ASP Scan (Weekly) for Oct 19, 2018

Undetected MDR-TB in South Africa
Carbapenem prescribing algorithm
Rapid susceptibility tests
AMR surveillance in South Korea
Biomarkers and sepsis management
C difficile on hospital bed sheets
Colistin resistance diagnostics
Dearth of point-of-care tests
New-antibiotic distribution

Study finds current diagnostic tests missing MDR-TB cases in South Africa

An international team of researchers found that the World Health Organization (WHO)-endorsed diagnostic tests for drug-resistant tuberculosis (TB) are missing a substantial number of multidrug-resistant (MDR) TB cases in South Africa. The study appeared yesterday in Lancet Infectious Diseases.

For the study, the team of researchers from France, Belgium, and South Africa screened records of 37,644 Mycobacterium tuberculosis-positive cultures that had been detected in four South African provinces from 2013 through 2016 using standard diagnostic tests, including two rapid molecular assays endorsed by the WHO (Xpert MTB/RIF and GenoType MTBDRplus version 2.0). While these tests detect most genetic mutations conferring resistance to the first-line TB drugs rifampicin and isoniazid, they don't detect the ile491Phe mutation in the rpoB gene, which is associated with poor rifampicin-based treatment outcomes. Although the worldwide prevalence of this mutation is considered low, a 2009 study in Swaziland had found that nearly 30% of MDR-TB cases contained that mutation.

To find out how many of the TB-positive cultures contained this mutation, the researchers randomly selected 277 isolates identified as isoniazid resistant and rifampicin sensitive and tested them with two alternative diagnostic tests, one of which specifically targets the rpoB ile491Phe mutation. They also conducted whole genome sequencing. The results revealed that 37 of 249 (15%) of the isolates previously classified as isoniazid monoresistant contained the genetic mutation and therefore could be reclassified as MDR-TB. The tests also found additional mutations associated with resistance to other first-line TB drugs, including four distinct mutations associated with resistance to bedaquiline, one of the newest antibiotics for treating MDR-TB cases.

As a result, the researchers determined that 68% of patients in the study who had been infected by strains carrying these mutations had undergone at least one unsuccessful previous first-line TB treatment, and could be contributing to the spread of these strains in the community.

"A substantial number of MDR tuberculosis cases harbouring the Ile491Phe mutation in the rpoB gene in South Africa are missed by current diagnostic strategies, resulting in ineffective first-line treatment, continued amplification of drug resistance, and concurrent silent spread in the community," the authors of the study wrote. 
Oct 17 Lancet Infect Dis study


Prescribing algorithm reduces carbapenem use in single-center study

A team of pharmacists and physicians at a small community hospital in California report that a carbapenem prescribing algorithm led to a threefold reduction in carbapenem use, according to a study yesterday in Infection Control and Hospital Epidemiology.

The algorithm developed at Sutter Tracy Community Hospital aimed to reduce overall carbapenem use by decreasing inappropriate use in patients. The hospital's antimicrobial stewardship committee was particularly concerned about the unrestricted use of imipenem-cilastatin, an antipseudomonal beta-lactam with an observed decrease in effectiveness against multidrug-resistant Pseudomonas aeruginosa. Using prospective audit and feedback, pharmacists evaluated all new orders for carbapenems and recommended alternative therapies when patients failed to meet the algorithm's criteria. The algorithm was implemented in December 2015.

In the quasi-experimental study, researchers collected 3 months of pre-intervention baseline data on carbapenem use, then compared carbapenem use in the immediate post-intervention period, 6 months post-intervention, and 1 year post-intervention. The primary end-points were carbapenem days of therapy adjusted per 1,000 patient-days (DOT) and the percentage of patients who met algorithm use criteria.

The researchers observed that DOT dropped from 131.8 at baseline to 40.1 in the immediate post-intervention period and remained low (42.9) at 6 months post-intervention. Although DOT climbed to 64.5 at 1 year post-intervention, it remained less than half of the baseline level. The percentage of patients who met algorithm use criteria climbed from 20% at baseline to 79% at 1 year post-intervention. The overall reduction in carbapenem use improved susceptibility to P aeruginosa and reduced pharmacy costs (compared with 2015) by $75,000 in 2016 and $65,000 in 2017.

The authors conclude, "Pharmacy-driven ASP [antimicrobial stewardship program]strategies may be particularly effective at both reducing antimicrobial utilization and improving antimicrobial susceptibility trends at small community hospitals."
Oct 17 Infect Control Hosp Epidemiol abstract


Paper lays out hurdles for developing rapid antibiotic susceptibility tests

Originally published by CIDRAP News Oct 18

An international group of specialists from hospitals, research institutes, public health agencies, and diagnostics firms yesterday published a paper outlining the challenges to developing novel and rapid antibiotic susceptibility tests (ASTs). The consensus statement was published in Nature Reviews Microbiology.

ASTs are necessary to ensure that patients with bacterial infections get the most appropriate treatment. They also enable healthcare facilities to collect data on local patterns of antibiotic resistance; this data can be used to craft policies guiding empiric antibiotic therapy and to design strategic actions to control the spread of antibiotic-resistant pathogens. But current AST methods are time consuming (between 12 and 48 hours), and even currently available rapid tests take several hours and lack full automation. And when infections are severe, a delay in appropriate treatment can be the difference between life and death.

"Therefore, to facilitate targeted (and personalized) antimicrobial prescribing practices and to help reduce the increasing global burden of antibiotic resistance, there is an urgent need for the development and implementation of novel and truly rapid AST platforms (that is, results being available in 30 min to 1 h)," the authors write.

But the development of widely used rapid AST platforms has been slow over the past decade, the authors explain, for a variety of reasons. These include complex legal and regulatory landscapes; a complicated, multi-step development process that favors large diagnostics companies over small- and medium-sized enterprises; issues with quality and quality control; and difficulties in demonstrating the clinical utility, validity, and cost-effectiveness of new ASTs.

The authors say they hope that laying out these challenges will lead to increased dialogue between AST developers and end users and, ultimately, improve patient care.

"Better communication about the importance of AST should lead to better collaboration between the public, academia, patient groups, policy makers and industry," they write. "Understanding AST platform development and implementation issues will lead to a better understanding of the barriers and solutions required by public and private entities in maximizing the availability and use of (new and rapid) AST platforms."
Oct 17 Nat Rev Microbiol paper


Report shows results from new South Korean AMR surveillance system

Originally published by CIDRAP News Oct 18

Scientists from South Korea today published the first year of results from the government's new antimicrobial resistance (AMR) surveillance system, Kor-GLASS, which is modeled after the WHO's Global AMR Surveillance System. The findings, along with a description of how Kor-GLASS was established, appear in Eurosurveillance.

From May 2016 through April 2017, non-duplicated isolates of major pathogens from blood, urine, feces, and urethral and cervical swabs were collected from six sentinel hospitals and tested at a central laboratory. Among 67,803 blood cultures, 3,523 target pathogens were recovered; Escherichia coli (1,536 isolates), Klebsiella pneumoniae (597), and Staphylococcus aureus (584) were the predominant bacterial species identified. Among 57,477 urine cultures, 6,394 E coli and 1,097 K pneumoniae isolates were recovered. From 12,782 stool cultures, 77 Salmonella spp. were recovered. None of the 3,111 genital cultures were positive for Neisseria gonorrhoeae.

Analysis of AMR prevalence in the major pathogens showed that 54.3% of the S aureus isolates were methicillin-resistant, 34.7% of E coli blood isolates and 27.0% of K pneumoniae blood isolates were resistant to cefotaxime, and 29.0% of Enterococcus faecium isolates were resistant to vancomycin. While resistance rates in E coli urine isolates were similar to those in blood isolates, K pneumoniaurine isolates exhibited higher rates of resistance than K pneumoniae blood isolates. In addition, carbapenem and colistin resistance were identified more frequently in K pneumoniae blood and urine isolates than E coli blood and urine isolates. Among Acinetobacter baumannii isolates, 76.1% were multidrug-resistant, and 13.8% were extensively drug-resistant.

Bloodstream infections in inpatients per 10,000 patient-days were highest for cefotaxime-resistant E coli with 2.1, followed by 1.6 for methicillin-resistant S aureus, 1.1 for imipenem-resistant A baumannii, 0.8 for cefotaxime-resistant K pneumoniae, and 0.4 for vancomycin-resistant E faecium.Urinary tract infections in inpatients were 7.7 and 2,1 per 10,000 patient-days for cefotaxime-resistant E coli and K pneumoniae, respectively.

The authors of the report say that the country's previous AMR surveillance system had two notable limitations: AST methods were not well-harmonized across the participating clinical laboratories, and duplicated isolates were not filtered out. This created problems with reliability and potential overestimation of national AMR rates. They believe the results from the first year of Kor-GLASS show that the system is reliable, devoid of collection bias or isolate duplication, and can be expanded to include more sentinel hospitals and cover more pathogens.

"Beyond monitoring AMR, this system is a useful tool for public health authorities to deal with AMR," they write. "Kor-GLASS's successful AMR monitoring system has encouraged the South Korean government to establish a 'one health' approach for AMR in 2017 and to further develop the project by 2019."
Oct 18 Eurosurveill surveillance and outbreak report
Oct 18 Eurosurveill perspective


Study profiles use of procalcitonin and other biomarkers for sepsis

Originally published by CIDRAP News Oct 18

Researchers who looked at the use of biomarkers to guide clinical assessment and treatment in sepsis patients found that use of procalcitonin (PCT) increased sixfold over the 4-year study period, while lactate and C-reactive protein use remained level. They reported their findings yesterday in Public Library of Science (PLoS) One.

In the US retrospective observational study, the team analyzed adult sepsis discharges from 2012 through 2015. Of 933,591 adult sepsis discharges during the study period, 731,392 (78%) had biomarker testing.

Researchers also found that PCT use was linked to decreased odds of in-hospital mortality but increased hospital costs per day. It was also associated with increased antimicrobial use and increased length of stay. They also noted that serial biomarker monitoring may be connected to improved outcomes in the most critically ill patients
Oct 17 PLoS One report


Study finds standard washing doesn't remove C diff from hospital sheets

Originally published by CIDRAP News Oct 16

A team of researchers from the United Kingdom report that Clostridioides difficile spores can survive on hospital sheets even after being washed with high-temperature water and industrial detergents, and that those spores could be contributing to outbreaks of C difficile infection (CDI) in hospitals.

In a study published today in Infection Control and Hospital Epidemiology, researchers from De Montfort University inoculated swatches of cotton sheets with a strain of C difficile, then laundered them with uncontaminated swatches in a simulated washer extractor cycle using an industrial bleach detergent. A control wash with no detergent was also conducted. In addition, they assessed spore survival on swatches of hospital sheets that were naturally contaminated with C difficile and washed, dried, and pressed at a commercial healthcare laundry according to National Health Service standards.

The results revealed that both the simulated and in-situ laundering processes failed the microbiological standards of containing no pathogenic bacteria. Even in the simulated washer extractor cycle with detergent, some spores from the two strains of C difficile survived the process and contaminated the sterile swatches. And in the naturally contaminated sheets, the commercial laundering process only reduced the spore load by 40%. Subsequent ribotyping of C difficile isolates recovered before and after washing showed that they were indistinguishable, indicating that spores recovered after washing were present before washing and were not a result of contamination during the washing cycle.

"The surviving spores may contribute to environmental contamination when the sheets are used for bed making in the healthcare environment," the authors of the study write. "Processing infected linen in commercial washer extractor cycles could disseminate low levels of C. difficile spores and may be contributing to sporadic outbreaks of CDI."

The authors say further research is needed to establish the role that hospital bedsheets may play in CDI outbreaks, and to determine what is needed to fully remove C difficile spores from bedsheets during the laundry process.
Oct 16 Infect Control Hosp Epidemiol abstract


Two tests do well in detecting colistin-resistant Enterobacteriaceae

Originally published by CIDRAP News Oct 16

Two commercial tests performed well in screening for colistin-resistant Enterobacteriaceae on rectal swabs, according to a study yesterday in Antimicrobial Agents and Chemotherapy.

Investigators from Paris-Sud University evaluated the performance of Superpolymyxin medium (made by ELITechGroup) and the Chromid Colistin R plates (made by bioMerieux) to screen for colistin-resistant Enterobacteriaceae from contaminated rectal swabs. Stools were tainted with a total of 94 enterobacterial isolates (E coliK pneumoniaeSalmonella enterica, and Enterobacter cloacae), including 53 colistin-resistant isolates.

Colistin is a "last resort" antibiotic used for some multidrug-resistant infections.

The sensitivity of detecting colistin-resistant Enterobacteriaceae was 86.8% (95% confidence interval [CI], 74.0% to 94.0%) using both tests, but the isolates that were not detected differed between the two media. Specificity was 97.9% (95% CI, 87.3% to 99.9%) for Superpolymyxin and 100% (95% CI, 90.4% to 100% for Chromid.

The researchers conclude that both tests "provide a useful tool to screen for colistin-resistant Enterobacteriaceae from patient samples (rectal swabs) regardless of the level and mechanism of colistin resistance."
Oct 15 Antimicrob Agents Chemother abstract


Patent filings for AMR point-of-care tests are declining, with funds lacking

Originally published by CIDRAP News Oct 16

Patent filings for point-of-care (POC) diagnostic tests for antimicrobial resistance have been slowly declining since reaching their peak in 2014, according to a study commissioned by the Longitude Prize, a UK program launched in 2014 to spur the development of such tests. The 14-page study was conducted by two intellectual property firms and released on Oct 14 at the World Health Summit in Berlin.

According to a blog post yesterday from Longitude Prize, which has awarded funding to 29 teams to develop POC tests to address antibiotic resistance, researchers looked at what patents are being filed and what technology is being developed, with an eye toward market implications.

Following a drop in filings in 2008 that seemed related to the global financial crisis, filings reached 118 globally in 2014. By 2015, however, the number fell to 94 patents, and researchers don't yet have a clear picture for 2016 and 2017 because of an 18-month delay in filing publication. The team notes that much of the new funding for antimicrobial resistance had targeted new antibiotics, with limited funds for new diagnostics.

Among other findings, the United States dominated the filings for patents for new tests, with 60%, followed by the United Kingdom with 8%. Japan, Australia, India, and South Africa all saw upward trends. Innovations for POC tests are led by private companies, accounting for 60% in the United States and Europe, and academic institutions were responsible for 32%.

At the same time, the percentage of patent filings related to bacterial tests have increased over the same period, while patent filings for World Health Organization priority pathogens have tailed off after an increase between 2009 and 2012, possibly because developers are focusing on more broadly applicable tests.

In addition, Longitude Prize teams say they're struggling to attract adequate funding and investment to bring the tests to market and validate them for regulatory bodies, and investors say prize expectations are too low to ensure a return on investment. "This is a warning to policy makers that initially there will be a need to ring-fence funds to make sure that new products are purchased," the Longitude Prize staff wrote in the blog post.
Oct 15 Longitude Prize blog post
Oct 12 Longitude Prize report
Dec 22, 2017, CIDRAP News story "Four groups get Longitude funds for point-of-care tests"


Market study finds new antibiotics often not widely distributed globally

Originally published by CIDRAP News Oct 16

Antibiotics launched since 1999 took awhile to attain fairly wide geographic dispersal and often targeted common conditions rather than antibiotic-resistant infections, according to a study today in PLoS One.

Of 25 new antibiotics reaching the market from 1999 through 2014, only 12 had registered sales in more than 10 countries. Those with the widest geographic availability had sales in more than 70 countries within 10 years, and in 30 countries within 3 years.

Just 13 (52%) of the new antibiotics had an indication for infections caused by antibiotic-resistant bacteria, with little diversity as far as the target pathogen and indication: 18 were for community-acquired respiratory tract infections, 14 for skin and skin-structure infections, and 12 for urinary tract infections (obviously, several had multiple indications). None targeted gram-negative bacteria, which are among the most troublesome.

The new antibiotics were largely produced in Japan (11 drugs) and the United States (6). Seven were launched in Japan and 12 in the US market. The antibiotics with the greatest geographic availability by 2014—ertapenem, linezolid, moxifloxacin, and tigecycline, which all reached more than 60 countries—originated from European or US companies and were launched in those regions. In general, drugs launched in Japan were less likely to be available in other nations, though antibiotics for drug-resistant infections tended to have greater geographic distribution.

The authors conclude, "Our findings show great variation in geographic availability of antibiotics, indicating that availability in multiple regions and country income classes is possible, but rarely seen within a few years of market authorization."
Oct 16 PLoS One study

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