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Research Provides Insights into Emerging Antibiotic Resistance

Human Health

Tuberculosis diagnoses dropped 18 percent from 2019 to 2020 according to the World Health Organization (WHO). Further, 15 percent fewer people worldwide started treatment regimens designed to treat first-line resistant Mycobacterium tuberculosis (Mtb). Unfortunately, this is likely due not to the number of cases going down, but rather because the COVID-19 pandemic has upended years of progress in reducing global Mtb burden and exacerbated the spread of drug-resistant disease. This puts further strain on newly developed antibiotics and their ability to treat susceptible disease.

Expectations for Delamanid antibiotic

Once such antibiotic is Delamanid, which was approved for medical use in 2014, and has rapidly been added to treatment regimens. Delamanid, developed by Otsuka and available in Europe since 2014, is an antimycobacterial drug. Approved shortly after Bedaquiline, both are the first drugs of new classes registered for tuberculosis treatment in 40 years. Unlike other recently developed antibiotics, both drugs have quickly been added to clinical studies and treatment regimens. While naturally occurring resistance to Bedaquiline is already being observed, data on resistance to Delamanid is currently sparse.

Due in part to the pandemic, as well as the lack of consistency in treatment therapy, it is expected that antibiotic resistance to Delamanid will develop over the coming years, so research has begun to study resistance mechanisms that will prevent proper dosing and treatment. Initial studies have disagreed on what amount of Delamanid is needed to inhibit the growth of 99 percent of wild type strains of Mtb, with some suggesting as high as 0.2µg/mL [1] while others point to a lower value. With the advent of whole genome sequencing, genome analysis can also add understanding in real-time and separate naturally occurring phylogenetic mutations from those that confer true resistance. By creating a catalog of known variants linked to phenotypic resistance, clinicians can be empowered to assess drug suitability prior to treatment initiation. 

Contributing to Mtb data

As part of MRIGlobal’s involvement in the NIH Mycobacterium tuberculosis Quality Assessment (TBQA) program, we presented analysis of the minimum inhibitory concentration (MIC) of Delamanid within Mtb in the project’s strain repository. Paired with full genomic characterization, the resulting data serves to provide preliminary insight into both susceptible and elevated MIC thresholds that are currently being surveyed in labs around the world. 

Our research showed preliminary phenotypic and genotypic information for 25 distinct, globally diverse isolates. While our phenotypic data showed some differences in MIC values, little to no correlation is observed in the genotypic data, from known or unknown variants in regions of interest. As such, our data point toward a higher MIC value, above 0.001 or 0.012 µg/mL, that has been proposed by some studies. While the genomic data is limited by our current understanding of mechanisms of resistance and gene targets, we find no data that point toward a lower MIC value. While no final breakpoints have been set by CLSI, FDA, or the WHO, data like this from labs around the world continue to be generated to inform eventual testing targets. 

While antibiotic susceptibility is sometimes conceptualized within a binary paradigm, MICs along with epidemiological cutoff values represent a range of real-world factors that play into treatment decisions. The lack of alternative antibiotics in cases of extremely resistant disease, combined with the increasing prevalence of genomic sequencing to inform treatment decisions further accelerate the necessity of this on-going research.

Getting started with MRIGlobal

Contact MRIGlobal to further understand our work in infectious diseases. We offer a broad portfolio of infectious disease testing assays and capabilities across diagnostic disciplines, from screening and diagnosis to genotyping, therapy, and monitoring. Those seeking analysis of infectious disease tests can trust in our breadth of experience and knowledge – not just on the subject matter, but FDA protocols as well.

As a not-for-profit contract research organization, we have proven ourselves as an objective partner driven to make our clients’ products more successful. We specialize in defense, human health, pharmaceutical sciences, in-vitro diagnostics, energy and environment, agriculture, and global health

To learn more about the work we’ve done or how we can help you, contact us today. If you are part of an agency, business, or academic institution seeking assistance with a project, use our Project Quote Tool to get started. 

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