Biology subjects

Adler, K.

Publications and source records attributed to Adler, K..

3 recordsLinked to original sources

bioRxiv2025

Bacteriophage pharmacodynamics studied in an in vitro pharmacokinetic model of infection

SynopsisO_ST_ABSBackgroundC_ST_ABSBacteriophage therapy offers an alternative way to counter the menace of increasing antimicrobial resistance. Despite its use in clinical practice for many decades the basic tools to study the translational pharmacodynamics of phages are not available and it is recognised that lack of understanding of phage pharmacokinetic/dynamics (PK/PD) is a severe limitation in individual patient use and clinical trial design. MethodsTraditional in vitro PK/PD evaluation tools were used to assess the antibacterial effect of single exposures of a bacteriophage cocktail against 4 strains of E. coli with potentially different patterns of response to phage. Initially, time-kill curves (TKC) were performed over 48hr and subsequently a dilutional in vitro model (IVM) was used to assess the antibacterial effects over 72hr. ResultsIn TKC, the four E. coli strains showed different patterns of kill and regrowth when exposed to phage with two strains showing a sustained drop in bacterial viable count and two showing initial kill and regrowth. Using the IVM similar bacterial pharmacodynamic patterns were observed, and phage titre increased inversely but consistently with E. coli kill. ConclusionsAn In vitro dilutional model can be used to study the antibacterial effect of a phage cocktail on E.coli showing strain-to-strain variation in bacterial killing and bacteriophage titre. Such models can be used to provide more nuanced information on phage pharmacokinetics/dynamics and translationally useful information for dosing in humans.

microbiology↗

bioRxiv2024

Development of antibacterial drug plus bacteriophage combination assays

SynopsisO_ST_ABSBackgroundC_ST_ABSThe methods to evaluate the interactions between Phages and antibacterials are unclear. As the laboratory methodologies used to assess conventional antibacterials are well established, we asseassed their efficacy in evaluating phage plus antibacterial. Methods100 multidrug resistant E. coli strains were used with three previously isolated and characterised E. coli phages of known efficacy. These phages UP17, JK08, 113 were assessed both individually and in a 1:1:1cocktail. In a Phage Microbial Inhibitory Concentration (PmIC) assay, a range of phage concentrations from 101 -108 were inoculated with 5x105/well bacteria in microtitre plates. The first lysed, clear well was taken as the PmIC. Amikacin(AMI) and meropenem(MERO) MICs were determined by microbroth dilution methods(ISO 2776-1:2019) and in combination AMI and MERO MICs were measured with a fixed Phage concentration of 105/well. MICs were performed in triplicate. Time-Kill curves(TKC) were conducted at fosfomycin concentrations of 133, 50 and 5mg/L with and without phage. ResultsThe PmIC50/90 for UP17 were >108/>108; JK08 107/>108; 113 107/>108 and the 1:1:1 cocktail 106/>108. AMI MIC50/90 were 0.5/>16 and MERO 0.12/>16mg/L. The addition of UP17 to AMI increased AMI MICs >2 fold in 78 strains. Equivalent increases in AMI MIC were seen with 39 strains with JK08, 54 strains with 113 and 45 strains with the cocktails. In contrast, meropenem MICs in the presence of phage were reduced >2 fold in 24 strains with UP17. Equivalent decreases in MERO MIC were seen with 34 strains with JK08, 26 strains with 113 and 29 strains with the cocktails. In TKCs addition of phage suppressed regrowth. ConclusionMicrobroth methodologies based on ISO 2776-1:2019 and TKCs allow the interaction between Phages and antibacterials to be studied. Optimisation may produce laboratory-based methods with translational value.

microbiology↗

bioRxiv2021

Clinical Phage Microbiology:A suggested framework and recommendations for the in-vitro matching steps ‎of phage therapy

Personalized-phage-therapy is a promising solution for the emerging crisis of bacterial infections that fail to be eradicated by conventional antibiotics. One of the most crucial elements of personalized-phage-therapy is the proper matching of phages and antibiotics to the target bacteria in a given clinical setting. However, to date, there is no consensus guideline for laboratory procedures that enable in vitro evaluation of phages intended for treatment. In this work, we suggest a framework and strategies identify appropriate phages and combine them with antibiotics in clinical microbiology laboratories. This framework, which we term here "Clinical Phage Microbiology" is based on our experience and other previously reported cases of both, successful and failed phage treatments. Additionally, we discuss troubleshooting methodologies for possible pitfalls and special cases that may need to be assessed before treatment including interactions with the host immune system, biofilms, and polymicrobial infections. We believe that the "Clinical Phage Microbiology" pipeline presented here should serve as the basis for standardization of laboratory protocols to match phages for personalized therapy.

microbiology↗