Multidrug Resistant Infections: Is the Clinical Infection Treatment Pathway Outdated?

For the sickest of patients who might be battling multidrug-resistant, gram-negative bacterial infections—particularly those with comorbidities—time is of the essence to get to a diagnosis and optimal treatment. Yet, medical science is designed to move deliberately—to do no harm—and to practice within the economic realities presented to providers. However, this current treatment paradigm might be set up to continue and proliferate the antimicrobial resistance (AMR) crisis, especially in the aforementioned patient population as they continue to cycle through the health care system repeatedly and have multiple treatments with antibiotics.

Current clinical practice is set up to use first-line, well-established therapies, so this often means utilizing older therapies. Add to this the newer concept of antimicrobial stewardship, and you may have clinicians who may be reluctant to use newer antibiotics for a few reasons including being a good antimicrobial steward, or there may not be enough study data to fully understand adverse effects and the efficacy of the newer antimicrobials.

In addition, patients in some long-term care settings may be delayed in getting diagnosed, and often patients can be given broad-spectrum antibiotics that may be limited in efficacy and leads to switching antibiotics and more exposure to these therapies and the possibility of AMR.

“We see people with repeated multiple antibiotic exposures, multiple infections. Even if it started out as maybe a staph infection or was E coli, over time with repeat infections and repeat courses of antibiotics, those [patients] are at greatest risk for a carbapenem-resistant pathogen,” Tom Lodise, PharmD, PhD, professor at the Albany College of Pharmacy and Health Sciences, and clinical pharmacy specialist at the Stratton VA Medical Center in Albany, New York, told Contagion. “These sort of [case scenarios] is where I think we need to be more aggressive…every day matters in the gram-negative space. We think about antibiotic stewardship—our fundamental pillar is getting it right up front. Despite this, we still find in over half of the patients with an antibiotic resistant gram-negative infection, they do not receive an active drug for the first 48 - 72 hours.”

Lodise says the time-to treatment concept which involves getting patients the diagnosis and on the correct antibiotic in a timely manner can be beneficial to patient outcomes.

“Every day matters with our gram-negative infections, and the longer we delay, there's substantial increases in both morbidity and mortality,” Lodise said.

Rapid Diagnostics

Rapid diagnostics is an area where the advancement of technology has vastly improved and is becoming an emerging part of medicine. As the name suggests, they can quickly reveal pathogens and viruses.

“Such assays have relatively short performance times, provide results to inform clinical decision making, and enable management at the point-of-care (POC),” wrote authors of the Centers for Disease Control and Prevention’s (CDC) Yellow Book.¹

However, there are some inherent challenges. For starters, laboratories in medical settings vary. Whereas in a large teaching hospital these tests may be available and there may be adequate staffing of laboratory professionals to conduct them, in many smaller community or mid-sized hospitals there may be limited resources to have such tests and personnel.

The laboratory field itself has become even more crucial, especially as the number of tests has increased and the diagnostics have become more complex. According to the CDC, there are more than 14 billion clinical lab tests performed in the US annually.² If one were to also consider the millions of COVID-19 tests administered over the last few years, this has put an enormous strain on medical laboratory professionals.

While the need for such vital personnel increases, the field has seen shortfalls.

“With the projected increases in the need for medical laboratory professionals, and the current high vacancy rates, the profession is suffering from a workforce shortage that is approaching crisis levels for medical laboratory technicians, medical laboratory scientists, histotechnicians and histotechnologists,” the American Society for Clinical Laboratory Science (ASCLS) wrote in a prior statement.

ASCLS stated some of the reasons for the shortages includes retirements, an increased demand for lab services, changes in the practice of clinical laboratory science due to technology advances, and vacancies that exceed the number of graduates.³

“Our professionals are critical. We are often not thought of in direct patient care, because we're laboratory based, diagnostic detective types," Rodney E. Rohde, PhD, MS, SM(ASCP)CM, SVCM, MBCM, FACSc regents’ professor, Texas State University, university distinguished chair & professor, Clinical Laboratory Science, told Contagion. “One of the things I like to tell people is that we’re the mechanics and the ground crew for that airplane you're getting on. You don't think about this every day, but you better hope they're alert, and they're doing their job.”

How Should We Utilize Newer Antibiotics?

The FDA has approved novel gram-negative antibiotics in recent years, but they have not necessarily seen the adoption or uptake of use that therapies in other areas of care might.

Sameer S. Kadri, MD, MS, FIDSA, intensivist and head, Clinical Epidemiology Section, Critical Care Medicine Department, National Institutes of Health Clinical Center, and a team of investigators looked at the utilization of novel, gram-negative antibiotics in US hospitals, and he says that medical providers appear to go the route of prescribing well-established antibiotics and even using ones that could be potentially toxic.

“I think there was a degree of comfort level with some of the older agents, even though they were toxic, when there was no agent available as an alternative. Now that there are agents available, I think, there is evidence in the form of trials that have led to the approval of these novel agents,” Kadri told Contagion. “But you know, there's not that much representation of patients with highly-resistant pathogens in some of those trials, and that does result in a little bit of uneasiness around whether the evidence is generalizable to the patients with highly-resistant pathogens.”

This may present scenarios where newer and novel antibiotics might be sitting on the pharmacy shelves. Kadri said one of the key takeaways from the study was a potential strategy to overcome this reticence of clinicians to prescribe these newer agents.

“I think an important factor is that hospitals that opted for testing susceptibility against these novel agents tended to [have] greater use of these novel agents,” Kadri said. “It's a reminder that there needs to be wider implementation of susceptibility testing capabilities across the country against novel agents that are released, so that clinicians like myself feel confident that the drug that we're using in our patients actually works.”

The Pasteur Act

Another potential strategy to address the greater adoption of new or novel antibiotics is the prospective Pasteur Act. Ideally, this act would entice pharmaceutical companies to develop more antibiotics by establishing an innovative payment contract (subscription model) where the federal government invests in highly novel antibiotics and antifungals through installment payments in exchange for free access to developers’ drugs in government programs once available.

The Pasteur Act was initially introduced in Congress in 2020, then reintroduced in both 2021 and earlier this year. When it was reintroduced back in April, 5 national organizations—the Biotechnology Innovation Organization, the Cystic Fibrosis Foundation, IDSA, the Partnership to Fight Infectious Disease, and The Pew Charitable Trusts—issued a joint statement on the topic.

“Antimicrobial resistance is not a partisan issue. It is an increasingly challenging public health emergency that reverberates far beyond just health care settings. Every 15 minutes, a person in the United States dies from an infection resistant to treatment with existing antimicrobial drugs. This means that since PASTEUR’s last introduction on June 16, 2021, more than 64,000 Americans have died because they did not have adequate medications to treat their infections,” the statement read.

Can We Change the Diagnostic and Treatment Paradigm?

The US is well-positioned and responsive to public health emergencies. We just witnessed this with the COVID-19 pandemic. Yes, missteps occurred—but in a public health emergency with a fluid, ever-changing situation with emerging variants to contend with, the country did its best to respond to it.

However, addressing slow-moving, serious issues where long-term planning is warranted is not something well-considered or brought to the forefront in American public health. Yes, there are public health officials thinking about these things, but a clarion call has not been heeded to address how we need to be thinking about the rise and severity of antimicrobial resistance.

Right now, all these challenges of limited laboratory professionals, slow adoption of newer antibiotics, and possibly an outdated treatment paradigm seem separate, but in reality, putting the pieces of the puzzle together can make the treatment pathway for patients with AMR infections more comprehensive.

The addition of susceptibility testing, the increase in the number of laboratory professionals, and the passage of the Pasteur Act may all be steps towards creating new treatment pathways and lead to better outcomes.

The question remains: should these problems be resolved with a larger public health initiative bringing it altogether, or can they come together organically and medical science evolve to address these issues without government involvement?

References

1. ^{Rapid Diagnostic Tests for Infectious Diseases CDC Yellow Book 2024. CDC. Last reviewed May 1, 2023. Accessed December 18, 2023. https://wwwnc.cdc.gov/travel/yellowbook/2024/posttravel-evaluation/rapid-diagnostic-tests-for-infectious-diseases#:~:text=}
2. ^{Clinical Standardized Programs. CDC. Last reviewed March 15, 2023. Accessed December 19, 2023. https://www.cdc.gov/labstandards/csp/index.html#:~:text=In%20the%20United%20States%2C%20approximately,Amendments%20(CLIA)%2Dcertified%20laboratories}
3. ^{Addressing the Clinical Laboratory Workforce Shortage. ASCLS. Accessed December 19, 2023. https://ascls.org/addressing-the-clinical-laboratory-workforce-shortage/}