Technology for accelerated wound healing

Researchers at Uppsala University and SLU have found a new way of accelerating wound healing. The technology involves using lactic acid bacteria as vectors to produce and deliver a human chemokine on site in the wounds. The research group is the first in the world to have developed the concept for topical use and the technology could turn out to be disruptive to the field of biologic drugs.

Treatment of large and chronic wounds are a high cost burden to the health care system since effective tools to accelerate healing are lacking. Wound care is today limited to mechanical debridement, use of different dressings and significant amounts of antibiotics preventing or treating wound infections. With the aging population, occurrence of chronic diseases such as diabetes and the alarming global spread of antibiotic resistance, a treatment that kick-starts and accelerates wound healing will have a significant impact.

There have been many attempts to solve the problem of chronic wounds that have failed. Drug candidates currently in late stage clinical trials comprise of growth factors, which are traditional protein-based biological drugs associated with high costs, and some trials have been prematurely terminated.

Researcher have developed a drug candidate, a next-generation biologic medical product, and are now publishing the fantastic results from the preclinical part where wound healing was strongly accelerated in mice," says Mia Phillipson, Professor at the Department of Medical Cell Biology, Division of Integrative Physiology, Uppsala University.

The acceleration of the healing process occurs due to changes in the microenvironment in the wound, which change the behaviour of specific immune cells. With the newly developed technology, the researchers can increase the level of a chemokine, CXCL12, for a sufficient time period through continuous delivery directly to the wound surface.

Bioavailability of CXCL12 is synergistically increased within the wound as the bacterial produced lactic acid causes a slight pH drop that inhibits degradation. The chemokine, CXCL12, is endogenously upregulated in injured tissue and by increasing the levels further, more immune cells are recruited and are more specialised to heal the wound, which accelerates the whole process.

The potent effect on acceleration of wound healing is demonstrated in healthy mice but also in two models of diabetes, one model of peripheral ischemia as well as in a model using human skin biopsies. There were clear differences in the composition of immune cells in the wounds and the immune cells present produced higher levels of TGFß at earlier time points. The treatment was local without systemic exposure.
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Antibiotics with narrower targets for respiratory infections

Researchers who studied pediatric treatment practices in patients with earaches, strep throat and other common infections found that narrow-spectrum antibiotics, which act against a smaller range of bacteria, had fewer adverse effects than broad-spectrum antibiotics, which target a broader variety of bacteria. When judged by both practical and clinical outcomes, narrow-spectrum antibiotics performed equally well or better than broad-spectrum ones, with fewer disruptions to family routines.

The study reflects an "antimicrobial stewardship" approach, guiding healthcare providers to prescribe the most appropriate antibiotic for a patient's specific type of infection, with the aim of improving individual outcomes and reducing the overall risk of antibiotic resistance in which disease-causing microorganisms develop resistance to commonly used antibiotics.

Many children unnecessarily receive broad-spectrum antibiotics for common infections, which can lead to antibiotic resistance and unnecessary side effects," said study leader Jeffrey Gerber, MD, PhD, associate director for Inpatient Research Activities in the Center for Pediatric Clinical Effectiveness at Children's Hospital of Philadelphia (CHOP). "This study showed that inappropriate prescribing of antibiotics also affects families.

The study team performed two complementary studies in 31 primary care practices in CHOP's pediatric network in Pennsylvania and New Jersey, between January 2015 and April 2016. They drew on electronic health records of infants and children up to age 12 diagnosed with an acute respiratory tract infection (ARTI) and prescribed an oral antibiotic. In a retrospective cohort of approximately 30,000 patients, 14 percent received broad-spectrum drugs and 86 percent received narrow-spectrum drugs.

The ARTIs in the analysis were acute otitis media (earache), Group A streptococcal pharyngitis (strep throat) and sinusitis (sinus infection). ARTIs account for the majority of antibiotic exposures in children. In addition to assessing clinical outcomes in a retrospective cohort of 30,000 children, the researchers studied a prospective cohort of 2,472 children, doing telephone interviews with caregivers to measure outcomes that parents had identified as their highest concerns: adverse drug effects.

The study team found a significantly higher risk of adverse events for broad-spectrum antibiotics compared to narrow-spectrum antibiotics (3.7 percent vs. 2.7 percent as documented by clinicians, and 35.6 percent vs. 25.1 percent, as reported by patients and families). The rates of treatment failure were not significantly different between both types of antibiotics. Research tells us that antibiotic stewardship programs not only reduce the overall burden of antibiotic resistance, but also improve patient outcomes.
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Alternative therapies for antibiotic resistance

Drug development strategies have focused on replacing antibiotics in extreme infections, such as sepsis, where every minute without an effective drug increases the risk of death. But the evolutionary process that brings forth antibiotic resistance doesn't happen nearly as often in those big infections as it does in the multitude of small ones like sinusitis, tonsillitis, bronchitis, and bladder infections.

 Antibiotic prescriptions against those smaller ailments account for about 90 percent of antibiotic use, and so are likely to be the major driver of resistance evolution. Bacteria that survive these many small battles against antibiotics grow in strength and numbers to become formidable armies in big infections, like those that strike after surgery.  It is advisable to give antibiotics less often and preserve their effectiveness for when they're really needed.

E. coli is widespread in the human gut, and some strains secrete enzymes that thwart antibiotics, while other strains don't.
 A broad-spectrum antibiotic can kill off more of the vulnerable, less dangerous bacteria, leaving the more dangerous and robust bacteria to propagate. Much too often, superbugs have made their way into hospitals in someone's intestines, where they had evolved high resistance through years of occasional treatment with antibiotics for small infections. Then those bacteria have infected patients with weak immune systems.

Drug developers facing dwindling antibiotic effectiveness against evolved bacteria have looked for multiple alternate treatments. Developing non-antibiotic therapies for strep throat, bladder infections, and bronchitis could prove easier, thus encouraging pharmaceutical investment and research.

For example, one particular kind of strep bacteria , group A streptococci, is responsible for the vast majority of bacterial upper respiratory infections. People often carry it without it breaking out. Strep bacteria secrete compounds that promote inflammation and bacterial spread. If an anti-virulence drug could fight the secretions, the drug could knock back the strep into being present but not sickening.

Strep infection can lead to rheumatic heart disease, a deadly condition that is very rare in the industrialized world. Some push-back against virulent bacteria until the body's immune system can take care of it. Developing a spray-on treatment with bacteriophages, viruses that attack bacteria can prevent the resistance.
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Bacteria obtain resistance from competitor

Bacteria not only develop resistance to antibiotics, they also can pick it up from their rivals. In a recent publication in Cell Reports, Researchers from the Biozentrum of the University of Basel have demonstrated that some bacteria inject a toxic cocktail into their competitors causing cell lysis and death. Then, by integrating the released genetic material, which may also carry drug resistance genes, the predator cell can acquire antibiotic resistance.

The frequent and sometimes careless use of antibiotics leads to an increasingly rapid spread of resistance. Hospitals are a particular hot spot for this. Patients not only introduce a wide variety of pathogens, which may already be resistant but also, due to the use of antibiotics to combat infections, hospitals may be a place where anti-microbial resistance can develop and be transferred from pathogen to pathogen. One of these typical hospital germs is the bacterium Acinetobacter baumannii. It is also known as the "Iraq bug" because multidrug-resistant bacteria of this species caused severe wound infections in American soldiers during the Iraq war.

The emergence and spread of multidrug resistance could be attributed, among other things, to the special skills of certain bacteria: Firstly, they combat their competitors by injecting them with a cocktail of toxic proteins, so-called effectors, using the type VI secretion system (T6SS), a poison syringe. They are able to uptake and reuse the released genetic material. In the model organism Acinetobacter baylyi, a close relative of the Iraq bug, Prof. Marek Basler's team at the Biozentrum of the University of Basel, has now identified five differently acting effectors. Some of these toxic proteins kill the bacterial competition very effectively, but do not destroy the cells.

The predator bacteria take up the released DNA fragments. If these fragments carry certain drug resistance genes, the specific resistance can be conferred upon the new owner. As a result, the antibiotic is no longer effective and the bacterium can reproduce largely undisturbed. Pathogens with such abilities are a major problem in hospitals, as through contact with other resistant bacteria they may accumulate resistance to many antibiotics -- the bacteria become multidrug-resistant. In the worst case, antibiotic treatments are no longer effective, thus nosocomial infections with multidrug-resistant pathogens become a deadly threat to patients.

The T6SS, as well as a set of different effectors, can also be found in other pathogens such as those which cause pneumonia or cholera. Interestingly, not all effectors are sufficient to kill the target cell, as many bacteria have developed or acquired antitoxins -- so-called immunity proteins. Antibiotics and anti-microbial resistance have existed for a long time. They developed through the coexistence of microorganisms and enabled bacteria to defend themselves against enemies or to eliminate competitors. This is one of the ways in which bacteria can conquer and colonize new environmental niches. With the use of antibiotics in medicine, however, the natural ability to develop resistance has become a problem. This faces researchers with the challenge of continually developing new antibiotics and slowing down the spread of drug resistance.
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Managing antibiotics can not reverse the resistance

Researchers have discovered that reducing the use of antibiotics will not be enough to reverse the growing prevalence of antibiotic resistance for some types of bacteria. Besides passing along the genes bestowing antibiotic resistance to their offspring, many bacteria can also swap genes among themselves through a process called conjugation.

The bacteria tested by researchers have fast conjugation rate, even if you don't use antibiotics the resistance can be maintained. Most resistance to antibiotics arises and spreads through natural selection. Some bacteria have genes that help them survive around of antibiotics, they quickly parent the next generation and pass on those genes.

Many of these genes, however, come at a cost. For example, a mutation may allow a bacterium to build a thicker membrane to survive a particular antibiotic, but that mutation might also make it more difficult for the cell to reproduce. Without the selective pressure of antibiotics killing off the competition, bacteria with this mutation should disappear over time.

The results indicate that for bacteria that swap resistance genes simply managing the amount of antibiotics being used will not turn the tide on the growing problem of resistance. To make any headway, drugs will also be needed that stop the sharing of genes and decrease the rate at which they are passed on through reproduction. One of the drugs is a benign natural product and FDA-approved antipsychotic.
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Throats can serve as reservoirs for gonorrhoea

Drug-resistant gonorrhoea can spread from an infected person's throat during oral sex. Oral gonorrhoea has increased due to oral sex and irregular use of condom.

Gonorrhoea is a sexually transmitted infection STI that can infect the genitals, throat, eyes and rectum. It spreads through unprotected sex.

The infection can also pass from an infected mother to a child during child birth. But it cannot be spread by kissing an infected person.

Common symptoms of gonorrhoea are: greenish yellowish discharge from penis or vaginal, a burning sensation when urinating, a rash on the penis and increased discharge from vaginal.

Untreated oral gonorrhoea can spread to the genitals, causing pelvic inflammatory disease, testicular pain, ectopic pregnancies and infertility.

Oral gonorrhoea is responsible for STI's antibiotic resistance, the bacteria in the throat are exposed to antibiotics when using the drugs for treating the infection. These throat bacteria reduce the effectiveness of the drug.
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Meningococcal B vaccine may prevents gonorrhoea

Vaccine used against a bacteria that causes brain inflammation can prevents gonorrhoea. Presently, using a condom or abstaining from sex are ways of preventing gonorrhoea.

Gonorrhoea can cause painful pelvic inflammation in women, and infertility in men and women. It can also spread into the bloodstream to cause life-threatening infections in other parts of the body. Infected pregnant woman can pass it to her fetus and cause blindness.

The disease spreads easily because many carriers are unaware of the disease, until they experience the symptoms. Gonorrhoea is becoming untreatable because of antibiotic resistance, there is an increased imperative to examine different vaccine for the treatment.

Researchers examined gonorrhoea cases among people who have used meningococcal B vaccine for Meningococcal bacteria, they noticed a decline in gonorrhoea after the use of meningococcal B vaccine.
This shows that meningitis vaccine can prevents gonorrhoea.
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