Preparing for pandemics of antibiotic resistant bacteria

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.