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. 2023 Aug 2;6:100147. doi: 10.1016/j.bioflm.2023.100147

Fig. 4.

Fig. 4

Schematic presentation of antimicrobial treatments. The row A represents first dose treatment; row B represents second dose treatment; row C represents third dose treatment. EPA1+SAFA/EPA1+SAFA/EPA1+SAFA (1A, 1B, 1C) represent multiple dose treatment regimens of phages at a MOI of 1. In the first dose treatment, phages disrupt and penetrate the biofilm matrix and infect the bacteria cells, helping the penetration of larger molecules such as nutrients. The additional second and third doses of phage treatment continue to target phage-sensitive cells. However, BIM cells proliferate and dominate the biofilm population. GEN/GEN/GEN (2A, 2B, 2C) represent 3 multiple dose treatment regimens of GEN at MIC for P. aeruginosa, 4ug/mL. In the first dose treatment, GEN infects sensitive cells in the upper layer of biofilm. However, single GEN treatment results in GEN-insensitive cell proliferation. The evolved bacteria can proliferate and dominate the biofilm population, rendering the second and third antibiotic treatments ineffective. EPA1+SAFA/GEN/GEN (3A, 3B, 3C) represent multiple dose treatment regimens of antimicrobials: EPA1+SAFA, GEN, and GEN, respectively. In the first dose of treatment, phages disrupt and penetrate the biofilm matrix and infect the bacteria cells. It helps the penetration of larger molecules such as nutrients and antibiotics. However, initial phage treatment induces BIM cell proliferation. The following GEN treatments targets proliferating BIMs and GEN-sensitive cells. Nonetheless, GEN treatments can inhibit phage replication and result in reduced phage efficiency. SIM/SIM/SIM (4A, 4B, 4C) represent multiple dose treatment regimens of the simultaneous combination of EPA1+SAFA and GEN at MOI of 1 and MIC value (4ug/mL, i.e. the MIC for P. aeruginosa). Phages disrupt and penetrate the biofilm matrix and infect the bacteria cells. It helps the penetration of larger molecules such as nutrients and antibiotics. Phages and antibiotics use different mechanisms of action. Following the first dose of treatment, the proliferating phage- or GEN-insensitive cells are targeted by another antimicrobial agent, which is supplied to the environment by the second and third doses of treatment.