What Is a Bacteriophage and What Is Its Clinical Utility in Fighting Infection?

Bacteriophages—viruses that infect and kill bacteria—are gaining attention as a promising adjunct or alternative to antibiotics, particularly in the face of rising multidrug-resistant (MDR) infections. Although the concept was new to me (JRH) until recently, after reading the recent review by Ramchandar and Bradley,1 I recalled a case encountered during a Grand Rounds session at the University of Chicago several years ago.

The patient presented with an Enterobacter abdominal abscess, which was seemingly resistant to every available antibiotic with the possible exception of colistin, leaving our therapeutic options limited and the patient in a difficult situation. At the time, none of us discussed bacteriophage therapy as an option. However, the Ramchander and Bradley1 review prompted me to consider how bacteriophage therapy might have been a possible therapeutic intervention and changed the course of care for this patient.

As Ramchander and Bradley1 note, bacteriophages (or simply “phages”) are highly specific viruses that target individual bacterial pathogens. They can be used alone or in combination with antibiotics. This specificity not only reduces the risk of collateral damage to the microbiome but also offers hope against bacteria that have evolved resistance to multiple classes of antibiotics.1

The biology of phages is compelling. A phage attaches to a specific receptor on a bacterial cell wall via a tail connected to its protein capsid. Inside the capsid is double-stranded DNA. Once attached, the phage injects its genetic material into the bacterial cell. This viral DNA takes over the bacterial cellular machinery, directing the production of new phage particles. Eventually, the bacterium bursts (lyses), releasing new phages to continue the infection cycle. The proteins holins and endolysins play key roles in lysing the bacterial cell from within—holins perforate the inner membrane and endolysins digest the peptidoglycan cell wall.2

As with any biological warfare, the enemy adapts. Bacteria have developed mechanisms to resist phage attack, such as altering receptor sites to prevent phage binding or deploying CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-associated systems to target and destroy foreign DNA.1,2 Nonetheless, the co-evolutionary arms race between phages and bacteria continues, providing researchers with tools to stay one step ahead.

Historically, bacteriophage therapy is not new. The clinical experience with the utilization of bacteriophage therapy began around 1915 after the initial discovery by British scientist Fredrick Twort with confirmation by Felix d'Herelle, a French-Canadian microbiologist, in association with a dysentery outbreak in French troops.1 Notably, d'Herelle and his hospital interns ingested a bacteriophage preparation before it was administered to a young boy with dysentery, who fully recovered.1,3 Despite early promise, phage therapy fell out of favor in the West with the rise of broad-spectrum antibiotics in the mid-20th century.1,3

In recent years, as MDR pathogens have surged, Western researchers and clinicians have revisited phage therapy with renewed urgency. Compassionate use cases have demonstrated its potential, especially in patients with critical illness who have failed conventional therapy. One well-known case involved a patient with cystic fibrosis with Mycobacterium abscessus infection who received engineered bacteriophages; the patient's condition improved significantly following treatment.4

In pediatric populations, literature is still emerging but growing. Over the past 30 years, at least 14 case reports have documented phage therapy in children—often patients who are medically complex with MDR infections who experienced clinical improvement.1 Notably, a randomized controlled trial in adults with chronic Pseudomonas infections associated with otitis media showed preliminary efficacy and safety of a topical phage formulation.5 These cases highlight not only therapeutic promise but also the need for more systematic research.

Technological advances have accelerated the feasibility of phage therapy. Scientists have built extensive “phage libraries”—catalogs of phages matched to specific bacterial strains. With next- generation sequencing and genetic engineering, phages can now be customized to improve their host range, increase lytic activity, or evade bacterial defense mechanisms.1,2

Overall, the review of the biology of bacteriophages and their clinical utility is unique and exciting. No doubt despite this promise, challenges remain given live viral therapies must often be tailored to individual infections. With that, a whole host of issues related to standardization, production quality, and resistance monitoring will require close attention. Nonetheless, the potential benefits—particularly for patients with limited or no antibiotic options—make bacteriophage therapy a frontier worth exploring. And no doubt, this topic is of great interest to pediatricians, especially as we encounter growing numbers of children with medical fragilities, many with indwelling devices or frequent hospitalizations, who have risk factors for MDR infections. Phage therapy may offer an innovative tool in our antimicrobial arsenal.

In summary, Ramchandar and Bradley1 provide a timely overview of the science and clinical relevance of bacteriophages in pediatrics. As our un- derstanding deepens, we hope to see expanded research, refined therapeutic approaches, and thoughtful integration into clinical care. For now, we remain at the beginning of what may become a new chapter in the treatment of infectious diseases, and it is an exciting time for us all to learn about this new therapeutic modality.