John H. Rex

Olorofim, a novel dihydroorotate dehydrogenase inhibitor, may be efficacious in patients with disseminated coccidioidomycosis (DCM) who lack alternative treatment options. This single-group, open-l... Visual Olorofim in Treatment of Patients With Poorly Controlled Disseminated Coccidioidomycosis Olorofim, a novel dihydroorotate dehydrogenase inhibitor, may be efficacious in patients wit... Background: Olorofim, a novel dihydroorotate dehydrogenase inhibitor, may be efficacious in patients with disseminated coccidioidomycosis (DCM) who lack alternative treatment options. Objective: To...

The problem of antimicrobial resistance (AMR) has become particularly relevant in countries with developed healthcare systems and intensive agriculture over the past 20 years. According to the UN General Assembly on September 22, 2022, antimicrobial resistance (AMR) is already a global problem, causing almost 5 million deaths per year, and by 2050 the annual number of additional deaths worldwide could increase to 10 million persons per year. Currently, to counter the spread of AMR in the world, a partnership of 4 world organizations (WHO, OIE, FAO and UNEP) has been created, leaving the basis for the global concept of “One Health”, which is an integrated, unifying approach aimed at Sustainably balancing and optimizing the health of people, animals and ecosystems. In order to protect the population, the Government of the Russian Federation adopted the “Strategy for preventing the spread of antimicrobial resistance in the Russian Federation for the period until 2030”. The COVID-19 pandemic has impacted the spread of infections caused by multidrug-resistant bacteria worldwide. On the one hand, restrictions and preventive measures introduced in connection with the COVID-19 pandemic, such as reduced travel, distancing, hand hygiene, and environmental treatment, help reduce the spread of infections; on the other hand, the use of antibiotics in patients with COVID-19 is not always justified has exacerbated the public health threat posed by AMR, and as the pandemic progresses throughout the world, the importance of resistance has increased significantly. The resistance of microorganisms to antimicrobial drugs requires improving measures to prevent and limit the spread and circulation of pathogens with antimicrobial resistance, ensuring systemic monitoring of the spread of antimicrobial resistance, and studying the mechanisms of the emergence of antimicrobial resistance.

John H Rex, Kevin Outterson; Antibacterial R&D at a crossroads: We’ve pushed as hard as we can … now we need to start pulling!, Clinical Infectious Disease

The antibacterial agents currently in clinical development are predominantly derivatives of well-established antibiotic classes and were selected to address the class-specific resistance mechanisms and determinants that were known at the time of their discovery. Many of these agents aim to target the antibiotic-resistant priority pathogens listed by the WHO, including Gram-negative bacteria in the critical priority category, such as carbapenem-resistant Acinetobacter, Pseudomonas and Enterobacterales. Although some current compounds in the pipeline have exhibited increased susceptibility rates in surveillance studies that depend on geography, pre-existing cross-resistance both within and across antibacterial classes limits the activity of many of the new agents against the most extensively drug-resistant (XDR) and pan-drug-resistant (PDR) Gram-negative pathogens. In particular, cross-resistance to unrelated classes may occur by co-selection of resistant strains, thus leading to the rapid emergence and subsequent spread of resistance. There is a continued need for innovation and new-class antibacterial agents in order to provide effective therapeutic options against infections specifically caused by XDR and PDR Gram-negative bacteria.

In the face of rising rates of antibacterial resistance, many responses are being pursued in parallel, including ‘non-traditional’ antibacterial agents (agents that are not small-molecule drugs and/or do not act by directly targeting bacterial components necessary for bacterial growth). In this Perspective, we argue that the distinction between traditional and non-traditional agents has only limited relevance for regulatory purposes. Rather, most agents in both categories can and should be developed using standard measures of clinical efficacy demonstrated with non-inferiority or superiority trial designs according to existing regulatory frameworks. There may, however, be products with non-traditional goals focused on population-level benefits that would benefit from extension of current paradigms. Discussion of such potential paradigms should be undertaken by the development community.

Ertapenem provides activity against many pathogens commonly associated with hospital-acquired and ventilator-associated bacterial pneumoniae (HABP and VABP, respectively), including methicillin-susceptibleStaphylococcus aureusand numerous Gram-negative pathogens with one major gap in coverage,Pseudomonas aeruginosa. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were conducted to evaluate ertapenem against the most prevalentEnterobacteriaceaecausing HABP/VABP.

The emergence of azole resistance in Aspergillus fumigatus as well as an increasing frequency of multiresistant cryptic Aspergillus spp. necessitates exploration of new classes of antifungals.

Background: Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP. Methods: Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method. Results: The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation–free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7–10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation–free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement). Conclusions: We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.

The emergence and spread of antimicrobial resistance is one of the major global issues currently threatening the health and wealth of nations, with effective guidelines and intervention strategies urgently required. Such guidelines and interventions should ideally be targeted at individuals, communities, and nations, requiring international coordination for maximum effect. In this respect, the European Joint Programming Initiative on Antimicrobial Resistance Transnational Working Group ‘Antimicrobial Resistance - Rapid Diagnostic Tests’ (JPIAMR AMR-RDT) is proposing to consider a ‘mix-and-match’ package for the implementation of point-of-care testing (PoCT), which is described in this publication. The working group was established with the remit of identifying barriers and solutions to the development and implementation of rapid infectious disease PoCT for combatting the global spread of antimicrobial resistance. It constitutes a multi-sectoral collaboration between medical, technological, and industrial opinion leaders involved in in vitro diagnostics development, medical microbiology, and clinical infectious diseases. The mix-and-match implementation package is designed to encourage the implementation of rapid infectious disease and antimicrobial resistance PoCT in transnational medical environments for use in the fight against increasing antimicrobial resistance.