Research in animal models published in Nature Communications shows that an approved antibiotic regimen for multidrug-resistant (MDR) tuberculosis (TB) may not work for TB meningitis. Limited human studies also provide evidence that a new combination of drugs is needed to develop effective treatments for TB meningitis due to MDR strains.
In the study from Johns Hopkins Children’s Center, the investigators showed that the Food and Drug Administration (FDA)-approved regimen of three antibiotics – bedaquiline, pretomanid and linezolid (BPaL) – used for treating TB of the lungs due to MDR strains, is not effective in treating TB meningitis because bedaquiline and linezolid struggle to cross the blood-brain barrier.
Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, is a global public health threat. About 1%–2% of TB cases progress into TB meningitis, the worst form of TB, which leads to an infection in the brain that causes increased fluid and inflammation.
“Most treatments for TB meningitis are based on studies of treatments for pulmonary TB, so we don’t have good treatment options for TB meningitis,” explains Sanjay Jain, M.D., senior author of the study and director of the Johns Hopkins Medicine Center for Infection and Inflammation Imaging Research.
In 2019, the FDA approved the BPaL regimen to treat MDR strains of TB, specifically those that lead to pulmonary TB. However, there are limited data on how well these antibiotics cross the blood-brain barrier.
In an effort to learn more, the research team synthesised a chemically identical and imageable version of the antibiotic pretomanid. They conducted experiments in mouse and rabbit models of TB meningitis using positron emission tomography (PET) imaging to noninvasively measure pretomanid penetration into the central nervous system as well as using direct drug measurements in mouse brains. In both models, researchers say PET imaging demonstrated excellent penetration of pretomanid into the brain or the central nervous system. However, the pretomanid levels in the cerebrospinal fluid (CSF) that bathes the brain were many times lower than in the brains of mice.
“When we have measured drug concentrations in the spinal fluid, we have found that many times they have no relation to what’s happening in the brain,” says Elizabeth Tucker, MD, a study first author and an assistant professor of anaesthesiology and critical care medicine. “This finding will change how we interpret data from clinical trials and, ultimately, treat infections in the brain.”
Next, researchers measured the efficacy of the BPaL regimen compared with the standard TB treatment for drug-susceptible strains, a combination of the antibiotics rifampin, isoniazid and pyrazinamide. Results showed that the antibacterial effect in the brain using the BPaL regimen in the mouse model was about 50 times lower than the standard TB regimen after six weeks of treatment, likely due to restricted penetration of bedaquiline and linezolid into the brain. The bottom line, says Jain, is that the “regimen that we think works really well for MDR-TB in the lung does not work in the brain.”
In another experiment involving healthy participants, three male and three female aged 20–53 years, first-in-human PET imaging was used to show pretomanid distribution to major organs, according to researchers.
Similar to the work with mice, this study revealed high penetration of pretomanid into the brain or central nervous system with CSF levels lower than those seen in the brain. “Our findings suggest pretomanid-based regimens, in combination with other antibiotics active against MDR strains with high brain penetration, should be tested for treating MDR-TB meningitis,” says study author Xueyi Chen, MD, a paediatric infectious diseases fellow, who is now studying combinations of such therapies.
Limitations included the small quantities of the imageable version of pretomanid per subject (micrograms) used. However, current evidence suggests that studies with small quantities of a drug are a reliable predictor of the drug biodistribution.
Scanning Electron Micrograph of Pseudomonas aeruginosa. Credit: CDC/Janice Carr
Using a modified version of the bacterium Mycoplasma pneumoniae, researchers have designed the first ‘living medicine’ to treat lung infections. Their method is reported in the journal Nature Biotechnology. The treatment targets Pseudomonas aeruginosa, a common source of hospital-acquired infections and which is naturally multi-drug resistant.
Researchers removed the M. pneumoniae‘s ability to cause disease and repurposing it to attack P. aeruginosa instead. The modified bacterium is used in combination with low doses of antibiotics that would otherwise not work on their own.
Researchers tested the efficacy of the treatment in mice, finding that it significantly reduced lung infections. The ‘living medicine’ doubled mouse survival rate compared to not using any treatment. Administering a single, high dose of the treatment showed no signs of toxicity in the lungs. Once the treatment had finished its course, the innate immune system cleared the modified bacteria in a period of four days.
P. aeruginosa infections are difficult to treat because the bacteria lives in communities that form biofilms. Biofilms can attach themselves to various surfaces in the body, forming impenetrable structures that escape the reach of antibiotics.
P. aeruginosa biofilms can grow on the surface of endotracheal tubes used by critically-ill patients who require mechanical ventilators to breathe. This causes ventilator-associated pneumonia (VAP), a condition affecting 9–27% of patients who require intubation. The incidence exceeds 50% for patients intubated because of severe COVID. VAP can extend the duration in intensive care unit for up to 13 days and kills 9–13% of patients.
The authors of the study engineered M. pneumoniae to dissolve biofilms by equipping it with the ability to produce various molecules including pyocins, toxins naturally produced by bacteria to kill or inhibit the growth of Pseudomonas bacterial strains. To test its efficacy, they collected P. aeruginosa biofilms from the endotracheal tubes of patients in intensive care units. They found the treatment penetrated the barrier and successfully dissolved the biofilms.
“We have developed a battering ram that lays siege to antibiotic-resistant bacteria. The treatment punches holes in their cell walls, providing crucial entry points for antibiotics to invade and clear infections at their source. We believe this is a promising new strategy to address the leading cause of mortality in hospitals,” says Dr María Lluch, co-corresponding author of the study.
With the aim of using the ‘living medicine’ to treat VAP, the researchers will carry out further tests before reaching the clinical trial phase. The treatment is expected to be administered using a nebuliser.
M. pneumoniae is one of the smallest known species of bacteria. Dr Luis Serrano first had the idea to modify the bacteria and use it as a ‘living medicine’ two decades ago. Dr Serrano is a specialist in synthetic biology, a field that involves repurposing organisms and engineering them to have new, useful abilities. With just 684 genes and no cell wall, the relative simplicity of M. pneumoniae makes it ideal for engineering biology for specific applications.
One of the advantages of using M. pneumoniae to treat respiratory diseases is that it is naturally adapted to lung tissue. After administering the modified bacterium, it travels straight to the source of a respiratory infection, where it sets up shop like a temporary factory and produces a variety of therapeutic molecules.
By showing that M. pneumoniae can tackle infections in the lung, the study opens the door for researchers creating new strains of the bacteria to tackle other types of respiratory diseases such as lung cancer or asthma. “The bacterium can be modified with a variety of different payloads – whether these are cytokines, nanobodies or defensins. The aim is to diversify the modified bacterium’s arsenal and unlock its full potential in treating a variety of complex diseases,” says ICREA Research Professor Dr. Luis Serrano.
In addition to designing the ‘living medicine’, Dr. Serrano’s research team are also using their expertise in synthetic biology to design new proteins that can be delivered by M. pneumoniae. The team are using these proteins to target inflammation caused by P. aeruginosa infections.
Though inflammation is the body’s natural response to an infection, excessive or prolonged inflammation can damage lung tissue. The inflammatory response is orchestrated by the immune system, which release mediator proteins such as cytokines. One type of cytokine, IL-10, has well-known anti-inflammatory properties and is of growing therapeutic interest.
Dr Serrano’s research group used protein-design software to engineer new versions of IL-10 purposefully optimised to treat inflammation. The cytokines were designed to be created more efficiently and to have higher affinity, meaning less cytokines are needed to have the same effect.
The researchers engineered strains of M. pneumoniae that expressed the new cytokines and tested its efficacy in the lungs of mice with acute P. aeruginosa infections. They found that engineered versions of IL-10 were significantly more effective at reducing inflammation compared to the wild type IL-10 cytokine.
According to Dr Ariadna Montero Blay, co-corresponding author of that study, “live biotherapeutics such as M. pneumoniae provide ideal vehicles to help overcome the traditional limitations of cytokines and unlock their huge potential in treating a variety of human diseases. Engineering cytokines as therapeutic molecules was critical to tackle inflammation. Other lung diseases such as asthma or pulmonary fibrosis could also stand to benefit from this approach.”
A clinic trial published in The Lancet Microbe found that a promising approach to that ‘decolonised’ Staphylococcus aureus by using a probiotic instead of antibiotics. The probiotic Bacillus subtilis markedly reduced S. aureus colonisation in trial participants without harming the gut microbiota.
Staphylococcus aureus are colonising bacteria that often live in the nose, on the body and in the gut but if the skin barrier is broken or the immune system weakened, they can cause serious disease.
Preventing S. aureus infections by “decolonising” the body has gained increased attention as antibiotic resistance has spread, but large amounts of antibiotics are needed, damaging other microbiota and promoting more antibiotic resistance. So far, it appears that only nasal S. aureus colonisation can be targeted with topical antibiotics without doing too much harm, but bacteria quickly can recolonise in the nose from the gut.
Probiotics may be a way to complement or replace antibiotics, of which Bacillus is especially promising because it is administered orally as spores that can survive passage through the stomach and then temporarily grow in the intestine. In prior studies, Dr Otto’s group discovered an S. aureus sensing system needed for S. aureus to grow in the gut. They also found that fengycins, Bacillus lipopeptides that are part peptide and part lipid, stop the S. aureus sensing system from functioning, eliminating the bacteria.
In the clinical trial, conducted in Thailand, the research team tested whether this approach works in people. They enrolled 115 healthy participants, all of whom were colonised naturally with S. aureus. A group of 55 people received B. subtilis probiotic once daily for four weeks; a control group of 60 people received a placebo. After four weeks researchers evaluated the participants’ S. aureus levels in the gut and nose. They found no changes in the control group, but in the probiotic group they observed a 96.8% S. aureus reduction in the stool and a 65.4% reduction in the nose.
“The probiotic we use does not ‘kill’ S. aureus, but it specifically and strongly diminishes its capacity to colonise,” Dr. Otto said. “We think we can target the ‘bad’ S. aureus while leaving the composition of the microbiota intact.”
The researchers also found that levels of S. aureus bacteria in the gut far exceeded S. aureus in the nose, which for decades has been the focus of staph infection prevention research. This finding adds to the potential importance of S. aureus reduction in the gut.
“Intestinal S. aureus colonisation has been evident for decades, but mostly neglected by researchers because it was not a viable target for antibiotics,” Dr Otto said. “Our results suggest a way to safely and effectively reduce the total number of colonising S. aureus and also call for a categorical rethinking of what we learned in textbooks about S. aureus colonisation of the human body.”
The researchers plan to continue their work by testing the probiotic in a larger and longer trial. They note that their approach probably does not work as quickly as antibiotics, but can be used for long periods because the probiotic as used in the clinical trial does not cause harm.
In Asia, researchers found that antibiotic residues in wastewater and wastewater treatment plants risk contributing to antibiotic resistance, and the drinking water may pose a threat to human health. Published in The Lancet Planetary Health, their comprehensive analysis also determined the relative contribution of various sources of antibiotic contamination in waterways, such as hospitals, municipals, livestock, and pharmaceutical manufacturing.
“Our results can help decision-makers to target risk reduction measures against environmental residues of priority antibiotics and in high-risk sites, to protect human health and the environment,” says first author Nada Hanna, researcher at the Department of Global Public Health at Karolinska Institutet. “Allocating these resources efficiently is especially vital for resource-poor countries that produce large amounts of antibiotics.”
Antibiotics can enter the environment during their production, consumption and disposal. Antibiotic residues in the environment, such as in wastewater and drinking water, can contribute to the emergence and spread of resistance.
Major antibiotics producers and users
The researchers looked for levels of antibiotic residues that are likely to contribute to antibiotic resistance from different aquatic sources in the Western Pacific Region (WPR) and the South-East Asia Region (SEAR), regions as defined by the World Health Organization. China and India, among the world’s largest producers and consumers of antibiotics, fall within these regions.
To find the data, researchers made a systematic review of the literature published between 2006 and 2019, including 218 relevant reports from the WPR and 22 from the SEAR. They also employed a method called Probabilistic Environmental Hazard Assessment to determine where the concentration of antibiotics is high enough to likely contribute to antibiotic resistance.
Ninety-two antibiotics were detected in the WPR, and forty five in the SEAR. Antibiotic concentrations exceeding the level considered safe for resistance development (Predicted No Effect Concentrations, PNECs) were observed in wastewater, influents and effluents of wastewater treatment plants and in receiving aquatic environments. Wastewater and influent of wastewater treatment plants had the highest risks. The relative impact of various contributors, such as hospital, municipal, livestock, and pharmaceutical manufacturing was also determined.
Potential threat to human health
In receiving aquatic environments, the highest likelihood of levels exceeding the threshold considered safe for resistance development was observed for the antibiotic ciprofloxacin in drinking water in China and the WPR.
“Antibiotic residues in wastewater and wastewater treatment plants may serve as hot spots for the development of antibiotic resistance in these regions and pose a potential threat to human health through exposure to different sources of water, including drinking water,” says Nada Hanna.
Limitations to be considered when interpreting the results are the lack of data on the environmental occurrence of antibiotics from many of the countries in the regions and the fact that only studies written in English were included.
Antibiotics play a vital role in the management of bacterial infections, reducing morbidity, and preventing mortality. A 2011 report from the United Kingdom estimated that they have increased life expectancy by 20 years. However, the extensive use of antibiotics has resulted in drug resistance that threatens to reverse their life-saving power and if the situation is not reversed, it has been estimated that by 2050, 10 million people will die annually of drug-resistant infections.
Such estimates of future deaths are obviously uncertain, but there is strong evidence the problem is already very serious. A major study published earlier this year in the Lancet estimated that globally around 1.27 million deaths in 2019 were directly due to antibiotic resistance. The study identified sub-Saharan Africa as the hardest-hit region.
What is AMR?
Sham Moodley, a community pharmacist from Durban and the vice chairperson of the Independent Community Pharmacy Association (ICPA) explains that antimicrobial resistance (AMR) is the ability of microorganisms (bacteria, viruses, fungi, and protozoa) to withstand treatment with antimicrobial drugs. “It is vitally important as it directly impacts our ability to treat and cure common infectious diseases, including pneumonia, urinary tract infections, gonorrhoea and tuberculosis,” he says.
According to Professor Olga Perovic, Principal Pathologist at the National Institute of Communicable Diseases’ Centre for Healthcare-associated Infections, Antimicrobial Resistance and Mycoses (CHARM), there are six factors fuelling the AMR crisis. These are over-prescribing and dispensing of antibiotics by health workers, patients not finishing their full treatment course of antibiotics, poor infection control in hospitals and clinics, lack of hygiene and poor sanitisation in the community, lack of new antibiotics being developed, and the overuse of antibiotics in livestock and fish farming.
Under overuse, she stresses the misuse of antibiotics to treat upper respiratory tract infections, which are typically viral rather than bacterial. Antibiotics are powerless against viruses. Another driver of inappropriate or overprescribing of antibiotics, she says, may be the lack of testing of specimens for the presence of bacteria and their susceptibility to treatment.
How can we prevent AMR?
Dr Marc Mendelson, Professor of Infectious Diseases and Head of the Division of Infectious Diseases and HIV Medicine at Groote Schuur Hospital, the University of Cape Town as well as chairperson of the Ministerial Advisory Committee on Antimicrobial Resistance, says reducing the use of antibiotics is about preventing the need for prescription in the first place. (Mendelson’s recent SAMJ article provides excellent further reading on AMR in South Africa.)
“So, reducing the burden of infections through the provision of clean water and safe sanitation (reduces diarrhoeal diseases) and vaccination programmes (reduces diarrhoea and pneumonia for instance),” he says. “Education and awareness raising of the public and (sadly) healthcare professionals as to the correct use of antibiotics is also critical.”
Broadly speaking, all the experts we interviewed agreed that we should use far fewer antibiotics and only use them when they are absolutely necessary. But actually making this happen is surprisingly complex.
Part of the complexity, for example, is that resistance profiles and disease profiles are different in different places. Geraldine Turner, a pharmacist at Knysna Hospital in the Western Cape, says there is a need for guidelines tailored to the South African context or linked to the local epidemiology. This, she says, can play an important role in determining the correct antibiotics to be used.
It is also not just an issue of what antibiotics are prescribed for humans.
“A big driver of antimicrobial resistance is overuse in agriculture and collaboration with stakeholders in this regard is required,” says Turner. She says we need policies that facilitate improved integration among environmental, animal, and human sector interventions.
Moodley agrees that a multidisciplinary, One Health approach is needed at every level of care and in both human and animal health sectors.
“It is important we reinforce the principle that antimicrobial medicines for human use are only supplied on the authority of a healthcare professional and that antimicrobial medicines for either human or animal use are only supplied in accordance with country legislation and regulations,” he says.
The role of stewardship programmes
One response to the AMR crisis is antimicrobial stewardship programmes or ASPs. Moodley describes ASPs as a systematic approach used “to optimise appropriate use of all antimicrobials to improve patient outcome and limit the emergence of resistant pathogens whilst ensuring patient safety.”
Perovic says, “In healthcare institutions, resistant bacteria can spread easily within and from patient to patient. That is why there are guidelines, which we call ASPs in the medical and veterinary fields, on how and when antibiotics are prescribed as well as how to implement infection prevention and control measures, particularly for patients with health risks such as diabetes, high blood pressure, and cancer.”
“In hospitals,” explains Mendelson, “ASPs will consist of a governance body such as an AS Committee that directs a work programme of stewardship, often with AS teams as the implementers of policy. AS teams can involve anything from single pharmacists or physicians, through one to two dedicated individuals, through to all-singing all-dancing multi-disciplinary teams in academic teaching hospitals, comprising infectious diseases specialists, microbiologists, pharmacists, [and] infection prevention and control nurses.”
ASPs are not only important at institutional levels, adds Moodley, but imperative for every individual prescriber/practitioner to implement to reduce AMR in our population.
Critical role for pharmacists
Mendelson stresses that pharmacists are integral to antibiotic stewardship in South Africa and globally. “Community pharmacists give advice to patients seeking symptomatic relief and reduce doctors’ visits, which can result in antibiotic prescriptions when not needed,” he says. In hospitals, dispensing pharmacists help optimise the antibiotics prescribed to patients by checking indication for the antibiotic, dose, dosing frequency, and duration. “Some hospitals have pharmacists on the wards, again, checking and helping to optimise the use of antibiotics,” he says.
“Pharmacists play an important role in recommending symptomatic treatments for non-specific symptoms and particularly, the common cold, which is a major cause of inappropriate antibiotic prescribing, requiring simple paracetamol with or without decongestants. Unfortunately, a recent pilot study suggests that a small number of community pharmacies are dispensing antibiotics without a prescription, which is not allowed in South Africa,” says Mendelson.
Turner concurs that pharmacists play a crucial role in ensuring that the correct antibiotics are used appropriately and only if indicated. She says pharmacistsare also in a good position to counsel and advise patients on the correct use of antibiotics.
Strategy framework
The key policy document setting out South Africa’s response to AMR is the South Africa Antimicrobial Resistance Strategy Framework of 2018-2024. The framework outlines nine strategic objectives – they include improving the appropriate use of diagnostic investigations to identify pathogens, guiding patient and animal management and ensuring good quality laboratory, enhancing infection prevention and control, promoting appropriate use of antimicrobials in humans and animals as well as legislative and policy reform for health systems strengthening.
Mendelson is positive about what has been achieved so far. “There have been major improvements to the surveillance and reporting of antibiotic resistance and antibiotic use in humans and animals, development of a greater one health (human, animal, and environmental health) response. There was a formation of national training centres for antibiotic stewardship and empowerment of under-resourced provinces to train and develop Antimicrobial Stewardship programmes and there have been improvements in governance and delivery of infection prevention and control measures in hospitals and development of education programmes for healthcare workers in South Africa,” he says.
But Mendelson also says that challenges remain in promoting prescribing behaviour change amongst the health workforce in SA and the expectations and social position that antibiotics hold in society.
As with several other health policies, there are questions on whether the plan has been backed up with funding.
“The national strategic framework remains largely unfunded (shared by most low- and middle-income countries) but this does hamper progress in developing programmes of interventions,” says Mendelson. “In food production, reducing [the] use of antibiotics is an important goal but will require investment in reducing drivers of infection in the animals that produce food. Legislation to bring all antibiotic prescribing in food production under veterinarian control will be an important intervention,” says Mendelson.
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.
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.”
A Left upper extremity with multiple large erythematous, fluctuant to nodular lesions ultimately diagnosed as disseminated cutaneous Mycobacterium chelonae infection. B Images of the left upper extremity lesions prior to (Dec 2020) and following (August 2021) addition of bacteriophage therapy. C PET/CT prior to (March 2021) and following (August 2021) addition of bacteriophage therapy. Credit: Nature
Reporting in the journal Nature, clinicians describe the use of a bacteriophage to treat a flesh-eating infection by an antibiotic-resistant bacteria, with excellent clinical response. Bacteriophages, from the Greek ‘bacteria eater’, are viruses which target bacteria.
Bacteriophage (or more simply ‘phage’) therapy is being explored as a solution to the growing threat of antimicrobial resistance. Despite the exotic-sounding name, bacteriophage therapy is nothing new – in fact, its first application in 1919 predates the discovery of penicillin in 1929. However, their use has not been accompanied with robust research, meaning that there is still uncertainty regarding their use in modern medicine.
The authors report treating Mr. M, a 56 year-old man with disseminated cutaneous Mycobacterium chelonae infection with a single bacteriophage in conjunction with antibiotic and surgical management. He had previously received extensive antimicrobial courses as well as surgical debridement, but the bacterial infection persisted.
M. chelonae is a rapidly growing nontuberculous mycobacterium, ubiquitous in the environment and is known to have antimicrobial resistance. In rare cases, it causes infections in immunocompromised patients. To treat the infection, the researchers used a bacteriophage called Muddy, which had been isolated from a South African eggplant.
After the phage therapy skin started, lesions significantly improved both on examination and in PET/CT scans. Furthermore, two biopsies at two and five months post-treatment revealed no evidence of granulomas or AFB on histopathology and tissue cultures have remained negative. The patient has had no adverse events from the phage therapy and administered the intravenous therapy at home for more than six months.
Bacteriophage therapy is hampered by the development of phage resistance, which can potentially be countered using an appropriately-designed phage cocktail. In this case, the researchers were limited to Muddy, since no other phages tested were highly active against the patient’s strain of M. chelonae. Although resistance to Muddy is likely to occur, it was not detected in vitro, consistent with the infrequency of phage resistance in M. abscessus isolates. Resistance in vivo leading to loss of treatment efficacy was also not observed, which together suggest that phage resistance of NTM pathogens may not be the impediment encountered with other pathogens.
A second barrier to the successful treatment of bacterial infections with phage therapy is the complex interaction between the host immune system and the bacteriophage. In this case, the patient maintained stably improved disease and negative microbiologic and histopathologic studies despite a neutralising antibody response to the phage.
The authors suggested that the phage quickly reduced the burden of infection, allowing the ongoing antimicrobial therapy to have an effect. The phage also became self-replicating at the infection site – administration after the onset of neutralising antibodies therefore became unnecessary.
There are still significant challenges to phage therapy becoming widespread. The mains ones are 1) doctors need to know the bacterial strain behind the infection and 2) they need to have several phages on hand that specifically target that strain. Compounding the latter problem, most pharmaceutical companies are hesitant to focus on developing phage therapies. Since phage therapy is over 100 years old, it is difficult to patent and generate revenue to justify the initial development costs.
Scanning Electron Micrograph of Pseudomonas aeruginosa. Credit: CDC/Janice Carr.
A study from Australia’s scientific organisation CSIRO has revealed that antimicrobial resistant (AMR) bacteria in urinary tract infections are more lethal, especially Enterobacteriaceae. The findings are published online in Open Forum Infectious Diseases.
Antimicrobial resistance (AMR) bacteria can be passed between humans: through hospital transmission and community transmission. While hospital acquired resistance is well researched, there are few studies focusing on the burden of community transmission.
To address this, the study analysed data from 21 268 patients across 134 Queensland hospitals who acquired their infections in the community. The researchers found that patients were almost two and a half (2.43) times more likely to die from community acquired drug-resistant UTIs caused by Pseudomonas aeruginosa and more than three (3.28) times more likely to die from community acquired drug-resistant blood stream infections caused by Enterobacteriaceae than those with drug-sensitive infections. The high prevalence of UTIs make them a major contributor to antibiotic use, said CSIRO research scientist, Dr Teresa Wozniak.
“Our study found patients who contracted drug-resistant UTIs in the community were more than twice as likely to die from the infection in hospital than those without resistant bacteria,” Dr Wozniak said. “Without effective antibiotics, many standard medical procedures and life-saving surgeries will becoming increasingly life-threatening. “Tracking the burden of drug-resistant infections in the community is critical to understanding how far antimicrobial resistance is spreading and how best to mitigate it.”
The study’s findings will provide further guidance for managing AMR in the community, such as developing AMR stewardship programs that draw on data from the population being treated.
CEO of CSIRO’s Australian e-Health Research Centre, Dr David Hansen, said the magnitude of the AMR problem needs to be understood to mitigate it. “Tracking community resistance is difficult because it involves not just one pathogen or disease but multiple strains of bacteria,” Dr Hansen said. “Until now we haven’t been using the best data to support decision making in our fight against AMR. Data on community acquired resistance is an important contribution to solving the puzzle. “Digital health has an important role in using big data sets to describe patterns of disease and drive important population health outcomes.”
The spectacular structure of the protective armour of superbug C. difficile has been revealed for the first time showing the close-knit yet flexible outer layer – like chain mail. This assembly prevents molecules getting in and provides a new target for future treatments, according to the scientists at Newcastle, Sheffield and Glasgow Universities who have uncovered it. Credit: Newcastle University, UK
The spectacular structure of the protective armour of C. difficile has been revealed for the first time showing the close-knit yet flexible outer layer – like a mediaeval knight’s chain mail.
This tight arrangement keeps molecules from getting in and provides a new target for future treatments, according to the scientists who have uncovered it.
Published in Nature Communications, the team of scientists outlined the structure of the main protein, SlpA, that forms the links of the chain mail and how they link up to form a pattern and create this flexible armour. One of the many ways that Clostridioides difficile has to protect itself from antibiotics is a special layer that covers the cell of the whole bacteria – the surface layer or S-layer. This flexible armour protects against the entry of drugs or molecules released by our immune system to fight bacteria.
Using a combination of X-ray and electron crystallography, the team determined the structure of the proteins and their arrangement.
Corresponding author and lead researcher Dr Paula Salgado said: “I started working on this structure more than 10 years ago, it’s been a long, hard journey but we got some really exciting results! Surprisingly, we found that the protein forming the outer layer, SlpA, packs very tightly, with very narrow openings that allow very few molecules to enter the cells. S-layer from other bacteria studied so far tend to have wider gaps, allowing bigger molecules to penetrate. This may explain the success of C.diff at defending itself against the antibiotics and immune system molecules sent to attack it.
“Excitingly, it also opens the possibility of developing drugs that target the interactions that make up the chain mail. If we break these, we can create holes that allow drugs and immune system molecules to enter the cell and kill it.”
Antimicrobial resistance (AMR), a growing problem, was declared by WHO as one of the top 10 global public health threats facing humanity. One of the many bacteria that have evolved resistance to antibiotics, C. diff infects the human gut and is resistant to all but three current drugs. Antibiotics only compound the problem, as the good bacteria in the gut are killed alongside those causing an infection and, as C. diff is resistant, it can grow and cause diseases ranging from diarrhoea to death due to massive lesions in the gut. Since the only way to treat C.diff is to take antibiotics, it creates a vicious cycle of recurrent infections.
This knowledge could lead to the development of C. diff specific drugs that break the protective layer, creating holes to allow drug molecules to penetrate and kill the cell.
Dr Rob Fagan, who helped carry out the electron crystallography work, said: “We’re now looking at how our findings could be used to find new ways to treat C. diff infections such as using bacteriophages to attach to and kill C. diff cells – a promising potential alternative to traditional antibiotic drugs.”
