ASP Scan (Weekly) for Apr 27, 2018

Gonorrhea treatment adherence
CRE sepsis trends
Pan-resistant infections in England
Antibiotic development partnership
Mass distribution of azithromycin
Probiotics and CDI
New CARB-X funding
Candida auris risk in Europe
Changing resistance gene
Global antibiotic prescribing
Urinary tract infection treatment
Evolution of colistin resistance
Regional hospital antibiograms

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

CDC report finds high adherence to recommended gonorrhea treatment

A new surveillance report from the US Centers for Disease Control and Prevention (CDC) found a high level of adherence to the agency's recommended treatment for uncomplicated gonorrhea.

In today's Morbidity and Mortality Weekly Report (MMWR), CDC researchers estimate that 81.3% of reported patients with gonorrhea received the recommended regimen of 250 mg of ceftriaxone plus 1 g of azithromycin. The CDC recommends adherence to the dual antimicrobial therapy to slow the spread of drug-resistant gonorrhea, which has become a rising concern among public health officials around the world.

The estimate comes from a review of data collected on a random sample of reported gonorrhea cases in seven jurisdictions participating in the STD Surveillance Network (SSuN). A total of 91,719 cases were reported, and 8,393 (9.2%) were randomly sampled. Patients diagnosed with gonorrhea in STD clinics (90.8%) or family planning/reproductive health clinics (93.8%) were more likely to receive the recommended regimen than patients diagnosed in other settings (79.5%), and men who have sex with men were more likely to receive appropriate treatment than heterosexual men and women (84.8% vs. 79.4%).

Overall, 18.7% of patients received other regimens, most frequently ceftriaxone only, ceftriaxone and doxycycline, and azithromycin only. These treatments are not recommended due to concerns about emerging resistance and treatment failure.

"Despite the high level of treatment adherence documented in this analysis, improving provider adherence to treatment recommendations for antibiotic use across the full spectrum of health care settings is an integral part of a comprehensive approach to combating the emergence of antimicrobial-resistant gonorrhea," the authors write. "State and local health departments should continue to work with the providers and patients to assure timely detection and treatment of gonorrhea according to current CDC treatment recommendations."
Apr 27 MMWR report


Hospital study finds sharp rise in CRE-related sepsis

A study looking at carbapenem-resistant gram-negative sepsis in patients hospitalized in a St Louis facility between 2012 and 2015 found a dramatic increase, researchers reported yesterday in the American Journal of Infection Control.

The retrospective cohort study took place at an urban academic medical center and included patients ages 18 and older who were positive for carbapenem-resistant Enterobacteriaceae (CRE) or carbapenem-resistant non-Enterobacteriaceae (CRNE) from any body site. Of 448 patients included in the study, 24.8% were positive for CRE and 75.2% were positive for CRNE. Researchers saw a significant increase in the number of CRE sepsis cases over the study period, driven mainly by Enterobacter species.

Though clinical outcomes didn't vary between the CRE and CRNE groups, the team found unique differences between patients with CRE sepsis and those with CRNE sepsis. For example, patients with CRE sepsis were more likely to have genitourinary infection, while their counterparts with CRNE sepsis were more likely to be admitted to the intensive care unit (ICU), have a respiratory tract infection, and have a history of previous hospitalization and antibiotic exposures. Deaths were slightly higher, but not at a statistically significant level, in those with CRNE sepsis.

The most striking finding they found was a shift in burden over the 4-year study period; CRNE infections were responsible for 90% of cases in 2012, but were only attributed to 60% of cases by 2014. Researchers also saw a sharp increase in sepsis caused by Enterobacter species, but they said it's not clear what's behind the rise, which has also been reported in a recent analysis of Veteran's Health Administration data. Alongside that rise, the team also noted a significant decline in CRE infections caused by Klebsiella pneumoniae, for which other studies have also shown declining or stable levels.

They concluded that more extensive infection control and antibiotic stewardship steps, especially aimed at Enterobacter species, may be needed to address the worrisome increase in CRE infections.
Apr 26 Am J Infect Control abstract


Dozens of pan-resistant bacterial infections reported in England

Untreatable antibiotic-resistant infections have affected 36 patients in England over the last 5 years, according to a story yesterday in the Telegraph.

Figures obtained by the paper from Public Health England (PHE) through a Freedom of Information request show that from 2013 through 2018, 36 cases of pan-resistant infections were recorded. PHE defines a pan-resistant infection as one caused by bacteria resistant to every antibiotic tested.

Twenty-nine of the cases were caused by pan-resistant Pseudomonas bacteria, and six were Klebsiella infections. The other case was an untreatable gonorrhea infection that was recently reported by PHE. 

"While there is only a small number of bacteria identified that were resistant to a number of treatments in recent years, they serve as an example of the threat antibiotic resistance poses to public health," Susan Hopkins, MD, PHE's director of antimicrobial resistance and healthcare acquired infections, told the paper.
Apr 26 Telegraph story


US, Chinese companies announce partnership on combination antibiotic

Massachusetts-based biopharmaceutical company Entasis Therapeutics has announced a partnership with China's Zai Lab Limited to develop and commercialize a novel beta-lactam/beta-lactamase inhibitor combination in the Asia-Pacific region, according to a company press release.

The drug, ETX2514SUL, is a combination of Entasis's novel beta-lactamase inhibitor ETX2514 and sulbactam. Currently in Phase 2 development, ETX2514SUL is for the treatment of serious multidrug-resistant infections caused by Acinetobacter baumannii. According to national surveillance, there are over 200,000 A baumannii infections in China each year. The pathogen is becoming increasingly resistant to carbapenems, which greatly limits treatment options.

Under the agreement, the two companies will cooperate in conducting a phase 3 clinical trial in China, and Zai Lab will have an exclusive license to market the drug in specified countries in the Asa-Pacific region. 
Apr 25 Entasis press release


Study: Mass distribution of azithromycin reduces childhood mortality in Africa

Originally published by CIDRAP News Apr 26

A study today in the New England Journal of Medicine reports that childhood mortality in sub-Saharan African communities randomly assigned to mass distribution of azithromycin was lower than in those assigned a placebo. But the authors warn that resistance emerging from mass distribution of the antibiotic could curb or reverse any potential benefit.

In a cluster-randomized trial conducted by an international team of researchers, communities in Malawi, Niger, and Tanzania were assigned to four biannual mass distributions of either oral azithromycin or placebo to children ages 1 to 59 months. Because azithromycin has been shown to reduce rates of infectious diseases like malaria, trachoma, and pneumonia in poor rural communities, and a case-control study in Ethiopia suggested mass distribution of the drug might reduce childhood mortality, the investigators wanted to see if mass distribution in three geographically distinct areas in Africa could have an impact on childhood mortality.

A total of 1,533 communities underwent randomization, with 97,047 children in the azithromycin group and 93,191 in the placebo group. Over five census visits, 323,302 person-years were monitored. At the end of the trial, the annual mortality rate for eligible children in the three countries was 14.6 deaths per 1,000 person-years in the communities that received azithromycin and 16.5 deaths per 1,000 person-years in the communities that received placebo. Mortality was 13.5% lower overall in the communities that received azithromycin, with a larger impact seen in Niger (18.1% lower) than in Malawi (5.7% lower) and Tanzania (3.4% lower). Children in the ages 1 to 5 months who received azithromycin saw the greatest benefit, with 24.9% lower mortality compared with those who received placebo.

The trial did not investigate how azithromycin prevented death, but the authors of the study say research into that question is already underway. In addition, they say further follow-up is warranted to determine whether the mortality effect observed in the trial changes with subsequent rounds of treatment. That could provide insight into the potential impact of side effects and emerging resistance.

They conclude, "Any policy that recommends mass distribution of oral azithromycin to address childhood mortality would need to consider not only cost but also the risk of side effects, especially the potential for the induction or amplification of antibiotic resistance."
Apr 26 N Engl J Med study


Studies assess effect of probiotics in C difficile infection

Originally published by CIDRAP News Apr 26

Two studies today in Infection Control and Hospital Epidemiology suggest that probiotics may be a prevention tool for Clostridium difficile infection (CDI).

In the first study, an international group of researchers analyzed 18 randomized controlled trials with data on 6,851 patients that compared probiotic prophylaxis to placebo or to no treatment and that reported CDI as an outcome. They found that probiotics reduced CDI odds by nearly two-thirds in both the unadjusted model (odds ratio [OR] 0.37) and the adjusted model (OR 0.35). In addition, a subgroup analysis suggested that, compared to no probiotics, multispecies probiotics were more beneficial than single species probiotics, as was using probiotics in clinical settings where the CDI risk was greater than 5%. Odds for serious adverse events were similar in both groups.

The authors of the study concluded that the results provide moderate quality evidence for probiotic prophylaxis may be a useful and safe CDI prevention strategy. "While it's not a perfect solution for a bacterium that has proven very difficult to prevent and treat, probiotics could offer patients another line of defense," lead author Bradley Johnson, PhD, of Dalhousie University said in a press release from journal publisher the Society for Healthcare Epidemiology of America (SHEA).

In the second study, a separate team of researchers evaluated a before-and-after quality improvement intervention program in which all eligible antibiotic recipients at a tertiary care hospital received capsules containing a three-probiotic mixture, to be taken within 12 hours of their initial dose of antibiotics. Comparing the hospital-onset CDI incidence during the 12-month baseline and intervention periods, the researchers found that the incidence rate was similar—6.9 per 10,000 patient days in the baseline period vs. 7.0 per 10,000 patient days in the intervention period. But they also detected a significant decrease in CDI during the final 6 months of the intervention compared with the first 6 months. Overall adherence to the protocol was low, with only 26% of eligible patients receiving a probiotic.

The authors say the delayed effect may have been related to poor adherence to the protocol for probiotic administration and a delayed gradual reduction in environmental contamination.
Apr 26 Infect Control Hosp Epidemiol study #1
Apr 26 Infect Control Hosp Epidemiol study #2
Apr 26 SHEA press release


CARB-X to fund development of next-generation aminoglycoside

Originally published by CIDRAP News Apr 26

CARB-X today announced an initial award of up to $2.4 million to biopharmaceutical company Achaogen for the development of a next-generation aminoglycoside antibiotic.

According to a press release from CARB-X (the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator), the funding will help Achaogen further develop an aminoglycoside that has been engineered to overcome resistance mechanisms. The hope is that this next-generation aminoglycoside will be able to treat drug-resistant pathogens such as Enterobacteriaceae, Pseudomonas aeruginosa, and A baumannii.

"We are honored to have CARB-X's support in advancing our novel aminoglycoside program, which we believe has significant potential to address the growing multi-drug resistance problem in gram-negative bacteria," Achaogen chief scientific officer Lee Swem, PhD, said in the press release.

Achaogen could receive up to $9.6 million more in two additional stages based on the achievement of certain project milestones.

Since it was established in 2016, CARB-X has awarded nearly $80 million to accelerate the development of new antibiotics, diagnostics, and other products to address antibiotic resistance.
Apr 26 CARB-X press release


ECDC urges adapting Candida auris lab testing, early control measures

Originally published by CIDRAP News Apr 24

In an updated risk assessment on Candida auris, an emerging difficult-to-treat fungus that can spread in healthcare settings, the European Centre for Disease Prevention and Control (ECDC) said yesterday that the rising number of cases in Europe is concerning because of problems with lab identification and overall lack of awareness.

The antimicrobial-resistant fungus, first reported in Japan, has spread to five continents, and the ECDC said that from 2013 through 2017, 620 cases have been reported in six European countries. The illnesses are often resistant to multiple classes of antifungal medications. The ECDC published an initial risk assessment in December 2016.

In a press release, Dominique Monnet, PharmD, PhD, who leads the ECDC's Antimicrobial Resistance and Healthcare-associated Infections Disease Program, said there's a need to raise awareness in European health facilities, so they can adapt lab testing strategies and implement control measures early enough to stem more hospital outbreaks.

"The occurrence of new outbreaks can be expected. It is therefore of concern that some countries lack national laboratory reference capacity for mycology, or have no information on Candida auris cases available at national level," he said.
Apr 23 ECDC press release
Apr 23 ECDC 
risk assessment


Antimicrobial resistance evolution tied to regulatory gene

Originally published by CIDRAP News Apr 24

Researchers from Oxford University have uncovered the genetic catalysts behind antibiotic resistance evolution. The work was published yesterday in Nature Ecology & Evolution.

The scientists tested the hypothesis that different bacteria develop resistance at different rates by challenging species of the Pseudomonas genus—bacteria that cause disease in humans, animals, and plants—with the antibiotic ceftazidime.

They found that different species of Pseudomonas developed resistance to ceftazidme at different rates because of the actions of a master regulatory gene, called ampR.

"Species that carry the ampR gene evolve resistance at a higher rate than species that lack this gene," said lead author Craig MacLean, PhD, from Oxford's department of zoology, in a press release. "ampR has this effect because it makes it easier for random mutations to increase the expression of antibiotic resistance genes."

The researchers then blocked the development of ampR in P aeruginosa with an enzyme inhibitor called avibactam. When used with ceftazidime, avibactam helped slow antibiotic resistance, a technique, the authors said, that will need to be replicated in in-vivo experiments.
Apr 23 Nat Ecol Evol study 
Apr 23 University of Oxford press release


Global hospital survey highlights antibiotic Rx, high guideline compliance

Originally published by CIDRAP News Apr 23

The first data published by the Global Point Prevalence Survey reveal that penicillins with beta-lactamase inhibitors, third-generation cephalosporins, and fluoroquinolones were the most frequently prescribed antibiotics, and guideline compliance was 77.4%. The data, from 2015, were published Apr 19 in The Lancet Global Health.

The researchers used a standardized web-based surveillance method to gather data from 303 hospitals treating adults in 53 countries, including 8 lower-middle-income and 17 upper-middle-income nations. Of the 86,776 patients, 29,891 (34.4%) received at least one antimicrobial. Of the 41,213 prescriptions for antimicrobials, 36,792 (89.3%) were for systemic use. In addition to the data on the three most popular antibiotics, the authors reported that carbapenems were most frequently prescribed in Latin America and west and central Asia.

Of patients who received at least one antimicrobial, 5,926 (19.8%) received a targeted antibacterial for systemic use, and 1,769 (5.9%) received a treatment for multidrug-resistant organisms. The reason for treatment was recorded for 31,694 antimicrobial prescriptions (76.9%), and a stop or review date was specified in 15,778 (38.3%). Local antibiotic guidelines were missing for 7,050 (19.2%) of the 36,792 systemic antibiotic prescriptions, and guideline compliance was 77.4%.

The authors conclude, "The Global Point Prevalence Survey complements WHO's [World Health Organization's] Global Antimicrobial Surveillance System (which provides a standardised approach for collection, analysis, and sharing of data for antimicrobial resistance) by providing a validated method for measuring the quality of antimicrobial prescribing and the effect of interventions to improve prescribing."

They add, "These data will help to improve the quality of antibiotic prescribing through education and practice changes, particularly in low-income and middle-income countries that have no tools to monitor antibiotic prescribing in hospitals."

The study was funded by France-based biotechnology company bioMerieux.
Apr 19 Lancet Glob Health study


Study: Nitrofurantoin beats fosfomycin for uncomplicated UTI

Originally published by CIDRAP News Apr 23

A 5-day course of nitrofurantoin resolved a higher rate of uncomplicated urinary tract infections (UTIs) than one dose of fosfomycin, according to a new study published in the Journal of the American Medical Association (JAMA). Both antibiotics are first-line therapies for UTIs.

In the multicenter international study, 377 women with a confirmed UTI were randomly dosed with either a 5-day course of nitrofurantoin (100 mg three times a day) or one, 3-gram dose of fosfomycin. The primary outcome was clinical resolution at day 28. Seventy percent of patients who received nitrofurantoin were clinically cleared of their UTIs by day 28, compared with 58% of patients who received fosfomycin.

Nitrofurantoin was particularly effective in treating infections caused by Escherichia coli, with 78% of patients being cured by day 28, compared with 50% in the fosfomycin group.

An accompanying editorial in JAMA said the study uses a rigorous study design to reaffirm nitrofurantoin's place as the preferred first-line choice in treating UTIs, which accounts for approximately 10 million ambulatory visits and an estimated $2 billion in total costs each year in the United States. 
Apr 22 JAMA 
Apr 22 JAMA editorial


French case study shows evolution of colistin-resistant bacteria

Originally published by CIDRAP News Apr 23

French researchers tracked the evolution of a K pneumoniae carbapenemase (KPC) strain of bacteria for more than 4.5 years in a patient who ultimately died from sepsis. The case study, published in Clinical Infectious Diseases, shows the bacteria is capable of several genomic and phenotypic diversifications and mutations in a relatively short period, even from drug resistance to susceptibility.

The patient contracted the bacterium via a contaminated endoscope at a French tertiary care hospital in 2009. The patient was seeking treatment from chronic infection in the liver's bile ducts.

Researchers collected 17 isolates until the patient died in 2014. All 17 isolates were subjected to whole-genome sequencing. During the study period, a total of 98 genetic events occurred, and the average evolutionary rate of the KPC strain was 7.5 single nucleotide polymorphisms per year per genome.

Most interestingly, the researchers reported, "The contaminating strain was colistin resistant but after two years of carriage, all isolates became susceptible to colistin."
Apr 21 Clin Infect Dis study  


Study finds regional antibiograms may benefit community hospitals

Originally published by CIDRAP News Apr 23

A study of 20 community hospitals in North Carolina and Virginia determined that a regional antibiogram can provide useful information to these hospitals even for low-prevalence pathogens, according to a study today in Infection Control and Hospital Epidemiology.

Antibiograms are profiles of antimicrobial susceptibility testing results of a specific pathogen to a battery of antimicrobial drugs. To determine the feasibility and value of developing a regional antibiogram for community hospitals, Duke University scientists analyzed data on 69,778 bacterial isolates across 13 gram-negative pathogen-antibiotic combinations. Combinations ranged from 174 to 27,428 results, for a median of 1,100.

The team found that, across all pathogen-antibiotic combinations, 69% of local susceptibility rates fell within 1 standard deviation (SD) of the regional mean, and 97% fell within 2 SDs. But no individual hospital had more than 1 pathogen-antibiotic combination with a local susceptibility rate of more than 2 SDs of the regional mean, and all local susceptibility rates were within 2 SDs of the regional mean for low-prevalence pathogens.

The authors conclude, "Small community hospitals frequently cannot develop an accurate antibiogram due to a paucity of local data. A regional antibiogram is likely to provide clinically useful information to community hospitals for low-prevalence pathogens."
Apr 23 Infect Control Hosp Epidemiol abstract

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