# Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases
## 2 New Anti-Infectious Treatments against MDR and Persistent Bacteria
### Phage Therapy Alone or in Combination with Antibiotics to Treat MDR and Persistent Bacteria  
Clearly some alternative antibacterial therapies must emerge in order to halt the spread of MDR organisms. In this context, phage therapy is an antibacterial approach that involves using natural bacterial viruses (known as bacteriophages or phages) that infect and lyse bacteria to treat or prevent infectious disease [38; 39]. These viruses are natural predators of bacteria and, as recently reviewed by [PERSON] and colleagues [40], phages were used as a primary treatment for bacterial diseases from their discovery in the 1900s for a period of 25 years, until they were absolutely eclipsed by antibiotics. One of the advantages of phage therapy over broad-spectrum antibiotics is the high specificity toward target bacterial pathogens, with no adverse effects on the host itself or the host commensal microbiota [41], thus minimizing secondary effects. One interesting aspect of phage therapy is the synergistic interactions between phages and the host immune system [42]. Indeed, as it is not beneficial for phages to kill all of the host bacteria at the infection site (otherwise, they could not continue to replicate), they can be expected to control the bacterial pathogens and significantly reduce the population, thus providing the patient's immune system the chance to eliminate the remaining pathogens. Here, we cite a few examples of phage-based treatments of MDR and persistent infections. In 2017, [PERSON] and colleagues reported that a 68-year-old diabetic patient with necrotizing pancreatitis complicated by an MDR _A. baumannii_ infection was successfully treated with a personalized phage-based therapy consisting of nine lytic phages [43]. Five days after the bacteriophage-based therapy was started, once the infection was controlled, minocycline was administered, and infection was finally overcome. In 2011, [PERSON] et al. described the successful use of six lytic _P. aeruginosa_ phages as an adjunctive therapy for a recurrent bladder infection in a 67-year-old woman, most likely caused by a persistent subpopulation of _P. aeruginosa_ cells [44]. Antibiotics alone failed to overcome the infection, as is usually the case with recalcitrant, persistent bacteria. However, the combined use of meropenem and colistin and this phage cocktail led to the improvement of symptoms and a significant reduction in bacterial load, and the treatment was well-tolerated by the patient. The cocktail was applied every 12 h for 10 days and, from day eight onward, the bacterial count decreased until no viable bacteria were longer detected. Studies carried out by research teams led by [PERSON] [45] and [PERSON] [46] showed that the therapeutic effect was improved by starting treatment with antibiotic once the phages already started to fight infections caused by _P. aeruginosa_. Both of these studies highlight the importance of the sequential application of both treatments in order to achieve good results, as it appears that bacterial pathogens become more vulnerable to some antibiotics after phage treatment [47] and that the phages can even restore their sensitivity to antibiotics [48]. Importantly, phages can use bacterial efflux pumps as receptors, which would affect the clearance of antibiotics, one of the most widespread resistance mechanisms of bacteria [47]. In 2019, [PERSON] and colleagues described an engineered lysogenic phage (Ab105-2 phi\(\Delta\)CI) in which repressor CI protein was deleted, thus becoming lytic [49]. These researchers used a sophisticated assay in the first study using a mutant lytic phage in combination with imipenem and meropenemantibiotics. The combination caused a significant decrease in _A. buumannii_ MDR cells both in vitro and in vivo, with lower MICs needed for these carbapenems to be effective against the resistant pathogen. The anti-biofilm activity of phage phi11 endolysin, which can kill staphylococcal biofilms via its two endopeptidase domains, was described for the first time in 2007 [50].