## 5 Codelivery Platforms for Combination Antibiotic Therapy
In another example described above, co-encapsulation of colistin and rifampicin in the micelles not only reduced systemic toxicity of colistin but also provided a synergistic antimicrobial effect against antibiotic-resistant strains of _E. coli_, _P. aeruginosa_, and _A. baumannii_[25]. In addition, nanocarrier systems have also been exploited to combine antibiotics with adjuvants (active molecules do not kill bacteria but instead enhance the effect of an antibiotic) (Table 4). A classic example of a commercial antibiotic-adjuvant combination is Augmentin, which combines a \(\beta\)-lactam antibiotic (amoxicillin) with a \(\beta\)-lactamase inhibitor (clavulanic acid). In this regard, [PERSON] et al. recently developed a polymeric nanocarrier system based on benzoxaborole-conjugated dextran (a \(\beta\)-lactamase inhibitor macromolecule) for precise transport of \(\beta\)-lactam antibiotics to strains overexpressing \(\beta\)-lactamases (Figure 11A) [135]. Thanks to the high affinity of benzoxaborole with cis-diol structures on bacterial cell walls, the nanocarriers enabled specific recognition and rapid internalization toward bacteria and distinctly inhibited the catalytic activity of bacterially secreted \(\beta\)-lactamase. Using a wound infection model, the cefoxitin-loaded nanocarrier system significantly enhanced the ability to kill drug-resistant _E. coli_ compared to the free-form drug by specifically overcoming the membrane barrier and acquired resistance mechanism of \(\beta\)-lactamase overproduction. In another approach, the nanocarrier-based drug combination therapy has been widely applied for the treatment of biofilm infections by co-delivering antibiotics and biofilm-dispersing enzymes, which are capable of degrading EPS components, such as proteins, eDNA, polysaccharides, or quorum-sensing molecules (Table 4) [136; 137; 138; 139]. The dispersing compounds could revert the biofilm bacteria back to their planktonic growth mode, rendering bacteria susceptible to conventional antibiotics. On the other hand, the reduction in viscosity by enzyme activity potentially increased the penetration of antibiotics-loaded NPs into the deeper layers of the biofilm where persister cells reside. As a result, these dual-purpose nanocarriers could degrade the biofilm effectively, reduce biofilm biomass, and simultaneously enhance the antibiotic's effect. Similarly, [PERSON] et al. developed a multifunctional NP system that displays the synergistic activity of antimicrobial cationic polymer and antibiotics against antimicrobial pathogens (Figure 11B) [103]. Besides the drug co-delivery purpose, the system possessed most nanocarrier-based strategies for localized antibiotic delivery, as mentioned in this review. Indeed, using dextran as a hydrophilic shell and poly(\(\beta\)-amino ester)-guanidine-phenylboronic acid (PBAE-G-B) as hydrophobic core, the resulting NPs could encapsulate hydrophobic antibiotics (e.g., rifampicin) in a physiological environment. On the one side, the dextran shell possessed a strong affinity with lectins expressed by bacteria and macrophages, thereby enhancing the bioavailability of the NPs. On the other side, the PBAE-G-B could be responsive to both low pH and high ROS of the inflammatory microenvironment and converted to hydrophilic cationic polymers (PBAE-G) with potent antimicrobial activity. Subsequently, this hydrophobic/hydrophilic transition combined with the disruption of the phenylboronic ester bonds (second pH/ROS-responsive) between PBAE-G-B polymer and dextran destabilized the NPs, causing the simultaneous release of the cationic polymers and the antibiotic, thereby effectively killing the pathogens. As a result, the complex system effectively eliminated the biofilm and intracellular infections and exhibited efficacy against antibiotic-resistant bacteria (_E. coli_, _P. aeruginosa_, _M. smegmatis_, MRSA) in both in vitro and in vivo models.