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Antibody Protects Against Both Zika and Dengue, Mouse Study Shows

Antibody Protects Against Both Zika and Dengue, Mouse Study Shows

Brazil and other areas hardest hit by the Zika virus – which can cause babies to be born with abnormally small heads – are also home to dengue virus, which is spread by the same mosquito species.

A new study led by researchers at Washington University School of Medicine in St. Louis shows that an antibody that protects against dengue virus is also effective against Zika in mice.

Antibodies remain in the bloodstream for weeks, so one or a few doses of an antibody-based drug given over the course of a woman’s pregnancy potentially could protect her fetus from Zika, with the added benefit of protecting her from both Zika and dengue disease, the researchers said. Dengue causes high fever, severe headaches, and joint and muscle pain in children and adults but does not directly harm fetuses.

“We found that this antibody not only neutralizes the dengue virus but, in mice, protects both adults and fetuses from Zika disease,” said Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine and the study’s senior author.

Since dengue and Zika are related viruses, the researchers reasoned that an antibody that prevents dengue disease may do the same for Zika. Diamond and graduate student Estefania Fernandez collaborated with Gavin Screaton, MD, DPhil, of Imperial College London, who had generated a panel of human anti-dengue antibodies years before.

The scientists infected nonpregnant adult mice with Zika virus and then administered one of the anti-dengue antibodies one, three or five days after infection. For comparison, another group of mice was infected with Zika virus and then given a placebo. Within three weeks of infection, more than 80 percent of the untreated mice had died, whereas all of the mice that received the anti-dengue antibody within three days of infection were still alive, and 40 percent of those that received the antibody five days after infection survived.

To find out whether the antibody also could protect fetuses from infection, the researchers infected female mice on the sixth day of their pregnancies with Zika virus and then administered a dose of antibody or a placebo one or three days later.

On the 13th day of gestation, the amount of Zika’s genetic material was 600,000 times lower in the placentas and 4,900 times lower in the fetal heads from the pregnant mice that were treated one day after infection, compared with mice that received the placebo. However, administering the antibody three days after infection was less effective: It reduced the amount of viral genetic material in the fetal heads nineteen fold and in the placentas twenty-threefold.

These findings suggest that for the antibody to effectively protect fetuses from Zika infection, it must be administered soon after infection. Such a goal may be unrealistic clinically because women rarely know when they get infected.

However, giving women the antibody as soon as they know they are pregnant could provide them with a ready-made defense against the virus should they encounter it. Antibody-based drugs have been used for decades to provide temporary protection against infectious diseases such as rabies when there is no time to vaccinate or, as in the case of Zika, when there is no vaccine available.

The key to using this antibody as a preventive drug would be to make sure that antibody levels in a woman’s bloodstream stay high enough to protect her fetus for the duration of her pregnancy.

Diamond and colleagues are working on identifying how much antibody a pregnant woman would need to ensure that her fetus is protected from Zika. They also are exploring ways to extend the antibody’s half-life in the blood, to reduce the number of times it would need to be administered.

Having anti-dengue antibodies circulating in the bloodstream for months on end poses a risk, though, because antibodies that protect against one strain of dengue virus sometimes worsen symptoms if a person is infected by another dengue strain.

To avoid the possibility of accidentally aggravating an already very painful disease, the researchers mutated the antibody in four spots, making it impossible for the antibody to exacerbate dengue disease.

“We mutated the antibody so that it could not cause antibody enhancement of dengue infection, and it was still protective,” said Diamond, who is also a professor of pathology and immunology, and of molecular microbiology. “So now we have a version of the antibody that would be therapeutic against both viruses and safe for use in a dengue-endemic area, because it is unable to worsen disease.”

This article was published in bioscience technology website dated ‘Sep. 27, 2017’

Antibiotics often inappropriately prescribed for hospitalized kids, global study suggests

Antibiotics often inappropriately prescribed for hospitalized kids, global study suggests

Nearly a third of all antibiotics prescribed for hospitalized children globally were intended to prevent potential infections rather than to treat disease, according to the results of a worldwide survey published in the Journal of the Pediatric Infectious Diseases Society. A large proportion of these preventive, or prophylactic, prescriptions also were for broad-spectrum antibiotics or combinations of antibiotics, or were for prolonged periods, which can hasten the development of antibiotic-resistant bacteria and drug-resistant infections.

“This pattern and high rate of prophylactic prescribing indicates a clear overuse of antibiotics,” said study author Markus Hufnagel, DTM&H, of the University of Freiburg in Germany. “Hopefully, our study results will help to raise awareness among health professionals about appropriate prescribing of antibiotics in children,” Dr. Hufnagel said.

The study provides a snapshot of antibiotic prescriptions for 6,818 children who were inpatients at 226 pediatric hospitals in 41 countries, including four hospitals in the United States, during one day in 2012. There were 11,899 total prescriptions for antibiotics, and 28.6 percent of these were for prophylactic use, researchers found. Among hospitalized children who received at least one antibiotic prescription, 32.9 percent (2,242 children) were prescribed an antibiotic to prevent a potential infection rather than to treat a current one.

Of the antibiotics prescribed for prophylactic use, 26.6 percent were to prevent potential infections associated with an upcoming surgery, and the vast majority of these antibiotics were given for more than one day. The remaining 73.4 percent of the prophylactic prescriptions were intended to potentially prevent other types of infections. Approximately half (51.8 percent) of all preventive antibiotic prescriptions were for broad-spectrum antibiotics. In 36.7 percent of cases, two or more systemic antibiotics were prescribed at the same time.

These patterns contradict current recommendations for appropriate prophylactic antibiotic use. Guidelines often call for using narrow-spectrum antibiotics for shorter periods, in an effort to limit the development of antibiotic resistance. The study findings suggest clear targets for improving antibiotic prescribing in pediatric patients, according to the authors. These include reducing prolonged, preventive antibiotic use before surgery, limiting the use of broad-spectrum and combinations of antibiotics, and reducing antibiotic use, overall, for prophylactic rather than therapeutic use.

Additional education for clinicians and improved implementation of current guidelines for antibiotic use to prevent surgical infections are needed, Dr. Hufnagel said. More in-depth guidelines that address the use of prophylactic antibiotics for a broader range of medical conditions than current guidelines do are also needed, as well as efforts to communicate these guidelines to health care providers and to analyze how the recommendations are used.

This article was published in Science Daily dated ‘Mar. 22, 2018’

New Strategy Makes Bacteria More Vulnerable to Antibiotics

New Strategy Makes Bacteria More Vulnerable to Antibiotics

Scientists at MIT have discovered a way to make bacteria more vulnerable to a class of antibiotics known as quinolones, which include ciprofloxacin and are often used to treat infections such as Escherichia coli and Staphylococcus aureus.

The new strategy overcomes a key limitation of these drugs, which is that they often fail against infections that feature a very high density of bacteria. These include many chronic, difficult-to-treat infections, such as Pseudomonas aeruginosa, often found in the lungs of cystic fibrosis patients, and methicillin-resistant Staphylococcus aureus (MRSA).

“Given that the number of new antibiotics being developed is diminishing, we face challenges in treating these infections. So efforts such as this could enable us to expand the efficacy of existing antibiotics,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering and the senior author of the study.

Arnaud Gutierrez, a former MIT postdoc, and Saloni Jain, a recent Boston University PhD recipient, are the lead authors of the study, which appears in the December 7 online edition of Molecular Cell.

Overcoming bacterial defenses

Bacteria that have become tolerant to a drug enter a physiological state that allows them to evade the drug’s action. (This is different from bacterial resistance, which occurs when microbes acquire genetic mutations that protect them from antibiotics.) “Tolerance is not well-understood, and we don’t have the means to circumvent it or overcome it,” Collins says.

In a study published in 2011, Collins and his colleagues found that they could increase the ability of antibiotics known as aminoglycosides to kill drug-tolerant bacteria by delivering a type of sugar along with the drug. The sugar helps to boost the metabolism of the bacteria, making it more likely that the microbes will undergo cell death in response to the DNA damage caused by the antibiotic.

However, aminoglycosides can have serious side effects, so they are not widely used. In their new study, Collins and his colleagues decided to explore whether they could use a similar approach to boost the effectiveness of quinolones, a class of antibiotics used more often than aminoglycosides. Quinolones work by interfering with bacterial enzymes called topoisomerases, which help with DNA replication and repair.

With quinolones, the researchers found that it wasn’t enough to add just sugar; they also had to add a type of molecule known as a terminal electron acceptor. Electron acceptors play an essential role in cellular respiration, the process that bacteria use to extract energy from sugar. In cells, the electron acceptor is usually oxygen, but other molecules, including fumarate, an acidic organic compound that is used as a food additive, can also be used.

In tests in high-density bacterial colonies grown in a lab dish, the researchers found that delivering quinolones along with glucose and fumarate could eliminate several types of bacteria, including Pseudomonas aeruginosa, Staphylococcus aureus, and Mycobacterium smegmatis, a close relative of the bacterium that causes tuberculosis.

“If you simply add a carbon source like glucose, that’s not enough to enable the quinolone to kill. If you simply add oxygen, or another terminal electron acceptor, that by itself is not enough to cause killing either. But if you combine the two, you can eradicate the tolerant infection,” Collins says.

Metabolic state

The findings suggest that high-density bacterial infections rapidly consume nutrients and oxygen from their environment, which then provokes them to enter a starvation state that helps them to survive. In this state, they greatly reduce their metabolic activity, which allows them to avoid the cell death pathway that is normally triggered when DNA is damaged by antibiotics.

“This finding highlights that the metabolic state of the bug significantly influences how the antibiotic will impact the bug. And, for the antibiotic to be effective as a killing agent, it requires downstream cellular respiration as part of the process,” Collins says.

The researchers now hope to test this approach in bacterial infections in animals, and they are also exploring how to best deliver the drug combination for different types of infections. A topical treatment could work well for Staphylococcus aureus infections, while an inhaled version could be used to treat Pseudomonas aeruginosa infections of the lungs, Collins says.

Collins also hopes to test this approach with other types of antibiotics, including the class that includes penicillin and ampicillin.

“This study encourages work to find new ways to stimulate bacterial respiration and thereby enhance the production of reactive oxygen (or even non-oxygen) species during antibiotic treatment, for better eradication of bacterial pathogens, particularly those having low metabolic activity that may render them tolerant to antimicrobials,” says Karl Drlica, a professor at the Public Health Research Institute at Rutgers New Jersey Medical School, who was not involved in the research.

The research was funded by the Defense Threat Reduction Agency, the Broad Institute of MIT and Harvard, and a gift from Anita and Josh Bekenstein.

This article was published in Scitechdaily dated ‘Dec. 07, 2017’