development of prophylactic phage therapy approaches. Besides, we also reveal that exposure to mucus upregulates bacterial virulence and that this is exploited by phages for infection, adding one additional layer to the metazoan-bacterium-phage biological interactions and ecology. This phenomenon might be widespread in the biosphere and thus crucial for understanding mucosal diseases, their outcome and treatment.
... This matter of timing is not necessarily absolute, however, as improvements in technology that deliver faster testing for bacterial susceptibility to treatment phages should eventually allow for the more rapid initiation of treatments, i.e., on the order of hours or even minutes rather than days. The testing of bacterial susceptibility to different phage types, in any case, can range from testing analogous to phage typing to determinations of plaque formation (101)(102)(103) and to other, more sophisticated phage-based technologies (104,105). ...
The use of viruses infecting bacteria (bacteriophages or phages) to treat bacterial infections has been ongoing clinically for approximately 100 years. Despite that long history, the growing international crisis of resistance to standard antibiotics, abundant anecdotal evidence of efficacy, and one successful modern clinical trial of efficacy, this phage therapy is not yet a mainstream approach in medicine. One explanation for why phage therapy has not been subject to more widespread implementation is that phage therapy research, both preclinical and clinical, can be insufficiently pharmacologically aware. Consequently, here we consider the pharmacological obstacles to phage therapy effectiveness, with phages in phage therapy explicitly being considered to serve as drug equivalents. The study of pharmacology has traditionally been differentiated into pharmacokinetic and pharmacodynamic aspects. We therefore separately consider the difficulties that phages as virions can have in traveling through body compartments toward reaching their target bacteria (pharmacokinetics) and the difficulties that phages can have in exerting antibacterial activity once they have reached those bacteria (pharmacodynamics). The latter difficulties, at least in part, are functions of phage host range and bacterial resistance to phages. Given the apparently low toxicity of phages and the minimal side effects of phage therapy as practiced, phage therapy should be successful so long as phages can reach the targeted bacteria in sufficiently high numbers, adsorb, and then kill those bacteria. Greater awareness of what obstacles to this success generally or specifically can exist, as documented in this review, should aid in the further development of phage therapy toward wider use.
... Bacteriophage therapy for severe musculoskeletal infections has a number of historical precedents. In fact, in Eastern Europe, osteomyelitis is one of the major indications for which phage therapy has been applied during the last century, and patient reports have demonstrated high efficacy and safety [25][26][27][28]. However, it should be noted that these studies have important methodological limitations. ...
Bacteriophage therapy has recently attracted increased interest, particularly in difficult-to-treat infections. Although it is not a novel concept, standardized treatment guidelines are currently lacking. We present the first steps towards the establishment of a "multidisciplinary phage task force" (MPTF) and a standardized treatment pathway, based on our experience of four patients with severe musculoskeletal infections. After review of their medical history and current clinical status, a multidisciplinary team found four patients with musculoskeletal infections eligible for bacteriophage therapy within the scope of Article 37 of the Declaration of Helsinki. Treatment protocols were set up in collaboration with phage scientists and specialists. Based on the isolated pathogens, phage cocktails were selected and applied intraoperatively. A draining system allowed postoperative administration for a maximum of 10 days, 3 times per day. All patients received concomitant antibiotics and their clinical status was followed daily during phage therapy. No severe side-effects related to the phage application protocol were noted. After a single course of phage therapy with concomitant antibiotics, no recurrence of infection with the causative strains occurred, with follow-up periods ranging from 8 to 16 months. This study presents the successful outcome of bacteriophage therapy using a standardized treatment pathway for patients with severe musculoskeletal infection. A multidisciplinary team approach in the form of an MPTF is paramount in this process.
Urinary tract infections are widespread bacterial infections affecting millions of people annually, with Escherichia coli being the most prevalent. Although phage therapy has recently gained interest as a promising alternative therapy for antibiotic-resistant bacteria, several studies have raised concerns regarding the evolution of phage resistance, making the therapy ineffective. In this study, we discover a novel coli myophage designated as Killian that targets E. coli strains, including the uropathogenic E. coli (UPEC) strain CFT073. It requires at least 20 minutes for 90% of its particles to adsorb to the host cells, undergoes subcellular activities for replication for 30 minutes, and eventually lyses the cells with a burst size of about 139 particles per cell. Additionally, Killian can withstand a wide variety of temperatures (4–50°C) and pHs ( 4 – 10 ). Genome analysis reveals that Killian’s genome consists of 169,905 base pairs with 35.5% GC content, encoding 276 open reading frames; of these, 209 are functionally annotated with no undesirable genes detected, highlighting its potential as an antibiotic alternative against UPEC. However, after an 8-hour phage treatment at high multiplicities of infection, bacterial density continuously increases, indicating an onset of bacterial growth revival. Thus, the combination study between the phage and three different antibiotics, including amikacin, ciprofloxacin, and piperacillin, was performed and showed that certain pairs of phage and antibiotics exhibited synergistic interactions in suppressing the bacterial growth revival. These findings suggest that Killian-antibiotic combinations are effective in inhibiting the growth of UPEC.
IMPORTANCE
Phage therapy has recently been in the spotlight as a viable alternative therapy for bacterial infections. However, several studies have raised concerns about the emergence of phage resistance that occurs during treatment, making the therapy not much effective. Here, we present the discovery of a novel E. coli myophage that, by itself, can effectively kill the uropathogenic E. coli , but the emergence of bacterial growth revival was detected during the treatment. Phage and antibiotics are then combined to improve the efficiency of the phage in suppressing the bacterial re-growth. This research would pave the way for the future development of phage-antibiotic cocktails for the sustainable use of phages for therapeutic purposes.
In contrast to the many reports of successful cases of personalized bacteriophage therapy, randomized controlled trials of non-personalized bacteriophage products did not bring the expected results. Here, we present the outcomes of a retrospective, observational analysis of the first 100 consecutive cases of personalized bacteriophage therapy of difficult-to-treat infections facilitated by a Belgian consortium. The most common indications were lower respiratory tract, skin & soft tissue, and bone infections, and involved combinations of 26 bacteriophages, individually selected and sometimes pre-adapted to target the causative bacterial pathogens. Clinical improvement and eradication of the targeted bacteria were reported for 77.2% and 61.3% of infections, respectively. Eradication was 70% less probable when no concomitant antibiotics were used (odds-ratio = 0.3; 95% confidence interval = 0.127 - 0.749). In vivo selection of bacteriophage resistance and in vitro bacteriophage-antibiotic synergy were documented in 43.8% (7/16 patients) and 90% (9/10) of evaluated patients, respectively. Bacteriophage immune neutralization was observed in 38.5% (5/13) of screened patients. (BT100 study, ClinicalTrials.gov registration: NCT05498363 .)
Phages of highly pathogenic bacteria represent an area of growing interest for bacterial detection and identification and subspecies typing, as well as for phage therapy and environmental decontamination. Eight new phages—YpEc56, YpEc56D, YpEc57, YpEe58, YpEc1, YpEc2, YpEc11, and YpYeO9—expressing lytic activity towards Yersinia pestis revealed a virion morphology consistent with the Podoviridae morphotype. These phages lyse all 68 strains from 2 different sets of Y. pestis isolates, thus limiting their potential application for subtyping of Y. pestis strains but making them rather promising in terms of infection control. Two phages—YpYeO9 and YpEc11—were selected for detailed studies based on their source of isolation and lytic cross activity towards other Enterobacteriaceae. The full genome sequencing demonstrated the virulent nature of new phages. Phage YpYeO9 was identified as a member of the Teseptimavirus genus and YpEc11 was identified as a member of the Helsettvirus genus, thereby representing new species. A bacterial challenge assay in liquid microcosm with a YpYeO9/YpEc11 phage mixture showed elimination of Y. pestis EV76 during 4 h at a P/B ratio of 1000:1. These results, in combination with high lysis stability results of phages in liquid culture, the low frequency of formation of phage resistant mutants, and their viability under different physical–chemical factors indicate their potential for their practical use as an antibacterial mean.
The Belgian Society for Viruses of Microbes (BSVoM) was founded on 9 June 2022 to capture and enhance the collaborative spirit among the expanding community of microbial virus researchers in Belgium. The sixteen founders are affiliated to fourteen different research entities across academia, industry and government. Its inaugural symposium was held on 23 September 2022 in the Thermotechnical Institute at KU Leuven. The meeting program covered three thematic sessions launched by international keynote speakers: (1) virus–host interactions, (2) viral ecology, evolution and diversity and (3) present and future applications. During the one-day symposium, four invited keynote lectures, ten selected talks and eight student pitches were given along with 41 presented posters. The meeting hosted 155 participants from twelve countries.
The production and use of antibiotics increased significantly after the Second World War due to their effectiveness against bacterial infections. However, bacterial resistance also emerged and has now become an important global issue. Those most in need are typically high-risk and include individuals who experience burns and other wounds, as well as those with pulmonary infections caused by antibiotic-resistant bacteria, such as Pseudomonas aeruginosa, Acinetobacter sp, and Staphylococci. With investment to develop new antibiotics waning, finding and developing alternative therapeutic strategies to tackle this issue is imperative. One option remerging in popularity is bacteriophage (phage) therapy. This review focuses on Staphylococcus aureus and how it has developed resistance to antibiotics. It also discusses the potential of phage therapy in this setting and its appropriateness in high-risk people, such as those with cystic fibrosis, where it typically forms a biofilm.
Background:
Bacteriophage therapy has a long history in the treatment of musculoskeletal and skin/soft tissue infections, particularly in the former Soviet Union. Due to the global rise in antimicrobial resistance, phage application has experienced a resurgence of interest and expanded to many countries.
Objectives:
This narrative review aims to provide clinical microbiologists, infectious disease specialists and surgeons a brief history of bacteriophage therapy for human musculoskeletal and soft tissue infections, as well as data on current practices and ongoing clinical studies.
Sources:
A search of PubMed and Clinicaltrials.gov was performed to identify relevant studies. Search terms were 'bacteriophage therapy', 'musculoskeletal infection' and 'soft tissue infection'. The bibliography of all retrieved articles was checked for additional relevant references.
Content:
Past and current data on the use of bacteriophage therapy for human musculoskeletal, skin and soft tissue infections are evaluated. Moreover, we present the clinical trials registered in public databases. Based on current clinical experience and data, several scenarios of bacteriophage application for human therapy are examined. Finally, we discuss legislative hurdles in the regulatory approval process and present future perspectives for bacteriophage therapy.
Implications:
Antimicrobial resistance is one of the most important global public health challenges. Several different alternatives to conventional antibiotics are under development; bacteriophage therapy is one of them. Currently, therapeutic use of phages is restrained by regulatory hurdles and largely limited to sporadic authorization in compassionate use or under temporary approval as new drugs in Europe and the US. Although bacteriophage therapy seems to be safe and clinical results of phage treatment are promising, future data from high-quality (randomized controlled) trials could provide a better understanding of the reasonable minimal criteria required for expansion of bacteriophage therapy.
Frederick William Twort and Felix d'Hérelle independently discovered bacteriophages in 1915 and 1917, respectively. This led to the early trials of using bacteriophages to treat infectious diseases worldwide. The earliest reported use of bacteriophages therapeutically in the United States was in 1922. With the subsequent discovery of antibiotics in the 1940s, and because of disappointing results of phage therapy in the next decade, use of bacteriophages as therapeutic agents declined in western countries. This paper addresses two questions in the field: what is the historical record of the successes and failures of phage therapy in the United States and, what led to abandoning phage therapy in the United States? We examined the literature from 1915 to 1965, and we present a numerical analysis of the papers published during that period. We report key historical factors leading to a decline in the use of phage therapy in the United States by the 1950s. Since bacteriophages were first used therapeutically, several changes have occurred: increased antimicrobial drug resistance and a better knowledge of the biology of bacteriophages are important examples. Early assessments leading to the rejection of phage therapy in the United States were perhaps appropriate. However, it is time to reconsider the role of bacteriophages in treatment of bacterial infections.
Salmonella typhi specifi c bacteriophage i.e. GRCST exhibited potential bacteriolytic activity against n=4, ESBL producing S. typhi isolates in vitro. The GRCST possesses an icosahedral head with 50 nm size and contractile tail belongs to Myoviridae Vi01-like family. The experimental outcome of in vivo studies in BALB/c mice induced with S. typhi bacteraemia treated with 1.5×10 7 PFU GRCST showed 100% survival with zero causality was recorded. On contrary, only 67% and 83% survival rate was observed in the group of mice which received standard antibiotic ciprofl oxacin. The IgG and IgM titres of anti-phage GRCST antibodies were detected, with increased 4100 fold, 600 fold respectively. This result demonstrates that the antibodies elicited by GRCST are non-neutralizing.
Advance bacteria have acquired several mechanisms to deal with antibiotics and are becoming more powerful with the passage of time. Klebsiella pneumoniae belonging to the class of Enterobacteriaceae is also a part of this race and is becoming resistant to almost all types of antibiotics. Colistin which was the last option for treatment is now becoming susceptible to the resistant strains of Klebsiella pneumoniae. The modified strain is contributing to human infection via antibiotic resistance and is becoming virulent with the passage of time leading to increase morbidity and mortality rates. On the basis of observations and studies, the first part sum up some important facts associated with the onset of resistance in Klebsiella pneumoniae and the symptoms associated with the wild and virulent types. Owing to the ability of antibiotic resistance of K. pneumonia cause some infections (UTI and Liver abscesses) in humans are discussed in second part of review.
Phage therapy is a century-old technique employing viruses (phages) to treat bacterial infections. In the clinic, phage therapy often is used in combination with antibiotics. Antibiotics, however, interfere with critical bacterial activities, such as DNA and protein synthesis, which also are required for phage infection processes. Resulting antagonistic impacts of antibiotics on phages nevertheless are not commonly determined in association with phage therapy studies using standard, planktonic approaches. Here we assess the antagonistic impact of two antibiotics, colistin and ciprofloxacin, on the bactericidal, bacteriolytic, and new virion production activities of Pseudomonas aeruginosa podovirus PEV2, using a broth culture, optical density-based ‘lysis profile’ assay. Though phage-antibiotic combinations were more potent in reducing cell viability than phages or antibiotics alone, colistin substantially interfered with phage PEV2 bacteriolytic and virion-production activities at minimum inhibitory concentration (MIC). Ciprofloxacin, by contrast, had no such impact at 1x MIC or 3x MIC. At higher but still clinically relevant concentrations (9× MIC) burst sizes were still significant (~30 phages/infected bacterium). We corroborated these lysis profile results by more traditional measurements (colony forming units, plaque forming units, one-step growth experiments) and two other P. aeruginosa phages. To our knowledge this is the first study in which detailed antibiotic impact on P. aeruginosa phage infection activities has been determined under conditions similar to those used to determine antibiotic MICs and could point especially to ciprofloxacin as a minimally antagonistic phage therapy co-treatment of P. aeruginosa infections.
The increasing prevalence of bacterial pathogens with multiple antibiotic resistance requires development of new approaches to control infections. Phage therapy is one of the most promising approaches. In recent years, research organizations and a number of pharmaceutical companies have intensified investigations aimed at developing bacteriophage-based therapeutics. In the United States and European countries, special centers have been established that experimentally apply phage therapy to treat patients who do not respond to antibiotic therapy. This review describes the features of bacteriophages as therapeutic tools, critically discusses the results of clinical trials of bacteriophage preparations, and assesses the prospects for using phage therapy to treat certain types of infectious diseases.
This overview discusses the literature data on the use of bacteriophages in the treatment of both acute and chronic infectious diseases caused by antibiotic-resistant pathogens. Traditionally, phage therapy is based on the use of naturally occurring phages for infection and lysis of bacteria at the site of infection. It has fundamental advantages over antibiotic therapy. At the same time, it has some disadvantages. Currently, the application of biotechnological methods, such as the development of the recombinant bacteriophages, makes it possible to eliminate the shortcomings of antimicrobial phage therapy and to expand its opportunities due to the use of lytic proteins of phages and their modified derivatives.
Bacteriophages (phages for short) are increasingly put forward as potential (additional) tools in the fight against the worldwide antibiotic crisis. However, the setup of clinical trials, which are necessary to demonstrate the efficacy of phages and to optimize their clinical application protocols, and consequently to their implementation in the clinic is still hindered by the lack of an adapted regulatory framework. Although some (local) progresses have been made in recent years, no real paradigm shift has occurred. This chapter discusses the current status in Europe with regard to the two most pertinent barriers to phage therapy: the regulatory and intellectual property protection issues.
The recently isolated phages phi ST3 and phi ST1 were compared as to their lysis behaviour in about 100 different P. aeruginosa strains. The growth of phi ST3 varies greatly in different host strains. We demonstrated one case of "non-classical", host-dependent modification and restriction. Here the capability to adsorb, and consequently to reproduce in a given host strain differs, depending on which modification the phage acquired in its former host. The DNA-containing phage phi ST1 displays stable lysis properties in the majority of the host strains. This makes phi ST1 a candidate for therapeutic phage preparations. One of the reasons for stable lysis properties is the apparent selection against recognition sites of restriction enzymes in its genome.
Sensitivity to therapeutic bacteriophages and antibiotics of 2063 cultures causing purulent inflammatory diseases was studied. Sensitivity of Staph. aureus to therapeutic bacteriophages was higher (88.5%) than that to benzylpenicillin (33.7%), ampicillin (64.3%), erythromycin (53.7%) and close to that to aminoglycosides, tetracycline, lincomycin and chloramphenicol. The number of Ps. aeruginosa strains sensitive to the phages amounted to 67.1%. E. coli and Proteus were sensitive to therapeutic bacteriophages in 32.4 and 29% of the cultures respectively. All of the streptococcal strains isolated from the patients were resistant to phages. A favourable clinical effect of phages was observed in 37 out of 80 patients. The results of the study showed the advisability of the wide use of bacteriophages in combined treatment of purulent inflammatory diseases.