Antimicrobial resistance

Antimicrobial Resistance: Multiple Threats, Multiple Responses

Posted by

0


Antimicrobial Resistance (AMR)

To stem the rising tide of antimicrobial resistance, innovative companies are racing to develop new therapeutics, vaccines, and monitoring tools

When we turn our attention to emerging global threats, we know what to expect: grim statistics, dire predictions, and—perhaps worst of all—disturbing revelations that no preventive or corrective actions commensurate with the threats have been mustered. The threat we know as antimicrobial resistance (AMR) is no exception.

Consider this warning from the United Nations: “According to recent estimates, in 2019, 1.27 million deaths were directly attributed to drug-resistant infections globally. By 2050, up to 10 million deaths could occur annually. If unchecked, AMR could shave $3.4 trillion off GDP annually and push 24 million more people into extreme poverty in the next decade.”

Grim statistics? Check. Dire predictions? Check. And what about revelations that preventive or corrective actions have been insufficient? Well—as much as we might hate to admit it—Check.

According to the World Health Organization (WHO), its own Global Action Plan on Antimicrobial Resistance, a plan endorsed by the World Health Assembly in 2015, isn’t being realized: “Although antimicrobial resistance is recognized as a global threat requiring urgent action, over the past six years little progress has been made in improving awareness of antimicrobial resistance, monitoring antimicrobial consumption, implementing infection prevention and control programs, and optimizing antimicrobial use in the human sector.”

The WHO has also complained that there has been little progress on yet another action item—the development of new medicines, vaccines, and other interventions. Here, the WHO suggests that the problem is “market failure.” This is a well-known problem, particularly with respect to the development of new antibiotics. New antibiotics are so few and so important as a last resort that they must be administered sparingly lest they, like so many older antibiotics, become useless through overuse and concomitant induction of antibiotic resistance.

The economic disincentives are clear. Why commit to developing antimicrobials if they are to be used sparingly, which has the effect of limiting sales volumes? Also, antimicrobials are typically administered infrequently (in the case of vaccines) or for short durations (in the case of therapeutics), further limiting sales volumes. Yet some companies, a few of which appear in this article, are undeterred. They are optimistic about developing new antibiotics, vaccines, and phage therapies to combat antimicrobial resistance.

Working to bring new antibiotics to the market

Lyndsay Meyer, director of U.S. Corporate Communications at GSK, emphasizes that the company has been developing antibiotics for over 70 years: “We are building off our long and successful history in this space by developing innovative vaccines and medicines for bacterial and fungal infections.” She notes that GSK currently has more than 30 R&D projects relevant to antimicrobial resistance.

Meyer stresses that GSK is one of the few companies that is actively developing new classes of antibiotics. “Newer antibiotics are used sparingly to curb antibiotic resistance—and rightly so,” she explains. “However, this makes it a struggle for companies to turn a profit.”

She emphasizes that gepotidacin—which already met its primary efficacy endpoint in GSK’s recent Phase III trials—could become the first novel oral antibiotic treatment for uncomplicated urinary tract infections in over 20 years. This novel drug inhibits bacterial DNA replication by a distinct mechanism that involves independent binding to two different type II topoisomerase enzymes.

Gepotidacin provides activity against most strains of Escherichia coli, including isolates that are highly resistant to current antibiotics. What makes the drug so effective is the way it independently binds to two different enzymes, which would require the bacteria  to develop mutations in both enzymes to become resistant to the drug.

Meyer notes that GSK also has an exclusive license agreement with Spero Therapeutics for another antibiotic to treat complicated urinary tract infections—tebipenem pivoxil hydrobromide (tebipenem HBr). She explains that the drug belongs to a class of antibiotic agents called carbapenems, which are typically reserved for severe bacterial infections or suspected multidrug-resistant bacterial infections.

Developing vaccines for difficult-to-treat conditions

At LimmaTech Biologics, CSO Michael Kowarik, PhD, and COO Patricia Martin, PhD, believe that vaccines help minimize antimicrobial resistance by preventing drug-resistant infections in the first place. They also believe that vaccines are advantageous because they are specific to individual pathogens. As a result, they do not harm the natural microbiome that is so critical to human health.

Kowarik highlights that LimmaTech is developing a pipeline of vaccine candidates that target gonorrhea, shigellosis, and other yet-to-be-disclosed indications.

Figure 1 Gonorrhea Vaccine
LimmaTech Biologics is developing a vaccine to overcome the immune evasion mechanisms of Neisseria gonorrhoeae, the bacterium that causes gonorrhea. The company reports that it is using a production platform that introduces multiple antigens in a single production run, and that allows the incorporation of an optimized adjuvant.

He explains how Neisseria gonorrhea, the bacterium responsible for gonorrhea, is now showing resistance to multiple classes of antibiotics: “The problem with this pathogen is that it has developed multiple decoy mechanisms to evade the immune system. For example, it exhibits significant variation in the antigens on its surface proteins and can easily alter its surface structure during infection.”

LimmaTech is developing a vaccine candidate against N. gonorrhea that is currently in preclinical testing. “To target this issue of surface variability,” Kowarik notes, “our gonorrhea vaccine candidates contain multiple immunogenic antigens that are invariable—or conserved—and not altered during infection.” He adds that these antigens can be produced in a single-step process, which streamlines the development timelines of the vaccine and improves cost-effectiveness.

Martin reports that the company is also working on vaccines against Shigella bacteria, which are responsible for shigellosis. “Shigellosis is a major cause of inflammatory diarrhea that results in over 200,000 deaths every year,” she points out. “Compounding the problem, multidrug resistance in Shigella bacteria is rising dramatically.”

She says that LimmaTech is currently evaluating the safety and immunogenicity of a Shigella vaccine candidate in a Phase I/II clinical trial in Kenyan children. She notes that the vaccine was developed using a technique called bioconjugation. This technique is necessary because the polysaccharides on the surface of Shigella species do not always elicit a strong immune response.

“At the core of our approach,” she details, “is a bacterial enzyme that forms precise linkages between surface polysaccharides and an immunogenic protein.” The Shigella vaccine is tetravalent, that is, it incorporates four antigens. It covers up to 85% of diseases produced by Shigella.

Using bacteriophages to target specific bacteria

Cocktails or fixed combinations of engineered bacteriophages are being developed by Locus Biosciences to combat the development and spread of antibiotic resistance. Locus’s cocktails are designed to target specific conditions such as urinary tract infections. According to the company, these cocktails can target over 95% of the bacteria causing an infection.

A bacteriophage—which means bacteria eater in Greek—is a virus that preys on bacteria. “The major advantage of bacteriophages over traditional antibiotics is their ability to target and kill the specific bacteria causing the infection,” says Paul Garofolo, the co-founder and CEO of Locus Biosciences. “This leaves the good bacteria—the so-called healthy microbiome—unaffected.

Locus Biosciences' figure 2 Phage Technology
Locus Biosciences develops CRISPR-Cas3-enhanced bacteriophage (crPhage) products to treat bacterial infections and microbiome dysbioses. The products, which leverage the ability of bacteriophages to target specific bacteria, introduce Cas3, which “shreds” bacterial DNA. The products also leverage the ability of bacteriophages to replicate and induce
cell lysis.

Locus suggests that its bacteriophage cocktails would be suitable as an early-use option in the treatment of antibiotic-resistant infections—as opposed to a last-line option. Garafolo asserts, “Following the diagnosis of a specific condition like a urinary tract infection, our fixed phage cocktails allow a doctor to pull the drug right off the shelf and use it when it’s needed.”

Garofolo says that Locus’s phages are modified to encode a bacterial genome–targeting CRISPR construct. When the phages infect bacteria, the array is transduced into the bacterial genome, where elements of the construct are expressed that kill the bacterium. One of these elements is Cas3. Unlike the more familiar Cas9, which works like a pair of scissors, Cas3 acts more like a shredder.

“Cas3 and Cas9 differ in what they do upon recognizing a DNA sequence in the bacterial genome,” Garofolo elaborates. “While Cas9 makes a clean cut in DNA, Cas3 degrades thousands to tens of thousands of base pairs. Cas3 ensures the death of the bacterial cell.”

Thus far, Locus’s approach has an impressive safety record, with the FDA designating multiple phage products as GRAS or generally regarded as safe for several food safety applications. For pharmaceutical products, Garafolo says that Locus is beginning to conduct clinical trials.

Locus is currently in the middle of a Phase II trial for its lead bacteriophage therapy, LBP-EC01, an engineered fixed cocktail of CRISPR-Cas3-enhanced bacteriophages targeting drug-resistant urinary tract infections caused by E. coli. The company also has preclinical programs targeting Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. “Together,” Garafolo declares, “these are four of the top bacterial species contributing to the multidrug resistance threat worldwide.”

Software for alerting hospitals of infectious outbreaks

Sam Sihvonen, the co-founder and CEO of Solu Healthcare, notes that Solu means cell in Finnish. The Helsinki-based company is developing a real-time microbial database to monitor how bacteria, viruses, and fungi evolve over time. “Our easily accessible data,” Sihvonen asserts, “can be used to improve the diagnosis and treatment of hospital infections, saving money and lives.”

Solu has developed novel software-based algorithms that alert hospitals about which antibiotic-resistance genes are found in outbreaks. According to Sihvonen, Solu’s algorithms make use of existing resistance databases that the scientific community has developed over the past few decades.

Solu’s genomic analysis algorithms are based on raw data from whole genome sequencing. Whole genome sequencing—which uses various commercial technologies to extract DNA and produce the final sequence—is very effective at identifying causative variants for follow-up studies.

“The great thing about whole genome sequencing is that you can capture all existing variants, including new genetic variants,” Sihvonen explains. “This is not possible with a lot of targeted PCR approaches and phenotypic screening methods.” Furthermore, he stresses that the technique can now be performed within hours, a key requirement for Solu’s technology.

Sihvonen says that a lot of information can be obtained from Solu’s algorithms. For instance, they can identify the species and strains of bacteria. They can also determine which antimicrobial resistance genes are found in a sample.

Finally, Solu’s algorithms can elucidate how different outbreaks are linked. “For instance,” Sihvonen points out, “they can provide information about whether Patient A infected Patient B or Patient C. Information like this needs to be quickly uncovered once outbreaks are suspected in hospitals.”

Future of antimicrobial resistance

Sihvonen stresses that rapid bacterial evolution and natural selection in microorganisms will probably always be a problem. He concludes that “it is unlikely that we are ever going to completely eradicate antibiotic resistance.” Furthermore, Garofolo predicts that antibiotics will continue to form the bedrock of modern medicine in the foreseeable future. He adds, however, that he thinks “the goal will be to complement traditional antibiotics with novel medicines like phage treatments and vaccines.”

Antimicrobial treatment imprecision: an outcome-based model to close the data-to-action loop

Posted by

0


Health-care systems, food supply chains, and society in general are threatened by the inexorable rise of antimicrobial resistance. This threat is driven by many factors, one of which is inappropriate antimicrobial treatment. The ability of policy makers and leaders in health care, public health, regulatory agencies, and research and development to deliver frameworks for appropriate, sustainable antimicrobial treatment is hampered by a scarcity of tangible outcome-based measures of the damage it causes. In this Personal View, a mathematically grounded, outcome-based measure of antimicrobial treatment appropriateness, called imprecision, is proposed. We outline a framework for policy makers and health-care leaders to use this metric to deliver more effective antimicrobial stewardship interventions to future patient pathways. This will be achieved using learning antimicrobial systems built on public and practitioner engagement; solid implementation science; advances in artificial intelligence; and changes to regulation, research, and development. The outcomes of this framework would be more ecologically and organisationally sustainable patterns of antimicrobial development, regulation, and prescribing. We discuss practical, ethical, and regulatory considerations involved in the delivery of novel antimicrobial drug development, and policy and patient pathways built on artificial intelligence-augmented measures of antimicrobial treatment imprecision.

Three ways to combat antimicrobial resistance

Posted by

3


With a dearth of new antibiotics coming to market, researchers are finding creative ways to keep bacteria at bay.

Coloured scanning electron micrograph of MRSA bacteria
Staphylococcus aureus on the microscopic fibres of a wound dressing.

The need to find new antibiotics is pressing, but many scientists and policy makers are tackling antimicrobial resistance from other angles. Nature Index takes a look at three methods in more detail.

A plasma wash

Plasma-activated water, enriched with chemically unstable versions of oxygen and nitrogen — also known as radical and reactive species — is being considered as potential new disinfectant. “If bacteria are overwhelmed with radicals then they end up dying,” says Katharina Richter, a biomedical researcher at the University of Adelaide in Australia.

Richter and her colleagues are studying how fast plasma-activated water can clear wounds infected with methicillin-resistant Staphylococcus aureus (MRSA) compared with wounds left untreated. They’re also comparing the technique against administering an antibiotic through an intravenous drip. She says the initial results, which are yet to be published, are encouraging. “The treatment improved the wound and cleared the infection faster than without treatment,” she says. It wasn’t as effective as treatment with antibiotics, but Richter says the experimental design could be to blame. “We compared it with IV antibiotics and that isn’t comparing apples with apples. It would be fairer to compare it to antibiotics given topically. Our next study will have better controls.”

Metallic marvel

Bacteria, although single cells in nature, do get together and help each other to evade drugs and antiseptics. One way they do that is by forming biofilms — groups of bacteria living in a slimy milieu of their own making. Biofilms protect the individual cells residing within; it’s thought that roughly 80% of chronic human infections are caused by biofilms.Nature Index 2022 Biomedical sciences

The metallic element, gallium, interrupts bacteria’s uptake of iron, which eventually starves the microbes of nutrition. Because of this, gallium-laced drugs are one avenue being explored as a way to undermine biofilms. Scientists at the University of Manchester, UK, have found that gallium compounds can reduce the growth of bacteria by as much as 87% (J. M. Baker et al. Life Sci. 305, 120794; 2022). This work builds on the results of researchers at Shanghai Jiao Tong University in China showing that gallium can effectively dissolve the structure of MRSA biofilms, allowing the bacteria to be killed with one-tenth of the usual dose of an antibiotic (W. Xia et al. ACS Infect. Dis. 7, 2565–2582; 2021). Research is now focusing on how best to deliver the gallium and in what doses.

Molecular visas

An antibiotic should have three key characteristics: solubility; the capacity to readily bind to bacteria; and the ability to penetrate cell membranes. That makes designing a new antibiotic a tough task.

Instead of creating completely new antibiotics, therefore, some researchers are sifting through large digital libraries to predict which existing compounds might already have what it takes. “There are established methods for assessing the first two characteristics in a matter of minutes, but permeation is the missing piece of the puzzle,” says Javad Deylami, a computational chemist at the biotech start-up BIOptimize in Singapore.

That means that scientists are often assessing compounds that would theoretically be good at killing bacteria, but fall short at the first hurdle of getting inside the bacteria, says Deylami. “It’s like they reach a border but don’t have a visa to pass.”

Deylami has constructed a computerized version of the outer cell membrane of a bacterium on which he conducts simulations, testing the ability of molecules to penetrate the membranes. His model determines the forces affecting a would-be drug as it passes or fails, allowing Deylami to calculate the permeability of compounds.

Running known molecular structures through the program, Deylami’s team is able to learn, with the help of artificial intelligence, what qualities a compound needs to increase its permeability. That knowledge should help them to hunt through massive libraries to find existing drugs that have these properties.

Source: Nature

AMR May Be the ‘Next Pandemic’

Posted by

0


Feds lead investment in antimicrobial resistance, but more private help is needed, BARDA says

A conceptual computer rendering of bacteria

In an editorial published Saturday, The Lancet noted that strategies to improve antimicrobial resistance (AMR) “have been consistently recommended.”

However, “[i]nnovation has been extremely slow,” the editorial continued. “Vaccines are available for only one of the six leading pathogens … The clinical pipeline for antibiotics is too small to tackle the increasing emergence and spread of AMR.”

“National leaders now have an obligation to move AMR to a higher position in their political agendas,” the editorialists argued. “Research efforts should be accelerated to address knowledge and innovation gaps and to inform policy and practices.”

The day before the editorial’s publication, MedPage Today spoke with Chris Houchens, PhD, director of the division of Chemical, Biological, Radiological, and Nuclear (CBRN) Medical Countermeasures for the Biomedical Advanced Research and Development Authority (BARDA). We discussed BARDA’s investments in addressing AMR, the potential of vaccines for AMR, and why private investment in this space lags, among other issues.

The following is an edited version of our conversation:

Give me your assessment on the AMR issue. I’ve heard it referred to as the next big pandemic; I’m wondering if you agree about that.

Houchens: I would agree it is the next pandemic. In fact, it’s a pandemic that’s already occurring [and] responsible for, I think, close to 23,000 deaths every year in the United States.

It’s going to be very challenging to ever develop that definitive antibiotic that addresses bacterial infection, all the different indications which the bug is not going to figure out how to get around.

Is it a pandemic of COVID-19 proportions? Or is it ever going to be as transmissible as Ebola? Probably not.

You’re in a very, very precarious state, that there is very limited private equity support. There is not a return on investment, because … people that are taking these drugs, they take them for 2 or 3 weeks at a time, rather than for the rest of their lives. It’s a small population that takes them, there’s generics on the market, and these drugs are going to fail in 4 or 5 years. [But] likely at some point you or somebody you know, somebody that’s close to you, is going to be impacted by this. It’s almost like global warming.

What do you think it would take? Or is it even possible to get more pharmaceutical investment in the space?

Houchens: There are a lot of private equity investors who are happy to invest in technologies and products and things like that, that serve a public good. They don’t have to make a lot of money doing it, but they don’t want to lose money doing it, either. A new antibiotic, it’s going to require $1 billion in investment to get it to the market, then those investors are going to want to see at least $2 billion in return in sales.

It’s going to require that antibiotics are appropriately priced or reimbursed, whether it’s through changes in how CMS reimburses [or] another possibility is that companies that develop products, they receive a payment from the government, companies getting a payment for the delivery of an approved antibiotic that would be commensurate with the value of that antibiotic and [investments] the company have made.

I have to make clear: I’m not endorsing the policies. I’m talking about some of the policies that have been discussed.

Give me a high-level summary of the major programs BARDA are working on within the space.

Houchens: There are three major investment areas. One is CARB-X. This is a partnership that we established in 2016 with Boston University. And it brought in other funders like NIH, the Wellcome Trust, the governments of the United Kingdom and Germany, and also the Gates Foundation.

CARB-X was established to support the early-stage research and development of antibiotics … up through phase 1 development — at which point then we transition to the BARDA portfolio, where we support all the way to product licensure. Then we have a third area that we use that’s called Project BioShield. That is to support the post-licensure activities.

We’re actually 6 years now since we established CARB-X. We’ve invested $200 million. Our other partners have provided an additional $300 million. Other investors have provided another $2.2 billion. Nine of those [funded products] have graduated from CARB-X. Nine other products have also entered phase 1 development. … Right now the project has 54 active programs [out of 92 programs over the last 6 years]. Our bet was a 5-year project, and the U.S. government has made a commitment to continue CARB-X for another 10 years. Nine [products] entered clinical trials. We picked two up into our BARDA portfolio, into our clinical development portfolio.

So, does that mean we can expect those to be on the market at some point in the near future?

Houchens: At some point? Absolutely. The genesis of CARB-X was … gaps between discovery of a new antibiotic and getting it into clinical development, where there wasn’t a lot of accessibility. So, you did not see a lot of candidates coming through that early phase of development.

That brings us to the BARDA clinical portfolio. We have had that [since] 2010. We also recognized that there’s a critical need for developments for … bacteria that are responsible for the majority of hospital infections. They’re responsible for secondary bacterial infections that are often going to accompany any sort of health emergency. And also, at the end of the day, the real goal is to make sure that we are making antibiotics available.

And over the past 11 years, 12 years, we’ve invested $1.6 billion in product development for AMR. We support 18 [novel candidates] in advanced development. Seven of those are in phase 3. We anticipate that we’ll probably get two new approvals in the next year. We have one product in phase 2 and we have five products in phase 1. We also have a number of products that are already out and available now in preclinical development.

We supported the development of three drugs backed by the FDA over the last few years. The problem is these companies that got [the] products went bankrupt soon after product approval.

[Note: BARDA has helped cultivate 33 AMR candidates, resulting in three FDA approvals, a spokesperson told MedPage Today in an email following the interview.]

The post-approval phase for antibiotics is very, very cost-intensive. So, the third phase of our investment [is] to buy a drug and put it into the stockpile. And that is company revenue that they can use in turn to go back and build their skills and build a margin. It allows the company to gain the ability to market that drug for the new diseases, these new indications.

We anticipate that we’re going to put out a call for proposals pretty soon that’s going to look for two new antibiotics that we can support as a target for BioShield.

How much can BARDA really do? And how much will these efforts really help when it comes to addressing the problem of AMR? How about outside of government? Are we relying almost entirely on government to end this problem?

Houchens: I’m sorry to say, but yeah. Until an antibiotic can be valued appropriately for the health system on the delivery of healthcare, I just don’t see that any other entity is going to put their money on the line. And that’s the state that we play in, which is addressing market failures.

When we were at the World Anti-Microbial Resistance Congress, there was a lot of talk about vaccines. Not a lot of information was shared there. So, I’m wondering what you know about the potential for a vaccine?

Houchens: I think that there’s value in vaccines. Now, there are not a lot of indications where you could [have] patient populations that are at very high risk for specific bacterial infections. There are some cases for the elderly population in healthcare settings, long-term care settings, that are more susceptible to Pseudomonas infections, for example.

You’re not going to have the same patient population as you do for a cardiovascular drug or diabetes drug. You’d have to conduct a study with maybe 50,000 to 100,000 individuals, just to ensure that you have enough patients who are likely to go on to get a bacterial infection. So, all those are the economic forces that are pushing against the development of vaccines. Now, there may be some situations where you could see the use of a vaccine and the evaluation of a vaccine, in a post-exposure prophylaxis study.

[One] way that we could evaluate new vaccines for bacterial infections is looking at situations where you have likely exposures and vaccinating those individually. But again, they’re very challenging studies, very expensive studies to conduct, on a very limited patient population.

Right. So, do you have any idea as to why some of these companies are looking at this?

Houchens: They’re hoping to be able to demonstrate some value that’s going to differentiate their vaccine. They’re really invested, it doesn’t cost a lot of money to do that clinical research and development. We’re talking tens of millions of dollars compared to hundreds of millions or a billion dollars for the clinical development [of new drugs]. So, it’s easier for you to get smaller investment from venture capital for some of these, what could be very transformational vaccines.

What you saw at the World Anti-Microbial Resistance Congress, you’re seeing early-stage research and development of the vaccines that is not very capital intensive.

Is there anything that you wanted to add, anything important you feel like I didn’t cover?

Houchens: It’s going to continue to collapse [baring major change]. And those healthcare providers are going to lose access to these life-saving drugs.

Antimicrobial resistance killing more than HIV and malaria

Posted by

0


medication

A patient prepares to take his medication.

Speed read

  • Antibiotic-resistant infections led to more than 1.2 million deaths in 2019 – Lancet study
  • True picture could be much worse, with added impact of COVID-19, experts warn
  • Urgent policy measures needed in developing countries, say researchers

Antibiotic-resistant bacterial infections resulted in more than 1.2 million deaths worldwide in 2019, exceeding the number caused by HIV/AIDS and malaria, says a study spanning 204 countries and territories.

One in five of the deaths occurred in children under the age of five, with low- and middle-income countries bearing the highest burden, according to the analysis published in The Lancet, titled Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis.

The researchers say gaps in data in lower-income countries mean the full picture could be even worse, while other experts say the pandemic is also likely to have exacerbated the problem due to COVID-19 patients receiving antibiotics for secondary bacterial infections.

“Antimicrobial abuse has dramatically increased during the pandemic.”

Madhukar Pai, McGill University in Montreal, Canada

Antimicrobial resistance (AMR) is the development of resistance by various bacteria and other microbes against antimicrobial agents or antibiotics, including those used against common infections like lower respiratory tract and bloodstream infections.

The analysis in The Lancet points to an immediate need to scale up action on AMR and recommends urgent measures for policymakers, such as optimising existing antibiotic use, and improving infection monitoring and control.

“This is the most comprehensive study on the global burden of bacterial drug-resistant infections ever conducted,” said Christiane Dolecek, a co-author of the study and a professor who leads on global AMR research at Oxford University’s Centre for Tropical Medicine and Global Health and the Mahidol Oxford Tropical Medicine Research Unit.

“We hope that this report makes clear the impact now and future threat of this 21st century pandemic, and that it energises political leaders and the global community to implement the necessary measures to keep communities and patients safe and reduce this preventable burden,” she told Scidev.Net.

AMR’s global footprint

According to the study, AMR played a part in an estimated 4.95 million deaths and was directly responsible for an estimated 1.27 million deaths in 2019. This compares to 860,000 and 640,000 deaths respectively from HIV/AIDS and malaria in the same year.

Sub-Saharan Africa faced the highest burden, with 24 deaths per 100,000 people resulting directly from AMR, while the figure was 22 per 100,000 in South Asia. The number of AMR-linked deaths in those regions numbered 99 and 77 per 100,000, respectively.

The analysis also showed that of the 23 pathogens studied in the research, six bacteria – including Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae – directly caused the deaths of 929,000 people and were associated with 3.57 million deaths.

In Sub-Saharan Africa, deaths attributable to AMR mainly resulted from Streptococcus pneumoniae (16 per cent) or Klebsiella pneumoniae (20 per cent), while in high-income countries nearly 50 per cent of the deaths attributable to AMR were due to Escherichia coli (23 per cent) or Staphylococcus aureus (26 per cent).

Amesh Adalja, a senior scholar at the Johns Hopkins Center for Health Security in the US, told Scidev.Net that antimicrobial resistance was one of the major public health threats of our time. “It threatens to pull us back to the pre-penicillin era,” he said.

To fight the scourge, says Dolecek, good vaccination coverage, especially of pneumococcal conjugate and flu vaccines, is needed, along with improved water and sanitation and better access to health services. “We need high quality, affordable and accessible simple rapid tests to reliably distinguish bacterial from viral infections on the spot in clinics,” she added.

Dolecek also recommended antibiotic stewardship initiatives to assess and improve how clinicians prescribe antibiotics and patients use them, and to curb inappropriate use.

According to the US Centers for Disease Control and Prevention (CDC), “improving antibiotic prescribing and use is critical to effectively treat infections, protect patients from harms caused by unnecessary antibiotic use, and combat antibiotic resistance.”

COVID-19 impact ‘not captured’

Madhukar Pai, Canada research chair in epidemiology and global health, and a professor at McGill University in Montreal, Canada, told SciDev.Net: “This is an important study that underscores the importance of antimicrobial resistance. But the impact of the COVID-19 pandemic is not captured.

“I hope it will be addressed in future updates of this study, because antimicrobial abuse has dramatically increased during the pandemic, with very high use of antimicrobial drugs such as azithromycin, doxycycline, ivermectin and hydroxychloroquine.”

COVID-19 patients admitted to hospital are often administered antibiotics to treat secondary infections, despite only a minority of cases having bacterial co-infections, according to a report in the BMJ.

“While these drugs are not effective for COVID-19, their widespread abuse makes me worried about antimicrobial resistance in the coming years,” added Pai.

The study says investment in the development pipeline for new antibiotics and access to second-line antibiotics where required are “essential” measures to counter this threat.

Diptendra Sarkar, a public health analyst and professor at the Institute of Post Graduate Medical Education and Research, in Kolkata, India, believes that irrational, non-evidence-based antibiotic use is responsible for the AMR crisis in developing countries.

“Immediate global action is necessary,” he told SciDev.Net. “All stakeholders, which include government regulatory authorities, medical professional bodies and the pharmaceutical industry, must initiate dialogues and draft a national, evidence-based, antibiotic policy.

Regulatory bodies in developing countries must prepare a roadmap for community and hospital infection audits, he said, adding: “Educating health care providers and strong surveillance is the way forward.”

Ceftriaxone-Resistant Neisseria gonorrhoeae Arrives in North America

Posted by

0


The first known case of ceftriaxone-resistant gonorrhea is identified from a woman in Canada.

 

Antimicrobial resistance has, increasingly, limited treatment options for gonorrhea. The CDC recommends dual therapy with ceftriaxone and azithromycin. Few ceftriaxone-resistant isolates have been reported; only five have been reported worldwide through October 2017, most in Asia and none in North America. Investigators from Canada now report on a 23-year-old woman with genital gonorrhea first diagnosed with a nucleic acid amplification test (NAAT) and subsequently through culture.

Agar dilution antimicrobial susceptibility testing confirmed the isolate’s resistance to ceftriaxone (minimum inhibitory concentration = 1 µg/mL), cefixime (MIC = 2 µg/mL), ciprofloxacin (MIC = 32 µg/mL), and tetracycline (MIC = 4 µg/mL) and susceptibility to azithromycin (MIC = 0.5 µg/mL). Although there are no formal breakpoints for cefixime or ceftriaxone resistance, the reported MICs are tenfold higher than what is considered reduced susceptibility. The patient reported having a sexual partner who had unprotected sex during a trip to China and Thailand before their month-long relationship. Molecular typing showed that the isolate carried the penA-60 allele, which was identical to that found in a ceftriaxone-resistant isolate identified in 2015 in Japan.

Comment

Historically, antimicrobial resistance in Neisseria gonorrhoeae emerged in Asia and then spread to other countries including the U.S., usually first in Hawaii or the West Coast (N Engl J Med 2012; 366:485). Because gonorrhea is now mostly diagnosed through nonculture methods such as NAATs, surveillance for antimicrobial susceptibility is a public health priority. The CDC’s GISP surveillance system, set up in 1986, has found fewer than 1.5% of isolates with reduced susceptibility to ceftriaxone (defined as MIC ≥0.125 µg/mL) and none with resistance, defined as an MIC ≥0.25 µg/mL (MMWR Morb Mortal Wkly Rep 2016; 65:1). Now that a ceftriaxone-resistant N. gonorrhoeae isolate has been identified in North America, clinicians must be vigilant and consider performing a culture in cases where the infection was acquired in Asia or, like in this case, when the patient had sexual contact with someone who had unprotected intercourse in Asia.

Why the world needs to start getting serious about its use of antibiotics

Posted by

0


A recent report showed that 10 million people around the world could die every year in 2050 because many diseases are growing increasingly resistant to the drugs we use to treat them.

This chart from Statista, using predictions from the Review on Antimicrobial Resistance, shows the alarming comparison of people who could die from treatable diseases compared to other causes of death if new drugs are not developed.

The Independent’s Oliver Wright, who first covered the story, writes that the report calls for incentives for drug companies to develop “last resort” treatments and for controls on the use of drugs to minimise resistance.

 

Antibiotic Resistance Will Kill 300 Million People by 2050

Posted by

0


New report says pharma companies make more money from other drugs, so shy away from new antibiotic development
MRSA

The true cost of antimicrobial resistance (AMR) will be 300 million premature deaths and up to $100 trillion (£64 trillion) lost to the global economy by 2050.

The true cost of antimicrobial resistance (AMR) will be 300 million premature deaths and up to $100 trillion (£64 trillion) lost to the global economy by 2050. This scenario is set out in a new report which looks to a future where drug resistance is not tackled between now and 2050.

The report predicts that the world’s GDP would be 0.5% smaller by 2020 and 1.4% smaller by 2030 with over 100 million premature deaths. The Review on Antimicrobial Resistance, chaired by Jim O’Neill, is significant in that it is a global review that seeks to quantify financial costs.

This issue goes beyond health policy and, on a strictly macroeconomic basis, it makes sense for governments to act now, the report argues. “One of the things that has been lacking is putting some pound signs in front of this problem,” says Michael Head at the Farr institute, University College London, UK, who sees hope in how a response to HIV came about. “The world was slow to respond [to HIV], but when the costs were calculated the world leapt into action.”

He recently totted up R&D for infectious diseases in the UK and found gross underinvestment in antibacterial research: £102 million compared to a total of £2.6 billion. Other research shows that less than 1% of available research funds in the UK and Europe were spent on antibiotic research in 2008–2013.

Bleak future
RAND Europe and KPMG both assessed the future impact of AMR. They looked at a subset of drug resistant pathogens and the public health issues surrounding them forKlebsiella pneumonia, Escherichia coli, Staphylococcus aureus, HIV, tuberculosis and malaria. The RAND Europe scenario modelled what would happen if antimicrobial drug resistance rates rose to 100% after 15 years, while infection rates held steady. The KPMG scenario looked at resistance rising to 40% from today’s levels and the number of infections doubling. Malaria resistance results in the greatest number of fatalities, while E. coli resistance accounts for almost half the total economic impact as it is so widespread and its incidence is so high.

“You can look at antibiotic resistance as a slow moving global train wreck, which will happen over the next 35 years,” says health law expert Kevin Outterson at Boston University, US. “If we do nothing, this report shows us the likely magnitude of the costs.”

Outterson headed up a recent Chatham House report on new business models for antibiotics that highlighted the problem of inadequate market incentives. “If I came out with a new cardiovascular drug, it could be worth tens of billions of dollars a year,” he says. “But if we had the same innovative product as an antibiotic, we would save it for the sickest and it would sell modestly in the first decade. So market uptake is extraordinarily limited for innovative antibiotics and all for excellent public health reasons.”

Incentivising action
The solution is to de-link return on investment and volume sales. “Instead of companies getting their return on R&D investment by selling volumes of product, they would be paid something by governments or health players for access to that antibiotic,” he explains. Outterson is now working on a report that will outline how this could work.

Another approach is to re-use old drugs. “Developing new antibiotics will take many years and we cannot wait,” says Ursula Theuretzbacher at the Center for Anti-Infective Agents in Vienna, Austria. “In the meantime we decided we need to improve the usage of some selected old drugs that had not been in use for many years.” An EU-funded project, AIDA, is running clinical trials on five drugs developed before the 1980s.

Theuretzbacher has been pleased by public money going into helping small companies move their innovative antibiotics towards market. In the US, companies such as Achaogen, Cempra and Trias, acquired by Cubist, itself just bought up by Merck, have made use of these schemes. Meanwhile, in Europe, there are several EU funded projects, Wellcome Trust schemes and public–private partnerships such as theInnovative Medicines Initiative and its New Drugs for Bad Bugs programme.

Richard Smith, health systems economist at the London School of Hygiene & Tropical Medicine, UK, was a member of the RAND team and adviser to KPMG. He says the report’s headline figures are not an exaggeration and are more likely an underestimate. “It takes into account effects on labour productivity and labour workforce issues, but we don’t know what the public reaction will be: from previous pandemics and outbreaks we know behavioural effects can be much worse on an economy than the impact of the disease,” he says. The report concluded that they “most likely underestimate the true costs of AMR” due to a lack of reliable data.

“When we understand a threat, governments respond with energy and with money,” Outterson says. The US recently agreed to put over $5 billion into fighting Ebola. “The threat posed by bacterial resistance is even greater than that of Ebola,” he adds. “If this report accurately predicts the world we live in in 2050, then we will have failed on a monumental scale to preserve a global public good.”

Antimicrobial resistance: global report on surveillance 2014.

Posted by

0


Overview

Antimicrobial resistance (AMR) threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses and fungi. An increasing number of governments around the world are devoting efforts to a problem so serious that it threatens the achievements of modern medicine. A post-antibiotic era – in which common infections and minor injuries can kill – far from being an apocalyptic fantasy, is instead a very real possibility for the 21st Century.

This WHO report, produced in collaboration with Member States and other partners, provides for the first time, as accurate a picture as is presently possible of the magnitude of AMR and the current state of surveillance globally.

The report makes a clear case that resistance to common bacteria has reached alarming levels in many parts of the world and that in some settings, few, if any, of the available treatments options remain effective for common infections. Another important finding of the report is that surveillance of antibacterial resistance is neither coordinated nor harmonized and there are many gaps in information on bacteria of major public health importance.

Strengthening global AMR surveillance is critical as it is the basis for informing global strategies, monitoring the effectiveness of public health interventions and detecting new trends and threats. As WHO, along with partners across many sectors moves ahead in developing a global action plan to mitigate AMR, this report will serve as a baseline to measure future progress.

World is losing battle against drug resistance, warns WHO

Posted by

0


WHO poster on antimicrobial resistanceAntimicrobial resistance is a growing problem worldwide

 

A “post-antibiotic” era, in which many common infections no longer have a cure, is on the horizon, the WHO warned today — as scientists reported the discovery of superbugs resistant to almost all known antibiotics in water supplies in New Delhi, India.

“In the absence of urgent corrective and protective actions, the world is heading towards a post-antibiotic era, in which many common infections will … once again, kill unabated,” Margaret Chan, director-general of the WHO, said today, in an address to mark World Health Day, which this year is devoted to combating drug resistance.

“We are at a critical point where antibiotic resistance is reaching unprecedented levels and new antibiotics are not going to arrive quickly enough,” said Zsuzsanna Jakab, the WHO’s regional director for Europe.

“Until all countries tackle this, no country alone can be safe.”

Last year, at least 440,000 new cases of multidrug-resistant tuberculosis were detected, and the more serious, extensively drug-resistant tuberculosis has been reported in 69 countries to date, said the WHO.

Meanwhile, the malaria parasite is acquiring resistance to even the latest generation of medicines and resistance is also emerging to antiretroviral medicines for people with HIV/AIDS.

There are few antibiotics under development — only two new classes of antibiotic have been discovered in the last three decades compared with 11 in the 50 years before that.

The empty pipeline is partly the result of drug companies’ reluctance to spend millions developing a new antibiotic, only to be told by regulators to restrict its use in order to manage the spread of resistance.

“[Antibiotic] discovery needs to be underpinned by new financial mechanisms that allow companies to receive a return on their investment in new drugs, while limiting their use to situations of greatest need,” David Brennan, chief executive of AstraZeneca, told a World Health Day event.

“If leaders in government, science, economics, public policy, intellectual property and philanthropy can come together, we will maximise the opportunities to develop and implement the creative solutions that will truly make a difference to tackling anti-microbial resistance,” he said, according to the Dow Jones Newswires.

The dangers of rising drug resistance are underscored by the discovery, published today in The Lancet Infectious Diseases, that a gene that confers resistance to almost all known antibiotics is present in Indian water supplies.

Scientists from Cardiff University in the United Kingdom tested water samples within a 12-kilometre radius of New Delhi. They found the gene, known as New Delhi metallo-beta-lactamase (NDM-1), in a variety of bugs in two of 50 tap water samples and 50 of 171 community waste seepage samples, such as pools in streets.

Most worryingly, the study found the gene in cholera (Vibrio cholera) and dysentery (Shigella boydii).

The scientists said the discovery “has important implications for people living in the city who are reliant on public water and sanitation facilities”.

They added that “international surveillance of resistance, incorporating environmental sampling as well as examination of clinical isolates, needs to be established as a priority”.

Mohd Shahid, a researcher at the Jawaharlal Nehru Medical College and Hospital, Uttar Pradesh, India, wrote in an accompanying commentary: “Coordinated, concrete, and collective efforts are needed, initially, to limit … widespread dissemination, and finally to combat this emerging threatening resistance problem”.

The WHO today published a policy package that sets out the measures governments and their national partners need to take to combat drug resistance. It says they should develop and implement national plans; strengthen surveillance and laboratory capacity; ensure uninterrupted access to essential medicines of assured quality; regulate and promote rational use of medicines; enhance infection prevention and control; and foster innovation and research and development for new tools against drug resistance.

source: scivx/lancet