Bacteriophages Improve Outcomes in Experimental Staphylococcus aureus Ventilator-associated Pneumonia

Abstract

At a Glance Commentary Scientific knowledge on the subject Antibiotic resistance challenges current practice. New antimicrobials approved for clinical application are scarce, and this underscores the urgent need for alternative strategies. Phage therapy is a promising approach for the treatment of antibiotic resistant bacteria, however infection specific, proof-of-concept experimental studies are currently missing. What this study adds to the field We assessed the efficacy of phage therapy for the treatment of experimental ventilator associated pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) in rats. Phage treatment improved survival compared to placebo and was equally as effective as traditional antibiotics in controlling MRSA infection. Combination of phages with antibiotics did not further improve outcome in this experimental setting.

Nebulized Bacteriophages for Prophylaxis of Experimental Ventilator-Associated Pneumonia Due to Methicillin-Resistant Staphylococcus aureus

“…Mortality in experimental models of VAP due to MRSA correlates with high bacterial loads in the lungs (7). In support of this, surviving animals treated with prophylactic aerophages had ~500 times less MRSA in the lungs compared with either untreated controls, or treated animals that succumbed to infection ( Fig.…”

“…Following aerophage application, animals were returned to their cages. Animals were euthanized at 0, 2, 6, and 24 hours (n = 3 per time point) at which point the lungs were homogenized and phages were quantified in double-layer agar plates as described previously (7). To determine if increasing the number of aerophages would improve experimental outcomes, the phage cocktail was concentrated via isopycnic ultracentrifugation through a caesium chloride (CsCl 2 ) gradient, the residual CsCl 2 was removed via filtration (Amicon Ultra Centrifugal Filters; Merck, Germany), and the phages were resuspended in 0.9% sodium chloride to a final concentration of 1 × 10 11 PFU/mL.…”

“…We next employed our established model of severe MRSA VAP essentially as described elsewhere (7). Briefly, animals (n = 10 per treatment group) received a single dose of either 3 × 10 10 PFU or 3 × 10 11 PFU of aerophages as described above and were returned to their cages.…”

“…Quantification of MRSA burdens in the lungs and spleen was performed following tissue homogenization as described previously (7). Histopathological analyses were performed as described previously (7), and a histopathological score was calculated for lung tissues according to parameters detailed in Supplemental Table 2 (Supplemental Digital Content 1, http://links.lww.com/CCM/F449). Infected and untreated animals (n = 7) were included as controls to validate the lethality of the model.…”

“…One strategy is the application of bacterial viruses known as phage therapy, which has been rediscovered for the treatment of many diverse, antibiotic-resistant infections (for a recent review, see reference [6]). In the context of VAP, intravenously administered phages have been shown to be as effective as standard of care antibiotics for the treatment of pneumonia due to methicillin-resistant S. aureus (MRSA) in an experimental model of VAP in rats (7). Phages have the added benefits of effectiveness against bacterial biofilms, and mechanisms of action that are distinct from typical antibiotics, which limits the threat of antibiotic resistance (8 questions relating to phage therapy remain, including when, how and how many bacteriophages should be delivered (8,9).…”