John Parkinson

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 

 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 

. “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 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.

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.

 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.

“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 

. “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.”

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 

. “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.”

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?

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=

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

Addressing the Clinical Laboratory Workforce Shortage. ASCLS. Accessed December 19, 2023. https://ascls.org/addressing-the-clinical-laboratory-workforce-shortage/

Articles

The current treatment paradigm might need to evolve to adjust to rapid diagnostics and narrowing down the antibiotics to aid in optimal outcomes for sicker patients with gram-negative infections.

Multidrug Resistant Infections: Is the Clinical Infection Treatment Pathway Outdated?

Credit: US Centers for Disease Control and Prevention

This article was originally published in ContagionLive.

The US Centers for Disease Control and Prevention (CDC) has announced recommendations for screening and testing for hepatitis B virus (HBV), calling for all adults in the US to be universally tested for HBV at least once in their lifetime and to test for total antibody to HBcAg, which may determine HBV in the window period and pick-up recent infection.

The new guidance, which is the first update since 2008, is aimed at providing more awareness around HBV and getting more people involved in the continuum of care. CDC is also expanding continual risk-based testing to include more groups, activities, exposures, and conditions, while noting the limitations to risk-based testing.

“Risk-based testing alone has not identified most persons living with chronic HBV infection and is inefficient for providers to implement,” the authors wrote.

Listed below are the new screening/testing HBV recommendations put forth:



• HBV screening at least once during a lifetime for adults aged ≥18 years (new recommendation)
• During screening, test for hepatitis B surface antigen (HBsAg), antibody to HBsAg, and total antibody to HBcAg (total anti-HBc) (new recommendation)

• HBV screening for all pregnant persons during each pregnancy, preferably in the first trimester, regardless of vaccination status or history of testing

• Pregnant persons with a history of appropriately timed triple panel screening and without subsequent risk for exposure to HBV (i.e., no new HBV exposures since triple panel screening) only need HBsAg screening

• Testing for all persons with a history of increased risk for HBV infection, regardless of age, if they might have been susceptible during the period of increased risk
• Periodic testing for susceptible persons, regardless of age, with ongoing risk for exposures, while risk for exposures persists

HBV awareness remains a significant health care challenge, despite existing therapies to treat it as well as prophylactic HBV vaccines to prevent it. It’s estimated that more than half of patients with HBV are unaware of their infection, mainly because virus presents asymptomatically in the majority of positive cases. Some people do eventually develop chronic hepatitis (elevation of AST/ALT), cirrhosis, or liver cancer.

Although there is no cure for HBV, treatment with any of the number of multiple antivirals available can make the virus a manageable, chronic condition.

On the vaccine side, there are prophylactic HBV vaccines, but uptake is limited. It has been reported that 70% of adults in the US were unvaccinated as of 2018.

In addition to the comprehensive screening and testing updates, the authors would like to see continued collaboration with laboratories to bundle the three HBV tests so they can be ordered together. And they also acknowledge the need to understand hepatitis D (HDV) more effectively to guide future recommendations for HDV screening among persons with HBV infection.

Conners EE, Panagiotakopoulos L, Hofmeister MG, et al. Screening and Testing for Hepatitis B Virus Infection: CDC Recommendations — United States, 2023. MMWR Recomm Rep 2023;72(No. RR-1):1–25. DOI: 

The new guidance is the first update since 2008, replacing the previous risk-based recommendations. 

CDC Recommends Universal Screening for Hepatitis B Virus

A female patient in her mid 70s is admitted to a local hospital after presenting with shortness of breath and cognitive impairment that includes confusion. She has existing comorbidities that include edema and COPD after a long history of smoking.

A chest x-ray diagnoses the patient with pneumonia. And after a blood test, it’s confirmed the patient has bacterial pneumonia, but the precise organism is not determined. Because of the limited knowledge of the exact bacterium, the patient’s clinician treats her with broad spectrum antibiotics because of concerns related to multidrug resistant organisms such as Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA).

The patient’s condition quickly worsens, and she falls into unconsciousness. She is placed on artificial breathing apparatus, and her family is called as the clinician treating her believes she may expire if she does not improve.

This becomes a wait-and-see situation with the family in limbo awaiting a potential worse-case scenario.

Fortunately, the antibiotics begin to take effect and the patient recovers, but not after the patient and her family have gone through a harrowing experience. Someday, possibly in the near future, patients may not need to go through this care scenario as clinicians may have the ability to identify the exact bacterium and prescribe the proper antibiotics—all in a shorter time.

In the aforementioned case, which continues to happen across the US health care system, clinicians are limited by the types of testing available and guidelines on how they treat. They treat broadly with antibiotics, and hope for the best possible outcomes.

The community hospital where the patient was treated had limited laboratory testing capabilities. The good news is diagnostic technologies are evolving, and lab panels have improved dramatically. These panels offer specificity and speed that can identify the bacteria quickly and reduce the time to optimal therapy (TTOT), thus leading to potentially more optimal treatment outcomes.

One example has been the development of multiplex polymerase chain reaction (PCR) panels that can be used to identify the rapid detection of pathogens in blood cultures, cerebrospinal fluid stool, and respiratory tract specimens.

Adoption of rapid PCR panels for positive blood cultures has been growing, and antimicrobial stewardship programs at many institutions perform audit and feedback based upon the results of such panels as a basis for interventions.

And the proliferation of these panels has helped to grow out the concept of diagnostic stewardship. This novel concept creates an emphasis to streamline the diagnosis process and get to TTOT more quickly. According to the CDC, “Diagnostic stewardship is defined as ordering the right tests for the right patient at the right time to inform and optimize patient care.”



Although these new rapid diagnostics enable specificity and speed, the challenges to widespread usage remain expense and availability. And even for those hospitals that can access such panels, it remains a priority to use them judiciously.

Lab Perspective: Who Will Run the Tests and Interpret Results?

Much like everything else in medicine, the laboratory is another field that is evolving. With these emerging rapid diagnostics comes the increased need to have more laboratory professionals run and interpret results of complex tests.And yet, labs have seen a series of challenges including more testing due to COVID-19—leading to burnout and staffing shortages.

“We've had these staffing issues for many years prior to the pandemic,” explained Rodney E. Rohde, PhD, MS, SM(ASCP)CM, SVCM, MBCM, FACSc, university distinguished professor and chair of the Clinical Laboratory Science Program in the College of Health Professions at Texas State University where he also serves as the associate director of the Translational Health Research Center. “The pandemic has exacerbated these issues.”

Rohde remains in touch with many of his former students and says the pandemic has made for an interesting situation for lab professionals by increasing their value. It has created a hired gun atmosphere for experienced personnel where they are getting recruited to work with different institutions and leaving behind inexperienced lab technicians in their existing institutions.

“We're seeing some vacuums in trauma centers and major hospitals where now you don't have a mix of seasoned veterans and rookies,” Rohde explained. “I've talked with different people who are a little bit in panic mode, where they'll have one person, for example, working a night shift at a middle-of-the-road hospital that has some trauma issues in the middle of the night or during the day and the lab professional is left alone. And while we value every single medical lab scientist that we educate, we all know that on-the-job experiences, dealing with crises, and complex decision making should happen in the realm of seasoned veterans being around.”

Within the challenge remains the ability to determine and process so many tests, and this is where the rubber meets the road for diagnostic stewardship to go from novel concept to widespread reality.

Rohde points to education and the lab’s collaboration with clinicians as being potential strategies to aid in determining what tests are necessary. On the education side, he points to the new doctorate of clinical laboratory sciences (DCLS) degree, which is at three major universities. Rohde says lab professionals who have a few years experience may want to get their doctorate. 

With PhDs in hand, lab scientists can get more involved on the clinical side, especially as it pertains to testing.

“Those individuals will be rounding with physicians from a laboratory medicine standpoint, they'll be interacting with nurses, pharmacists, and the team in a way to help educate and inform proper and accurate test selection, ie stewardship, versus bartering every test, or ordering the same test over and over day after day when you may only need it once every five days,” Rohde stated.

Clinician Perspective: Solving the Testing Expense Issue

Although the advent of rapid diagnostics is a very needed addition, there remains the expense behind ordering these panels. And testing guidelines have not caught up to the new diagnostic technologies in determining who needs such tests.

As such, treatment guidelines are done on an institution by institution basis. One potential strategy to help in this area is using a combination of predictive tools and guidelines to help decide when rapid diagnostics are needed.

For example, clinicians have used the Drug Resistance in Pneumonia (DRIP) tool to aid in predicting cases of bacterial pneumonia that prove resistant to antibiotics. It can, however, still lead to some use of broad-spectrum antibiotics and over coverage.

Matthew Sims, MD, PhD, director of Infectious Disease Research, Corewell Health East, is a proponent of using the established DRIP in concert with rapid diagnostics. Sims and his team have done a lot of research using the rapid diagnostic the Unyvero Lower Respiratory Tract Panel (LRTP) and aided in obtaining its FDA approval.

In his research, he decided to study combining the two tools to see if they could improve diagnosis and tailor antibiotic treatment by creating an algorithm.

“Using an existing patient pool from a clinical trial of the LRTP, a DRIP score was determined for each patient. When data elements of the DRIP score were unavailable a DRIPmax and DRIPmin were calculated assuming all missing elements were positive or negative respectively,” Sims and his coinvestigator wrote about their methods. “The sensitivity and specificity of the DRIP score vs culture and LRTP were determined. An algorithm for antibiotic selection based on the results of the DRIP score combined with the LRTP was applied to each patient.”

This combination helped in finding patients who were susceptible to drug resistance.

“What we found is that if you use just the DRIP score as your initial cut and we’re going to run the [LRTP] panel on patients who have a score of four or more—which is the cutoff—you catch almost everyone who has a drug-resistant pathogen,” Sims stated.

Sims and his coinvestigator, medical student Richard Ramirez, developed their study’s results into a subsequent poster, “Combining DRIP Score and Rapid Diagnostics for Improved Antibiotic Stewardship,” which Sims presented at the infectious disease conference, ID Week 2022 in October.

Ultimately, the ability to bore down on diagnosis and timely, proper treatment is critical, especially in severe medical cases. And although the near term is undetermined in how to resolve these cost and guideline issues, innovation rules the day and modern medicine will find solutions to fix the problem.

“It's not something you can implement overnight, but we are seeing absolute payoff with our DCLS graduates that are aligning with healthcare systems and hospitals, not only in life and quality of patient care, but in actual dollars saved,” Rohde said. “If you don't order all of these tests, especially some of these expensive molecular assays, you can actually help the bottom line of a hospital and a medical lab. It's part of the ongoing conversation alongside other things to be more accurate, and quicker turnarounds—and all of those things that we need to do to improve patient care.” 

1. Miller M, et al. Early experience with the BioFire pneumonia panel. Contagion. 2020;05 (05): 16-17.

2. Banerjee R, Teng CB, Cunningham SA, et al. Randomized trial of rapid multiplex polymerase chain reaction-based blood culture identification and susceptibility testing. Clin Infect Dis. 2015;61(7):1071-1080. doi:10.1093/cid/civ447

3. Current Stewardship Report. Centers for Disease Control and Prevention. Last reviewed October 6, 2022. Accessed December 20, 2022. https://www.cdc.gov/antibiotic-use/stewardship-report/current.html

This novel concept can benefit patients and clinicians alike by appropriately applying new technologies to identify bacteria more efficiently and decrease the time to optimal therapy.

Diagnostic Stewardship: An Emerging Component With Far-Reaching Treatment Implications

Recently, the monkeypox incidence rates have greatly increased, prompting both the 

 to declare health emergencies for the virus. The former just declared in recent days, and allows for optimal mobilization of funding and resources to address the virus.

In July, the WHO stated the disease was a Public Health Emergency of International Concern (PHEIC). At that time, monkeypox infections have been reported in 68 countries where the virus is not endemic. Globally, there were just under 17,000 confirmed monkeypox infections.

The Centers for Disease Control and Prevention (CDC) discussed prioritizing specific high-risk groups for monkeypox clinical care and education in its latest Morbidity and Mortality Weekly Report (MMWR).

“Public health efforts should prioritize gay, bisexual, and other men who have sex with men, who are currently disproportionately affected, for prevention and testing, address equity, and minimize stigma, while maintaining vigilance for transmission in other populations,” MMWR reported. “Clinicians should test persons with rash consistent with monkeypox, regardless of whether the rash is disseminated or was preceded by prodrome.”

In the US, 2891 cases were reported from May-July 2022, in 43 states, Puerto Rico, and the District of Columbia. CDC received case report forms for 1195 (41%) cases as of July 27.

Among the report forms, the confirmed cases in the United States occurred in 99% of men, and “94% of whom reported recent male-to-male sexual or close intimate contact.”

Racial and minority groups are being disproportionately affected, as noticed by the report.

“Among the 88% of cases with available data, 41% were among non-Hispanic White (White) persons, 28% among Hispanic or Latino (Hispanic) persons, and 26% among non-Hispanic Black or African American (Black) persons.”

And the presentations are atypical with fewer persons experiencing prodrome and more experiencing genital rashes.

The WHO has been involved in both smallpox and monkeypox health campaigns and reported in May the vaccines developed for the former also protect against the latter.

“Vaccines used during the smallpox eradication program also provided protection against monkeypox. Newer vaccines have been developed of which one has been approved for prevention of monkeypox,” WHO wrote in a statement.

WHO is recommending people in high-risk groups—including men who have sex with men and health care workers—get vaccinated.

In the US, states have had a limited vaccine supply. Vaccines are only being provided for people who are close contacts of those with confirmed cases.

And with the recent increase in demand, there may be some shortages in some areas in the US. For example, The San Francisco Department of Public Health (SFDPH) initially requested 35,000 doses of the monkeypox vaccine, and within the last week, San Francisco had only received approximately 12,000 doses.

CDC and the Food and Drug Administration (FDA) have developed a process to help clinicians secure an antiviral therapy, tecovirimat (Tpoxx), for monkeypox treatment. This falls under the expanded access investigational new drug (EA-IND). Clinicians can begin the process to secure tecovirimat by going 

Tecovirimat is manufactured by SIGA Technologies, and is approved for smallpox and is being studied for monkeypox treatment. 

spoke with SIGA Technologies Chief Scientific Officer Dennis Hruby, PhD,

Latest monkeypox updates from CDC and WHO.