Phage-antibiotic combination is a superior treatment against Acinetobacter baumannii in a preclinical study

• Published in: EBioMedicine 2022-06, Vol.80, p.104045-104045, Article 104045
• Main Authors: Gordillo Altamirano, Fernando L., Kostoulias, Xenia, Subedi, Dinesh, Korneev, Denis, Peleg, Anton Y., Barr, Jeremy J.
• Format: Article
• Language: English
• Subjects: Acinetobacter baumannii; Acinetobacter Infections - drug therapy; Acinetobacter Infections - microbiology; Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antimicrobial resistance; Bacteriophages - genetics; Ceftazidime; Ceftazidime - pharmacology; Ceftazidime - therapeutic use; Drug Resistance, Multiple, Bacterial; Humans; Mice; Microbial Sensitivity Tests; Phage therapy; Phage-resistance; Preclinical study; Synergism
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2022.104045

Clinical phage therapy is often delivered alongside antibiotics. However, the phenomenon of phage-antibiotic synergy has been mostly studied in vitro. Here, we assessed the in vivo bactericidal effect of a phage-antibiotic combination on Acinetobacter baumannii AB900 using phage øFG02, which binds to capsular polysaccharides and leads to antimicrobial resensitisation in vitro. We performed a two-stage preclinical study using a murine model of severe A. baumannii AB900 bacteraemia. In the first stage, with an endpoint of 11 h, mice (n = 4 per group) were treated with either PBS, ceftazidime, phage øFG02, or the combination of phage and ceftazidime. The second stage involved only the latter two groups (n = 5 per group), with a prolonged endpoint of 16 h. The primary outcome was the average bacterial burden from four body sites (blood, liver, kidney, and spleen). Bacterial colonies from phage-treated mice were retrieved and screened for phage-resistance. In the first stage, the bacterial burden (CFU/g of tissue) of the combination group (median: 4.55 × 105; interquartile range [IQR]: 2.79 × 105–2.81 × 106) was significantly lower than the PBS (median: 2.42 × 109; IQR: 1.97 × 109–3.48 × 109) and ceftazidime groups (median: 3.86 × 108; IQR: 2.15 × 108–6.35 × 108), but not the phage-only group (median: 1.28 × 107; IQR: 4.71 × 106–7.13 × 107). In the second stage, the combination treatment (median: 1.72 × 106; IQR: 5.11 × 105–4.00 × 106) outperformed the phage-only treatment (median: 7.46 × 107; IQR: 1.43 × 107–1.57 × 108). Phage-resistance emerged in 96% of animals receiving phages, and all the tested isolates (n = 11) had loss-of-function mutations in genes involved in capsule biosynthesis and increased sensitivity to ceftazidime. øFG02 reliably drives the in vivo evolution of A. baumannii AB900 towards a capsule-deficient, phage-resistant phenotype that is resensitised to ceftazidime. This mechanism highlights the clinical potential of using phage therapy to target A. baumannii and restore antibiotic activity. National Health and Medical Research Council (Australia).