Category: Antibiotics

Categories : Antibiotics COVIDTags :

The COVID Pandemic has Worsened Antimicrobial Resistance

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The COVID pandemic has set back years of progress against antimicrobial resistance, with resistant hospital-onset infections and deaths increasing by at least 15% in the first year of the pandemic alone, according to a new  report from the US CDC.

About 3 million people in the US are infected with antimicrobial-resistant pathogens, often acquired in healthcare settings, with about 50 000 people dying. Some estimates predict that by 2050, there could be more deaths from antibiotic resistance than from cancer.

Corrie Detweiler, a professor of molecular, cellular, and developmental biology at CU Boulder, has spent her career trying to develop solutions to antimicrobial-resistance. CU Boulder Today spoke with her about why so many antimicrobial drugs won’t work anymore, how COVID made things worse and what can be done to make things better.

Prior to the pandemic, how were we doing in addressing this issue?

“A lot of progress had been made, particularly in hospital-acquired infections, based on a better understanding of the problem and better guidelines about when to use antibiotics. Between 2012 and 2017, for instance, deaths from antimicrobial resistance fell by 18% overall and nearly 30% in hospitals. That all fell apart during COVID.”

Why? How did COVID spawn an uptick?

We didn’t know how to treat COVID, and, understandably, there was a fair amount of chaos in the medical system. People were using antibiotics more, often inappropriately. About 80% of COVID patients received antibiotics. People were given them prophylactically, prior to knowing they had a lung bacterial infection. That’s not to say that none of (the patients) needed them. Some did. But the more you use antibiotics, the more you select for resistance. And that’s how you eventually get a superbug. 

What can society do to address this? 

First, we need to go back to this idea of stewardship in hospitals – to only give out antibiotics when there is a clear need. We were doing the right thing. And then something terrible came along and messed it up, and it demonstrated that what we were doing was working well. That’s a good thing. Second, we need to discover and develop novel classes of antibiotics. The last time a new class of antibiotics hit the market was in 1984. The fundamental problem is that they’re not profitable to develop, compared to say a cancer drug. You can go to the drugstore and get a course of amoxicillin for $8. We need programs that reward industry and academic labs like ours for doing the early research.

What does your lab do?

We’re using basic biology to try to figure out new ways to kill bacteria during an infection and identify compounds that work differently than existing drugs. 

Source: University of Colorado

Categories : AntibioticsTags :

Anti-Ligands: New Antibiotics Targeting Bacterial Adhesion

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Female scientist in laboratory
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In a study published in Microbiology Spectrum, researchers detail how they have turned to attacking one of the critical proteins bacteria use to create an infection – adhesins, which confer the ability to adhere to cells. They also suggest that targeting adhesins with ‘anti-ligands’ could form a new class of antibiotics.

As their first decisive step in establishing a foothold in an organism, bacteria adhere to host cells. Infection pathogens use this adhesion to first colonise the host organism, and then to trigger an infection, which as a worst case scenario can end being fatal. Precise understanding of the bacteria’s adhesion to host cells is a key to finding therapeutic alternatives that block this critical interaction in the earliest possible stage of an infection.

The international collaborative effort has now explained the exact bacterial adhesion mechanism using the human-pathogenic bacterium Bartonella henselae. This pathogen causes ‘cat-scratch disease‘, which affects the lymph nodes draining the area where a cat scratch or bite occurs, causing regional lymphadenopathy. The bacterial adhesion mechanism was deciphered with the help of a combination of in-vitro adhesion tests and high-throughput proteomics. Proteomics is the study of all the proteins present in a cell or a complex organism.

The research group, led by University Hospital Frankfurt and Goethe University Frankfurt, shed light on a key mechanism: the bacterial adhesion to the host cells can be traced back to the interaction of a certain class of adhesins, trimeric autotransporter adhesins, with fibronectin, a common protein in human tissue. Adhesins are components on the surface of bacteria which enable the pathogen to adhere to the host’s biological structures. Homologues of the adhesin identified here as critical are also present in many other human-pathogenic bacteria, such as the multi-resistant Acinetobacter baumannii, which the World Health Organization (WHO) has classified as the top priority for research into new antibiotics.

The researchers visualised the exact points of interaction between the proteins using cutting-edge protein analytics. They also demonstrated that experimental blocking of these processes almost entirely prevents bacterial adhesion. Therapeutic approaches that aim to prevent bacterial adhesion in this way could represent a promising treatment alternative as a new class of antibiotics (known as ‘anti-ligands’) to treat the constantly growing array of multi-resistant bacteria.

Source: Goethe University Frankfurt

Categories : Antibiotics HospitalsTags :

Antibiotic Stewardship and Sepsis Management: Achieving the Best of Both

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Lessening sepsis’s deadly effects means quickly recognising its signs and symptoms, and initiating antibiotic treatments, but some experts have wondered whether this may contribute to antibiotic overuse, especially with time-to-treatment performance measures. A new study published in JAMA Internal Medicine showed that it was possible to effectively treat sepsis while engaging in antibiotic stewardship.

The study led by Hallie Prescott, MD, of the University of Michigan Health Division of Pulmonary and Critical Care and Vincent Liu, MD, of Kaiser Permanente Division of Research, looked at data from more than 1.5 million patients from 2013–2018. Patients included came to the emergency department with signs of systemic inflammatory response syndrome (SIRS), which includes increased heart rate, abnormal body temperature, among other signs.

The research team analysed antibiotics use in these patients, including number receiving antibiotics, when treatment started, treatment duration medications and the broadness of spectrum of the antibiotics.

“We showed in the overall cohort, that antibiotic use decreased. There was a slight decrease in the proportion treated within 48 hours, a more impressive decrease in the average number of days of antibiotic treatment, and also a decrease in the use of broad-spectrum antibiotics,” said Dr Prescott.

About half of the people who met the criteria for SIRS received antibiotics within 12 to 48 hours after admission, a practice that decreased slightly over time. At the same time, 30-day mortality, length of hospitalisation, and the development of multi-drug resistant bacteria also decreased.

“This study adds to our national conversation about how to combat sepsis most effectively. It also confirms that we now need to look for new opportunities to mitigate sepsis by finding patients at high risk before they arrive at the hospital, identifying hospitalised patients most likely to benefit from specific treatments, and enhancing their recovery after they survive sepsis,” said Dr Liu.

Dr Prescott agrees: “The pushback has been [time-to-treatment for sepsis] should not be a performance measure because it’s going to cause more harm than good, and I think our data shows it probably does more good than harm. We have shown that 152 hospitals have been able to make improvements in stewardship and sepsis treatment at the same time, contrary to popular belief.”

Source: Michigan Medicine – University of Michigan

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

S. Typhi is Developing Antibiotic Resistance

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Bacteria causing Typhoid fever are becoming increasingly resistant to the macrolide and quinone antibiotic classes, according to a study published in The Lancet Microbe. The largest genome analysis of Salmonella enterica serovar Typhi also reveals that resistant strains, mostly from South Asia, have spread to other countries nearly 200 times since 1990.

Typhoid fever is a global public health concern, causing 11 million infections and more than 100 000 deaths per year. While it is most prevalent in South Asia, making 70% of global cases, it also has significant impacts in sub-Saharan Africa, Southeast Asia, and Oceania, highlighting the need for a global response.

Typhoid fever infections are treatable with antibiotics, but their effectiveness is threatened by the emergence of resistant S. Typhi strains. Thus far, little is known about the rise and spread of resistant S. Typhi has so far been limited, with most studies based on small samples, prompting researchers led by Stanford University to conduct a wider spread study.

The study researchers genetically sequenced 3489 S. Typhi isolates obtained from blood samples collected between 2014 and 2019 from people in Bangladesh, India, Nepal, and Pakistan with confirmed cases of typhoid fever. A collection of 4169 S. Typhi samples isolated from more than 70 countries between 1905 and 2018 was also sequenced and included in the analysis.

Resistance-conferring genes in the 7658 sequenced genomes were identified using genetic databases. Strains were classified as multidrug-resistant (MDR) if they contained genes giving resistance to classical front-line antibiotics ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole. The authors also traced the presence of genes conferring resistance to the crucially important macrolides and quinolones.

The analysis shows resistant S. Typhi strains have spread between countries at least 197 times since 1990. While these strains most often occurred within South Asia and from South Asia to Southeast Asia, East and Southern Africa, they have also been reported in the UK, USA, and Canada.

Since 2000, MDR S. Typhi has declined steadily in Bangladesh and India, and remained low in Nepal (less than 5% of Typhoid strains), though it has increased slightly in Pakistan. However, these are being replaced by strains resistant to other antibiotics.

For example, gene mutations giving resistance to quinolones have arisen and spread at least 94 times since 1990, with nearly all of these (97%) originating in South Asia. Quinolone-resistant strains accounted for more than 85% of S. Typhi in Bangladesh by the early 2000s, increasing to more than 95% in India, Pakistan, and Nepal by 2010.

Azithromycin resistance mutations have emerged at least seven times in the past 20 years. In Bangladesh, strains with these mutations emerged around 2013, and since then their population size has steadily increased. The findings add to recent evidence of the rapid rise and spread of S. Typhi strains resistant to third-generation cephalosporins, another class of antibiotics critically important for human health.

“The speed at which highly-resistant strains of S. Typhi have emerged and spread in recent years is a real cause for concern, and highlights the need to urgently expand prevention measures, particularly in countries at greatest risk. At the same time, the fact resistant strains of S. Typhi have spread internationally so many times also underscores the need to view typhoid control, and antibiotic resistance more generally, as a global rather than local problem.”

Dr Jason Andrews, Study Lead Author Stanford University

The authors acknowledge some limitations to their study. S. Typhi sequences are underrepresented in several regions, particularly many countries in sub-Saharan Africa and Oceania, where typhoid is endemic. More sequences from these regions are needed to improve understanding of timing and patterns of spread.

Even in countries with better sampling, most isolates come from a small number of surveillance sites and may not be representative of the distribution of circulating strains. As S. Typhi genomes only cover a fraction of all typhoid fever cases, estimates of resistance-causing mutations and international spread are likely underestimated. These potential underestimate highlight the need to expand genomic surveillance to provide a more comprehensive window into the emergence, expansion, and spread of antibiotic-resistant organisms.

Source: EurekAlert!

Categories : AntibioticsTags :

Faecal Microbiota Transplantation is Effective for Recurrent C. Diff

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C difficile. Source: CDC

Research just published in Clinical Infectious Diseases has found that Faecal Microbiota Transplantation, or FMT, is an optimal cost-effective treatment for first recurrent Clostridioides difficile infection (CDI).

“The most effective therapies for CDI are also the cost effective therapies,” said co-investigator Radha Rajasingham, MD. “FMT should be moved earlier in the treatment algorithm for CDI. Our model suggests it is effective and cost effective when used in patients after a single episode of recurrent CDI.”

Mathematical modelling was used to understand both the effectiveness and cost effectiveness of earlier use of FMT in the treatment of CDI, which normally arises from the disruption of healthy gut bacteria.

While this disease is caused by antibiotics, it is often treated with antibiotics, including fidaxomicin for initial, non-severe CDI or vancomycin for severe CDI, followed by FMT for any recurrent CDI.s. Unfortunately in many cases, CDI recurs in the same person again. This cycle of infection is called recurrent CDI.

Current guidelines recommend using FMT as a last resort for people with recurrent CDI. The goal of this research was to examine the benefits of using FMT earlier in the cycle of CDI.

“Based on this analysis, we would recommend that rather than waiting for multiple recurrent CDI, providers should consider FMT use for any recurrent CDI,” said co-author Byron Vaughn, MD, MS.

The authors suggest future research examine the role of FMT to prevent all recurrent CDI or even as primary prevention of CDI in high risk individuals.

Source: University of Minnesota Medical School

Categories : Antibiotics ExerciseTags :

Antibiotic Use Impedes Athletes’ Performance

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Tired woman after exercise
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New research published in the journal Behavioural Processes demonstrates that by killing essential gut bacteria, antibiotics ravage athletes’ motivation and endurance. This study, which examined mice, suggests there is a big difference in the gut microbiome of athletes and couch potatoes.

Much research has been done on how exercise impacts the gut microbiome, but this study is one of few to examine the reverse – how gut bacteria also impact voluntary exercise behaviours. Engaging in voluntary exercise involves both motivation and athletic ability.

“We believed an animal’s collection of gut bacteria, its microbiome, would affect digestive processes and muscle function, as well as motivation for various behaviours, including exercise,” said Theodore Garland, UCR evolutionary physiologist in whose lab the research was conducted. “Our study reinforces this belief.”

Researchers confirmed through faecal samples that after 10 days of antibiotics, gut bacteria were reduced both in a group of ‘athletic’ mice bred for running on wheels and those that were not. Since no sickness behaviour was seen in the mice, exercise changes were ascribed solely to changes in antibiotic-induced changes in the gut bacteria.

Wheel running in the athletic mice was reduced by 21%, and the high runner mice did not recover their running behaviour even 12 days after the antibiotic treatment stopped.

Meanwhile, for the normal mice, antibiotics caused no difference in the running behaviour.

“A casual exerciser with a minor injury wouldn’t be affected much. But on a world-class athlete, a small setback can be much more magnified,” said Monica McNamara, UCR evolutionary biology doctoral student and the paper’s first author. “That’s why we wanted to compare the two types of mice.” Knocking out the normal gut microbiome might be compared with an injury.

One way the microbiome might affect exercise in mice or in humans is how carbohydrate metabolites are used by the muscles.

“Metabolic end products from bacteria in the gut can be reabsorbed and used as fuel,” Garland said. “Fewer good bacteria means less available fuel.”

The researchers would next like to identify the gut bacteria contributing to increased athletic performance. “If we can pinpoint the right microbes, there exists the possibility of using them as a therapeutic to help average people exercise more,” Garland said.

Lack of exercise is a risk factor for many diseases, and researchers would like to find ways of encouraging it more.

“Though we are studying mice, their physiology is very similar to humans. The more we learn from them, the better our chances of improving our own health,” Garland said.

Research into foods that can increase desirable gut bacteria is ongoing, and Garland recommends a balanced diet in addition to regular exercise to promote health.

Source: University of California, Riverside

Categories : Antibiotics Cardiovascular DiseaseTags :

Gut Bacteria can Reduce Effectiveness of Antihypertensive Drugs

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A new study published this month in the journal Hypertension has shown gut bacteria can reduce the effectiveness of certain antihypertensive drugs. The research provides the first clues into why some people not respond well to medication.

Among those with hypertension, an estimated 20% have resistant hypertension, where their blood pressure remains high despite aggressive treatment.

“The only thing doctors can really do in these patients is adding or switching medications and increasing the dose with the hope they can find something that works,” said Dr Tao Yang, an assistant professor at University of Toledo and the study’s first and lead author. “Until now, we haven’t had any clear indication what the mechanism is for resistant hypertension. Our research could provide a first step toward identifying new ways to effectively overcome treatment-resistant hypertension.”

Recent research has focused on the link between blood pressure and the gut microbiome. That work has helped to unravel potential causes of hypertension beyond diet and exercise. However, Dr Yang’s research is the first to examine the impact of gut bacteria on blood pressure medication itself.

In the study, UToledo scientists compared the effectiveness of the antihypertensive drug quinapril in rats with normal gut bacteria against those with gut microbiota depleted by high doses of antibiotics.

Researchers found a clear difference between the two, with animals that were given antibiotics first responding much better to quinapril.

Analysis of the gut bacteria composition in the animals identified the bacteria Coprococcus as the culprit. Laboratory experiments proved that Coprococcus comes, a dominant bacteria species in this genus, can break down quinapril and ramipril, resulting in the compromised blood pressure-lowering effects.

While the study was confined to animal models and lab experiments, researchers did find at least one intriguing case study that seems to support the notion that this could be applicable to humans.

That 2015 report, published in the International Journal of Cardiology, described a woman with a long history of treatment-resistant hypertension whose blood pressure was controlled without any antihypertensive medication for the two weeks she was taking antibiotics for a post-surgical infection. Her blood pressure was able to be controlled with only one medication for six months after stopping antibiotics, before again becoming treatment-resistant.

“This is just one report and more research is needed. However, this suggests that gut bacteria can play a very real and very important role in regulating the efficacy of blood pressure medication,” Dr Yang said.

The research group intends to further explore the interaction between additional blood pressure medications and other common types of gut bacteria.

Though long-term use of antibiotics isn’t a realistic strategy for addressing treatment-resistant hypertension, Dr Yang said it should be possible for someone to alter their microbiota through probiotics, prebiotics and changes in diet.

“The ultimate goal of my research is to identify ways we can specifically target the bacteria in an individual’s gut to improve drug efficacy,” he said. “This has the potential to benefit a lot of people.”

Source: University of Toledo

Categories : AntibioticsTags :

Fungal Infections Occur When Antibiotics Disrupt Gut Immune System

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Patients prescribed antibiotics in hospital are more likely to get fungal infections because of disruption to the gut immune system, according to a new study published in Cell Host and Microbe.

The study authors suggested that using immune-boosting drugs alongside the antibiotics could reduce the health risks from these complex infections.

Invasive candidiasis is an invasive fungal infection that can endanger hospitalised patients receiving antibiotics to prevent sepsis and other bacterial infections (such as C. diff). Fungal infections can be more difficult to treat than bacterial infections, but the underlying factors causing these infections are not well understood.

The study’s researchers discovered that antibiotics disrupt the immune system in the intestines, meaning that fungal infections were poorly controlled in that area. Unexpectedly, the team also found that where fungal infections developed, gut bacteria were also able to escape, leading to the additional risk of bacterial infection.

Not only does the study demonstrate the potential for immune-boosting drugs, but also it also highlights how antibiotics can other effects on the immune system. This in turn underscores the importance of careful stewardship of available antibiotics.

Lead author Dr Rebecca Drummond said: “We knew that antibiotics make fungal infections worse, but the discovery that bacterial co-infections can also develop through these interactions in the gut was surprising. These factors can add up to a complicated clinical situation — and by understanding these underlying causes, doctors will be better able to treat these patients effectively.”

In the study, the team administered a broad-spectrum antibiotic cocktail to mice and then infected them with Candida albicans, the most common fungus that causes invasive candidiasis in humans. They found that although infected mice had increased mortality, this was caused by infection in the intestine, rather than in the kidneys or other organs.

In a further step, the team pinpointed what parts of the immune system were missing from the gut after antibiotic treatment, and then added these back into the mice using immune-boosting drugs similar to those used in humans. They found this approach helped reduce the severity of the fungal infection.

The researchers followed up the experiment by studying hospital records, where they were able to show that similar co-infections might occur in humans after they have been treated with antibiotics.

“These findings demonstrate the possible consequences of using antibiotics in patients who are at risk of developing fungal infections,” added Dr Drummond. “If we limit or change how we prescribe antibiotics we can help reduce the number of people who become very ill from these additional infections — as well as tackling the huge and growing problem of antibiotic resistance.”

Source: University of Birmingham

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Fungal Microbiota May Explain Antibiotics’ Long Term Effects in Infants

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Gut microbiome. Credit: Darryl Leja, NIH

In infants treated with antibiotics, fungal gut microbiota are more abundant and diverse compared with the control group even six weeks following the start of the antibiotic course, according to a study published in the Journal of Fungi. The study’s authors suggest that reduced competition from gut bacteria being killed by antibiotics left more space for fungi to multiply.

“The results of our research strongly indicate that bacteria in the gut regulate the fungal microbiota and keep it under control. When bacteria are disrupted by antibiotics, fungi, Candida in particular, have the chance to reproduce,” explained PhD student Rebecka Ventin-Holmberg from the University of Helsinki.

A new key finding in the study was that the changes in the fungal gut microbiota, together with the bacterial microbiota, may be partly responsible for the long-term adverse effects of antibiotics on human health.

Antibiotics are the most commonly prescribed drugs for infants, causing changes in the gut microbiota at its most important developmental stage. These changes are more long-term compared to those in adults.

“Antibiotics can have adverse effects on both the bacterial and the fungal microbiota, which can result in, for example, antibiotic-associated diarrhoea,” Ventin-Holmberg said.

“In addition, antibiotics increase the risk of developing chronic inflammatory diseases, such as inflammatory bowel disease (IBD), and they have been found also to have a link to overweight,” she added.

These long-term effects are thought to be caused, at least in part, by an imbalance in the gut microbiota.

This study involved infants with a respiratory syncytial virus (RSV) infection who had never previously received antibiotics. While some of the children were given antibiotics due to complications, others received no antibiotic therapy throughout the study.

“Investigating the effects of antibiotics is important for the development of techniques that can be used to avoid chronic inflammatory diseases and other disruptions to the gut microbiota in the future,” Ventin-Holmberg emphasised.

While there have been many studies on the effect of antibiotics on bacterial microbiota, there has been a lack of studies on fungal microbiota. This study’s findings indicate that fungal microbiota may also have a role in the long-term effects of imbalance in the gut microbiota.

“Consequently, future research should focus on all micro-organisms in the gut together to better understand their interconnections and to obtain a better overview of the microbiome as a whole,” Ventin-Holmberg noted.

Source: University of Helsinki

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Nanoparticle Could Boost Polymyxin B for Gram-negative Sepsis

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Patient's hand with IV drip
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To treat Gram-negative sepsis, Purdue University researchers are developing an injectable nanoparticle that can safely deliver Polymyxin B at high enough levels to inactivate endotoxins. Their research is published in Science Advances.

With an estimated annual mortality of between 30 and 50 deaths per 100 000 population,this condition ranks in the top 10 causes of death. One in three patients who die in a hospital has sepsis. Sepsis is a systemic illness caused by microbial invasion of normally sterile parts of the body, occurring when the body’s immune response to an infection or injury goes unchecked. The condition makes blood vessels leaky, leading to inflammation and blood clots, leading to impaired blood flow and possible death.

Professor Yoon Yeo leads a Purdue University team developing biocompatible nanoparticles that treat sepsis systemically through intravenous injection.

Prof Yeo said Polymyxin B, a traditional antibiotic, can inactivate endotoxins that cause a specific type of sepsis, but it may be too toxic for systemic application. For sepsis therapy, it mostly has been tested in extracorporeal blood cleaning, which is cumbersome and time consuming.

“Our nanoparticle formulations reduce dose-limiting toxicity of Polymyxin B without losing its ability to inactivate endotoxins,” Prof Yeo said.

In mouse models of sepsis, 100% treated with the Purdue nanoparticle were protected from excessive inflammation and survived.

“This technology holds promise as a safe, convenient option for patients and physicians,” Prof Yeo said.

Source: Purdue University