In vitro Pharmacokinetic/pharmacodynamic models for dose de-escalation of antibiotics

Project Summary/Abstract: Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are problematic because of associated high 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 removal by the host immune system and lead to antibiotic-treatment failures due to bacterial tolerance, development of antibiotic resistance, and limited antibiotic penetration. Vancomycin is the recommended therapy for MRSA MDIs and the antibiotic 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. Dalbavancin is the so called “last line antibiotic”, a new lipoglycopeptide being used to treat MRSA infections. Our preliminary data furthermore have shown that neither daptomycin nor dalbavancin monotherapies are effective in eradicating high MRSA bacterial loads. In this context, the first aim of this project investigates the impact of a single dose of dalbavancin in combination with a single dose of daptomycin in biofilm state (in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with components of prosthetic material for biofilm growth). This aim is particularly important for combating MRSA infections associated with MDIs in out-patient settings. Bacteriophages (phages) have been found to readily serve as anti-biofilm agents, and in some cases can also encode biofilm matrix hydrolyzing depolymerases. Therefore, the second aim proposes a single dose of dalbavancin adjunctive to a single dose of daptomycin (day 1) and daily administration of bacteriophage Sb-1 to eradicate MRSA infections in biofilm state (in vitro PK/PD models as stated in aim 1). We will use pharmacokinetic monitoring to achieve dose de-escalation of antibiotics in antibiotic-phage treatment. Collectively, this proposal will apply pharmacokinetic measurements, such as area under the concentration- time curve to achieve dose-de-escalation in phage-antibiotic treatment regimens. The proposed research is significant in the context of preserving current and future antibiotics and provides critical information regarding resistance prevention/re-sensitization using antibiotic-phage co-treatments. We will test our central hypotheses by evaluating the susceptibility of biofilm embedded MRSA to the various proposed antibacterial combinations and then perform in vitro two-compartment PK/PD biofilm models with humanized pharmacokinetics to optimize these novel therapies. We expect that through optimizing therapy of MRSA-biofilm infections, we will improve patient care and prolong the useful life of dalbavancin and daptomycin for the management of MRSA MDIs.