Bacteriophages, also known as phages, are viruses that specifically infect bacteria and destroy host cells through lysis after their replication. Because they do not infect human cells, they are a potential therapeutic option for therapeutic use against bacterial infections. Phages were discovered in the early 20th century, and from the 1930s onward, they have been studied and used therapeutically in several countries. Dedicated institutes have been established in Poland, Georgia, and other former Soviet states, some of which are still active today.

With the widespread adoption of antibiotics, interest in phage therapy has declined in Western nations. This has changed with the rise of treatment-resistant bacterial infections, which are now considered major global health threats. Antimicrobial resistance accounts for an estimated 5.8 million deaths annually, both directly and indirectly, and may worsen without effective countermeasures.

Global health authorities, including the World Health Organization and the EU, have prioritized the development of new antibiotics and alternative approaches. This renewed focus has driven a resurgence in phage therapy.

The selection of appropriate phages is critical for their clinical application. Some prophages integrate their genomes into the host cell and enter a lysogenic cycle, meaning that they do not immediately destroy the host. These prophages often carry resistance genes and can alter bacterial pathogenicity, limiting their therapeutic use. In contrast, clinical applications focus on lytic phages, which eliminate host cells through the release of endolysins during the lytic cycle.

The clinical application of phages is constrained by several factors. Evidence supporting the efficacy and safety of phage preparations, including those approved outside the EU, is still limited. In addition, the regulatory frameworks governing their production and clinical use remain underdeveloped.

Phage preparations are classified as biological medicinal products. In Germany, no phage-based therapies have been approved for routine clinical use so far. Therefore, their use is restricted to exceptional cases under compassionate use and only when no effective standard treatment is available for the patient. In these situations, physicians must provide a clear clinical rationale and demonstrate that the patient is likely to benefit from the therapy.

This regulatory approach differs from those of other EU countries. Belgium introduced a pragmatic framework for compounded phage preparations in 2016, enabling tailored treatments under defined conditions. Portugal adopted a similar model in 2024, and several other EU member states have taken steps to improve access to phage therapy. The Belgian framework is increasingly viewed as a potential model for broader EU regulations that could support more consistent and timely access for selected patients.

Phages are not intended to replace antibiotics but to complement them. Their role is to enhance antibacterial activity and, in some cases, help restore antibiotic effectiveness. In clinical practice, phages are administered alongside antibiotics rather than alone. However, key gaps in literature remain unaddressed. Research priorities have not yet been clearly defined, particularly in identifying phages with different therapeutic properties and well-characterized genetic profiles for specific therapeutic uses.

Properties and Development

Bacteriophages are ubiquitous and are present wherever bacterial hosts are present, particularly in natural water sources, wastewater, and the human body. They colonize the gastrointestinal tract, skin, and oral cavity. The collection of phages within specific body niches is referred to as the phageome and has become a topic of interest for several years.

Despite advances in phage biology, the translation of naturally occurring phages into therapeutic agents remains complex. Potentially suitable candidates must be carefully identified, isolated, purified, and characterized, and then produced under controlled conditions. This multistep process is technically demanding and essential for ensuring safety, specificity, and reproducibility in therapeutic applications.

Wastewater is a key reservoir of bacteriophages and is widely used to isolate potential therapeutic candidates. These phages were first screened against specific bacterial strains in laboratory cultures to confirm their activities. If effective, they can be isolated, purified, and processed under controlled conditions for potential clinical use. Genetic modifications can further enhance their activity and may help limit the emergence of bacterial resistance, which develops through mechanisms similar to those seen in antibiotic resistance.

To further improve efficacy, researchers use approaches such as “phage training.” In this approach, phages are adapted to target specific bacteria under controlled conditions. This can occur through coevolution, where both the phage and bacterium evolve together, or through directed evolution, where the bacterium remains unchanged and only the phage adapts to the new environment. Coevolutionary models appear to be more effective because they enable ongoing interactions with resistant bacterial strains and can broaden phage activity across multiple strains of the same species.

In parallel, research has expanded to focus on phage-derived enzymes rather than on whole phages. These agents, known as endolysins or enzymobiotics, rapidly degrade the bacterial cell walls. However, their clinical application remains limited, particularly for gram-negative bacteria, where the outer membrane restricts access to the cell wall. Current research is exploring strategies to improve membrane permeability and enhance the antibacterial activities of these agents.

Specialized biobanks, often referred to as phage banks, support the identification of characterized and potentially therapeutic phages. Databases such as PhageDive enable targeted searches for suitable candidates for phage therapy. PhageDive is a specialized database and research project established by the Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures,a German Collection of Microorganisms and Cell Cultures which maintains a repository of approximately 1000 bacteriophages.

Clinical Application

Phage therapy is gradually being introduced into clinical practice. Phages active against commonly circulating multidrug-resistant pathogens, including Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, are of primary relevance. These organisms are major causes of healthcare-associated infections and pose a substantial risk, particularly to individuals with serious underlying conditions or impaired immune function.

In Germany, antibiotic resistance was reported as the direct cause of 9660 deaths in 2019, with 45,700 deaths associated with resistant infections.

Some of these outcomes may be preventable with combined antibiotic and phage therapies. In recent years, individualized treatment approaches have shown promising results. Specialized centers have been established across several EU countries, including Belgium, France, Portugal, Poland, the Czech Republic, and Slovenia. These centers maintain phage banks, produce therapeutic preparations, and provide expertise for cases in which access remains restricted to nonapproved, case-by-case clinical use when no effective standard therapy is available.

In Germany, phage therapy is currently available only in research settings and clinical trials. One example is the Phage4Cure project, which is developing an inhaled “phage cocktail” targeting P aeruginosa. Phage4Cure is a joint project of the Leibniz Institute DSMZ, Fraunhofer Institute for Toxicology and Experimental Medicine, The Joint Department: Infectious Diseases, Respiratory Medicine and Critical Care Medicine at Charité Universitätsmedizin Berlin, and Charité Research Organization.

To date, clinical experience has been most encouraging in treatment-resistant P aeruginosa lung infections and prosthetic-joint infections. In France, a phase 2 pilot study, PhagoDAIR I, evaluated the efficacy of an injectable phage cocktail targeting S aureus infection. This treatment is administered in combination with the standard surgical approach of debridement, antibiotics, and implant retention in adults with knee and hip prosthesis.

However, robust clinical evidence remains limited. Existing randomized controlled trials have not provided conclusive proof of efficacy, partly because of their methodological limitations.

However, this research gap is beginning to close. A retrospective analysis from Belgium that included 100 personalized treatments across 12 countries between 2008 and 2022 reported clinical improvement in 77% of cases and pathogen eradication in 61% of cases. The probability of eradication was 70% lower when antibiotics were not used in conjunction with phage therapy.

These early findings suggest potential clinical value, although further validation is required. Phages also have properties that support their therapeutic use, including stability across a range of pH levels and temperatures, tolerance to pressure, and suitability for inhaled delivery. Purified preparations are also associated with long shelf lives.

Research networks have been established to advance research in this field. In Germany, the German Center for Infection Research (DZIF) Translational Phage Network is designed to promote the best possible implementation of bacteriophage research, development, and therapy. (DZIF) TransPhage Net supports collaboration and knowledge exchange, and the first guideline for personalized bacteriophage therapy are currently under development.

Although widespread clinical use will take time, phage therapy is expected to expand and complement the available antimicrobial agents.

This story was translated from Univadis Germany, part of the Medscape Professional Network.