*4.1.3 Anti-inflammatory drugs*

As is the case with anthelmintic drugs, anti-inflammatory drugs have demonstrated antibacterial activity against *A. baumannii* in monotherapy and in combination with polmyxins *in vitro*. Glatiramer acetate has presented activity against reference strains and clinical bacteremic isolates of A. baumannii by disrupting the biofilm formation [42]. In addition, ebselen has presented antibacterial effect against *A. baumannii* by reducing their bacterial growth at MICs of 32 μM due to the inhibition of the siderephore TonB [51]. In combination with polymyxins, auranofin, a drug used for the treatment of rheumatoid arthritis, and celecoxib have exhibited synergy with polymyxin B and colistin against reference strains of *A. baumannii* respectively [19, 58].

### *4.1.4 Other drugs*

Other drugs with different modes of action and clinical indications have been evaluated as antibacterial agents against *A. baumannii* in monotherapy and in combination with antibiotics. Simvastatin, used in the treatment of atherosclerotic cardiovascular disease and hypercholesterolemia, has exhibited antibacterial activity in combination with sub-inhibitory concentrations of colistin against a collection of clinical isolates of *A. baumannii*, reducing the MIC of simvastatin from >256 mg/L to a range between 8 and 32 mg/L [59]. Two antiprotozoal drugs have been also evaluated in monotherapy and in combination with antibiotics. Robenidine has presented bactericidal activity alone and in combination with polymyxin B nanopeptide against reference strains of *A. baumannii in vitro* [60]. Pentamidine, in turn, has present synergy with novobiocin, a drug used for Gram-positive cocci infections, in vitro and in murine sepsis model by a reference strain of *A. baumannii* [29].

## **4.2** *Pseudomonas aeruginosa*

*Pseudomonas aeruginosa* is one of the most relevant pathogens causing human opportunistic infections in immunocompromised patients and severe nosocomial infections [61–63]. Indeed, *P. aeruginosa* is the top pathogen causing ventilatorassociated pneumonia and burn wound infections and is a major cause of nosocomial bacteremia [62–64]. An MDR pattern is commonly observed in *P. aeruginosa* clinical isolates, raising the threat of difficult-to-treat infections [65–67]. These MDR isolates are generally susceptible to polymyxins and resistant to imipenem and ceftazidime [68]. New beta-lactamases inhibitors, combined with existing antibiotic families, such as ceftazidime/avibactam, ceftolozane/tazobactam, and imipenem/relebactam, against specific carbapenemases, have recently been developed [69]. Compared with *A. baumannii*, much more work has been done regarding the development of repurposing drugs for *P. aeruginosa* in preclinical and clinical stages.

#### *4.2.1 Anticancer drugs*

Different studies have been performed on *P. aeruginosa* to evaluate the antibacterial effect of anticancer drugs. Regarding SERM drugs, raloxifene attenuated *in vitro* and in *C. elegans* model the virulence of *P. aeruginosa* by binding to PhzB2 which is involved in the production of pyocyanin [24]. Whereas, tamoxifen exhibit therapeutic efficacy in murine model of peritoneal sepsis by PAO1 strain by decreasing the bacterial loads in spleen, lungs and blood and increasing the mice survival [36]. In addition, cisplatin was found to inhibit microbial cells growth [17, 20] by the upregulation of the recA gene in *P. aeruginosa* [20]. 5-fluorouracil, in turn, has been used against a collection of 5850 mutants of the PA14 strain, revealing positive activity via the regulation of a large number of genes involved in QS and biofilm formation [41, 70]. In combination with antibiotics, two anticancer drugs have been tested. Mitomycin C and mitotante in combination with tobramycin-ciprofloxacin [17] and polymyxin B [49], respectively, have shown synergy against MDR clinical and polymyxin-resistant isolates of *P. aeruginosa*, respectively. Finally, gallium nitrate is one the most studied and advanced cancer drug in clinical development against *P. aeruginosa* infection with promising data. Gallium nitrate has demonstrated an inhibitory effect on bacterial growth in *P. aeruginosa* at concentrations >3.13 μM *in vitro* [71, 72]; although the presence of pyoverdine and proteases in human serum reduce the efficacy of gallium nitrate against *P. aeruginosa* [73]. At non-bactericidal concentrations, gallium nitrate can

**107**

function [39].

*4.2.4 Antidepressive drugs*

*Drugs Repurposing for Multi-Drug Resistant Bacterial Infections*

increase the forced expiratory volume in these patients [75].

affect the production of virulence factors of *P. aeruginosa* [71, 74]. In murine models of acute and chronic lung infections by *P. aeruginosa* gallium nitrate has reduced the lung injury and bacterial loads in tissues of animals [71]. At clinical stage, a phase II clinical trial has been started in 2016 evaluating the capacity of gallium nitrate to improve the pulmonary function in 60 patients with cystic fibrosis by *P. aeruginosa*. The results of this trial showed that treatment with gallium nitrate

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

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

Regarding the antidepressive drugs, amitriptyline has reduced the inflammation in the lung of cystic fibrosis mice and prevented infection by *P. aeruginosa* [77]. At clinical stage, a phase II clinical trial evaluating the effect of amitriptyline on the

*DOI: http://dx.doi.org/10.5772/intechopen.93635*

*4.2.2 Anthelmintic drugs*

involving *P. aeruginosa* [14].

*4.2.3 Anti-inflammatory and immunosuppressive drugs*

#### *Drugs Repurposing for Multi-Drug Resistant Bacterial Infections DOI: http://dx.doi.org/10.5772/intechopen.93635*

affect the production of virulence factors of *P. aeruginosa* [71, 74]. In murine models of acute and chronic lung infections by *P. aeruginosa* gallium nitrate has reduced the lung injury and bacterial loads in tissues of animals [71]. At clinical stage, a phase II clinical trial has been started in 2016 evaluating the capacity of gallium nitrate to improve the pulmonary function in 60 patients with cystic fibrosis by *P. aeruginosa*. The results of this trial showed that treatment with gallium nitrate increase the forced expiratory volume in these patients [75].
