Phage Therapy as an Alternative to Antibiotics: Harnessing Phages in Oral Medicine

Bacteriophages are a group of viruses that can adhere to bacteria, inject their genome into the bacterial cell, and eventually induce bacterial lysis (Naureen et al. 2020). Their discovery dates to the beginning of the 20^th century, and their clinical implementation in the treatment of bacterial infections was tested shortly after. However, due to the introduction and development of antibiotic therapy, phage therapy was greatly abandoned by Western science (Marongiu et al. 2022).

Nowadays, humanity stands on the verge of the post-antibiotic era (Kwon and Powderly 2021), with a desperate need to find alternatives to treat infection of multidrug-resistant (MDR) bacteria, mostly belonging to the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter sp.). Contemporary scientific data indicate that the emergence of antibiotic resistance in bacterial pathogens is a growing concern for global health (Ventola 2015; Frieri et al. 2017; Hofstee et al. 2020; Mancuso et al. 2021). There is a risk that bacteria causing infections that have been treatable with antibiotics will become resistant to these drugs within the next few decades. This imminent threat has prompted a response from the scientific community in diverse fields, with researchers undertaking efforts to identify novel, more efficacious antibiotics (Miethke et al. 2021).

There is a need to find alternative solutions that could mitigate the impact of this looming crisis. One of these is bacteriophage therapy, also known as phage therapy (PT). This approach traces its origins to the early 20th century, yet it has only recently garnered significant attention (Figure 1). The concept involves the use of carefully selected bacteriophages to combat pathogenic bacteria (Sawa et al. 2024).

Figure 1.

The number of papers retrieved from PubMed using the keyword ‘phage therapy’ that were published between 1946 and 2024 shows a significant increase in research in recent years.

This narrative review examines the potential of phage therapy, which can be utilized to both prevent and treat bacterial infections, particularly in dental settings. It revises forms of its administration, analyses the results of published clinical trials, and discusses its safety and potential risks.

Many scientists have observed bacteriophage activity since the late 19th century. However, th e first to understand that they were dealing with a new organism, rather than, for example, an enzyme, was the French Canadian imicrobiologist Félix d’Hérelle t (Marongiu et al. 2022). In 1915, during World War I, he investigated the outbreak of severe haemorrhagic dysentery among French troops. He made filtrates of faeces that were free from bacteria. Then, he spread them on the agar cultures of Shigella spp strains collected from sick soldiers. He observed blank spots that he later named plaques. Two years later, in 1917, he presented his findings during a meeting of the Academy of Sciences, and he proposed the name “bacteriophage”ofrom bacteria and the Greek word phage, which translates as “to eat” (Chanishvili 2012). He realized the importance of his discovery, so after conducting small animal trials and testing phages for safety on himself, he proceeded to clinical trials on humans, initiating what is now known as PT (Marongiu et al. 2022).

In 1919, three young brothers with symptoms of dysentery were admitted to the hospital where Félix d’Hérelle worked. Their sister had died of this disease a day before. One day after the introduction of phage therapy, they fully recovered. He later treated in a similar way cholera with positive results, which encouraged other researchers to test the therapy. For example, British Lieutenant Colonel John Morison used phage therapy as a prophylaxis for cholera in the Indian region of Naogaon (now Bangladesh). He allegedly administered phages to 530,000 people, which resulted in zero cases of cholera in that region between 1925 and 1935. In contrast, during the same period in the neighbouring region, 1,500 people died of the disease (Summers 1993).

Despite many clinical successes, there were voices in the scientific community that d’Hérelle and his colleagues conducted experiments that did not meet scientific standards and, therefore, did not provide a factual basis for using this form of therapy. Notably, he was accused of lacking controlled conditions and statistical significance in his results. In connection with the above, the scientific community at the time did not accept PT as an effective treatment method and continued to rely on preventive measures, such as improved hygiene and vaccinations (Summers 1993).

In 1930, two American physicians, E. D. Crutchfield and B. F. Stout, conducted a study on 57 patients with staphylococcal wound infections using phage therapy, achieving a success rate of over 90% (Crutchfield and Stout 1930). This result encouraged d’Hérelle to bring his discovery to the market and start mass production. However, over time, it became apparent that the effectiveness of these phage preparations was significantly lower than initially reported in preliminary studies, which discouraged pharmaceutical companies, patients, and scientists alike. The decrease in efficacy was caused by several factors, including poor storage conditions of the preparations, their short shelf life, the use of mercury as a preservative, the failure to inactivate them by gastrointestinal substances, and the implementation of phage therapy to treat viral infections (Ho 2001; Marongiu et al. 2022).

The subsequent introduction of the first antibiotics (penicillin and sulfanilamide), which was then considered a breakthrough in contrast to bacteriophages where each phage affected only one type of bacterium, led to a further decline in the popularity of PT in the West (Marongiu et al. 2022).

During d’Hérelle work at the Institute Pasteur in Paris, he met Georgian bacteriologist Georgiy Eliava. Eliava was fascinated by d’Hérelle’s discoveries, and in 1923, he founded the Institute of Bacteriology in Tbilisi, the capital of Georgia. It received massive support from the authorities of the Soviet Union, who wanted to catch up with the West, also in the field of bacteriology. Unfortunately, in 1937, during the Great Purge, Eliava was declared an enemy of the people and then shot. This fact led the USSR to lose a scientist recognized in the West (Marongiu et al. 2022). Despite this, the Soviets continued to develop and use phage therapy (Summers 2001). The Iron Curtain after World War II hindered the flow of scientific knowledge and strengthened the belief of phages as a communist medicine among Western scientists (Summers 2012).

Further controversy was also caused by d’Herell’s views, which some scientists even described as heresy. He claimed that phages, which naturally exist in the human microbiota, are responsible for the body’s immunity and that phages can spread just like pathogens they are supposed to kill, so one should not pay too much attention to personal hygiene. He argued that contamination with faeces can paradoxically contribute to the improvement of the patient’s condition because, in this way, one receives new portions of phages (Fruciano and Bourne 2007).

In 1946, at St. Mary’s Hospital in London, the same hospital where penicillin was discovered, F. Himmelweit presented the concept of therapy based on the joint administration of phages and penicillin. The assumption was that this would lead to a reduction in the emergence of penicillin-resistant strains. The preliminary results of the research were auspicious, which was probably due to the different effects of penicillin and phages on bacteria. Unfortunately, this principle was not widely accepted in the scientific community (Mac-Neal et al. 1946; Fruciano and Bourne 2007).

It is estimated that in the process of finding new antibiotics, only five of the 5,000 to 10,000 molecules tested make it through to the first stage of testing, but only one of these is approved for use in humans. Given the enormous costs and complexity of developing new antibiotics, as well as the increasing multi-drug resistance of bacteria, the scientific world is seeking alternatives. Today, more than 100 years after d’Herell’s discovery, PT is being rediscovered and increasingly tested; however, scientists agree that it needs to be standardized, and more clinical studies are warranted (Gordillo Altamirano and Barr 2019; Suh et al. 2022).

Phages, as representatives of viruses, are unable to function and replicate outside the host organism. They are the most abundant organisms on Earth, and in addition to bacteria, it has been proven that they can occur inside archaea and even eukaryotes (Lehti et al. 2017; Naureen et al. 2020). The reproductive cycles of bacteria and phages are closely linked; however, each cycle produces between 100 and 200 new phages but only two daughter bacterial cells. This phenomenon suggests that there would be a significant disproportion in the number of bacteria or even their disappearance, but this does not occur. To understand this, it is essential to have a comprehensive understanding of phage biology and its impact on bacteria (Naureen et al. 2020).

Bacteriophages have a complex structure, particularly when compared to simpler viruses, such as those with only a capsid and genetic material. It consists of DNA or RNA, single or double-stranded, enclosed in a protein capsid that occurs in three forms: head with tail, head without tail, and filamentous form (Naureen et al. 2020). Tailed phages (collected in the Caudoviricetes class) are the most common group, previously represented as the families Myoviridae, Siphoviridae, and Podoviridae (Figure 2). However, the predominant feature they exhibited was morphology; presently, the emphasis is on classification based on the genome. Despite this, attention is drawn to the importance of morphological similarities. Hence, the terms myovirus, siphovirus and podovirus remain in use (Turner et al. 2023).

Figure 2.

The diagram illustrates a simplified representation of the structural composition of different types of tailed phages class (Caudoviricetes): 1. Head - a protein structure, often icosahedral in shape, containing the phage’s genetic material (single or double strand of DNA or RNA); 2. Tail - a tubular structure used by the phage to inject its genetic material into the host cell; 3. Tail fibres or spikes - enable the phage to recognize and attach to the appropriate receptors on the surface of the bacterial cell and determine the specificity of the bacteriophage to a particular bacterium; 4. Base plate - anchors the tail fibres and binds them to the surface of the bacterium, enabling the infection to begin. Graphic design was based on Nobrega et al. (2018).

There are four different phage life cycles: lytic, lysogenic, pseudo-lysogenic and chronic. Only lytic phages are currently considered the most suitable for treating humans (Figure 3) (Lin et al. 2017). First, the phage must attach to the bacterial cell wall by recognizing its specific receptor on the bacterial surface. Some phages possess the ability to produce specific enzymes, such as hydrolases, which can degrade the polysaccharide envelope of a bacterium, thereby exposing the appropriate receptors (Wittebole et al. 2014). After attaching to the cell wall, the phage creates a hole in it through which it injects its genetic material into a bacterium while the protein capsid remains outside. In the case of lytic phages, the bacterial ability to reproduce viral proteins and genetic material is exploited downstream. Phage assembly is followed by lysis of the bacterial cell and the release of new viral particles. The amount of viruses released depends on several factors, including the type of virus, the type of bacterium, and environmental conditions (Wittebole et al. 2014; Naureen et al. 2020).

Figure 3.

Diagram illustrating the lytic cycle of a bacteriophage, highlighting its mechanism of bacterial cell destruction – a key process in phage therapy: 1. Attachment; 2. Penetration; 3. Biosynthesis; 4. Replication and maturation; 5. Lysis. Graphic design based on Adesanya et al. (2020).

The specificity of phage therapy predicated on the necessity to administer a particular phage to combat a specific bacterium and the brief duration of phage activity within the body necessitate the development of novel methodologies for phage administration to patients. In addition to oral or intravenous administration, there are also inhalation, implantation of biomaterials, intraperitoneal, intramuscular, subcutaneous, intranasal, endotracheal, rectal, intrauterine, vaginal or transdermal routes of administration (Dąbrowska 2019; Rotman et al. 2020). It had been suspected that phages might be rendered ineffective by the presence of low gastric acid pH, which required their administration in conjunction with acid-neutralizing medications. However, subsequent research has demonstrated that the co-administration of these drugs with phages results in no alteration to their efficacy (Dąbrowska 2019). The oral route of administration is efficacious in treating gastrointestinal diseases (Qadir et al. 2018; Dąbrowska 2019). For instance, a study was conducted on the treatment of Clostridioides difficile infection using phage therapy in an animal model, resulting in a reduction in C. difficile colonization and a delay in the onset of symptoms (Nale et al. 2016). However, the oral route of administration is the least effective for systemic penetration of phages. It is essential to note that increasing the administered dose of phages results in enhanced systemic penetration. A systematic analysis has demonstrated the superiority of parenteral administration, whether intravenous (IV), intramuscular (IM), or intraperitoneal (IP) over oral dosing (Dąbrowska 2019).

Regarding IV administration, Speck and Smithyman, in their work on the safety of intravenous phage therapy, have described the use of highly specific phage cocktails in treating rhinosinusitis caused by Staphylococcus aureus. Furthermore, they discussed a potential application of phage therapy in the management of acute infective endocarditis (Speck and Smithyman 2016). This condition may be caused by bacteraemia following oral surgery (e.g. tooth extraction) in a high-risk patient.

Recent studies on the intramuscular (IM) administration of phages are lacking; however, a significant number of such studies have been documented in the Soviet scientific literature. For instance, in the treatment of typhoid fever, patients were divided into three groups: intramuscular (IM), oral, and combined intramuscular and oral administration. The most unfavourable outcomes were observed for oral administration, while significantly superior outcomes were demonstrated in other groups (Chanishvili 2012).

To date, no studies on IP administration have been conducted in humans. However, animal research demonstrated the efficacy of this route of administration, surpassing the effectiveness of phage inhalation, for instance, in the treatment of pneumonia caused by Burkholderia cenocepacia (Carmody et al. 2010).

Following systemic administration, phages can reach virtually all tissues and organs of the body, including, but not limited to, skeletal muscle, heart, bone marrow, salivary glands, kidneys, and even the brain and bones (Dąbrowska 2019). However, oral administration may be ineffective due to the poor penetration of phages into the circulation, and intravenous administration appears to be significantly more efficacious (Dąbrowska 2019; Vila et al. 2024).

Regarding oral diseases, the most efficacious treatment may be rinsing the affected area with a phage solution or the local application of a slow-releasing hydrogel, which enables the appropriate concentration of phages within the oral cavity.

It is widely accepted that PT is safe and has no severe side effects (Uyttebroek et al. 2022; Kim et al. 2024; Palma and Qi 2024). The safety of phage therapy stems from the specificity of the phage, which can target a particular bacterial cell exclusively. This selectivity distinguishes it from antibiotics, which can affect the host microbiota. The specificity of phage action also means that pathological bacteria acquire phage resistance much less frequently than with antibiotics. While it is acknowledged that phage administration can elicit an immune response, to date, there is no evidence that phages are capable of directly attacking human cells. In the presence of compatible bacterial cells, phages can replicate; otherwise, they tend to self-regulate (Uyttebroek et al. 2022).

A substantial body of scientific research (Uyttebroek et al. 2022; Kim et al. 2024; Palma and Qi 2024) has demonstrated the safety of phage therapy in treating patients. No severe adverse reactions have been reported; however, some authors have noted inadequate standardization of safety studies (Chung et al. 2023). However, it is acknowledged that there exists a risk of toxic shock precipitated by the release of bacterial endotoxins following phage-induced bacterial lysis (de Tejada et al. 2015; Aslam et al. 2019). A 2017 study provides a notable example. It documented the case of a 2-year-old child infected with multidrug-resistant Pseudomonas aeruginosa, complicated by sepsis. The patient exhibited a chronic medical condition characterized by DiGeorge syndrome, a complex congenital heart defect involving an interrupted type B aortic arch, and an allergy to antibiotics, among other co-morbidities. The presence of both allergies and infection with MDR P. aeruginosa led researchers to consider bacteriophage therapy as a potential treatment. The child was administered two bacteriophages, resulting in the resolution of the sepsis. However, this intervention led to an exacerbation of the underlying heart failure, most likely attributable to the release of endotoxins following bacterial degradation (Duplessis et al. 2018).

Despite extensive research conducted over several decades on phage administration and its potential adverse effects, no documented cases of anaphylactic shock have been reported in patients receiving phage therapy (Speck and Smithyman 2016; Doub et al. 2020; Chung et al. 2023).

The safety of PT in children has been well-documented (Howard-Jones et al. 2022). To the best of our knowledge, there are no reports on the safety of phage therapy in pregnancy.

The issue of the absence of appropriate legal regulations is raised in this work and numerous other studies on phages. As stated in the historical introduction, PT was utilized on a broader scale in the Union of Soviet Socialist Republics (USSR) following World War II, with a particular emphasis on Georgia Republic. It was also used in Poland. Following Poland’s accession to the European Union in 2004, this therapy has become more comprehensive and systematic. Nowadays, it is considered an experimental treatment based on the Act on the Professions of Physician and Dentist, the Constitution of the Republic of Poland, as well as EU regulations, such as Directive 2005/28/EC, and the European Medicines Agency. PT is exclusively administered by the Phage Therapy Unit, a constituent of the Hirszfeld Institute of Immunology and Experimental Therapy (Yang et al. 2023).

In contrast, in countries such as Georgia and Russia, the regulatory landscape is significantly different, with phage preparations, including ‘Intestiphage’ and ‘Pyophage’, available for purchase without a prescription. Regarding Georgia, the prescription-only provision for personalized phage medicines is permitted in designated pharmacies. However, these products have not been recognized by Western regulatory authorities (Yang et al. 2023).

Many species of bacteria form a biofilm, a complex environment composed of polysaccharides, proteins, and lipids that are designed to protect the bacteria from external factors. In practical terms, biofilms can effectively block antibiotic access to bacterial cells, making the treatment of infections significantly more challenging (Yuan et al. 2019).

There are numerous reports of bacteriophages’ effectiveness in penetrating the bacterial biofilms of bacteria such as P. aeruginosa or Streptococcus suis. However, these studies indicate the need for further trials and the potential possibility of antibiotic-phage combination therapy (Hanlon et al. 2001; Meng et al. 2011; Yuan et al. 2019).

Bacterial biofilms, which pose a serious clinical challenge due to their ability to block access to antibiotics, are present in many parts of the body, such as the oral cavity (Rath et al. 2021), intestines (Jandl et al. 2024), and the female reproductive tract (Obuobi and Škalko-Basnet, 2024). A mixture of aerobic and anaerobic bacterial strains generally constitutes it. As previously outlined, the capacity of phages to penetrate deeply into biofilms offers a promising prospect for the effective management of the bacteria that form these structures, potentially in conjunction with or as an alternative to antibiotics (Figure 4).

Figure 4.

The biofilm in the oral cavity can lead to oral infections such as dental caries, gingivitis, or periodontal disease, and a carefully selected phage cocktail may have a potential effect on biofilm degradation.

Although phages isolated from the oral cavity have not yet been used clinically, they have shown promising results in vitro. The SMHBZ8 phage is a prime example, as it has been demonstrated to be efficacious in combating both planktonic and biofilm cultures of Streptococcus mutans. This phage has the potential for practical use in future clinical trials (Zhu et al. 2025).

For PT to be considered a complete alternative to antibiotic therapy, it would also need to be used as part of the prevention of bacterial infections. Broad-spectrum antibiotics, such as amoxicillin, are often administered to patients to prevent infection. Preventive action is challenging with phages due to their specificity; however, it is possible to create specific cocktails consisting of multiple different phages that are suitable for the groups of bacteria most likely to cause infections in a given area. The finding that encapsulated phages exhibit prolonged persistence within the human body (Singla et al. 2015; Malik et al. 2017) may provide a rationale for exploring the potential of phages in preventing bacterial infections. However, further research is necessary to test this hypothesis. A promising example of the prophylactic use of phage therapy is the study by Yu-Huai Ho et al., in which phage against A. baumannii carbapenem-resistant (CRAB) was aerosolized in intensive care units. This study demonstrated a reduction in the incidence of CRAB from 8.57 per 1,000 patient days in the hospital to 5.11 per 1,000 patient days (Ho et al. 2016). Another similar study was conducted by Chun-Chieh Tseng et al. in a unit with patients undergoing extracorporeal membrane oxygenation (ECMO). As before, an aerosol was used, this time containing a cocktail of four phages against the bacteria most commonly causing nosocomial infections in ECMO patients: A. baumannii, K. pneumoniae, P. aeruginosa and Stenotrophomonas maltophilia. As a result, no ECMO patient whose environment was decontaminated with phage aerosol became infected with any of the four target bacteria (Tseng et al. 2025).

The utilization of phages for prophylactic purposes in the domains of oral and general surgery is a matter of considerable complexity. The termn ”antibiotic prophylaxis” may refer to the administration of a broad-spectrum antibiotic to a patient at high risk of infective endocarditis prior to a dental procedure, such as tooth extraction. However, it is worth noting that phages require the presence of bacteria to be active and to carry out their life cycles. Consequently, these measures should be administered during or even after the procedure, in which case there is no question of prophylaxis. Advancements in phage encapsulation methodologies have the potential to extend the duration of phage presence in the body and delay clearance, thereby enabling the prophylactic use of phages prior to scheduled surgical interventions (Singla et al. 2015).

Currently, one of the most popular methods of phage therapy (PT) is what can be described as profiled or even personalized PT. It is based on sampling the causative strain and selecting the appropriate phages for clinical administration. This method is most suitable for patients with intractable or recurrent infections caused by antibiotic-resistant bacteria. The following are examples of such use.

A patient with a spinal abscess caused by multi-drug-resistant P. aeruginosa underwent surgery during which the abscess was drained and a personalized cocktail of three bacteriophages, specifically prepared for the procedure, was administered into the abscess cavity along with a bicarbonate solution. At the same time, an antibiotic (cefiderocol) was administered intravenously. The pre-existing back pain disappeared after the operation, but there was diarrhoea associated with C. difficile. For the second surgery, related to the screw-in osteosynthesis implants, phages and antibiotics were again administered. In the months that followed, the patient experienced no pain or adverse effects (Ferry et al. 2022).

Another promising example of the use of personalized phage therapy is that of a 30-year-old female victim of the 2016 Brussels airport terrorist attack. The patient suffered severe injuries, including to her left thigh. The left thigh wound was found to be infected with pan-drug resistant (PDR) K. pneumoniae. Antibiotic treatment was implemented, which led to numerous side effects without eradicating the infection. After exhausting other treatment options, PT was administered 702 days after the accident. Phages were administered locally through a catheter left over from a previous procedure. They were given for 6 days along with a general course of antibiotics. There was a dramatic improvement in the patient’s condition, with the permanent eradication of the K. pneumoniae infection (Eskenazi et al. 2022).

A retrospective observational analysis of 100 cases of personalized PT for difficult-to-treat infections showed that this therapy is most effective when combined with antibiotics. Without co-administration of antibiotics, bacterial eradication by phages alone was 70% less likely to occur. These examples imply that, in some cases, antibiotics and phage therapy can be synergistic (Pirnay et al. 2024).

The potential of PT to treat bacterial infections in any organ or tissue in the body is a promising avenue for further research (Figure 5).

Figure 5.

The diagram indicating the possible areas of PT use: oral cavity (Khalifa et al. 2016; Guo et al. 2024), blood (Górski et al. 2017), bones and joints (Peng et al. 2024), wounds (Jault et al. 2019), gastrointestinal tract (Nale et al. 2016) and respiratory system (Abedon 2015).

In the oral cavity, bacteria pose a significant challenge, given their role in the development of various conditions, including dental caries, pulp inflammation, periodontal disease, abscesses, peri-implantitis, and bone necrosis. This comprehensive list illustrates the diverse array of oral issues that can arise from bacterial infection (Figure 6). Antibiotics are frequently employed in the treatment of these; however, PT has the potential to either complement or replace them.

Figure 6.

Examples of potential applications of PT in dentistry: 1. Osteonecrosis; 2. Necessity of endodontic re-treatment; 3. Periodontal treatment; 4. Periimplantitis.

Bacteria and phages have coexisted for centuries, and we know that bacteria developed mechanisms that allow them to avoid phages. Bacterial defence against phages occurs at several stages of the phage reproductive cycle. These include modification of the bacterial surface to prevent phage adhesion, prevention of phage DNA entry and replication, cleavage of the phage genome, CRISPR-Cas systems, or abortive infection (Abi system), which involves the suicidal death of a bacterium attacked by a phage before its duplication occurs. Comprehension of these mechanisms may play a crucial role in counteracting the acquisition of phage resistance by bacteria (Hampton et al. 2020; Safari et al. 2020; Teklemariam et al. 2023).

However, unlike antibiotics, phages do not remain passive in the face of increasing bacterial resistance; instead, they produce systems that allow them to continue attacking bacteria. They adapt to new receptors on the bacterial surface, create anti-restriction modification systems, produce mutations that bypass CRISPR-Cas, or even create genes that counter the CRISPR-Cas system (Hampton et al. 2020; Safari et al. 2020; Teklemariam et al. 2023).

From a clinical perspective, it is noteworthy that phage administration in the form of a phage cocktail, rather than phage monotherapy, appears to be an effective method for preventing the development of bacterial resistance (Chan et al. 2013).

As demonstrated by the following case report, the combination of antibiotic and phage therapy has been successfully implemented in several instances. The report details the treatment of a patient who, following a motorcycle accident, developed an infection of the tibia caused by multidrug-resistant Acinetobacter baumannii and Klebsiella pneumoniae. In the absence of effective antibiotic treatment, the patient was at risk of losing his limb. However, combined phage and antibiotic therapy resulted in rapid healing and complete eradication of the bacteria from the infected site. No adverse effects of the therapy were observed (Nir-Paz et al. 2019).

Combined antibiotic and phage therapy has been demonstrated to yield significant and interesting results. The available research suggests that combining both forms of therapy increases and/or prolongs the effective action of the antibiotic. It has been hypothesized that phage infection exerts selective pressure on bacteria, causing them to mutate and reduce the expression of factors related to toxicity, antibiotic resistance, and growth inhibition. Consequently, even if a bacterial strain develops resistance to phages, it becomes less toxic and more susceptible to antibiotics (Li et al. 2021; Diallo and Dublanchet 2022).

Further research is needed into this phenomenon. In addition, assigning specific phages to specific antibiotics and developing a sequence for administering them to patients must be undertaken, so that treatment is as effective and safe as possible (Diallo and Dublanchet 2022).

According to the World Health Organization, by 2050, approximately 10 million people worldwide may die annually due to the multidrug-resistant bacterial infections (de Kraker et al. 2016). This predicament underscores the need for the development of novel antibiotics or alternative therapeutic modalities.

Considering the studies presented in this review, it seems probable that PT may become a viable alternative to antibiotic therapy in the future, or at least a support for it.

In principle, its application is feasible in any medical discipline where bacterial infections are a problem, including dentistry, where it can potentially be used in caries prevention, re-endodontic treatment, peri-implantitis, periodontitis or even osteomyelitis.

PT has been demonstrated to have considerable potential; however, numerous challenges must be overcome before it can be implemented on a large scale clinically. These include the necessity for additional clinical trials, long-term observational studies on efficacy and safety, and the establishment of appropriate and uniform regulations, including phage administration regimens similar to those employed for other drugs. It is also necessary to reduce production costs and extend their shelf life.

The renaissance of phage therapy, or its rediscovery, evokes optimism for the future and the ongoing effective combat against bacterial diseases.