## 5 Combination of Antimicrobial Cationic Polymers with Antibiotics
aeruginosa_ in comparison to a free drug allowing for a reduction of the antibiotic dose. Various dual systems based on PEGylated PPI and ciprofloxacin have been designed and tested against _S. aureus_ and _C. pneumonia_[166]. [PERSON] et al. [167] conjugated azithromycin with PAMAM dendrimers for the treatment of chlamydia which demonstrated that this dual agent exhibited an additive effect in comparison to antibiotics alone. In another attempt to prove a synergistic effect between dendrimers and antibiotics, [PERSON] et al. [168] combined poly(ethylene imine) (PEI) with 10 different families of hydrophilic and hydrophobic antibiotics to test the effect against _P. aeruginosa_. The enhanced antibacterial activity was confirmed for novobiocin, cephalosporporins, rifamycins and chloramphenicol, while other antibiotic families, such as polymyxins and fluoroquinolones, showed antagonism and indifference, respectively. Recently, it has been investigated that ionically charged metallopolymers based on cationic cobaltocenium moieties show antimicrobial activity by reducing \(\upbeta\)-lactamase enzymes activity and disrupting cell walls. Furthermore, these organometallic compounds can complex antibiotics by the formation of a stable ion-pairing as reported by [PERSON] et al. [169], who bioconjugated some \(\upbeta\)-lactam antibiotics, including penicillin-G, amoxicillin, ampicillin and cefazolin to cationic cobaltocenium-containing polymers. Based on the synergistic effect produced by both compounds, this system revealed high efficiency against MRSA with low cytotoxicity attributed to the adsorption of metallopolymer to the negatively charged MRSA surface (similar to other cationic antimicrobial polymers) which promotes damage in the cell walls and at the same time, allows the release of complexed antibiotics (Figure 11). Figure 11: Antibiotic release from antibiotic-metallopolymer ion-pairs via lipoteichoic acid or \(\upbeta\)-lactamases. Reproduced with permission from reference [169]. Copyright 2014 ACS. Concerning the combinations of metallopolymers with antibiotics, [PERSON] et al. [170] proposed a robust three component system based on cationic cobaltocenium, phenylboronic acid and \(\beta\)-lactams together in a single macromolecule. The synergistic effect emerged from the electrostatic absorption to negatively charged cell membranes by the cationic cobaltocenium moiety, while boronic acid attached to lipopolysaccharidesaccharides on the bacterial cells promoted the reinstatement of the vitality of antibiotics. Likewise, new antimicrobial systems have been proposed for preventing biofilm formation using existing clinically used drugs attached to a NO donor group. In this respect, [PERSON] et al. [171] reported an attractive approach based on polymeric NPs capable of storing NO and gentamicin. The NPs were found to simultaneously release both agents and demonstrated synergistic effects, suppressing the growth of _P. aeruginosa_ biofilm and planktonic cultures by more than 90% and 95%, respectively. Furthermore, a novel technology for simultaneously releasing NO and antibiotics (i.e., gentamicin, tetracycline) through an electrochemical NO release catheter device demonstrated a synergistic effect against biofilm and biofilm released cells [172]. Selected examples of antimicrobial polymers co-administered with antibiotics and its mechanism of action are summarized in Table 4.  
\begin{table}
\begin{tabular}{c c c c c} \hline \hline \multicolumn{1}{c}{**Schematic Representation of the**} & \multicolumn{1}{c}{**Antibiotic**} & \multicolumn{1}{c}{**Microorganism**} & \multicolumn{1}{c}{**Synergistic Effect**} & \multicolumn{1}{c}{**Ref**} \\ \cline{3-6} \multicolumn{1}{c}{**Antimicrobial Polymer**} & \multicolumn{1}{c}{**Antibiotic**} & \multicolumn{1}{c}{**Tested**} & \multicolumn{1}{c}{**Synergistic Effect**} & \multicolumn{1}{c}{**Ref**} \\ \hline \hline \multirow{6}{*}{
\begin{tabular}{c} **C**\({}_{\text{C}}\)**\({}_{