Tag Archives: Pneumonia

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

Fomepizole helps overcome antibiotic-resistant pneumonia in mice, study finds

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Pneumococcal disease leads to over three million hospitalizations and hundreds of thousands of deaths annually. A study publishing March 16 in the open access journal PLOS Biology by Carlos J. Orihuela at the University of Alabama at Birmingham, Alabama, United States, and colleagues suggests that the FDA-approved drug Fomepizole may reduce disease severity in the lungs of mice with some forms of bacterial pneumonia and enhance the efficacy of the antibiotic erythromycin as well.

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. While vaccines to protect against the bacteria are available, these vaccines are not effective against all strains, with some versions being especially problematic as they are multidrug-resistant. Currently, there are very limited treatment options for combating multidrug-resistant S. pneumoniae infections.

In order to test the effects of novel treatments for antibiotic-resistant S. pneumoniae, the researchers conducted a series of experiments with mice. Fomepizole is an FDA-approved drug normally used as an antidote for the ingestion of toxic alcohols (such as methanol or ethylene glycol), and works by inhibiting the enzyme alcohol dehydrogenase. Researchers inoculated mice with a multidrug-resistant S. pneumoniae and tested the effect of fomepizole in a combinatorial treatment with antibiotics. They quantified the bacterial burden in the organs of infected mice, comparing the experimental group with the control group.

The researchers found that using Fomepizole blocked normal energy production by S. pneumoniae and enhanced the bacteria’s susceptibility to antibiotics and reduced bacterial burden in the lungs of mice with pneumonia. The combination treatment was effective in preventing the development of invasive disease. Future research is needed however, as this novel drug treatment has not been replicated in clinical studies on humans, who may present with complicating factors such as comorbidities, advanced age, or environmental variables that may play a role in disease outcomes.

Orihuela adds, “Pharmacological targeting of fermentation pathways is a new way to enhance the susceptibility of some bacteriato antimicrobials. Combination treatment of erythromycin and fomepizole, an alcohol dehydrogenase inhibitor, prevented the in vivo dissemination of antibiotic-resistant Streptococcus pneumoniae.”

  • Hansol Im, Madison L. Pearson, Eriel Martinez, Kyle H. Cichos, Xiuhong Song, Katherine L. Kruckow, Rachel M. Andrews, Elie S. Ghanem, Carlos J. Orihuela. Targeting NAD+ regeneration enhances antibiotic susceptibility of Streptococcus pneumoniae during invasive disease. PLOS Biology, 2023; 21 (3): e3002020 DOI: 10.1371/journal.pbio.3002020

    • PLOS
    Microbiology

    A New Treatment for Lung Infections: Scientists Have Created a Unique “Living Medicine”

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    Scientists have created the first “living medicine” to cure lung infections. This innovative treatment is aimed at Pseudomonas aeruginosa, a bacteria known for its resistance to many antibiotics and a frequent cause of infections in hospitals.

    This treatment involves the use of a modified form of the Mycoplasma pneumoniae bacterium, which has had its disease-causing abilities removed and reprogrammed to target P. aeruginosa. The modified bacterium is used in conjunction with low doses of antibiotics that would not be effective on their own.

    Researchers tested the efficacy of the treatment in mice, finding that it significantly reduced lung infections. The “living medicine” doubled mouse survival rate compared to not using any treatment. Administering a single, high dose of the treatment showed no signs of toxicity in the lungs. Once the treatment had finished its course, the innate immune system cleared the modified bacteria in a period of four days.

    The findings are published in the journal Nature Biotechnology and were funded by the “la Caixa” Foundation through the CaixaResearch Health call. The study was led by researchers at the Centre for Genomic Regulation (CRG) and Pulmobiotics in collaboration with the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona and the Institute of Agrobiotechnology (IdAB), a joint research institute of Spain’s CSIC and the government of Navarre.

    P. aeruginosa infections are difficult to treat because the bacteria live in communities that form biofilms. Biofilms can attach themselves to various surfaces in the body, forming impenetrable structures that escape the reach of antibiotics.

    P. aeruginosa biofilms can grow on the surface of endotracheal tubes used by critically-ill patients who require mechanical ventilators to breathe. This causes ventilator-associated pneumonia (VAP), a condition that affects one in four (9-27%) patients who require intubation. The incidence exceeds 50% for patients intubated because of severe Covid-19. VAP can extend the duration in the intensive care unit for up to thirteen days and kills up to one in eight patients (9-13%).

    The authors of the study engineered M. pneumoniae to dissolve biofilms by equipping it with the ability to produce various molecules including pyocins, toxins naturally produced by bacteria to kill or inhibit the growth Pseudomonas bacterial strains. To test its efficacy, they collected P. aeruginosa biofilms from the endotracheal tubes of patients in intensive care units. They found the treatment penetrated the barrier and successfully dissolved the biofilms.

    “We have developed a battering ram that lays siege to antibiotic-resistant bacteria. The treatment punches holes in their cell walls, providing crucial entry points for antibiotics to invade and clear infections at their source. We believe this is a promising new strategy to address the leading cause of mortality in hospitals,” says Dr. María Lluch, Chief Scientific Officer at Pulmobiotics, co-corresponding author of the study and principal investigator at the International University of Catalonia.

    With the aim of using “living medicine” to treat VAP, the researchers will carry out further tests before reaching the clinical trial phase. The treatment is expected to be administered using a nebulizer, a device that turns liquid medicine into a mist which is then inhaled through a mouthpiece or a mask.

    M. pneumoniae is one of the smallest known species of bacteria. Dr. Luis Serrano, Director of the CRG, first had the idea to modify the bacteria and use it as a ‘living medicine’ two decades ago. Dr. Serrano is a specialist in synthetic biology, a field that involves repurposing organisms and engineering them to have new, useful abilities. With just 684 genes and no cell wall, the relative simplicity of M. pneumoniae makes it ideal for engineering biology for specific applications.

    One of the advantages of using M. pneumoniae to treat respiratory diseases is that it is naturally adapted to lung tissue. After administering the modified bacterium, it travels straight to the source of a respiratory infection, where it sets up shop like a temporary factory and produces a variety of therapeutic molecules.

    By showing that M. pneumoniae can tackle infections in the lung, the study opens the door for researchers to create new strains of the bacteria to tackle other types of respiratory diseases such as lung cancer or asthma. “The bacterium can be modified with a variety of different payloads – whether these are cytokines, nanobodies, or defensins. The aim is to diversify the modified bacterium’s arsenal and unlock its full potential in treating a variety of complex diseases,” says ICREA Research Professor Dr. Luis Serrano.

    In addition to designing the ‘living medicine’, Dr. Serrano’s research team is also using their expertise in synthetic biology to design new proteins that can be delivered by M. pneumoniae. The team is using these proteins to target inflammation caused by P. aeruginosa infections.

    Though inflammation is the body’s natural response to an infection, excessive or prolonged inflammation can damage lung tissue. The inflammatory response is orchestrated by the immune system, which releases mediator proteins such as cytokines. One type of cytokine – IL-10 – has well-known anti-inflammatory properties and is of growing therapeutic interest.

    Research published in the journal Molecular Systems Biology by Dr. Serrano’s research group used protein-design softwares ModelX and FoldX to engineer new versions of IL-10 purposefully optimized to treat inflammation. The cytokines were designed to be created more efficiently and to have a higher affinity, meaning less cytokines are needed to have the same effect.

    The researchers engineered strains of M. pneumoniae that expressed the new cytokines and tested its efficacy in the lungs of mice with acute P. aeruginosa infections. They found that engineered versions of IL-10 were significantly more effective at reducing inflammation compared to the wild-type IL-10 cytokine.

    According to Dr. Ariadna Montero Blay, co-corresponding author of the study in Molecular Systems Biology, “live biotherapeutics such as M. pneumoniae provide ideal vehicles to help overcome the traditional limitations of cytokines and unlock their huge potential in treating a variety of human diseases. Engineering cytokines as therapeutic molecules was critical to tackle inflammation. Other lung diseases such as asthma or pulmonary fibrosis could also stand to benefit from this approach.”

    Reference: “Engineered live bacteria suppress Pseudomonas aeruginosa infection in mouse lung and dissolve endotracheal-tube biofilms” by Rocco Mazzolini, Irene Rodríguez-Arce, Laia Fernández-Barat, Carlos Piñero-Lambea, Victoria Garrido, Agustín Rebollada-Merino, Anna Motos, Antoni Torres, Maria Jesús Grilló, Luis Serrano and Maria Lluch-Senar, 19 January 2023, Nature Biotechnology.
    DOI: 10.1038/s41587-022-01584-9

    Center for Genomic Regulation

    Microbiology

    A quick new way to screen virus proteins for antibiotic properties

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    As conventional antibiotics continue to lose effectiveness against evolving pathogens, scientists are keen to employ the bacteria-killing techniques perfected by bacteriophages, the viruses that infect bacteria.

    One major challenge standing in their way is the difficulty of studying individual bacteriophage (phage) proteins and determining precisely how the virus wields these tools to kill their host bacteria. New research from Lawrence Berkeley National Laboratory (Berkeley Lab) could help speed things along.

    “We developed a high-throughput genetic screening approach that can identify the part of the bacterial cell targeted by a potent type of phage weapon called ‘single-gene lysis proteins,'” said Vivek Mutalik, a staff scientist in Berkeley Lab’s Biosciences Area and co-author on a new study describing the work in Nature Chemical Biology. “With rising antibiotic resistance, we urgently need antibiotic alternatives. Some of the smallest phages that we know of code for single-gene lysis proteins (Sgls), also known as ‘protein antibiotics,’ to inhibit key components of bacterial cell wall production that, when disrupted, consistently kill the cell.”

    There appears to be at least one type of phage for every known strain of bacteria, and they are thought to be the most abundant biological entities on Earth. In fact, there are an estimated 1031 phage particles on the planet right now, or the equivalent of one trillion phages for every grain of sand. Each of these phages evolve alongside their chosen host strain, allowing them to counter bacterial resistance traits, as they arise, with improved biological weaponry.

    This massive abundance, specificity, and efficacy means that there are plenty around to study, and that we should theoretically be able to use phages to control any harmful microbe. Phages are also harmless to non-bacterial cells, another reason they are so appealing as medicines and biocontrol tools.

    The problem arises when trying to isolate a single phage from the environment and determine which microbe it targets and how. Scientists are often unable to assess phage-bacteria battles based on genomic sequence alone or study them in action because many bacteria can’t be cultured in a lab — and even if they could, there’s an inherent catch-22 of needing to know ahead of time which bacteria to culture in order to study the phages that infect and kill them.

    To sidestep these obstacles and identify the cellular targets of Sgls, Mutalik and his colleagues used a technology the team previously invented called Dual-Barcoded Shotgun Expression Library Sequencing (Dub-seq). Dub-seq allows scientists to employ a coded library of DNA fragments to investigate how unknown genes function, and can be applied to complicated environmental samples that contain the DNA of many organisms — no culturing needed. In this study, the authors used six Sgls from six phages that infect different bacteria and identified the part of the bacterial cell wall or supporting molecules that each Sgl attacks. In collaboration with scientists from Texas A&M University, they conducted a detailed characterization of the function of one Sgl.

    This work showed that the Sgl proteins target pathways for cell wall building that arose very early in the evolutionary history of bacteria and are still used by nearly all bacteria (including pathogenic bacteria). Since the Sgl proteins attack such fundamental and ubiquitous targets, they can kill bacteria other than the phage’s target strain — confirming they have great potential as antibiotics.

    “Phages are extraordinary innovators when it comes to destroying bacteria. We’re really excited to uncover novel bacterial pathogen-targeting mechanisms that could be leveraged into therapies,” said first author Benjamin Adler, a postdoctoral fellow in Jennifer Doudna’s lab at UC Berkeley.

    Now that the team has evaluated the Dub-seq approach for tackling this question, they can apply it to the thousands of single-gene lysis producing phages awaiting characterization in environmental samples that the team has collected from the ocean, soils, and even the human gut. The inspiration for the next breakthrough medicine could be in there, waiting.

  • Benjamin A. Adler, Karthik Chamakura, Heloise Carion, Jonathan Krog, Adam M. Deutschbauer, Ry Young, Vivek K. Mutalik, Adam P. Arkin. Multicopy suppressor screens reveal convergent evolution of single-gene lysis proteins. Nature Chemical Biology, 2023; DOI: 10.1038/s41589-023-01269-7

    • DOE/Lawrence Berkeley National Laboratory
    Microbiology

    Increase in multidrug-resistant gram-negative bacteria in German hospitals linked to patients from Ukraine

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    Reviewed by Emily Henderson, B.Sc.Feb 2 2023

    The pathogens reach German hospitals with refugees and war casualties. Researchers recommend precautionary screening for hospitals.

    Since the outbreak of the war in Ukraine, certain hospital pathogens that are resistant to many antibiotics have been detected with striking frequency in German hospitals. Due to a combination of two enzymes, some strains of the pathogen Klebsiella pneumoniae are resistant even to carbapenems, which are classified as antibiotics of last resort. In collaboration with the Robert Koch Institute (RKI), the National Reference Centre (NRC) for multidrug-resistant Gram-negative bacteria, based at Ruhr University Bochum, has proved that many of the reported cases are associated with patients from Ukraine. The researchers therefore recommend that this group should be screened prior to hospital admission. They published their findings in the journal Eurosurveillance on 15 December 2022.

    Proof of a conspicuous connection

    The isolates of the bacterium Klebsiella pneumoniae, which have been detected in large numbers in samples from German hospitals since the spring of 2022, produce a combination of two different so-called carbapenemases, NDM-1 and OXA-48, which are able to cleave carbapenem antibiotics.

    We noticed that many of the respective samples had a connection to Ukraine, that the corresponding patients had fled from there, for example, or had been hospitalized in Germany as war casualties.”

    Dr. Niels Pfennigwerth from the NRC

    Subsequent investigations proved that there was indeed a connection, which was also reflected in the surveillance data collected by the Robert Koch Institute.

    “Our analyses have shown that it is very likely that outbreaks with these bacterial strains have occurred in Germany as a result of the hospitalization of Ukrainian patients,” says Niels Pfennigwerth.

    The NRZ and RKI team therefore recommend precautionary screening of persons with a connection to Ukraine when admitted to German hospitals. “If the screening confirms that the person is infected with the pathogen, they will be isolated in the hospital and very strict hygiene measures will be implemented,” points out the researcher.

    People who are otherwise healthy often don’t notice that they have been exposed to such pathogens. In hospitals, however, the pathogens can be transmitted to people who are severely compromised due to illness or injury, especially via the hands of the medical personnel. In this case, Klebsiella pneumoniae can cause pneumonia, wound infections or urinary tract infections, to name but a few. Due to its resistance even to antibiotics of last resort, which are reserved exclusively for severe cases that need to be treated in hospital, treatment may no longer be possible at all in the worst case scenario.

    Source:

    Ruhr-Universitaet-Bochum

    Journal reference:

    Sandfort, M., et al. (2022) Increase in NDM-1 and NDM-1/OXA-48-producing Klebsiella pneumoniae in Germany associated with the war in Ukraine. Eurosurveillance. doi.org/10.2807/1560-7917.ES.2022.27.50.2200926.

    Microbiology

    Maternal and perinatal outcomes of women infected with SARS-CoV-2 during the Omicron wave in Italy

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    Bhavana KunkalikarBy Bhavana KunkalikarJan 25 2023Reviewed by Danielle Ellis, B.Sc.

    In a recent study published in the Clinical Microbiology and Infection, researchers assessed the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination on pregnant women during the Omicron wave.

    Study: Vaccination against SARS-CoV-2 in pregnancy during the Omicron wave: the prospective cohort study of the Italian obstetric surveillance system. Image Credit: GolF2532/Shutterstock
    Study: Vaccination against SARS-CoV-2 in pregnancy during the Omicron wave: the prospective cohort study of the Italian obstetric surveillance system. Image Credit: GolF2532/Shutterstock

    Background

    During the coronavirus disease 2019 (COVID-19) pandemic, pregnant women were more likely than the general population to develop severe COVID-19. In utero mother-to-child viral transmission was shown to be uncommon, and infected mothers demonstrated a strong immune response with anti-SARS-CoV-2 antibodies passed on to newborns.

    Despite many studies indicating a substantial maternal antibody response to SARS-CoV-2 immunization and the absence of safety issues, the vaccination rate among pregnant women remained lower than that of the general population. Only a few studies have been undertaken to date on the impact of the SARS-CoV-2 Omicron variant on unvaccinated and vaccinated pregnant women.

    About the study

    In the present study, researchers compared the perinatal and maternal outcomes of SARS-CoV-2-infected women in Italy during the SARS-CoV-2 Omicron variant wave based on their vaccination protection.

    The current national prospective cohort research involved pregnant women who tested COVID-19-positive within seven days of hospitalization in any Italian maternity unit between January 1 and May 31 2022. In addition, women reported whether they had received the SARS-CoV-2 vaccine, as well as the when (before and/or at the time of pregnancy) and how many doses were received.

    The primary outcome measure was SARS-CoV-2 disease severity, classified as mild, moderate, or severe. The two most severe severity categories, determined by pneumonia diagnosis, were grouped together for statistical analysis as “moderate or severe COVID-19 disease” (MSCD). Secondary outcomes comprised preterm birth, stillbirth, delivery mode, admission to the neonatal intensive care unit (NICU), and early neonatal mortality before hospital release.

    MSCD protection was taken into account as an exposure variable. Women vaccinated with a minimum of one vaccine dose at the time of pregnancy, and those vaccinated with the full vaccine schedule and the first booster vaccine were protected against MSCD. On the other hand, unvaccinated women and participants who were vaccinated with either one or two vaccine doses prior to pregnancy and tested positive for SARS-CoV-2 at 22 or more gestational weeks were deemed unprotected. Women with incomplete vaccination information and those who were vaccinated with one or two doses prior to pregnancy and who tested positive for SARS-CoV-2 at less than 22 gestational weeks were deemed “unknown in terms of protective status.”

    Results

    Between January 1 and May 31, 2022, a total of 2,774 women who tested positive for SARS-CoV-2 within seven days of hospitalization were enrolled. Information was available about the protection status of 2147 women, while no significant clinical or socio-demographic variations were noted between these women and the entire cohort.

    According to the study’s definition, almost 1,069 (49.8%) individuals were protected against MSCD. Of them, 74 were vaccinated with one vaccine during pregnancy, while 596 received two, including a minimum of one dose administered during pregnancy, while 327 received their first booster. In contrast, 1,078 women were deemed unprotected, including 989 women who were unvaccinated and 89 who tested positive for SARS-CoV-2 at 22 or more weeks of gestation after receiving one or two doses before pregnancy. All except 26 women were immunized with the conventional vaccinations alone or in conjunction with messenger ribonucleic acid (mRNA) vaccines.

    Compared to protected women, unprotected women displayed a higher likelihood of being younger, less educated, of foreign nationality, and symptomatic. Also, 96.4% were hospitalized for childbirth or obstetrical causes, whereas 3.6% were hospitalized due to COVID-19. Eight of the latter acquired severe disease, 12 developed a moderate disease, and 58 developed a mild disease.

    MSCD illness was uncommon overall but more prevalent among unprotected women than among protected women. Among the 41 MSCD cases, 27 of 29 unprotected women had not received any vaccine, while two were vaccinated with two doses prior to pregnancy. Three of the 12 protected women received the booster, while nine received two doses, among which the first was received before and the second was received during pregnancy.

    Among unprotected women, seven out of eight severe infection cases and one maternal fatality occurred. COVID-19 pneumonia was deemed the cause of death, reported two weeks after delivery. Unprotected women had a greater incidence of MSCD compared to protected women, Asian women, and those with a history of comorbidities.

    Sensitivity analysis revealed that unprotected women had considerably higher MSCD risk than protected women. Furthermore, 8.7% of newborns were born preterm, predominantly late preterm, with no significant variations between unprotected and protected women, but C-section was reported in 34.4% and 29.3% of women, respectively. The rate of preterm birth was greater among MSCD-infected women compared to those with milder cases and those with CS. Also, out of 619 CS cases, five were urgent/emergent due to COVID-19, and all involved MSCD-affected women.

    Conclusion

    Overall, the study findings documented a low prevalence of severe SARS-CoV-2 infection in pregnant women and considerable efficacy of the COVID-19 vaccine in providing protection. These statistics can serve as the foundation for informing pregnant women uncertain about the vaccine’s efficacy and demonstrating the importance of vaccination in protecting their newborns.

    Journal reference:
    Microbiology

    Genetic disorder that causes immunodeficiency and susceptibility to opportunistic infections discovered

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    Reviewed by Emily Henderson, B.Sc.Jan 23 2023

    An international consortium co-led by Vanderbilt University Medical Center immunogeneticist Rubén Martínez-Barricarte, PhD, has discovered a new genetic disorder that causes immunodeficiency and profound susceptibility to opportunistic infections including a life-threatening fungal pneumonia.

    The discovery, reported Jan. 20 in the journal Science Immunology, will help identify people who carry this in-born error of immunity (IEI). “Our findings will provide the basis for genetic diagnosis and preventive treatment for these groups of patients,” Martínez-Barricarte said.

    IEIs, also known as primary immunodeficiencies, are genetic defects characterized by increased susceptibility to infectious diseases, autoimmunity, anti-inflammatory disorders, allergy, and in some cases, cancer.

    To date, 485 different IEIs have been identified. It is now thought that they occur in one of every 1,000 to 5,000 births, making them as prevalent as other genetic disorders, including cystic fibrosis and Duchene’s muscular dystrophy.

    Despite recent medical advances, about half of patients with IEIs still lack a genetic diagnosis that could help them avoid debilitating illness and death. That’s why this research is so important.

    The error in this case is a mutation in the gene for the protein IRF4, a transcription factor that is pivotal for the development and function of B and T white blood cells, as well as other immune cells.

    As a postdoctoral fellow at The Rockefeller University, Martínez-Barricarte was part of an international research team that, in 2018, identified an IRF4 mutation associated with Whipple’s disease, a rare bacterial infection of the intestine that causes diarrhea, weight loss, and abdominal and joint pain.

    Martínez-Barricarte is now an assistant professor of Medicine in the Division of Genetic Medicine, and of Pathology, Microbiology & Immunology in the Division of Molecular Pathogenesis.

    In 2020, after moving his lab to VUMC, he began collaborating with Aidé Tamara Staines-Boone, MD, and her colleagues in Monterrey, Mexico. They were caring for a young boy who was suffering from severe and recurrent fungal, viral, mycobacterial, and other infections.

    Martínez-Barricarte and his team sequenced the protein-encoding regions of the boy’s genome and discovered a de novo IRF4 mutation, which originated in the patient and was not inherited from his parents.

    Upon consulting with IRF4 experts at the Imagine Institute for the study and treatment of genetic diseases in Paris, they were told that seven other groups were independently characterizing the same mutation. They now collaborate as the IRF4 International Consortium.

    In the current study, the consortium identified seven patients from six unrelated families across four continents with profound combination immunodeficiency who experienced recurrent and serious infections, including pneumonia caused by the fungus Pneumocystis jirovecii. Each patient had the same mutation in the DNA-binding domain of IRF4.

    Extensive phenotyping of patients’ blood cells revealed immune cell abnormalities associated with the disease, including impaired maturation of antibody-producing B cells, and reduced T-cell production of infection-fighting cytokines.

    Two knock-in mouse models, in which the mutation was inserted into the mouse genome, exhibited a severe defect in antibody production consistent with the combined immune deficiency observed in the patients.

    The researchers also discovered the mutation had a “multimorphic” effect detrimental to the activation and differentiation of immune cells.

    While the mutant IRF4 binds to DNA with a higher affinity than the native form of the protein (in a hypermorphic way), its transcriptional activity in common, canonical genes is reduced (hypomorphic), and it binds to other DNA sites (in a neomorphic way), altering the protein’s normal gene expression profile.

    This multimorphic activity is a new mechanism for human disease. “We anticipate that variants with multimorphic activity may be more widespread in health and disease,” the researchers concluded.

    Co-authors from Martínez-Barricarte’s lab included graduate students Jareb Pérez Caraballo and Xin Zhen, and research assistant Linh Tran. His research was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (grant #AI171466).

    Source:

    Vanderbilt University Medical Center

    Journal reference:

    IRF4 International Consortium (2023) A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency. Science Immunology. doi.org/10.1126/sciimmunol.ade7953.

    Microbiology

    Probiotic markedly reduces S. Aureus colonization in phase 2 trial

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    A promising approach to control Staphylococcus aureus bacterial colonization in people — using a probiotic instead of antibiotics — was safe and highly effective in a Phase 2 clinical trial. The new study, reported in The Lancet Microbe, found that the probiotic Bacillus subtilis markedly reduced S. aureus colonization in trial participants without harming the gut microbiota, which includes bacteria that can benefit people. The research was conducted by researchers at the National Institutes of Health led by Michael Otto, Ph.D., an NIH senior investigator at the National Institute of Allergy and Infectious Diseases (NIAID).

    Methicillin-resistant S. aureus, or MRSA, is familiar to many people as a cause of serious disease. Less well known is that S. aureus often lives in the nose, on the body and in the gut without causing any harm. However, if the skin barrier is broken, or the immune system compromised, these colonizing bacteria can cause serious skin, bone, lung, and blood infections.

    The prevention of S. aureus infections using approaches to “decolonize” the body has gained increased attention as the spread of antibiotic resistance limits treatment options. Some decolonization strategies are controversial because they also require large amounts of antibiotics, raising concerns about damage to the microbiota and the development of antibiotic resistance. So far, it appears that only nasal S. aureus colonization can be targeted with topical antibiotics without doing too much harm, but bacteria quickly can recolonize in the nose from the gut.

    Probiotics, digestive supplements containing live microorganisms, may be a way to complement or replace antibiotics. Probiotic Bacillus is especially promising because it is administered orally as spores that can survive passage through the stomach and then temporarily grow in the intestine. In prior studies, Dr. Otto’s group discovered an S. aureus sensing system needed for S. aureus to grow in the gut. They also found that fengycins, Bacillus lipopeptides that are part peptide and part lipid, prevent the S. aureus sensing system from functioning, thereby eliminating the bacteria.

    In the clinical trial, conducted in Thailand, the research team tested whether this approach works in people. They enrolled 115 healthy participants, all of whom were colonized naturally with S. aureus. A group of 55 people received B. subtilis probiotic once daily for four weeks; a control group of 60 people received a placebo. After four weeks researchers evaluated the participants’ S. aureus levels in the gut and nose. They found no changes in the control group, but in the probiotic group they observed a 96.8% S. aureus reduction in the stool and a 65.4% reduction in the nose.

    “The probiotic we use does not ‘kill’ S. aureus, but it specifically and strongly diminishes its capacity to colonize,” Dr. Otto said. “We think we can target the ‘bad’ S. aureus while leaving the composition of the microbiota intact.”

    The researchers also found that levels of S. aureus bacteria in the gut far exceeded S. aureus in the nose, which for decades has been the focus of staph infection prevention research. This finding adds to the potential importance of S. aureus reduction in the gut.

    “Intestinal S. aureus colonization has been evident for decades, but mostly neglected by researchers because it was not a viable target for antibiotics,” Dr. Otto said. “Our results suggest a way to safely and effectively reduce the total number of colonizing S. aureus and also call for a categorical rethinking of what we learned in textbooks about S. aureus colonization of the human body.”

    The researchers plan to continue their work by testing the probiotic in a larger and longer trial. They note that their approach probably does not work as quickly as antibiotics, but can be used for long periods because the probiotic as used in the clinical trial does not cause harm. Study collaborators in Thailand are from Rajamangala University of Technology Srivijaya, and Prince of Songkla University.

  • Pipat Piewngam, Sunisa Khongthong, Natthrit Roekngam, Yongyuth Theapparat, Somkiat Sunpaweravong, Damrongsak Faroongsarng, Michael Otto. Probiotic for pathogen-specific Staphylococcus aureus decolonisation in Thailand: a phase 2, double-blind, randomised, placebo-controlled trial. The Lancet Microbe, 2023; DOI: 10.1016/S2666-5247(22)00322-6

    • NIH/National Institute of Allergy and Infectious Diseases
    Microbiology

    Screening patients for hidden reservoirs of bacteria could supplement infection-control efforts in hospitals

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    Reviewed by Emily Henderson, B.Sc.Jan 12 2023

    Hospitals have strict hygiene and sanitation protocols to protect patients from bacteria that rarely sicken healthy people but can be deadly for vulnerable patients already hospitalized with serious illnesses. Nearly 100,000 people die every year in U.S. hospitals of infections they develop after being admitted. But despite intense infection-control efforts, new strains of bacteria keep on emerging, seemingly out of nowhere, to sicken people in hospitals worldwide.

    Researchers at Washington University School of Medicine in St. Louis have found evidence pointing to an unexpected source of such bacteria: the hospitalized patients themselves. Studying mice, the researchers discovered that urinary tract infections (UTIs) can arise after sterile tubes, called catheters, are inserted into the urinary tract, even when no bacteria are detectable in the bladder beforehand. Such tubes are commonly used in hospitals to empty the bladders of people undergoing surgery. In the mice, inserting the tubes activated dormant Acinetobacter baumannii (A. baumannii)bacteria hidden in bladder cells, triggering them to emerge, multiply and cause UTIs, the researchers said.

    The findings, published Jan. 11 in Science Translational Medicine, suggest that screening patients for hidden reservoirs of dangerous bacteria could supplement infection-control efforts and help prevent deadly infections.

    You could sterilize the whole hospital, and you would still have new strains of A. baumannii popping up. Cleaning is just not enough, and nobody really knows why. This study shows that patients may be unwittingly carrying the bacteria into the hospital themselves, and that has implications for infection control. If someone has a planned surgery and is going to be catheterized, we could try to determine whether the patient is carrying the bacteria and cure that person of it before the surgery. Ideally, that would reduce the chances of developing one of these life-threatening infections.”

    Mario Feldman, PhD, co-senior author, professor of molecular microbiology

    A. baumannii is a major threat to hospitalized people, causing many cases of UTIs in people with urinary catheters, pneumonia in people on ventilators, and bloodstream infections in people with central-line catheters into their veins. The bacteria are notoriously resistant to a broad range of antibiotics, so such infections are challenging to treat and easily can turn deadly.

    Feldman teamed up with co-senior author Scott J. Hultgren, PhD, the Helen L. Stoever Professor of Molecular Microbiology and an expert on UTIs, to investigate why so many A. baumannii UTIs develop after people receive catheters.

    Most UTIs among otherwise healthy people are caused by the bacterium Escherichia coli (E. coli). Research has shown that E. coli can hide out in bladder cells for months after a UTI seems to have been cured, and then re-emerge to cause another infection.

    Feldman and Hultgren -; along with co-first authors Jennie E. Hazen, a graduate student, and Gisela Di Venanzio, PhD, an instructor in molecular microbiology -; investigated whether A. baumannii can hide inside cells like E. coli can. They studied mice with UTIs caused by A. baumannii. They used mice with weakened immune systems because, like people, healthy mice can fight off A. baumannii.

    Once the infections had resolved and no bacteria were detected in the mice’s urine for two months, the researchers inserted catheters into the mice’s urinary tracts with a sterile technique. Within 24 hours, about half of the mice developed UTIs caused by the same strain of A. baumannii as the initial infection.

    “The bacteria must have been there all along, hiding inside bladder cells until the catheter was introduced,” Hultgren said. “Catheterization induces inflammation, and inflammation causes the reservoir to activate, and the infection blooms.”

    Since A. baumannii rarely causes symptoms in otherwise healthy people, many people who carry the bacteria may never know they’re infected, the researchers said. As part of this study, the researchers searched the scientific literature and discovered that about 2% of healthy people carry A. baumannii in their urine.

    “I wouldn’t put much weight on the precise percentage, but I think we can say with certainty that some percentage of the population is walking around with A. baumannii,” Feldman said. “As long as they’re basically healthy, it doesn’t cause any problems, but once they’re hospitalized, it’s a different matter. This changes how we think about infection control. We can start considering how to check if patients already have Acinetobacter before they receive certain types of treatment; how we can get rid of it; and if other bacteria that cause deadly outbreaks in hospitals, such as Klebsiella, hide in the body in the same way. That’s what we’re working on figuring out now.”

    Source:

    Washington University School of Medicine

    Journal reference:

    Hazen, J.E., et al. (2023) Catheterization triggers resurgent infection seeded by host Acinetobacter baumannii reservoirs. Science Translational Medicine. doi.org/10.1126/scitranslmed.abn8134.

    Microbiology

    Global Access Diagnostics joins consortium to co-develop on-farm rapid test for calf pneumonia, RaDiCal

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    From Global Access DiagnosticsDec 16 2022Reviewed by Danielle Ellis, B.Sc.

    Global Access Diagnostics (GADx), a social enterprise prioritizing equitable access to diagnostics and driving local manufacturing, today announced the development of RaDiCal, a one-step molecular lateral flow test to enable rapid diagnosis of pneumonia, one of the most significant diseases affecting calves. The test is being developed through a collaborative consortium, including representatives from the University of Surrey, University of Glasgow, Cardiff University, and Westpoint Farm Vets, to provide a low-cost platform to be used by vets or farmers on-farm. The project is funded by the Biotechnology and Biological Sciences Research Council (BBSRC).

    Pneumonia is one of the most significant diseases affecting calves, costing the UK cattle industry an estimated £50 million a year 1. Resulting from GADx’s participation in a BBSRC Endemic Livestock Disease Priming Partnerships workshop and driven by challenges outlined by farmers, the consortium is combining expertise in microbiology, veterinary infectious disease, and diagnostic test development to create RaDiCal. The test is a pioneering molecular lateral flow platform which can be linked to a mobile phone digital platform for easy interpretation of results, enabling farmers and vets to diagnose calves on-farm, and subsequently take rapid and informed action to facilitate improved disease management and support responsible antibiotic stewardship.

    Dr Alison Wakeham, Head of Agriculture and Animal Health, GADx, said: “GADx’s expertise in lateral flow technology allows us to support a variety of disease areas. By applying our platform within the livestock industry, we are glad to be able to help improve disease management for one of the most significant diseases affecting calves. Working alongside other experts in this field through the consortium and with the support of BBSRC funding, we are looking forward to progressing the project and bringing the transformative test to market. Being able to accurately diagnose and treat early in the disease cycle is critical to prevent spread and control outbreaks.”

    Professor Mark Chambers, Professor of Microbiology and Disease Intervention, University of Surrey, who is leading the project, commented: “The University of Surrey is delighted to be leading the RaDiCal project and will be using its experience of veterinary infectious diseases and test development within an exciting consortium of other academics and representatives from industry, large animal veterinary practice, and farmers themselves at the sharp end of managing calf pneumonia. Through this close partnership and on-going consultation we shall ensure we develop a test that meets the needs of the cattle industry.”

    Abi Reader, project partner, dairy farmer, Goldsland Farm, Chair NFU Cymru Milk Board and Chair CHeCS, added: “Calf Pneumonia puts an enormous burden on UK dairy farmers, causing increased veterinary costs and farming losses. RaDiCal will help reduce this impact and support farmers by enabling early intervention and improved calf welfare.”

    To support this research, the University of Surrey School of Veterinary Medicine is looking for veterinary surgeons who work with calves to share their experiences of using diagnostic tests and managing calf pneumonia.

    If you would like to participate, please complete this short, anonymous survey:

    English version – https://cardiff.onlinesurveys.ac.uk/calfrapidtest

    Welsh version – https://cardiff.onlinesurveys.ac.uk/prawfcyflym

    For more information about the project, please contact: Mark Chambers ([email protected])

    1. https://ahdb.org.uk/knowledge-library/pneumonia-in-calves