ASP Scan (Weekly) for Mar 20, 2020

Antibiotic allergies in Aussie nursing homes
Drug for recurrent C diff
C diff testing intervention
Carbapenem heteroresistance
Funds for new MDR gonorrhea drug
Antibiotic developer acquired
Australian AMR plan
Early antibiotics and asthma

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

Study: Antibiotic allergies prevalent in Australian nursing homes

Originally published by CIDRAP News Mar 19

A study today in Infection Control & Hospital Epidemiology reports a high prevalence of antibiotic allergy labels (AALs) in Australian nursing homes.

In a point-prevalence survey conducted in 407 Australian aged-care facilities on a single day from Jun 1, 2018 through Aug 31, 2018, a team of Australian researchers found that among 1,489 residents prescribed an antibiotic, 24% (356) had one or more documented AALs. The most common AAL was for penicillin (28.3%), followed by amoxicillin or amoxicillin/clavulanic acid (10.5%), cefalexin (7.2%), and trimethoprim (7.0%).

The presence of an AAL was associated with significantly less prescribing of penicillins (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.31 to 0.62, P < .001) and significantly more prescribing of lincosamides (OR, 4.81), macrolides (OR, 2.03), and tetracyclines (OR, 1.54). Seven residents (1.9%) were prescribed an antibiotic that was listed on the allergy section of their health record.

The authors of the study say the observed prevalence is high compared with similar reports for Australian hospital patients, which have reported AAL rates of 14% to 24%. They're particularly concerned about the increased use of lincosamides, macrolides, and tetracyclines among nursing home residents, since these broad-spectrum antibiotics contribute to increased risk of Clostridioides difficile infection (CDI) and infections caused by antibiotic-resistant pathogens.

"Future studies must evaluate the impact of prescribing second-line agents and the benefits of developing and implementing AAL delabelling programs tailored to aged-care settings," they write.
Mar 19 Infect Control Hosp Epidemiol abstract


Bezlotoxumab shows high efficacy against recurrent C diff

Originally published by CIDRAP News Mar 19

The results of a multicenter study show that bezlotoxumab had a success rate of more than 84% in preventing recurrent CDI (rCDI), US researchers reported today in Open Forum Infectious Diseases.

The retrospective study evaluated the records of 200 patients who received infusions of bezlotoxumab, a human monoclonal antibody, in combination with standard of care (SoC) antibiotics at 34 US infusion centers from April 2017 through December 2018.

While two large phase 3 clinical trials (MODIFY I and II) found that patients treated with bezlotoxumab and SoC therapy had a significantly lower rate of rCDI at 12 weeks, validation of these results in real-world settings is limited. In this study, investigators assessed rCDI at 90 days post-infusion.

Of the 200 patients, 173 (86%) had prior CDI episodes, and 79% had more than two risk factors for rCDI. SoC antibiotics included vancomycin (137, 68%), fidaxomicin (60, 30%), and metronidazole (3, 2%), all prescribed in combination with bezlotxoumab.

The median time intervals from positive C difficile test to bezlotoxumab and initiation of SoC to bezlotoxumab were 15 days and 11 days, respectively. Within 90 days, 31 of 195 patients (15.9%) experienced rCDI, corresponding to a success rate of 84.1%. Patients with two or more CDI recurrences before infusion had a higher risk of rCDI than those who had one recurrence or primary CDI (hazard ratio, 2.77; 95% CI, 1.14 to 6.76, P = 0.025).

The authors note that the findings of their rCDI study were comparable with those reported in the MODIFY trials, despite the presence of a sicker, higher-risk population with an extensive CDI history.

The study was funded by Merck & Co., which owns the license for bezlotoxumab.
Mar 19 Open Forum Infect Dis abstract


Study suggests clinical support tool safely reduces C diff testing

Originally published by CIDRAP News Mar 18

A computerized clinical support tool implemented at an academic medical center helped reduce rates of C difficile testing without an associated increase in adverse events in patients whose tests were prevented, researchers from the University of Virginia (UVA) School of Medicine reported today in Open Forum Infectious Diseases.

In the retrospective case control study, researchers examined the outcomes of patients admitted to the UVA Medical Center after the introduction of a computerized clinical decision support tool designed to reduce nucleic acid amplification tests (NAATs) for C difficile. NAAT tests are highly sensitive, but cannot distinguish between C difficile colonization and infection, and overdiagnosis of C difficile infection is thought to be linked to inappropriate testing in patients with low pre-test probability for infection.

A previous study had found a 41% reduction in C difficile testing at the hospital after introduction of the tool, and the researchers wanted to compare the safety of the intervention among patients with prevented tests and those with negative tests.

The multivariate analysis of 637 cases (490 negative, 147 prevented) showed that a prevented test was not significantly associated with the primary composite outcome of inpatient mortality or intensive care unit transfer compared with a negative test (adjusted odds ratio, 0.912, P = .747), and that patients in the prevented group had shorter lengths of hospital stay (median 6 days, compared with 9 in the negative-test group). Of the 147 patients with a prevented test, 54 (37%) went on to have a completed test within 7 days, and 11 were positive, resulting in a potential delay in diagnosis. But individual case reviews found that either clinical changes warranted the delay in testing or no adverse events occurred that were attributable to CDI—a finding that suggests the tool isn't discouraging appropriate testing.

"Diagnostic stewardship of C. difficile testing using computerized clinical decision support may be both safe and effective for reducing inappropriate testing," the authors of the study concluded. 
Mar 18 Open Forum Infect Dis abstract


Study highlights prevalence of heteroresistance in ESBL isolates

Originally published by CIDRAP News Mar 18

A new study by researchers at the University of Southern California School of Pharmacy has found that nearly a third of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae isolates from patients were identified as being heteroresistant to carbapenems. The findings were published yesterday in the Journal of Antimicrobial Chemotherapy.

In the study, 173 ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates from patients with recurrent infections that were reported as meropenem susceptible were tested for heteroresistance—a condition in which different bacterial populations from the same isolate exhibit varying susceptibilities to the same agent. Heteroresistance was screened by disc diffusion and confirmed by a modified population analysis profiling (PAP) method against ertapenem, imipenem, meropenem, and ceftolozane/tazobactam.

A total of 519 bacteria/carbapenem combinations were screened by disc diffusion, with 84 combinations identified as carbapenem heteroresistant (cHR). Modified PAP confirmed 70 bacteria/carbapenem combinations as cHR, with the heteroresistant phenotype most frequently observed against ertapenem. In total, 32% of the unique patient isolates (55/173) were identified as being heteroresistant to at least one carbapenem, and 16% of those patients (9/55) had a carbapenem non-susceptible isolate on a subsequent visit. More cHR isolates originated from a non-urinary source compared with non-cHR isolates (31% vs 19%, P = 0.02).

The authors of the study say the findings raise "significant concerns" about the continued use of carbapenems as first-line therapy for serious ESBL-producing E coli and K pneumoniae infections, and say more research is needed into the contribution of antibiotic exposure to the development of cHR phenotypes.
Mar 17 J Antimicrob Chemother abstract


CARB-X funds development of novel antibiotic for MDR gonorrhea

Originally published by CIDRAP News Mar 17

CARB-X announced today that it is awarding $2.86 million to Microbiotix of Worcester, Massachusetts, to develop a new oral antibiotic for multidrug-resistant (MDR) gonorrhea.

The novel antibiotic, which is in the early stages of preclinical development, aims to combat the disease by targeting and inhibiting the trans-translation pathway of MDR Neisseria gonorrhoeae, which is essential for the bacterium to grow and replicate.

"Proposed as a single dose oral therapy, this innovative program has great potential, not only to address the urgent threat posed by MDR N. gonorrhoeae, but also to address other sexually-transmitted infection (STI) pathogens commonly found as coinfections," Microbiotix President and CEO Terry Bowlin, PhD, said in a press release from CARB-X (the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator).

Drug-resistant gonorrhea has been labeled a priority pathogen by the World Health Organization and an urgent health threat by the US Centers for Disease Control and Prevention. An estimated 78 million people worldwide develop gonorrhea each year, and resistance to the last remaining antibiotics capable of treating the infection—ceftriaxone and azithromycin—is rising.

Microbiotix will be eligible for an additional $16 million in funding from CARB-X if the project meets certain development milestones. Since its launch in 2016, CARB-X has announced 59 awards totaling $198.5 million.
Mar 17 CARB-X press release


Antibiotic developer Tetraphase acquired by AcelRx

Originally published by CIDRAP News Mar 17

In another in a string of ominous signs for antibiotic development efforts, biopharmaceutical company Tetraphase Pharmaceuticals, maker of the novel tetracycline antibiotic eravacycline, announced yesterday that it has been acquired by AcelRx Pharmaceuticals.

The move comes less than 2 years after the Food and Drug Administration approved eravacycline (which is sold under the brand name Xerava) for the treatment of complicated intra-abdominal infections (cIAIs) caused by MDR pathogens. Tetraphase, of Watertown, Massachusetts, had received support from the Biomedical Advanced Research and Development Authority for development of the drug, which was seen as an important new weapon against antibiotic-resistant infections.

But, like other small companies in the antibiotic development space, Tetraphase has struggled financially. As drug-industry newsletter Endpoint News noted, Xerava generated only $3.6 million in sales in 2019, and Tetraphase's stock price tumbled from $61.40 on Aug 27, 2018—the date of FDA approval—to $1.45 on Mar 13.

Tetraphase and AcelRx, of Redwood City, California, said they were entering into a co-promotion agreement to market and promote Xerava for the treatment of cIAIs.

"We are excited to collaborate with AcelRx, a partner whose strategic goals complement our own," Tetraphase President and CEO Larry Edwards said in a company press release. "We continue to believe that Xerava is a key addition to the hospital anti-infective armamentarium, and believe that together with AcelRx we will be able to more effectively bring new treatments to patients in healthcare institutions."
Mar 16 Tetraphase press release
Mar 16 Endpoints News story


Australia releases new AMR strategy

Originally published by CIDRAP News Mar 17

The Australian government late last week released its national antimicrobial resistance (AMR) strategy for 2020 and beyond, calling for coordination across all sectors where antibiotics are used and close coordination with global efforts.

The 2020 strategy builds on the country's 2015 AMR response plan, which established the Antimicrobial Use and Resistance in Australia Surveillance System, created a One Health AMR online hub, and initiated surveillance projects in the animal sector. The new strategy will broaden those efforts to encompass AMR in food and the environment, and will include antifungal and antiviral resistance.

The government says the 2020 strategy will be underpinned by a series of national and sector-specific action plans outlining short- to medium-term goals. Among the key objectives are developing clear governance for AMR initiatives, preventing infections and the spread of resistance, establishing appropriate usage and stewardship practices, and creating a nationally coordinated surveillance system that covers all sectors.

"Across a number of sectors—locally, nationally and globally—efforts will be aligned and, through targeted collaboration, policy, practice and systems will be strengthened to minimise the development and spread of antimicrobial resistance," the report states. "Only such a holistic approach can ensure the continued availability of effective antimicrobials for decades to come."
Mar 13 Australia's 2020 and Beyond AMR strategy 


Study: Early antibiotics, nasal microbiota changes tied to asthma

Originally published by CIDRAP News Mar 17

A new study by US and Finnish researchers has found that receipt of antibiotics during infancy was associated with increased risk of developing childhood asthma, and that the antibiotics-asthma link was mediated in part by changes in nasal microbiota. The findings appeared in Clinical Infectious Diseases.

For the study, the researchers looked at a cohort of 923 children who were born in Finland from January 2008 to April 2010 and followed them from birth through 7.5 years of age. Specifically, they looked at antibiotic use through the first 11 months, longitudinal nasal microbiota profiles from 2 to 24 months, and development of asthma by age 7. The nasal microbiota profiles were assessed using 16S rRNA gene sequencing of nasal swabs collected from the children at 2, 13, and 24 months.

Using those data, the researchers then performed a causal mediation analysis to estimate the natural direct effect of systemic antibiotic treatments during age 0 to 11 months on the risk of developing asthma by age 7, and to what extent it was mediated by longitudinal changes in the nasal microbiota.

Of the 697 children included in the final analysis, 8.0% later developed asthma. Exposure to more than two antibiotic treatments by age 11 months was associated with a 4.0% increase in the absolute risk of developing asthma (total effect; 95% CI, 0.9% to 7.2%, P = 0.006), with a direct effect of a 3.3% increase (95% CI, 0.4% to 6.4%, P = 0.03).

Clustering of longitudinal nasal microbiota data identified six nasal microbiota profiles. Infants with more antibiotic treatments had a higher risk of having a profile with early Moraxella sparsity (per each antibiotic treatment, adjusted relative rate ratio, 1.38; 95% CI, 1.15-1.66; P < 0.001). Causal mediation analysis showed that this effect of antibiotics on asthma risk was mediated, in part, by longitudinal changes in the nasal microbiota (natural indirect effect, P = 0.008), accounting for 16% of the total effect.

"For clinicians, these findings lend additional support to the current guidelines that discourage unnecessary use of antibiotics, particularly in young children," the authors wrote. "Furthermore, our observations should not only facilitate further investigations into the complex interplay between antibiotic exposures, microbiota, and host response, but they also offer new avenues for prevention of childhood asthma."
Mar 14 Clin Infect Dis abstract

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