Table 2.

The effectiveness of antibiotics with bacteriophage against K. pneumoniae

Antibiotics	Bacteriophage	The effects of combined therapy	Ref
Ceftazidime/avibactam was administered at the recommended dosage (2 g/0.5 g, q8h)	Kp040741 and Kp040762	Objective improvements are seen in the patient’s general state and wounds on a clinical, microbiological, and radiological level as a consequence of this salvage treatment. In vitro, in 7-day mature biofilms and suspensions, the bacteriophage and antibiotic combination is highly efficient against the patient’s strain of K. pneumoniae.	[93]
Sulfamethoxazole-trimethoprim	Phage cocktail (lytic phages, namely, SZ-1, SZ-2, SZ-3, SZ-6, and SZ-8) (5 × 108 plaque forming units per mL of each phage)	The patient’s UTI was successfully treated with sulfamethoxazole-trimethoprim and phage cocktail, although ERKp strains were resistant to this combination. This combination also prevented the emergence of phage-resistant mutants in vitro. Therefore, researchers suggested a different approach to tailored phage treatment might be non-active antibiotic and bacteriophage synergism (NABS).	[106]
Gentamicin	Phage vB_KpnM_P-KP2	Mice were given P-KP2 after concentration (1.0 × 107 PFU/mouse, 1.0 × 108 PFU/mouse, or 1.0 × 109 PFU/mouse) or P-KP2 (1.0 × 109 PFU/mouse) in combination with gentamicin (gentamicin was given intranasally 30 min after P-KP2 administration) intraperitoneally at 1-hour post-infection. When treating fatal pneumonia brought on by K. pneumoniae W-KP2 (K47 serotype), P-KP2 was similar to gentamicin. Moreover, the mice with the infection were fully recovered by the combination therapy of gentamicin and P-KP2. To battle MDR infections, researchers’ work not only adds a new entry to the phage therapeutic library but also acts as a reference for future phage-antibiotic combinations.	[111]
Ciprofloxacin	KPO1K2 (Podoviridae, T7-like virus)	The biofilm was successfully removed by bacteriophage, and there was no discernible change in its capacity to remove biofilm when used in conjunction with ciprofloxacin. Nevertheless, the growth of resistant genotypes was dramatically halted by combined therapy using bacteriophage and ciprofloxacin. The few variations that did arise generated less cell-associated capsular polysaccharide, were more susceptible to mice peritoneal macrophages, and had a decreased potential to form biofilms. The outer membrane proteins of the bacterial isolates were also found to have altered shape and pattern. When compared to separate treatments, the combined therapy considerably inhibited the production of resistant variations and killed the bacteria.	[95]
Mitomycin C and imipenem	Lytic phage vB_KpnM-VAC13	In vitro and in vivo, the lytic phage vB_KpnM-VAC13 and mitomycin C exhibited synergistic effects on imipenem-resistant and persister isolates. The persisters were eradicated by the phage-imipenem combination, but the imipenem-resistant isolate that contained OXA-245 β-lactamase was not affected. Intriguingly, the combinations reduced the emergence of in vitro-resistant mutants of both isolates. Mitomycin C and imipenem were efficacious against the persister K. pneumoniae isolate when combined with the lytic phage vB_KpnM-VAC13. The imipenem-resistant K. pneumoniae strains that contain OXA-245 β-lactamase were also susceptible to the lytic phage-mitomycin C combination.	[112]
Amoxicillin	K. pneumoniae B5055 specific phages	In another study, a log reduction of 2.97 ± 0.11 and 3.51 ± 0.19 was observed when 8-day-old biofilm was exposed to a higher antibiotic concentration (512 µg/ml) or phage alone (Multiplicity of Infections (MoIs) = 0.01). The biofilm’s bacterial burden was significantly reduced when exposed to a combination of amoxicillin and phage. Therefore, the fact that the biofilm structure was more effectively destroyed when antibiotics were used with specific phages indicated that the phages could be effectively used in conjunction with antibiotic therapy. One additional benefit of combination therapy is its capacity to prevent the development of resistant mutations, which would otherwise be readily induced by phage or antibiotics alone.	[94]