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.

MilliporeSigma, a global life science tools and equipment supplier, is responding to the COVID-19 pandemic with products and solutions for scientists to detect and characterize viruses and to develop vaccines and therapies.
“We are committed to providing researchers with the necessary raw materials, products and services that can aid the global scientific effort to fight this novel virus. We have consolidated this product offering on a dedicated COVID-19 web page https://www.sigmaaldrich.com/covid-19.html, providing a one-stop-shop of approximately 125 products and corresponding information for academic labs and biopharmaceutical companies working to combat the virus, the company said in statement.
“We are not only focused on end-product solutions during this extraordinary time. To provide this level of support for the critical measures underway to contain and treat COVID-19 and to continue providing products that support the development and manufacturing of over-the-counter drugs to complex cell and gene therapies, we are working hard to ensure minimal disruption to our supply chain while remaining committed to the safety of our employees and customers.
“Our 59 manufacturing sites around the world remain operational to ensure that our biopharmaceutical customers have the products and services they need to serve the health needs of a global population.”
The company added that along with this, their top priority remains the safety and well-being of their employees.
“At each of our sites, we have stopped travel, arranged remote working whenever possible and implemented stringent safety measures, such as social distancing and enhanced hygiene protocol. We are leveraging virtual meeting technology to continue collaborating with the global scientific community.”
MilliporeSigma noted: “To aid the ongoing scientific response to COVID-19, we continue to monitor the global situation closely, establishing protocols and guidelines to minimize the impact whenever possible to our sites and supply. We have mobilized a global task force to actively evaluate the overall supply chain of both our products and key raw materials suppliers to mitigate any potential disruption. Leveraging business continuity plans, we remain dedicated to serving our customers in all markets. In China, our suppliers continue to increase their levels of resumed operations and, as shipping lanes in and out of China continue to improve, we are actively monitoring logistic routes and transportation options to fulfil our shipping requirements.
“Throughout all of this, we are following guidance outlined by the WHO, CDC and governments of impacted countries, and our global sites have relevant and approved preparedness plans and are empowered to act per their local scenarios, as necessary.”

A pan-European consortium of biotech companies announced April 23 that they will collaborate to develop and manufacture on a large scale a novel adenoviral vector-based vaccine against COVID-19.
The vaccine candidate is expected to enter clinical trials mid 2020 with vaccine production planned to start following the successful trials. If all goes according to plan, approximately 6 million doses of the vaccine are expected to be available early in 2021.
The consortium comprises Italian company ReiThera, German LEUKOCARE, and Belgian Univercells. They provide expertise in vector-based vaccine development, vaccine formulation and manufacturing, respectively. Their combined expertise is expected to enable efficient and ultra-fast vaccine development.
The vaccine technology is based on a novel, ReiThera-proprietary simian adenoviral vector with strong immunological potency and low pre-existing immunity in humans. Vaccines based on simian adenoviral vectors have been extensively evaluated in Phase 1 and 2 clinical trials and proved to be safe and immunogenic. ReiThera is currently preparing for a COVID-19 first-in-human trial to be started in Italy in mid 2020.
In parallel to its clinical development, the consortium will start manufacturing and stockpiling the vaccine. With these pilot scale processes, approximately 6 million doses of the vaccine are expected to be available early in 2021. Based on the Phase 1/2 clinical results and a path agreed with regulatory authorities, the intention with these doses will be to vaccinate the most exposed people such as medical and healthcare professionals and highly vulnerable individuals.
LEUKOCARE will contribute to the drug product development by developing a highly stable liquid vaccine formulation based on its well-established technology platform for formulations of viruses and viral vectors.
Univercells will take advantage of the previous successes of its scale-X bioreactor and NevoLine biomanufacturing platform to adapt and scale-up the technology platform and enable the mass production of ReiThera’s vaccine candidate.
Michael Scholl, Chief Executive Officer of LEUKOCARE, commented: “By combining the experience of the partners, the advanced stages of this vaccine development will allow for a swift response to the COVID-19 pandemic. Facing the current challenges, our approach for the fast and low-risk development of drug products with superior stability characteristics is even more important regarding timelines and social impact.”

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.