Phage therapy: an alternative approach to combating bacterial resistanceAbstract
Antimicrobial resistance is considered one of the greatest threats to global public health, being responsible for millions of deaths annually. Bacteria such as Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa have developed resistance to multiple classes of antibiotics, making treatment increasingly difficult. In this context, phage therapy has re-emerged as a promising alternative for the treatment of infections caused by multidrug-resistant bacteria. This study was conducted as a literature review based on articles indexed in PubMed, SciELO, and the National Library of Medicine (NLM) databases, considering publications from 2015 to 2025. Studies addressing the efficacy, advantages, limitations, and clinical applications of bacteriophages against multidrug-resistant bacteria were included. Clinical studies demonstrated favorable response rates of up to 66% and complete eradication in 42% of cases treated with personalized phage therapy. In vivo assays showed survival rates ranging from 80% to 100% in murine models infected with multidrug-resistant Acinetobacter baumannii. Recent studies also highlighted the efficacy of phage therapy in urinary tract infections and bacterial biofilm degradation, with reductions exceeding 90% in microbial viability in experimental models. Furthermore, biotechnological advances involving recombinant phages and the CRISPR-Cas system have expanded the therapeutic potential of phage therapy, particularly against biofilms and immune resistance mechanisms. Phage therapy represents an innovative and highly specific strategy for combating infections caused by multidrug-resistant bacteria due to its selective action and self-replication capacity. However, challenges related to immunogenicity, bacterial resistance to phages, and the lack of standardized regulatory frameworks still limit its large-scale clinical application, highlighting the need for further experimental and clinical studies.
Keywords:
phage therapy; bacteriophage; antimicrobial resistance; multidrug-resistant infection; therapeutic alternatives
Resumo
A resistência antimicrobiana é considerada uma das maiores ameaças à saúde pública global, sendo responsável por milhões de mortes anualmente. Bactérias como Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus e Pseudomonas aeruginosa desenvolveram resistência a múltiplas classes de antibióticos, dificultando cada vez mais o tratamento das infecções. Nesse contexto, a terapia fágica ressurgiu como uma alternativa promissora para o tratamento de infecções causadas por bactérias multirresistentes. Este estudo foi conduzido como uma revisão bibliográfica baseada em artigos indexados nas bases de dados PubMed, SciELO e National Library of Medicine (NLM), considerando publicações entre 2015 e 2025. Foram incluídos estudos que abordassem a eficácia, vantagens, limitações e aplicações clínicas dos bacteriófagos contra bactérias multirresistentes. Estudos clínicos demonstraram taxas de resposta favorável de até 66% e erradicação completa em 42% dos casos tratados com terapia fágica personalizada. Ensaios in vivo apresentaram taxas de sobrevivência entre 80% e 100% em modelos murinos infectados por Acinetobacter baumannii multirresistente. Estudos recentes também destacaram a eficácia da terapia fágica em infecções do trato urinário e na degradação de biofilmes bacterianos, com reduções superiores a 90% da viabilidade microbiana em modelos experimentais. Além disso, avanços biotecnológicos envolvendo fagos recombinantes e o sistema CRISPR-Cas ampliaram o potencial terapêutico da terapia fágica, especialmente contra biofilmes e mecanismos de resistência imunológica. A terapia fágica representa uma estratégia inovadora e altamente específica para o combate às infecções causadas por bactérias multirresistentes devido à sua ação seletiva e capacidade de autorreplicação. Entretanto, desafios relacionados à imunogenicidade, à resistência bacteriana aos fagos e à ausência de regulamentações padronizadas ainda limitam sua aplicação clínica em larga escala, evidenciando a necessidade de mais estudos experimentais e clínicos.
Palavras-chave:
terapia fágica; bacteriófagos; resistência antimicrobiana; infecções multirresistentes; alternativas terapêuticas
1. Introduction
Bacterial resistance represents one of the greatest threats to global public health, accounting for approximately 1.27 million deaths annually as a direct cause, and contributing to nearly 4.95 million deaths related to multidrug-resistant bacterial infections. This phenomenon is primarily driven by the inappropriate and excessive use of antibiotics in both clinical practice and agriculture, which promotes the selection of resistant strains and limits the efficacy of conventional therapies (Antimicrobial Resistance Collaborators, 2022).
Bacteria such as Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa have demonstrated resistance to multiple drug classes, including third-generation cephalosporins, fluoroquinolones, carbapenems, and methicillin (Silva and Aquino, 2018). This severely limits therapeutic options, making the search for more effective alternatives an urgent priority.
Beyond classical mechanisms of bacterial resistance, biofilms play a crucial role in antimicrobial recalcitrance. Biofilms are microbial communities adhered to surfaces and embedded within an extracellular matrix composed of polysaccharides, proteins, and extracellular DNA (eDNA). These structures significantly hinder antibiotic activity, rendering biofilm-associated bacteria up to 1,000 times more resistant than planktonic cells (Hall and Mah, 2017).
In light of the global antimicrobial resistance crisis, phage therapy has re-emerged as a promising alternative. This therapeutic approach employs bacteriophages—viruses capable of infecting and lysing specific bacteria—with high selectivity and the potential to preserve the host’s beneficial microbiota. Although bacteriophages were discovered in the early 20th century, their clinical use was overshadowed by the advent and widespread adoption of antibiotics, particularly in Western medicine. However, the increasing incidence of infections caused by multidrug-resistant pathogens has renewed scientific interest in this therapeutic strategy (Viertel et al., 2014).
2. Fundamentals of Phage Therapy
Phage therapy is a therapeutic approach that employs bacteriophages - viruses that infect and destroy bacteria - as an alternative or adjunct to conventional antibiotic therapy. Bacteriophages exhibit high host specificity, allowing for targeted action while minimizing collateral damage to the host’s microbiota (Viertel et al., 2014).
Phages bind to bacteria through specific receptors located on the bacterial cell wall, such as lipopolysaccharides (LPS), teichoic acids, proteins, or flagella, and subsequently inject their genetic material into the host cell. They then exploit the bacterial machinery for replication, culminating in bacterial lysis and the release of progeny phages (Kutter et al., 2015). Regarding phage inactivation within the host, animal models studies have shown that both the liver and spleen efficiently accumulate phage particles; however, the liver plays the primary role in their rapid inactivation, primarily through the activity of Kupffer cells (Dabrowska, 2019).
Bacteriophages may exhibit two main replication cycles: the lytic cycle and the lysogenic cycle. In the lytic cycle, phages infect bacterial cells, rapidly replicate, and induce host cell lysis, releasing newly formed viral particles into the environment. In contrast, lysogenic phages integrate their genetic material into the bacterial genome as prophages, remaining dormant for variable periods without immediately destroying the host cell. Due to the risk of horizontal gene transfer and the potential dissemination of virulence or antimicrobial resistance genes, lysogenic phages are generally considered unsuitable for therapeutic applications. Therefore, strictly lytic phages are preferred in phage therapy because of their predictable bactericidal activity and improved biosafety (Hatfull et al., 2022; Kutter et al., 2015) (Figure 1).
Schematic representation of the lytic cycle of bacteriophages and biofilm degradation mechanisms. Created with artificial intelligence assistance.
This specificity, combined with the self-amplifying nature of phages at the infection site, makes phage therapy a promising option against infections caused by multidrug-resistant bacteria - an increasingly prevalent and concerning scenario in modern clinical practice (Abedon et al., 2011).
2.1. Regulation of phage therapy
Despite the resurgence of phage therapy as a response to the growing antimicrobial resistance crisis, current regulatory frameworks remain one of the main obstacles to its widespread clinical implementation. Unlike conventional antibiotics, phage-based therapeutic products (Phage Therapy Medicinal Products – PTMPs) are often personalized, variable in composition, and developed on demand for specific infections. This makes them incompatible with traditional regulatory models designed for standardized, mass-produced pharmaceuticals (Fauconnier, 2019).
In the United States, the Food and Drug Administration (FDA) classifies phages as biological products. Currently, their therapeutic use is permitted only under expanded access programs, such as the Emergency Investigational New Drug (eIND), which authorizes compassionate use in severe, treatment-refractory cases. Although several clinical trials investigating phage-based products are ongoing, no phage-derived drug has yet received formal approval for commercial use (Yang et al., 2023).
Within the European Union, the European Medicines Agency (EMA) maintains a more conservative stance. While acknowledging the therapeutic potential of phages, the agency mandates that they follow the same regulatory standards as conventional drugs, including extensive clinical trials and compliance with Good Manufacturing Practices (GMP). This presents a significant challenge, particularly for personalized and hospital-prepared formulations. However, countries such as Belgium have partially overcome these barriers by adopting a magistral preparation model, with standardized quality testing and nationally recognized monographs (Fauconnier, 2019).
In Brazil The National Health Surveillance Agency (ANVISA) has yet to establish specific regulations for phage therapy. Although regulations exist for “Advanced Therapy Products” (RDC No. 505/2021) and for “microorganism cultures,” the therapeutic use of bacteriophages demands more focused discussion (Brasil, 2021). Nonetheless, the growing global threat of antimicrobial resistance highlights the need to advance regulatory efforts, enabling broader access to and research on this promising therapeutic alternative within the Brazilian context (Armanhi et al., 2023). Resolution RDC No. 505/2021 established regulatory guidelines for Advanced Therapy Medicinal Products in Brazil, including requirements related to manufacturing, quality control, clinical investigation, and traceability (Brasil, 2021). Although bacteriophages are not explicitly regulated within this framework, the resolution represents an important regulatory milestone that may support future discussions regarding individualized biological therapies, such as phage therapy. Nevertheless, significant challenges remain, including the lack of specific protocols for phage characterization, validation, large-scale production, and compassionate clinical use within the Brazilian healthcare system. Consequently, advances in national regulation will be essential to enable the safe clinical application of bacteriophages and to promote research and technological development involving phage therapy in Brazil (Armanhi et al., 2023).
The aim of this study was to gather and analyze the available experimental evidence regarding the efficacy of phage therapy in combating multidrug-resistant bacteria, as well as to evaluate the main advantages and limitations associated with the use of bacteriophages in the treatment of bacterial infections.
3. Materials and Methods
This study was conducted as a literature review aimed at gathering and analyzing the available experimental evidence regarding the efficacy of phage therapy in combating multidrug-resistant bacteria. The search for articles was carried out in national and international databases, including PubMed, SciELO, and the National Library of Medicine (NLM), considering publications published between 2015 and 2025 in order to include the most recent and relevant studies on the topic.
For article selection, descriptors in both Portuguese and English were used, such as “terapia fágica” or “phage therapy,” “bacteriófagos” or “bacteriophages,” “resistência antimicrobiana” or “antimicrobial resistance,” and “infecções multirresistentes” or “multidrug-resistant infections,” combined with Boolean operators (AND/OR) to refine the search. Original articles, in vivo or in vitro experimental studies, and case reports, as well as studies addressing the advantages and disadvantages of bacteriophage use in the treatment of bacterial infections, published in Portuguese or English and with full-text access freely available, were included. Duplicate studies, publications not directly related to phage therapy, articles published in languages other than those defined, and abstracts without full-text access were excluded.
The search conducted in the SciELO, PubMed, and National Library of Medicine databases resulted in 213 articles screened by title. Since they did not meet the inclusion and exclusion criteria, 71 articles were excluded, and 142 were evaluated based on their abstracts. After careful assessment, 10 articles were selected to compose the final sample of this review (the remaining studies were excluded for being duplicates or for not presenting experimental data or information regarding advantages and limitations), including 6 experimental studies on phage therapy and 4 articles addressing its advantages and limitations.
4. Results
4.1. Experimental studies on phage therapy
Phage therapy has demonstrated promising outcomes in multiple clinical reports and experimental studies, particularly in the treatment of infections caused by multidrug-resistant bacteria, including patient recovery from systemic infections following phage administration, as well as in vivo and in vitro experimental evidence supporting its therapeutic efficacy.
A remarkable example is presented in the study by Sawa et al. (2024), which reports several cases where phage therapy was successfully applied in severe or systemic infections: (1) a patient with a systemic infection caused by multidrug-resistant Acinetobacter who recovered after systemic phage administration; (2) a case of pan-resistant Pseudomonas aeruginosa successfully treated with phages; (3) a pediatric patient with extensively drug-resistant P. aeruginosa infection following liver transplantation, treated for approximately 86 days with combined phage and antibiotic therapy, achieving full recovery without significant adverse effects; and (4) a patient with persistent Klebsiella pneumoniae infection who, after two years of unsuccessful antibiotic therapy, received intravenous phage treatment and achieved complete recovery after only six days, with no adverse events or recurrence (Sawa et al., 2024).
In another study, Green et al. (2023) evaluated 12 cases of severe, treatment-refractory infections treated with personalized phages under the TAILΦR program at the Baylor College of Medicine. The study reported a 66% favourable clinical response (8 out of 12 cases), with complete bacterial eradication in 42% (5 out of 12) of patients. Importantly, no significant adverse events were observed, although some patients exhibited immune neutralization of the administered phages (Green et al., 2023).
Morgan et al. (2025) discussed the use of phage therapy in urinary tract infections (UTIs) - one of the most common bacterial conditions worldwide, associated with high recurrence and antibiotic resistance rates. The authors emphasized that lytic phages, due to their specificity and ability to degrade biofilms, can serve as alternatives or adjuvants, even enhancing bacterial susceptibility to certain antimicrobials. Although clinical literature remains limited, several case reports have demonstrated promising outcomes, such as successful clinical recovery in patients with recurrent UTIs caused by multidrug-resistant Escherichia coli and Klebsiella pneumoniae following phage cocktail treatment. Clinical trials, on the other hand, have confirmed the safety of phage therapy but reported variable efficacy, partly due to the lack of standardized phage selection and application protocols.
As previously discussed, bacterial biofilms (e.g., those formed by Pseudomonas aeruginosa, E. coli, and Staphylococcus aureus) exhibit extreme resistance to antibiotics, hindering the treatment of chronic infections. In a pioneering study employing genetically engineered phages and phage-derived enzymes, researchers observed more than 90% reduction in bacterial viability within E. coli and P. aeruginosa biofilms. Additionally, phage infection prevented biofilm reformation through extracellular matrix degradation and enhanced the efficacy of combined antibiotic therapy (Pires et al., 2016) (Figure 1).
LaVergne et al. (2018) reported a compassionate-use case involving a 77-year-old patient with a severe Acinetobacter baumannii infection at a craniectomy site. The bacterial isolate exhibited resistance to nearly all tested antibiotics, including carbapenems, aminoglycosides, and fluoroquinolones, remaining susceptible only to colistin. After therapeutic failure with colistin, rifampicin, and azithromycin, the U.S. Food and Drug Administration (FDA) authorized experimental phage therapy. Of 104 phages tested, five displayed lytic activity, and one was selected for treatment. The purified, endotoxin-free phage was administered intravenously at 2.14 × 107 PFU/mL every two hours for eight consecutive days (98 total doses). No relevant adverse effects were observed, and the patient exhibited marked local wound improvement with reduced exudate and partial healing. Although the patient ultimately died due to critical illness, the study demonstrated the safety, feasibility, and tolerability of intravenous phage administration, representing a significant advancement in the clinical use of phages for hospital-acquired infections caused by pan-resistant strains.
Complementarily, the experimental study by Leshkasheli et al. (2019) assessed the in vivo efficacy of two novel lytic phages of the Myoviridae family - vB_AbaM_3054 and vB_AbaM_3090 - isolated from environmental samples and active against extensively drug-resistant A. baumannii (XDRAB) clinical isolates. Both phages exhibited 89-95% lytic activity, absence of virulence or resistance genes, and high adsorption capacity. In vitro assays demonstrated complete lysis at various multiplicities of infection (MOI), with optimal results at MOI 100 and synergistic effects when the two phages were combined. In Galleria mellonella larvae, phage treatment resulted in 100% survival after 80 hours, compared to complete mortality in controls within 48 hours. In a murine bacteremia model, phage administration two hours post-infection ensured 80-100% animal survival, while the imipenem-treated group showed only 17% survival. Although based on experimental models, these findings highlight the high potential of phages to reduce mortality and control systemic infections caused by multidrug-resistant A. baumannii, demonstrating superior performance compared with conventional antibiotics.
For didactic purposes, the experimental studies described in the previous section were categorized according to bacterial species. The evidence indicates promising outcomes in the use of bacteriophages against pathogens such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus—all frequently associated with healthcare-related infections that are difficult to manage.
Clinical reports even document complete resolution of persistent infections following prolonged therapeutic failure with antibiotics (Sawa et al., 2024; Green et al., 2023; Morgan et al., 2025; Pires et al., 2016; LaVergne et al., 2018; Leshkasheli et al., 2019) (Table 1).
4.2. Advantages and limitations of phage therapy as a therapeutic alternative
The reviewed literature highlights several important advantages associated with phage therapy. One of the main benefits is the high specificity of bacteriophages, which selectively target pathogenic bacteria while preserving the host microbiota, unlike broad-spectrum antibiotics. In addition, phages are capable of self-replicating at the site of infection, potentially reducing the need for repeated dosing. Another major advantage involves their activity against bacterial biofilms, as phages and phage-derived enzymes are able to degrade components of the extracellular matrix and enhance bacterial eradication even in chronic infections. Recent studies have also emphasized the potential synergistic effects between phages and antibiotics, particularly in multidrug-resistant infections and biofilm-associated diseases (Morgan et al., 2025; Pires et al., 2016).
However, significant limitations still hinder the widespread clinical application of phage therapy. One of the main challenges is the emergence of bacterial resistance to phages through receptor mutations, restriction-modification systems, and CRISPR-Cas immune mechanisms. Furthermore, immunological neutralization of phages may reduce therapeutic efficacy in some patients following repeated administrations. Regulatory barriers also remain substantial, especially because personalized phage preparations do not fit within the conventional pharmaceutical approval models adopted by agencies such as the FDA, EMA, and ANVISA. Moreover, the lack of standardized protocols related to phage selection, purification, dosing, and administration compromises the reproducibility and large-scale implementation of phage therapy in clinical practice (Fauconnier, 2019; Hatfull et al., 2022; Sawa et al., 2024).
5. Discussion
The findings of the present review reinforce that phage therapy represents a promising alternative in the fight against bacterial resistance, particularly in infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. The analyzed literature demonstrates that bacteriophages exhibit high specificity, self-replication capability at the site of infection, and proven efficacy in clinically challenging cases. These observations are consistent with the studies of Viertel et al. (2014) and Kutter et al. (2015), which had already emphasized the therapeutic potential of phages in clinical contexts, highlighting their safety, selectivity, and the importance of their reintroduction into modern medicine.
Recent trials, such as the TAILΦR program developed in the United States, have reported remarkable therapeutic success rates, with 66% of patients showing favorable responses and 42% achieving complete eradication of severe infections treated with personalized phage formulations (Green et al., 2023). These outcomes demonstrate the efficacy and safety of this approach, although variability among bacterial strains and immunological neutralization still pose significant challenges (Sawa et al., 2024). In parallel, biotechnological advances such as the application of the CRISPR-Cas system and the engineering of recombinant phages have expanded the therapeutic spectrum, enabling the development of more targeted therapies that are resistant to immune responses and more efficient in eradicating bacterial biofilms (Pires et al., 2016; Citorik et al., 2014; Kilcher and Loessner, 2019). Thus, the integration between biotechnology and phage therapy emerges as one of the most promising strategies for combating multidrug-resistant infections.
Despite the promising therapeutic potential of bacteriophages, bacterial resistance to phages remains a major challenge for their large-scale clinical application. Bacteria may develop resistance through different mechanisms, including mutations or loss of phage receptors on the bacterial surface, production of extracellular matrix components that impair phage adsorption, restriction-modification systems, and CRISPR-Cas-mediated immune responses capable of degrading viral nucleic acids (Hatfull et al., 2022). Nevertheless, several strategies have been proposed to minimize this limitation, such as the use of phage cocktails containing multiple viral strains, sequential phage administration, and genetic engineering approaches designed to broaden the host range and overcome bacterial defense systems. In addition, the combination of phages and antibiotics has demonstrated synergistic effects capable of reducing the emergence of resistant bacterial populations.
The combination of bacteriophages and antibiotics has emerged as a promising strategy against multidrug-resistant infections. Phage-mediated biofilm degradation may enhance antibiotic penetration into the deeper layers of the biofilm, thereby increasing bacterial susceptibility to antimicrobial agents. Furthermore, phage infection can alter bacterial physiology and cell membrane permeability, potentiating antibiotic activity. Some studies also suggest that bacteria that develop resistance to phages may exhibit reduced fitness or restored susceptibility to certain antibiotics, further supporting the therapeutic potential of combined approaches (Pires et al., 2016; Morgan et al., 2025).
The literature consistently indicates that bacterial resistance remains one of the greatest challenges to public health, driving the search for innovative therapeutic alternatives such as bacteriophage use. Although the study by Silva and Aquino (2018) was not included in the results because it is a literature review, its content is relevant to the present discussion, compiling in vitro and in vivo evidence on novel antimicrobial approaches with therapeutic potential against E. coli, K. pneumoniae, P. aeruginosa, and S. aureus—pathogens frequently targeted by phage therapy. The authors emphasize that, despite substantial progress achieved in preclinical research and isolated clinical reports, methodological limitations persist and controlled clinical trials are still needed. This reinforces the importance of expanding studies aimed at the safe and effective use of biological alternatives to combat resistant infections.
Araújo Neto et al. (2023) addressed the topic from an epidemiological and social perspective, emphasizing that the indiscriminate use of antibiotics and self-medication remain determining factors for the rise of multidrug-resistant strains. Their analysis complements this discussion by demonstrating that the problem of bacterial resistance extends beyond laboratory development, encompassing behavioural factors and public health policy issues. Both studies strengthen the critical scenario that motivates the exploration of alternative therapies such as phage therapy, which stands out as a promising and highly specific strategy against multidrug-resistant bacteria, particularly in light of the growing ineffectiveness of conventional antibiotics.
6. Conclusion
In conclusion, the present review demonstrated that phage therapy represents a promising and innovative alternative for the treatment of infections caused by multidrug-resistant bacteria. The experimental and clinical evidence analyzed revealed favourable therapeutic outcomes against important pathogens such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus, including cases of severe and persistent infections refractory to conventional antibiotic therapy. In vivo and in vitro studies highlighted high survival rates, significant bacterial eradication, biofilm degradation capacity, and satisfactory safety profiles associated with phage administration. Furthermore, advances involving genetically engineered phages and personalized phage cocktails have expanded the therapeutic potential of bacteriophages, especially against biofilm-associated and extensively drug-resistant infections.
Despite these promising findings, important limitations still hinder the large-scale implementation of phage therapy in clinical practice. The lack of standardized protocols for phage selection, purification, dosage, and administration, as well as regulatory barriers and the possibility of bacterial or immunological resistance to phages, remain significant challenges. Therefore, future studies should focus on large-scale randomized clinical trials, development of international regulatory guidelines, and optimization of biotechnological approaches aimed at improving the efficacy, safety, and reproducibility of phage-based treatments. Collectively, the evidence reviewed supports the potential of phage therapy as an important complementary or alternative strategy in the global fight against antimicrobial resistance.
Data Availability Statement
Research data is available in the body of the article.
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