## 4 Targeted Delivery of Antibiotics to Sites of Infection
### Active Targeting
#### 4.2.1 Active Targeting to Bacterial Cells  
There are huge differences between pathogenic and host cells, especially their surfaces, providing an \"Achilles' heel\" to recognize bacterial pathogens. Several ligands have been employed to functionalize NPs in active-targeting strategies, including antibiotic molecules, carbohydrates, aptamers, peptides, antibodies, and cell membranes (Table 3). By linking these ligands to the surface of NPs, the antibiotic delivery systems can selectively bind to pathogenic microorganisms and release antimicrobials to kill or inhibit their growth, significantly improving the therapeutic efficacy of existing antimicrobial treatments. Many types of **antibiotics** exert their effects by targeting the cell wall or cell membrane of bacteria. By taking these available facilities, the antimicrobial agents can be used at low doses as target molecules, offering great potential for applying targeted antibiotic delivery. For example, vancomycin acts by binding to the D-Ala-D-Ala fractions of the peptide subunits on the cell wall of Gram-positive bacteria, and, in a few cases, to the inner membrane of Gram-negative bacteria having an abnormal outer membrane. Therefore, the conjugation of vancomycin on the surface of NPs was proposed in various types of antibiotic-loaded nanoplatforms to target pathogenic bacteria. Figure 9A is an illustrative example of a targeting micellar nanocarrier strategy via the antibiotic moieties [54]. The micelles could target bacterial walls using a vancomycin shell, which was then removed from the micelles via cleavage of hydrazone bonds under the acidic conditions surrounding the bacteria. Subsequently, the poly(\(\epsilon\)-caprolactone) core was degraded by lipase overexpressed at the site of infection, releasing the encapsulated ciprofloxacin. The potential synergy between three \"smart\" concepts (active targeting, pH, and enzyme-triggered drug release) and the antibiotic combination (ciprofloxacin and vancomycin) resulted significantly in increased antibacterial efficacy of the system. The micelle administration significantly improved the survival of _P. aeruginosa_-infected mice, reduced the bacterial burdens, and promoted the recovery of alveolar lesions in the lungs, compared with free drugs and micelles without ligand moieties. Likewise, antibodies are one of the other potential ligands used in the active-targeting strategy. Antibodies play an important role in the immune system through multiple mechanisms. For bacterial infections, the F\({}_{\text{ab}}\) region (antigen-binding fragment) of the antibody can bind specifically to antigens of the bacterium, resulting in neutralization of the pathogen and prevention of infection. Due to their high selectivity, antibodies have been used in several diagnostic or therapeutic applications for infections. For example, recently exploited antibody-antibiotic conjugates (AACs) have shown to be more effective than conventional antibiotics in treating some infections [120]. In a similar approach, our group has also developed an antibody-conjugated nanocarrier system that effectively delivers antimicrobial drugs to bacterial biofilm (Figure 9B) [33]. The targeting nanocarriers were prepared by the nanoprecipitation method using biocompatible polymers that allowed for the encapsulation of a variety of antimicrobial molecules. This is an important advantage because constantly developed antibacterial agents can easily be administrated in the targeting dosage form. A single intravenous administration of the antibiotic-loaded targeted NPs significantly enhanced bactericidal activity against _S. aureus_ biofilm compared to the free-form antibiotic and non-targeting NPs, as demonstrated in a mouse infection model. In another approach, the host cell membrane is also employed to decorate the surface of nanocarriers as active targeting. Indeed, as one of the most fundamental biological units, cells are responsible for performing many functions necessary for life.