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Microbiology

Antiviral drugs may be a new treatment strategy in the fight against Candida auris

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Reviewed by Megan Craig, M.Sc.May 25 2023

Antiviral drugs can make antifungals work again.

That, at its simplest, is the approach Mohamed Seleem’s lab at the Center for One Health Research has found may be a key treatment strategy in the battle against Candida auris, a frighteningly deadly fungal pathogen discovered in 2009 that is considered an urgent threat by the Centers for Disease Control and Prevention (CDC).

Candida auris, first discovered in Japan as an ear infection, has a staggering 60 percent mortality rate among those it infects, primarily people with compromised health in hospitals and nursing homes.

Recently, Seleem and Ph.D. students Yehia Elgammal and Ehab A. Salama published a paper in the American Society for Microbiology’s Antimicrobial Agents and Chemotherapy journal detailing the potential use of atazanavir, an HIV protease inhibitor drug, as a new avenue to improving the effectiveness of existing antifungals for those with a Candida auris infection.

A perfect storm of antimicrobial resistance, global warming and the COVID-19 pandemic has resulted in the rapid spread of Candida auris around the world, said Seleem, director of the center, a collaboration between the Virginia-Maryland College of Veterinary Medicine and the Edward Via College of Osteopathic Medicine.

We don’t have lots of drugs to use to treat fungal pathogens. We have only three classes of antifungal drugs. With a fungal pathogen, it’s often resistant to one class, but then we have two other options. What’s scary about Candida auris is it shows resistance to all three classes of the antifungal.

The CDC has a list of urgent threats, but on that list there is just one fungal pathogen, which is Candida auris. Because it’s urgent, we need to deal with it.”

Mohamed Seleem, the Tyler J. and Frances F. Young Chair in Bacteriology at Virginia Tech

Widespread use of fungicides in agriculture, in addition to the three classes of antifungal drugs used widely in medicine, has contributed to fungal pathogens developing more resistance, particularly Candida auris.

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Also, its rise has been linked to rising global temperatures and to easier spread through hospitals filled with COVID-19 patients in recent years during the global pandemic.

Atazanavir, an HIV protease inhibitor drug, has been found by Seleem’s lab to block the ability of Candida auris to excrete antifungals through its efflux pumps.

Think of a boat taking on water and hoses siphoning that water out of the boat to keep it afloat. Atazanavir stops up the hoses.

That allows the azole class of antifungal drugs to not be expelled as easily and perform better against Candida auris, the Seleem lab’s research has found.

The research on atazanavir builds on work three years ago by Seleem’s lab, then at Purdue University, finding potentially similar benefit in lopinavir, another HIV protease inhibitor.

HIV protease drugs are already in wide use among HIV patients, who can also be extra susceptible to Candida auris. Some HIV patients have likely been taking HIV protease drugs and azole-class antifungals in tandem for separate purposes, providing a potential source of already existing data that can be reviewed on whether those patients had Candida auris and what effects the emerging pathogen had on them.

Repurposing drugs already on the market for new uses can allow those treatments to reach widespread clinical use much more rapidly than would happen with the discovery of an entirely new drug, as existing drugs have already been tested and approved by the Food and Drug Administration and have years of further observation of effects in prescriptive use.

In 2022, the Center for One Health Research received a $1.9 million grant from the National Institutes of Health for the Seleem lab’s research on repurposing already approved drugs for treating gonorrhea.

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Source:

Virginia Tech

Microbiology

Honokiol inhibits replication of SARS-CoV-2 in several cell types

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Reviewed by Megan Craig, M.Sc.May 22 2023

A compound called honokiol, which is found in the bark of multiple species of magnolia tree, inhibits replication of SARS-CoV-2 virus in several types of cells, according to a team of researchers in the Netherlands. The research is published in Microbiology Spectrum, a journal of the American Society for Microbiology.

The researchers found that Honokiol inhibits replication of SARS-CoV-2 in several cell types, causing production of infectious SARS-CoV-2 particles in treated cells to fall to around 1,000th of the previous level.

The compound also inhibited replication of other highly pathogenic human coronaviruses, including MERS- and SARS-CoV.

This suggests that it has a broad spectrum of activity and would likely also inhibit novel coronaviruses that might emerge in the future.”

Martijn J. van Hemert, Ph.D., Associate Professor, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands

The motivation for the research was the lack of vaccines and treatments early in the pandemic, and the desire to be prepared for the next new coronavirus. To this end, van Hemert emphasized that his group, as well as others from around the world, responded to COVID-19 by testing many compounds for antiviral effects.

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“If honokiol can be developed into a drug, possibly in combination with other compounds, stockpiling it would help us to increase our preparedness for the emergence of the next coronavirus,” said van Hemert. “Broad-spectrum drugs could then be used to treat early patients and prevent spread, or they could be used prophylactically among healthcare workers, and in high-risk groups, such as among nursing home residents.”

Honokiol also has anti-inflammatory properties, van Hemert noted. That, he said, could be helpful in cases where patients wait until a relatively late stage of the disease to obtain medical treatment-;a frequent occurrence-;by which time the body’s own inflammatory responses to the infection are causing symptoms. “At that point, inhibition of virus replication might no longer be helpful, but honokiol’s anti-inflammatory response might mitigate the illness,” van Hemert explained.

Honokiol inhibits a later step of the viral replication cycle-;one that takes place after the virus has entered the cell. The investigators suspect that honokiol does so by triggering processes in the host cell that impede replication of the virus. It did so in the case of the original SARS-CoV-2 variants, and also in that of the more recent omicron variants.

At this early stage in the research, “Our study merely provides the basis for further research into potential therapeutic applications,” said van Hemert. “It is important to mention that it is too early to claim that honokiol might be used in SARS-CoV-2 patients. This requires much more research and-;if successful-;properly conducted clinical trials.”

Van Hemert learned about honokiol from Jack Arbiser, M.D., Ph.D., of Emory School of Medicine, during the early stages of the pandemic. Arbiser had been researching honokiol’s anticancer properties, and he told van Hemert he thought that the effects of the compound on the host cell might be beneficial for treatment of COVID-19 patients as well.

Clarisse Salgado-Benvindo, a Ph.D. student in van Hemert’s group, performed most of the experiments, using cultured cells that the researchers infected with SARS-CoV-2, or the highly pathogenic coronaviruses SARS-CoV and MERS-CoV. Experimenters worked inside a BSL-3 lab, which is a special high containment lab, while wearing protective suits with full-face masks to prevent infection.

Source:

American Society for Microbiology

Journal reference:

Salgado-Benvindo, C., et al. (2023) Honokiol Inhibits SARS-CoV-2 Replication in Cell Culture at a Post-Entry Step. Microbiology Spectrum. doi.org/10.1128/spectrum.03273-22.

Microbiology

Anticoronavirals: the development of COVID-19 therapies and the challenges that remain

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Neha MathurBy Neha MathurMay 8 2023Reviewed by Danielle Ellis, B.Sc.

In a recent article published in Nature Microbiology, researchers highlighted the pace of development of coronavirus disease 2019 (COVID-19) therapies during the pandemic and the challenges that hinder the widespread availability of anticoronavirals.

Study: Therapeutics for COVID-19. Image Credit: Viacheslav Lopatin/Shutterstock.com
Study: Therapeutics for COVID-19. Image Credit: Viacheslav Lopatin/Shutterstock.com

Background

COVID-19 is the third coronavirus disease in the past 20 years after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). While the two predecessors caused severe mortality, they did not cause a pandemic. On the contrary, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered a pandemic, and by 21 February 2023, it had caused more than 757 million confirmed cases, including >6.8 million deaths worldwide.

Vaccines and monoclonal antibody (mAb) treatments for COVID-19 became available within a year of the pandemic. Yet, there is a substantial need for more effective therapeutics to treat unvaccinated and immunocompromised patients and those whose vaccine immunity waned over time.

About the study

In this study, the authors highlighted four stages of SARS-CoV-2 infection that require different therapeutic interventions as critical for identifying COVID-19 therapeutic targets. At stage 1, when viral replication begins inside the host, oral or intravenous administration of monoclonal antibodies and antiviral therapies are effective. However, an ideal time for prophylactic administration of vaccines is Stage 0 preceding the infection.

Clinical trials have established that mAbs and antivirals effectively combat COVID-19 when administered up to 10 days after symptom onset and within three to five days following the onset of symptoms, respectively. COVID-19 patients in stage 2 develop viral pneumonia, cough and fever, lung inflammation causing shortness of breath, and lung aberrations, such as ground glass opacities.

The most serious is stage 3 characterized by a hyperinflammatory state or acute respiratory distress syndrome (ARDS). Some patients might also develop coagulation disorders or shock or systemic inflammatory response syndrome (SIRS). Thus, at stage 3, a patient needs antiviral drugs and immunomodulatory therapy.

Stage 4 represents post-COVID-19 conditions when patients experience hyperinflammatory illnesses, e.g., multi-system inflammatory syndrome in children (MISC), following acute SARS-CoV-2 infection. Unfortunately, possible preventative measures and treatment for post-acute sequelae of SARS-CoV-2 (PASC) are not fully understood. It is a growing area of unmet medical need; thus, extensive research efforts are ongoing to classify PASC, which might be a conglomeration of several syndromes, and determine its cause(s).

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The National Institutes of Health (NIH) Treatment Guidelines Panel makes recommendations for the treatment and prevention of COVID-19. Early in the pandemic, clinicians used azithromycin and hydroxychloroquine as a possible COVID-19 treatment for hospitalized patients based on in vitro evidence of their synergistic effect on SARS-CoV-2 infection. Later, clinical trials found this combination ineffective. Similarly, the NIH panel did not specify recommendations for empirical antimicrobials.

The NIH rejected giving vitamin/mineral supplements, e.g., zinc, for hospitalized COVID-19 patients. On the contrary, they recommended prompt use of supplemental oxygenation and high-flow nasal cannula in patients with ARDS. In the absence of effective treatments, clinical recommendations by NIH continue to change and evolve.

Early drug repurposing efforts targeted nucleotide prodrugs, e.g., remdesivir (or GS-5734), AT-527, favipiravir, and molnupiravir (or MK-4482). However, only three antivirals received full Emergency Use Authorization (EUA) approval from the United States Food and Drug Administration (US-FDA), remdesivir, molnupiravir, and nirmatrelvir.

Pre-clinical characterization of remdesivir for other coronaviruses, pharmacokinetic and safety evaluation in humans in a failed clinical trial for Ebola virus, all acquired before the beginning of the COVID-19 pandemic, enabled rapid progression of remdesivir.

A phase 3 study conducted among patients in outpatient facilities and nursing facilities showed that remdesevir administration within seven days of symptom onset decreased hospitalization risk by 87%. Thus, its approval extended to high-risk non-hospitalized patients as well. Currently, phase 1b/2a study for inhaled remdesivir, and pre-clinical evaluation of an oral prodrug based on remdesivir is ongoing.

Another randomized phase III trial evaluated ivermectin, metformin, and fluvoxamine, all repurposed drug candidates, for early COVID-19 treatment of overweight or obese adults. Earlier pivotal efficacy and clinical studies found that molnupiravir provided no clinical benefit in hospitalized COVID-19 patients.

Conversely, the MOVe-OUT outpatient study demonstrated that treatment initiated within five days of symptom onset reduced the hospitalization risk or death. Accordingly, molnupiravir attained an EUA in the US on in late 2021 for treatment of mild-to-moderately ill COVID-19 patients at high risk of progression to severe disease. However, an outpatient study suggested that molnupiravir might augment SARS-CoV-2 evolution in immunocompromised individuals.

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In the USA, multiple initiatives have been undertaken to identify candidate agents that may be repurposed as COVID-19 drugs. For instance, the Bill and Melinda Gates Foundation launched the Therapeutics Accelerator in March 2020, wherein they adopted a three-way approach to test approved drugs, screen drug repositories, and evaluate novel small molecules, including mAbs against SARS-CoV-2.

Encouragingly, apilimod, a PIKfyve kinase inhibitor developed for treating autoimmune diseases, is being tested for COVID-19 in clinical studies. Likewise, multiple clinical trials are ongoing for camostat mesilate, an inhibitor of transmembrane protease serine 2 (TMPRSS2), an approved chronic pancreatitis treatment in Japan.

Among anti-inflammatory and immunomodulating drugs, dexamethasone, a corticosteroid, baricitinib, a Janus kinase (JAK) inhibitor, and tocilizumab have received FDA approval. Among mAb therapies, casirivimab with imdevimab and bamlanivimab with etesevimab, Sotrovimab, Bebtelovimab, Tixagevimab–cilgavimab have received FDA approval. However, as SARS-CoV-2 continues to evolve, changes in the spike protein led to EUAs being withdrawn for all mAb therapies due to loss of efficacy.

Conclusions

There is a vast knowledge gap regarding COVID-19 pathogenesis. Despite the absence of a viral reservoir, severe disease persists for weeks or even months after COVID-19 recovery. Another intriguing area of investigation is why autoantibodies increase over time during COVID-19. In February 2022, the government of the United States of America (USA) started a flagship program, RECOVER, to understand, prevent and treat COVID-19-related long-term health effects.

Amid decreasing vaccine uptake and waning efficacy of mAbs as SARS-CoV-2 mutates, there is a need for new, safe, and effective COVID-19 therapies for population-level deployment and the potential to reduce resistance development. Researchers need to accelerate research targeting small molecule candidates that would mechanistically target the conserved region of SARS-CoV-2 and not become ineffective across mutant strains.

To be prepared for another pandemic, a large repository of small molecules that have already progressed through early pre-clinical and clinical evaluation is needed to develop drugs, like remdesivir, developed in a short span of two years.

More importantly, research efforts should continue to advance the development of antivirals for other pathogens, including coronaviruses, in preparation for the next pandemic.

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Journal reference:
Microbiology

Live attenuated nasal vaccine elicits superior immunity to SARS-CoV-2 variants in hamsters

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Reviewed by Emily Henderson, B.Sc.Apr 4 2023

Since the beginning of the COVID-19 pandemic, researchers have been working on mucosal vaccines that can be administered through the nose. Now, scientists in Berlin have developed a live attenuated vaccine for the nose. In “Nature Microbiology”, they describe the special immune protection it induces.

Coronaviruses spread primarily through the air. When infected people speak, cough, sneeze or laugh, they expel droplets of saliva containing the virus. Other people then breathe in these airborne pathogens and become infected themselves. A research team in Berlin decided to try to fight the virus that causes COVID-19 where it first takes hold: the mucous membranes of the nose, mouth, throat, and lungs. To do so, the scientists developed a live attenuated SARS-CoV-2 vaccine that is administered through the nose. In the latest issue of the journal “Nature Microbiology“, the interdisciplinary team describes how this live attenuated vaccine confers better immunity than vaccines injected into muscle.

Already in the fall of last year, two nasal vaccination formulations were approved for use in India and China. These contain modified adenoviruses – which typically cause respiratory or gastrointestinal illnesses – that are self-attenuating, meaning they either replicate poorly or stop replicating altogether, and therefore never trigger disease. Other live nasal vaccines are currently undergoing development and testing around the world.

Protection at the site of infection

The benefits of a nasal vaccine go far beyond just providing an alternative for people afraid of needles. When a vaccine is injected, it infers immunity primarily in the blood and throughout the entire body. However, this means that the immune system only detects and combats coronaviruses relatively late on in an infection, as they enter the body via the mucous membranes of the upper respiratory tract. “It is here, therefore, that we need local immunity if we want to intercept a respiratory virus early on,” explains the study’s co-last author Dr. Jakob Trimpert, a veterinarian and research group leader at the Institute of Virology at Freie Universität Berlin.

“Nasal vaccines are far more effective in this regard than injected vaccines, which fail or struggle to reach the mucous membranes,” emphasizes Dr. Emanuel Wyler, another co-last author. He has been researching COVID-19 since the start of the pandemic as part of the RNA Biology and Posttranscriptional Regulation Lab, which is led by Professor Markus Landthaler at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB).

In an ideal scenario, a live intranasal vaccine stimulates the formation of the antibody immunoglobulin A (IgA) directly on site, thus preventing infection from occurring in the first place. IgA is the most common immunoglobin in the mucous membranes of the airways. It is able to neutralize pathogens by binding to them and preventing them from infecting respiratory tract cells. At the same time, the vaccine stimulates systemic immune responses that help provide effective overall protection from infection.

Memory T cells that reside in lung tissue play a similarly useful role to antibodies in the mucosa. These white blood cells remain in affected tissue long after an infection has passed and remember pathogens they have encountered before. Thanks to their location in the lungs, they can respond quickly to viruses that enter through the airways.” The co-first author draws attention to one of the observations the team made during their study: “We were able to show that prior intranasal vaccination results in the increased reactivation of these local memory cells in the event of a subsequent SARS-CoV-2 infection. Needless to say, we were particularly pleased with this result.”

Dr. Geraldine Nouailles, immunologist and research group leader at the Department of Pneumology, Respiratory Medicine, and Intensive Care Medicine at Charité

Local immunity impedes viral infection

The scientists tested the efficacy of the newly developed intranasal COVID-19 vaccine on hamster models that had been established by Trimpert and his team at Freie Universität Berlin at the beginning of the pandemic. These rodents are currently the most important non-transgenic model organisms for research into the novel coronavirus, as they can be infected with the same virus variants as humans and develop similar symptoms. They found that after two doses of the vaccine, the virus could no longer replicate in the model organism. “We witnessed strong activation of the immunological memory, and the mucous membranes were very well protected by the high concentration of antibodies,” Trimpert explains. The vaccine could therefore also significantly reduce the transmissibility of the virus.

In addition, the scientists compared the efficacy of the live attenuated vaccine with that of vaccines injected into the muscle. To do so, they vaccinated the hamsters either twice with the live vaccine, once with the mRNA and once with the live vaccine, or twice with an mRNA or adenovirus-based vaccine. Then, after the hamsters were infected with SARS-CoV-2, they used tissue samples from the nasal mucosa and lungs to see how strongly the virus was still able to attack the mucosal cells. They also determined the extent of the inflammatory response using single-cell sequencing. “The live attenuated vaccine performed better than the other vaccines in all parameters,” Wyler summarizes. This is probably due to the fact that the nasally administered vaccine builds up immunity directly at the viral entry site. In addition, the live vaccine contains all components of the virus – not just the spike protein, as is the case with the mRNA vaccines. While spike is indeed the virus’s most important antigen, the immune system can also recognize the virus from about 20 other proteins.

Better than conventional vaccines

The best protection against the SARS-CoV-2 was provided by double nasal vaccination, followed by the combination of a muscular injection of the mRNA vaccine and the subsequent nasal administration of the live attenuated vaccine. “This means the live vaccine could be particularly interesting as a booster,” says the study’s co-first author Julia Adler, a veterinarian and doctoral student at the Institute of Virology at Freie Universität Berlin.

The principle of live attenuated vaccines is old and is already used in measles and rubella vaccinations, for example. But in the past, scientists generated the attenuation by chance – sometimes waiting years for mutations to evolve that produced an attenuated virus. The Berlin researchers, on the other hand, were able to specifically alter the genetic code of the coronaviruses. “We wanted to prevent the attenuated viruses from mutating back into a more aggressive variant,” explains Dr. Dusan Kunec, a scientist at the Institute of Virology at Freie Universität Berlin and another co-last author of the study. “This makes our live vaccine entirely safe and means it can be tailored to new virus variants,” stresses Kunec, who was instrumental in developing the vaccine.

The next step is safety testing: The researchers are collaborating with RocketVax AG, a Swiss start-up based in Basel. The biotech company is developing the live attenuated SARS-CoV-2 vaccine and preparing a phase 1 clinical trial in humans. “We are thrilled to be at the forefront of developing and manufacturing the live attenuated SARS-CoV-2 vaccine as a nasal spray at RocketVax. Our goal is to rapidly scale-up production and advance clinical development towards market access to provide protection against post-COVID symptoms for all. We see great potential in the market for seasonal nasal vaccines”, says Dr. Vladimir Cmiljanovic, CEO of RocketVax.

The future will show which nasal vaccine will ultimately provide better protection. The manufacturers of the nasal adenovirus vaccines developed in India and China have not yet applied for approval in Europe. But one thing is clear to the scientists: since they are administered as nasal sprays or drops, nasal vaccines are a good option for use in places with limited access to trained medical staff. They are also inexpensive to produce and easy to store and transport. Last but not least, live attenuated vaccines such as this one have been proven to provide cross-protection against related viral strains, and thus presumably also against future SARS-CoV-2 variants.

Source:

Max Delbrück Center for Molecular Medicine in the Helmholtz Association

Journal reference:

Nouailles, G., et al. (2023). Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters. Nature Microbiology. doi.org/10.1038/s41564-023-01352-8

Microbiology

Candida auris infection without epidemiologic links to a prior outbreak

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Dr. Priyom Bose, Ph.D.By Dr. Priyom Bose, Ph.D.Mar 23 2023Reviewed by Danielle Ellis, B.Sc.

The Centers for Disease Control and Prevention (CDC) has classified Candida auris (C. auris) as an urgent public threat due to its role in elevating mortality, its ability to persist in hospital environments, and the high possibility of developing pan-drug resistance.

Notably, a recent study published in the journal Open Forum Infectious Diseases has pointed out that surfaces near patients with C. auris quickly become re-contaminated after cleaning.

Existing research has not adequately elucidated the environmental reservoirs of C. auris. Further, few studies have reported epidemiologic links associated with C. auris infection. 

Study: The Emergence and Persistence of Candida auris in Western New York with no Epidemiologic Links: A Failure of Stewardship?. Image Credit: Kateryna Kon / ShutterstockStudy: The Emergence and Persistence of Candida auris in Western New York with no Epidemiologic Links: A Failure of Stewardship? Image Credit: Kateryna Kon / Shutterstock

Background

C. auris is a species of fungus that grows as yeast. It is one of the few species of the genus Candida which cause candidiasis in humans. In the past, C. auris infection was primarily found in cancer patients or those subjected to feeding tubes.

In the United States (US), the emergence of C. auris was traced to New York, and surveillance for this fungal infection was focused mainly on New York City to detect outbreaks. Recently, scientists investigated the association between genomic epidemiology and C. auris infection in Western New York.

A Case Study

The study describes the emergence of C. auris in a patient hospitalized at a small community hospital in Genesee County, New York (NY). In January 2022, C. auris was isolated from the urine culture of a 68-year-old male on the 51st day of hospitalization.

This patient had no known epidemiological connections outside his immediate community. Before his hospitalization, he was not exposed to other patients or family members associated with C. auris infection.

This patient had no history of organ transplantation, decubitus ulcers, hemodialysis, feeding tubes, or nursing home stays. He had an active lifestyle with a history of mild vascular dementia. He was hospitalized due to pneumonia and was prescribed azithromycin treatment.

Post hospitalization, he tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and was treated with dexamethasone (6 mg) daily for 10 days and remdesivir (200 mg) once, followed by 100 mg daily for five days.

Since the patient’s chest radiograph showed left lobar consolidation, he was further treated with empiric ceftriaxone and azithromycin. As the respiratory symptoms deteriorated, he received non-invasive positive pressure ventilation, with subsequent endotracheal intubation for eight days. He was successfully extubated. He developed a fever and received antimicrobial therapy for 73 days. The patient had a urinary catheter and a peripherally inserted central line in his arm for 35 days. 

Microbiology culture test and serum procalcitonin levels remained negative and within normal levels. On the 22nd day of hospitalization, Candida albicans were isolated from respiratory samples. On the 51st day, the urine culture revealed the presence of azole-resistant C. auris.

The isolated C. auris (MRSN101498) was forwarded to the Multidrug-resistant organism Repository and Surveillance Network (MRSN), where genomic sequencing was performed. After the patient was discharged, the hospital room was cleaned using hydrogen peroxide and peracetic acid, followed by ultraviolet-C light. Other patients who shared rooms with the patient with C. auris were tested for infection.

Study Outcomes

C. auris was not detected in the Western NY community hospital in the past year. Physicians stated that the patient received excessive antibiotic treatment for a prolonged period. Genomic studies revealed that the MRSN101498 genome sequence was closely related to the 2013 Indian strain with minor genomic differences. Interestingly, the K143R mutation in ERG11 was found in MRSN101498, which is associated with triazole resistance in Candida albicans.

Whole genome single nucleotide polymorphism (SNP) analysis also highlighted that MRSN101498 was strongly genetically related to four other isolates, with marginal differences.

These isolates were linked to an outbreak in March 2017 in a hospital 47 miles northeast of Rochester, NY. Based on the current findings, it is highly likely that isolates from Western NY share a recent common ancestor.

Study Importance

This case study is important for several reasons, including the absence of epidemiologic links to C.auris infection. Since reports from rural sectors are rare, this study addresses a vital surveillance ‘blind spot.’ 

However, the current study failed to identify the potential reservoirs of MRSN101498 in Western NY. Sporicidal disinfectants were inefficient for both Clostridioides difficile and C. auris. However, terminal cleaning protocols that included UV irradiation and sporicidal cleaning agents were able to eradicate C. auris effectively.

The current study highlights the role of excessive antibiotic exposure in the emergence of C. auris. It also indicates the challenges in eliminating fungi from hospital settings. The authors recommend proper antibiotic treatment and cleaning procedures for drug-resistant pathogens.

Journal reference:
Microbiology

New analysis shows how convalescent plasma can be used as effective, low-cost COVID-19 treatment

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Reviewed by Emily Henderson, B.Sc.Feb 22 2023

Three years into the COVID-19 pandemic, new variant outbreaks continue to fuel economic disruptions and hospitalizations across the globe. Effective therapies remain unavailable in much of the world, and circulating variants have rendered monoclonal antibody treatments ineffective. But a new analysis shows how convalescent plasma can be used as an effective and low-cost treatment both during the COVID-19 pandemic and in the inevitable pandemics of the future.

In astudy published in Clinical Infectious Diseases, an international team of researchers analyzed clinical data and concluded that among outpatients with COVID-19, antibodies to SARS-CoV-2 given early and in high dose reduced the risk of hospitalization.

If the results of this meta-analysis had somehow been available in March of 2020, then I am certain that millions of lives would have been saved around the world.”

Dr. Adam C. Levine, study author, professor of emergency medicine at Brown University’s Warren Alpert Medical School

While several other early treatments for COVID-19 have had similar results, including antivirals like Paxlovid and monoclonal antibodies, only convalescent plasma, the researchers concluded, is likely to be both available and affordable for the majority of the world’s population both now and early in the next viral pandemic.

“These findings will be helpful for this pandemic, especially in places like China, India and other parts of the world that lack access to antiviral medications like Paxlovid,” Levine said. “And because it provides information on how to more effectively use convalescent plasma as a therapy, this will be even more helpful in the next pandemic. This study is essentially a roadmap for how to do this right the next time.”

Blood plasma from people who have recovered from COVID-19 and contains antibodies against SARS-CoV-2 was used as a treatment early in the pandemic, Levine said -; months before monoclonal antibody treatment or vaccines became available, and more than a year before an effective oral drug therapy was clinically available.

Although convalescent plasma seemed promising, outpatient research was limited, and studies that did exist showed mixed results. One problem was that most studies were conducted in patients already hospitalized with COVID-19, Levine said, largely due to the convenience of conducting research with this population. The objective in the new study was to review all available randomized controlled trials of convalescent plasma in non-hospitalized adults with COVID-19 to determine whether early treatment can reduce the risk of hospitalization.

The analysis included data from five studies conducted in four countries, including Argentina, the Netherlands, Spain, and two in the United States. Levine previously supervised enrollment at Rhode Island Hospital in a clinical trial led by Johns Hopkins Medicine and Johns Hopkins Bloomberg School of Public Health. Across the five studies, a total of 2,620 adult patients had received transfusions of convalescent plasma from January 2020 to September 2022. The researchers conducted an individual participant data meta-analysis to assess how the transfusion timing and dose impacted the patient’s risk of hospitalization during the 28 days after infection.

In their analysis, the researchers found that 160 (12.2%) of 1,315 control patients were hospitalized compared with 111 (8.5%) of 1,305 patients treated with COVID-19 convalescent plasma -; 30% fewer hospitalizations.

Notably, the strongest effects were seen in patients treated both early in the illness and with plasma with high levels of antibodies. In these patients, the reduction in hospitalization was over 50%.

For future pandemics, the goal is to use plasma from donors who have high levels of antibodies, said corresponding study author Dr. David J. Sullivan, a professor of molecular microbiology and immunology at Johns Hopkins Bloomberg School of Public Health and School of Medicine. “This research suggests that we have been underdosing convalescent plasma for many previous pathogens, which impacts effectiveness,” Sullivan said. “It bears repeating: Early and high levels of antibodies increased the beneficial efficacy.”

Levine explained that because convalescent plasma was the only treatment available at the beginning of the pandemic, it was used widely -; and often incorrectly, on hospitalized patients who were already experiencing severe symptoms late in the course of COVID-19. Those symptoms were due to a ramped-up immune response to the virus, not the virus itself, Levine explained.

“By the time the patient was at the point where they’d reached the inflammatory phase that caused severe symptoms, it was too late for treatments like convalescent plasma or even monoclonal antibodies to work,” he said.

What is now known is that convalescent plasma works best when given early in the course of illness. That’s when it can neutralize the virus and get ahead of the body mounting an intense immune response, thereby preventing hospitalization and death, Levine said.

The five drug treatment trials in the analysis took place at a variety of global health care sites, he noted, including nursing homes, outpatient clinics and emergency departments. The diversity across the studies is a sign that the data is likely generalizable to many other types of populations and settings around the world, said Levine, who also directs the Center for Human Rights and Humanitarian Studies at the Watson Institute for International and Public Affairs at Brown.

Levine cited another recently published study in JAMA Network Open that showed that convalescent plasma is effective in reducing mortality in immunocompromised patients. This new meta-analysis provides evidence that convalescent plasma can also be effective in the larger population of adults who are not immunocompromised.

The U.S. Food and Drug Administration allowed early convalescent plasma use in December 2021 for those patients with COVID-19 who were also immunocompromised, but not yet for patients with COVID-19 who are not immunocompromised. The authors said they hope the new study will push the FDA, and other countries around the world, to make early treatment with COVID-19 convalescent plasma available to a much larger group of patients at risk for hospitalization.

A treatment that evolves with the pandemic

The findings come at a time when monoclonal antibodies, the most commonly used treatment for COVID-19, have been shown to be ineffective against new variants of the virus. In November, the FDA revoked emergency authorization of the last monoclonal antibody treatment because it wasn’t expected to have much of an effect against Omicron sub-variants.

In contrast to monoclonal antibody therapies, Levine said, convalescent plasma donated by patients who have recovered from the virus is a treatment that evolves with the pandemic. Because it has antibodies that attach to multiple different parts of the virus, there are still opportunities to attach to a receptor even after the virus mutates and morphs some of its receptors. It’s also less expensive to produce than pharmaceutical antivirals.

In the first year of the pandemic, Levine said, before the development of vaccines and effective treatments, researchers tried many treatment strategies in order to quickly find something that worked to save lives.

“When the next big pandemic hits, we’re going to be in a very similar situation,” Levine said. “Yet at least next time, we’ll have research like this to inform our strategy.”

Source:

Brown University

Journal reference:

Levine, A.C., et al. (2023) COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials. Clinical Infectious Diseases. doi.org/10.1093/cid/ciad088.

Microbiology

Chemicals accumulated in the vagina may contribute to spontaneous preterm birth

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Reviewed by Emily Henderson, B.Sc.Jan 13 2023

Chemicals that accumulate in the vagina, potentially originating from personal care products, may contribute to spontaneous preterm birth, according to a new study by researchers at Columbia University Vagelos College of Physicians and Surgeons.

The study of 232 pregnant women found that a handful of non-biological chemicals previously found in cosmetics and hygiene products are strongly associated with preterm birth.

Our findings suggest that we need to look more closely at whether common environmental exposures are in fact causing preterm births and, if so, where these exposures are coming from. The good news is that if these chemicals are to blame, it may be possible to limit these potentially harmful exposures.”

Tal Korem, PhD, study co-leader, assistant professor in the Program for Mathematical Genomics and the Departments of Systems Biology and Obstetrics and Gynecology at Columbia University

The study was published January 12 in Nature Microbiology.

Preterm birth, childbirth before 37 weeks of pregnancy, is the number one cause of neonatal death and can lead to a variety of lifelong health issues. Two-thirds of preterm births occur spontaneously, but despite extensive research, there are no methods for predicting or preventing spontaneous preterm birth.

Several studies have suggested that imbalances in the vaginal microbiome play a role in preterm birth and other problems during pregnancy. However, researchers have not been able to reproducibly link specific populations of microorganisms with adverse pregnancy outcomes.

The research team, co-led by Korem and Maayan Levy, PhD, of the University of Pennsylvania, decided to take a more expansive view of the vaginal microenvironment by looking at its metabolome. The metabolome is the complete set of small molecules found in a particular biological niche, including metabolites produced by local cells and microorganisms and molecules that come from external sources. “The metabolome can be seen as a functional readout of the ecosystem as a whole,” Korem says. “Microbiome profiling can tell us who the microbes are; metabolomics gets us close to understanding what the microbes are doing.”

In the current study, the researchers measured over 700 different metabolites in the second-trimester metabolome of 232 pregnant women, including 80 pregnancies that ended prematurely.

The study found multiple metabolites that were significantly higher in women who had delivered early than in those who delivered at full term.

“Several of these metabolites are chemicals that are not produced by humans or microbes-;what we call xenobiotics,” says Korem. “These include diethanolamine, ethyl-beta glucoside, tartrate, and ethylenediaminetetraacetic acid. While we did not identify the source of these xenobiotics in our participants, all could be found in cosmetics and hygiene products.”

Algorithm predicts preterm birth

Using machine learning models, the team also developed an algorithm based on metabolite levels that can predict preterm birth with good accuracy, potentially paving the way for early diagnostics.

Though the predictions were more accurate than models based on microbiome data and maternal characteristics (such as age, BMI, race, preterm birth history, and prior births), the new model still needs improvement and further validation before it could be used in the clinic.

Despite the current limitations, Korem says, “our results demonstrate that vaginal metabolites have the potential to predict, months in advance, which women are likely to deliver early.”

Source:

Columbia University Irving Medical Center

Journal reference:

Kindschuh, W.F., et al. (2023) Preterm birth is associated with xenobiotics and predicted by the vaginal metabolome. Nature Microbiology. doi.org/10.1038/s41564-022-01293-8.

Microbiology

Vaccinating against toxin produced by E. coli may protect against malnutrition and stunting

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Reviewed by Emily Henderson, B.Sc.Jan 9 2023

Diarrhea is no longer the killer it was in the mid-20th century, when an estimated 4.5 million children under age 5 died of it every year. While lifesaving oral rehydration therapy turned the tide, it doesn’t prevent infection. Millions of children in low- and middle-income countries still endure repeated bouts of diarrhea that weaken their bodies and leave them vulnerable to malnutrition and stunted growth, and less able to fight off a wide range of infections.

Researchers at Washington University School of Medicine in St. Louis have determined, in studies of human cells as well as mice, how some types of diarrhea-causing Escherichia coli (E. coli) bacteria damage the intestines to cause malnutrition and stunting. And they’ve shown that vaccinating against a toxin produced by E. coli protects infant mice from intestinal damage.

The findings suggest that a vaccine against this kind of E. coli could boost global efforts to ensure that all children not only make it to age 5, but thrive. The study is available online in Nature Communications.

“Ideally, we’d like to have a vaccine that prevents acute diarrhea, which still kills half a million children a year, and that also protects against long-term effects such as malnutrition, which is perhaps the bigger part of the problem now,” said senior author James M. Fleckenstein, MD, a professor of medicine and of molecular microbiology. “When kids become malnourished, their risk of dying from any cause goes up. The World Health Organization is in the process of deciding how to prioritize vaccines for kids in low- and middle-income countries, and I think these data suggest that vaccinating kids against E. coli diarrhea could be hugely beneficial in places that struggle with this.”

Fleckenstein studies a kind of E. coli known as enterotoxigenic E. coli, or ETEC -; so named for the two toxins it produces -; and its effects on children who live where the bacteria run rampant. E. coliis a common cause of diarrhea worldwide, but the strains found in the U.S. and other high-income countries typically don’t carry the same toxins as those in low- and middle-income countries. And that may make all the difference.

A 2020 study by Fleckenstein and Alaullah Sheikh, PhD -; then a postdoctoral researcher in Fleckenstein’s lab and now an instructor in medicine -; indicated that one of ETEC’s two toxins, heat-labile toxin, does more than trigger a case of the runs. The toxin also affects gene expression in the gut, ramping up genes that help the bacteria stick to the gut wall.

As part of the latest study, Fleckenstein and Sheikh discovered that the toxin suppresses a whole suite of genes related to the lining of the intestines, where nutrients are absorbed. The so-called brush border of the intestine is composed of microscopic, finger-like projections called microvilli that are tightly packed over the surface of the intestines like bristles on a brush. When Fleckenstein and Sheikh applied the toxin to clusters of human intestinal cells, the brush border disintegrated.

“Instead of being nice and tight and upright with thousands of microvilli per cell, they are short, floppy and sparse, kind of like if you had plucked out most of the bristles, and what was left was kind of raggedy,” said Sheikh, who led the 2020 and current studies. “That alone would have a negative impact on the body’s ability to absorb nutrients. But on top of that, we found that genes related to absorbing specific vitamins and minerals -; notably vitamin B1 and zinc -; also were downregulated. That could explain some of the micronutrient deficiencies we see in children repeatedly exposed to these bacteria.”

Children in low- and middle-income countries tend to get diarrhea over and over, and the risk of malnutrition and stunting goes up with each bout. Studying infant mice, the researchers found that a single infection with toxin-producing E. coli was sufficient to damage the brush border, while repeated infections led to extensive intestinal damage and growth lag. Pups infected with a strain of E. coli that lacks the toxin showed no such intestinal damage or stunting.

If the toxin is the problem, an immune response neutralizing the toxin may prevent the long-term effects, Fleckenstein and Sheikh reasoned. To find out, they vaccinated nursing mouse mothers with the toxin. Suckling mice are too young to be immunized themselves, but their vaccinated mothers produce antibodies that pass to the pups through breast milk. The researchers found that the intestines of infant mice from vaccinated mothers appeared healthy, suggesting that vaccination can protect against the intestinal damage leading to malnutrition.

“This is an argument for developing a vaccine for this kind of E. coli,” Fleckenstein said. “There are lifelong consequences of getting infected over and over in childhood. Vaccination combined with efforts to improve sanitation and access to clean water could protect children from the long-term effects and give them a better shot at long and healthy lives.”

Source:

Washington University in St. Louis

Journal reference:

Sheikh A, Tumala B, Vickers TJ, Martin JC, Rosa BA, Sabui S, Basu S, Simoes RD, Mitreva M, Storer C, Tyksen E, Head RD, Beatty W, Said HM, Fleckenstein JM. Enterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small intestinal epithelia. Nature Communications. Nov. 12, 2022. DOI: 10.1038/s41467-022-34687-7

Microbiology

Vaccination against E. coli could help prevent some forms of childhood malnutrition, stunting

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Reviewed by Emily Henderson, B.Sc.Dec 7 2022

Diarrhea is no longer the killer it was in the mid-20th century, when an estimated 4.5 million children under age 5 died of it every year. While life-saving oral rehydration therapy turned the tide, it doesn’t prevent infection. Millions of children in low- and middle-income countries still endure repeated bouts of diarrhea that weaken their bodies and leave them vulnerable to malnutrition and stunted growth, and less able to fight off a wide range of infections.

Researchers at Washington University School of Medicine in St. Louis have determined, in studies of human cells as well as mice, how some types of diarrhea-causing Escherichia coli (E. coli) bacteria damage the intestines to cause malnutrition and stunting. And they’ve shown that vaccinating against a toxin produced by E. coli protects infant mice from intestinal damage.

The findings suggest that a vaccine against this kind of E. coli could boost global efforts to ensure that all children not only make it to age 5, but thrive. The study is available online in Nature Communications.

Ideally, we’d like to have a vaccine that prevents acute diarrhea, which still kills half a million children a year, and that also protects against long-term effects such as malnutrition, which is perhaps the bigger part of the problem now. When kids become malnourished, their risk of dying from any cause goes up. The World Health Organization is in the process of deciding how to prioritize vaccines for kids in low- and middle-income countries, and I think these data suggest that vaccinating kids against E. coli diarrhea could be hugely beneficial in places that struggle with this.”

James M. Fleckenstein, MD, senior author, professor of medicine and of molecular microbiology

Fleckenstein studies a kind of E. coli known as enterotoxigenic E. coli, or ETEC -; so named for the two toxins it produces -; and its effects on children who live where the bacteria run rampant. E. coli is a common cause of diarrhea worldwide, but the strains found in the U.S. and other high-income countries typically don’t carry the same toxins as those in low- and middle-income countries. And that may make all the difference.

A 2020 study by Fleckenstein and Alaullah Sheikh, PhD -; then a postdoctoral researcher in Fleckenstein’s lab and now an instructor in medicine -; indicated that one of ETEC’s two toxins, heat-labile toxin, does more than trigger a case of the runs. The toxin also affects gene expression in the gut, ramping up genes that help the bacteria stick to the gut wall.

As part of the latest study, Fleckenstein and Sheikh discovered that the toxin suppresses a whole suite of genes related to the lining of the intestines, where nutrients are absorbed. The so-called brush border of the intestine is composed of microscopic, finger-like projections called microvilli that are tightly packed over the surface of the intestines like bristles on a brush. When Fleckenstein and Sheikh applied the toxin to clusters of human intestinal cells, the brush border disintegrated.

“Instead of being nice and tight and upright with thousands of microvilli per cell, they are short, floppy and sparse, kind of like if you had plucked out most of the bristles, and what was left was kind of raggedy,” said Sheikh, who led the 2020 and current studies. “That alone would have a negative impact on the body’s ability to absorb nutrients. But on top of that, we found that genes related to absorbing specific vitamins and minerals -; notably vitamin B1 and zinc -; also were downregulated. That could explain some of the micronutrient deficiencies we see in children repeatedly exposed to these bacteria.”

Children in low- and middle-income countries tend to get diarrhea over and over, and the risk of malnutrition and stunting goes up with each bout. Studying infant mice, the researchers found that a single infection with toxin-producing E. coli was sufficient to damage the brush border, while repeated infections led to extensive intestinal damage and growth lag. Pups infected with a strain of E. coli that lacks the toxin showed no such intestinal damage or stunting.

If the toxin is the problem, an immune response neutralizing the toxin may prevent the long-term effects, Fleckenstein and Sheikh reasoned. To find out, they vaccinated nursing mouse mothers with the toxin. Suckling mice are too young to be immunized themselves, but their vaccinated mothers produce antibodies that pass to the pups through breast milk. The researchers found that the intestines of infant mice from vaccinated mothers appeared healthy, suggesting that vaccination can protect against the intestinal damage leading to malnutrition.

“This is an argument for developing a vaccine for this kind of E. coli,” Fleckenstein said. “There are lifelong consequences of getting infected over and over in childhood. Vaccination combined with efforts to improve sanitation and access to clean water could protect children from the long-term effects and give them a better shot at long and healthy lives.”

Source:

Washington University School of Medicine

Journal reference:

Sheikh, A., et al. (2022) Enterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small intestinal epithelia. Nature Communications. doi.org/10.1038/s41467-022-34687-7.