In light of the COVID-19 pandemic, it may be easy to forget that another public health crisis continues to loom large: multidrug resistance.

The CDC and WHO have addressed the lack of strategies to address this issue. Little innovation is aimed at it, with relatively few new treatments in the pipeline.

Without new antibiotic treatments with innovative mechanisms, multidrug resistance will become more prevalent as time goes on.

 

Multidrug-resistant bacteria findings

According to CDC research published in 2020 in the New England Journal of Medicine, multidrug-resistant bacteria led to approximately 622,390 infections in hospitalized patients in 2017, with 83% acquired in the community.

Jernigan JA, Hatfield KM, Wolford H, et al. Multidrug-resistant bacterial infections in U.S. hospitalized patients, 2012-2017. N Engl J Med. 2020;382(14):1309-1319.

 

Methicillin-resistant Staphylococcus aureus (MRSA) and Enterobacteriaceae suggestive of extended-spectrum beta-lactamase (ESBL) production accounted for most cases—52% and 32%, respectively. 

The authors found mixed results regarding the frequency of multidrug-resistant bacteria. Between 2012 and 2017, the incidence of MRSA dropped from 114.18 to 93.68 cases per 10,000 hospitalizations, while ESBL levels increased by 53.3%.

“For some resistant pathogens, encouraging reductions in their incidence have been observed in recent years, which suggests that current prevention efforts, such as in health care settings, are yielding important benefits, although the burden remains high,” they wrote. 

Not all antibiotic resistance threats are decreasing, however.

“Further work is needed to sustain progress, including the continued development of new and more effective antibiotics, better antibiotic stewardship, and the identification of innovative interventions and strategies tailored to the spectrum of healthcare and community settings,” the authors added.

In the CDC’s 2019 antibiotic resistance report, experts stressed that dedicated prevention and infection control in the United States led to an 18% decrease in deaths due to antimicrobial-resistant infections, as well as a 30% decrease in hospital mortality.

A CDC follow-up report, however, discovered “much of that progress was lost, in large part, due to the effects of the pandemic. The pandemic pushed healthcare facilities, health departments, and communities near their breaking points in 2020, making it very hard to maintain the progress in combating antimicrobial resistance.”

 

Lack of investment

In 2020, the WHO called out a lack of private investment and innovation in new antibiotics as undercutting efforts to effectively counter drug-resistant infections.

Lack of new antibiotics threatens global efforts to contain drug-resistant infections. WHO. January 17, 2020.

 

Stakeholders agreed that a lack of financial investment plays a key role in fewer new antibiotics coming to market. The Center for Infectious Disease Research and Policy (CIDRAP) explained that the lack of “shots on goal” is the problem.

Dall C. Report highlights 'fragile and failing' antibiotic pipeline. CIDRAP. February 17, 2022.

 

Unlike most new drugs, new antibiotics are used sparingly and reserved mainly for cases in which older antibiotics prove ineffective.

“In addition, antibiotics are generally undervalued by hospital reimbursement systems relative to the societal benefits they provide, and those reimbursement systems often discourage use of novel antibiotics even when they are the appropriate treatment for an infection,” the CIDRAP wrote.

Typically, the work of discovering new antibiotics falls to small companies, which account for 81% of antibiotics currently in the pipeline. These companies have trouble selling their product at a profit. Of 12 antibiotics manufacturers that have gone public from 2012–2022, only five have survived. One company, Achaogen, went bankrupt within 1 year of FDA approval of its antibiotic. 

With Big Pharma eschewing antibiotic R&D, and small antibiotic manufacturers securing only a tiny fraction of venture capital available to big players like oncology (which raised about $7 billion compared with antibiotic companies’ $0.16 billion in 2020), the situation continues to look bleak. 

CIDRAP cited research that although 64 new chemical entities were in the antibacterial pipeline, only 44 remain when tuberculosis and Clostridioides difficile products are deducted. This number contrasts with the 260 COVID-19 antivirals that were in development between 2020–2021.

Another issue with newer antibiotics is that they only represent incremental change in chemical scaffolds and mechanisms of action. They aren’t truly new drugs, which are needed to mitigate resistance.

In global terms, CIDRAP supports an "all hands on deck" approach that incorporates four policy solutions: early-stage investment, late-stage investment for phase 2 and 3 trials, regulatory incentives to antibiotic manufacturers, and mechanisms to fix a broken system.

In line with these goals, the WHO and the Drugs for Neglected Diseases Initiative have partnered with the Global Antibiotic Research and Development Partnership to formulate new, improved antibiotics, with a goal of developing five novel therapies by 2025. 

 

What clinicians can do

Despite a lack of investment and innovation suggested as the root cause of the losing war against antibiotic resistance, clinicians can still take action against multidrug resistance.

Authors publishing in Frontiers in Medicine wrote, “Readily available patient's medical history and updated information about the local microbiological epidemiology remain critical for defining the baseline risk of MDR-GNB [multidrug-resistant Gram-negative bacteria] infections and firmly guiding empirical treatment choices, with the aim of avoiding both undertreatment and overtreatment.”

Bassetti M, Peghin M, Vena A, et al. Treatment of infections due to MDR gram-negative bacteria. Front Med (Lausanne). 2019;6:74.

 

The authors also recommended rapid diagnostic and laboratory workup in line with proper antimicrobial stewardship and de-escalation efforts.

A guiding principle could be the optimal use of antibiotics—including big guns such as meropenem/vaborbactam (Vabomere) and ceftolozane/tazobactam (Zerbaxa)—to delay resistance.

Physicians treating multidrug resistance should adhere to their hospital antibiotic stewardship policies and programs. In total, 84% of US hospitals hosted programs that meet the CDC’s Core Elements of Hospital Antibiotic Stewardship. The CDC partners with local and health state departments to detect and track pathogen resistance and makes this information available to hospitals and clinicians.

Measures the CDC presents as being effective in battling multidrug resistance include the safe use of urinary catheters/central lines, minimizing the spread of drug-resistant bacteria between healthcare institutions, tracking antibiotic use, infection control in long-term facilities, and minimizing emerging threats via early detection.