## 5 Codelivery Platforms for Combination Antibiotic Therapy  
Drug combinations are the mainstay of antibiotic-resistant infection treatments by generating synergistic effects of two or more antimicrobial drugs. However, owing to different pharmacokinetics, the most current combination regimens do not guarantee that all antimicrobials arrive at the site of infection at the predetermined concentration range for maximum synergy. In this regard, nanocarrier systems offer several advantages for multidrug delivery over the combination of free antibiotics. Co-encapsulation of the synergistic drug combination in the same carrier allows normalizing the pharmacokinetics of drugs with dissimilar physicochemical properties and stability. By using a targeting nanocarrier system, a precise drug-to-drug ratio can be directly delivered at the infectious site. In addition, the controlled release from nanocarriers also allows independent tuning of release rates of each drug optimally. This approach enables minimizing the amount of drug administered to achieve the desired synergistic effect, thereby reducing the side effects commonly encountered in drug combinations. Depending on the physicochemical properties, combined drugs can be covalently linked to the polymer backbone or physically co-encapsulated into the polymeric cores through drug-polymer association to ensure the drug release rate and ratio in a controlled manner. Several polymeric nanocarrier systems have been reported for delivering drug combinations, including antibiotic-antibiotic combinations and the pairing of an antibiotic with a non-antibiotic adjuvant molecule, as summarized in Table 4.  
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline  & **Drug Combination** & **Nanocarrier** & **Co-Delivery Purpose** & **Targeted Bacteria** & **Ref. ** \\ \hline \multirow{7}{*}{ \begin{tabular}{c} Rifampicin, \\ Levofloxacin \\ \end{tabular}  } & \multirow{3}{*}{Curdlan NPs} & \multirow{3}{*}{Simultaneous sustained release} & Intracellular \(M\). \\  & & & Targeted delivery & _smegmatis_ & [115] \\ \cline{3-5}  & & Four first-line anti-TB & & Reduction in dosing frequency & Intracellular \(M\). \\  & drugs & & Improvements in patient compliance & _tuberculosis_ & [127] \\ \cline{2-5}  & & Strepomycin, & Polymeric & & \\  & & Doxycycline & & Synergistic antimicrobial effect & Intracellular _ Brucella_ & [128] \\ \cline{2-5}  & & Rifampin, & & & \\  & & Azithromycin & & & \\  & & & Sustained drug release & & \\ \cline{2-5}  & & Amoxicillin, & & & \\  & & Clarithromycin, & & & \\  & & Omerazole & & & \\  & & & & & \\  & & & & & \\  & & & & & \\ \cline{2-5}  & & & & & \\  & & & & & \\ \cline{2-5}  & & Silver NPs, & & Synergistic effect (at 1:0.64 ratio) & & \\  & & & Drug protection from hydrolysis & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & \\ \cline{2-5}  & & Silver NPs, & & Synergistic effect (at 1:0.64 ratio) & & \\  & & & Drug protection from hydrolysis & & \\  & & & & & \\  & & & & \\  & & & & \\  & & & & \\  & & & & \\  & & & & \\ \cline{2-5}  & & Silver NPs, & & Synergistic protection from hydrolysis & & Resistant \(E\). coli & [131] \\ \cline{2-5}  & & Ampicillin & Polymersome & & &For example, the benefit of antibiotic combination therapies using polymeric nanocarriers has been reported for the treatment of infections caused by intracellular pathogens with combinations of up to four drugs such as _M. tuberculosis_ (rifampicin, isoniaizid, pyraz-inamide, ethambutol) [127], _Brucella melitensis_ (streptomycinycin, doxycycline) [128], and _Chlamydia trachomatis_ (rifampin, azithromycin) [129]. Treatment of _H. pylori_ infection requires a complex regimen including two antibiotics (clarithromycin, metronidazoleazole, or amoxicillin) and one proton pump inhibitor. These drugs could be combined in a single nanocarrier formulation, improving patient compliance and reducing the time and dose required for the complete eradication of infection [130].