Indications and Limitations of Phage Therapy in Human Medicine: Personal Experience and Literature Review

Bacteriophages, viruses that are widespread throughout the world, are highly specific for bacteria, usually of a single species and often of a particular strain. After being discovered and isolated 100 years ago, their use, called phage therapy, was instituted in medicine two years later and quickly used around the world to treat various bacterial infections. In the West, phage therapy was overshadowed in the second half of the 20th century by antibiotic therapy, which was then thought to be the definitive solution. But because of the increase in bacterial resistance to antibiotics, the idea of using bacteriophages in medicine has been reawakened. The innumerable observations reported over the years in the literature constitute an invaluable experience. We and some of our colleagues have, in the last decade treated some patients compassionately. With the available documentation and our own experience we discuss the potential indications and limitations of phage therapy. The observation of the increasing number of therapeutic failures in the announced perspective of a post-antibiotic era, we believe, that the introduction of bacteriophages into the therapeutic arsenal seems conceivable today to two preconditions: that their production as biologic drug meets current regulatory standards and that the benefit-risk assessment was conducted in a modern setting. Phage therapy could be applied as a substitution or supplement to antibiotic therapy under multiple circumstances in different modes, precise indications and limits.

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Bacteriophage Therapy for Critical Infections Related to Cardiothoracic Surgery

Antibiotics ◽

10.3390/antibiotics9050232 ◽

2020 ◽

Vol 9 (5) ◽

pp. 232 ◽

Cited By ~ 4

Author(s):

Evgenii Rubalskii ◽

Stefan Ruemke ◽

Christina Salmoukas ◽

Erin C. Boyle ◽

Gregor Warnecke ◽

...

Keyword(s):

Antibiotic Therapy ◽

Bacterial Infections ◽

Bacterial Resistance ◽

Phage Therapy ◽

Cardiothoracic Surgery ◽

Drug Resistant ◽

Bacteriophage Therapy ◽

Surgical Wounds ◽

Implanted Medical Devices ◽

Conventional Antibiotics

(1) Objective: Bacterial resistance to conventional antibiotic therapy is an increasingly significant worldwide challenge to human health. The objective is to evaluate whether bacteriophage therapy could complement or be a viable alternative to conventional antibiotic therapy in critical cases of bacterial infection related to cardiothoracic surgery. (2) Methods: Since September 2015, eight patients with multi-drug resistant or especially recalcitrant Staphylococcus aureus, Enterococcus faecium, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli infections were treated with bacteriophage preparations as a therapy of last resort according to Article 37 of the Declaration of Helsinki. Patients had infections associated with immunosuppression after organ transplantation or had infections of vascular grafts, implanted medical devices, and surgical wounds. Individualized phage preparations were administered locally, orally, or via inhalation for different durations depending on the case. All patients remained on conventional antibiotics during bacteriophage treatment. (3) Results: Patients ranged in age from 13 to 66 years old (average 48.5 ± 16.7) with seven males and one female. Eradication of target bacteria was reached in seven of eight patients. No severe adverse side effects were observed. (4) Conclusions: Phage therapy can effectively treat bacterial infections related to cardiothoracic surgery when conventional antibiotic therapy fails.

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Phage therapy of wound-associated infections

Folia Microbiologica ◽

10.1007/s12223-021-00946-1 ◽

2022 ◽

Author(s):

Anna Zyman ◽

Andrzej Górski ◽

Ryszard Międzybrodzki

Keyword(s):

Wound Healing ◽

Bacterial Infections ◽

Bacterial Resistance ◽

Phage Therapy ◽

World Health Organisation ◽

Good Manufacturing Practice ◽

Modern Medicine ◽

World Health ◽

Therapeutic Effects ◽

The World

AbstractPhages are viruses which can specifically infect bacteria, resulting in their destruction. Bacterial infections are a common complication of wound healing, and experimental evidence from animal models demonstrates promising potential for phage-dependent eradication of wound-associated infections. The studies discussed suggest that phage therapy may be an effective treatment, with important advantages over some current antibacterial treatments. Phage cocktails, as well as co-administration of phages and antibiotics, have been reported to minimise bacterial resistance. Further, phage-antibiotic synergism has been reported in some studies. The ideal dose of phages is still subject to debate, with evidence for both high and low doses to yield therapeutic effects. Novel delivery methods, such as hydrogels, are being explored for their advantages in topical wound healing. There are more and more Good Manufacturing Practice facilities dedicated to manufacturing phage products and phage therapy units across the world, showing the changing perception of phages which is occurring. However, further research is needed to secure the place of phages in modern medicine, with some scientists calling upon the World Health Organisation to help promote phage therapy.

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Bacteriophages: A Revisited Strategy for the Treatment of Severe Bacterial Infections

JOURNAL OF BIOENGINEERING AND TECHNOLOGY APPLIED TO HEALTH ◽

10.34178/jbth.v2i3.74 ◽

2020 ◽

Vol 2 (3) ◽

pp. 78-79

Author(s):

Roberto Badaro

Keyword(s):

Antibiotic Resistance ◽

Resistance Genes ◽

Bacterial Infections ◽

Bacterial Resistance ◽

Phage Therapy ◽

Bacterial Pathogen ◽

Severe Infection ◽

Current Increase ◽

Therapeutic Alternative ◽

The Ideal

Bacteriophages are viruses that infect and parasitize bacteria. The current increase in the incidence of antibiotic resistance in human bacteria has favoredthe study of phages as a therapeutic alternative (phage therapy). Phage therapy is defined as the administration of virulent phages directly to a patient to lyse the bacterial pathogen that is causing a clinically severe infection. The ideal route of administration and modification of bacteriopaghes genetically to deactivate bacterial resistance genes is the next future to antibiotic recovery sensitivity of MDR organisms.

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Helicobacter pyloriAntibiotic Resistance: Trends Over Time

Canadian Journal of Gastroenterology ◽

10.1155/2000/218256 ◽

2000 ◽

Vol 14 (10) ◽

pp. 895-899 ◽

Cited By ~ 18

Author(s):

Raymond G Lahaie ◽

Christiane Gaudreau

Keyword(s):

Bacterial Infections ◽

Bacterial Resistance ◽

Reliable Data ◽

Asian Countries ◽

Resistance To Antibiotics ◽

Treatment Regimens ◽

The World ◽

Trends Over Time ◽

H Pylori ◽

Resistance Rates

Resistance to antibiotics can be a major problem in the treatment of bacterial infections. As the use of antibiotics increases, bacterial resistance to these agents is rising and in many cases is responsible for the failure of treatment regimens. Although the treatment ofHelicobacter pyloriinfection requires the use of more than one antibiotic to obtain adequate eradication rates, the efficacy of the currently used antibiotic combinations has been shown to be decreased by resistance to one of the antibiotics. The use of antibiotics in regimens for the treatment ofH pyloriis increasing in many countries, including Canada. This increase is both in the use of these antibiotics alone for the treatment of nongastrointestinal infections and in their use in association with proton pump inhibitors for the treatment ofH pyloriinfection. In several European and Asian countries, where resistance to antibiotics is being monitored, it has been demonstrated thatH pyloriresistance to metronidazole and to clarithromycin increased throughout the 1990s. Thus far, the data available in Canada do not show increased resistance to either of these antibiotics. As for other antibiotics used in the treatment ofH pyloriinfection, such as tetracycline and amoxicillin, the rate of resistance to these agents is still very low and does not constitute a significant problem. Because the efficacy of the regimens used in the treatment ofH pyloriinfection is compromised by resistance to the antibiotics used, it is important thatH pyloriresistance rates in Canada and throughout the world continue to be monitored. Only with such reliable data can the most optimal regimens be recommended.

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Enhancing the antibacterial efficacy of low-dose gentamicin with 5 minute assistance of photothermy at 50 °C

Biomaterials Science ◽

10.1039/c8bm01539b ◽

2019 ◽

Vol 7 (4) ◽

pp. 1437-1447 ◽

Cited By ~ 28

Author(s):

Mengxue Ma ◽

Xiangmei Liu ◽

Lei Tan ◽

Zhenduo Cui ◽

Xianjin Yang ◽

...

Keyword(s):

Antibiotic Therapy ◽

Bacterial Infections ◽

Low Dose ◽

Bacterial Resistance ◽

Treatment Cycle ◽

Antibacterial Efficacy ◽

Implant Materials

Implant materials are prone to bacterial infections and cause serious consequences, while traditional antibiotic therapy has a long treatment cycle and even causes bacterial resistance.

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Principles of antibiotic therapy

Perspectives in Surgery ◽

10.33699/pis.2019.98.4.137-144 ◽

2019 ◽

Vol 98 (4) ◽

pp. 137-144

Keyword(s):

Antibiotic Therapy ◽

Antibiotic Prophylaxis ◽

Antibiotic Stewardship ◽

Bacterial Infections ◽

Bacterial Resistance ◽

Antimicrobial Agents ◽

Bacterial Pathogens ◽

Comprehensive Approach ◽

Contemporary Medicine ◽

Selection Of

The paper describes the basic sources and principles of antibiotic therapy in contemporary medicine in which the ability to treat bacterial infections may be lost. The main reason for that is the increasing resistance of bacterial pathogens to antibiotics. A possible solution is to implement a comprehensive program of antibiotic stewardship incorporating adequate consideration of indication and selection of antimicrobial agents including appropriate duration and way of administration. Another important component of the comprehensive approach to bacterial resistance and antibiotic therapy is adequately applied antibiotic prophylaxis in surgery.

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Phage Therapy as a Novel Strategy in the Treatment of Urinary Tract Infections Caused by E. Coli

Antibiotics ◽

10.3390/antibiotics9060304 ◽

2020 ◽

Vol 9 (6) ◽

pp. 304 ◽

Cited By ~ 4

Author(s):

Beata Zalewska-Piątek ◽

Rafał Piątek

Keyword(s):

Urinary Tract ◽

Urinary Tract Infections ◽

Biofilm Formation ◽

Bacterial Infections ◽

Phage Therapy ◽

Age Groups ◽

E Coli ◽

The World ◽

Novel Strategy ◽

Tract Infections

Urinary tract infections (UTIs) are regarded as one of the most common bacterial infections affecting millions of people, in all age groups, annually in the world. The major causative agent of complicated and uncomplicated UTIs are uropathogenic E. coli strains (UPECs). Huge problems with infections of this type are their chronicity and periodic recurrences. Other disadvantages that are associated with UTIs are accompanying complications and high costs of health care, systematically increasing resistance of uropathogens to routinely used antibiotics, as well as biofilm formation by them. This creates the need to develop new approaches for the prevention and treatment of UTIs, among which phage therapy has a dominant potential to eliminate uropathogens within urinary tract. Due to the growing interest in such therapy in the last decade, the bacteriophages (natural, genetically modified, engineered, or combined with antibiotics or disinfectants) represent an innovative antimicrobial alternative and a strategy for managing the resistance of uropathogenic microorganisms and controlling UTIs.

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COVID-19 and Antimicrobial Resistance: A Review

Infectious Diseases Research and Treatment ◽

10.1177/11786337211033870 ◽

2021 ◽

Vol 14 ◽

pp. 117863372110338

Author(s):

Yusuff Adebayo Adebisi ◽

Aishat Jumoke Alaran ◽

Melody Okereke ◽

Gabriel Ilerioluwa Oke ◽

Oladunni Abimbola Amos ◽

...

Keyword(s):

Antimicrobial Resistance ◽

Antibiotic Therapy ◽

Antimicrobial Stewardship ◽

Bacterial Infections ◽

Current Evidence ◽

Infectious Agents ◽

Mortality And Morbidity ◽

Medical Facilities ◽

The World ◽

Patients At Risk

As the world continues to respond to the coronavirus pandemic (COVID-19), there is a larger hidden threat of antimicrobial resistance (AMR) lurking behind. AMR remains worrisome in that the pathogens causing resistant infections to thrive in hospitals and medical facilities, putting all patients at risk, irrespective of the severity of their medical conditions, further compounding the management of COVID-19. This study aims to provide overview of early findings on COVID-19 and AMR as well as to provide recommendations and lesson learned toward improving antimicrobial stewardship. We conducted a rapid narrative review of published articles by searching PubMed and Google Scholar on COVID-19 and Antimicrobial Resistance with predetermined keywords. Secondary bacterial infections play crucial roles in mortality and morbidity associated with COVID-19. Research has shown that a minority of COVID-19 patients need antibiotics to treat secondary bacterial infections. Current evidence reiterates the need not to give antibiotic therapy or prophylaxis to patients with mild COVID-19 or to patients with suspected or confirmed moderate COVID-19 illness unless it is indicated. The pandemic has also brought to the fore the deficiencies in health systems around the world. This comes with a lot of lessons, one of which is that despite the advances in medicine; we remain incredibly vulnerable to infections with limited or no standard therapies. This is worth thinking in the context of AMR, as the resistant pathogens are evolving and leading us to the era of untreatable infections. There is a necessity for continuous research into understanding and controlling infectious agents, as well as the development of newer functional antimicrobials and the need to strengthen the antimicrobial stewardship programs.

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Pharmacologically Aware Phage Therapy: Pharmacodynamic and Pharmacokinetic Obstacles to Phage Antibacterial Action in Animal and Human Bodies

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.00012-19 ◽

2019 ◽

Vol 83 (4) ◽

Cited By ~ 14

Author(s):

Krystyna Dąbrowska ◽

Stephen T. Abedon

Keyword(s):

Bacterial Infections ◽

Bacterial Resistance ◽

Phage Therapy ◽

Anecdotal Evidence ◽

International Crisis ◽

Widespread Implementation ◽

Therapy Effectiveness ◽

Low Toxicity ◽

Body Compartments ◽

Further Development

SUMMARY 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.

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Phage Resistance Mechanisms Increase Colistin Sensitivity in Acinetobacter baumannii

10.1101/2021.07.23.453473 ◽

2021 ◽

Author(s):

Xiaoqing Wang ◽

Belinda Loh ◽

Yunsong Yu ◽

Xiaoting Hua ◽

Sebastian Leptihn

Keyword(s):

Bacterial Infections ◽

Bacterial Resistance ◽

Phage Therapy ◽

Resistance Mechanism ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Resistant Bacteria ◽

Phage Resistance ◽

Colistin Resistance ◽

Increased Sensitivity

Few emergency-use antibiotics remain for the treatment of multidrug-resistant bacterial infections. Infections with resistant bacteria are becoming increasingly common. Phage therapy has reemerged as a promising strategy to treat such infections, as microbial viruses are not affected by bacterial resistance to antimicrobial compounds. However, phage therapy is impeded by rapid emergence of phage-resistant bacteria during therapy. In this work, we studied phage-resistance of colistin sensitive and resistant A. baumannii strains. Using whole genome sequencing, we determined that phage resistant strains displayed mutations in genes that alter the architecture of the bacterial envelope. In contrast to previous studies where phage-escape mutants showed decreased binding of phages to the bacterial envelope, we obtained several not uninfectable isolates that allowed similar phage adsorption compared to the susceptible strain. When phage-resistant bacteria emerged in the absence of antibiotics, we observed that the colistin resistance levels often decreased, while the antibiotic resistance mechanism per se remained unaltered. In particular the two mutated genes that conveyed phage resistance, a putative amylovoran- biosynthesis and a lipo-oligosaccharide (LOS) biosynthesis gene, impact colistin resistance as the mutations increased sensitivity to the antibiotic.

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