Category: Antibiotics

Categories : Antibiotics PaediatricsTags :

An Antibiotic Alternative to Treating Kids’ Ear Infections

On By ModernMedia
This illustration depicted a three-dimensional (3D), computer-generated image, of a group of Gram-positive, Streptococcus pneumoniae bacteria. The artistic recreation was based upon scanning electron microscopic (SEM) imagery.

Doctors typically treat paediatric ear infections with antibiotics, but children don’t always complete the full course, accelerating resistance to these medications. Today, researchers report developing a single-use nanoscale system that’s unlikely to generate resistance. Using a compound similar to bleach in test animals, they show it can kill off Streptococcus pneumoniae, a common cause of ear infections, and it could someday be easily applied as a gel.

The researchers will present their results at the meeting of the American Chemical Society (ACS).

“We initially conceived of this idea by looking at the household cleaner bleach. Even though it has been used since the 19th century, bacteria do not appear to have developed any widespread resistance to this cleaner,” says Rong Yang, PhD, the project’s principal investigator.

But Yang quickly warns that people should not treat infections with bleach. The solution sold at stores is highly concentrated and caustic, but when used in a properly controlled manner at extremely low concentrations, the active ingredient in bleach is considered compatible with living tissue.

After realising that the active ingredient in the household cleaner could circumvent antibiotic resistance, the Cornell University researchers, set out to tackle a nearly universal childhood scourge: acute ear infections. These infections affect more than 95% of children in the US, and treatment typically requires taking antibiotics for five to 10 days. However, these regimens can cause problematic side effects, leading some families to discontinue the medication prematurely, particularly if symptoms resolve. But using these medications improperly can speed up the development of antibiotic resistance, which makes infections more difficult, if not impossible, to treat. This issue ranks among the biggest threats to global health, according to the World Health Organization.

Bacteria have more success fighting against some substances than others. Hypochloric acid from bleach belongs to a family of compounds, known as hypohalous acids, to which bacteria have yet to develop any significant resistance; most likely because of the numerous ways these highly reactive acids damage microbial cells, Yang says.

Because these substances break down quickly, Yang and her colleagues sought to generate one of them on an as-needed basis behind the eardrum in the middle ear, where ear infections occur. They found inspiration in an enzyme from giant kelp, which converts hydrogen peroxide (H2O2) to hypobromous acid (HOBr), a chemical relative of bleach.

Streptococcus pneumoniae, a frequent cause of ear infections, produces H2O2 to fight off other microbes. To mimic the kelp enzyme, which contains the metal vanadium, Yang and her colleagues designed nanowires made of vanadium pentoxide (V2O5). These produce HOBr only in the presence of the H2O2-producing bacteria, and their rod-like shape helps to keep them in place by reducing their ability to diffuse into body fluids.

In tests on chinchillas, which contract ear infections from the same pathogens as human children, they succeeded in eliminating most of the S. pneumoniae. Yang and colleagues found that after treatment with the nanowires, the animals’ once-inflamed eardrums returned to normal. Meanwhile, tests in healthy animals found evidence that the treatment did not interfere with hearing.

For these experiments, the researchers injected the nanowires directly into the middle ear. In more recent work in chinchillas, they developed a less invasive, more practical method for delivering the wires. By decorating the nanowires with peptides known to transport small particles across the eardrum, Yang and her team found they could deliver the treatment topically as a gel deposited into the ear canal. Once the gel was applied, the nanowires within it went through the intact tissue. They are also exploring other approaches for passing the nanowires through the eardrum.

Because other ear-infection-causing bacteria do not produce H2O2, the researchers are currently examining whether this system is effective in the presence of microbes other than S. pneumoniae, and how they might adapt it to fight the other bugs.

The researchers have not yet done studies to determine how long the system stays in place, although their evidence suggests the nanowires drain out of the middle ear after the infection clears. However, Yang suspects they could adapt the nanowires’ properties to stay in place for long periods afterward. This latter approach could make it possible to prevent recurrent infections that plague many children.

“If the bacteria return, the system could restart, so children wouldn’t need antibiotics repeatedly and breed more resistance along the way,” Yang says.

A video on the research is available at www.acs.org/Earaches.

Source: American Chemical Society

Categories : Antibiotics GeneticsTags :

Genetic Mechanism Increases Resistance to the Antibiotic Albicidin by 1000-fold

On By ModernMedia
Photo by Sangharsh Lohakare on Unsplash

A new analysis shows that infectious bacteria exposed to the promising antibiotic albicidin rapidly develop up to a 1000-fold increase in resistance via a gene amplification mechanism. Mareike Saathoff of Freie Universität Berlin, Germany, and colleagues presented these findings in the open access journal PLOS Biology.

Bacterial resistance to antibiotics is a growing problem associated with millions of deaths around the world every year. Understanding how bacteria evolve resistance is key to developing more effective antibiotics and strategies for using them.

In recent years, albicidin has emerged as a promising antibiotic capable of killing a wide range of bacterial species by disrupting their DNA replication. Researchers are working to develop new albicidin-based medications; yet, despite its promise, some bacteria are able to develop resistance to albicidin.

To further investigate albicidin resistance mechanisms, Saathoff and colleagues conducted a suite of experiments employing a broad set of tools, including RNA sequencing, protein analysis, X-ray crystallography, and molecular modeling. They found that two bacteria often associated with human infection, Salmonella typhimurium and Escherichia coli, develop resistance to albicidin when exposed to increasingly higher concentrations of the compound. Their analysis narrowed down the source of this resistance to an increase in the number of copies of a gene known as STM3175 (YgiV) in the bacterial cells, which is amplified in each new generation of cells as they multiply. STM3175 encodes a protein that interacts with albicidin in such a way that protects the bacteria from it.

Further experiments showed that the same albicidin-resistance mechanism is widespread among both pathogenic and harmless bacteria, including the microbes Vibrio vulnificus, which can infect wounds, and Pseudomonas aeruginosa, which can cause pneumonia and other infections. These findings could help inform the ongoing development of albicidin-based antibiotic strategies.

The authors add, “Our study reveals a gene duplication and amplification-based mechanism of a transcriptional regulator in Gram-negative bacteria, that mediates resistance to the peptide antibiotic albicidin.”

Source: Science Daily

Categories : Antibiotics PaediatricsTags :

Nasal Swabs, not Snot Colour, are The Best Way to Determine if Kids’ Sinusitis is Bacterial

On By ModernMedia
Photo by Andrea Piacquadio on Unsplash

In children with suspected sinusitis, a nasal swab to test for three types of bacteria can tell whether antibiotics are likely to be effective or not, according to a new JAMA study by researchers at the University of Pittsburgh and UPMC. They also found that nasal discharge colour was no help in differentiating a viral or bacterial infection.

“Sinusitis is one of the most common diseases we see in children, but it’s difficult to diagnose because it’s based on the duration of symptoms: If the child has a runny nose or congestion for more than 10 days, we suspect sinusitis,” said said lead author Nader Shaikh, MD. “For an ear infection, we can look inside the ear; for pneumonia, we listen to the lungs. But for sinusitis, we have nothing to go on from a physical exam. That was very unsatisfying to me.”

With the goal of developing a better tool to diagnose bacterial sinusitis, Shaikh and his team enrolled about 500 children with sinusitis symptoms from six centres across the US and randomly assigned them to receive either a course of antibiotics or placebo. The researchers also took nasal swabs from each child and tested for the three main types of bacteria involved in sinusitis.

Children who tested positive for the bacteria had better resolution of symptoms with antibiotic treatment compared to those who did not have bacteria. These findings suggest that testing for bacteria could be a simple and effective way to detect children who are likely to benefit from antibiotics and avoid prescribing antibiotics to those who wouldn’t.

“If antibiotics aren’t necessary, then why use them?” said Shaikh. “These medications can have side effects, such as diarrhoea, and alter the microbiome, which we still don’t understand the long-term implications of. Overuse of antibiotics can also encourage antibiotic resistance, which is an important public health threat.”

According to Shaikh, a common belief among parents and doctors is that yellow or green snot signals a bacterial infection. Although several small studies have suggested that nasal discharge colour is not meaningful, Shaikh and his team formally tested this idea by asking parents to identify the hue of their child’s snot on a colour card.

“If kids with green or yellow discharge benefitted more from antibiotics than those with clear-coloured discharge, we would know that colour is relevant for bacterial infection,” explained Shaikh. “But we found no difference, which means that colour should not be used to guide medical decisions.”

The researchers are now looking at how to best roll out nasal testing in the clinic. A major challenge is that bacterial culture-based tests used in the study are not easy for most family doctors to order and can take several days to get results. A more practical approach could be commercially available molecular testing, which could return results overnight, said Shaikh.

Another possibility could be development of rapid antigen tests that work like COVID-19 at-home testing kits. The researchers also plan to delve deeper into the data from this study to see whether there could be another type of biomarker in nasal discharge indicating the presence of bacteria that would be easier to test for.

Source: University of Pittsburgh

Categories : AntibioticsTags :

Novel Metal Complex Treatment Kills Antibiotic-resistant Bacteria

On By ModernMedia
Photo by CDC on Unsplash

An innovative treatment paves the way for reducing antimicrobial resistance in the treatment of a deadly infection in chickens, according to a new study in Veterinary Microbiology. The ground-breaking study investigated the effectiveness of a novel metal-derived complex in treating Avian Pathogenic Escherichia coli (APEC), a serious respiratory infection of chickens which has become increasingly more resistant to antibiotics. A growing body of evidence indicates that the APEC could potentially spread to humans.

University of Surrey’s Professor Roberto La Ragione said: “Antimicrobial resistance is one of the biggest threats to human and animal health. Not being able to use antibiotics to treat an infection not only prolongs an illness and associated welfare issues, but also increases the likelihood of it spreading.

“Coronavirus demonstrated how easily a pandemic can happen, and the threat of another is looking more likely as antibiotics to treat simple bacterial infections are no longer working.”

To test the effectiveness of the metal complex, manganese carbonyl, researchers worked with the Greater Wax Moth larvae and APEC. Split into two groups, the first received manganese carbonyl, whilst the second, the controls, received either a phosphate-buffered saline (PBS) or dimethyl sulfoxide (DMSO). After four days, the survival rate for the larvae which received manganese carbonyl was between 56–75%, whereas in the control group, the survival rate was between 25–45% (PBS) and 19-45 per cent (DMSO), demonstrating the protective effect of the complex.

The test was repeated in chickens infected with APEC, who again received either manganese carbonyl or PBS. Bacterial shedding identified in the faeces of the chickens was significantly lower 24 hours post-treatment in those who received manganese carbonyl compared to the PBS control group, indicating bacterial killing induced by the compound. This is supported by caecal samples taken three days post-treatment which again found significantly fewer bacteria in those that received manganese carbonyl. Examination of tissue samples from the livers of the birds indicated no toxic effects from the metal compound, which was observed in the larvae.

Dr Jonathan Betts, a Research Fellow at the University of Surrey School of Veterinary Medicine, said:

“The development of alternatives to antibiotics is vital to safeguard our future health. Metal complexes such as manganese carbonyl could do this, as we have shown not only are they effective, but they are much cheaper to produce than traditional antibiotics.

“Discovering the effectiveness of manganese carbonyl in treating APEC is a monumental step forward in tackling antimicrobial resistance as it shows we don’t necessarily need more antibiotics; we just need to think more innovatively in developing treatments.”

The international research team also included the University of Surrey, the Animal and Plant Health Agency, the University of Connecticut, the University of Sheffield and Institut für Anorganische Chemie, Julius-Maximilians-Universität Würzburg.

This study was made possible by a BBSRC grant to Professor La Ragione and Professor Poole.

Source: University of Surrey

Categories : AntibioticsTags :

Study Reveals Global Patterns of Antibiotic Resistance

On By ModernMedia
Proportion of third-generation cephalosporin resistance in Klebsiella pneumoniae, for blood infections, 2019 (data from ATLAS, Pfizer). Credit: Institut Pasteur, Eve Rahbé

To understand the main determinants behind worldwide antibiotic resistance dynamics, scientists developed a statistical model based on the ATLAS antimicrobial resistance surveillance database, the model revealed significant differences in trends and associated factors depending on bacterial species and resistance to certain antibiotics. For example, in some bacteria, resistance was strongly affected by global sales for those corresponding antibiotics, while national sales had minimal impact for most. The results of the study were published in the journal The Lancet Planetary Health.

For example, countries with high quality health systems were associated with low levels of antibiotic resistance among all the gram-negative bacteria investigated, while high temperatures were associated with high levels of antibiotic resistance in Enterobacteriaceae. Surprisingly, national antibiotic consumption levels were not correlated with resistance for the majority of the bacteria tested. The results suggest that antibiotic resistance control measures need to be adapted to the local context and to targeted bacteria-antibiotic combinations.

Antibiotic resistance (ABR) is currently one of the most urgent threats to global health. It is a natural phenomenon, but improper use of antibiotics is contributing to it by selecting resistance and complicating bacterial infection-control strategies. Worldwide surveillance of antibiotic resistance, especially under the aegis of WHO has been set up, and several databases have been created to record ABR worldwide, with the long-term aim of improving understanding of the causes to help tackle the phenomenon. Antibiotic resistance varies considerably depending on the bacterial species, but a recent Lancet study estimated that in 2019, 1.27 million deaths worldwide were attributable globally to ABR and ABR was associated with 4.95 million deaths.

To identify the main factors associated with worldwide antibiotic resistance dynamics, a multidisciplinary research team at the Institut Pasteur developed a statistical model and analysed antibiotic resistance data from the ATLAS database, which contains data collected since 2004 in more than 60 countries on every continent. The scientists analysed the data by testing a large number of determinants to reveal the main factors of antibiotic resistance and understand how they relate to the dynamics observed worldwide.

“Research teams study how antibiotic resistance emerges in a bacterium in a Petri dish or in an individual, but we are currently lacking a population-level, global overview that can be used to investigate links between resistance and specific factors like national health system quality for different species of pathogenic bacteria. To understand the dynamics of antibiotic resistance, it needs to be studied at every level. That is what this study sets out to do,” explains Eve Rahbé, PhD research student and first author of the study.

The first stage of the study was to select relevant factors that could influence antibiotic resistance dynamics. “Although some biological factors are known, it was also important for us to investigate hypotheses associated with socioeconomic and climate factors,” continues the scientist. A total of eleven independent factors were selected, including health system quality (based on the Global Health Security index), antibiotic consumption and national wealth (GDP per capita), as well as data on travel and climate variables. Statistical models were then developed to study potential associations between the ATLAS data and the selected factors.

The analysis of global data for the period 2006-2019 initially revealed an increase in resistance to carbapenems for several species, although global trends were stable for other resistances. The study also demonstrated that the dynamics and factors associated with antibiotic resistance depend on bacteria-antibiotic combinations. Surprisingly, however, national antibiotic consumption was not significantly associated with resistance for the majority of bacteria tested (except for quinolone consumption for fluoroquinolone-resistant Escherichia coli and Pseudomonas aeruginosa and carbapenem consumption for carbapenem-resistant Acinetobacter baumannii).

Conversely, high health system quality was associated with low levels of antibiotic resistance in all the gram-negative bacteria tested. High temperatures were associated with high levels of antibiotic resistance, but only for Enterobacteriaceae (Escherichia coli and Klebsiella pneumoniae).

“This study reveals the wide range of factors leading to antibiotic resistance among different pathogenic bacteria at global level, and the need to adapt resistance control approaches to the local context (country, transmission context) and the specific bacteria-antibiotic combination,” concludes Philippe Glaser, Head of the Institut Pasteur’s Ecology and Evolution of Antibiotic Resistance Unit and co-last author of the study.

Source: Institut Pasteur

Categories : Allergies AntibioticsTags :

Most Penicillin Allergy Labels are Unnecessary – Here’s How to Fix That

On By ModernMedia
Photo by Danilo Alvesd on Unsplash

Penicillin allergy affects up to 1 in 10 Americans yet most penicillin allergy labels are in fact incorrectly applied. In addition to limiting the choice of antibiotics to prescribe, the widespread mislabelling contributes to the growing threat of antibiotic resistance. A new procedure developed by researchers at Vanderbilt University Medical Center aims to fix that.

Some 75% of penicillin allergy labels come on by age 3 due to, for example, confusion with a viral rash. The majority of these rashes were never allergic, but the labels ‘stick’ into adulthood and carry many adverse consequences.

Many low-risk patients with a penicillin allergy were able to have their penicillin allergy label removed through a simple procedure known as “direct oral challenge” as part of a world-first multi-centre randomised control trial known as the Penicillin Allergy Clinical Decision Rule (PALACE) study, the results of which were published in JAMA Internal Medicine.

In the PALACE study, investigators randomised low-risk penicillin allergic patients to two different approaches to remove their allergy label. They either underwent the current standard of care to have skin testing followed if negative by oral challenge with a penicillin or they went straight to oral challenge (“direct oral challenge”) without preceding skin testing.

“The majority of patients labelled as penicillin allergic, more than 90%, have low-risk histories, meaning they did not have a history to suggest a severe or more recent reaction to a penicillin,” said PALACE study protocol member and Vanderbilt University Medical Center principal investigator Elizabeth Phillips, MD. “We would expect more than 95% of these patients to have negative testing and be able to take penicillin in the future.”

The study, undertaken by a team of researchers from specialised centres in North America and Australia, enrolled 382 adults who were assessed using a specialized risk assessment tool called PEN-FAST. Participants were randomly assigned to receive either a direct oral penicillin challenge or the standard approach (penicillin skin testing followed by an oral challenge). The primary goal was to determine if the direct oral penicillin challenge was no worse than the standard method of skin testing followed by oral challenge which needs to be performed in an allergist’s office.

Only one patient (0.5%) in each group experienced a positive reaction to the penicillin challenge, demonstrating that the direct oral penicillin challenge performs just as well as the standard method. Importantly, there were no significant differences in adverse events between the two groups, and no serious adverse events were reported.

The findings have wide-ranging implications for patients. By accurately identifying low-risk penicillin allergy patients, health care providers can ensure appropriate antibiotic prescriptions. Patients with a documented penicillin allergy are more likely to be prescribed alternative antibiotics, known as second-line antibiotics, which are often not as effective against certain infections and may have more side effects.

“Patients with penicillin allergy are more likely to get second-line or broader spectrum antibiotics that lead to risk of antibiotic resistance and serious infections such as antibiotic-associated diarrhoea due to Clostridioides difficile, which can spread through hospitals and become a major public health problem.” Phillips said. “In the US increasingly we also have a major problem with other antibiotic-resistant ‘superbugs’ such as multi-resistant gram-negative infections, Candida auris and even a resurgence of syphilis for which penicillin is the best treatment and the only treatment that should be used in pregnancy to prevent transmission to an unborn child.

“The evidence provided by the PALACE study will change clinical practice. Many patients in the United States do not have direct access to an allergist to provide specialised testing such as skin testing. Therefore, the ability to go to direct oral challenge with a penicillin in low-risk patients which can be carried out in any observed setting will make it easier for patients in the United States to access health care to safely and effectively remove the label of penicillin allergy,” she said.

Source: Vanderbilt University Medical Center

Categories : Antibiotics HospitalsTags :

‘Nothing Compares’ to Antibiotic Resistance Discovered in War-torn Ukraine

On By ModernMedia
Photo by Vony Razom 🇺🇦 on Unsplash

Researchers assisting microbiologists in Ukraine have found an extremely high level of bacterial resistance among the war-wounded patients treated in hospitals. The study, recently published in The Lancet Infectious Diseases, found resistance in many hospital-acquired infections stemming from damaged and overwhelmed healthcare infrastructure, with many samples resistant to the last-resort antibiotic colistin.

“I am quite thick-skinned and have witnessed numerous situations involving patients and bacteria. However, I must admit that I have never encountered bacteria as resistant as this before,” says Kristian Riesbeck, professor of Clinical Bacteriology at Lund University in Sweden.

There was never any doubt about helping out when Dr Oleksandr Nazarchuk, a microbiologist at a university in Vinnytsia, Ukraine, got in touch, says Kristian Riesbeck. Help was needed in Ukraine to assess the extent of antibiotic resistance in bacteria among severely injured patients in hospital.

In addition to all the human suffering caused by the war in Ukraine, another battle is being fought — an invisible war against resistant bacteria. This became evident when Kristian Riesbeck and his research colleagues analysed patient samples from seriously wounded patients, many of whom had burn injuries, in Ukraine. The patients had acquired infections while in hospital, primarily due to the overwhelmed wards and destroyed infrastructure.

Samples were collected from a total of 141 war victims, 133 adults who sustained injures during the war and eight infants diagnosed with pneumonia. These patients were admitted to three different hospitals in Ukraine, where they received emergency surgeries and intensive care to address their conditions.

“We observed that several the Gram-negative bacteria exhibited resistance to broad-spectrum antimicrobial agents, including newly developed enzyme-inhibiting antibiotics that are not yet available in the market. Moreover, nearly ten per cent of the samples contained bacteria that demonstrated resistance even to our ‘last-resort’ antibiotic, colistin. While we have encountered similar cases in India and China before, nothing compares to the extent of resistance observed in this study. As much as six per cent of all the samples contained bacteria resistant to every antibiotic we tested,” says Kristian Riesbeck.

He emphasizes that this clearly highlights the challenges posed by resistant bacteria in times of war. In particular, Kristian Riesbeck expresses concern regarding the resistance displayed by Klebsiella pneumoniae bacteria, as they have the potential to cause illness in individuals with a healthy and well-functioning immune system.

“This makes me very worried. It’s rare to encounter Klebsiella with such high levels of resistance, and it was not what we anticipated. While isolated cases have been documented in China, the magnitude of this situation surpasses anything we have seen before. While many countries are providing military aid and resources to Ukraine, it is equally crucial to assist them in addressing this ongoing situation. There is an evident risk of further spread of resistant bacteria, and this threatens the entire European region,” remarks Kristian Riesbeck.

Source: Lund University

Categories : AntibioticsTags :

Drug Slows Down Development of Antibiotic Resistance

On By ModernMedia
Methicillin resistant Staphylococcus aureus (MRSA) – Credit: CDC

As reported in the journal Science Advances, researchers at Baylor College of Medicine have come across a drug that, in laboratory cultures and animal models, significantly slows the development of antibiotic resistance in bacteira. The drug, called dequalinium chloride (DEQ), is a proof-of-concept for evolution-slowing drugs.

In this study, corresponding author Dr Susan M. Rosenberg and her colleagues looked for drugs that could prevent or slow down E. coli bacteria from developing resistance to two antibiotics when exposed to a third antibiotic, ciprofloxacin (cipro), the second most prescribed antibiotic in the US and one associated with high bacterial resistance rates.

The resistance is caused by new gene mutations that occur in the bacteria during infection. The drug DEQ reduces the speed at which new mutations are formed in bacteria, the team finds.

Previous work from the Rosenberg lab had shown that bacterial cultures in the lab exposed to cipro turn up mutation rate. They found a mutational “program” that is switched on by bacterial stress responses. Stress responses are genetic programs that instruct cells to increase production of protective molecules during stress, including stress from low concentrations of cipro. Low concentrations occur at the beginning and end of antibiotic therapies and if doses are missed.

The same stress responses also increase the ability to make genetic mutations, the Rosenberg group, then many other labs, have shown. Some of the mutations can confer resistance to cipro, while other mutations can allow resistance to antibiotics not yet encountered. Mutation-generating processes that are turned on by stress responses are called stress-induced mutation mechanisms.

Bacteria with antibiotic resistance mutations can then sustain an infection in the presence of cipro. This study is the first to show that in animal infections treated with cipro, the bacteria activate a known stress-induced genetic mutational process. Cipro resistance occurs mostly by the bacteria developing new mutations, both clinically and in the laboratory, rather than by acquiring genes that confer antibiotic resistance from other bacteria.

Looking to prevent the development of antibiotic resistance, the researchers screened 1120 drugs approved for human use for their ability to dial down the master bacterial stress response, which they showed counters the emergence of resistance mutations. In addition, and counterintuitively, they wanted “stealth” drugs that would not slow bacterial proliferation, which would confer a growth advantage to any bacterial mutants that resist the mutation-slowing drug itself. That is, drugs that are not antibiotics themselves.

“We found that DEQ fulfilled both requirements. Given together with cipro, DEQ reduced the development of mutations that confer antibiotic resistance, both in laboratory cultures and in animal models of infection, and bacteria did not develop resistance to DEQ,” said first author Yin Zhai, a postdoctoral associate in the Rosenberg lab. “In addition, we achieved this mutation-slowing effect at low DEQ concentrations, which is promising for patients. Future clinical trials are needed to evaluate the ability of DEQ to decelerate bacterial antibiotic resistance in patients.”

Source: Baylor College of Medicine

Categories : Antibiotics Obstetrics & GynaecologyTags :

Targeting A Particular Bacteria Reduced Endometriosis Lesions

On By ModernMedia
Photo by Andrea Piacquadio on Pexels

A research group from Nagoya University in Japan has discovered that using an antibiotic to target Fusobacterium reduced the formation of lesions associated with endometriosis, a gynaecological disorder characterised by endometrial tissue growing outside of the uterus. Their findings, published in Science Translational Medicine, suggest an alternative treatment for this disorder based on antibiotics.

Endometriosis affects one in ten women between the ages of 15 and 49. The disorder can cause lifelong health problems, including pelvic pain and infertility. Although it can be treated using hormone therapy and surgical resection, these procedures sometimes lead to side effects, recurrence, and a significant impact on pregnancy.

The group led by Professor Yutaka Kondo (he, him) and Assistant Professor Ayako Muraoka (she, her) from the Nagoya University Graduate School of Medicine, in collaboration with the National Cancer Center, found that the uterus of mice infected with Fusobacterium had more and heavier lesions. However, mice that had been given an antibiotic to eradicate Fusobacterium saw improved lesion formation.

The team’s findings strongly suggest that targeting Fusobacterium is an effective non-hormonal antibiotic treatment for endometriosis. Dr Kondo praised the potential for easier diagnosis and treatment. “Eradication of this bacterium by antibiotic treatment could be an approach to treat endometriosis for women who are positive for fusobacteria infection, and such women could be easily identified by vaginal swab or uterus swab,” he said.

This study also shows the benefit of looking at upstream events to determine causative agents. The initial finding was that a protein called transgelin (TAGLN) was often upregulated in patients with endometriosis. This was unsurprising because the protein is associated with processes that are important in the development of endometriosis. However, this finding led them to determine that transforming growth factor beta (TGF-β) seemed to cause the upregulation of TAGLN. Since TGF-β is released by macrophages, the natural anti-inflammatory response and immune regulation cells of the body, this led them to conclude that these macrophages were being activated in response to Fusobacterium.

“In this study, we demonstrated that the Fusobacterium-TAGLN-endometriosis axis is frequently dysregulated in endometriosis,” said Dr Kondo. “Our data provide a strong and novel rationale for targeting Fusobacterium as a non-hormonal antibiotic-based treatment for endometriosis.”

Clinical trials of antibiotic treatment for human patients are ongoing at the Department of Obstetrics and Gynecology at Nagoya University Hospital.

Source: Nagoya University

Categories : Antibiotics PaediatricsTags :

Antibiotic-resistant Bugs Claim Over 200 000 Infants Globally per Year, Finds Major Study

On By ModernMedia
Photo by Christian Bowen on Unsplash

By Adele Baleta for Spotlight

“The death of a child affects us all. Witnessing the loss of a newborn baby who has sepsis is terribly traumatic, especially so when antibiotics used to treat the child are ineffective,” says neonatologist Professor Sithembiso Velaphi.

“It’s very heavy for a mother to carry her baby, give birth, watch as her newborn gets seriously sick from infection, suffers while being pricked with drips and pumped with drugs to try and save the child – only for her to leave the hospital empty handed. It’s painful,” says Velaphi, who is the head of Paediatrics at Chris Hani Baragwanath Academic Hospital in Johannesburg.

Professor Sithembiso Velaphi, head of Paediatrics at Chris Hani Baragwanath Academic Hospital in Johannesburg. PHOTO: Kim Cloete for GARDP

Nurses and doctors feel sad and crushed too when they cannot save a newborn’s life because of antibiotic resistance to bacterial infections. “We need to prioritise the development of antibiotics to treat these babies. For us, success is seeing a baby get better and going home,” he says.

Velaphi was speaking to Spotlight about a landmark global observational study published in the journal  Plos Medicine (June 8) which found that many neonates (within 60 days of birth) get life-threatening bloodstream infections, or sepsis, and are dying because the antibiotics used to treat them are not effective. This is the first global overview to assess the extent of the problem. Spotlight last year reported on interim findings from the same study.

The study, called NeoOBS, led by the Global Antibiotic Research and Development Partnership (GARDP) recruited more than 3 200 babies in 19 hospitals in 11 countries – South Africa, Kenya, Uganda, Thailand, Vietnam, India, Greece, Italy, Bangladesh, Brazil, and China.

The researchers reported great variability in mortality rates of babies with sepsis across the 19 hospitals, ranging from 1% to 27.3%.

Sepsis affects up to 3 million babies a year globally. Importantly, the study’s 80 authors estimate that 214 000 newborns die every year from sepsis that has become antibiotic resistant, and this is mostly in low- to middle-income countries (LMIC). Many survivors suffer from neurodevelopmental problems. Treatment options have become increasingly limited as about 40% of infections are reported to be resistant to standard antibiotic treatments.

Many infections acquired in hospital

Almost 60% of infection-related deaths were due to infections acquired at the 19 hospitals under review. Klebsiella pneumoniae was the most common pathogen isolated.

Of the 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared to only six trials recruiting neonates, researchers say.

New antibiotic treatments are urgently needed, especially in LMICs where almost 1 in 5 babies with sepsis died. Premature babies are particularly vulnerable to infections because of their immature immune systems.

More than 200 different antibiotic combinations were used by hospitals included in the NeoOBS study, with repeated switching of antibiotics due to high resistance to treatments. This showed a pattern of limited use of the World Health Organization’s recommended first-line treatment.

Many doctors have had to opt for last-line antibiotics such as carbapenems because of the high degree of antibiotic resistance in their units or because they were the only treatment available.

Outlining various challenges, Velaphi says the risk of infections is very high in hospital settings where there is often a shortage of nurses, beds, and space between patients making it difficult to stop the spread of infection.  Chris Hani Baragwanath has an 18-bed Intensive Care Unit (ICU) that is almost always full and when the situation is desperate there is a spillover of patients into the high-care area. The pressure on the facility is huge and the influx of people from other countries has made it even more challenging, he says.

“There is a major problem of infection control, specifically related to high-risk babies – sick babies with complications who need interventions such as drips and even surgery. This increases the chances of infection. “More than 70% of all deaths ascribed to prematurity at the hospital were due to hospital-acquired multi-drug resistant infections,” he says.

The NeoSep 1 trial

The authors say the NeoOBS study has yielded “a wealth of high-quality data” needed to design trials for much-needed and appropriate treatments for sepsis in babies. Encouragingly, and building on from the observational study the first global hospital-based neonatal sepsis trial called NeoSep 1 is underway in Kenya and South Africa. Chris Hani Baragwanath is taking part in the trial together with Tygerberg Hospital in Cape Town and KEMRI, Kilifi County Hospital in Kenya. It’s planned that the trial will be expanded to other countries and regions in 2024 with the aim of recruiting 3 000 newborns.

A Personalised Randomised Controlled Trial (PRACTical) design will be used. According to GARDP and partners the design is a new way of comparing antibiotic treatments for neonatal sepsis. In addition, doctors can choose treatment regimens that are likely to work well for newborns in their specific hospital settings.

Researchers say the development pipeline for new antibiotic treatments is limited and the lack of a universal, effective standard of care creates huge challenges in conducting research to tackle neonatal sepsis. The PRACTical design has been specifically developed to address these challenges in important public health emergencies such as neonatal sepsis. (You can read more about how this type of trial works in the Lancet.)

The trial will compare the safety and efficacy of three new combinations of older antibiotics (fosfomycin-amikacin, flomoxef-amikacin, and flomoxef-fosfomycin) against the current standard of care. It will also assess and validate the doses of two antibiotics (fosfomycin and flomoxef) for use in newborns. The trial will also evaluate new combinations of generic antibiotics.

“We are hoping the trial will provide robust evidence that the antibiotic combinations are safe and effective and that this will lead to a change in both WHO and local treatment guidelines,” says Christina Obiero, Principal Investigator for the NeoSep1 trial for KEMRI at Kilifi County Hospital in a statement.

Severity and recovery scores

Principal Investigator for the NeoSep1 trial at Tygerberg Hospital, Professor Adrie Bekker tells Spotlight, “We have so few antibiotics that work effectively against these very sick babies. And even for those that we have, we are still not 100% sure how to dose these drugs to get accurate concentrations in the blood and to also make sure that the outcomes in these babies are as good as can be. This trial will help give us confidence that we are delivering more effective treatment.”

Bekker who is also Professor in the Division of Neonatology, Department of Paediatrics and Child Health at Stellenbosch University says a positive outcome of the NeoOBS study is the development of two important tools which can be used in ICUs globally.

The first is the NeoSep Severity Score which is a compilation of common symptoms and signs that can occur in a baby with clinical sepsis. The second is the NeoSep Recovery Score, which will assist clinicians in deciding if they can stop antibiotics earlier.

The tools are expected to help prevent the often excessive and inappropriate use of antibiotics for over too long a period, which compounds the problem of antibiotic resistance globally.

Diagnosis in older age groups, children, and adults, is generally easier.

“It’s sometimes difficult for a clinician to know whether a baby actually has neonatal sepsis because it can present very subtly and not always with the same symptoms,” Bekker explains.

The blood culture is the gold standard for diagnosing neonatal sepsis, but Bekker says only around 10% of blood cultures will grow an organism even if the baby has sepsis, making it very difficult to get a diagnosis. “And because it’s such an aggressive disease and a baby can die very quickly from it, clinicians tend to rather over-treat than under-treat. That is correct but, just as important as it is to start antibiotics quickly, it’s important to stop them if they are not necessary. The NeoSeps Severity score will help doctors identify babies that are at very high risk from sepsis and those that would need treatment immediately.

Velaphi says a major challenge is the time it takes for an outcome of the blood culture and the general protocol is to start antibiotics immediately. Waiting between 24 to 48 hours can be too late for a child who may have sepsis and could die. On the other hand, antibiotics may be given to children who do not have sepsis and this adds to the frequency of antibiotic resistance. “So, you are damned if you do and you are damned if you don’t.”

He says we need new diagnostic tests that are reliable and that have a high degree of sensitivity and specificity. “We need antibiotics that work to reduce mortality,” he adds.

Republished from Spotlight under a Creative Commons NoDerivatives 4.0 Licence.

Source: Spotlight