*4.3.1 Anticancer drugs*

Anticancer drugs were developed against *E. coli* and *K. pneumoniae in vitro* and in animal models. Tamoxifen has been reported to exhibit activity in the immunocompetent and neutropenic murine model of peritoneal sepsis by *E. coli* ATCC 25922 strain by decreasing the bacterial loads in spleen, lungs and blood and increasing the mice survival [36]. Tamoxifen metabolites N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen have presented antibacterial activity *in vitro* with MIC50 and MIC90 of 16 mg/L, against a 47 MDR clinical isolates of *E. coli* [36]. The activity of mitomycin C in monotherapy and in combination with tobramycin and ciprofloxacin together was increased against MDR clinical isolates of *E. coli* and *K. pneumoniae in vitro* [17, 18]. While, mitotane in combination with polymyxin B against polymyxinresistant *K. pneumoniae* increased the activity of polymyxin B *in vitro* [49].

**109**

*Drugs Repurposing for Multi-Drug Resistant Bacterial Infections*

Four anthelmintic drugs, niclosamide, oxyclozanide, rafoxanide and ivermectin were shown to present synergy with colistin against Col-R *K. pneumoniae* [30, 46–48, 57]. Compared to Col-R isolates of *A. baumannii* and *P. aeruginosa* much lesser effect has been observed regarding the effect of these drugs in combination with colistin against Col-R isolates of *K. pneumoniae*. Additionally, in the murine model of peritoneal sepsis model by Col-R clinical isolate of *K. pneumoniae*, rafoxanide in monotherapy and in combination with CMS compared with control animals and with CMS alone, increased mouse survival to 50 and 67%, and reduced bacterial loads in tissues and blood between 2.5 and 3 log10cfu/g or mL, and 2 and 3

In the case of anti-inflammatory drugs, two drugs have presented synergistic effect with antibiotics against *E. coli* and *K. pneumoniae*. The first one is celecoxib which has potentiated the activity of colistin against *E. coli* and *K. pneumoniae* [19]. In turn, betamethasone has presented synergy with ceftazidime and ofloxacin against some isolates of *E. coli* [76]. Similar to *A. baumannii* and *P. aeruginosa*, glatiramer acetate has presented antibacterial effect against reference strains of *E. coli* by disrupting the biofilm formation [42]. Moreover, ebselen has been shown to present antibacterial effect against *E. coli* by reducing their bacterial growth at MICs <128 μM due to the inhibition of TonB [51], and azathioprine has exhibited anti-biofilm activity against *E. coli* through the inhibition of WspR *in vitro* [43]. Finally, GTS-21 in combination with M1 muscarinic acetylcholine receptor agonist have been shown to reduce the mortality of mice in sepsis model by *E. coli* in 4 and 24 h [38]. At clinical stage, an interventional clinical trial on anti-inflammatory effects of oral administration of GTS-21 on the inflammatory response in 7 patients with endotoxemia by LPS of *E. coli* showed that GTS-21 reduced the levels of proinflammatory cytokines in the

Other drugs with different modes of action and clinical indications have been evaluated as antibacterial agents in monotherapy and in combined therapy with a large list of antibiotics against *E. coli* and *K. pneumoniae in vitro* and in animal models. Amoxapine has been reported to present therapeutic efficacy in an experimental murine model of respiratory infection by *K. pneumoniae* [93]. In addition, pentamidine in combination with different antibiotics ([novobiocin, erythromycin and rifampin] and [amikacin, tobramycin, tigecycline and rifampin]) has presented synergistic activity *in vitro* against different clinical isolates of *E. coli* harboring *mcr-1* and *K. pneumoniae* producing carbapenemases, respectively [94]. In turn, robenidine has been recently showed to present only synergy with polymyxin B nanopeptide against reference strains of *K. pneumoniae in vitro* [60]. Finally, auronafin and simvastatin exhibited synergy with sub-inhibitory concentrations of polymyxin B and colistin against a collection of reference strains of *E. coli* and *K. pneumoniae in vitro*, reducing the MIC of auronafin from >256 mg/L to 0.25–1 mg/L and the MIC of simvastatin from

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

log10cfu/g or mL, respectively [47].

plasma of these patients [91, 92].

>256 mg/L to 8–32 mg/L, respectively [58, 59].

*4.3.4 Other drugs*

*4.3.3 Anti-inflammatory drugs*

*4.3.2 Anthelmintic drugs*
