2026-06-27 | Inhalable bacteriophage endolysins: a novel therapeutic strategy for drug-resistant bacterial pulmonary infections - a comprehensive review.
Pulmonary infections caused by multidrug-resistant (MDR) bacteria pose a severe global health threat with high mortality rates, especially in hospital-acquired pneumonia. The stagnation of new antibiotic development underscores the urgent need for alternative therapeutics. This review summarizes recent advances in the application of bacteriophage endolysins against major MDR respiratory pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. We focus on their mechanisms of action, synergistic effects with antibiotics, and efficacy against biofilms. Endolysins demonstrate potent and species-specific lytic activity against a broad spectrum of MDR bacteria. A key advantage is their low propensity for inducing resistance. Critically, when administered via optimized inhalation delivery systems, endolysins can achieve high local concentrations in the lungs - though this depends on factors such as the aerosol device, formulation properties and patient-related variables - effectively eradicating pathogens in animal models of pneumonia with minimal systemic toxicity. This direct pulmonary delivery approach bypasses many challenges associated with systemic administration and enhances therapeutic outcomes. Endolysins represent a promising paradigm shift in combating drug-resistant bacterial pulmonary infections. Their rapid lytic activity, synergy with conventional antibiotics, and suitability for inhalable formulation position them as a potent adjunct or alternative therapy. While challenges in stabilization and large-scale production remain, advancing inhalation delivery systems for endolysins holds immense potential to holds immense potential to revolutionize the treatment of recalcitrant respiratory infections.
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2026-06-25 | Salvage Treatment of Ventilator-Associated Pneumonia Using Sulbactam-Durlobactam in a Preterm Neonate: A Case Report.
Ventilator-associated pneumonia (VAP) is a leading cause of nosocomial infections in neonatal intensive care units (NICUs) and is associated with significant morbidity, mortality, and prolonged hospitalization, particularly in preterm neonates. Management is complicated by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogens, with very limited evidence supporting the use of reserve antibiotics in this population. We report a male neonate born at 25 weeks of gestation (birth weight 740 g) who developed severe VAP caused by XDR Acinetobacter calcoaceticus-baumannii complex and Pseudomonas aeruginosa. After failure of multiple antibiotic regimens, including ampicillin, amikacin, meropenem, vancomycin, cefepime with inhaled colistin, tigecycline, and ceftazidime-avibactam combined with fosfomycin, the infant was treated with sulbactam-durlobactam (25 mg/kg/dose every 6 h) in combination with ceftazidime-avibactam. After 12 days of this regimen, the neonate was successfully extubated. This case highlights the therapeutic challenges of XDR infections in extremely preterm neonates and suggests that sulbactam-durlobactam may represent a viable salvage treatment option. Further pharmacokinetic and clinical studies are needed to establish optimal dosing and safety in the neonatal population.
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2026-06-17 | Engineering low-endotoxin lipid A in a double auxotroph Pseudomonas aeruginosa to develop safer whole-cell vaccines.
Pseudomonas aeruginosa is a highly adaptable Gram-negative bacterium causing severe respiratory infections, particularly in vulnerable populations. The rise of antimicrobial resistance highlights the urgent need for effective vaccines. We previously developed a live-attenuated vaccine candidate, PAO1 ΔmurI Δalr ΔdadX, a genetically stable double auxotrophic strain that exhibited dose-dependent reactogenicity upon intranasal administration in mice, likely due to lipid A component of lipopolysaccharide (LPS). To reduce LPS-associated toxicity while preserving immunogenicity, we engineered novel strains by inactivating genes involved in lipid A biosynthesis (htrB1, htrB2) or modification (pagP, pagL). Lipid A structural modifications were confirmed by MALDI-TOF MS. Mutants were evaluated for Toll-like receptor 4 (TLR4) activation, virulence attenuation, and their ability to induce immune responses and protection in an acute pneumonia model. All engineered strains displayed modified lipid A structures. Mutations in htrB1 and htrB2 reduced TLR4 activation and significantly attenuated virulence following intraperitoneal challenge in mice. Inactivation of pagL resulted in minimal attenuation, whereas pagP inactivation led to marked attenuation without altering TLR4 activation. In the acute pneumonia model, all mutants elicited robust systemic and mucosal immune responses, and conferred strong protection, despite transient weight loss following intranasal administration. Targeted lipid A modification represents an effective strategy to reduce in vitro reactogenicity while preserving immunogenicity in live-attenuated P. aeruginosa vaccine candidates. Although further optimization may minimize residual in vivo effects, these findings support the potential of engineered strains as vaccine candidates for preventing respiratory infections caused by P. aeruginosa.
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