Phage therapy dates back to the beginning of the 20th century, even before Alexander Fleming’s discovery of penicillin in 1928 [68]. The first phage activity dated back to 1896, when Ernest Hankin reported that the waters from the rivers Ganges and Yamuna in India possessed antibacterial activity against Vibrio cholerae [69]. In the late 1910s, and following initial work by the English bacteriologists Ernest Hankin and Frederick Twort, a French microbiologist from the Pasteur Institute (Felix d’Herelle, 1917) identified viruses that specifically and selectively parasitized bacteria and named them “bacterium eaters” (bacteriophages) [70,71]. It was d’Herelle who first developed the notion of using phages therapeutically to treat bacterial infection with encouraging results [69]. However, since the discovery and development of antibiotics, Phage therapy was largely abandoned in the Western world due to the efficacy and promise held by antibiotics, with the exception of the Soviet Union and some Eastern European countries [69]. Recently, and in the face of the rapid emergence of resistant bacteria, phages (estimated to exceed 1031 particles) have re-emerged as alternative and complementary therapies to control bacterial infections [72]. Thus, phage therapy has shown to be an interesting alternative in the fight against multi-drug resistant bacteria [73]. Phages or bacteriophages are lytic viruses that exclusively and specifically infect bacterial species, showing bactericidal effects against both Gram-positive and Gram-negative bacteria [74,75]. In contrast, some tend to be specific to a particular species or strain of bacteria [76]. The tailed double-stranded DNA phages (order Caudovirales) are the most studied group and are thought to account for 96% of all phages and are easily isolated from various environmental sources (soil, wastewater, and aquatic environments) [73]. By adhering, via tail proteins, to specific surface receptors of bacteria, phages insert their genetic material into their bacterial hosts [69]. Several types of life cycles can be triggered by bacteriophages, of which the two most frequent are the lytic and lysogenic cycles [68]. During the lysogenic cycle, the virion DNA is incorporated in the bacterial genome. The resulting prophage replicates its genetic material within the bacterial cell without damaging it until the lytic cycle is trigger [68,77]. Undoubtedly, prophages are supposed to be shunned and lytic phages are selected. During the lytic cycle, the phage uses the cellular machinery to yield as many as 20,000 new virions per infected bacterial cell in optimal conditions [68]. These phages secrete lytic enzymes (endolysins) that hydrolyze the bacterial cell wall to ensure phage release [77,78]. Since then, it has become clear that phage therapy and the application of its endolysins offer the possibility to apply more specific antibacterial treatments and propose a potential solution to the problem of antibiotic resistance [79]. The table below (Table 1) shows some advantages of applying phage therapy to fight bacterial infections.

Before the dawn of antibiotics, phage therapy had been used to treat a broad range of bacterial infection diseases, including cholera [89,90,91], pediatric dysentery [92], bubonic plague [93], typhoid fever, skin and surgical site infections, peritonitis, septicemia, and external otitis [92,93]. However, in 1934, the failed attempts to reproduce positive findings had inspired the opposition from the Council on Pharmacy and Chemistry of the American Medical Association [91]. This opposition has not prevented parts of Eastern Europe (such as Georgia, Poland and Russia) from continuing to use phages in routine medical practice and today provide us with a rich source of empirical data [94]. For example, The Eliava Institute of Bacteriophage, Microbiology, and Virology in Georgia is one of the longest-running institutions where phage therapy has been provided to frequent bacterial diseases related to urology, pediatrics, internal medicine, and gynecology [71]. Recently, phage therapy has been re-employed in the United States and Europe, for the treatment of infections related to burn injuries or soft tissue and skin trauma, osteomyelitis, sepsis, bacteremia, and otitis media as well as urinary tract, pulmonary, and prosthetic device-associated infections, especially when mono- or multi-infected patients with multi-resistant bacteria are without effective treatment options or are terminally ill [71,95]. In Table 2 below, we quote the references of the main applications of phage therapy (as an adjuvant or alternative therapy to antibiotics) conducted on human patients infected with various types of MDR bacteria [2]. Results from these studies indicate that this therapy has immense potential with applications in human medicine.

Although phage therapy has come a long way, and is considered a promising alternative to antimicrobial agents, they have a dark, poorly explored side (Table 3). These limitations complicate the design of clinical protocols, undermine confidence in phage application, and need to be cleared before establishing successful phage therapy on a global scale.