ASP Scan (Weekly) for Apr 05, 2019

Animal antibiotics legislation
Panning prophylactic azithromycin
Staphylococcus breakpoints
Antibiotics for flu in young kids
Pediatric C diff risk factors
Stewardship in nursing homes
US MDR-TB treatment
Metrics for pediatric stewardship
Lack of water, sanitation in hospitals
Stewardship in French ICUs
Rapid diagnostics partnership
Resistance genes in live poultry
Illegal antibiotic Rx in Sri Lanka

Maryland legislature votes to tighten animal antibiotics law

The Maryland State Senate and House of Delegates yesterday passed bills to strengthen a state law that restricts the routine use of antibiotics in animals that aren't sick.

According to a news release from U.S. PIRG (Public Interest Research Group), the Senate and House versions of the bills (SB471/HB652) aim to strengthen and codify regulations for the Keep Antibiotics Effective Act, which was passed by the Maryland legislature in 2017 without a signature from the governor. Supporters of the legislation argued that regulations enacted by the Maryland Department of Agriculture (MDA) in January 2019 contained significant loopholes and undermined the intent of the law.

The bills add new definitions and clarify definitions of certain terms in the MDA regulations, including "administered in a regular pattern," "control of the spread of disease or infection," "elevated risk," "prophylaxis," and "treat a disease or infection." They also add a requirement for veterinarians to report the use of medically important antibiotics yearly to ensure compliance with the law.

"To keep our miracle drugs working when people and animals need them, we have to stop squandering them on livestock that are not sick," Mae Wu, senior attorney at the Natural Resources Defense Council (NDRC), said in the release. "This bill will help make Maryland a leader in the fight against the growing epidemic of drug-resistant infections."

NRDC was one of more than a dozen public health and environmental advocacy groups supporting the legislation. The bill now goes to Governor Larry Hogan.
Apr 4 U.S. PIRG news release


Clinical trial finds no long-term benefit from prophylactic azithromycin

A team of American and Tanzanian researchers reported today in Clinical Infectious Diseases that biannual treatment with azithromycin did not have a beneficial effect on diarrhea, cough, fever, or anemia in young Tanzanian children.

The cluster-randomized, placebo-controlled study was conducted in 30 communities in the Kilosa district of Tanzania from January 2015 to August 2017 to determine whether there was a difference in morbidity in a cohort of children ages 1 to 36 months who were randomized to biannual treatment with azithromycin or placebo. The study was embedded into the larger MORDOR trial, which found a year ago that a single dose of azithromycin every 6 months in children ages 1 to 59 months in Niger, Malawi, and Tanzania was associated with a reduction in mortality compared with placebo.

The researchers wanted to see if the reduction in mortality observed in the MORDOR trial could be linked to azithromycin's clinical versatility against a wide range of infections. Previous studies of mass drug administration with azithromycin have shown a protective effect against diarrhea, malaria parasitemia, and respiratory illnesses, but only within 1 month of treatment. In this study, children were monitored every 6 months for signs and symptoms of diarrheal disease, acute respiratory illness, and anemia.

Among the 700 children in the study (350 in each treatment arm), the researchers found no difference in rates of diarrhea, fever, or anemia by treatment arm at baseline and at all phases of follow-up. The decline over time in reported cough was statistically significant in the children who received azithromycin compared with the placebo group, but when adjusted for clustering and age, the difference in decline between the two treatment arms had a P value of .09, which is generally associated with non-significance.

The authors of the study say further research into the mechanisms for reduced mortality observed in the MORDOR trial is needed.
Apr 5 Clin Infect Dis abstract
Apr 28, 2018, CIDRAP News scan on MORDOR study


Treatment of Staph bloodstream infections should start ASAP, study finds

University of Southern California researchers today defined the breakpoint duration of Staphylococcus aureus bacteremia (SAB) that is predictive of poor outcomes in an effort to optimize antibiotic prescribing and noted that management should target bacterial clearance as soon as possible.

In the multicenter, prospective, observational study of 884 adult, hospitalized patients with SAB, 63% had short (1- to 2-day), 28% intermediate (3- to 6-day), and 9% prolonged (7 days or longer) bacteremia, and those in the prolonged group had the highest proportion of methicillin-resistant SAB. The study appears in Clinical Infectious Diseases.

The scientists found that the choice of antibiotic therapy did not significantly affect bacteremia duration, but the time to source control procedure was delayed in the prolonged and intermediate groups compared with the short group. They also noted that metastatic complications (12% vs 23% vs 33%), length of stay (9 vs 12 vs 24 days), and 30-day mortality (5% vs 11% vs 22%) were progressively worse as bacteremia duration increased. They also determined that every added day of bacteremia was associated with relative risk of death of 1.16, with a significant increase in risk starting at 3 days.

The authors conclude, "Optimal management of SAB should target bacterial clearance as soon as possible to minimize incremental risk of mortality with each day of positive blood culture. Delay in source control but not type of anti-staphylococcal therapy was significantly associated with prolonged bacteremia and worse outcomes."
Apr 5 Clin Infect Dis abstract


Global study of flu burden in tots shows 41% antibiotic prescribing rate

A study yesterday in BMC Infectious Disease of children under 3 years old shows not only the heavy burden of flu globally but also the continued misuse of antibiotics for the disease, as 41% of the patients received antibiotics.

French and Dutch investigators analyzed data from 2,210 participants included in the placebo arm of a phase 3 trial who had never been vaccinated for influenza and were observed for one or two flu seasons from 2014 to 2016. Among the group, who were from nine countries in both the Northern and Southern Hemisphere, 255 participants had virologically confirmed flu, for an attack rate of 11.5%. The children ranged in age from 6 to 35 months.

Most cases (57.0%) resulted in outpatient visits, but 1.1% required overnight hospitalization. Among all patients, 24.3% had grade 3 fever, 8.7% lower respiratory infection, 6.1% acute otitis media (AOM, or ear infection), and 1.9% pneumonia.

The vast majority of children (93.2%) received fever-reducing drugs, analgesics, or non-steroidal anti-inflammatory drugs. Fully 41.4%, however, received antibiotics for the disease, which is caused by a virus. The antibiotic prescribing rate was 23.5% in South Africa, 38.9% in European nations, and 45.7% in the Philippines.

The authors write, "A few of these antibiotic prescriptions could have been for influenza-associated AOM or acute lower respiratory infection, which were observed in 15% of influenza cases," but they add, "unnecessary antibiotic use in influenza appears to be a continuing problem and may be contributing to the spread of antibiotic-resistant bacteria."
Apr 4 BMC Infect Dis study


Study notes recent antibiotics as C difficile risk factor in young children

A study today in Epidemiology and Infection found that antibiotic exposure within the preceding 12 weeks was a significant risk factor for community-associated Clostridioides difficile infection (CA-CDI) in young children.

The aim of the study, which was led by researchers from the US Centers for Disease Control and Prevention (CDC), was to evaluate potential healthcare- and community-related risk factors for CA-CDI in children aged 1 to 5 years. Although several studies have assessed CA-CDI risk factors in adults, data on children are limited. Participants for the case-control study from eight sites were enrolled in the CDC's Emerging Infections Program from October 2014 through February 2016, and caregivers were interviewed regarding relevant exposures.

Overall, 136 children (68 matched pairs) were enrolled. More case-patients than controls had a comorbidity (33.3% vs 12.1%, P = 0.01), recent high-risk outpatient exposures (34.9% vs 17.7%, P = 0.02), recent antibiotic use (54.4% vs 19.4%, P < 0.0001), or recent exposure to a household member with diarrhea (41.3% vs 21.5%, P = 0.04). In multivariable analysis, only antibiotic exposure in the preceding 12 weeks was significantly associated with CA-CDI (adjusted matched odds ratio, 6.25; 95% confidence interval, 2.18 to 17.96). The most frequently reported indication for antibiotic use was ear, sinus, or respiratory infection.

"Decreasing unnecessary outpatient antibiotic prescribing, particularly for acute respiratory tract infections, might reduce CA-CDI in this population," the authors of the study write. "Further investigation of other potential risk factors, including outpatient healthcare and household exposures, is needed."
Apr 5 Epidemiol Infect abstract


CDC study finds room for improving stewardship in US nursing homes

Originally published by CIDRAP News Apr 4

Forty-two percent of the nursing homes enrolled in the National Healthcare Safety Network (NHSN) met all seven of the CDC's Core Elements of Antibiotic Stewardship in 2016, CDC researchers reported today in Clinical Infectious Diseases.

Analysis of data from the NHSN's annual survey for nursing homes showed that 1,262 out of 2,982 reported implementing all seven core elements, with the vast majority of facilities fulfilling the tracking (95%), action (94%), accountability (91%), and leadership elements (87%). Access to drug expertise was reported by 77% of nursing homes, while 73% fulfilled education recommendations and 62% met the criteria for reporting.

Bivariate analysis showed that for-profit ownership, nursing home chain affiliation, and staff hours devoted to infection prevention and control activities were statistically significantly associated with implementing all seven core elements.

The results are similar to the findings of the 2014 NHSN survey, which found that 41% of nursing homes had implemented all seven core elements. The Centers for Medicare and Medicaid Services started requiring nursing homes to have antibiotic stewardship programs in 2016.

The authors of the study conclude, "These results are promising, with only 3 elements fulfilled by <80% of NHs [nursing homes]. However, there is still room for improvement across all core elements in NHs, particularly in the areas of drug expertise, reporting, and education."
Apr 4 Clin Infect Dis abstract


Few US patients eligible for shorter MDR-TB treatment

Originally published by CIDRAP News Apr 4

In another CDC study today in Clinical Infectious Diseases, researchers from the Division of Tuberculosis Elimination reported that only 10% of multidrug-resistant tuberculosis (MDR-TB) cases in the United States would be eligible for a shorter treatment regimen. And although treatment costs would be reduced significantly for eligible patients, the reduction in societal costs would be minimal.

The researchers assessed eligibility for the 9-to-12-month regimen among US MDR-TB cases that had full drug susceptibility testing and were reported to the US National TB Surveillance System (NTSS) from 2011 through 2016. The shorter series was recommended by the World Health Organization (WHO) in 2016 for patients with extrapulmonary TB, pregnancy, previous second-line TB medication exposure, and resistance to pyrazinamide, ethambutol, kanamycin, moxifloxacin, ethionamide, or clofazimine. The investigators also estimated the costs of the shorter regimen compared with the conventional 20-month treatment, and the economic impact on overall MDR-TB cost burden and on individual patients.

During 2011 through 2016, 586 MDR-TB cases were reported to the NTSS, and 59 (10%) were eligible for shorter treatment. Of the 527 ineligible cases, 347 (66%) had reported resistance to a medication in the shorter regimen. Among the 386 ineligible cases who had full drug susceptibility testing, most were resistant to ethambutol (64%) and/or pyrazinamide (56%), often in combination with other drug resistance. Sensitivity analysis showed that if those with prior TB were not excluded, the proportion of eligible patients would rise to 12%.

Applying the shorter regimen to those eligible would reduce the direct costs by 25% to 41% ($12,000 to $46,000) compared with the conventional regimen, and direct costs plus productivity losses would be reduced by 37% to 46%. But because the number of eligible patients is so small, the overall societal cost burden would be reduced by only 4%. 
Apr 4 Clin Infect Dis abstract


Paper defines metrics for pediatric antimicrobial stewardship programs

Originally published by CIDRAP News Apr 3

A team of Canadian physicians and pharmacists has identified metrics that can be used to measure the impact of pediatric antimicrobial stewardship programs (ASPs), according to a new paper in Pediatrics.

Using a modified Delphi approach, the team developed two surveys that were sent to experts and stakeholders to establish consensus on metrics for evaluating the processes and outcomes of pediatric ASPs. The metrics were subdivided into four ASP domains: antimicrobial consumption, microbiologic outcomes, clinical outcomes, and process measures.

Respondents were asked to rank the scientific merit, impact, feasibility, and accountability of each metric. Consensus was defined as more than 75% of survey respondents agreeing that a metric had scientific merit, and selections were finalized with a face-to-face meeting and a third survey.

Overall, 38 participants from 15 pediatric hospitals across Canada completed all three rounds of the Delphi survey. In the domain of antimicrobial consumption, the two selected metrics were days of therapy per 1,000 patient-days and total antimicrobial days. The clinical and process outcomes chosen were 30-day readmission rate and adherence to ASP recommendations, respectively. A microbiologic outcome was felt to be important and feasible, but consensus could not be obtained on a measure. Several barriers to implementation of the metrics were identified, including information technology limitations at various centers.

"Wide adoption of these pediatric ASP metrics among national and international programs will facilitate international comparative intervention studies," the authors of the paper conclude. "These metrics should be considered when planning the infrastructure necessary to monitor the effectiveness of pediatric ASPs."
Apr 1 Pediatrics article


Report highlights lack of water, sanitation in global healthcare facilities

Originally published by CIDRAP News Apr 3

One in four healthcare facilities around the world lacks consistent access to basic water services, and many lack other services that are crucial to preventing infections and reducing the spread of antimicrobial resistance, according to a report today from the WHO and UNICEF.

The report, the first from the WHO/UNICEF on access to water, sanitation, and hygiene (WASH) in healthcare facilities, found that 12% of healthcare facilities globally, used by an estimated 896 million people, had no water service. In addition, 14% had limited water service, meaning they had access to either an improved water source that was off site or did not have water at the time of the survey. A little more than half (55%) of healthcare facilities in least-developed countries (LDCs) had basic water services.

More than one in five healthcare facilities reported having no sanitation service, which translates to more than 1.5 billion people having either no toilets or unimproved toilets (such as pit latrines) at their healthcare facility.

The report also found that one out of six healthcare facilities globally (16%) had no hygiene service, including hand hygiene stations at points of care and soap and water at toilets, and only 27% of facilities in LDCs had basic healthcare waste management.

"Not only does the lack of WASH services in health care facilities compromise patient safety and dignity, it also has the potential to exacerbate the spread of antimicrobial-resistant infections and undermines efforts to improve child and maternal health," WHO Director-General Tedros Adhanom Ghebreyesus, PhD, and UNICEF Executive Director Henrietta Fore, MPA, write in the foreword to the report.

An accompanying "practical steps" report details eight actions governments can take to improve WASH services.
Apr 3 WHO press release
Apr 3 WHO full report
Apr 3 WHO practical steps report


Survey finds French ICUs short on key stewardship elements

Originally published by CIDRAP News Apr 2

A nationwide survey has found that elements of antibiotic stewardship programs have been implemented in most French intensive care units (ICUs), but to varying degrees, French researchers reported yesterday in the Journal of Antimicrobial Chemotherapy.

The cross-sectional online survey was sent to French ICU specialists in January 2018, and 113 out of 206 (55%) responded. Access to local epidemiology regarding bacterial resistance was reported in 84% of ICUs, but routine access to antibiotic prescribing guidelines and antibiotic consumption data—two essential elements of stewardship programs—were reported in only 54% and 65% of ICUs, respectively. In addition, only 46% reported limiting the duration of antibiotic therapy.

Other notable findings included 94% of ICUs reporting an antibiotic stewardship program leader, 62% and 59% of ICUs reporting the availability of molecular biology and mass spectrometry techniques for rapid identification of bacteria, and 46% reporting therapeutic drug-monitoring of beta-lactams. Only 43% of respondents knew the expression antimicrobial/antibiotic stewardship.

The authors of the study say the findings suggest that antibiotic stewardship measures implemented at the hospital level are not necessarily rolled out in all departments and that monitoring of core elements of stewardship programs might be needed, particularly in key departments such as ICUs.
Apr 1 J Antimicrob Chemother abstract 


New rapid diagnostics partnership announced

Originally published by CIDRAP News Apr 1

A new public-private partnership to address inappropriate antibiotic use and antimicrobial resistance (AMR) through wider use of rapid diagnostics was launched today at an event in Madrid.

VALUE-Dx, a project of the Innovative Medicines Initiative, brings together six in vitro diagnostics companies with 20 non-industry partners to "generate evidence on the medical, economic, and public health value of diagnostics in tackling AMR," according to a news release from project partner, the University of Edinburgh. The project will focus on acute respiratory tract infections acquired in community care settings, one of the most frequent causes of inappropriate prescribing.

"This is an exciting and groundbreaking opportunity to address one of the greatest barriers to adoption of rapid diagnostics," Till Bachman, PhD, deputy head of infection medicine at the University Edinburgh, said in a statement. "It will shift the focus from the cost to the added value diagnostics provide in the fight against AMR."

Other partners include bioMerieux, Accelerate Diagnostics, the University of Antwerp, and the European Society of Clinical Microbiology and Infectious Diseases. The project is co-funded by the European Commission, Wellcome Trust, and private companies, with a budget of €14 million ($15.7 million) over 4 years. 
Apr 1 University of Edinburgh news release


Chinese study finds many diverse resistance genes in live poultry

Originally published by CIDRAP News Apr 1

A new study in the Journal of Infection suggests that live poultry markets in China are a significant reservoir for antibiotic resistance genes (ARGs).

In the study, Chinese researchers used large-scale metagenomic sequencing to explore the diversity and abundance of ARGs in the gut microbiomes of poultry in live-poultry markets (LPMs). Because these markets are known to be a high-risk environment for the spread of avian flu to people, the researchers theorized they may also be a potential site for the dissemination of animal-origin ARGs. For their analysis, the authors collected 753 poultry fecal samples from 22 cities in 18 provinces, sequenced the genomes of 130 representative samples to create a catalogue of gut microbial genes, and compared the genes with genes from the pig gut and human gut microbiomes.

Overall, the analysis revealed the presence of 539 ARGs in live poultry that could be classified into 235 different ARG types. Both the number of ARGs and ARG types in live poultry were significantly higher than they were in humans and pigs, suggesting a greater diversity and enrichment of ARGs in live poultry. The overall abundance of ARGs was also highest in live poultry, followed by pigs and then humans. A total of 65 ARG types were shared among the three groups. Mapping of the ARG types to their corresponding antibiotics showed that tetracycline-resistance genes were the most abundant in all three groups.

Using polymerase chain reaction and Sanger sequencing, the researchers then investigated the distribution of the MCR-1 gene in all 753 live poultry fecal samples, finding it in 449 samples (59.6%). The MCR-1 gene was present in samples from all 18 provinces, and positive rates were similar in chickens, ducks, pigeons, and geese. The gene was also found in seven wild birds, and the researchers also identified MCR-3 and MCR-5 genes.

"The LPM is a special environment in China, where city dwellers have the opportunity to contact live animals and the viruses and bacteria carried by them," the authors of the study write. "We propose that LPMs represent a high-risk environment for the dissemination of animal-origin ARGs to public health."
Mar 29 J Infect study


Illegal antibiotic prescribing in Sri Lanka

Originally published by CIDRAP News Apr 1

An experimental study involving fake patients revealed a high level of illegal antibiotic prescribing in community pharmacies in Sri Lanka, according to a new study in Antimicrobial Resistance and Infection Control.

The cross-sectional study involved visits to 242 community pharmacies by 32 trained "pseudo-patients" (pharmacy school students or recent graduates) who pretended to have a relative with clinical symptoms of four randomly selected common infections. Three of the infections were viral (acute sore throat, common cold, acute diarrhea) and one was bacterial (uncomplicated urinary tract infection [UTI]). Each pseudo-patient requested an unspecified medicine for the condition, and a research assistant recorded the interaction. Sri Lankan law prohibits the supply of an antibiotic without a prescription.

In 41% (99/242) of visits, antibiotics were sold illegally without a prescription in response to the reported clinical symptoms, with two-thirds (65/99) being sold for underlying viral infections. Antibiotics were provided for 55% of uncomplicated UTIs, 50% of acute diarrhea cases, 42% acute sore throat cases, and 15% of common colds. Patient history was obtained in less than a quarter of interactions, and pharmacy staff recommended a visit to a physician in only 18% (44/242) of cases; yet in 25% (11/44) of those interactions, an antibiotic was still obtained. Roughly half of the pseudo-patients were advised on how and how often to take the antibiotics, and less than a quarter were advised on when to stop taking them. In nearly two thirds of instances, antibiotics were sold by a staff member other than a qualified pharmacist.

While the availability of a pharmacist reduced the likelihood of illegal antibiotic sales (odds ratio, 0.53; 95% confidence interval, 0.31 to 0.89, P = 0.016), it did not appear to reduce inappropriate prescribing.

"In addition to strict implementation of policies, awareness and educational interventions must be implemented to improve appropriate antibiotic dispensing practice among pharmacists and their staff," the authors of the study conclude.
Mar 29 Antimicrob Resist Infect Control study

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