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Phage-Antibiotic Combinations: What We Know, What We Don’t, and Where the Field Must Go Next
Phage-Antibiotic Combinations: What We Know, What We Don’t, and Where the Field Must Go Next
Emerging preclinical, compassionate-use, and randomized trial data suggest phage–antibiotic combinations may benefit select patients with multidrug-resistant infections, yet critical gaps in standardization and evidence remain.
Image credit: SIDP
What We Know
Antimicrobial resistance continues to outpace antibiotic development, leaving clinicians with increasingly limited options for multidrug-resistant infections.1-3 In this context, bacteriophages have reemerged as a potential adjunctive therapeutic strategy rather than a replacement for antibiotics. Phage-antibiotic combinations (PACs) have gained attention for their ability to enhance bacterial killing, limit the emergence of resistance, and, in some cases, restore susceptibility to existing antibiotics. At the same time, clinical implementation remains highly variable, and the supporting evidence base is fragmented. This piece focuses on the current state of the field, emphasizing what is known, what remains uncertain, and what is needed to translate biological promise into reproducible clinical impact.
For readers less familiar with clinical phage therapy, PAC use is not analogous to selecting an antibiotic from a standardized formulary. In current practice, phages are most often matched to the patient’s isolate through laboratory screening against available phage libraries, sometimes requiring iterative testing to identify active single phages or combinations. Unlike antibiotics, there are no standardized susceptibility panels, breakpoints, or universally stocked products, and selection workflows differ across centers. Although off-the-shelf phage cocktails are under development and may ultimately simplify access, most clinical PAC use today remains personalized. This individualized matching process requires time for screening, preparation, and regulatory coordination, which inherently limits feasibility in rapidly progressive infections and makes PACs more practical in refractory or chronic infections where treatment can be deliberately planned.
From a biological standpoint, the rationale for PACs is compelling. Preclinical studies have consistently demonstrated phage–antibiotic synergy across multiple organisms and antibiotic classes.4 In some cases, phage pressure appeared to resensitize bacteria to antibiotics to which they had previously been resistant, while in others, phages disrupted biofilms or enhanced antibiotic penetration.5,6 These findings have been replicated across diverse experimental models, suggesting that the interaction between phages and antibiotics is not merely additive, but potentially synergistic.
Clinically, PACs have most often been deployed in compassionate-use settings for patients with refractory, multidrug-resistant infections. Published experiences have frequently involved pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, and Acinetobacter baumannii and infections including pneumonia, osteomyelitis, prosthetic joint infections, and endocarditis.7-9 In parallel, a small but growing number of randomized controlled trials of bacteriophage (phage) therapy have demonstrated overall safety and feasibility in selected populations, though efficacy signals have been variable and highly context dependent.8,10
While these reports are highly heterogeneous, a consistent signal is observed: PACs appear safe, and clinical improvement is often observed following combination therapy in patients who have exhausted standard options. Importantly, these observations support feasibility and potential benefit, but stop short of establishing efficacy.
What We Don’t Know
Despite increasing clinical experience and emerging randomized trial data, major gaps continue to limit the interpretation and broader application of PACs. Clinical PAC data vary widely in phage selection, antibiotic choice, timing of administration, and outcome definitions. There is no consensus on optimal dosing, frequency, or duration of phage therapy, and available data do not support standardized regimens for any specific infection or route of administration.9,10 Although repeated dosing is commonly used to maintain phage concentrations at infection sites, the ideal schedule remains undefined and likely varies by phage product, pathogen burden, and infection location.
Operational and laboratory gaps augment these clinical uncertainties. Phage susceptibility testing (PST), analogous to antibiotic susceptibility testing, is not standardized, and there is no validated correlation between in vitro activity and clinical outcomes.9 Rapid, reproducible methods to screen phage activity, test combinations, or assess impact on biofilms are not widely available, limiting evidence-based selection of phages or cocktails for individual patients.
Endpoints range from microbiologic clearance to subjective clinical improvement, making cross-study comparisons difficult. There is also limited guidance on optimal pairing of phages with specific antibiotics, appropriate sequencing of therapies, or how best to monitor for emerging phage resistance. Without standardized study designs or agreed-upon endpoints, even well-documented successes are challenging to generalize. As a result, it remains difficult to determine when PACs provide benefit beyond optimized antibiotic therapy alone and which patients are most likely to respond.
Where the Field Must Go Next
At present, PACs are best positioned as an adjunctive option for patients with refractory multidrug-resistant infections, particularly in chronic disease settings where prolonged timelines allow for phage selection, manufacturing, and iterative treatment. In contrast, the logistical demands of phage matching and production often limit feasibility in acute, rapidly progressing infections, where immediate empiric therapy is required. The most realistic near-term applications therefore include bone and joint infections, prosthetic and device associated biofilm infections, chronic wound infections, and chronic airway infections such as in patients with cystic fibrosis.9,10 These infections are often characterized by biofilm formation, limited antibiotic penetration, and repeated treatment failure, conditions under which PACs may offer added value.6,9 Their use remains largely confined to specialized centers with established phage access pathways, regulatory experience, and laboratory infrastructure, and should complement rather than replace optimized antimicrobial therapy.
Advancing PACs from promising signals to reproducible clinical tools will require deliberate investment in both evidence generation and infrastructure. Priorities should include prospective, well designed clinical trials, along with standardized clinical, microbiologic, and resistance-related endpoints that enable meaningful cross-study comparison. Parallel efforts are needed to expand shared phage libraries, implement rapid and validated PST, and strengthen regulatory and manufacturing pathways to improve access and turnaround times. Progress will depend on coordinated collaboration among clinicians, microbiologists, translational researchers, and regulators. Without intentional investment in rigor, standardization, and infrastructure, PACs risk remaining anecdotal rather than transformative.
The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org
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I didn't know "bacteriophages" did exist but thanks for this article
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