The first case of phage therapy for biliary tract infection caused by superbugs!

Biliary tract infection (BTI) is a disease with high morbidity and mortality, often associated with structural abnormalities such as common bile duct stones and malignant tumors. Although Pseudomonas aeruginosa is not the primary pathogen of BTI, its significant heteroresistance and strong biofilm-forming ability often lead to refractory and chronic infections, posing significant challenges to clinical treatment. In recent years, lytic phages have shown significant potential in combating drug-resistant bacterial infections. In China, the field of phage therapy is developing rapidly, currently focusing on personalized treatment, but its application in biliary tract infections remains limited.

Recently, a collaborative study by Professor Hu Bijie's team from Zhongshan Hospital, Fudan University, and Associate Professor Le Shuai's team from Army Medical University was published in hLife, titled "Personalized Bacteriophage Therapy for Chronic Biliary Tract Pseudomonas aeruginosa Infections." This study reports the first clinical application case of personalized phage therapy for biliary tract infection.

The study details the treatment of an 88-year-old female patient with recurrent biliary tract infections since 2019. Despite multiple anti-infective treatments and percutaneous transhepatic cholangial drainage (PTCD), her condition did not improve. In 2022, a bile culture revealed a multidrug-resistant Pseudomonas aeruginosa infection. After informed consent, phage therapy was initiated, successfully alleviating her condition. This study provides a new approach to biliary tract infection treatment, demonstrating the potential of phage therapy to combat drug-resistant infections, offering hope to more patients with refractory infections.

The research team screened four phages (φPA-A60, φPA-A69, φPA-A70, and φPA-A78) from a phage library that exhibited high lytic activity against the patient's Pseudomonas aeruginosa. A GMP-compliant phage cocktail was prepared and administered directly into the patient's biliary system via PTCD catheters, once daily for nine days. Initially, the patient's symptoms improved significantly, with bile color returning to normal and inflammatory markers (such as C-reactive protein and procalcitonin) levels dropping markedly. However, during treatment, phage-resistant strains emerged that were resistant to all dsDNA phages in the library. Genomic analysis revealed that these resistant strains had mutations in lipopolysaccharide (LPS) biosynthesis genes, leading to loss of O-antigen and resistance to phage infection. This indicated that the first round of phage therapy effectively cleared the dominant pathogen, but the emergence of resistant strains led to persistent infection.

In response to the resistant strains, the team used the dsRNA phage phiYY for a second round of treatment. PhiYY can infect O-antigen-deficient mutants and had previously shown good results in treating lung infections. After six days of treatment, the patient's clinical symptoms further improved, and although Pseudomonas aeruginosa was not completely eradicated, the bacterial load was significantly decreased.

The team conducted whole-genome sequencing of Pseudomonas aeruginosa strains before and after treatment, revealing the evolutionary process of the bacteria under phage pressure. After the first round of treatment, resistant strains lost O-antigen through gene mutations and large chromosomal deletions, evading phage infection. In the second round, although phiYY was effective against O-antigen-deficient strains, the infection was not completely cleared. Sequencing analysis of the persistent Pseudomonas aeruginosa strains revealed different mutations leading to O-antigen loss in different strains, suggesting that bacterial heterogeneity and biofilm formation may be reasons for the difficulty in completely eradicating the infection.

This study is the first to confirm the safety and efficacy of phage therapy in biliary tract infections, providing a new approach to treatment. Although completely eradicating the infection remains challenging, phage therapy has shown significant effects in alleviating symptoms and reducing bacterial load. In the future, the research team will further optimize phage therapy strategies to address the challenges posed by bacterial resistance, heterogeneity, and biofilms.