ASP News Scan for Nov 11, 2016

Resistance gene frequency
;
Plasmid-mediated resistance
;
New CABP antibiotic
;
ASP impact on C diff rates
;
Drug-resistant malaria

Our weekly wrap-up of antimicrobial stewardship & antimicrobial resistance scans

How monitoring resistance gene frequency can help combat AMR

Originally published by CIDRAP News on Nov 10.

A paper published yesterday in Open Biology argues that monitoring resistance gene frequency might be a better way to track and combat antimicrobial resistance (AMR) and could enable swifter, more accurate treatment of patients with bacterial infections.

To date, management of AMR has focused on tracking the rise of drug-resistant pathogens. But the authors of the paper argue that while such surveillance is essential, it only documents that end stage of the resistance process and ignores the root cause of AMR—the development and spread of genes that confer resistance to organisms. In addition, limiting the measurement of pathogenic organisms to the clinical setting ignores the reservoir of resistance genes available to pathogens in the wider environment.

Therefore, lead author Carolyn Michael, PhD, et al propose directly monitoring the entire genetic resistance resource available to microbes and measuring and analyzing the frequency of resistance-providing genes in both clinical and non-clinical environments, including shopping centers, transportation hubs, and sewage treatment centers. Doing so, they argue, will allow for better estimates of the changing scope of the AMR problem.

"Doing this will let us see rising numbers of resistance genes before they get to a pathogen and also keep an eye on the different types of resistance genes already in pathogens," Michael says in a University of Technology Sydney news release.

In addition, Michael and her colleagues write, understanding the rise and fall of resistance genes in the environment can guide both local and global antimicrobial stewardship efforts by helping clinicians know which antimicrobials are likely to be ineffective. And that, in turn, could lead to better treatment.
Nov 9 Open Biology
article
Nov 9 University Technology Syndey
news release


Study finds plasmids can accelerate evolution of antibiotic resistance
Originally published by CIDRAP News on Nov 9.     

A study published Monday in Nature Ecology and Evolution suggests plasmids may play more of a role in spreading and facilitating antibiotic resistance than previously thought.

Plasmids, which are mobile pieces of DNA, have long been known to spread resistance by facilitating the horizontal transfer of antibiotic-resistant genes between bacteria. An example of how plasmids work is found in MCR-1, a colistin-resistance gene that was identified in Escherichia coli bacteria in China and has since been found in more than 30 countries. But what is less clear is the role that plasmids play as catalysts in gene evolution.

To explore that question, researchers from the University of Oxford used a novel experimental model to determine whether bacteria carrying antibiotic resistance genes on plasmids have evolutionary advantages over bacteria that have resistance genes on chromosomes. The model involved creating strains of E Coli with a beta-lactamase gene on either the chromosome or a multi-copy plasmid, then exposing the strains to increasing concentrations of the antibiotic ceftazidime.

What the researchers found was that beyond facilitating horizontal gene transfer, the plasmid accelerated the development of ceftazidime resistance in the E coli strains by facilitating the evolution of novel variants of the gene, increasing the rate of appearance of those variants, and then amplifying the effects through greater gene expression.

"Our paper demonstrates that plasmids can also act as evolutionary catalysts that accelerate the evolution of new forms of resistance," senior author Craig MacLean, PhD, an associate professor in the department of zoology at Oxford, said in a university press release. "This occurs because bacteria usually carry more than one copy of a plasmid, which allows resistance genes carried by plasmids to rapidly evolve new functions—in this case, the ability to degrade an antibiotic. Additionally, plasmids automatically amplify the number of copies of these new and improved resistance genes."

MacLean and his colleagues say their findings have general implications for the "evolution of antibiotic resistance, adaptation and innovation in bacteria," and argue that they highlight the importance of developing new drugs that can block plasmid replication.
Nov 7 Nature Ecology and Evolution study
Nov 8 University of Oxford press release


FDA advisory panel recommends new antibiotic for approval
Originally published by CIDRAP News on Nov 8.

An advisory panel to the US Food and Drug Administration (FDA) voted on Nov 3 to recommend a new antibiotic to treat community-acquired pneumonia (CABP), despite concerns over liver toxicity.

In a 7-6 vote, members of the FDA's Antimicrobial Drugs Advisory Committee recommended approval of the drug solithromycin, a macrolide antibiotic that has activity against macrolide-resistant CABP pathogens. But while the panel voted unanimously (13-0) that there was substantial evidence of solithromycin's efficacy, and that the drug works as well as moxifloxacin in patients with CABP, they also voted 12-1 that the risk of hepatoxicity has not been adequately characterized.

Reuters reports that clinical trials of solithromycin showed greater number of patients taking the drug developed elevated liver enzymes than those taking moxifloxacin, a possible sign of underlying liver damage. But there were no cases of acute liver injury. The panel recommended that drug maker Cempra Inc. be required to conduct additional studies on potential liver damage after the drug is approved.

"We appreciate the meaningful discussion from today's panel. Their supportive view and thoughtful comments on approaches to ensuring appropriate use are consistent with Cempra’s commitment to make solithromycin available to the right patients for a five to seven day course of an oral and/or IV macrolide as monotherapy for CABP," Cempra president and CEO Prabhavathi Fernandes PhD, said in a company press release.

Cempra argues that new antibiotics for the treatment of CABP are much needed, as rates of pneumococcal resistance to macrolides can exceed 50%.

The FDA is not bound by the advisory panel's recommendations.
Nov 4 Cempra Inc. press release
Nov 4 Reuters story

 

Study finds limiting use of '4C' antibiotics can reduce C diff infection rates
Originally published by CIDRAP News on Nov 8.

A new study out of Scotland suggests that limiting the use of antibiotics associated with Clostridium difficile infection risk can reduce C difficile infection rates in hospital and community populations.

The study, published Nov 4 in the Lancet Infectious Diseases, was an observational and quasi-experimental time-series analysis that aimed to measure the impact of an antibiotic stewardship program (ASP) in northeast Scotland that emphasized reduction in hospital and community use of antibiotics linked to C difficile infection. The antibiotics—known as the 4Cs—included ciprofloxacin/fluoroquinolones, co-amoxiclav, clindamycin, and cephalosporins. After implementation, use of the 4C antibiotics was reduced by 50% in hospitals and the community.

Other infection control and prevention measures in the ASP included a hand-hygiene campaign, national auditing and inspections of hospital environment cleanliness, and reduced inappropriate use of proton-pump inhibitors. The total effect of interventions, which were initiated in 2009, was defined as the difference between the C difficile infection burden with the ASP and projected scenarios without stewardship.

From 1997 to 2012, investigators identified 4,885 cases of hospital-onset C difficile and 1,625 cases of community-onset C difficile. Controlling for multiple cofounders, the authors estimated that after implementation of the ASP, C difficile infection prevalence fell by 68% in hospitals and 45% in the community compared to projected scenarios without the ASP. Further analysis indicated that declines in C difficile could be explained by the removal of antibiotic selection pressure favoring multidrug-resistant ribotypes R001 and R027, which have been associated with higher incidence and more severe disease. No significant effects from other measures of the ASP were identified.

"Our study adds to existing evidence that antibiotic stewardship might be an effective tool for the control of C difficile infection in both hospitals and the community," the authors wrote.
Nov 4 Lancet Infect Dis study
Nov 4 Lancet Infect Dis commentary


Studies identify genetic markers for drug-resistant malaria

Originally published by CIDRAP News on Nov 7.

Two papers published last week in The Lancet Infectious Diseases describe the identification of molecular markers associated with drug resistance in Plasmodium falciparum malaria.

The two papers were genome-wide association studies of Cambodian strains of P falciparum that were looking to find molecular markers for resistance to piperaquine, a drug that is used in artemisinin combination therapies. As malaria in the Greater Mekong subregion becomes increasingly resistant to artemisinin and the partner drugs that are used to treat the P falciparum parasite—which accounts for most malaria cases and deaths—molecular markers are urgently needed to help public health officials monitor the spread of resistance and recommend alternative treatments.

In addition to Cambodia, artemisinin resistance has been detected in Laos, Myanmar, Thailand, and Vietnam.

In one study, led by researchers from the National Institute of Allergy and Infectious Diseases (NIAID) and the UK's Wellcome Trust Sanger Institute, investigators compared the complete genomes of 297 parasites isolated from Cambodian malaria patients to a reference malaria parasite genome and identified two genetic markers—amplifications of the exo-E425G and plasmepsin 2 and 3 genes—associated with the parasites' ability to resist piperaquine. The researchers believe that the amplification of the plasmepsin 2 and 3 genes may play a functional role in enabling parasites to resist piperaquine.

In the other study, researchers from the Institut Pasteur in Cambodia did a gene-wide association study on 31 malaria strains to define the resistant in-vitro phenotype. They found that an increased plasmepin 2 gene copy number was strongly associated with dihydroartemisinin-piperaquine treatment failure.

"The converging results of these studies make plasmepsin 2–3 amplification a robust marker for piperaquine resistance in the region," an accompanying commentary notes. "P falciparum transfected with multicopy plasmepsin 2–3 will be an invaluable tool to explore underlying resistance mechanisms."

Information about the distribution of these drug resistance markers, a press release from NIAID explains, is being used by officials in Cambodia and neighboring countries to determine the spread of piperaquine resistance and help guide treatment approaches.
Nov 3 Lancet Infect Dis study
Nov 3 Lancet Infect Dis
study
Nov 3 Lancet Infect Dis
commentary
Nov 3 NIAID
press release

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