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A new type of antibiotic can effectively treat an antibiotic-resistant infection by disarming instead of killing the bacteria that cause it. Researchers report their findings in the October 2 issue of mBio, the online open-access journal of the American Society for Microbiology.
"Traditionally, people have tried to find antibiotics that rapidly kill bacteria. But we found a new class of antibiotics which has no ability to kill Acinetobacter that can still protect, not by killing the bug, but by completely preventing it from turning on host inflammation," says Brad Spellberg of the UCLA Medical Center and David Geffen School of Medicine, a researcher on the study. New drugs are badly needed for treating infections with the bacterium Acinetobacter baumannii, a pathogen that most often strikes hospital patients and immune- compromised individuals through open wounds, breathing tubes, or catheters.
The bacterium can cause potentially lethal bloodstream infections. Strains of A. baumannii have acquired resistance to a wide range of antibiotics, and some are resistant to every FDA-approved antibiotic, making them untreatable. Spelling and his colleagues found that in laboratory mice it was possible to mitigate the potentially lethal effects of the bacterium by blocking one of its toxic products rather than killing it. "We found that strains that caused the rapidly lethal infections shed lipopolysaccharide [also called LPS or endotoxin] while growing. The more endotoxin shed, the more virulent the strain was," says Spellberg. This pinpointed a new therapy target for the researchers: the endotoxin these bacteria shed in the body.
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A simple cut to your finger could leave you fighting for your life. Luck will play a bigger role in your future than any doctor could. The most basic operations - getting an appendix removed or a hip replacement - could become deadly. Cancer treatments and organ transplants could kill you. Childbirth could once again become a deadly moment in a woman's life. It's a future without antibiotics. This might read like the plot of science fiction novel - but there is genuine fear that the world is heading into a post-antibiotic era.
The World Health Organization has warned that "many common infections will no longer have a cure and, once again, could kill unabated". The US Centers of Disease Control has pointed to the emergence of "nightmare bacteria". And the chief medical officer for England Prof Dame Sally Davies has evoked parallels with the "apocalypse". Antibiotics kill bacteria, but the bugs are incredibly wily foes. Once you start treating them with a new drug, they find ways of surviving. New drugs are needed, which they then find ways to survive.
Some bacteria are becoming resistant to our best drugs
Deadly
As long as new drugs keep coming, resistance is not a problem. But there has not been a new class of antibiotics discovered since the 1980s. This is now a war, and one we are in severe danger of losing. Antibiotics are more widely used than you might think and a world without antibiotics would be far more dangerous. They made deadly infections such as tuberculosis treatable, but their role in healthcare is far wider than that. Surgery that involves cutting open the body poses massive risks of infection. Courses of antibiotics before and after surgery have enabled doctors to perform operations that would have been deadly before. Cancer treatments such as chemotherapy and radiotherapy can damage the immune system. A course of antibiotics is prescribed to provide a much-needed boost alongside your body's own defences.
Anyone with an organ transplant faces a lifetime of drugs to suppress the immune system, otherwise it attacks the transplant, so antibiotics are used to protect the body. "It's a pretty grim future, I think a lot of major surgery would be seriously threatened," said Prof Richard James from the University of Nottingham. "I used to show students pictures of people being treated for tuberculosis in London - it was just a row of beds outside a hospital, you lived or you died - the only treatment was fresh air." And this, he says, is what running out of drugs for tuberculosis would look like in the future. But this is all in the future isn't it? "My lab is seeing an increasing number of resistant strains year on year," said Prof Neil Woodford, from the Health Protection Agency's antimicrobial resistance unit.
Down to luck
Activated carbon filters can remove about 40 percent of carcinogens and antibiotics from these waters. But a tiny solar-powered filter made of two bacterial proteins absorbs more than 50 percent more of the pollutants. In addition, the filter - developed by a team at the University of Cincinnati - can release the captured antibiotics so they can be reused.
Antibiotics and chemicals enter waterways through sewage and run-off from yards and farms. They can breed resistant bacteria and kill helpful microorganisms, degrading the health of aquatic ecosystems. The nano-filters, each smaller than the diameter of a human hair, employ a protein used by drug-resistant bacteria to excrete waste, but the researchers have turned it around so it sucks compounds in. Another protein, which responds to sunlight, provides the pumping power for the filter.
Environmental engineer David Wendell, one of the developers, calls the innovation an environmentally friendly and cost-effective way to extract and recover antibiotics from surface waters. He foresees the possibility that, one day, a collection of nano-filters could be anchored downstream from urban or farming areas to capture harmful compounds in water. Details of the development and testing of the new filter appear in the journal Nano Letters.
Solar-Powered Proteins Filter Antibiotics from Water
Researchers at Brigham and Womens Hospital in Boston, Massachusetts, led by biomedical engineer Jeffrey Karp, say they saw a need for an improved medical adhesive and looked to nature for ideas. When we started looking into the parasite literature, we quickly stumbled upon worms and, in particular, this spiny-headed worm that has a needle-like proboscis [nose] that inserts in the intestine of fish ... and only the needles swell, so it kind of mechanically locks into place," said Karp, describing a freshwater-fish parasite called Pomphorhynchus laevis, whose swelling and locking needle-nose design gave his team a model for the new and improved surgical bandage with unique adhesive properties.
Karp's prototype, a microneedle-lined bandage that plumps up when exposed to water, locks painlessly into the patient's subdermal tissue and adheres 3-and-a-half times more strongly than any clinical bandage now in use. The elongated microneedle tips, made with a rigid plastic core, attach to stiff plastic inner and outer layers of highly absorbent material that is similar to the inside of a disposable diaper. When wet, the needles form a mechanical bond with the tissue. The microneedle patch is also designed to eliminate two specific problems with surgery involving skin-grafts.
According to Karp, who consulted with Dr. Bo Pomahac, head of face transplant surgery at Brigham and Womens, when conventional staples hold skin grafts in place, they can produce holes 2-to-3 times larger than the width of the staple itself, allowing for potentially harmful bacterial infections. The grafts, Karp says, are also susceptible to filling with accumulated fluids, which can prevent healing. Instead of using staples," Karp said, "we would apply a microneedle patch directly on top of the skin graft that will push down to the underlying tissue and essentially lock that graft in place."
Karp also envisions impregnating microneedle patches with antibiotics and other drugs that would infuse slowly into wounds, helping to keep them clean and quick-healing. Researchers are attempting to develop a microneedle patch that can be used to help seal, and heal, internal organs following surgery. When it comes to removing the bandage, Karp doesnt think it would hurt more than pulling out surgical staples, which penetrate skin more deeply than the microneedles on the new bandage patch. The work by Karp and colleagues was funded in part by the National Institutes of Health. An article describing a new micro-needle surgical bandage is published in Nature Communications.
Source
The increasing number of bacteria resistant to antibiotics poses a problem, however researchers at the Moffitt Cancer Center devised a mathematical model to determine the correct sequence of antibiotic treatment to counter resistance. The researchers believe treating bacteria with combinations of antibiotics over time may reduce or even eliminate resistant organisms. "Our results suggest that, through careful ordering of antibiotics, we may be able to steer evolution to a dead end from which resistance cannot emerge," said Daniel Nichol, a doctoral student at the University of Oxford and researcher at the Moffitt Cancer Cancer, in a press release.
Antibiotics are increasingly less effective against infections, however the right combinations given in the right order may be able to turn back the tide on pathogen resistance to the drugs.
Researchers used a Markov matrix to determine the probability of E.coli to survive in antibiotics, analyzing 15 antibiotics for efficacy based on the mathematical model. They found that 70 percent of combinations of two to four drugs promoted resistance to the antibiotics. The order drugs are administered makes a significant difference, researchers wrote in the study, because certain combinations have the ability to either promote or prevent bacteria from evolving to survive antibiotic treatment.
Careless, or at least less careful, use of unnecessarily strong antibiotics can help promote the development of resistance, they said, suggesting that more research be done on the most effective combinations to treat specific bacteria. "Our results can be easily tested in the laboratory, and if validated could be used in clinical trials immediately, as all of the compounds we studied are FDA approved and commonly prescribed," said Dr. Jacob Scott, of Moffitt's radiation oncology and integrated mathematical oncology departments. The study is published in PLOS: Computational Biology.
Method developed to fight antibiotic resistance using current antibiotics
The breast cancer drug tamoxifen boosts the immune system, and was shown to be effective against Methicillin-resistant Staphylococcus aureus, or MRSA, in lab experiments, according to researchers at the University of California San Diego. Tamoxifen, which blocks estrogen receptors in breast tissue, is used by hundreds of thousands of women and men with advanced breast cancer. The drug's known effects on other cells led researchers to study other ways to use it. "While known for its efficacy against breast cancer cells, many other cell types are also exposed to tamoxifen," said Dr. Victor Nizet, a professor of pediatrics and pharmacy at the UCSD, in a press release. "The 'off-target effects' we identified in this study could have critical clinical implications given the large number of patients who take tamoxifen, often every day for years."
Tamoxifen helped mice infected with Methicillin-resistant Staphylococcus aureus, or MRSA, live about five times as long as those treated with a control drug.
For patients with estrogen-receptor positive breast cancer, tamoxifen blocks the receptors, helping make other treatments such as chemotherapy and radiation more effective. Researchers focused, however, on the drug's 'off-target effect' on the production of a type fatty molecule called ceramide that enhances the ability of white blood cells called neutrophils to engulf and defeat bacteria. In the lab, researchers found that neutrophils treated with tamoxifen produced three times more neutrophil extracellular traps, or NETs, a group of proteins, enzymes and peptides neutrophils use to kill bacteria.
The researchers treated mice with tamoxifen to test its ability to boost the immune system. After exposing the rodents to MRSA, another dosage of tamoxifen was given and the mice were monitored for five days. Although none of the control mice live more than a day, about 35 percent of the mice treated with tamoxifen survived for five days. Five times fewer MRSA were found in peritoneal fluid taken from the mice's abdomens. "The threat of multidrug-resistant bacterial pathogens is growing, yet the pipeline of new antibiotics is drying up," Nizet said. "We need to open the medicine cabinet and take a closer look at the potential infection-fighting properties of other drugs that we already know are safe for patients." The study is published in Nature Communications.
Breast cancer drug helps immune response against MRSA
Medical staff is at greater risk for infection by pathogens than they should because of improper removal of gloves and gowns, according to simulations in a study conducted with hospital employees. After the study, staff were instructed on the Centers for Disease Control and Prevention's recommendations for personal protective equipment. The potential for contamination dropped significantly -- but not all the way. Researchers in the study, published in JAMA Internal Medicine, recruited 435 staff members from four northeast Ohio hospitals between October 2014 and March 2015 to find the potential for contamination while changing out of used gloves and gowns.
Even when procedures are followed properly, staff contaminated themselves about 30 percent of the time.
Participants were asked to put on gloves and gowns, and then given fluorescent lotion and asked to rub it on their gloved hands. They were the asked to take the gloves off. Researchers found that staff members contaminated their skin, clothes, or both 46 percent of the time. Among the four hospitals, contamination rates ranged from 42.5 percent to 50.3 percent, and 52.9 percent of the time the contamination could be blamed on improper usage of the gloves. When the participants made a mistake, they were contaminated 70 percent of the time -- but even when they did everything correctly, participants were contaminated 30 percent of the time.
Intervention to retrain staff in proper usage of personal protective equipment over the course of one to three months resulted in a decrease of contamination rates from 60 percent to 18.9 percent. "These results have clear implications for the safety of health care workers and the spread of hospital-acquired infections," researchers wrote in a commentary published in JAMA Internal Medicine with the study. "It has been documented that higher levels of microbial contamination of hospital surfaces lead to higher rates of healthcare worker contamination with multidrug-resistant organisms." "Because environmental bioburden is a concern for the cross-transmission of hospital-acquired pathogens, the microbial burden of health care worker hands and apparel represents another element in this equation. Collectively, this increased contamination of the animate and inanimate environment contributes to the risk of hospital-acquired infections," researchers wrote in the commentary.
Medical staff open to contamination because of gowns, gloves - UPI.com
A report on the bacteria, published in The Lancet, a medical journal, prompted Chinese authorities to consider banning the use of some antibiotics in animals. The bacteria in China, found in pigs, were resistant to even the strongest of antibiotics, a medicine called colistin. Fifteen percent of raw meat samples tested — and 16 human patients — were infected.
Dr. Peter Barlow of Scotland's Edinburgh Napier University, who has worked at the U.S. Centers for Disease Control and Prevention, told VOA that "it's actually the use of this antibiotic in livestock that’s promoted this. And because antibiotics are used so widely in livestock and in humans, it’s got us to the stage where we’re facing a problem with antibiotic resistance in a lot of different types of bacteria."
Chinese scientists have identified a genetic mutation known as MCR-1 that provides the antibiotic resistance — and it can easily spread across different species of bacteria. Evidence of resistant strains of bacteria have also been found in Laos and Malaysia, scientists said.
Margaret Chan, director general of the World Health Organization, this week joined the chorus of warnings. “The world is heading toward a post-antibiotics era in which common infections will once again kill," she said. "If current trends continue, sophisticated interventions like organ transplantation, joint replacement, cancer chemotherapy and care of preterm infants will become more difficult or even too dangerous to undertake."
Barlow said urgent action was needed to avert such a catastrophe. “We need a really effective global strategy for dealing with antibiotic use, both in humans and in livestock," he said. "And I think we need increased and sustained investment in antibiotic drug discovery."
'Antibiotic Apocalypse’ a Step Closer, Scientists Warn
Lilly Adams, with the consumer advocacy group Food and Water Watch, is one of many activists working to stop what she sees as the overuse of antibiotics on factory farms. "Eighty percent of our antibiotics in the United States actually are used on factory farms to compensate for really filthy, crowded conditions," she said. "This just isn't how antibiotics are meant to be used. So this overuse of the antibiotics is causing antibiotic-resistant bacteria to grow in the farms, and this spreads into the environment." And that has been linked to more infections in humans that do not respond to available drugs, and an estimated 700,000 deaths a year globally.
Consumer pressure forces change
Many farmers, including Tory Hancock of Ploughshares Community Farm, already raise livestock without antibiotics. "You give the animals a stress-free environment and a healthy diet, you know, really good feed, and you generally don't need it," she said. And many customers willingly pay more for antibiotic-free beef, as well as bacon from antibiotic-free pigs. In fact, consumer pressure has been a major force in bringing about that change, says Anna Zorzet, a scientist and activist who spoke at the American Association for the Advancement of Science annual meeting. "Sweden was the first country in the world to ban the use of antibiotics as growth promoters in 1986, and the EU followed suit in 2006," she said. "The farmers felt that they couldn't justify the use of antibiotics, and the public opinion was quite a lot against it."
Europeans see improvements
Many Northern European countries now ban regular antibiotics for healthy livestock, and they also have stricter rules for human antibiotics. It has paid off, according to Diarmaid Hughes, a Swedish professor of bacteriology. "Consistently, the Nordic countries – Sweden, Finland, Norway, Denmark – have lower rates of resistance for all of the major infections," he said. "And you see the countries of southern and eastern Europe where regulation is much more lax, they have much, much higher rates of resistance. And in many cases it's completely out of control, so the message is that regulating usage and the total amount that you use really does have an effect."
The use of antibiotics in livestock helps the animals stay healthy and grow faster, but bacteria develop resistance to the drugs, and those resistant bacteria can spread to people.
Hughes says the entire world needs these policies. Otherwise, he warns, antibiotic-resistant pathogens will cause more deaths from currently treatable illnesses such as pneumonia, cholera and tuberculosis. In addition, he says, deaths after routine surgery for an injured knee or a heart attack may become commonplace. "All of these will become very dangerous operations,” Hughes said, “because you have to give them effective antibiotics to have a safe operation."
Changes ahead for US farms
The antibiotic, eravacycline, is being studied in a pivotal 450-patient Phase III trial for intra-abdominal infections. Tetraphase expects to have the data in the fourth quarter after which it will apply for U.S. approval that could come in 2018. "The FDA has been very supportive of getting new antibiotics approved, so clearly we have a fast-track agreement with them once we get the positive data," Macdonald told Reuters. He said he believes eravacycline could garner annual sales that would take it at least halfway to blockbuster status. "If you have a successful gram negative drug like eravacycline, you're looking at somewhere in the $500-to-$700-million range. I think that's certainly reachable," Macdonald said.
Eravacycline is a synthetic tetracycline derivative for drug-resistant bacterial infections administered intravenously in hospital. The company is also enrolling for a 1,000-patient eravacycline trial in complicated urinary tract infections. Tetraphase is developing the drug with the help of a $80 million grant from the Biomedical Advanced Research and Development Authority (BARDA), a division of the U.S. Department of Health and Human Services. It currently has enough funding to take it through the second half of 2018, the CEO said.
Antibiotic resistance and the emergence of so-called super bugs, caused by widespread antibiotic overuse and the ability of bacteria to evolve, is seen as a global health threat. The U.S. government has been very helpful in funding for new antibiotics, Macdonald said. In September, Medicines Co and Roche received significant funding from BARDA to help develop antibiotics. Many major drugmakers abandoned antibiotic development because they are not nearly as profitable as other medicines, such as cancer drugs, and marketing them aggressively would likely only exacerbate the overuse problem.
Tetraphase expects to also apply for European approval late this year, and hopes to find a partner to sell the drug outside the United States. "We can do it in the U.S. on our own," Macdonald said. "For us to be able to provide the growth we need and keep our investor base happy, that's a much better business model to do it ourselves," he added. "If you want to commercialize it worldwide, we're not capable of doing that." The 75-employee company with a market value under $200 million will build a small sales force for eravacycline, Macdonald said. Tetraphase already has someone with commercial experience from Merck & Co and Cubist to oversee the eravacycline launch, once approved. "We just need the data," Macdonald said.
Tetraphase antibiotic may reach up to $700 million in annual sales: CEO
Dr. Trish Perl, chief of infectious diseases at University of Texas Southwestern Medical Center, said if there are no effective antibiotics, it will affect the entire practice of medicine. “You all of a sudden understand what it was like to practice medicine maybe 50, 70, 80 years ago, when there weren't antibiotics,” Perl said. Without antibiotics, surgery will become much more dangerous. Doctors will be unable to treat diseases caused by E. coli, a bacterium that causes urinary tract infections and diarrhea. Even a virus such as the flu, which can lead to bacterial pneumonia, will mean these viruses will ultimately claim even more lives.
New antibiotics needed
New antibiotics are urgently needed against bacteria that pose the greatest threat to human health. Those most at risk: residents of nursing homes, hospital patients, and children. Children may have weaker immune systems than adults, and they receive smaller doses of antibiotics than adults do. “For the longest time we've had a number of different antibiotics in the pipeline at any given time, so whenever we ran out of the ability to use one, we would move to the next one," Dr. Michael Bell, an expert in drug-resistant pathogens at the Centers for Disease Control and Prevention, told VOA. But that's no longer possible. Joe Larsen, the director of biological, chemical and radiological and nuclear countermeasures at the Department of Health and Human Services, said his department drew up a list of pathogens several years ago that were becoming resistant to antibiotics.
Funding needs to change
“There are antibiotics in the pipeline, but the numbers are insufficient ... to deal with the increasing rates of antibiotic-resistant bacteria,” he said. Larsen's department invests in pharmaceutical and bio-tech firms to make drugs, vaccines and diagnostics for public health emergency preparedness. Larsen is hopeful that a new antibiotic will be approved by the Food and Drug Administration later this year. He also said two to three more antibiotics are being developed that should be available in a year or two. The WHO said it's too expensive for pharmaceutical companies to develop new antibiotics on their own because they wouldn't recoup their investment. Larsen agrees that the way antibiotics are commercialized needs to change.
Bacteria are constantly changing
One reason is that the more an antibiotic is used, the less effective it becomes. That's because bacteria are constantly changing and finding new ways to resist the drugs that kill them. Once they find a way, they can pass on the gene so other bacteria can become drug-resistant as well. To preserve the effectiveness of an antibiotic, Larsen said the profits from selling these drugs can't be linked to the volume of sales the way the market normally works. He said the solution lies in public-private partnerships between governments and pharmaceutical or biotech firms. In the meantime, antibiotic resistance is very real. Lauri Hicks, who leads research on antibiotic use and resistance trends at the CDC, said, “We are seeing greater than 2 million episodes of antibiotic resistant infections each year in the U.S. alone. Twenty-three thousand of these episodes result in death.”
Don’t overuse antibiotics
The Centers for Disease Control and Prevention has asked hospitals and doctors to be careful not to overuse antibiotics. But beyond overuse, Bell, of the CDC, said there are other reasons these drugs are being rendered powerless. “Antibiotic resistance is being generated by not only using too many antibiotics, but also by spread of infection by lack of hygiene, from unintended contact with soiled surfaces, so the infection-control side is equally important,” he said. Patients can also help. On its website, the CDC says to take antibiotics as prescribed and finish the prescription, even if you feel better. Still, urgent action on a global level is needed to prevent the catastrophe that a post-antibiotic era would cause.
Doctors Alarmed by Post-antibiotic Future
