Editor's Note: Infections caused by multidrug-resistant Gram-negative bacteria have become a major threat to global public health, yet clinical research on the related antibacterial agents has long been confronted with challenges such as complex trial design, pronounced heterogeneity of resistance mechanisms, and unequal access to drugs. At the 4th One Health Conference of Antimicrobial Resistance Containment, Professor Patrick Harris of the Royal Brisbane and Women's Hospital, Australia, gave a dedicated presentation entitled "Clinical Trials in Multidrug-Resistant Gram-Negative Bacteria — Where Are We? What Do We Need?" Infectious Disease Frontier invited Professor Patrick Harris for an in-depth dialogue on the difficulties of clinical trial design, progress in novel agents, international collaboration, and infection prevention and control.Infectious Disease Frontier: What are the unique challenges in designing clinical trials targeting multidrug-resistant (MDR) Gram-negative bacteria, and how do these trials differ from those of conventional antibacterial agents?
Professor Patrick Harris: This is an excellent question and a major challenge. Antimicrobial resistance has become a serious problem, and current trends suggest that it will only become more severe.
Gram-negative pathogens, such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, are extremely complex. Unlike Gram-positive bacteria such as Staphylococcus aureus, for which there may be only one or two resistance profiles to consider, Gram-negative bacteria have far more complicated resistance mechanisms.
Take P. aeruginosa as an example. Multiple genetic mechanisms, acquired genes, intrinsic genes, transcription factors, and other factors collectively determine its resistance to different antimicrobial agents. Other Gram-negative bacteria, including K. pneumoniae and E. coli, exhibit substantial variation in beta-lactamases, extended-spectrum beta-lactamases (ESBLs), plasmid-mediated resistance genes, and other resistance determinants. Resistance patterns can differ dramatically between regions, bacterial strains, and even individual hospitals.
Designing clinical trials that can effectively, robustly, and consistently address such diverse resistance patterns and resistance rates across the world is extremely challenging.
Another issue is the substantial variation in drug availability across different regions. Agents available in Australia may not be available in China, Europe, Thailand, or South Africa.
To conduct trials that can genuinely inform clinical practice, we need to draw on experiences from other areas of infectious diseases. Examples include the RECOVERY and REMAP-CAP trials during the COVID-19 pandemic, trials involving pneumonia and viral infections, and the SNAP trial for S. aureus infections. These practice-changing trials rapidly brought together thousands of researchers through international networks and recruited sufficient numbers of patients to provide meaningful answers to important clinical questions.
Our challenge is to design clinical trials with sufficient statistical power to enroll large numbers of patients from different regions worldwide, including areas with a particularly high burden of antimicrobial resistance. We also need robust methodologies that can accommodate this heterogeneity statistically and ultimately generate answers that help clinicians make treatment decisions.
Unfortunately, although trials conducted by regulatory agencies and pharmaceutical companies are necessary, they often do not provide the specific patient-level treatment information that clinicians actually need.
Infectious Disease Frontier: What significant progress has been made in recent years in clinical trials of novel antibacterial agents targeting multidrug-resistant (MDR) Gram-negative bacteria? Which agents or treatment regimens show the greatest promise?
Professor Patrick Harris: Antimicrobial drug development has received considerable criticism over the years, and to some extent, this criticism is justified.
The 1950s, 1960s, and 1970s were a golden era for antibiotic development. Significant investments were made in designing new drugs, and new classes of antibiotics entered the market every year. Innovation has indeed slowed over recent decades, but it would be inaccurate to say that no new antibiotics are being developed.
In particular, the rapid development of novel beta-lactamase inhibitors has opened up tremendous opportunities for drug innovation. These inhibitors target the various beta-lactamases encountered in patients with infections. Combination regimens pairing these inhibitors with existing or novel beta-lactam antibiotics are particularly promising and represent an exciting area of development.
However, the situation is complex. These agents target different bacterial species and different resistance mechanisms. Designing clinical trials that can specifically address the clinical questions associated with each of these pathogens is the next major challenge.
In addition, several entirely new approaches are attracting attention, including bacteriophage therapy, monoclonal antibody therapy, CRISPR-based approaches, and gene editing. These non-traditional antimicrobial strategies could potentially serve as adjuncts to antibiotics or even replace antibiotics altogether in certain settings.
There is a great deal of exciting work underway in this area. However, we still need robust clinical trial data to answer the relevant questions and guide clinicians on how best to use these approaches.
Infectious Disease Frontier: In your opinion, how can clinical trial data be better translated into treatment decisions for patients with complex infections?
Professor Patrick Harris: I believe we need to establish systems that closely connect clinical trials with routine clinical practice.
Traditional clinical trial approaches are cumbersome, slow, expensive, and inefficient. To use an analogy, they are like organizing a football match: first, you build a stadium, arrange a match between two teams, and then dismantle the stadium before building another one for the next match.
That is essentially how traditional clinical trials work. They are highly inefficient, often take years to complete, and may answer only a single research question. They also frequently struggle to recruit enough patients to reach definitive conclusions. This can lead to delays of several years, during which clinicians lack the evidence needed to guide their treatment decisions.
We can learn a great deal from platform trials in oncology. These trials allow multiple research questions to be addressed within a single trial infrastructure, making use of existing teams, databases, ethics approvals, and protocols. New research questions can be incorporated whenever new drugs become available or new diagnostic technologies emerge.
Once such an international clinical trial infrastructure has been established, efficiency can improve substantially, allowing important clinical questions to be answered in a much more timely manner.
Infectious Disease Frontier: From a global perspective, what innovations are needed in future clinical trials targeting multidrug-resistant (MDR) Gram-negative bacteria? How can international collaboration be strengthened to accelerate the development and improve access to new antibacterial agents?
Professor Patrick Harris: One major challenge in clinical trials is enrolling patients as quickly as possible.
Traditional microbiological testing is relatively slow, particularly for drug-resistant pathogens. Identification alone may take several days, and susceptibility testing for second- or third-line antibiotics is often not performed upfront in routine diagnostic laboratories.
Therefore, incorporating novel diagnostic tools, such as rapid molecular testing and even whole-genome sequencing, into clinical trials is extremely important. These technologies can help identify eligible patients more rapidly and facilitate timely enrollment.
Although this approach is expensive and complex, it is essential if we genuinely want to understand the efficacy of these drugs. To evaluate their therapeutic effects properly, they need to be administered early to critically ill patients. If treatment is delayed by four or five days, it becomes difficult to accurately assess their true efficacy.
The challenge from an equity perspective is how to implement these approaches in many regions around the world where resources are limited and expensive rapid diagnostic tests are unaffordable.
Developing affordable, low-burden, low-complexity, and reliable diagnostic methods is therefore a highly valuable challenge worth exploring.
Infectious Disease Frontier: Beyond novel antibiotics, which other intervention strategies should be prioritized in clinical research?
Professor Patrick Harris: Prevention is clearly one of the key priorities. If an infection can be prevented from occurring in the first place, there is no need to use antibiotics, including expensive last-resort agents. The problem is resolved before it even arises.
Of course, this becomes more challenging once an infection has already become established in a hospital. Nevertheless, infection prevention and control is the first step in addressing all these challenges.
This extends beyond infection control within hospitals. It also involves the environment, food chains, animal husbandry, and antimicrobial use in the community. AMR is a nationwide issue, not merely a clinical problem.
I am fortunate to work in Australia, where antimicrobial resistance rates are relatively low. However, this is the result of stringent antimicrobial use policies.
For example, antibiotics are rarely used in chicken production and livestock farming. Antimicrobial prescribing in the community is strictly regulated, and hospitals have rigorous antimicrobial stewardship programs.
In addition, we use proactive whole-genome sequencing. Whenever we identify a carbapenem-resistant Gram-negative bacterium, sequencing is completed within a few days. This allows us to rapidly identify potential sources of infection, determine whether other isolates have recently been detected, and assess whether there is evidence of transmission within a hospital ward. These findings enable infection prevention and control teams to implement targeted interventions before an outbreak occurs.
Once again, however, developing affordable, low-complexity approaches that can be implemented in many regions around the world without access to advanced technologies remains a genuine challenge. Such approaches could also play a highly effective role in preventing infections before they occur and before expensive antimicrobial agents become necessary.
Infectious Disease Frontier: Could you share your impressions of attending this One Health conference?
Professor Patrick Harris: So far, the conference has been very impressive. Although it has only been underway for half a day, I have already been particularly impressed by the AI-powered translation.
I was initially concerned that I would not be able to understand the presentations, as my Chinese is very poor. However, the translation has worked remarkably well, and I have been able to follow all the discussions. What China has accomplished in this area is truly impressive.
The atmosphere at the conference is vibrant, and there are many interesting speakers. I am very much looking forward to hearing more presentations over the next day or two. I am sure this will be a very exciting conference.
