Abstract
Extensively drug-resistant Acinetobacter baumannii (XDR A. baumannii) poses a crucial challenge due to high mortality and limited therapies. Here, we report the successful application of phage-antibiotic synergy in a critically ill patient with two months of ineffective antibiotic treatment. The patient was diagnosed with severe pneumonia due to recurrent infection of XDR A. baumannii, causing severe pulmonary dysfunction. A nebulized phage inhalation combined with intravenous administration of polymyxin B, amikacin, and fosfomycin successfully brought about measurable clinical improvements in 8 days. The clearance of XDR A. baumannii in sputum cultures, coupled with decreased partial pressure of carbon dioxide, substantial absorption of bilateral pulmonary lesions, reduced density of residual infiltrates, and decreased pleural effusion in the patient, collectively confirmed therapeutic efficacy. Our case indicate that bacteriophage-antibiotic therapy is promising to prevent the emergence of resistant mutants and enhance antibacterial efficacy in patient with similar infections.
1 Introduction
Acinetobacter baumannii (A. baumannii) is a pathogenic bacterium with intrinsic phenotypic resistance to multiple antibiotics, and can easily acquire resistance genes (1). Drug-resistant A. baumannii infections are a vital cause of mortality and morbidity among immunocompromised patients with hospital-acquired and ventilator-associated pneumonia (2). These infections are highly prone to progression to lobar consolidation, bacteremia, and even septic shock, thereby leading elevated mortality rates (3, 4). Current treatment strategies for drug-resistant A. baumannii pneumonia primarily involve antibiotic combination medication and regimen optimization, which are based on drug susceptibility results (5, 6). Endorsed by the 2024 Infectious Diseases of America guidelines, sulbactam-durlobactam combined with background carbapenem therapy is the preferred regimen for carbapenem-resistant A. baumannii pulmonary infection (6). However, rapidly emerged bacterial resistance limit the antibiotic option, causing recurrent infections, prolonged clinical course, and severe lung function impairment (3). Thus, targeted and rapid therapies for drug-resistant bacterial infection are urgently needed.
Bacteriophages are viruses which precisely infect and lyse host bacteria through receptor-binding and enzymatic degradation mechanisms. With emerging drug resistance and their mechanism distinct from antibiotic, phages have gained renewed interest as an alternative or complementary therapeutic tool, particularly for treating drug-resistant bacterial infections (7, 8). Nevertheless, the lytic efficacy of phages is limited by excessive specificity and narrow antimicrobial spectrum, preventing comprehensive bacterial clearance. Due to reduced potential for resistance and broad spectrum activity, bacteriophage and antibiotic synergy have demonstrated great bactericidal potential against various drug-resistant clinical strains, including Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus (9–12). Here, we report the combined use of phage and antibiotic for an elder in intensive care unit with severe A. baumannii pneumonia, who experienced recurrent infection after antibiotic therapy. The infection precipitated acute respiratory distress syndrome (ARDS) and subsequent pulmonary failure, which was severely compounded by pre-existing chronic obstructive pulmonary disease (COPD). The bacteriophage-antibiotic treatment yielded positive outcomes in 8 days, including resolution of pulmonary infiltration, reduced respiratory distress, and decreased levels of inflammatory factors. The clearance of extensively drug-resistant (XDR) A. baumannii in sputum revealed the effectiveness of the phage-antibiotic combinational therapy in eliminating drug-resistant bacterial infection and recovering crucial lung function.
2 Case presentation
The patient was a woman in her 80s with a history of hypertension, COPD, and bronchial asthma. She was admitted with a 20-day history of cough, phlegm, chest tightness, wheezing, dyspnea, and fever. Following the onset of infection-precipitated ARDS and subsequent pulmonary failure, she was mechanically ventilated under sedation and analgesia, with a Richmond Agitation-sedation Scale Score of −3 (deep sedation). The patient presented with an elevated partial pressure of carbon dioxide (PaCO2) of 51.2 mmHg, indicative of hypoventilation. Laboratory findings included a markedly elevated white blood cell count of 19.70 × 10⁹/L (neutrophils 92.1%, lymphocytes 4.2%, monocytes 3%), a normal platelet count of 329 × 10⁹/L, and a high C-reactive protein level of 203.4 mg/L. These results showed a severe inflammation and probable immune damage of the patient. Both the sputum culture from the day of admission and a prior culture from an external hospital identified A. baumannii. Initial chest X-ray revealed bilateral multifocal pulmonary infiltrates, with small left-sided pleural effusion, suggestive of severe bacterial pneumonia at admission. The patient underwent empirical antibiotic treatment with cefuroxime, polymyxin E, and linezolid, and subsequent antimicrobial susceptibility-guided therapy for 2 months (Figure 1A). The regimens are as follows: cefuroxime at 1.5 g every 8 h, polymyxin E at 150 mg every 12 h, and linezolid at 0.6 g every 12 h. The drug susceptibility result revealed an XDR phenotype of A. baumannii isolate, which represented resistance to multiple antibiotics such as ceftazidime, cefepime and ciprofloxacin (Figure 1B). The patient presented with refractory chronic infection and became exacerbated. Recurrently positive cultures for XDR A. baumannii and aggravated right-sided pleural effusion also indicated failure of the antibiotic therapy.
Figure 1
Bacteriophage-antibiotic therapy for extensively drug-resistant A. baumannii. (A) Timeline of the treatment. (B)In vitro antimicrobial susceptibility profile of A. baumannii isolate. (C) Susceptibility of A. baumannii isolates to phage determined by plaque assays. The titer of the bacteriophage was 1.25 × 1010PFU/mL. (D) The radiograph after continuous antibiotic treatment revealed progression of right-sided pleural effusion. Following 8 days of bacteriophage-antibiotic therapy, radiograph showed significant absorption of bilateral pulmonary lesions, reduced density of residual infiltrates and decreased pleural effusion. (E) The relative shadow density of chest X-ray at the white dotted regions. (F) The white cells count and PaCO2 of the patient. The reference range of the white cells count (WS/T 246—2005) and PaCO2 was shown in dashed lines.
To address the recurrent infection of XDR A. baumannii, we initiated a phage cocktail aerosol inhalation combined with intravenous administration of antibiotics to enhance therapeutic efficacy. The bacteriophages were isolated from sewage water samples collected from Shenzhen Third People’s Hospital (self-screened). In vitro assays confirmed the strong lytic efficacy of the selected bacteriophage against clinical A. baumannii isolates obtained from the patient (Figure 1C). Genome sequencing analyses revealed that this lytic phage did not contain any virulence genes and has similarities with Acinetobacter phage Arbor (NCBI accession number, ON237674.1, 99.82% identity, 91% coverage). Nebulized phage was administered in 20-min sessions, twice a day (8 × 109 PFU in 5 mL saline) via high-frequency nebulizer to eradicate the pathogen, with treatments operated in the morning and afternoon. Ethical approval was obtained from the Ethics Commission of Shenzhen Third People’s Hospital (Approval number, 2021–068-03). Simultaneously, intravenous antibiotics were administered according to the following regimen: polymyxin B at a loading dose of 1 million units, followed by 500,000 units every 12 h, amikacin at 200,000 units every 12 h, and fosfomycin at 8 g every 8 h. The combined therapy was continued for 8 days in the intensive care unit without any changes.
Following bacteriophage-antibiotic therapy, the mental state of patient significantly improved, with the Richmond Agitation-sedation Scale Score changing from −3 (deep sedation) on admission to −1 (drowsy but arousable) after treatment. Follow-up tests revealed significant declines in inflammatory markers, with the white blood cell count declined from 19.70 × 10⁹ to 8.39 × 10⁹ cells/L, and C-reactive protein levels dropped from 203.40 to 67.33 mg/L, which indicated progressive resolution of the infection (Figure 1F). Chest X-ray after bacteriophage-antibiotic treatment showed substantial absorption of bilateral pulmonary lesions, reduced density of residual infiltrates, and decreased pleural effusion (Figures 1D,E). This was further supported by improved alveolar ventilation, with PaCO₂ levels decreasing from 51.2 to 37.4 mmHg. Moreover, sputum cultures from 5 consecutive sets showed no pathogenic bacterial growth. The bacteriophage-antibiotic therapy achieved the rapid and effective rescue of the patient’s pulmonary function and inflammatory status, demonstrating a favorable therapeutic response.
3 Discussion
In this case, the elderly patient with a history of COPD developed ARDS and subsequent pulmonary dysfunction due to XDR A. baumannii infection, facing profound therapeutic challenges. Moreover, delayed initiation of targeted therapy at advanced disease stages limited the possibility for maximal benefit. Under these circumstances, pulmonary infection with XDR A. baumannii was particularly difficult to manage. Prolonged broad-spectrum antibiotic therapy yielded a suboptimal response, with neither clinical improvement nor microbiological clearance. Serial sputum cultures over an extended course of empiric antibiotic therapy confirmed recurrent infection of XDR A. baumannii. Even subsequent susceptibility-guided treatment failed, with recrudescence of XDR A. baumannii and evidence of progressive pulmonary disease, indicating incomplete bacterial clearance and reflecting the limitations of current antibiotic regimens.
Phages and antibiotics act via complementary mechanisms, with phages lysing bacteria and antibiotics suppressing planktonic and residual bacterial populations (13). The core advantages of combining phages with antibiotics are their synergistic antibacterial efficacy, reduced resistance potential and expanded bactericidal spectrum (11, 14). Compared with antibiotics, bacteriophages offer unique advantages, including targeted bactericidal activity, reduced off-target toxicity, and a lower propensity for resistance development (13, 15). Nevertheless, its lytic activity is limited by excessive specificity, and is often insufficient for complete bacterial eradication. The introduction of adjunctive phage therapy marked a turning point. In cases of phage treatment of A. baumannii, the combined use of phage and antibiotic may prevent the development of phage resistance and the mutation of drug susceptibility (16). Previous in vitro studies have demonstrated that combining phages with antibiotics can prevent the emergence of resistant mutants and enhance bactericidal efficacy (11, 17). In this case, the combined therapeutic strategy of phage and antibiotics (polymyxin B, amikacin, and fosfomycin) achieved synergistic bactericidal effect in vitro. The progressive clearance of XDR A. baumannii burden, paralleled by marked clinical improvement in radiographic findings, respiratory function, and systemic inflammation, all highlighted the rapid and effective antibacterial synergy of phage-antibiotic combination therapy. The rapid control of infection suggests the early deployment of such combination therapy. It may restrict resistance evolution and liberate patients with respiratory failure due to drug-resistant bacterial infection within a narrow therapeutic window.
Although bacteriophage-antibiotic therapy yielded favorable therapeutic responses in this patient, it still faces several challenges, including long-term stability, toxin release by lysed bacteria and optimal dosing regimens. Besides, the sequence and types of antimicrobial application are critical determinants of treatment success (11). For instance, study on methicillin-resistant Staphylococcus aureus (MRSA) infection indicated optimal effectiveness when phage treatment preceded antibiotics (18). While in our case, concurrent administration of phages and antibiotics achieved favorable outcomes. These differences underscore the complexity of phage-antibiotic interactions, which may range from synergistic to antagonistic effects depending on the bacterial strain and drug class (9–11, 19). Both therapeutic efficacy and potential adverse effects of phage-antibiotic interactions and dosing strategies require further mechanistic investigation.
4 Conclusion
Drug-resistant infections constrain antibiotic options, and rapid infection progression in patients with medical conditions presents major clinical challenges. Bacteriophages effectively lyse antibiotic-resistant bacteria, bypassing conventional antimicrobial resistance mechanisms. Timely synergistic therapy is crucial. The short-term treatment with phage and synergistic antibiotics successfully eliminated XDR A. baumannii, promptly halted disease progression.
Statements
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Ethics statement
The studies involving humans were approved by Ethics Commission of Shenzhen Third People’s Hospital (Approval number, 2021-068-03). The studies were conducted in accordance with the local legislation and institutional requirements. The participants’ guardians provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s)’ guardians for the publication of any potentially identifiable images or data included in this article.
Author contributions
JL: Data curation, Investigation, Methodology, Writing – original draft, Writing – review & editing, Formal analysis, Visualization, Software. GD: Investigation, Writing – original draft, Writing – review & editing, Data curation, Formal analysis, Software, Validation. LZ: Investigation, Writing – original draft, Writing – review & editing, Data curation, Formal analysis. PX: Writing – original draft, Writing – review & editing, Data curation, Formal analysis. PZ: Investigation, Writing – original draft, Writing – review & editing, Funding acquisition, Project administration, Conceptualization, Data curation, Supervision. YZ: Investigation, Resources, Supervision, Writing – original draft, Writing – review & editing, Conceptualization, Formal analysis, Funding acquisition, Validation. HL: Writing – original draft, Writing – review & editing, Funding acquisition, Conceptualization, Formal analysis, Supervision, Validation. MZ: Data curation, Funding acquisition, Investigation, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing, Conceptualization.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was financially supported by the National Key R&D Program of China (2023YFC2308300, 2023YFA0915600), Shenzhen Medical Research Fund (D250402006), Natural Science Foundation of China (82372271), Key Area Projects for Universities in Guangdong Province (2022DZX2022), Guangdong Province Medical Science and Technology Research Fund (A2024400), Shenzhen Science and Technology Program (JCYJ20220530163005012, JCYJ20240813102021028, JCYJ20240813102012017), Shenzhen Clinical Medical Center for Emerging infectious diseases (LCYSSQ20220823091203007), Major Project of Guangzhou National Laboratory (GZNL2024A01009), and Shenzhen High-level Hospital Construction Fund (23250G1005, 24250G1027, 24250G1019).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1.
Gao F Zhou R He Y Zhang Y Bao C Feng G . Bio-mimicking nanoparticle system facilitates sonodynamic-mediated clearance of extensively drug-resistant bacteria. ACS Biomater Sci Eng. (2025) 11:2988–3002. doi: 10.1021/acsbiomaterials.4c02455,
2.
Mohd Sazlly Lim S Zainal Abidin A Liew SM Roberts JA Sime FB . The global prevalence of multidrug-resistance among Acinetobacter baumannii causing hospital-acquired and ventilator-associated pneumonia and its associated mortality: A systematic review and meta-analysis. J Infect. (2019) 79:593–600. doi: 10.1016/j.jinf.2019.09.012,
3.
Rodríguez-Aguirregabiria M Lázaro-Perona F Cacho-Calvo JB Arellano-Serrano MS Ramos-Ramos JC Rubio-Mora E et al . Challenges facing two outbreaks of carbapenem-resistant Acinetobacter baumannii: from cefiderocol susceptibility testing to the emergence of cefiderocol-resistant mutants. Antibiotics. (2024) 13:784. doi: 10.3390/antibiotics13080784,
4.
Lee Y-T Kuo S-C Yang S-P Lin Y-T Chiang D-H Tseng F-C et al . Bacteremic nosocomial pneumonia caused by Acinetobacter baumannii and Acinetobacter nosocomialis: a single or two distinct clinical entities?Clin Microbiol Infect. (2013) 19:640–5. doi: 10.1111/j.1469-0691.2012.03988.x,
5.
Bavaro DF Belati A Diella L Stufano M Romanelli F Scalone L et al . Cefiderocol-based combination therapy for “difficult-to-treat” gram-negative severe infections: real-life case series and future perspectives. Antibiotics. (2021) 10:652. doi: 10.3390/antibiotics10060652,
6.
Cj K C G A-C U . Acinetobacter baumannii treatment strategies: a review of therapeutic challenges and considerations. Antimicrob Agents Chemother. (2025) 69:e0106324. doi: 10.1128/aac.01063-24
7.
Köhler T Luscher A Falconnet L Resch G McBride R Mai Q-A et al . Personalized aerosolised bacteriophage treatment of a chronic lung infection due to multidrug-resistant Pseudomonas aeruginosa. Nat Commun. (2023) 14:3629. doi: 10.1038/s41467-023-39370-z,
8.
Li N Li L He B Li D Jin W Wu Y et al . Personalized bacteriophage therapy for chronic biliary tract Pseudomonas aeruginosa infections. hLife. (2025) 3:275–83. doi: 10.1016/j.hlife.2025.03.004
9.
Yj C S K M S J K . Synergistic antimicrobial effects of phage vB_AbaSi_W9 and antibiotics against Acinetobacter baumannii infection. Antibiotics. (2024) 13:680. doi: 10.3390/antibiotics13070680,
10.
Otava UE Tervo L Havela R Vuotari L Ylänne M Asplund A et al . Phage-antibiotic combination therapy against recurrent Pseudomonas septicaemia in a patient with an arterial stent. Antibiotics. (2024) 13:916. doi: 10.3390/antibiotics13100916,
11.
Akturk E Pinto G Ostyn L Crabbé A Melo LDR Azeredo J et al . Combination of phages and antibiotics with enhanced killing efficacy against dual-species bacterial communities in a three-dimensional lung epithelial model. Biofilms. (2025) 9:100245. doi: 10.1016/j.bioflm.2024.100245,
12.
Kunz Coyne AJ Bleick C Stamper K Kebriaei R Bayer AS Lehman SM et al . Phage-antibiotic synergy against daptomycin-nonsusceptible MRSA in an ex vivo simulated endocardial pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother. (2024) 68:e0138823. doi: 10.1128/aac.01388-23,
13.
Su J Tan Y Liu S Zou H Huang X Chen S et al . Characterization of a novel lytic phage vB_AbaM_AB4P2 encoding depolymerase and its application in eliminating biofilms formed by Acinetobacter baumannii. BMC Microbiol. (2025) 25:123. doi: 10.1186/s12866-025-03854-3,
14.
Le S Wei L Wang J Tian F Yang Q Zhao J et al . Bacteriophage protein Dap1 regulates evasion of antiphage immunity and Pseudomonas aeruginosa virulence impacting phage therapy in mice. Nat Microbiol. (2024) 9:1828–41. doi: 10.1038/s41564-024-01719-5,
15.
Ling H Lou X Luo Q He Z Sun M Sun J . Recent advances in bacteriophage-based therapeutics: insight into the post-antibiotic era. Acta Pharm Sin B. (2022) 12:4348–64. doi: 10.1016/j.apsb.2022.05.007,
16.
Aslam S Lampley E Wooten D Karris M Benson C Strathdee S et al . Lessons learned from the first 10 consecutive cases of intravenous bacteriophage therapy to treat multidrug-resistant bacterial infections at a single center in the United States. Open Forum Infect Dis. (2020) 7:ofaa389. doi: 10.1093/ofid/ofaa389,
17.
Hong Q Chang RYK Assafiri O Morales S Chan H-K . Optimizing in vitro phage-ciprofloxacin combination formulation for respiratory therapy of multi-drug resistant Pseudomonas aeruginosa infections. Int J Pharm. (2024) 652:123853. doi: 10.1016/j.ijpharm.2024.123853,
18.
Loganathan A Bozdogan B Manohar P Nachimuthu R . Phage-antibiotic combinations in various treatment modalities to manage MRSA infections. Front Pharmacol. (2024) 15:1356179. doi: 10.3389/fphar.2024.1356179,
19.
Łusiak-Szelachowska M Międzybrodzki R Drulis-Kawa Z Cater K Knežević P Winogradow C et al . Bacteriophages and antibiotic interactions in clinical practice: what we have learned so far. J Biomed Sci. (2022) 29:23. doi: 10.1186/s12929-022-00806-1,
Summary
Keywords
bacteriophage therapy, drug resistance, Acinetobacter baumannii , respiratory infection, pulmonary disease
Citation
Lin J, Dai G, Zhang L, Xu P, Zhao P, Zhou Y, Lu H and Zheng M (2025) Case Report: Bacteriophage-antibiotic therapy for extensively drug-resistant Acinetobacter baumannii in critically ill patient with respiratory infection. Front. Med. 12:1716306. doi: 10.3389/fmed.2025.1716306
Received
30 September 2025
Revised
08 November 2025
Accepted
30 November 2025
Published
17 December 2025
Volume
12 - 2025
Edited by
Karolina Henryka Czarnecka-Chrebelska, Medical University of Lodz, Poland
Reviewed by
Shuai Le, Army Medical University, China
Naomi Sulinger Hoyle, Skagit Regional Health, United States
Gilbert Verbeken, Queen Astrid Military Hospital, Belgium
Updates
Copyright
© 2025 Lin, Dai, Zhang, Xu, Zhao, Zhou, Lu and Zheng.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Pengfei Zhao, pengfeizhao@aliyun.comMingbin Zheng, mingbinzheng@126.comHongzhou Lu, luhongzhou@fudan.edu.cnYang Zhou, yangzhou@szsy.sustech.edu.cn
†These authors have contributed equally to this work and share first authorship
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.