**4.1** *Acinetobacter baumannii*

MDR *A. baumannii* is a well-recognized current global health threat that needs urgent effective solutions [1, 2]. Last-resort treatments such as colistin are no longer effective in an increasing number of cases, leading to a mortality rate of around 35–60% in hospitalized patients with ventilator-associated pneumonia [54, 55]. The number of antibiotics approved by the FDA cannot keep up with the pace at which resistance is acquired by *A. baumannii*. The therapeutic potential of different repurposing drugs against *A. baumannii* has been tested in preclinical models, most of them in combination with polymyxins (colistin and polymyxin B) or its prodrug colistimethate sodium (CMS).


#### **Table 2.**

*List of repurposing drugs under clinical trial development against Gram-negative critical-priority pathogens.*

**105**

*Drugs Repurposing for Multi-Drug Resistant Bacterial Infections*

The antibacterial activity of anticancer drugs has been reported *in vitro* and *in vivo* non-vertebrate and vertebrate models by *A. baumannii*. Gallium nitrate has demonstrated an inhibitory effect on bacterial growth in a collection of 58 MDR clinical isolates of *A. baumannii in vitro* [33]. This antibacterial activity is maintained in *G. mellonella* model. The administration of this drug alone and in combination with colistin, at concentrations mimicking the human therapeutic dose of gallium nitrate used for cancer patients (28 μM), significantly increased the survival of larvae after infection by A. baumannii [33]. When a vertebrate model was used such as murine models of acute and chronic lung infections by *A. baumannii*, gallium nitrate has reduced lung injury and bacterial loads in tissues [32]. Moreover, the combination of mitomycin C with tobramycin and ciprofloxacin together has increased *in vitro* the activity of this anticancer drug against MDR clinical isolates of *A. baumannii* [17]. Whereas, mitotane combined with polymyxin B against polymyxin B-resistant *A. baumannii* has presented synergy with polymyxin B, increasing the activity of polymyxin B *in vitro* and in murine model of burn wound infection by reducing the bacterial load in wounds [49]. Another group of anticancer drugs developed to combat breast cancer is the SERMs. Tamoxifen has been reported to exhibit activity in the immunocompetent and neutropenic murine model of peritoneal sepsis by ATCC 17978 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), produced after tamoxifen metabolizing by cytochrome P450 [56], have presented antibacterial activity in vitro with MIC50 and MIC90 of 8 and 16 mg/L, respectively, against a collection 100 MDR and pan-drug resistant (PDR)

The potential activity of the anthelmintic drug has been also tested *in vitro* and in animal models by *A. baumannii*. Niclosamide, oxyclozanide, rafoxanide and ivermectin have been shown to potentiate the activity of colistin against clinical isolates of Col-R *A. baumannii in vitro* [30, 46–48, 57]. In the murine model of peritoneal sepsis by Col-R *A. baumannii* clinical isolate, rafoxanide plus CMS, a prodrug of colistin, compared with CMS alone increased mice survival to 53.8% and reduced bacterial loads in tissues and blood between 3 and 4 log10cfu/g or mL, respectively [47]. Only, rafoxanide has exhibited antibacterial activity in monotherapy in this

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

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

clinical isolates of *A. baumannii* [36].

model of infection, but not *in vitro* [47].

*4.1.3 Anti-inflammatory drugs*

*A. baumannii* respectively [19, 58].

*4.1.2 Anthelmintic drugs*

*4.1.1 Anticancer drugs*
