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.”
Microbiologists and clinical laboratory managers in the US may find it valuable to examine this peer-reviewed study into AMR involved in blood stream infections. It could contain useful insights for diagnosing patients suspected of BSIs in US hospitals where sepsis prevention and antibiotic stewardship programs are major priorities.
“Antimicrobial resistance undermines modern medicine and puts millions of lives at risk,” said Tedros Adhanom Ghebreyesus, PhD, Director-General, World Health Organization, in a WHO press release. “To truly understand the extent of the global threat and mount an effective public health response to [antimicrobial resistance], we must scale up microbiology testing and provide quality-assured data across all countries, not just wealthier ones.” Clinical laboratories in the US may be called upon to submit data on bloodstream infections in this country. (Photo copyright: WHO.)
Clinical Laboratories in EU Report Huge Increase in Carbapenem Resistance
To perform their study, researchers measured the increase in Acinetobacter BSIs between 2020 and 2021, the first two years of the COVID-19 pandemic. Their data originated from qualitative regular antimicrobial susceptibility testing (AST) from blood samples collected by local clinical laboratories in the European Union/European economic area (EU/EEA) nations.
The researchers limited their dataset to Acinetobacter BSI information from the European medical laboratories that documented results of carbapenem susceptibility testing for the bacterial species.
Carbapenems are a class of very powerful antibiotics that are typically used to treat severe bacterial infections. A total of 255 EU/EEA clinical laboratories reported their data for the study. The scientists found that the percentages of Acinetobacter resistance varied considerably between EU/EEA nations, so they separated the countries into three different groups:
Nations in Group One—The Netherlands, Belgium, Austria, Estonia, Denmark, Germany, Iceland, Finland, Luxembourg, Ireland, Norway, Sweden, and Malta—experienced less than 10% resistance to carbapenems.
Nations in Group Two—Slovenia, Czech Republic, and Portugal—had carbapenem resistance between 10% and 50%.
Nations in Group Three—Croatia, Bulgaria, Greece, Cyprus, Italy, Hungary, Lithuania, Latvia, Romania, Poland, Spain, and Slovakia—demonstrated carbapenem resistance equal or greater than 50%.
The study also found that Acinetobacter BSIs rose by 57% and case counts increased by 114% in 2020 and 2021 when compared to 2018 and 2019. The percentage of resistance to carbapenems rose to 66% in 2020 and 2021, up from 48% in 2018 and 2019.
Antimicrobial Resistance Especially High in Hospital Settings
The researchers further arranged the data into three hospital ward types: intensive care unit (ICU), non-ICU, and unknown. The increase in BSIs caused by Acinetobacter species resistant to carbapenems was greater in ICU-admitted individuals (144%) than non-ICU-admitted individuals (41%).
There are more than 50 species of Acinetobacter bacteria and various strains are often resistant to many types of commonly-used antibiotics. Symptoms of an Acinetobacter infection usually appear within 12 days after a person comes into contact with the bacteria. These symptoms may include:
Urinary tract infections,
Healthy people have a low risk of contracting an Acinetobacter infection with the highest number of these infections occurring in hospitals and other healthcare settings. Acinetobacter bacteria can survive for a long time on surfaces and equipment, and those working in healthcare or receiving treatment are in the highest risk category.
The prevalence of this type of bacteria increases in relation to the use of medical equipment, such as ventilators and catheters, as well as antibiotic treatments.
The WHO report examined data collected during 2020 from 87 different countries and found that common bacterial infections are becoming increasingly resistant to treatments. Both Klebsiella pneumoniae and Acinetobacter can be life threatening and often require treatment with strong antibiotics, such as carbapenems.
More research is needed to determine the reasons behind increases in Acinetobacter infections as reported in European hospitals and other healthcare settings, and to ascertain the extent to which they are related to hospitalizations and the upsurge in antimicrobial resistance during the COVID-19 pandemic.
Microbiologists and clinical laboratory managers in the US may want to learn more about the fIndings of this European study involving AMR and use those insights to plan accordingly for any future increase in bloodstream infections in this country.
On top of everything else during this pandemic, drug-resistant infections are threatening the most vulnerable patients in COVID-19 ICUs
New study by researchers at the University of Minnesota highlights the continuing need for microbiologists and clinical laboratories to stay alert for COVID-19 patients with drug-resistant infections. In their study, researchers highlighted CDC statistics about the number of Candida auris (C. auris) infections reported in the United States during 2020, for example.
Candida auris is a particularly nasty fungus. It spreads easily, is difficult to remove from surfaces, and can kill. Worst of all, modern drugs designed to combat this potentially deadly fungus are becoming less effective at eradicating it, and COVID-19 ICU patients appear especially vulnerable to C. auris infections.
COVID-19 and C. auris a Potentially Devastating Combination
Hospitals in many areas are at a critical capacity. Thus, hospital-acquired infections such as sepsis can be particularly dangerous for COVID-19 patients. Adding to the problem, C. auris requires special equipment to identify, and standard medical laboratory methods are not always enough. Misidentification is possible, even probable.
A paper in the Journal of Global Antimicrobial Resistance (JGAR), titled, “The Lurking Scourge of Multidrug Resistant Candida Auris in Times of COVID-19 Pandemic,” notes that “A particularly disturbing feature of COVID-19 patients is their tendency to develop acute respiratory distress syndrome that requires ICU admission, mechanical ventilation, and/or extracorporeal membrane oxygenation. … This haunting facet of COVID-19 pandemic has severely challenged even the most advanced hospital settings. Yet one potential confounder, not in the immediate attention of most healthcare professionals, is the secondary transmission of multidrug resistant organisms like the fungus Candida auris in COVID-19 ICUs. … C. auris outbreaks occur in critically ill hospitalized patients and can result in mortalities rates ranging from 30% to 72%. … Both C. auris and SARS-CoV-2 have been found on hospital surfaces including on bedrails, IV poles, beds, air conditioner ducts, windows and hospital floors. Therefore, the standard COVID-19 critical care of mechanical ventilation and protracted ventilator-assisted management makes these patients potentially susceptible to colonization and infections by C. auris.”
One study mentioned in the JGAR paper conducted in New Delhi, India, looked at 596 cases where patients were admitted to the ICU with COVID-19. Fifteen of them had infections caused by C. auris. Eight of those patients died. “Of note, four patients who died experienced persistent fungemia and despite five days of micafungin therapy, C. auris again grew in blood culture,” according to reporting on the study in Infection Control Today (ICT).
Some C. auris mortality rates are as high as 72%. And patients with weakened immune systems are at particular risk, “making it an even more serious concern when 8% to 9% of roughly 530,000 ICU patients in the United States have COVID-19,” ICT reported.
Apparently, the COVID-19 pandemic has created circumstances that are particularly suited for C. auris to spread. “Given the nosocomial transmission of SARS-CoV-2 by those infected, many hospital environments may serve as venues for C. auris transmission as it is a known environmental colonizer of ICUs,” wrote the JGAR paper authors.
CDC Reports and Recommendations
Along with being especially dangerous for people with weakened immune systems, C. auris infections also produce symptoms similar to those of COVID-19, “including fever, cough, and shortness of breath,” according to the CDC’s website. People admitted to ICUs with COVID-19 are especially vulnerable to bacterial and fungal co-infections. “These fungal co-infections are reported with increasing frequency and can be associated with severe illness and death,” says the CDC.
C. auris outbreaks in the United States have mostly been in long-term care facilities, but the pandemic seems to be changing that and more outbreaks have been detected in acute care facilities, the CDC reported. The lack of appropriate personal protective equipment (PPE), changes in infection control routines, and other factors could be to blame for the increase.
Just as community spread is an issue with COVID-19 variants, so too is it a concern with C. auris infections. “New C. auris cases without links to known cases or healthcare abroad have been identified recently in multiple states, suggesting an increase in undetected transmission,” the CDC noted.
As of January 19, 2021, according to the CDC the case count of C. auris infections in the US was 1,625, with California, Florida, Illinois, New Jersey, and New York having more than 100 cases each.
Using Clinical Laboratory Tests to Identify C. Auris
One of the big concerns about C. auris is that it is so difficult to detect, and that medical laboratories in some countries simply do not have the technology and resources to identify and tackle the infection.
“As C. auris diagnostics in resource-limited countries is yet another challenge, we feel that alerting the global medical community about the potential of C. auris as a confounding factor in COVID-19 is a necessity,” wrote the authors of the paper published in the Journal of Global Antimicrobial Resistance.
As if the COVID-19 pandemic has not been enough, drug resistant bacteria, viruses, and deadly fungi are threatening to wreak havoc among SARS-CoV-2 infected patients. Microbiologists and medical laboratory scientists know that testing for all types of infections is vitally important, but especially when it comes to infections caused by antibiotic-resistant bacteria (ARB) and other dangerous organisms that demonstrate antimicrobial resistance (AMR).
Microbiologists and clinical laboratory professionals will want to stay informed about the number of C. auris cases identified in the US and the locations and settings where the fungus was detected. They will want to be on the alert within their hospitals and health networks, as well as with the doctor’s offices served by their labs.
The UE study sheds light on the types of bacteria in
wastewater that goes down hospital pipes to sewage treatment plants. The study
also revealed that not all infectious agents are killed after passing through
waste treatment plants. Some bacteria with antimicrobial (or antibiotic)
resistance survive to enter local food sources.
The scientists concluded that the amount of AMR genes found
in hospital wastewater was linked to patients’ length-of-stays and consumption
of antimicrobial resistant bacteria while in the hospital.
In a paper the University of Edinburgh published on medRxiv, the researchers wrote: “There was a higher abundance of antimicrobial-resistance genes in the hospital wastewater samples when compared to Seafield community sewage works … Sewage treatment does not completely eradicate antimicrobial-resistance genes and thus antimicrobial-resistance genes can enter the food chain through water and the use of [processed] sewage sludge in agriculture. As hospital wastewater contains inpatient bodily waste, we hypothesized that it could be used as a representation of inpatient community carriage of antimicrobial resistance and as such may be a useful surveillance tool.”
Additionally, they wrote, “Using metagenomics to identify
the full range of AMR genes in hospital wastewater could represent a useful
surveillance tool to monitor hospital AMR gene outflow and guide environmental
policy on AMR.”
Antibiotic resistance occurs when bacteria change in response to medications to prevent and treat bacterial infections, according to a World Health Organization (WHO) fact sheet. The CDC estimates that more than 23,000 people die annually from two million antibiotic-resistance infections.
Wastewater, the UE scientists suggest, should not go to
waste. It could be leveraged to improve hospitals’ detection of patients with antimicrobial
resistance, as well as to boost environment antimicrobial-resistance polices.
They used metagenomics (the study of genetic material
relative to environmental samples) to compare the antimicrobial-resistance
genes in hospital wastewater against wastewater from community sewage
The UE researchers:
First collected samples over a 24-hour period from various areas in a tertiary hospital;
They then obtained community sewage samples from various locations around Seafield, Scotland;
Antimicrobial-resistance genes increased with longer length of patient stays, which “likely reflects transmission amongst hospital inpatients,” researchers noted.
Fey suggests that further research into using sequencing
technology to monitor patients is warranted.
“I think that monitoring each patient and sequencing their
bowel flora is more likely where we’ll be able to see if there’s a significant
carriage of antibiotic-resistant organisms,” Fey told MedPage Today. “In
five years or so, sequencing could become so cheap that we could monitor every
patient like that.”
Fey was not involved in the University of Edinburgh
Given the rate at which AMR bacteria spreads, finding antibiotic-resistance
genes in hospital wastewater may not be all that surprising. Still, the University
of Edinburgh study could lead to cost-effective ways to test the genes of
bacteria, which then could enable researchers to explore different sources of
infection and determine how bacteria move through the environment.
And, perhaps most important, the study suggests clinical
laboratories have many opportunities to help eliminate infections and slow
antibiotic resistance. Microbiologists can help move their organizations forward
too, along with infection control colleagues.
In studies, the automated microbial susceptibility testing device for smartphone performed with 98.2% accuracy, meeting FDA criteria
Imagine doing antimicrobial susceptibility testing outside a clinical laboratory. That’s the goal of researchers on the West Coast who are developing a smartphone-based diagnostic device with the capability of performing this type of point-of-care testing (POCT).