June 11, 2021

Dr. Michael Rybak and WSU Applebaum team receive NIH R21 grant to investigate antibiotic-bacteriophage combination

Wayne State University Professor of Pharmacy Practice Michael Rybak received funding as the principal investigator for a new NIH R21 grant from the National Institutes of Allergy and Infectious Diseases for a total amount of $423,000. The title of the grant is "Anti-biofilm activity of bacteriophage-antibiotic combinations against MRSA" (1R21AI163726-01). 

Co-investigators include Eugene Applebaum College of Pharmacy and Health Sciences Anti-infective Research Laboratory (ARL) Research Scientist Dr. Razie Kebriaei and Assistant Professor of Pharmacy Practice Dr. Andrew Berti.

Bacteriophages are viruses that attack bacteria. Rybak and his team are using them in combination with antibiotics to fight antibiotic-resistant bacterial pathogens. 

"Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of medical device infections (MDIs) and treatment failure is commonplace due to the production of bacterial biofilm and subsequent antibiotic inactivity and resistance development," Rybak said. 

"Antibiotic-bacteriophage combination is an alternative treatment approach for combating MDIs; however, there is limited to no information on the use of bacteriophage antibiotic combinations. We propose a comprehensive analysis of bacteriophage-antibiotic interaction that evaluates bactericidal activity of various combinations against MDIs in static and dynamic settings and is translatable to clinical scenarios."

Andrew Berti, PharmD, PhD Assistant Professor of Pharmacy Practice Co-investigator	Razie Kebriaei, PhD Research Scientist Co-investigator	Michael Rybak, PharmD, MPH, PhD Professor of Pharmacy Practice Primary Investigator

Summary/Abstract

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are problematic because of the high associated treatment failures and elevated mortality rates. Staphylococci including MRSA are the major cause of medical device infections (MDIs) due to their strong capability to form biofilms. These bacterial biofilms resist host immune system and lead to antibiotic failure due to limited antibiotic penetration, bacterial tolerance and development of antibiotic resistance. Vancomycin is the recommended therapy for MRSA MDIs and daptomycin is the primary antibiotic alternative to vancomycin for these infections; however, the development of daptomycin resistance especially post vancomycin therapy has been reported with increasing frequency. Although combination therapy of vancomycin or daptomycin with beta-lactam antibiotics such as ceftaroline have demonstrated improved activity in vitro, these combinations have not shown significant enhancements in MDIs caused by Staphylococci. Therefore, due to the lack of effective MDI treatments, novel antibacterial options are critically needed. Obligately lytic bacteriophages (phages) infect bacteria, replicate within the cell, lyse the cell to release their progeny and reinitiate the infection cycle. These phages eradicate both antibiotic susceptible and resistant bacteria in planktonic and biofilm forms. The combination of phage and antibiotics have shown to re-sensitize previously multi-drug resistant bacteria to antibiotics. Synergistic and antagonistic interactions in phage-antibiotic combinations are highly dependent on the mechanism of bacterial inhibition of the antibiotic paired to the phage, bacterial host state (biofilm versus planktonic) and bacterial growth age. Here we are offering a systematic investigation of phage antibiotic combination using various standard of care antibiotics (SOC) to examine the aforementioned parameters. The proposed research is significant especially due to lack of information regarding the use of phage with SOC antibiotics against biofilm embedded MRSA strains. Our central hypothesis is that the combination of phage-antibiotic will reduce the vancomycin and daptomycin exposures required for efficacy against biofilm embedded MRSA and further prevent the emergence of antibiotic resistance. We will test our central hypothesis by first evaluating susceptibility of biofilm embedded MRSA to various phage-antibiotic combinations and then performing in vitro two-compartment PK/PD biofilm models with humanized pharmacokinetics to optimize novel phage-antibiotic combination therapies. We expect that through optimizing therapy of MRSA-biofilm infections, we will improve patient care and prolong the useful life of vancomycin and daptomycin for the management of MRSA MDIs.

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Further reading

May 15, 2020: Professor Michael Rybak wages war against antibiotic resistance

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