麻豆传媒

An estimated 750,000 deaths linked to antimicrobial resistance (AMR) could be prevented every year through available vaccines, water and sanitation, and infection control methods, according to a series of four papers in on sustainable access to antibiotics.

"The window of opportunity to ensure our ability to treat bacterial infections is shrinking," series co-author Ramanan Laxminarayan, PhD, of One Health Trust in Bengaluru, India, said in a . "For too long, the problem of AMR has been seen as either not urgent or too difficult to solve. Neither is true. We need immediate action and the tools to do so are widely available."

If the world does not prioritize action on AMR now, the global death toll -- currently 4.95 million per year from infections linked to AMR -- will increase, with young infants, older people, and those with chronic illnesses or requiring surgical procedures at the highest risk, authors said.

The series provides an overview of the global scope of AMR over the past decade, and includes an analysis that shows how current interventions can effectively reduce AMR. Increasing investment in new antibiotics, vaccines, and diagnostics that are affordable and accessible worldwide is a crucial part of reducing AMR. The authors called for setting achievable global targets to reduce disease burden from AMR by 2030.

The Scope of the Problem

Of the 7.7 million estimated deaths attributed to bacterial infections each year, 4.95 million are associated with drug-resistant pathogens, and 1.27 million are caused by bacteria resistant to available antibiotics, Iruka Okeke, PhD, of the University of Ibadan in Nigeria, and colleagues wrote in the of the series.

AMR puts not only vulnerable individuals -- such as newborns, the chronically ill, and older people -- at risk, but also entire health systems, they pointed out.

"A third of newborn deaths are attributable to infection and half of those to sepsis and increasingly, the pathogens no longer respond to the most readily available antibiotics," the authors wrote. And, in older people, progress in treating noninfectious diseases such as cancer and diabetes is hindered by AMR infections.

Rates of resistance, especially for gram-negative infections, have increased dramatically around the globe over the past decade. In Europe, for example, in 2019-2021, increasing rates of resistance were reported, particularly carbapenem-resistant Acinetobacter spp causing bloodstream infections in 2017-2021. In 2015, 426,277 antimicrobial-resistant healthcare-associated infections accounted for an estimated .

Antimicrobial use in humans and animals is the key driver of resistance, the authors noted, pointing out that over the past two decades. Ironically, improved access to antimicrobial drugs led to overuse and made first-line antimicrobials less effective, resulting in use of antimicrobials reserved for second-line treatment, thus fueling more resistance.

Existing Interventions Can Prevent AMR Deaths

A modeling analysis indicated that using existing approaches to mitigate AMR in low-to-middle income countries (LMICs) could prevent about 18% of all AMR-associated deaths in those countries, according to Joseph Lewnard, PhD, of the University of California at Berkeley, and colleagues in the of the series.

"Focusing on interventions with demonstrated effectiveness in preventing infections must be at the heart of global action to tackle AMR," Lewnard said. "Preventing infections reduces the use of antibiotics and reduces selection pressure for AMR so that the drugs will work when they are most needed."

Improving infection prevention and control programs in health settings in LMICs with substantial AMR burden could prevent more than 337,000 AMR-associated deaths every year -- 8% of the total 4.3 million deaths that occur annually in those countries, the researchers found. Universal access to high-quality water, sanitation, and hygiene services would prevent 247,800 of AMR-associated deaths. Pediatric vaccines could prevent 181,500 of AMR-associated deaths from both direct prevention of resistant infections and reductions in antibiotic consumption.

"Our findings indicate that reducing global AMR burden by 10% by the year 2030 is achievable with existing interventions," Lewnard and colleagues wrote. "Our results should guide investments in public health interventions with the greatest potential to reduce AMR burden."

New Antibiotics, Vaccines, and Diagnostics Are Needed

It is abundantly clear that in addition to antibiotic stewardship, new drugs, vaccines, and diagnostics are needed to combat AMR, Laxminarayan and colleagues wrote in the of the series.

Antimicrobial agents currently in phase III development are primarily derivatives of established drug classes that are altered to overcome class-specific resistance mechanisms, the authors noted. Most of these are beta-lactamase inhibitor combinations, and many have high cross-resistance to available antibiotics and are not useful for empirical treatment.

"The traditional antibiotic development model is unlikely to be profitable for pharmaceutical companies without incentives," which are needed to subsidize drug development, the authors commented. "The era of profitable blockbuster antibiotics is over."

Reducing the cost of antibiotic development through public-private partnerships or public sector funding is one strategy to not only develop new antibiotics but also keep them affordable, the authors wrote.

However, inexpensive antibiotics are unprofitable, they noted, and lack of production due to unprofitability can lead to shortages of antibiotics. Retailers are more likely to stock carbapenems and third-generation cephalosporins than amoxicillin or other beta-lactam antibiotics, they said.

The authors also pointed to a need for global regulatory harmonization to decrease costs of new therapeutics and improve access worldwide. Different regulatory requirements across regions leads to the need for duplicate trials and leads to approval delays.

The development of vaccines targeting not only resistant bacteria but also common viral pathogens are essential to reducing AMR, the authors wrote. Vaccines against resistant strains of bacteria, such as Streptococcus pneumoniae and Salmonella serotype Typhi can directly reduce AMR and mortality. Also, vaccines against common respiratory viral pathogens, such as respiratory syncytial virus and influenza, are also important in reducing AMR since they reduce associated antibiotic use.

Finally, diagnostics are crucial in establishing whether antibiotics are needed and drug susceptibility, the authors wrote. "Diagnostic testing capacity in primary care, however, is scarce globally, many antibiotics are unnecessarily dispensed for self-limiting, mostly viral infections," they commented. New diagnostic technologies emerged during the COVID-19 pandemic, but technologies may not translate into a reduction in inappropriate antibiotic prescribing, they noted.

"Technology development should focus on immediate pathogen identification and antibiotic susceptibility testing directly on specimens from patients," the authors said, but in LMICs, such tests are not widely used. "Test results are useful only to the extent they are used -- a challenge even in high-resource settings."

Achievable Global Targets

Global targets to address the problem of AMR are needed, Marc Mendelson, PhD, of the University of Cape Town in South Africa, and colleagues wrote in the of the series. They proposed that the following targets should be met by 2030:

• 10% reduction in mortality from AMR

• 20% reduction in inappropriate antibiotic use

• 30% reduction in inappropriate animal antibiotic use

They called for these targets to be introduced at the high-level meeting of the United Nations General Assembly taking place in September 2024.