## 3 Controlled Antibiotic Delivery  
### Sustained Antibiotic Delivery  
The concept of a sustained-release formulation is a crucial aspect of antibiotic delivery [34]. In chronic infection treatment, a long course of sufficient antibiotic exposure is essential to ensure the eradication of the microorganism. However, maintaining the antibiotic concentrations within a therapeutic window (between the drug's maximum tolerated and lowest effective doses) is often difficult to achieve in conventional dosage forms. In addition, due to limited bioavailability, many antibiotics have a short half-life and need to be administered frequently, resulting in poor patient compliance. In this regard, polymeric nanocarriers may serve as reservoirs to provide sustained antibiotic release profiles with a lower dosing frequency [35]. The sustainable antibiotic release from a polymeric matrix occurs via three main mechanisms: solute diffusion, polymeric matrix swelling or erosion/degradation, and loss of the antibiotic-polymer bond. These mechanisms may act simultaneously or independently at different stages of a delivery process, depending on the composition (polymer, drug, excipient), the ratio, physical or chemical interaction among components, particle size, and manufacturing methods [36, 37]. This allows antibiotic concentrations at the site of infection to be maintained at the required effective levels for a prolonged period of time, maximizing the therapeutic effect while minimizing the adverse effects of antibiotics. Another undoubted advantage of the sustained-release nano-formulation is the improvement in patient compliance, as frequent administration can be reduced. For example, in an attempt to overcome bacterial infections that occur at sites with high shear forces, such as infective endocarditis, corneal infection, and urinary tract infections, challenging effective antibiotic retention, [PERSON] et al. developed a bioadhesive NP-hydrogel hybrid to enhance localized antimicrobial drug delivery (Figure 3A) [38]. The combination of two distinct delivery platforms, PLGA NPs and hydrogel, allows the hydrogel network properties to be independently tailored for adhesion while maintaining sustained drug release kinetics from the NPs. The nanocarrier-based system showed superior antibiotic retention under high shear stress on biological surfaces, including a bacterial film, a mammalian cell monolayer, and mouse skin tissue. Similarly, another application of PLGA nano-formulations prolonged the concentration of antibiotics available in the precorneal area, providing a better curative effect than conventional antibiotic eye drops [39]. In order to improve patient compliance in tuberculosis chemotherapy, [PERSON] et al. developed an extended-release antibiotic delivery system based on PLGA NPs that allowed co-loading three first-line anti-tuberculosis (TB) drugs (isoniazid, rifampicin, and pyrazinamide) [41]. In vivo investigations revealed that three doses of oral/nebulized nano-formulation (fortnightly) could yield undetectable mycobacterial colony-forming units, an excellent preclinical outcome comparable to 45 doses of conventional oral drugs. In the same approach, by using a sustained-release nano-formulation for the treatment of intracellular _Brucella_ infection, [PERSON] et al. demonstrated a seven-fold dose-sparing benefit when comparing the bacterial counts in the spleen and liver from mice treated with a weekly dose of antibiotic-loaded polyanhydride NPs and with the daily dose of the free drug [42]. Surprisingly, slow-release nano-formulations have also been widely used for unstable antimicrobials or those with many side effects to ensure therapeutic efficacy and minimize side effects. For example, loading of lysozyme in chitosan NPs effectively preserved the antibacterial activity of the loaded enzyme and showed a sustained drug release profile for 3 weeks in vitro [43].