The clinical problem is especially consequential in intensive care, neonatal units and patients who are immunocompromised, hospitalized for prolonged periods or undergoing invasive procedures. S. marcescens is associated with ventilator-associated pneumonia, catheter-related bloodstream infections, complicated urinary tract infections, postoperative wound infections and empyema. Genomic surveillance across 35 countries has identified 12 phylogenetic lineages, with Sm5, Sm6 and Sm7 showing strong associations with human infection and enrichment for high-risk antimicrobial-resistance genes. The organism’s chromosomal ampC gene contributes to intrinsic resistance to several early-generation beta-lactams, although clinically significant AmpC overexpression is uncommon, reported in fewer than approximately 5% of isolates in the evidence summarized by the review. Mobile elements carrying carbapenemase and extended-spectrum beta-lactamase genes have nevertheless reduced the value of many standard beta-lactams, including carbapenems.

The resulting treatment gap has encouraged renewed interest in phages, viruses that infect and lyse bacteria. Their narrow host specificity can distinguish a clinical isolate from much of the surrounding microbiota, while replication at an infection site may increase local exposure. Some anti-Serratia phages also encode depolymerases that degrade capsular or extracellular polymeric material, potentially exposing bacterial receptors and improving access to cells embedded in biofilms. These properties are attractive in principle, but they are not interchangeable with demonstrated human benefit. A retrospective analysis of 242 infected patients reported 28-day all-cause mortality of 50.0% in those with multidrug-resistant isolates, yet the review found insufficient clinical data from which to calculate response rates, comparative efficacy, optimal dosing or reliable treatment durations for phage therapy.

Phage activity begins with recognition of a specific bacterial receptor. In S. marcescens, lipopolysaccharide and its O-antigen are experimentally established receptors for several phages, including kappa, FSB3, FSB55 and phiIF3. Biochemical work with phage kappa identified LPS as its primary receptor, while mutants defective in the LPS O-side chain became resistant to several LPS-dependent phages. In strain Db11, disruption of an O-antigen transporter impaired both productive infection and adsorption by phiIF3; only two of 25 additional Db11 phages retained the ability to infect that mutant. The flagellum provides a mechanistically different route of entry. Deletion of fliC, which encodes flagellin, made S. marcescens ATCC 274 resistant to the flagellotropic phage chi. These observations explain why a phage active against one isolate may fail against another: strain-specific O-antigens, capsule phenotypes and flagellar expression can change receptor availability.

Resistance to phages can also arise after adsorption. S. marcescens strains carry diverse restriction–modification systems, CRISPR–Cas arrays, cyclic-oligonucleotide-based antiphage signaling systems and abortive-infection-associated defenses, although none is present or functionally equivalent in every isolate. A type II restriction–modification system known as SmaI has been characterized, while genomic surveys have found lineage-dependent differences in the wider restriction–modification repertoire. CRISPR systems have been detected in only a subset of strains, and some spacers resemble sequences from Serratia phages, indicating historical interaction without proving current antiviral activity. An S. marcescens CBASS system uses a sequential “cGASylation” mechanism to activate a cyclic antiviral signal and a cell-death-associated response. Abortive infection can also halt phage propagation at the expense of the infected cell. Because the bacterial defense repertoire varies by strain and phages may evolve countermeasures, the genomic presence of a defense locus alone cannot predict susceptibility to a particular therapeutic phage.

Preclinical development is less mature for S. marcescens than for several other multidrug-resistant Gram-negative pathogens. Most studies concern individual phages or small isolate panels, and relatively few evaluate mature biofilms, representative clinical collections, animal infection models or clinically relevant phage–antibiotic combinations. Candidate viruses are typically enriched from sewage, soil, hospital wastewater or clinical material, plaque-purified and characterized phenotypically. Clearing in a spot assay does not prove productive infection, so apparent activity must be confirmed through plaque formation, efficiency-of-plating measurements, viable-count endpoints and evidence of progeny production. Host-range panels should represent contemporary clinical diversity in resistance profile, lineage, O-antigen, capsule, biofilm behavior, infection source, geography and time; the review notes that no international guideline establishes a universal minimum number of isolates. Complete genome sequencing is required to exclude lysogeny, toxin, virulence, antimicrobial-resistance and other undesirable determinants, alongside functional confirmation of a strictly lytic lifecycle.

Biofilm-associated activity is a distinctive target for further testing. The podovirus UFV01, isolated using a clinical S. marcescens strain, carries a tail-fiber-associated depolymerase that degraded extracellular polymeric material and reduced preformed Escherichia coli biofilms without productively infecting the cells. This “bystander” effect demonstrates matrix degradation rather than phage-mediated killing, and it does not establish therapeutic efficacy. A phage such as WSPA, recovered with a multidrug-resistant clinical isolate as enrichment host, showed lytic activity against a panel of contemporary multidrug-resistant strains and no identified virulence or resistance genes, but its tested panel was limited and it had no in vivo or clinical validation. Depolymerase activity, plaque morphology and broad host range are therefore useful screening features, but they cannot substitute for testing under physiological conditions and in infection models.

Direct human evidence remains exceptionally sparse. The review identified a 2025 case report of a 59-year-old patient with persistent postoperative pneumonia and empyema after lung-cancer resection. Pleural fluid remained culture-positive for an extensively drug-resistant S. marcescens strain after 120 days of unsuccessful antibiotic treatment. The strictly lytic phage Spe5P4 was delivered intrapleurally and by nebulization at a reported concentration of 10⁹ PFU/mL, together with meropenem and amikacin, drainage and supportive care. The patient’s dyspnea and chest pain resolved within 72 hours, oxygen saturation normalized, pleural fluid measurements declined and imaging showed lung re-expansion with near-complete resolution of effusion by day 140. No phage-related adverse events were reported, and post-treatment isolates showed reduced fluoroquinolone resistance. However, the uncontrolled single-case design and concurrent antibiotics, drainage and supportive care prevent attribution of improvement to Spe5P4 alone; the report establishes preliminary feasibility in one patient, not efficacy.

Organism-specific preclinical findings are stronger than the clinical record but remain narrow. In a lethal BALB/c mouse model of S. marcescens infection, immediate administration of phage phiSM9-3Y produced 100% survival, while a 60-minute delay reduced protection to approximately 60% even with a higher phage dose. In a Galleria mellonella model infected with the clinical bloodstream isolate UMH9, a single 10⁷-PFU dose of Sm10b_1 increased six-day survival from 0% to 67% relative to untreated larvae. These models demonstrate in vivo antibacterial activity against S. marcescens, but neither reproduces the full immune, anatomical, physiological and comorbidity complexity of human infection. Phage–antibiotic combinations also cannot be assumed to be synergistic. Some antibiotics can inhibit phage replication by suppressing bacterial metabolism, whereas other combinations enhance killing or biofilm disruption. Each phage, isolate, antibiotic, concentration and treatment sequence therefore requires direct testing, with both bacterial killing and viable phage titers measured.

Translation is additionally constrained by variable pharmacokinetics, bacterial resistance, immune neutralization, manufacturing and regulation. Administered PFU does not reliably predict the active concentration at an infection site because distribution, adsorption, in situ amplification, local clearance and bacterial susceptibility all affect exposure. Local delivery may concentrate phages in pleural or pulmonary compartments, whereas systemic administration can expose them to sequestration and neutralizing immune responses; the clinical significance of anti-phage antibodies remains uncertain. Personalized preparations also require consistent identity, titer, purity, sterility, endotoxin control, potency and storage stability, while cocktails require assessment of component balance, stability and interference. The review’s priorities are standardized isolate-specific susceptibility testing, receptor-informed and diverse phage libraries, quantitative cocktail design, pathogen-specific pharmacokinetic and pharmacodynamic studies, serial monitoring of bacteria and phages, and prospective controlled trials with antibiotic-only and combination comparators. Until those steps are completed, the evidence supports biological plausibility and limited proof of concept, but not reproducible efficacy or generalizable clinical feasibility for multidrug-resistant S. marcescens infections.

Subject of Research: Evaluation of bacteriophage therapy for multidrug-resistant Serratia marcescens infections

Article Title: Phage therapy for multidrug-resistant Serratia marcescens infection: mechanisms, preclinical evidence, and translational challenges

Article References: Zhang, S., Tao, H., Zhao, S., & Wei, Y. (2026). Phage therapy for multidrug-resistant Serratia marcescens infection: mechanisms, preclinical evidence, and translational challenges. Frontiers in Microbiology, 17, Article 1959850. https://doi.org/10.3389/fmicb.2026.1959850

Image Credits: AI Generated

DOI: 10.3389/fmicb.2026.1959850

Keywords: bacteriophage therapy, Serratia marcescens, multidrug resistance, carbapenem resistance, biofilms, phage receptors, phage-antibiotic synergy, clinical evidence, antiphage defenses, translational research, Phage, therapy

Bacteriophages, the viruses that infect and kill bacteria, were first explored as therapeutic agents in the early twentieth century, shortly after their discovery by Frederick Twort and Félix d’Hérelle. While Western medicine largely abandoned the approach after the arrival of antibiotics, parts of Eastern Europe and the former Soviet Union never stopped using it. The new review, authored by a large consortium of researchers led by Roman Pantůček and Jiří Doškař of Masaryk University in Brno, documents how the Czech lands participated in this long tradition and how that historical foundation has been systematically rebuilt and modernized since the year 2000.

The review’s authors describe a national ecosystem in which academic institutions, biotechnology companies, and university hospitals work in parallel rather than in isolation. According to their analysis, more than 30 competitively funded research projects have been launched in the Czech Republic since 2000, addressing the central technical challenges that stand between laboratory phage research and routine clinical use. These projects have tackled phage safety assessment, genomic characterization of therapeutic candidates, formulation and delivery strategies, synergy between phages and conventional antibiotics, and the difficult problem of manufacturing phage preparations under Good Manufacturing Practice, the regulatory quality standard required for medicines.

The technical depth of this national effort is considerable. Genomic characterization, for example, is now understood as a non-negotiable prerequisite for any phage intended for human use, since phage genomes can harbor toxin genes or other undesirable cargo, and whole-genome sequencing allows candidate viruses to be screened before they ever reach a patient. The Czech teams have applied these methods extensively to staphylococcal phages, an area in which Masaryk University researchers have long specialized, reflecting the country’s historical focus on Staphylococcus aureus infections and conditions such as osteomyelitis, a stubborn bone infection that is notoriously difficult to treat with antibiotics alone and where topical phage preparations such as the long-standing Czech product Stafal found early application.

Stafal itself occupies an important place in the review’s historical narrative. Developed and produced in Czechoslovakia for decades, the staphylococcal phage preparation was used in the treatment of bacterial infections and became one of the few phage products in Europe with continuous production and clinical availability across the political upheavals of the twentieth century. Its survival into the modern era gave Czech researchers and clinicians a continuity of practical experience that few other Western or Central European countries can claim, and it served as a bridge between the empirical phage medicine of the past and today’s evidence-based, molecularly characterized approaches.

Clinical translation is now advancing along two complementary tracks. The first is treatment on a named-patient basis, a compassionate framework that allows physicians to administer phage preparations to individual patients with severe, otherwise untreatable infections, often under national regulations that accommodate unlicensed medicines when no authorized alternative exists. The second track consists of formal clinical trials, which the review describes as ongoing. Moving from anecdotal case reports to controlled studies is widely regarded by the phage therapy community as the decisive step toward regulatory acceptance, and the Czech combination of clinical partners and domestic GMP-compliant production places the country in a strong position to generate the kind of standardized evidence that regulators require.

The review also emphasizes that the Czech phage effort extends well beyond human medicine. In veterinary practice, phages have been investigated as alternatives to antibiotics in livestock, where reducing antimicrobial use has become a priority both for controlling resistance and for meeting European policy targets. In agriculture, researchers have explored phage-based biocontrol of plant pathogenic bacteria, an application studied at the Czech Academy of Sciences’ plant virology institute in České Budějovice. Food safety represents a third area of application, with phages offering a way to reduce pathogenic bacteria on food products without chemical residues. Together these sectors demonstrate a breadth of phage expertise that reinforces the human medicine pipeline, since methods for phage isolation, characterization, and formulation are largely transferable across applications.

Structural biology has added a distinctive dimension to the national program. At the Central European Institute of Technology in Brno, researchers including Pavel Plevka and Tibor Füzik apply cryo-electron microscopy to determine the atomic structures of phage particles, revealing how these viruses recognize their bacterial hosts and deliver their genetic material. Such structural insight is increasingly relevant to rational phage engineering, in which viruses are modified to broaden their host range, evade bacterial defense systems, or improve their stability in pharmaceutical formulations. The presence of world-class structural biology alongside classical phage biology and industrial production is precisely the kind of interdisciplinary integration the review identifies as a national strength.

Looking forward, the authors identify several priorities that will determine whether Czech phage therapy can move from promising practice to sustainable standard of care. Sustainable access to standardized phage preparations is paramount: phage therapy is inherently individualized, because phages must be matched to the specific bacterial strain infecting each patient, and bacteria can evolve resistance to individual phages, so therapeutic preparations typically consist of carefully designed cocktails of multiple viruses. Maintaining libraries of well-characterized phages, updating them in response to evolving bacterial populations, and producing them reproducibly under GMP conditions is logistically and financially demanding in ways that conventional small-molecule antibiotics are not. The review argues that this challenge must be addressed within the rapidly evolving European regulatory framework, which is only now beginning to define how individualized biological therapies should be assessed, authorized, and reimbursed.

The broader significance of the Czech experience extends across the continent. As antimicrobial resistance is projected to cause millions of deaths annually in the coming decades, European health systems are actively searching for non-traditional antibacterial therapies, including enzybiotics, phage-derived enzymes that degrade bacterial cell walls, alongside whole-phage treatments. The review’s conclusion is that the Czech Republic has established the substantial expertise and infrastructure needed to serve as an important European contributor to this effort, offering a working model of how a long national tradition, when combined with modern genomics, structural biology, regulatory engagement, and industrial capability, can be transformed into a coherent pathway for integrating phage-based interventions into twenty-first-century healthcare.

Subject of Research: Phage therapy research, clinical practice, and development in the Czech Republic as a contribution to phage therapy in Europe

Article Title: Past and present phage therapy research and practice in the Czech Republic – contribution to phage therapy in Europe

Article References: Pantůček, R., Doškař, J., Boštík, J., Kocourková, D., Petrzik, K., Koptíková, J., Benešík, M., Plevka, P., Füzik, T., Mašlaňová, I., Botka, T., Nepeřený, J., Zeller, D., Kuntová, L., Snopková, K., Hrala, M., & Moša, M. (2026). Past and present phage therapy research and practice in the Czech Republic – contribution to phage therapy in Europe. Virology Journal. https://doi.org/10.1186/s12985-026-03296-x

Image Credits: AI Generated

DOI: 10.1186/s12985-026-03296-x

Keywords: phage therapy, bacteriophages, antimicrobial resistance, Czech Republic, Staphylococcal infections, Stafal, GMP manufacturing, clinical trials, enzybiotics, biocontrol, osteomyelitis, phage-antibiotic synergy