DRG highlights some of the most interesting findings at the 28th ECCMID
Recently I had the opportunity to attend the 28th European Conference on Clinical Microbiology and Infectious Diseases in Madrid, Spain. With a record-breaking numbers of attendees, there were many simultaneous sessions, and plenty of information covering different topics of interest in infectious diseases and clinical microbiology. After four intense days of talks, posters and very productive discussions with other attendees, highlighting the most impactful topics was challenging, but these are my choices:
- β-lactamase/ β-lactamase inhibitor (BL/BLI) combinations, the class that keeps on giving. Leveraging their clinical success and specialists’ familiarity, these combinations continue to capture significant development efforts, with multiple new molecules that offer improved efficacy and broader spectrum of activity in the pipeline. In addition to several presentations focusing on the currently marketed agents, such as Merck’s Zerbaxa, Pfizer/Allergan’s Avycaz/Zavicefta and Melinta Therapeutics’ Vabomere, other emerging agents captured my attention. Merck presented data from a Phase III trial comparing the efficacy of their latest BL/BLI, imipenem/cilastatin/relebactam against imipenem/cilastatin + colistin in imipenem non-susceptible pathogens. In this trial, Merck’s antibiotic demonstrated non-inferiority to the comparator, reflected in a higher clinical response and a lower all-cause mortality rates at day 28. Allecra presented additional data on AAI101, a novel penicillanic acid sulfone β-lactamase inhibitor being developed in combination with cefepime, while Roche and VenatoRx presented in vitro data on their own inhibitors, nacubactam and VNRX-5133, respectively. Although in different stages of development, each of those three agents offers properties that may address some of the current unmet needs in the treatment of gram-negative pathogens.
- Antibiotics with novel mechanisms of action are on the horizon. Long identified as an area of interest, the development of antibiotics with novel mechanisms of activity is not without challenges. However, several companies have embraced the challenge, leading to some promising molecules in different stages of development. Swiss developer Polyphor presented additional data on their potent Pseudomonas-specific molecule murepavadin, currently in Phase III, as well as new data on their next generation outer membrane protein targeting antibiotics (OMPTAs), which offer a broader spectrum of activity against gram-negative pathogens. Melinta Therapeutics offered insights into one advanced lead from their ESKAPE program, RX-P382, a molecule that belongs to the pyrrolocytosine class, with activity against not only Enterobacteriaceae but also the difficult-to-treat non-fermenters baumannii and P. aeruginosa. Spero Therapeutics’ SPR-741 is perhaps one of the most curious molecules. A polymyxin antibiotic, it has no intrinsic activity against bacteria, but when combined with a β-lactam it restores that agent’s activity against ESBL and carbapenem resistant Enterobacteriaceae.
- MERINO trial evaluated piperacillin/tazobactam in the treatment of bloodstream infections (BSIs) by expanded spectrum β-lactamase (ESBL) producing microorganisms. In a room bursting at the seams, the much anticipated MERINO trial may have put an end, or at least contributed to the end of the ongoing debate of the carbapenem-sparing role of piperacillin/tazobactam for infections due to ESBL-producing organisms. This was a randomized trial that enrolled nearly 400 patients with confirmed infections caused by ESBL-producing Enterobacteriaceae, and had all-cause mortality at 30 days as the primary endpoint. Analysis of the results showed a higher mortality rate in the piperacillin/tazobactam arm than in the meropenem arm (12.3% vs 3.7%, respectively), favoring the use of meropenem. In the secondary endpoints, meropenem also attained higher rates of success and lower rates of failure, although those differences were not statistically significant. The results surprised many of those present in the room, who were eagerly awaiting confirmatory evidence that piperacillin/tazobactam could be an effective carbapenem-sparing therapy. These results will have important implications, and may lead to a continued reliance in the use of carbapenems, particularly in the setting of infections due to ESBLs. However, it also presents an opportunity for drugs in development to address a need for effective carbapenem-sparing agents, albeit one that will be a tall order to meet.
- Rapid identification and susceptibility testing will enable a faster and more appropriate use of antibiotics. In the recent years a myriad of technologies such as CRISPR, CAR-T or gene therapy have become available and have been widely adopted, but the clinical microbiology laboratory continues to rely on decades old assays to identify and to determine a pathogen’s susceptibility to different antibiotics, constituting a barrier to rapid adoption of a more targeted therapy. The interest (and need) for assays that decrease the time to effective therapy led to an important investment, with various products at different stages of development, including some of them already commercialized. The list of developers is long, and I could not list them all here without forgetting some. However, two of them caught my attention, perhaps due to their use in clinical practice and the technology driving them. Accelerate Diagnostics’ Accelerate Pheno System promises to offer pathogen identification and antibiotic susceptibility testing from positive blood cultures in less than 10 hours, a stark contrast to the baseline 48 hours required by traditional techniques. T2 Biosystems, powered by T2 Magnetic Resonance technology, can identify a panel of bacteria directly from blood within hours. Unlike Accelerate’s device it does not evaluate antibiotic susceptibility, but rather allows for earlier adoption an antibiotic therapy tailored to the pathogens identified. While these assays are relatively new and expensive, they have the potential to improve clinical outcomes and to decrease costs associated with longer lengths of stay in the hospital.
- The importance of the microbiome in the treatment and management of infectious diseases is broad. In the past years, much attention has been given to the role of microbiome across multiple therapeutic areas, and infectious diseases is the area where microbiome-based treatments are in the most advanced stages of development. The influence of the microbiome in infectious diseases is extensive, as evidenced by numerous presentations on the topic, including the prevention of CDI recurrences, protection against bacterial infections, and its use as a source of antibacterial therapies. Because of the relevance of the microbiome in disease pathology, there is not only interest in understanding how to modulate it, but also how to protect it. Two companies in particular are using elegant approaches to achieve this protection, which consists of the removal of antibiotics that reach the gut before they can have harmful consequences. Synthetic Biologics is developing ribaxamase, a β-lactamase capable of inactivating β-lactams in the gut, while Volterra’s DAV132 delivers a load of activated charcoal to the gut, which removes moxifloxacin, a quinolone antibiotic. These protective methods have the potential to decrease episodes of difficile infection, and to decrease the selective pressure in the gut, thereby limiting the development of antibiotic resistance.
These were just some of my picks of companies doing exciting research into antiinfective approaches, but there were many other interesting presentations. Bacterial infections and antibiotic resistance are responsible for thousands of deaths, and it is estimated that in a not too distant future, millions can die every year due to infections that no longer respond to the available treatments. While we are far from addressing this important issue, data presented at this conference has made the future a little brighter.
Follow the links to learn more about DRG’s antibacterials markets extensive coverage, including Gram-Negative, MRSA, and C. difficile infections:
Nuno Antunes is a Senior analyst on Infectious, Niche, & Rare Disease team at DRG, currently covering the hospital antibiotic markets, including Gram-Negative Infection and C. difficile Infection.