Tag Archives: Vancomycin

Extended-pulsed fidaxomicin Found Superior to Standard-dose vancomycin To Treat C.difficile Infection In Older Adults

In a randomized, controlled, open label phase 3b/4 trial (ClinicalTrials.gov identifier: NCT02254967), hospitalized patients age 60 years and older with confirmed C difficile infection were recruited from 86 European hospitals. Patients were randomly assigned to receive extended-pulsed fidaxomicin (200-mg oral tablets, twice daily on days 1–5, then once daily on alternate days on days 7-25) or vancomycin (125-mg oral capsules, 4 times daily on days 1-10).

Of the 177 patients receiving fidaxomicin, 124 (70%) achieved the primary end point of sustained clinical cure 30 days posttreatment, compared with 106 (59%) of 179 who received vancomycin (odds ratio 1.62; 95% CI 1.04-2.54, P =.03).

Multivariate analysis, which included treatment arm and baseline stratification factors (infection severity, cancer presence, age, and number of previous C difficile infection occurrences) as covariates, also indicated fidaxomicin to be superior (P =.035). A subanalysis of microbiota diversity concluded that microbiota recovery was greater in the fidaxomicin group, and a Cox proportional hazards model suggested that the hazard of infection recurrence in the vancomycin group was 3.8 times greater.

This study demonstrates the superiority of extended-pulsed fidaxomicin treatment over standard treatment with vancomycin. The researchers note the absence of blinding and racial diversity in the study group as limitations and recommend that future investigations should study this treatment course in patients age 60 years and younger and should compare this treatment course with standard fidaxomicin treatment protocols.

Disclosure

The study was funded by Astellas Pharma Inc, who were involved in all stages of the study, including manuscript preparation.

Reference

Guery B, Menichetti F, Anttila V-J, et al.; for the EXTEND Clinical Study Group. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial. [published online December 19, 2017]. Lancet Infect Dis. doi: 10.1016/S1473-3099(17)30751-X

 

To read the article in its entirety please click on the following link:

https://www.infectiousdiseaseadvisor.com/clostridium-difficile/extended-pulsed-fidaxomicin-vs-vancomycin-sustained-clostridium-difficile-infection-cure/article/738757/

Researchers Long Efforts Find Super-Antibiotics May Combat Vancomycin-Resistant Bacteria

Vancomycin, long considered a “drug of last resort,” kills by preventing bacteria from building cell walls. It binds to wall-building protein fragments called peptides, in particular those that end with two copies of the amino acid D-alanine (D-ala). But bacteria have evolved. Many now replace one D-ala with D-lactic acid (D-lac), sharply reducing vancomycin’s ability to bind to its target.

The world’s last line of defense against disease-causing bacteria just got a new warrior: vancomycin 3.0. Its predecessor—vancomycin 1.0—has been used since 1958 to combat dangerous infections like methicillin-resistant Staphylococcus aureus.

But as the rise of resistant bacteria has blunted its effectiveness, scientists have engineered more potent versions of the drug—vancomycin 2.0.

Now, version 3.0 has a unique three-pronged approach to killing bacteria that could give doctors a powerful new weapon against drug-resistant bacteria and help researchers engineer more durable antibiotics.

“This is pretty special,” says Scott Miller, a chemist at Yale University who was not involved in the new work. “It’s really the culmination of a decades-long effort.”

Vancomycin, long considered a “drug of last resort,” kills by preventing bacteria from building cell walls. It binds to wall-building protein fragments called peptides, in particular those that end with two copies of the amino acid D-alanine (D-ala). But bacteria have evolved. Many now replace one D-ala with D-lactic acid (D-lac), sharply reducing vancomycin’s ability to bind to its target.

Today, that resistance has spread so that dangerous infections like vancomycin-resistant enterococci (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA) are becoming more common. According to the U.S. Centers for Disease Control and Prevention, about 23,000 Americans die from 17 antibiotic-resistant infections each year (although it’s difficult to parse out how much is due to vancomycin resistance).

To solve the D-lac problem, researchers led by Dale Boger, a chemist at the Scripps Research Institute in San Diego, California, began synthesizing new versions of vancomycin that bind to peptides ending in D-ala and D-lac.

They succeeded in 2011. Meanwhile, other groups developed new ways of killing bacteria with vancomycin: One alteration found a novel way to halt cell wall construction, whereas another caused the outer wall membrane to leak, leading to cell death.

TO READ ARTICLE IN ITS ENTIRETY:  

http://www.sciencemag.org/news/2017/05/superantibiotic-25000-times-more-potent-its-predecessor

Now, Boger and his colleagues have assembled all three weapons into one single vancomycin analog.

The new antibiotic is at least 25,000 times more potent against microbes such as VRE and VRSA, they report this week in the Proceedings of the National Academy of Sciences.

Moreover, when Boger’s team tested vancomycin-resistant bacteria against the new three-part analog, the microbes were unable to evolve resistance even after 50 rounds.

Many antibiotics begin to fail after just a few rounds.

This suggests the new compound may be far more durable than current antibiotics, Boger says.

“Organisms just can’t simultaneously work to find a way around three independent mechanisms of action,” he says. “Even if they found a solution to one of those, the organisms would still be killed by the other two.”

Miller adds that antibiotics are often found by trial and error when researchers test a new compound to see whether it stops bacterial growth. By contrast, this work shows the power of rationally designing novel antibiotics to hit microbes where they are weak. “Getting something to do two things by design is hard. Getting something to do three things by design is even harder.”

Still, Boger cautions that the new compound isn’t yet ready for human trials. Next up, he and his colleagues plan to cut down on the 30 chemical steps it takes to make the new compound, in the hopes of producing it more cheaply.

Then they’ll test their drug in animals, and finally humans. If it passes this gauntlet, humanity’s last line of defense against dangerous infections will become considerably stronger.