Abstract
The spread of multidrug antibiotic resistance (MDR) is a widely recognized crisis in the treatment of bacterial infections, including those occurring in military communities. Recently, the World Health Organization published its first ever list of antibiotic-resistant “priority pathogens” – a catalog of 12 families of bacteria that pose the greatest threat to human health with A. baumannii listed in the “Priority 1: Critical” category of pathogens. With the increasing prevalence of antibiotic resistance and limited development of new classes of antibiotics, alternative antimicrobial therapies are needed, with lytic bacteriophage (phage) specifically targeted against each of the high priority bacterial infections as a potential approach currently in development toward regulatory approval for clinical use. Balb/c mice were prophylactically administered PBS or phage selected against A. baumannii strain AB5075. After 3 weeks, mice were anesthetized, wounded (dorsal), and challenged topically with AB5075. Following infection, mice were subsequently treated with PBS or phage for three consecutive days, and evaluated for 3 weeks to assess the safety and efficacy of the phage treatment relative to the control. We assessed mortality, bacterial burden, time to wound closure, systemic and local cytokine profiles, alterations in host cellular immunity, and finally presence of neutralizing antibodies to the phage mixture. In our study, we found that prophylactic phage administration led to a significant reduction in monocyte-related cytokines in serum compared to mice given PBS. However, we detected no significant changes to circulating blood populations or immune cell populations of secondary lymphoid organs compared to PBS-treated mice. Following prophylactic phage administration, we detected a marked increase in total immunoglobulins in serum, particularly IgG2a and IgG2b. Furthermore, we determined that these antibodies were able to specifically target phage and effectively neutralize their ability to lyse their respective target. In regards to their therapeutic efficacy, administration of phage treatment effectively decreased wound size of mice infected with AB5075 without adverse effects. In conclusion, our data demonstrate that phage can serve as a safe and effective novel therapeutic agent against A. baumannii without adverse reactions to the host and pre-exposure to phage does not seem to adversely affect therapeutic efficacy. This study is an important proof of concept to support the efforts to develop phage as a novel therapeutic product for treatment of complex bacterial wound infections.
Highlights
The Infectious Diseases Society of America (IDSA) has categorized antimicrobial resistance as “one of the greatest threats to human health worldwide” (Hospenthal et al, 2011)
We found in mice administered phage, the spleen possessed the highest titer of phage (2.02 × 105 ± 1.34 × 105 PFU/mL) followed by liver (8.71 × 102 ± 1.29 × 102 PFU/mL) and lymph nodes (LN) (4.43 × 105 ± 1.97 × 102 PFU/mL), whereas control animals had undetectable titers in all organs (Figure 2)
We found that phosphate-buffered saline (PBS)–PBStreated mice subsequently infected with AB5075: lux had a high bacterial bioburden 24 h after infection as measured by capturing the bacterial luminescence signal using an in vivo imaging system (IVIS)
Summary
The Infectious Diseases Society of America (IDSA) has categorized antimicrobial resistance as “one of the greatest threats to human health worldwide” (Hospenthal et al, 2011). The primary culprits have been identified as the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), and can cause severe local and systemic infections (Murray et al, 2009; Hospenthal et al, 2011). Because of the severity of their injuries, patients with combat-trauma are at a high risk for acquiring nosocomial infections from MDR bacteria due to prolonged hospitalization, inter-institutional transfer, exposure to invasive devices (e.g., central venous catheters, etc.), and exposure to antibiotics (Safdar and Maki, 2002). Pathogens of the ESKAPE (E. faecium, S. aureus, Klebsiella spp., A. baumannii, P. aeruginosa, and Enterobacter spp.) classification were identified as the most frequent isolates associated with combat-trauma wound infections (Keen et al, 2010). We investigated the efficacy of phage as a prophylactic and therapeutic regimen, and the impact that pre-immunization to phage has on subsequent efficacy
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