*4.2.2 Anthelmintic drugs*

The anthelmintic drugs niclosamide, oxyclozanide, rafoxanide and ivermectin have been shown to restore the activity of colistin against a collection of Col-R *P. aeruginosa in vitro* [46–48, 57]. Not only in combination with colistin, oxyclozanide has presented synergy with tobramycin to destruct the biofilm formation, permeabilizing the cells membrane and depolarizing the membrane potential of *P. aeruginosa* strains resistant to tobramycin *in vitro* [28]. In the murine model of peritoneal sepsis by Col-R *P. aeruginosa* clinical isolate, rafoxanide plus CMS compared with CMS alone, increased mice survival to 73.3%, and reduced bacterial loads in tissues and blood between 3 and 5 log10cfu/g or mL, respectively [47]. In monotherapy, niclosamide and rafoxanide have exhibited antibacterial activity against *P. aeruginosa*. One *in vitro* study has indicated that niclosamide presented an anti-virulent effect against *P. aeruginosa* via the inhibition of QS and virulence genes, reducing elastase and pyocyanin levels [15]. Two additional *in vivo* studies have reported that niclosamide and rafoxanide showed therapeutic efficacy in *G. mellonella* larvae and in murine peritoneal sepsis models by a reference strain and Col-R clinical isolate of *P. aeruginosa*, respectively [15, 47]. Nevertheless, the absorption of niclosamide is lower. To increase this absorption, formulation of niclosamide under nanosuspension has been performed and showed lower toxicity in a rat lung infection model involving *P. aeruginosa* [14].

### *4.2.3 Anti-inflammatory and immunosuppressive drugs*

Similar with *A. baumannii*, anti-inflammatory and immunosuppressive drugs have presented antibacterial activities in monotherapy and in combination with antibiotics against *P. aeruginosa*. The activity of glatiramer acetate against reference and clinical isolates of *P. aeruginosa* from chronic respiratory infections in cystic fibrosis patients has been observed by disruption of the biofilm formation [42]. With the same mechanism of action, ebselen and azathioprine has exhibited activity against *P. aeruginosa* [43, 45]. In turns, celecoxib and betamethasone have presented synergy with colistin, and with ceftazidime, erythromycin and ofloxacin against *P. aeruginosa* in vitro, respectively [19, 76]. Similarly, meloxicam has been reported to be in vitro active alone and in combination with the sub-MIC of tetracycline, gentamicin, tobramycin, ciprofloxacin, ceftriaxone, ofloxacin, norfloxacin, ceftazidime against PAO1 strain, by inhibiting the biofilm formation [27]. Finally, GTS-21 has improved *P. aeruginosa* clearance in a murine model of ventilatorassociated pneumonia and reduced acute lung injury by enhancing macrophage function [39].
