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Clinical Laboratories and Pathology Groups

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San Diego University Researchers Believe Bacteriophages May Be the Future of Eradicating Multi-Drug Resistant Superbugs

Clinical laboratories and microbiologists may soon have new powerful tools for fighting antimicrobial resistant bacteria that saves lives

Superbugs—microbes that have developed multidrug resistance—continue to cause problems for clinical laboratories and hospital antibiotic stewardship programs around the world. Now, scientists at San Diego State University (SDSU) believe that bacteriophages (phages) could provide a solution for dealing with multi-drug resistant superbugs.

Phages are miniscule, tripod-looking viruses that are genetically programmed to locate, attack, and eradicate a specific kind of pathogen. These microscopic creatures have saved lives and are being touted as a potential solution to superbugs, which are strains of bacteria, viruses, parasites, and fungi that are resistant to most antibiotics and other treatments utilized to counteract infections.

“These multi-drug-resistant superbugs can cause chronic infections in individuals for months to years to sometimes decades,” Dwayne Roach, PhD, Assistant Professor of Bacteriophages, Infectious Disease, and Immunology at SDSU told CNN. “It’s ridiculous just how virulent some of these bacteria get over time.”

Labs across the country are conducting research on phages in eradicating superbugs. Roach’s lab is currently probing the body’s immune response to phages and developing purification techniques to prepare phage samples for intravenous use in patients.

“There are a lot of approaches right now that are happening in parallel,” said Dwayne Roach, PhD (above), Assistant Professor of Bacteriophages, Infectious Disease, and Immunology at San Diego State University (SDSU), in a CNN interview. “Do we engineer phages? Do we make a phage cocktail, and then how big is the cocktail? Is it two phages or 12 phages? Should phages be inhaled, applied topically, or injected intravenously? There’s a lot of work underway on exactly how to best do this.” Clinical laboratories that test for bacterial infections may play a key role in diagnosis and treatment involving bacteriophages. (Photo copyright: San Diego State University.)

Building Libraries of Phages

When certain a bacterial species or its genotypes needs to be annihilated, a collection of phages can be created to attack it via methods that enter and weaken the bacterial cell. The bacteria will attempt to counter the intrusion by employing evasive actions, such as shedding outer skins to eliminate the docking ports utilized by the phages. These maneuvers can cause the bacteria to lose their antibiotic resistance, making them vulnerable to destruction. 

Some research labs are developing libraries of phages, accumulating strains found in nature in prime breeding grounds for bacteria to locate the correct phage for a particular infection. Other labs, however, are speeding up the process by producing phages in the lab.

“Rather than just sourcing new phages from the environment, we have a bioreactor that in real time creates billions upon billions of phages,” Anthony Maresso, PhD, Associate Professor at Baylor College of Medicine in Houston told CNN. “Most of those phages won’t be active against the drug-resistant bacteria, but at some point, there will be a rare variant that has been trained, so to speak, to attack the resistant bacteria, and we’ll add that to our arsenal. It’s a next-generation approach on phage libraries.”

Maresso and his team published their findings in the journal Clinical Infectious Diseases titled, “A Retrospective, Observational Study of 12 Cases of Expanded-Access Customized Phage Therapy: Production, Characteristics, and Clinical Outcomes.”

For the Baylor study, 12 patients were treated with phages customized to each individual’s unique bacterial profile. The antibiotic-resistant bacteria were exterminated in five of the patients, while several others showed improvement.

Clinical trials are currently being executed to test the effectiveness of phages against a variety of chronic health conditions, including:

Using a phage cocktail could be used to treat a superbug outbreak in real time, while preventing a patient from a future infection of the same superbug. 

“The issue is that when patients have infections with these drug-resistant bacteria, they can still carry that organism in or on their bodies even after treatment,” Maroya Walters, PhD, epidemiologist at the federal Centers for Disease Control and Prevention (CDC) told CNN.

“They don’t show any signs or symptoms of illness, but they can get infections again, and they can also transmit the bacteria to other people,” she added.

The colorized transmission electron micrograph above shows numerous phages attached to a bacterial cell wall. Phages are known for their unique structures, which resemble a cross between NASA’s Apollo lunar lander and an arthropod. (Caption and photo copyright: Berkeley Lab.)

More Studies are Needed

According to CDC data, more than 2.8 million antimicrobial-resistant (AMR) infections occur annually in the United States. More than 35,000 people in the country will die as a result of these infections.

In addition, AMR infections are a huge global threat, associated with nearly five million deaths worldwide in 2019. Resistant infections can be extremely difficult and sometimes impossible to treat.

“It’s estimated that by 2050, 10 million people per year—that’s one person every three seconds—is going to be dying from a superbug infection,” epidemiologist Steffanie Strathdee, PhD, Associate Dean of Global Health Services and co-director at the Center for Innovative Phage Applications and Therapeutics (IPATH) at the UC San Diego School of Medicine, told CNN.

The CDC’s 2019 report on bacteria and fungi antimicrobial resistant threats named five pathogens as urgent threats:

More research is needed before phages can be used clinically to treat superbugs. But if phages prove to be useful in fighting antibiotic-resistant bacteria, microbiologists and their clinical laboratories may soon have new tools to help protect patients from these deadly pathogens.

—JP Schlingman

Related Information:

Superbug Crisis Threatens to Kill 10 Million Per Year by 2050. Scientists May Have a Solution

About Antimicrobial Resistance

2019 AR Threats Report

Bacteriophage

Why Antibiotics Fail, and How We Can Do Better

A Retrospective, Observational Study of 12 Cases of Expanded-Access Customized Phage Therapy: Production, Characteristics, and Clinical Outcomes

Cataloging Nature’s Hidden Arsenal: Viruses That Infect Bacteria

UCSB Researchers Discover Superior Culture Medium for Bacterial Testing, along with New Insights into Antimicrobial Resistance

CDC Ranks Two More Drug-Resistant Microbes as ‘Urgent Threat’ to Americans; Clinical Laboratories Are Advised to Increase Awareness of Antimicrobial Resistance

In a separate study, HHS finds a 40% increase in sepsis cases, as more patients succumb to infections without effective antibiotics and antimicrobial drugs

Given the drastic steps being taken to slow the spread of the Coronavirus in America, it’s easy to forget that significant numbers of patients die each year due to antibiotic-resistant bacteria (ARB), other forms of antimicrobial resistance (AMR), and in thousands of cases the sepsis that follows the infections.

This is why the Centers for Disease Control and Prevention (CDC) issued the report “Antibiotic Resistance Threats in the United States, 2019 (2019 AR Threats Report)” last fall. The federal agency wants to call attention the emergence of new antibiotic-resistant bacteria and fungi. In its report, the CDC lists 18 bacteria and fungi that pose either urgent, serious, or concerning threats to humans. It also placed one fungus and two bacteria on a “watch” list.

The CDC’s website states that “more than 2.8 million antibiotic-resistant infections occur in the US each year, and more than 35,000 people die as a result.” And a CDC news release states, “on average, someone in the United States gets an antibiotic-resistant infection every 11 seconds and every 15 minutes someone dies.”

Those are huge numbers.

Clinical laboratory leaders and microbiologists have learned to be vigilant as it relates to dangerously infectious antimicrobial-resistant agents that can result in severe patient harm and death. Therefore, new threats identified in the CDC’s Antibiotic Resistance Threats in the United States report will be of interest.

Drug-resistant Microbes That Pose Severe Risk

The CDC has added the fungus Candida auris (C. auris) and carbapenem-resistant Acinetobacter (a bacteria that can survive for a long time on surfaces) to its list of “urgent threats” to public health, CDC said in the news release. These drug-resistant microbes are among 18 bacteria and fungi posing a greater threat to patients’ health than CDC previously estimated, Live Science reported.

In 2013, the CDC estimated that about two million people each year acquired an antibiotic-resistant (AR) infection that killed as many as 23,000. However, in 2019, the CDC reported that those numbers were low and that the number of deaths due to AR infections in 2013 was about twice that amount. During a news conference following the CDC announcement, Michael Craig (above), a Senior Adviser for the CDC’s Antibiotic Resistance Coordination and Strategy Unit said, “We knew and said [in 2013] that our estimate was conservative … and we were right,” Live Science reported. In 2019, CDC reported 2.8 million antibiotic-resistant infections annually with more than 35,000 related deaths in the US alone. (Photo copyright: Centers for Disease Control and Prevention.)

The CDC considers five threats to be urgent. Including the latest additions, they are:

Dark Daily has regularly covered the healthcare industry’s ongoing struggle with deadly fungus and bacteria that are responsible for hospital-acquired infections (HAI) and sepsis. This latest CDC report suggests healthcare providers continue to struggle with antimicrobial-resistant agents.

Acinetobacter Threat Increases and C. auris a New Threat since 2013

Carbapenem-resistant Acinetobacter, a bacterium that causes pneumonia and bloodstream and urinary tract infections, escalated from serious to urgent in 2013. About 8,500 infections and 700 deaths were noted by the CDC in 2017. 

C. auris, however, was not addressed in the 2013 report at all. “It’s a pathogen that we didn’t even know about when we wrote our last report in 2013, and since then it’s circumvented the globe,” said Michael Craig, Senior Adviser for the CDC’s Antibiotic Resistance Coordination and Strategy Unit, during a news conference following the CDC announcement, Live Science reported.

Today, C. auris is better understood. The fungus resists emerging drugs, can result in severe infections, and can be transmitted between patients, CDC noted.

Last year, Dark Daily reported on C. auris, noting that as of May 31 the CDC had tracked 685 cases. (See, “Potentially Fatal Fungus Invades Hospitals and Public Is Not Informed,” August 26, 2019.)

By year-end, CDC tracking showed 988 cases in the US.

More Patients Getting Sepsis as Antibiotics Fail: HHS Study

In a separate study published in Critical Care Medicine, a journal of the Society of Critical Care Medicine (SCCM), the US Department of Health and Human Services  (HHS) found that antibiotic-resistant bacteria and fungi are resulting in more people acquiring sepsis, a life-threatening condition, according to an HHS news release.

Sepsis increased by 40% among hospitalized Medicare patients from 2012 through 2018, HHS reported.   

“These (untreatable infections) are happening here and now in the United States in large numbers. This is isn’t some developing world thing. This isn’t a threat for 2050. It’s a threat for here and now,” Cornelius “Neil” Clancy, MD, Associate Chief of Veterans Affairs Pittsburg Health System (VAPHS) and Opportunistic Pathogens, told STAT.

It is troubling to see data about so many patient deaths related to antibiotic-resistant infections and sepsis cases when the world is transfixed by the Coronavirus. Nevertheless, it’s important that medical laboratory leaders and microbiologists keep track of how the US healthcare system is or is not responding to these new infectious agents. And, to contact infection control and environmental services colleagues to enhance surveillance, ensure safe healthcare environments and equipment, and adopt appropriate strategies to prevent antibiotic-resistant infections.   

—Donna Marie Pocius

Related Information:

CDC:  Biggest Threats and Data: 2019 Antibiotic Resistance Threats in the United States

More People in the U.S. Dying from Antibiotic-Resistant Infections Than Previously Estimated; Significant Progress Since 2013 Could be Lost Without More Action

These Two Drug-Resistant Microbes Are New “Urgent Threats” to Americans’ Health

CDC Report: 35,000 Americans Die of Antibiotic-Resistant Infections Each Year

The Superbug Candida Auris is Giving Rise to Warnings and Big Questions

On the Emergency of Candida Auris Climate Change, Azoles, Swamps, and Birds

Largest Study of Sepsis Cases Among Medicare Beneficiaries Finds Significant Burden

Sepsis Among Medicare Beneficiaries: The Burdens of Sepsis 2012 to 2018

Dark Daily: Hospital-Acquired Infection

Potentially Fatal Fungus Invades Hospitals and Public is Not Informed

University of Edinburgh Study Finds Antimicrobial Bacteria in Hospital Wastewater in Research That Has Implications for Microbiologists

The highly infectious bacteria can survive treatment at local sewage plants and enter the food chain of surrounding populations, the study revealed

Researchers at the University of Edinburgh (UE) in Scotland found large amounts of antimicrobial-resistance (AMR) genes in hospital wastewater. These findings will be of interest to microbiologists and clinical laboratory managers, as the scientists used metagenomics to learn “how abundances of AMR genes in hospital wastewater are related to clinical activity.”

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.

Using Metagenomics to Surveille Hospital Patients

Antimicrobial resistance is creating super bacteria that are linked to increases in hospital-acquired infections (HAIs) nationwide. Dark Daily has reported many times on the growing danger of deadly antimicrobial resistant “super bugs,” which also have been found in hospital ICUs (see “Potentially Fatal Fungus Invades Hospitals and Public Is Not Informed,” August 26, 2019.)

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.”

AMR bacteria also are being spread by human touch throughout city subways, bus terminals, and mass transportation, making it difficult for the Centers for Disease Control and Prevention (CDC) to identify the source of the outbreak and track and contain it. This has led microbiologists to conduct similar studies using genetic sequencing to identify ways to track pathogens through city infrastructures and transportation systems. (See, “Microbiologists at Weill Cornell Use Next-Generation Gene Sequencing to Map the Microbiome of New York City Subways,” December 13, 2013.)

Antimicrobial stewardship programs are becoming increasingly critical to preventing the spread of AMR bacteria. “By having those programs, [there are] documented cases of decreased antibiotic resistance within organisms causing these infections,” Paul Fey, PhD, of the University of Nebraska Medical Center, told MedPage Today. “This is another indicator of how all hospitals need to implement stewardship programs to have a good handle on decreasing antibiotic use.” [Photo copyright: University of Nebraska.]

Don’t Waste the Wastewater

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 points. 

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;
  • Finally, they complete the genetic sequencing on an Illumina HiSeq4000 System.

The researchers reported these findings:

  • 181 clinical isolates were identified in the samples of wastewater;
  • 1,047 unique bacterial genes were detected across all samples;
  • 19 genes made up more than 60% of bacteria in samples;
  • Overriding bacteria identified as Pseudomonas and Acinetobacter environmental samples (Pseudomonas fluorescens and Acinetobacter johnsonii) were most likely from hospital pipes;
  • Gut-related bacteria—Faecalibacterium, Bacteroides, Bifidobacterium, and Escherichia, were more prevalent in the hospital samples than in those from the community;
  • 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 research.

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.  

—Donna Marie Pocius

Related Information:

Secrets of the Hospital Underbelly: Abundance of Antimicrobial-Resistance Genes in Hospital Wastewater Reflects Hospital Microbial Use and Inpatient Length of Stay

Antibiotic-Resistance Genes Trouble Hospital Water; Study Emphasizes Importance of Antibiotic Stewardship Programs, Expert Says

Fact Sheet: Antibiotic Resistance

United States Gathers 350 Commitments to Combat Antibiotic Resistance, Action Must Continue

Genomic Analysis of Hospital Plumbing Reveals Diverse Reservoir of Bacterial Plasmids Conferring Carbapenemase Resistance

Dark Daily E-briefings: Hospital-Acquired Infections

NIH Study Reveals Surprising New Source of Antibiotic Resistance that Will Interest Microbiologists and Medical Laboratory Scientists

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