Clinicians call for more inclusive trials for new antibiotics
A letter today in the Journal of Infectious Diseases argues for relaxed criteria for patient exclusion in randomized controlled trials (RCTs) for new drugs to treat multidrug-resistant infections.
The letter, written by two Israeli clinicians, describes three patients with severe infections caused by carbapenem-resistant bacteria that presented during a single day at a hospital in Haifa. None of the three patients, the authors note, was eligible for an ongoing RCT at the hospital to assess the antibiotic cefiderocol—a novel siderophore cephalosporin in late-stage development—versus the best available therapy for bloodstream and other severe multidrug-resistant infections. All were treated with colistin as the only covering antibiotic.
These cases, the authors argue, point out a paradox. While it's estimated that more than 700,000 patients die each year from infections caused by multidrug-resistant pathogens, and plenty of patients with carbapenem-resistant infections are described in epidemiologic studies, finding patients for drug approval RCTs is difficult. That's because RCTs are often biased toward uncomplicated patients with a low risk of death, and the patients with the types of conditions described in their letter—neutropenia, severe sepsis, and organ failure—are often excluded from such studies. Yet these are the patients who may have the greatest need for new treatments.
While efforts to improve testing and approval requirements of new drugs for unmet needs have been commendable, the authors write, "We would like a discussion about the changes in regulatory guidance to the industry that would relax criteria for patient exclusion to ensure that the patients in [an] RTC resemble a bit more the patients in need of the antibiotic under study."
Dec 12 J Infect Dis letter
Commentary: Vaccines needed in the fight against AMR
Vaccines could and should play a key role in stemming the antimicrobial resistance (AMR) crisis, according to a commentary today in Nature.
The commentary, co-authored by the chief scientist at GlaxoSmithKline Vaccines and professors from Harvard T.H. Chan School of Public Health and Cincinnati Children's Hospital, calls for a global strategic effort to prioritize development of a portfolio of vaccines to target AMR.
Their reasoning is based on several factors. For one, they argue, vaccines almost never prompt bacteria to develop resistance. In addition, scientists have had much more success over the last 30 years developing new vaccines than they've had discovering new antibiotics. Since the 1980s, 22 new vaccines have been deployed in the clinic, while no new truly new class of antibiotics has been discovered or engineered. And vaccine technology continues to evolve.
Given this reality, and the fact that several current vaccines—such as the pneumococcal and influenza vaccines—have already helped directly and indirectly reduce the need for antibiotics, the authors say vaccines must be considered an essential element of the fight against AMR, along with new antibiotics, diagnostics, surveillance, and stewardship. Launching an effort to develop a portfolio of vaccines against AMR, they say, will require policymakers and stakeholders to raise awareness about the potential of vaccines to combat AMR, to persuade governments and drug companies of the cost-effectiveness of investing in vaccines, and to prioritize which bacterial strains should be targeted.
"Over the past few years, key institutional stakeholders — notably the [World Health Organization], the [United Nations General Assembly], the World Bank, the G20 group of countries, the European Union and the UK and US governments — have called for researchers to develop new antibiotics to expand our arsenal in the war against superbugs," the authors write. "We appeal to these organizations to call now for a multi-layered strategy that prioritizes the development of vaccines to target resistant strains."
Dec 12 Nature comment