Phage Therapy Potentiates Second-Line Antibiotic Treatment against Pneumonic Plague

Abstract

Plague pandemics and outbreaks have killed millions of people during the history of humankind. The disease, caused by the bacteria Yersinia pestis, is currently treated effectively with antibiotics. However, in the case of multidrug-resistant (MDR) bacteria, alternative treatments are required. Bacteriophage (phage) therapy has shown efficient antibacterial activity in various experimental animal models and in human patients infected with different MDR pathogens. Here, we evaluated the efficiency of фA1122 and PST phage therapy, alone or in combination with second-line antibiotics, using a well-established mouse model of pneumonic plague. Phage treatment significantly delayed mortality and limited bacterial proliferation in the lungs. However, the treatment did not prevent bacteremia, suggesting that phage efficiency may decrease in the circulation. Indeed, in vitro phage proliferation assays indicated that blood exerts inhibitory effects on lytic activity, which may be the major cause of treatment inefficiency. Combining phage therapy and second-line ceftriaxone treatment, which are individually insufficient, provided protection that led to the survival of all infected animals—a synergistic protective effect that represents a proof of concept for efficient combinatorial therapy in an emergency event of a plague outbreak involving MDR Y. pestis strains.

Rapid Induction of Protective Immunity against Pneumonic Plague by Yersinia pestis Polymeric F1 and LcrV Antigens

“…In this report, the elicitation of rapid protection was interrogated in the case of pneumonic plague using the well-established murine model consisting of exposure of mice to the pathogen by intranasal inoculation. This model was shown to preserve the pathogenicity characterizing respiratory manifestations of primary pneumonic plague ( Supplementary Figure S1 ) [ 10 , 19 , 21 , 22 , 23 , 24 ].…”

“…The recent isolation of virulent Y. pestis strains resistant to multiple antibiotics, including those recommended for therapy, and the concern that such altered phenotypes may be maliciously introduced into virulent strains for biological warfare or bioterrorism necessitates the development of additional countermeasures [ 6 , 7 , 8 ]. Indeed, the recent application of second-line antibiotics, additional therapeutic modalities, and the combination of antibiotic and phage therapy shows promising results in the mouse model of the pneumonic plague [ 9 , 10 ].…”

A Bacteriophage Cocktail TargetingYersinia pestisProvides Strong Post-Exposure Protection in a Rat Pneumonic Plague Model

“…Significantly, even when disease-causing bacteria were antibiotic-sensitive, administering phages together with traditional antibiotics was reported to improve the clinical outcome (reviewed in (20)). Although the underlying mechanisms for this phenomenon have not been rigorously elucidated, it is likely that simultaneously exposing a pathogen to two antibacterial agents possessing different modes of actions (i.e., phages and antibiotics) resulted in more effective bacterial killing than did treatment with just the traditional antibiotic alone (26). Indeed in this study, a combination of phage and antibiotic therapy was able to achieve complete protection when neither therapy was effective alone.…”

“…Several previous studies have shown in vitro phage efficacy against Y. pestis (22–24); however, a few studies have demonstrated in vivo efficacy (25, 26). In one study, phage treatment was shown to delay progression of pneumonic plague; however, all mice still succumbed unless antibiotic therapy was co-administered (26). Here, we assessed a four-phage preparation, YPP-401, to target Y. pestis in vitro and in vivo .…”

Advancement of Phage Therapy Approaches in The Battle of Multi-Drug Resistance: A Review

“…Despite being in its infancy, research on the connections between phage treatment and innate and adaptive immunity is essential. Phage treatment is becoming increasingly viable for use as an antibacterial agent to combat illness as more thorough studies are released by leading Western scientists and corporations 186,187 . The public and the medical community may become more interested in phage treatment, particularly in countries like the US, where the regulatory framework is less conducive to its implementation in the near future 188,189 .…”