This white paper serves as a practical guide to enhance the understanding of Antimicrobial resistance (AMR), which is a growing global health crisis that threatens human, animal, and environmental health. AMR results in higher rates of illness and death, as infections become increasingly difficult to manage, and it is projected to surpass cancer as the leading cause of death by 2050, underscoring the critical importance of addressing this issue across local, state, and global levels.
Study may also result in new clinical laboratory tools for determining antimicrobial resistance and efficacy of existing antibiotics
Researchers find it increasingly difficult to develop antibiotics that are effective against strains of bacteria that display antibiotic resistance—a subset of antimicrobial resistance (AMR). However, a new study provides a glimmer of hope and may spur clinical laboratories to look at this research in novel ways.
Conducted at the University of California Santa Barbara, the study looked at more than 500 antibiotic-bacteria combinations. The researchers discovered that several widely used, FDA-approved, antibiotics may be more useful than previously thought against a large range of bacterial infections, said infectious disease specialist Judy Stone, MD, in an article she penned for Forbes titled, “Why Antibiotics Fail—and How We Can Do Better.”
The researchers also discovered a common culture medium that enables a better assessment of the properties of various strains of bacteria to resist different antibiotics.
Clinical laboratories and microbiologists are tasked with plating and growing bugs to identify a specific bug, what strain of bug, and whether that strain has resistance to specific antibiotics. Thus, this research touches on what they do daily. It is something that may provide microbiologists with new approaches to detect AMR more accurately.
“We know there are a variety of reasons why antibiotics don’t work as predicted, from wrongly prescribed doses to infrequent administration, but another less noticeable reason is that lab testing can show a bacteria is susceptible to antibiotics when it’s actually not. You know, the whole in vitro (culture plate) versus in vivo (life) balance,” wrote Judy Stone, MD, infectious disease expert, in her Forbes article. Clinical laboratories may soon have a better way of identifying antibiotic resistance in deadly bacteria. (Photo: LinkedIn profile.)
UCSB Antimicrobial Study Details
Antibiotic-resistant infections are responsible for more than 32,000 deaths in the US and 1.27 million globally every year, Forbes reported. A study like this can have a far-reaching impact.
To conduct their study, Michael Mahan, PhD, Professor of Molecular, Cellular, and Developmental Biology at UCSB, and his team at the Mahan Lab on the UCSB campus, used Fisher Scientific’s Gibco Dulbecco’s Modified Eagle Medium (DMEM), a basal medium for supporting the growth of many different mammalian cells.
The DMEM predicted antibiotic effectiveness better than Mueller Hinton Broth (MHB), another growth medium from Thermo Fisher Scientific that has been used in clinical laboratories by World Health Organization (WHO) decree since 1968, Forbes reported.
Assays were run against 13 isolates from nine species of bacteria to determine the efficacy of 15 different antibiotics. Using DMEM, the team found different sensitivities in 15% of the bacterial isolates tested in vitro compared to MHB.
In Mahan’s follow-up tests, which looked at mice infected with different bacteria, MHB was accurate in 54% of test predictions while DMEM was accurate 77% of the time. Part of the reason, Mahan believes, is because DMEM is more physiologic and closer in conditions to people (in vivo), Forbes reported.
“People are not Petri plates—that is why antibiotics fail. Testing under conditions that mimic the body improves the accuracy by which lab tests predict drug potency,” said Mahan in a UCSB press release.
“I think it has merit. I think this study has been very well-designed … and showed that this makes clinical sense … If it bears out in humans, it will be clinically very significant,” pulmonologist Ken Yomer Yoneda, MD, Professor Emeritus, Department of Internal Medicine at UC Davis Health, told Forbes.
Though the major limitation of the study is that it was conducted on mice and not humans, Yoneda said it gives an indication of potential success with humans. “If it bears out in humans it will be clinically very significant,” he told Stone for her Forbes article.
Rodney Rohde, PhD, Professor and Chair of Clinical Lab Science Program at Texas State University also shared enthusiasm on the findings. According to Stone, “[Rohde] was ‘intrigued’ by the finding that using a physiologic media predicted ‘a change in susceptibility’ thresholds used to categorize patient isolates as susceptible or resistant.
“He was also ‘excited about the results of increasing diagnostic accuracy’ with especially difficult-to-treat organisms,” she noted.
“Rohde added that the issue of these clinical breakpoints—setting the level at which an organism is defined as ‘sensitive’ or ‘resistant’ to an antibiotic is a hot topic, undergoing considerable discussion in lab circles. Multiple agencies need to reach agreement for the standards that are used globally, both in the US and Europe,” Stone wrote.
Old Drug, New Tricks
According to the UCSB press release, “Physicians are aware of the flaws in the gold-standard test [MHB]. When recommended antibiotics do not work, they must rely on their experience to decide on the appropriate antibiotic(s) for their patients. This study provides a potential solution to address the disparity between antibiotics indicated by standard testing and actual patient outcomes.”
Infectious disease physician Lynn Fitzgibbons, MD, remarked in the UCSB press release, “Re-evaluation of FDA-approved antibiotics may be of far greater benefit than the time and cost of developing new drugs to combat antimicrobial resistance, potentially leading to significant life-savings and cost-savings.”
In her Forbes article, Stone wrote, “Pharmaceutical companies are abandoning the acute infectious disease market and few new antibiotics are in sight. Pharma is profit driven and antibiotics are simply not as lucrative as life-style drugs (like Viagra/Cialis or Rogaine for hair loss) or those for chronic diseases. So, Mahan et al.’s findings are welcome news indeed.”
Once further studies validate the UCSB study findings and allow their use in clinical settings for patient care, clinical laboratories and microbiologists may have new tools for accurately determining a bacterium’s ability to resist existing antibiotics or its susceptibility to antibiotics not currently used to treat certain infections.
Study findings could lead to new biomarker targets for clinical laboratories working to identify AMR bacteria
Reducing and managing antimicrobial resistance (AMR) is a major goal of researchers and health systems across the globe. And it is the job of microbiologists and clinical laboratories to identify microbes that are AMR and those which are not to guide physicians as to the most appropriate therapies for patients with bacterial infections.
“AMR is a silent pandemic of much greater risk to society than COVID-19. In addition to 10 million deaths per year by 2050, the WHO estimates AMR will cost the global economy $100 trillion if we can’t find a way to combat antibiotic failure,” Timothy Barnett, PhD (above), Deputy Director and head of the Strep A Pathogenesis and Diagnostics team at Wesfarmers Centre of Vaccines and Infectious Diseases, told News Medical. Additional research may provide new targets for clinical laboratories tasked with identifying antimicrobial resistant bacteria. (Photo copyright: University of Western Australia.)
Rendering an Antibiotic Ineffective
According to the University of Oxford, about 1.2 million people died worldwide in 2019 due to AMR, and antimicrobial-resistant infections played a role in as many as 4.95 million deaths that same year. The World Health Organization (WHO) declared AMR one of the top ten global public health threats facing humanity.
While investigating antibiotic sensitivity of Group A Streptococcus—a potentially deadly bacteria often detected on the skin and in the throat—the Australian researchers uncovered a mechanism that enabled bacteria to absorb nutrients from their human host and evade the antibiotic sulfamethoxazole, a commonly-prescribed treatment for Group A Strep.
“Bacteria need to make their own folates to grow and, in turn, cause disease. Some antibiotics work by blocking this folate production to stop bacteria growing and treat the infection,” Timothy Barnett, PhD, Deputy Director of the Wesfarmers Centre of Vaccines and Infectious Diseases and head of the Strep A Pathogenesis and Diagnostics team, told News Medical.
“When looking at an antibiotic commonly prescribed to treat Group A Strep skin infections, we found a mechanism of resistance where, for the first time ever, the bacteria demonstrated the ability to take folates directly from its human host when blocked from producing their own. This makes the antibiotic ineffective and the infection would likely worsen when the patient should be getting better,” he added.
According to their study, the researchers identified an energy-coupling (ECF) factor transporter S component gene that allows Group A Strep to acquire extracellular reduced folate compounds that likely “expands the substrate specificity of an endogenous ECF transporter to acquire reduced folate compounds directly from the host, thereby bypassing the inhibition of folate biosynthesis by sulfamethoxazole.”
The study indicates that this new form of antibiotic resistance is indistinguishable under traditional testing used in microbiology and clinical laboratories, which in turn makes it difficult for clinicians to prescribe effective antibiotics to fight an infection.
Understanding AMR before It Is Too Late
The research suggests that understanding AMR is more complicated and intricate than previously thought. Barnett and his team believe their discovery is just the “tip of the iceberg” and that it will prove to be a far-reaching issue across other bacterial pathogens in addition to Group A Strep.
“Without antibiotics, we face a world where there will be no way to stop deadly infections, cancer patients won’t be able to have chemotherapy and people won’t have access to have life-saving surgeries,” Barnett told News Medical. “In order to preserve the long-term efficacy of antibiotics, we need to further identify and understand new mechanisms of antibiotic resistance, which will aid in the discovery of new antibiotics and allow us to monitor AMR as it arises.”
More research and clinical studies are needed before this discovery can become technology that clinical laboratories can use to test if microbes are AMR. The scientists at Wesfarmers Centre of Vaccines and Infectious Diseases are now developing testing methods to detect the presence of the antibiotic resistant mechanism and determine the best treatment options.
“It is vital we stay one step ahead of the challenges of AMR and, as researchers, we should continue to explore how resistance develops in pathogens and design rapid accurate diagnostic methods and therapeutics,” Kalindu Rodrigo, a PhD student in the Barnett lab and one of the authors of the study told News Medical. “On the other hand, equal efforts should be taken at all levels of the society including patients, health professionals, and policymakers to help reduce the impacts of AMR.”
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Clinical laboratories and microbiology tests provide key tools for physicians engaged in antibiotic stewardship programs
One important and continuing trend in healthcare is the need for hospitals, nursing homes, and other medical providers to introduce effective antibiotic stewardship programs (ASPs). The findings of a recent study on antibiotic stewardship emphasize the need for improvement and suggest guidelines that will involve and engage clinical laboratories.
In a recent brief of a study The Pew Charitable Trusts (Pew) conducted with the CDC and various public health and medical experts, Pew wrote, “Minimizing inappropriate antibiotic use in hospitals is a vital element in the fight against antibiotic resistance because more than half of patients admitted to hospitals will receive these drugs. Determining how much antibiotic prescribing is inappropriate and setting national targets to reduce such use are necessary steps for guiding clinical efforts and policies that promote improved antibiotic use.”
To do this, and Pew and the CDC are suggesting “widespread adoption of effective antibiotic stewardship programs, which promote responsible antibiotic prescribing, in order to minimize the harmful effects of inappropriate or unnecessary antibiotic use for patients and slow the spread of resistance.”
And because clinical laboratories perform all the in-hospital testing for ASPs, they will be big part of this effort.
Pew/CDC Set New National Targets for Antibiotic Use Improvement
The Pew brief states that in 2018 the researchers began “to evaluate antibiotic use in hospitals and set national targets to improve prescribing.” The brief adds that “Because of the complexity and diversity of illnesses among hospitalized patients, and the limitations on available clinical data for all antibiotic use in hospitals, the panel focused its analysis on four categories of prescribing that account for the most common antibiotic therapies in US hospitals. Using national prescribing data, the experts examined the use of two types of antibiotics—vancomycin and fluoroquinolones—and antibiotic treatments associated with two conditions: community-acquired pneumonia (CAP) and hospital-acquired urinary tract infection (UTI).”
It their paper published in JAMA Network Open, titled, “Assessment of the Appropriateness of Antimicrobial Use in US Hospitals,” the Pew/CDC researchers wrote, “In this cross-sectional study of 1,566 patients at 192 hospitals, antimicrobial use deviated from recommended practices for 55.9% of patients who received antimicrobials for community-acquired pneumonia or urinary tract infection present at admission or who received fluoroquinolone or intravenous vancomycin treatment.”
Infection Control Today reported that the CDC and Pew set the following goals for hospitals, but did not give a deadline for improvement:
Decrease antibiotic inappropriate prescribing in CAP and UTI cases by 90%.
Decrease overprescribing of fluoroquinolones and vancomycin by 95%.
“Meeting these national reduction targets will require widespread adoption of effective antibiotic stewardship programs, which promote responsible antibiotic prescribing in order to minimize the harmful effects of inappropriate or unnecessary antibiotic use for patients and slow the spread of resistance,” noted the Pew brief, which also pointed out that hospitals should provide incentives to report antibiotic use and impact of stewardship programs to the CDC’s National Healthcare Safety Network (NHSN).
‘Ample Room for Improvement’
The Pew/CDC panel of experts analyzed hospitalized patient data from August 2017 through May 2020. Of those patients, the researchers found that:
219 had CAPs,
452 had UTIs,
550 had received fluoroquinolones, and
403 had received vancomycin.
They also found that:
56% of antibiotic prescriptions were wrong in the type of antibiotic, how long it was used, or why it was chosen.
79% of antibiotic prescriptions for CAP were inappropriate.
77% of antibiotic prescriptions did not suit UTI patients.
47% of fluoroquinolone prescriptions were unsupported.
27% of vancomycin prescriptions were amiss.
The researchers concluded that providers have “ample room for improvement,” the Pew brief notes.
“A substantial percentage of CAP, UTI, fluoroquinolone, and vancomycin treatment was unsupported by medical record data collected (55.9% overall and as high as 79.5% for CAP),” the researchers wrote in their published study.
Pew/CDC Researchers Find Many Antibiotic Prescription Errors
According to the Pew/CDC researchers, missteps in antibiotic usage include:
Treating inpatients too long with antibiotics.
Selecting antimicrobials inconsistent with guidelines.
Absence of signs and symptoms of infection.
Lack of clinical laboratory tests or microbiologic evidence of infection.
The study revealed antibiotic duration errors were most prevalent in the CAP patients, some being treated with antibiotics for more than seven days.
“Almost 60% of the inappropriate prescribing is attributed to exceeding the recommended seven days of treatment, and the use of the wrong antibiotic accounts for most of the remaining inappropriate (CAP) cases,” the Pew brief explained.
Antibiotics Prescribed without Evidence of Infection
As medical laboratory professionals know, microbiology tests identify presence and type of bacteria in urine. But the Pew/CDC researchers reported they found UTI cases that lacked evidence of infection.
“In most instances—where antibiotic use was not supported—the antibiotics were prescribed to patients who lacked symptoms or microbiology test results consistent with UTIs,” according to their report.
Antibiotics Overprescribed to COVID-19 Patients
Another study conducted by The Pew Charitable Trusts “assessed the frequency of bacterial infections and antibiotic prescribing patterns in hospitalized patients diagnosed with COVID-19 in the US.” The researchers, according to the Pew brief on that study, titled, “Could Efforts to Fight the Coronavirus Lead to Overuse of Antibiotics?” used “IBM Watson Health’s electronic health records [EHR] database to capture data about approximately 5,000 patients and nearly 6,000 hospital admissions from February through July 2020.”
The researchers of that study found potential antibiotic misuse among COVID-19 patients as well.
52% received at least one antibiotic prescription.
36% had multiple antibiotics.
96% were treated with antibiotics within 48 hours of admission and likely before infection was confirmed.
“Our data shows that there was very likely a significant amount of unnecessary antibiotic prescribing among hospitalized COVID-19 patients,” Rachel Zetts, Officer, Antibiotic Resistance Project at The Pew Charitable Trusts, told Becker’s Hospital Review. “Overprescribing on this scale could negatively impact the progress we’ve made in the fight against antibiotic resistance over the years, so encouraging physicians to reduce inappropriate antibiotic use and equipping them with the tools needed to do so is critical.” Those tools include test results clinical laboratories produce in support of antibiotic stewardship programs. (Photo copyright: The Pew Charitable Trusts.)
Clinical Laboratories are Key Partners
Hospital-based clinical laboratory leaders may want to contact physicians and infection control colleagues and work toward correcting use of antibiotics in patient care. And microbiologists are advised to aggressively communicate available medical laboratory test data about UTI infections, which the Pew/CDC study suggests can be missed.
Medical laboratories provide testing to diagnose infections and to identify strains of infectious agents that may be antibiotic-resistant. Therefore, lab leaders will be key partners in hospitals’ efforts to reduce infections and prevent antibiotic resistance.
