## 3 Controlled Antibiotic Delivery
### Sustained Antibiotic Delivery
In a study by [PERSON] et al., silver cation-loaded polyphosphoester NPs were developed as an effective and safe treatment for lung infections (Figure 3B) [40]. This dosage form maintained a continuous delivery of silver in a sustained manner over 5 days, which enhanced in vitro antibacterial activities against cystic fibrosis-associated pathogens (e.g., _P. aeruginosa_, _S. aureus_, _Burkholderia_ sp.) and decreased cytotoxicity to human bronchial epithelial cells compared to silver acetate. Figure 3: Examples of extended-release antimicrobial delivery systems based on polymeric nanocarriers. (**A**) (Left) Schematic illustration of tissue-adhesive nanoparticle-hydrogel hybrid (PLGA NP-gel) biomaterial system for sustained antibiotic release. (Right) The accumulative release profile of antibiotic Ciprofloxacin (Cipro) from Cipro-loaded PLGA NP-gel and Cipro-loaded blank gel without PLGA NPs in PBS buffer (adapted with permission from [38], copyright 2016 ACS). (**B**) (Left) Overall design of the degradable amphiphilic block terpolymer for assembly into NPs capable of silver-based antimicrobial delivery. (Right) Sustained-release profiles of silver cations from the NPs at 37 \({}^{\circ}\)C in pure water and PBS buffer (reproduced with permission from [40], copyright 2015 Royal Society of Chemistry). An important consideration with new antibiotic dosage forms is the pharmacokinetic-pharmacodynamic relationship. Intriguingly, the sustained-release formulations potentially improve the therapeutic index of time-dependent antibiotics. For these agents, the time that therapeutic concentrations are above the minimum inhibitory concentration (T > MIC) is the primary parameter and should be kept for a minimum standard to achieve the desired clinical outcomes. By maintaining a constant plasma drug concentration over MIC for a prolonged period, extended-release dosage forms maximize the therapeutic effect of antibiotics while minimizing antibiotic resistance [34; 44]. On the contrary, in cases of concentration-dependent antibiotics (depending on the peak concentration C\({}_{\text{max}}\)/MIC) or those with high toxicity, the administration of the sustained-release dosage form may not show a beneficial clinical outcome and perhaps even may show a risk of harm [45]. Indeed, premature antibiotic release from the nanocarrier before reaching the site of infection may lead to many adverse effects on normal tissues and on the microbiome. On the other hand, declining amounts of antibiotics released during the final stage of the release process result in the potential for prolonged sub-MIC concentrations at the site of action, thereby compromising the therapeutic efficacy of the system. To overcome these limitations, current nanocarrier-based delivery systems have been upgraded to a \"smart\" level, enabling a controlled drug release via specific stimuli in the infectious site. The triggers can involve physiological conditions in the target tissue (e.g., changes in pH, the activity of certain enzymes, redox condition) or can also be external (e.g., light irradiation, ultrasound, magnetic field). Selecting the proper stimuli in different situations is the key to designing an effective antibiotic delivery system. However, it should be noted that this approach is complex, requiring biocompatible and highly flexible materials that can undergo structural or chemical modifications in response to these stimuli. The following subsections will focus on recent developments in the design of stimuli-responsive nanocarrier systems for antibiotic delivery, including endogenous stimuli and exogenous stimuli.