Phage-antibiotic synergy attenuates Acinetobacter baumannii resistance in refractory pneumonia: a precision
Lei Zhang1,2, Kexin Yan3, Pengli Xu1
1National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China.
Abstract:
Extensively drug-resistant (XDR) Acinetobacter baumannii pneumonia carries severe pneumonia, respiratory failure and high mortality, showing limited therapeutic options in critically ill patients. Although bacteriophage (phage) therapy represents a promising alternative against drug-resistant infections, its clinical use remains largely empirical. Here, we reported a systematically planned phage-antibiotic combination strategy in a critically ill patient with refractory XDR A. baumannii pneumonia. A virulent phage targeting the patient-derived strain was isolated from hospital wastewater and classified within the class Caudoviricetes, with no virulence, toxin, or antibiotic resistance genes. In vitro time-kill assays showed that phage monotherapy failed to persistently suppress bacteria proliferation, whereas phage-antibiotic therapy achieved synergistic inhibition of A. baumannii growth for over 48 h. The patient received nebulized phage therapy (5 × 109 PFU/mL twice daily) combined with intravenous fosfomycin (8 g, every 8 hours), amikacin (0.2 g, every 12 hours), and polymyxin B (500, 000 U, every 12 hours). Clinically, treatment was associated with rapid normalization of arterial carbon dioxide tension (PaCO2), clearance of A. baumannii sputum cultures by day 4, declining inflammatory markers, and no treatment-related toxicity.Longitudinal metagenomic sequencing further revealed approximately 52-fold reduction in pathogen abundance and significant decrease of A. baumannii-associated antimicrobial resistance genes (ARGs) in the lung, highlighting the potential of precision phage-antibiotic therapy for recalcitrant XDR bacterial infections.
Insights
Phage-antibiotic therapy effectively treated extensively drug-resistant Acinetobacter baumannii pneumonia in a critically ill patient. This combination strategy reduced pathogen load and resistance genes, offering a promising approach for severe bacterial infections.
Area of Science:
- Infectious Diseases
- Microbiology
- Genomics
Background:
- Extensively drug-resistant (XDR) Acinetobacter baumannii pneumonia presents a critical challenge with high mortality and limited treatment options.
- Bacteriophage therapy is a potential alternative for drug-resistant infections, but clinical applications are often empirical.
Purpose of the Study:
- To report a systematically planned phage-antibiotic combination strategy for a patient with refractory XDR A. baumannii pneumonia.
- To evaluate the efficacy and safety of this precision therapy in a critically ill patient.
Main Methods:
- Isolated a virulent bacteriophage targeting the patient's A. baumannii strain.
- Conducted in vitro time-kill assays to assess phage-antibiotic synergy.
- Administered nebulized phage therapy combined with intravenous antibiotics (fosfomycin, amikacin, polymyxin B).
- Utilized longitudinal metagenomic sequencing to analyze pathogen abundance and antimicrobial resistance genes (ARGs) in lung samples.
Main Results:
- Phage monotherapy showed limited efficacy, while phage-antibiotic therapy achieved synergistic bacterial inhibition in vitro.
- The patient showed clinical improvement, including normalization of PaCO2, clearance of A. baumannii sputum cultures, and reduced inflammatory markers.
- No treatment-related toxicity was observed.
- Metagenomic sequencing revealed a significant reduction in pathogen abundance and A. baumannii-associated ARGs in the lung.
Conclusions:
- Precision phage-antibiotic therapy demonstrated significant clinical efficacy and safety in treating refractory XDR A. baumannii pneumonia.
- This combination approach offers a promising strategy for managing severe, multidrug-resistant bacterial infections.
- Further research into phage-antibiotic synergy is warranted for recalcitrant infections.
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