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.
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.
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.”
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.
“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.
Genes that make bacteria resistant to antibiotics are much more widespread in our environment than was previously realised. A new study published in Microbiome shows that bacteria in almost all environments carry resistance genes, with a risk of them spreading and aggravating the problem of bacterial infections that are untreatable with antibiotics.
“We have identified new resistance genes in places where they have remained undetected until now. These genes can constitute an overlooked threat to human health,” says Erik Kristiansson, a professor in the Department of Mathematical Sciences.
According to the World Health Organisation (WHO), antibiotic resistance is one of the greatest threats to global health. When bacteria become resistant to antibiotics, it becomes difficult or impossible to treat illnesses such as pneumonia, wound infections, tuberculosis and urinary tract infections. According to the UN Interagency Coordination Group on Antimicrobial Resistance (IACG) 700,000 people die each year from infections caused by antibiotic-resistant bacteria.
Looking for resistance genes in new environments
The genes that make bacteria resistant have long been studied, but the focus has traditionally been on identifying those resistance genes that are already prevalent in pathogenic bacteria. Instead, in the new study from Sweden, researchers have looked at large quantities of DNA sequences from bacteria to analyse new forms of resistance genes in order to understand how common they are. They have traced the genes in thousands of different bacterial samples from different environments, in and on people, in the soil and from sewage treatment plants. The study analysed 630 billion DNA sequences in total.
“The data requires a great deal of processing before information can be obtained. We have used metagenomics, a methodology, that allows vast quantities of data to be analysed,” says Juan Inda Díaz, a doctoral student in the Department of Mathematical Sciences, and the article’s lead author.
The study showed that the new antibiotic resistance genes are present in bacteria in almost all environments. This also includes human microbiomes and, more alarmingly, pathogenic bacteria, which can lead to more infections that are difficult to treat. The researchers found that resistance genes in bacteria that live on and in humans and in the environment were ten times more abundant than those previously known. And of the resistance genes found in bacteria in the human microbiome, 75% were not previously known at all.
The researchers stress the need for more knowledge about the problem of antibiotic resistance.
“Prior to this study, there was no knowledge whatsoever about the incidence of these new resistance genes. Antibiotic resistance is a complex problem, and our study shows that we need to enhance our understanding of the development of resistance in bacteria and of the resistance genes that could constitute a threat in the future,” says Kristiansson.
Preventing bacterial outbreaks in healthcare
The research team is currently working on integrating the new data into the international EMBARK project (Establishing a Monitoring Baseline for Antibiotic Resistance in Key environments). The project is coordinated by Johan Bengtsson-Palme, an assistant professor in the Department of Life Sciences at Chalmers, and aims to take samples from sources such as wastewater, soil and animals to get an idea of the way in which antibiotic resistance is spreading between humans and the environment.
“It is essential for new forms of resistance genes to be taken into account in risk assessments relating to antibiotic resistance. Using the techniques we have developed enables us to monitor these new resistance genes in the environment, in the hope that we can detect them in pathogenic bacteria before they are able to cause outbreaks in a healthcare setting,” says Bengtsson-Palme.
The method used by the researchers is called metagenomics, and is not new, but so far has not been used to analyse new types of antibiotic resistance genes in such large quantities. Metagenomics is a method of studying the metagenome, which is the complete gene set of all different organisms in a given sample or within a given environment. Using the method, it is also possible to study microorganisms that cannot be grown in a lab.
Methicillin resistant Staphylococcus aureus (MRSA) bacteria, the bane of hospital infection control strategies. Image by CDC on Unsplash.
Governments around the world must do more to tackle the growing threat of antimicrobial-resistant infections, new research suggests – with South Africa falling quite short in the rankings.
The review, published in The Lancet Infectious Diseases, assessed national action plans developed by more than 100 countries to tackle the threat from antimicrobial resistance (AMR). It comprehensively graded international AMR efforts and national action plans and generate comparable quantitative results across countries and regions.
National action plans focus on designing policies to curb AMR and devising tools to implement the policies – but they do not adequately factor in monitoring and evaluation.
The new research, carried out by experts at the universities of Leeds, Edinburgh and Hamburg, is the first large-scale analysis of these plans. They were designed after encouragement from the World Health Organisation, which has declared AMR one of the top 10 public health threats facing humanity.
Lead author Jay Patel, undergraduate dental student in the University of Leeds’ School of Dentistry, said: “Our analysis showed that countries were highly focused on designing AMR policies, and thinking about what tools would be required to implement those, but they generally did not consider how they would monitor and evaluate the impact of those efforts.
“This suggests that the international response may be inadequate to meet the scale and severity of AMR. This is particularly concerning in low and middle-income countries, where action plan activities often lack sustainable funding – relying instead on funds from foreign donors and philanthropies.
“The available evidence also suggests that simply developing a national action plan may not necessarily mean a country is more prepared to respond to the threat of AMR.
“Our study shows that the global response to AMR, and preparedness for the predicted challenges of AMR, require improvement in all locations around the world.”
The research team says governments across the world must strengthen their responses to AMR.
In 2017, the World Health Organization encouraged member states to develop national action plans stipulating how countries would tackle AMR. More than 100 countries have produced action plans, with several being implemented – but there had been no global analysis of the contents of these plans.
The 114 action plans, which were created in 2020-21, were evaluated against 54 elements, such as education, stewardship, and accountability, and each awarded a score out of 100. A mean score out of 100 for each country’s plan was then taken from these results.
The findings
At 43 points for AMR governance, South Africa falls far short of the top score of 85, and rather closer to the lowest score of 29. Reproduced from The Lancet. Figure 2b, Patel et al., 2023. (Open Access)
Norway’s response was the highest scoring with 85, followed by the USA with 84 and the UK with 83. The lowest scoring countries were Ukraine and Sierra Leone with 29 points each, and Barbados and Micronesia with 28 points. With 43 points, South Africa trailed behind Brazil, Namibia, Rwanda and Egypt – and received 0 for research and development as well as the effectiveness of its monitoring and evaluation.
The study found that across all plans, there was a greater focus on policy design and implementation tools, but efforts to monitor and evaluate activities are generally poorly-considered.
Of all areas evaluated, accountability and feedback mechanisms were the joint-lowest scoring, followed by education.
Training and professional education across human health, veterinary, and agricultural sectors were insufficient in many countries, with several lacking a sustainable workforce strategy to deliver antimicrobial stewardship policies.
Countries scored well on participation, demonstrating a shared awareness that AMR can only be successfully addressed through engagement with multiple sectors spanning human, animal and environmental health. Infection prevention and control was frequently recognised as a critical objective.
New antibiotics are urgently needed to tackle resistant bacteria. Researchers at the University of Zurich and the company Spexis have now modified the chemical structure of naturally occurring peptides to develop antimicrobial molecules that bind to novel targets in the bacteria’s metabolism.
In a study recently published in Science Advances, chemist Oliver Zerbe, head of the NMR facilities at the University of Zurich now discusses the development of a highly effective class of antibiotics that fight Gram-negative bacteria in a novel way.
The WHO classifies this group of bacteria as extremely dangerous. The group, whose resistance is particularly high due to their double cell membrane, includes carbapenem-resistant enterobacteria, for example.
Natural peptide chemically optimised
The starting point for the researchers’ study was a naturally occurring peptide called thanatin, which insects use to fend off infections. Thanatin disrupts an important lipopolysaccharide transport bridge between the outer and inner membrane of Gram-negative bacteria, as revealed a few years ago in a study by now retired UZH professor John Robinson. As a result, these metabolites build up inside the cells, and the bacteria perish. However, thanatin isn’t suitable for use as an antibiotic drug, among other things due to its low effectiveness and because bacteria quickly become resistant to it.
The researchers therefore modified the chemical structure of thanatin to enhance the peptide’s characteristics. “To do this, structural analyses were essential,” says Zerbe. His team synthetically assembled the various components of the bacterial transport bridge and then used nuclear magnetic resonance (NMR) to visualize where and how thanatin binds to and disrupts the transport bridge. Using this information, researchers from Spexis AG planned the chemical modifications that were necessary to boost the peptide’s antibacterial effects. Further mutations were made to increase the molecule’s stability, among other things.
Effective, safe and immune to resistance
The synthetic peptides were then tested in mice with bacterial infections – and yielded outstanding results. “The novel antibiotics proved very effective, especially for treating lung infections,” says Zerbe. “They are also highly effective against carbapenem-resistant enterobacteria, where most other antibiotics fail.” In addition, the newly developed peptides aren’t toxic or harmful to the kidneys, and they also proved stable in the blood over a longer period – all of which are properties that are required for gaining approval as a drug. However, further preclinical studies are needed before the first tests in humans can begin.
When choosing the most promising peptides for their study, the researchers made sure that they would also be effective against bacteria that have already developed resistance to thanatin. “We’re confident this will significantly slow down the development of antibacterial resistance,” says Zerbe. “We now have the prospect of a new class of antibiotics becoming available that is also effective against resistant bacteria.”
Researchers have developed a new method that combines palmitoleic acid, gentamicin, and non-invasive ultrasound to help improve drug delivery in chronic wounds that have been infected with Staphylococcus aureus and protected by thick biofilms. Their results were published in Cell Chemical Biology.
Chronic wounds are notoriously challenging to treat because of bacterial infections like S. aureus, which can also be resistant to antibiotics.
To defend itself from the immune system and other threats, S. aureus can band together, creating a slick, slimy biofilm around itself. The biofilm barrier is so thick that neither immune cells nor antibiotics can penetrate through and neutralise the harmful bacteria.
Using a new strategy, researchers at the UNC School of Medicine and the UNC-NC State Joint Department of Biomedical Engineering were able to reduce the challenging MRSA infection in the wounds of diabetic mice by 94%. They were able to completely sterilise the wounds in several of the mice, and the rest had significantly reduced bacterial burden.
“When bacteria are not completely cleared from chronic wounds, it puts the patient at high risk for the infection recurring or of developing a secondary infection,” said senior author Sarah Rowe-Conlon, PhD. “This therapeutic strategy has the potential to improve outcomes and reduce relapse of chronic wound infections in patients. We are excited about the potential of translating this to the clinic, and that’s what we’re exploring right now.”
Biofilms act as a physical barrier to many classes of antibiotics. Virginie Papadopoulou, PhD, was curious to know if non-invasive cavitation-enhanced ultrasound could create enough agitation to form open spaces in the biofilm to facilitate drug-delivery.
Liquid droplets which can be activated by ultrasound, called phase change contrast agent (PCCA), are applied topically to the wound. An ultrasound transducer is focused on the wound and turned on, causing the liquid inside the droplets to expand and turn into microscopic gas-filled microbubbles, when then move rapidly.
The oscillation of these microbubbles agitates the biofilm, both mechanically disrupting it as well as increasing fluid flow. Ultimately, the combination of the biofilm disruption and the increased permeation of the drugs through the biofilm allowed the drugs to come in and kill the bacterial biofilm with very high efficiency.
“Microbubbles and phase change contrast agents act as local amplifiers of ultrasound energy, allowing us to precisely target wounds and areas of the body to achieve therapeutic outcomes not possible with standard ultrasound,” said Dayton. “We hope to be able to use similar technologies to locally delivery chemotherapeutics to stubborn tumours or drive new genetic material into damaged cells as well.”
When the bacterial cells are trapped inside the biofilm, they are left with little access to nutrients and oxygen. To conserve their resources and energy, they transition into a dormant or sleepy state. The bacteria, which are known as persister cells in this state, are extremely resistant to antibiotics.
Researchers chose gentamicin, a topical antibiotic typically ineffective against S. aureus due to widespread antibiotic resistance and poor activity against persister cells. The researchers also introduced a novel antibiotic adjuvant, palmitoleic acid, to their models.
Palmitoleic acid, an unsaturated fatty acid, is a natural product of the human body that has strong antibacterial properties. The fatty acid embeds itself into the membrane of bacterial cells, and the authors discovered that it facilitates the antibiotic’s successful entry into S. aureus cells and is able to kill persistent cells and reverse antibiotic resistance.
Overall, the team is enthusiastic about the new topical, non-invasive approach because it may give scientists and doctors more tools to combat antibiotic resistance and to lessen the serious adverse effects of taking oral antibiotics.
“Systemic antibiotics, such as oral or IV, work very well, but there’s often a large risk associated with them such as toxicity, wiping out gut microflora and C. difficile infection,” said Rowe-Conlon. “Using this system, we are able to make topical drugs work and they can be applied to the site of infection at very high concentrations, without the risks associated with systemic delivery.”
Antibiotics administered before and during surgery should be discontinued immediately after a patient’s incision is closed, according to updated recommendations for preventing surgical site infections.
Experts found no evidence that continuing antibiotics after a patient’s incision has been closed, even if it has drains, prevents surgical site infections. Continuing antibiotics does increase the patient’s risk of C. difficile infection, which causes severe diarrhoea, and antimicrobial resistance.
Strategies to Prevent Surgical Site Infections in Acute Care Hospitals: 2022 Update, published in the journal Infection Control and Healthcare Epidemiology, provides evidence-based strategies for preventing infections for all types of surgeries from top experts from five medical organisations led by the Society for Healthcare Epidemiology of America.
“Many surgical site infections are preventable,” said Michael S. Calderwood, MD, MPH, lead author on the updated guidelines. “Ensuring that healthcare personnel know, utilise, and educate others on evidence-based prevention practices is essential to keeping patients safe during and after their surgeries.”
Surgical site infections are among the most common and costly healthcare-associated infections, occurring in approximately 1% to 3% of patients undergoing inpatient surgery. Patients with surgical site infections are up to 11 times more likely to die compared to patients without such infections.
Other recommendations:
Obtain a full allergy history from patients who self-report penicillin allergy. Many patients with a self-reported penicillin allergy can safely receive cefazolin, a cousin to penicillin, rather than alternate antibiotics that are less effective against surgical infections.
For high-risk procedures, especially orthopaedic and cardiothoracic surgeries, decolonise patients with an anti-staphylococcal agent in the pre-operative setting. Decolonization, which was elevated to an essential practice in this guidance, can reduce post-operative S. aureus infections.
For patients with an elevated blood glucose level, monitor and maintain post-operative blood glucose levels between 110 and 150mg/dL regardless of diabetes status. Higher glucose levels in the post-operative setting are associated with higher infection rates. However, more intensive post-operative blood glucose control targeting levels below 110mg/dL has been associated with a risk of significantly lowering the blood glucose level and increasing the risk of stroke or death.
Use antimicrobial prophylaxis before elective colorectal surgery. Mechanical bowel preparation without use of oral antimicrobial agents has been associated with significantly higher rates of surgical site infection and anastomotic leakage. The use of parenteral and oral antibiotics prior to elective colorectal surgery is now considered an essential practice.
Consider negative-pressure dressings, especially for abdominal surgery or joint arthroplasty patients. Placing negative-pressure dressings over closed incisions was identified as a new option because evidence has shown these dressings reduce surgical site infections in certain patients. Negative pressure dressings are thought to work by reducing fluid accumulation around the wound.
Additional topics covered in the update include specific risk factors for surgical site infections, surveillance methods, infrastructure requirements, use of antiseptic wound lavage, and sterile reprocessing in the operating room, among other guidance.
Hospitals may consider these additional approaches when seeking to further improve outcomes after they have fully implemented the list of essential practices. The document classifies tissue oxygenation, antimicrobial powder, and gentamicin-collagen sponges as unresolved issues according to current evidence.
