7th joint conference "Joint Microbiology & Infection Conference 2024" of the DGHM and VAAM

Chair

Professor

Abstract: Antimicrobial resistance is a major threat to human health globally and has changed the way medicine is practiced. Infections previously treated with oral antibiotics now require intravenous treatment, and, because whether an antimicrobial resistant bacterium may be causing infection is often unknown when therapy is initiated, unnecessarily broad-spectrum antibiotics are frequently prescribed, or alternatively, the prescribed regimen may not even treat the infection because of unrecognized underlying resistance. In addition, antibiotics are given to those who do not need them because they do not have a bacterial infection. Antibacterial resistance involves hundreds of microbial species, dozens of antibiotics, and many clinical syndromes. While development of new therapeutics and antimicrobial stewardship are needed, better diagnostics and appropriate use thereof need to be better incorporated.  
The classic three-step diagnostic paradigm used in medicine, taught to students, and applied by medical professionals, involves asking whether a clinical presentation could be due to infection (step 1 – based on history, physical examination, initial tests), what the causative microorganism(s) might be (step 2 – based on culture, serologic testing, molecular testing for microorganisms), and finally, which treatment should be administered (step 3 – based on culture-based antimicrobial susceptibility testing). This approach, although intellectually interesting, is at once contributing to the antimicrobial resistance crisis and failing because of it. Creative use of technology can help; fortunately, we are in a technology revolution in terms of microbial diagnostics. There have been major advances in the application of proteomics, nucleic acid amplification tests and sequencing-based diagnostics, microbial imaging, microbial metabolomics, and advanced host response assessment for infectious diseases in recent years, and point-of-care diagnostics are transforming where testing can be done. Modern diagnostic tests can curb emergence of antimicrobial resistance by informing improved antibiotic use (a patient and societal benefit), leading to avoidance of unneeded testing and treatment (a patient benefit), decreasing transmission of infectious diseases (a societal benefit) and informing new discoveries and better delivery of healthcare (which will have future benefits).  
This presentation will overview how, with improved diagnostic testing, medicine can undo the classic and slow diagnostic paradigm, using diagnostics that detect microorganisms and directly call out ideal therapy in a single step, so-called, microbial “theranostics”. 

Microbial Theranostics – A Resistance Combatting Strategy

Prof.

Plenary Speaker

Plenary Lecture

Abstract: M. tuberculosis lineage 2 is one of the most widely dispersed lineages in the world, and is particularly associated with the spread of multi-resistant strains in Eurasia. However, the reasons for the success of Lineage 2 are only partially understood. My presentation will develop and underline the importance of an integrative approach to answer this question. Firstly, using Bayesian phylogenomics and demogenetics analyses, based on hundreds or thousands of complete genomes, I will illustrate the strength, spread and timing of major L2 epidemics, which highlight and confirm the dominance of this lineage both in terms of antibiotic resistance and epidemiological success.  In addition, we will also see how major socio-economic events reinforce ongoing epidemics. In the second part, which focuses on the underlying mechanisms, I will summarize how predictive simulations, epidemicity indices, genome-wide association studies and, finally, laboratory fluctuation assays have enabled us to make progress on this subject.  
For example, we were able to show that the collapse of the Soviet Union and, later, the Russian economic crisis were the main drivers of epidemics rebounds. L2 strains showed a significant (P < 0.01) pattern of accelerating mutation rate along the tree branches, and this on a scale of only 30 years. Furthermore, fluctuation assays showed that modern Central Asian lineage 2 strains acquire rifampicin resistance about twice as fast as ancestral L2 or Lineage 4 strains. The same applies to bedaquiline, for which basal Beijing strains outperform L4 strains. The fact that L2-derived strains have significantly higher mutation rates than other lineages is likely to enhance their adaptive landscape, as well as their propensity to acquire resistance/compensatory mutations.  


Evolutionary history and adaptive landscape of the M. tuberculosis Beijing lineage

Abstract: Antifungal drug tolerance and resistance are distinct responses to drugs that inhibit fungal growth. Intrinsic tolerance is a relatively stable property of each isolate characterized by a subpopulation of cells that grow in drug concentrations that inhibit the growth of the overall population. Strains with higher tolerance have a larger subpopulation of cells that can grow in the drug and, on average, those tolerant cells overcome cell cycle arrest earlier than cells with lower tolerance levels. Intrinsic tolerance levels, which differ between C. albicans isolates, are influenced by growth conditions and stresses including temperature, pH, and osmotic stress, with different isolates affected by these conditions and stresses to different degrees. These intrinsic differences between tolerance in different strains are likely a function of the broad diversity of genetic backgrounds, and the many genes involved in the tolerance response. We are testing the hypothesis that antifungal drug tolerance requires a broad range of interdependent physiological processes that operate to different degrees in different isolates across the diversity of the C. albicans species.   
 
Acquired tolerance emerges in newly drug-tolerant cells, usually as a consequence of drug selection. Heterotolerance is a transiently stable type of acquired tolerance usually conferred by the transient genome changes such as aneuploidy or copy number variations. It is thought that the increased level of genes that promote het extra copies of genes that affect drug responses. Relative drug concentration has a dramatic effect on the evolution of survival strategies: Hetero-tolerant colonies arise frequently  
(~1/1000 cells within a single liquid passage) in cultures exposed to supra-MIC drug concentrations, whereas heteroresistance (transiently acquired resistance) appears only after multiple passages at sub-MIC drug concentrations.  Isolates with heterotolerance often carry one of several recurrent aneuploid chromosomes, alone or in combination with other chromosomes.   We are leveraging a large collection (> 1500 isolates) of C. albicans to better understand how genetic, physiological and environmental factors affect the evolutionary trajectories and dynamics with which antifungal drug tolerance and resistance emerge and persist. 

Plenary Session 6 (DGHM)
Challenges in AMR

Appointment

Chair

Programme

Plenary Session 6 (DGHM)Challenges in AMR

Appointment

Chair

Programme

Plenary Session 6 (DGHM)
Challenges in AMR