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Superbugs and failing drugs

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Bacteria that develop resistance to antibiotic drugs – superbugs – pose a major global health threat to humanity. In a concerted effort to stave off this threat, several global programmes have been established and numerous new research initiatives are being carried out. Whether they are successful is yet to be seen. International Hospital reports.
Antimicrobial or antibiotic resistance is a major emerging global health threat which continues to escalate around the world. In the EU it is responsible for around 33,000 deaths each year according to the European Commission [1] and is estimated to cost the EU EUR 1.5 billion per year in healthcare costs and productivity losses.
In the United States, the Centers for Disease Control and Prevention (CDC) estimates that more than 2.8 million antibiotic-resistant infections occur in the country each year, and more than 35,000 people die as a result [2].
In the CDC’s 2019 Antimicrobial Resistance Threats Report, Robert R. Redfield, M.D., Director of the CDC, emphasises that we should stop referring to a coming post-antibiotic era. “It’s already here,” he says. “You and I are living in a time when some miracle drugs no longer perform miracles and families are being ripped apart by a microscopic enemy. The time for action is now and we can be part of the solution.”
So, what exactly is antimicrobial resistance (AMR)? Simply put, antimicrobial resistance occurs when microorganisms – such as bacteria, viruses, fungi, protozoa and helminths (worm-like parasites) – mutate or develop a resistance gene when they are exposed to antimicrobial drugs, such as antibiotics, antifungals, antivirals, antimalarials, and antihelminthics. As a result, the drugs become ineffective and infections persist in the body, increasing the risk of morbidity and mortality as well as the spread of the disease to others.
The issue is of such global importance that a political declaration was endorsed by Heads of State at the United Nations General Assembly in New York in September 2016 signalling the world’s commitment to taking a broad, coordinated approach to address the root causes of antimicrobial resistance across multiple sectors, especially human health, animal health and agriculture.
In 2015, the World Health Organization (WHO) established the Global Antimicrobial Resistance and Use Surveillance System (GLASS) [3]. The system calls on countries to monitor and report on antibiotic resistance. The WHO noted in a report published June 1 this year, that in the past three years, participation has grown exponentially. GLASS now aggregates data from more than 64,000 surveillance sites with more than 2 million patients enrolled from 66 countries across the world. In 2018 the number of surveillance sites was 729 across 22 countries.
Hanan Balkhy, Assistant Director-General for antimicrobial resistance at WHO, explained: “The enormous expansion of countries, facilities and patients covered by the new AMR surveillance system allows us to better document the emerging public health threat of AMR.”
On the back of this data, the Organization notes that high rates of resistance among antimicrobials frequently used to treat common infections, such as urinary tract infections or some forms of diarrhoea, indicate that the world is running out of effective ways to tackle these diseases. For instance, the rate of resistance to ciprofloxacin, an antimicrobial frequently used to treat urinary tract infections, varied from 8.4% to 92.9% in 33 reporting countries.
In addition, the WHO expressed concern that the trend will further be fuelled by the inappropriate use of antibiotics during the COVID-19 pandemic. The Organization points out that evidence shows that only a small proportion of COVID-19 patients need antibiotics to treat subsequent bacterial infections and, as such, has issued guidance [4] not to provide antibiotic therapy or prophylaxis to patients with mild COVID-19 or to patients with suspected or confirmed moderate COVID-19 illness unless there is a clinical indication to do so.
Solutions
What can be done to counter AMR? Although antimicrobial resistance occurs naturally over time, usually through genetic changes, there are a number of countermeasures. Primarily, healthcare practitioners should reduce the misuse and overuse of antimicrobials which are accelerating AMR. The WHO notes, for example, that in many places, antibiotics are overused and misused in people and animals, and often given without professional oversight. Examples of misuse include when they are taken by people with viral infections like colds and flu, and when they are given as growth promoters in animals or used to prevent diseases in healthy animals.

CDC’s 2019 Antimicrobial Resistant Threats Report

The CDC’s 2019 AR Threats Report lists 18 antibiotic-resistant bacteria and fungi in three categories based on the level of concern to human health – urgent, serious, and concerning. The ‘urgent’ list includes the following five threats:
Carbapenem-resistant Acinetobacter
Carbapenem-resistant Acinetobacter cause pneumonia and wound, bloodstream, and urinary tract infections. Nearly all these infections happen in patients who recently received care in a healthcare facility. They are estimated to have caused 700 deaths in the US in 2017.
Candida auris
C. auris is an emerging multidrug-resistant yeast. It can cause severe infections and spreads easily between hospitalized patients and nursing home residents.
Clostridioides difficile
C. difficile causes life-threatening diarrhoea and colitis (an inflammation of the colon), mostly in people who have had both recent medical care and antibiotics. Estimated death per year in the US: 12,800.
Carbapenem-resistant Enterobacteriaceae (CRE)
CRE are a major concern for patients in healthcare facilities. Some Enterobacteriaceae are resistant to nearly all antibiotics, leaving more toxic or less effective treatment options. Estimated deaths in the US in 2017: 1,100.
Drug-resistant Neisseria gonorrhoeae
N. gonorrhoeae causes the sexually transmitted disease gonorrhoeae that can result in life-threatening ectopic pregnancy and infertility, and can increase the risk of getting and giving HIV.
See the report for the complete list. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf

Study shows SARS-COV-2 can be carried in aerosol up to 4 metres from infected person

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A new study by Chinese researchers to check aerosol and surface distribution of SARS-COV-2 in an Intensive Care Unit (ICU) and General Ward (GW) with COVID-19 infected patients found that the virus can be detected in the air up to 4 metres away from patients. In addition, they found the virus was widely distributed on floors and recommend that persons disinfect shoe soles before walking out of wards containing COVID-19 patients.
They also found the virus on computer mice, trash cans, and sickbed handrails.
The early release study was published April 10 in Emerging Infectious Diseases.
The aerosol distribution of the virus has been controversial with previous findings based on very small studies which may not reflect real conditions in a hospital at full capacity. This new study, however, tested surface and air samples in a busy hospital in Wuhan from February 19 through March 2 at the height of outbreak in that city.
The study is particularly pertinent for healthcare workers treating COVID-19 patients and offers a number of conclusions and recommendations.

  1. SARS-CoV-2 was widely distributed in the air and on object surfaces in both the ICU and GW, implying a potentially high infection risk for medical staff and other close contacts.
  2. The SARS-CoV-2 aerosol distribution characteristics in the GW indicate that the transmission distance of SARS-CoV-2 might be 4 metres.
  3. The environmental contamination was greater in the ICU than in the GW; thus, stricter protective measures should be taken by medical staff working in the ICU.

They also found that as the virus settles on the floor it could be tracked around the hospital where healthcare workers from the ICU and GW had walked, such as the floor of the pharmacy.
On this evidence the authors highly recommend that persons disinfect shoe soles before walking out of wards containing COVID-19 patients.
The researchers note that as of March 30 no healthworkers at the hospital had become infected and point out that appropriate precautions can effectively prevent infection.
The authors note that the results of their nucleic acid test do not indicate the amount of viable virus. And that because the minimal infectious dose is unknown, the aerosol transmission distance cannot be strictly determined.
doi: 10.3201/eid2607.200885

Thirona, taking AI from spin-off to 40 countries in 6 years

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Thirona, a Dutch start-up company specialising in AI to analyse medical images, is offering one of their products for free to medical imaging specialists in an effort to combat the COVID-19 pandemic. International Hospital speaks to Dr Eva van Rikxoort, the Managing Director and founder of Thirona, about the company and its products.
International Hospital: Thirona is a Dutch company established in 2014. Can you give our readers a bit of background about the company?
Eva van Rikxoort: Thirona started in 2014 as a spin-off from the Radboud University in Nijmegen. We started with two full-time employees and we have built our company to 25 full-time employees and 20 part-time medical analysists. Together, we developed artificial intelligence software to analyse chest CT scans, chest X-ray images and retina images. Healthcare specialists around the world use our AI software for diseases like asthma, COPD, tuberculosis and diabetic retinopathy.
IH: What led you to set it up?
EVR: I was doing research on chest CT analysis at the Radboud University with my co-founder Prof. Bram van Ginneken. We saw that there was a gap between research that was being done on potential clinical solutions and putting those into clinical practice; Thirona was founded with the vision to bridge that gap.
IH: What products did you have at that time?
EVR: We started with two launching customers for one solution – our AI solution for chest CT analysis.
IH: Where does the name Thirona come from?
EVR: The name Thirona comes from the Celtic goddess named Thirona, worshipped for healing. Although more commonly spelled as ‘Sirona’ in the Latin alphabet, the spelling Thirona was chosen to reflect our roots in thoracic image analysis.
IH: Delft Imaging appears to be part of Thirona. Can you tell us a bit more about Delft Imaging and the relationship between Thirona and Delft Imaging?
EVR: Technically, Thirona and Delft Imaging are separate companies, although we collaborate extensively and practically work together as sister companies. Where Thirona specialises in artificial intelligence software for medical imaging, Delft Imaging specialises in diagnostic innovations that can be used in developing countries. For example, our AI solution for chest X-ray analysis (CAD4TB) is developed by Thirona and distributed by Delft Imaging.
IH: Can you tell us briefly about your key products and where they are being used?
EVR: We essentially offer three categories of products. AI software for chest CT analysis focusing on COPD and asthma, called LungQ; AI software for X-ray analysis – focusing on tuberculosis, called CAD4TB; and AI software for the analysis of retinal images – focusing on DR, AMD and Glaucoma, called RetCAD. LungQ allows for the quantification of chest CTs and is used for patient monitoring, treatment planning and clinical trial analysis.It is mostly used across the United States and European Union. CAD4TB is used in 40 countries around the world and has screened more than 6 million people for tuberculosis. RetCAD is being rolled out across Europe and Asia.
IH: If we look at how the company has grown over the past 5-6 years — can you explain what has been the driving force behind the growth?
EVR: As a spin-off of the Radboud University, our company (and our solutions) is rooted in science. Every software product we develop is thoroughly validated (through 150+ publications to date) and that level of validation drives our growth, I believe; our customers know the type of quality we aim to offer.
IH: What guided your research and development? In other words, why did you take the product development route you have taken?
EVR: We are a demand-driven organisation. Meaning, we develop and work on where our customers and partners have needs to be supported. That has led us on the route we have been on for the past sevearl years.
IH: What are the main challenges have you faced and how have you overcome them?
EVR: One of the main challenges was keeping the same culture in the company during the growth from a small team of a few people with similar backgrounds to a larger more diverse team. We did this by installing a management team structure. By making it a focus for each team allowed us to overcome any difficulties.
IH: Most recently, you are offering a free AI-powered COVID-19 tool – the CAD4COVID-Xray. I understand it has been developed on the back of your successful TB-screening AI tool, CAD4TB. Can you explain how the CAD4TB tool works and how you adapted it for COVID-19 screening.
EVR: Yes, we developed two AI-powered COVID-19 tools actually: one for chest X-ray analysis and one for chest CT. Both have been built on the technical foundation of our existing and proven CAD4TB and LungQ solutions. Because there were underlying algorithms already in place, we were able to rapidly pivot these for the detection of COVID-19.
IH: How will this tool help healthcare facilities and COVID-19 patients?
EVR: CAD4COVID-XRay and CAD4COVID-CT automatically detect COVID-19 related abnormalities and thereby help with triage before any follow-up testing, like RT-PCR. This helps to reduce the workload of healthcare personnel and alleviate the burden on RT-PCR tests. Furthermore, both solutions show the percentage of affected lung tissue, thereby helping to track disease progress and recovery.
IH: How has the AI tool been validated? Has it been approved for use in Europe? In which other countries / regions has it been approved?
EVR: We have done several studies for both solutions (a publication on CAD4COVID-XRay was recently published in Radiology), through which we were able to prove that the software performs on par with expert human readers. For both solutions we have applied for class IIa CE certification, which we expect to receive soon.
IH: Are the CAD4COVID tools specific to certain platforms?
EVR: Both solutions are system agnostic. They process DICOM images which can be from any type of system.
IH: Are you receiving many requests for the CAD4COVID-Xray AI tool?
EVR: The response has been tremendous, which is probably also because we made the software available free-of-charge. CAD4COVIDXRay was launched first (March 31st) and has since been made available to 30+ healthcare facilities across more than 20 countries. We are especially focusing on resource-constrained settings (mostly in developing countries) because in those settings CT often has limited availability, making X-ray all the more important. CAD4COVID-CT was launched a month later and is available at 15+ facilities across 10 countries. We are also integrating it in several platforms through collaborations with partner companies like Smart Reporting.
IH: Why are you offering it for free?
EVR: We knew that for CAD4COVID to have the biggest impact during the pandemic and provide the most support to healthcare specialists globally, we needed to roll it out rapidly. In order to do that, we wanted to avoid as many hurdles as possible that could cause a delay in facilities being able to use the software. We believe cost is a big factor in that. That’s why we, supported by several organisations, have made it available to use free-of-charge.
IH: Can it be shared easily with healthcare facilities that want to use it?
EVR: Yes, people can fill in a form on www.delft.care/cad4covid (for CAD4COVID-XRay) and www.thirona.eu/cad4covid (for CAD4COVID-CT) and our team will reach out to them to help them set it up for their facility.
IH: Is any training required to use the CAD4COVID tools?
EVR: The tool is designed to be very intuitive, but we have developed an onboarding tool to guide new users on how to use the software effectively.
IH: Lastly, what’s in the pipeline for Thirona and how do you envisage development of the field of AI in medical imaging?
EVR: We are quickly expanding into other areas like cystic fibrosis on chest CT analysis, silicosis on chest X-ray analysis and cataract on retinal images. I believe that AI still has to prove itself in many settings, for many different use cases, but that it will become more and more accepted over time, and we already see this happening at incredible speed. In time, AI will leverage the efforts of our healthcare specialists, helping them to diagnose and determine treatment planning quicker, more effectively and reduce their workload in the meantime.

Mental health expert urges people to accept grief and other feelings amid COVID-19 pandemic

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As the COVID-19 pandemic upends life as people know it, changing daily routines, limiting social interactions and shaking their sense of safety, a mental health experts from U.S. hospital Cleveland Clinic’s Mellen Center is stressing that it is perfectly acceptable to feel sad about all of it.
She points out that grief is a natural response to loss – whether it is the loss of a loved one, or the loss of a sense of normalcy.
“We are experiencing a lot of disappointment right now – in both small and big ways – and grief is going to be a factor,” says clinical health psychologist Amy Sullivan, PsyD, ABPP.
“It’s really important that we process this and stay connected to other people in safe ways,” she adds.
Regarding how people should go about dealing with all of these difficult and unexpected feelings bubbling up, she says there is no right or wrong way. However, she offers four suggestions that can help people to cope with current events.
1. Look through the lens of grief and process emotions
She says that the stages of grief can provide a helpful framework for navigating these complex emotions. Experts recognize these stages as denial, anger, bargaining, despair, and acceptance. However, these experts also know that people do not step neatly from one stage to the next in this exact order, she says.
“Grief can come in waves and change on a very regular basis. Our feelings can change on a daily, or even an hourly, basis,” she explains.
Dr. Sullivan adds it is normal to go from feeling despair one day to anger the next.
“The first thing we need to do is to recognize that it is normal to have these waves of emotions that are happening on a regular basis,” Dr. Sullivan says.
Next, she says, acknowledge the loss whether it is knowing or losing someone with COVID-19, losing jobs, missing friends or family.
“Those are all very sad, difficult things for people to manage,” Dr. Sullivan says.
“Feel what you are feeling – whether it is being overwhelmed, anxious, powerless or anything else, it can help to identify and name these emotions,” she advises.
“It can be quite powerful to sit with those feelings for a few moments – to really recognize those emotions and normalize them,” she says.
However, she advises people to set a time limit on this, suggesting they give themselves five minutes to feel that emotion, and then move on to something that they know is a positive coping skill for them.
“It is important for us to accept where our feelings are at the moment and process through them, and then move into a more positive position of acceptance,” she says.
She says this can be done by identifying their own best coping mechanisms
“This is a time when people need to become innovative and develop their own individual sense of coping that works for them during this time,” she says. Examples might include deep breathing, mindfulness exercises, journaling, talking with another person, or going for a walk.
“If it comes to a point where someone cannot handle these feelings on their own, they need to seek mental health help,” Dr. Sullivan says.
2. Fight the urge to disengage
Dr. Sullivan stresses that staying connected is a powerful tool for coping during hard times. Whether that comes in the form of video chatting or sending a good old-fashioned letter, staying in touch with family, friends, neighbours and coworkers can help people to keep a positive attitude, she says.
She adds that many trained mental and behavioural health professionals are currently seeing patients through virtual visits, so that if people are having trouble coping, this could be a solution.
3. Focus on what can be controlled
Dr. Sullivan says that when there is so much uncertainty about the future, it is easy for people to get carried away, playing out the worst-case scenarios in their heads, for example worrying about themselves or someone else getting COVID-19, or wondering if things will ever get back to normal.
“Anticipating negative events can bring a sense of anxiety or fear,” Dr. Sullivan says.
She advises that, instead of agonizing over the things that cannot be known or controlled, people should be aware of what they do have control over. For example, they can choose how much news or social media they consume in a day, and they can decide what they eat. She recommends being mindful about these choices, and focusing on staying in the present.
4. Be open to joy
Lastly, Dr. Sullivan advises people to find joy and gratitude in the small things, like a video chat with family members, or the rush of fresh air when they open a window or step outside. She adds that if they are under a lockdown order, they can find ways to appreciate the opportunity to step back from the hustle and bustle of everyday life and being home.

Preparing for pandemics of antibiotic resistant bacteria

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Even as the world grapples with COVID-19, there is another looming public health problem. Antibiotic resistance, according to some experts, may turn out as bad, or even worse, than the current pandemic.

Similarities in European and US fatalities

In November 2018, the Stockholm-based European Centre for Disease Prevention and Control (ECDC) released a study which estimated that about 33,000 people died each year in Europe, due to anti-microbial resistance (AMR).
One of the most disturbing findings was that 39 percent of the burden is caused by infections with bacteria which had resistant to last-line antibiotics such as carbapenems and colistin. This, the ECDC observed, was worrying as the latter antibiotics were often the last treatment options available. When these are no longer effective, it is extremely difficult or, in many cases, impossible, to treat infections.
The ECDC report also explained that 75% of the burden of disease due to resistant bacteria was due to healthcareassociated infections (HAIs), and that this could be reduced through adequate infection prevention and control measures.
Fatalities in the United States due to AMR are similar to those in Europe. In early March, just as COVID-19 was beginning to gain momentum in Europe, the Centers for Disease Control and Prevention (CDC) stated that more than 35,000 people die as a result of AMR in the US each year.

Not a new challenge

The problem of antibiotic-resistant bacteria is not new. Awareness of the fast-emerging challenge, and its scale, has been present for decades. It is also routinely re-kindled.
In March 1994, ‘Newsweek’ magazine highlighted the threat in a cover story titled ‘End of the Miracle Drugs.’ A few months later, in September, ‘Time’ magazine followed up with a feature titled ‘Revenge of the Killer Microbes.’
The challenge moved to the centre of global attention in April 2011, when the World Health Organization (WHO) warned that indiscriminate use of antibiotics was giving rise to resistant ‘superbugs’, which could render the drugs useless. Also that same year, the EU warned that anti-microbial resistance was a public health priority, with the Commission adopting an action plan against the rising AMR threat.
Three years later, the WHO warned about the impending arrival of a ‘post-antibiotic era.’
In 2016, the O’Neill report, commissioned by the UK government, suggested that, without action, AMR will cause the deaths of 10 million people a year by 2050.

COVID-19 and bacterial infections

It is now over a quarter century since the dramatic warnings by ‘Time’ and ‘Newsweek’.
Given the high levels of awareness about infection and hygiene at present due to COVID-19, some believe that this is the best moment to launch a concerted campaign to control the growth of antibioticresistant bacteria.
One of the factors which would favour such timing is a report from Stanford University School of Medicine. This found that secondary infections to be commonplace in hospitalized COVID-19 patients.
The authors note that though much more data would be required, severely ill patients are ten times more likely to have bacterial or fungal secondary infections than viral. They also observed that “ICU patients with prolonged illness/intubation have more frequent detection of multidrug-resistant Gram-negative pathogens, likely reflecting hospital-acquired infection.”

Air travel, animals would spread bacterial pandemics too

It is now evident that one of the factors behind the speed at which COVID-19 became a global pandemic was air travel. The impact of increasing antibiotic resistance is no different. For example, the blaNDM-1 ‘superbug’ gene was detected in India in 2007 but was found shortly thereafter in hospital patients in Sweden and Germany. In 2013, it was found at Svalbard in the Arctic.
Once again, just as with COVID-19, variants of blaNDM-1 have appeared locally, evolving with time as they move.
Such dispersal, in both bacteria and viruses, are not only caused by human travel. Wildlife, such as migratory birds, not only carry ‘bird flu’, but also resistant bacteria and genes from contaminated water or soils.

Antibiotic use

One of the most problematic aspects of the AMR challenge is inappropriate antibiotic use.
In 2016, the EU Council issued advice under its One Health approach and called on the Commission and Member States to develop EU-wide guidelines on prudent use of antibiotics.
Once again, the gap between threat perception and action is large.
At the turn of the previous decade, the ‘British Medical Journal’ urged authorities to harmonize antibiotic prescribing practices in order to tackle resistance. This followed a multi-year effort by the EU Commission to study community-acquired lower respiratory tract infections (CA-LRTI), which were resistant to antibiotics.
The Network of Excellence project, which was called GRACE (Genomics to combat Resistance against Antibiotics Communityacquired LRTI in Europe), identified wide variations in antibiotic use, in spite of little impact on patients’ recovery times. Although the GRACE website (www.grace-lrti.org) no longer exists, some of its findings were alarming.
For coughs, for example, antibiotic prescribing by physicians ranged from 20 percent in some countries to 90 percent in others. Ressitance levels were confirmed to be especially high. Some 70 percent of bacteria responsible for HAIs were resistant to at least one of the drugs most commonly used to treat infections. Some organisms were resistant to all approved antibiotics and needed to be treated with experimental and potentially toxic drugs.

Variations in impact of resistant bacteria

The impact of antibiotic-resistant bacteria varies greatly between countries. As a result, EU strategies to prevent and control antibiotic-resistant bacteria require coordination at both European and global level.
Since 2014, the ECDC has sough to monitor antibiotic consumption in the EU via the European Surveillance of Antimicrobial Consumption Network (ESAC-Net). Towards this, it has has been using the number of packages per 1,000 inhabitants per day (ipd), as a surrogate for prescriptions, to make comparisons.
At the end of 2017, a study in ‘Eurosurveillance’ using ECDC data showed consumption of antibiotics across Europe ranged from 1.0 to 4.7 packages per 1,000 ipd. However, further analysis revealed that “consumption of antibiotics for systemic use per 1,000 ipd was on average 1.3 times greater in France than in Belgium when considering prescriptions in the numerator” and “2.5 times greater when considering packages.”

Lessons from below

In reality, resistance has been with us ever since antibiotics began to be used, and resistant strains of bacteria have been with us since life began. Resistance has, however, recently accelerated due to use, or rather over-use. Antibiotics typically kill the majority of bacteria at an infection site, but not all. Some bacteria are naturally resistant. Others acquire the genes which carry resistance from other bacteria, especially from our digestive and respiratory systems.
Knowledge of antibiotic resistance development pathways in bacteria has been revolutionised after a research expedition by microbiologists 500 meters below the earth’s surface a cave at Carlsbad Caverns National Park in the US State of New Mexico. The researchers, whose discoveries were described in April 2012 by ‘National Geographic’ magazine, found no fewer than 100 types of bacteria coating the cave walls.
Until that moment, the bacteria had no contact with humans. This was due to geology. Between 4 and 7 million years ago, the cave had been isolated by a massive mantle of rock. Even water takes some 10,000 years to reach the depths of the cave.
Though the bacteria in the cave are non-pathogenic, researchers subsequently discovered that they were resistant to many classes of antibiotics. This held up the possibility that the bacteria would offer new means to investigate the genetic pathways by which resistance to antibiotics is developed.

Insights for new antibiotic development

Until recently, studies had suggested that the bulk of antibioticresistant genes ought to take at least several thousand years to develop. However, resistance to new antibiotics begins within months or even weeks of their launch. Microbiologists have long suspected that this is because bacteria not only routinely exchange genes from other bacteria but that benign bacteria may provide a huge pool of ancient antibiotic-resistance genes ready to be transferred to their pathogenic cousins.
The isolated bacteria in the New Mexico cave have begun providing clues about such theories – and provide new insights into designing the next generation of antibiotics. One of the biggest is that the internally-hardwired resistance is true only for natural antibiotics. The cave bacteria are sensitive to man-made antibiotics.

Turning around antibiotics

More work continues in the Carlsbad Caverns. Barely weeks ago, it was reported that the researchers came across an underground pool of water which is likely to contain other microbial organisms.
So far, the pharmaceutical industry has responded to increasing resistance by developing new and stronger antibiotics. However, given the fact that bacteria evolve rapidly, and even new antibiotics quickly lose their effectiveness, less attention has been paid to new antibiotic development. It is hoped that the findings at Carlsbad Caverns will provide lessons and show us ways to turn such a process around.

New research provides cause for encouragement

Recent findings from academic research in the US and Europe give cause for encouragement that we may soon see a new class of antibiotics.
In early June, a team of Princeton University researchers reported that a compound, SCH-79797, simultaneously punctured the walls of Gram negative bacteria and destroyed the folate in their cells, while being immune to antibiotic resistance.
Gram-negative bacteria are protected by an outer layer which neutralises most antibiotics. Indeed, for almost three decades, there has been no new class of drugs against them.
SCH-79797 is described as being akin to a poisoned arrow, providing synergy between two ways of attack – an arrow to break the wall and poison against folate. The compound is expected to inspire new derivatives and has been named Irresistin, since it can be used against even the toughest opponents – from E. coli to MRSA (methicillin resistant Staphylococcus aureus).
A few days after the discoveries from Princeton University were reported, the journal ‘Nature Communications’ described efforts by scientists at Britain’s University of Liverpool and the University of Utrecht in the Netherlands to develop a viable drug based on teixobactin – a new class of potent antibiotic capable of killing superbugs.
Teixobactin was hailed as a ‘game changer’ after it was discovered in 2015, due to its ability kill multi-drug resistant bacterial pathogens such as MRSA without developing resistance.

COVID-19: Evidence-based advice for health workers having difficult conversations about end of life

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A Loughborough University academic is providing guidance to clinicians who are likely to be having – and training people who will have – difficult conversations with patients suffering from COVID-19 or those closest to them. Professor Ruth Parry, an expert in healthcare communication and interaction, has outlined a series of evidence-based principles with the help of her Loughborough colleague Becky Whittaker, Sharan Watson, of the University of Derby, and Dr Ruth England, of Royal Derby Hospital.
The team shared the recommendations with NHS Health Education England and these have been used to develop a series of open access resources that aim to support healthcare staff who will be having difficult conversations in relation to the coronavirus.
The principles, which have also been added to the International Association for Hospice and Palliative Care’s COVID-19 resources list*, are based on research by Professor Parry and other communication scientists worldwide who have recorded and analysed thousands of difficult conversations across various health and social care settings in the UK, Australia, Japan, and the US.
Professor Parry, who receives funding from the National Institute for Health Research (NIHR), says her guidance steers away from providing recommended phrases or scripts as it is important to equip health workers with the tools to communicate flexibly according to individual circumstances.
Having a conversation by phone, conversations where the staff member who is to do the talking is wearing PPE (Personal Protection Equipment), and conversations with people who have varying degrees of knowledge and distress are all examples of circumstances that can impact how a conversation should be constructed.
What’s more, Professor Parry says giving difficult news over the phone or when wearing Personal Protection Equipment are circumstances that staff would normally want to avoid – in normal circumstances, the health services strive to ensure that these difficult conversations are led by highly experienced professionals, face-to-face, and in calm environments.
Professor Parry has divided her advice into key areas. They include (with a brief overview of what they cover):

  • Prepare yourself and the environment as best you can

Health workers should clarify in their mind what they want to say and why, and find a comfortable and private setting, as best they can.

  • Start the conversation with ‘signposting’

Conversations should be started by giving the person on the receiving end an outline of what will follow – for instance, if it is an update, and/or that there is a decision to be made.

  • How to show compassion and empathy throughout

This can be portrayed through tone of voice, phrases that attend to emotion, and showing understanding without claiming one can possibly fully understand how the person on the receiving end is feeling.

  • What does the person you are talking to know, expect, and feel?

Health workers should find out what the person they are talking to already knows and how they feel about it as this will help them fit what they go on to say to the individual person they are talking to.

  • Are they with someone, can they talk to someone afterwards?

If this is a phone call, finding out who is with a person or who they could talk to afterwards is important, says Professor Parry, but this question should not be asked right at the start of a conversation as it could easily be heard as very bad news. Even when there is very bad news to come, building towards it gradually is better than clearly signalling it from the start; a gradual move towards the news reduces the risk of sending the person on the receiving end into severe shock.

  • Bring the person (further) towards an understanding of the situation – how things are, what has happened or is likely to happen

Professor Parry’s advice is to describe some of the things that are wrong with the unwell person, in such a way that the person speaking is forecasting that bad news is going to come. The point is to bring about gradual recognition, rather than shock.

  • Dealing with crying

Deliveries should be modified to be softer and more lilting if this happens. Speakers should allow silence, repeat brief further sympathy – ‘I’m so sorry’, and acknowledge the distress before moving on and giving more information.

  • Moving towards the end of the conversation with ‘screening’ – ‘are there things you would like to ask, that I have not said, or explained enough?’

Phrases like ‘anything else’ should be avoided because, in some circumstances, this can be interpreted as the speaker not expecting there to be anything else. Offering ‘Are there things I have not covered or explained enough?’ removes the implication that the person has not understood things.

  • Moving towards the end of the conversation with words of comfort and attention to what happens next

If possible, health workers should try to deliver something that is of comfort and that they can say truthfully, says Professor Parry. They should also explain what happens next, advise who the person they are talking to can contact for support and, if necessary, explain how pain or other symptoms will be controlled.
Professor Parry has also provided advice to help somewhat reduce the emotional burden on the healthcare worker – for example, she recommends they find someone to debrief with before and after a difficult conversation. Of the importance of the guidance and what she hopes it will achieve, Professor Parry said: “Healthcare workers are now having to have break bad news and have difficult conversations on an unprecedented scale.
“The kind of research I do makes it possible to pin down, to articulate, precisely how skilled, compassionate healthcare staff communicate, and pass this on to others.
“I hope that our guidance will help all staff having to break bad COVID-19 news to patients or their loved ones, to feel confident and able to communicate well, whilst looking after their own wellbeing.”
The full guidance document has been shared on the Real Talk website – a platform for communication training resource designed to use in face-to-face training events for health and social care staff – and can be downloaded as a PDF here.

Cleveland Clinic study confirms no association between medications for chronic cardiac diseases and COVID-19

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Despite recent controversy suggesting that popular medications prescribed to lower blood pressure may increase the risk of infection by the novel coronavirus and lead to more severe outcomes in COVID-19, a retrospective study by Cleveland Clinic, Ohio, US, has supported the view that there is no foundation to these claims, although the researchers called for larger studies as the pandemic develops.
The medications in question are Angiotensin-converting enzyme (ACE) inhibitors and Angiotensin II receptor blockers (ARBs), both of which dilate blood vessels to increase the amount of blood pumped by the heart. The result is lowered blood pressure and increased blood flow, which helps to lower the heart’s workload and reduce the risk of heart failure. The medications are commonly prescribed in cases of coronary artery disease, heart failure, diabetes and hypertension (high blood pressure).
“Our analysis found no association between ACEI or ARB use and COVID-19 test positivity,” says Cleveland Clinic cardiologist Ankur Kalra, MD, the study’s corresponding author.
“These medications are important tools in the management of coronary artery disease, heart failure, diabetes and hypertension. As there may be a risk to withdrawing these agents, our findings support current professional society guidelines to not discontinue ACEI or ARB therapy in the context of the COVID-19 pandemic,” he added.
The Cleveland Clinic study looked at 18,472 individuals tested for COVID-19 at its locations in Florida and Ohio, with a mean age of 49 (± 21 years), and who were predominantly female (60%) and white (69%). Testing for COVID-19 was positive in 1,735 patients, or 9.4% of the total sample.
First study author Neil Mehta, MD of the Department of Medicine at the Cleveland Clinic Lerner College of Medicine, says: “Our findings with regard to clinical outcomes and measures of COVID-19 severity while on ACEI or ARB therapy give some reassurance. However, they must be interpreted with caution, due to the small sample size and the limitations of observational studies. They require replication and reanalysis in larger patient samples later in the course of the ongoing COVID-19 pandemic.”
A secondary analysis among COVID-19-positive patients showed no association between use of these medications and risk for mechanical ventilation.

Can your pets get infected with the coronavirus?

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A small study published 8 April 2020 in Science by researchers in China found that cats are highly susceptible to SARS-CoV-2 and can pass the virus on to other cats via airborne transmission. However, dogs showed low susceptibility, and livestock including pigs, chickens, and ducks were not susceptible to the virus.
They did not study specifically whether cats can pass the virus to humans, although this seems likely as cats can pass the virus to other cats via airborne transmission.
From their findings, the researchers suggest that surveillance for SARS-CoV-2 in cats should be considered as an adjunct to elimination of COVID-19 in humans.>/p>
Two viruses – SARS-CoV 2/F13/environment/2020/Wuhan, isolated from an environmental sample collected in the Huanan Seafood Market in Wuhan (F13-E), and SARS-CoV-2/CTan/human/2020/Wuhan (CTan-H), isolated from a human patient – were used in the study.
The researchers first investigated the replication of SARS-CoV-2 in cats. Seven subadult cats (aged 6-9 months) were intranasally inoculated with 105 PFU of CTan-H. Two animals were scheduled to be euthanized on days 3 post infection (p.i.) and 6 p.i., respectively, to evaluate viral replication in their organs. Three subadult cats were placed in separate cages within an isolator. To monitor respiratory droplet transmission, an uninfected cat was placed in a cage adjacent to each of the infected cats.
In the transmission study, viral RNA was detected in the faeces of two virus-inoculated subadult cats on day 3 p.i., and in all three virus-inoculated subadult cats on day 5 p.i. Viral RNA was detected in the faeces of one exposed cat on day 3 p.i. The pair of subadult cats with viral RNA-positive faeces were euthanized on day 11 p.i., and viral RNA was detected in the soft palate and tonsils of the virus-inoculated animal and in the nasal turbinate, soft palate, tonsils, and trachea of the exposed animal indicating that respiratory droplet transmission had occurred in this pair of cats. Antibodies against SARS-CoV-2 were detected in all three virus-inoculated subadult cats and one exposed cat.
They replicated the study in juvenile cats and found “massive lesions in the nasal and tracheal mucosa epitheliums, and lungs”, indicating that SARS-CoV-2 can replicate efficiently in cats, with younger cats being more permissive.
Additionally, and importantly, the study showed that the virus can transmit between cats via the airborne route.
For the study in dogs, five 3-month-old beagles were intranasally inoculated with 105 PFU of CTan-H, and housed with two uninoculated beagles in a room. Oropharyngeal and rectal swabs from each beagle were collected over a series of days.
Viral RNA was detected in the rectal swabs of two virus-inoculated dogs on day 2 p.i and in the rectal swab of one dog on day 6 p.i. However, they note that “infectious virus was not detected in any swabs collected from these dogs”.
Two virus-inoculated dogs showed antibodies. The other two virus-inoculated dogs and the two contact dogs were all seronegative for SARS-CoV-2.
The dog study was repeated in pigs, chickens and ducks and viral RNA was not detected in any swabs collected from these animals or from naïve contact animals. All were seronegative for SARS-CoV-2.
doi: 10.1126/science.abb7015

The importance of ventilation to prevent spread of Covid-19

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Using laser light techniques, University of Amsterdam physicists and medical researchers have found that small cough droplets, potentially containing virus particles, can float in the air in a room for many minutes, especially when the room is poorly ventilated. Good ventilation in public spaces (e.g. public transport, nursing homes) is therefore crucial to slow down the spread of the coronavirus. The results were published in The Lancet Respiratory Medicine on 28 May 2020.
The research was carried out by physicists Daniel Bonn, Stefan Kooij and Cees van Rijn from the UvA Institute of Physics, together with medical researchers Aernout Somsen (Cardiology Centers of the Netherlands) and Reinout Bem (Amsterdam University Medical Centers).
The researchers asked healthy test persons to speak and to cough, and used laser light to analyse the droplets that were produced. Both during speech and coughing, large amounts of small droplets (between roughly 1 and 10 micrometres in size) were observed. During coughing, larger droplets (up to 1 millimeter in size) are also produced. Those droplets fall to the ground within one second, however, and therefore have a much smaller probability of transmitting viruses.
The small droplets only move very slowly to the ground due to the large amount of air drag they experience. The researchers found that such droplets can stay in the air for several minutes. After a single cough, it takes about five minutes for the number of small droplets in the air to be halved. These tiny droplets are therefore much more dangerous when it comes to possible transmission of the coronavirus.
Ventilation
When the same measurements were repeated in a well-ventilated room, the results improved dramatically. With only mechanical ventilation turned on, half of the droplets disappeared within 2.5 minutes, but in a room that also had a door and window open, the number of droplets was halved after 30 seconds – ten times faster than in the unventilated room.
The result is important for making better policies to slow down the spread of the coronavirus. Despite physical distancing, spaces like public transportation and nursing homes can still be centres for spreading the virus if insufficiently ventilated. When droplets remain in the air for a long time, proximity tracing via smartphone apps is also an insufficient precaution. The researchers therefore recommend healthcare authorities consider recommendations to ensure adequate ventilation wherever possible in public spaces
Small droplet aerosols in poorly ventilated spaces and SARS-CoV-2 transmission – The Lancet Respiratory Medicine https://doi.org/10.1016/S2213-2600(20)30245-9 Indoor environments
Meanwhile, in a similar study, scientists from Surrey’s Global Centre for Clean Air Research (GCARE), with partners from Australia’s Queensland University and Technology, argue that the lack of adequate ventilation in many indoor environments – from the workplace to the home – increases the risk of airborne transmission of Covid-19.
They note that Covid-19, like many viruses, is less than 100mn in size but expiratory droplets (from people who have coughed or sneezed) contain water, salts and other organic material, along with the virus itself. However, as the water content from the droplets evaporate, the microscopic matter becomes small and light enough to stay suspended in the air and over time the concentration of the virus will build up, increasing the risk of infection – particularly if the air is stagnant like in many indoor environments.
The study highlights improving building ventilation as a possible route to tackling indoor transmission of Covid-19.
Could fighting airborne transmission be the next line of defence against COVID-19 spread? www.sciencedirect.com/science/article/pii/S2590252020300143 Modelling
Additionally, a study carried out in March this year by four Finnish research organisations modelled the transport and spread of coronavirus through the air. They note that preliminary results indicate that aerosol particles carrying the virus can remain in the air longer than was originally thought, so it is important to avoid busy public indoor spaces. This also reduces the risk of droplet infection, which remains the main path of transmission for coronavirus.
The research has been has been submitted for peer-review and published on https://arxiv.org/abs/2005.12612. The paper details how they have modelled the airborne transport of different-sized droplets. These are emitted through coughing, so the study evaluated the quantities of particles that someone could come into contact with upon entering a supermarket or any other indoor public space.
Assistant professor at Aalto University, and project coordinator, Ville Vuorinen, says that both previous related research, and a number of well-known infection spikes, indicate a substantial risk of coronavirus through inhalation of aerosol particles, as well as direct droplet transmission and transmission from surfaces. The 3D flow simulations and analyses carried out in the project also support these ideas.
The 3D simulation shows how droplets of varying size travel in an indoor airflow https://youtu.be/f7I0O0C_eqg credit: Aalto University / Finnish Meteorological Institute / VTT / University of Helsinki / IT Center for Science CSC. Animation: Jyrki Hokkanen, CSC – IT Center for Science Ltd.

Pilot study provides promising results for use of convalescent plasma as treatment for COVID-19

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Chinese researchers have for the first time shown in a pilot study that the use of convalescent plasma from cured COVID-19 patients provides promising results in the treatment of others with more severe disease.
In the preprint study at medRxiv (http://doi.org/dqrs; 2020), K. Duan et al. report that the administration of a single, high-dose of neutralizing antibodies is safe and provides encouraging results with regards to the reduction of viral load and improvement of clinical outcomes.
In the study, ten severe patients confirmed by real-time viral RNA test were enrolled prospectively. One dose of 200 mL convalescent plasma (CP) derived from recently recovered donors with the neutralizing antibody titers above 1:640 was transfused to the patients as an addition to maximal supportive care and antiviral agents.
After CP transfusion, the level of neutralizing antibody increased rapidly up to 1:640 in five cases, while that of the other four cases maintained at a high level (1:640). All patients showed significant improvement in or complete disappearance of clinical symptoms – including fever, cough, shortness of breath, and chest pain – within 3 days.
The authors state that along with increased oxyhaemoglobin saturation – indicative of recuperating lung function – several parameters also improved, including increased lymphocyte counts and decreased C-reactive protein. Radiological examinations showed varying degrees of absorption of lung lesions within 7 days. The viral load was undetectable after transfusion in seven patients who had previous viremia. No severe adverse effects were observed.
The study shows that CP therapy could potentially improve clinical outcomes through neutralizing viremia in severe COVID-19 cases, however, the authors note that further investigation is needed in larger well-controlled trials to assess the optimal dose and time point.

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