ASP Scan (Weekly) for Feb 19, 2021

Hospital wastewater impact on resistance
New funds, CEO for antibiotic development fund
Herbicide-linked antibiotic resistance in soil
UK antibiotic decline during COVID
FDA clears path for phage trial
MDR Campylobacter in animals, meat
Trial for resistant-TB drug

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

Swedish study finds hospital wastewater selects for multidrug-resistance

A new study conducted in Sweden provides evidence that hospital wastewater selects for multidrug-resistant strains of bacteria while killing antibiotic-sensitive bacteria.

In the study, published late last week in Environment International, a team led by researchers from Sweden's University of Gothenburg conducted a series of laboratory experiments to test whether filtered wastewater from a major Swedish hospital, as well as treated and untreated municipal wastewater, select for antibiotic resistance. Compared with the municipal wastewater, the hospital wastewater had the highest concentrations of antibiotics (including cefadroxil, ciprofloxacin, linezolid, and amoxicillin).

When the researchers exposed a sample of 149 Escherichia coli isolates to the different wastewater samples, they found that the hospital effluent significantly increased resistance to several antibiotics (cefadroxil, ceftazidime, and tobramycin) and the proportion of multidrug-resistant isolates. Further experiments with these isolates and E coli isolates with less resistance showed that exposure to hospital wastewater inhibited the growth of susceptible isolates, while multidrug-resistant isolates continued to grow.

The researchers then reproduced these findings in water samples containing many different types of bacteria, finding that exposure to hospital wastewater significantly increased the abundance of antibiotic-resistant E coli, while killing off more susceptible strains. In comparison, untreated municipal wastewater had a very small effect, and treated wastewater had no effect.

"The results were very clear," lead study author Joakim Larsson, PhD, who directs the Centre for Antibiotic Resistance Research at the University of Gothenburg, said in a university press release. "In all assays, we could see that antibiotic-sensitive bacteria were rapidly killed by the hospital wastewater, while the multi-resistant ones continued to grow."

Larsson and his colleagues say more research is needed to determine which antibiotics are contributing to antibiotic resistance, but add that the results point to the need to evaluate ways to reduce the risks associated with hospital wastewater.
Feb 13 Environ Int study
Feb 16 University of Gothenburg press release


Antibiotic development effort notes $140 million in donations, new CEO

Originally published by CIDRAP News Feb 18

The AMR Action Fund announced today the appointment of a new chief executive officer and more than $140 million in investments from the Boehringer Ingleheim Foundation, The European Investment Bank, and the Wellcome Trust.

The investments in the AMR Action Fund, a public-private partnership launched in July 2020 to boost the antibiotic development pipeline, are its first non-pharmaceutical industry investments. The fund is an industry-led initiative developed by the International Federation of Pharmaceutical Manufacturers and Associations, and includes Eli Lilly, Pfizer, Merck, Johnson & Johnson, GlaxoSmithKline, and Novartis among its backers. The fund plans to invest more than $1 billion in smaller biotech companies with the aim of bringing two to four new antibiotics to market by 2030.

"This fund will provide a lifeline for companies navigating the expensive and technically complex later stages of antibiotic development," Wellcome Trust director Jeremy Farrar, MD, PhD, said in an AMR Action Fund press release. "We are particularly pleased that the fund will place an emphasis on equitable access and responsible stewardship which is crucial to solving this global health challenge."

Taking the helm of the AMR Action Fund will be Henry Skinner, PhD, who brings decades of experience in the biomedical research, pharmaceutical, and venture capital industries.

"I am honored to join the AMR Action Fund and its incredibly important mission," Skinner said in a press release. "Having worked on this issue from many angles throughout my career, I know how badly novel antibiotics are needed, and I also know how many obstacles currently prevent them from being developed and reaching patients."
Feb 18 AMR Action Fund investment press release
Feb 18 AMR Action Fund 
CEO press release


Study finds herbicides increase antibiotic resistance genes in soil

Originally published by CIDRAP News Feb 17

New research by scientists from China and the United Kingdom shows that three widely used herbicides increase the prevalence of antibiotic resistance genes in soil bacteria, along with the mobile genetic elements that enable those genes to move between bacteria. The research appeared yesterday in Molecular Biology and Evolution.

In a series of experiments, the scientists showed that application of the herbicides glyphosate, glufosinate, and dicamba to soil microcosms over 60 days significantly increased the total abundance of antibiotic resistance genes in soil bacteria, with glyphosate showing a ninefold increase in antibiotic resistance genes compared with control soil samples. In addition, glufosinate and glyphosate significantly increased total abundances of mobile genetic elements, with glyphosate and glufosinate having more of an impact than dicamba.

Further experiments suggest that the herbicides may promote antibiotic tolerance by changing bacterial gene expression, or by selecting for mutations that increase tolerance to antibiotics during prolonged herbicide exposure. The scientists also found that herbicide exposure increased bacterial cell membrane permeability and conjugation of multidrug-resistant plasmids, which promote the movement of antibiotic resistance genes between bacteria.

To assess whether these laboratory findings translated to real-world settings, the scientists sampled soil from 21 agricultural sites across China and compared soil exposed to glyphosate with soil that had been free of herbicide use for 5 years. They found that glyphosate application was associated with higher relative abundances of both antibiotic resistance genes and mobile genetic elements.

The authors of the study note that although the presence of antimicrobial resistance genes and mobile genetic elements in harmless soil bacteria may not pose a health threat, fertilization of fields with untreated animal manure that typically contains opportunistic pathogens could result in those bacteria acquiring resistance genes and spreading. The authors say that the effect of herbicides on soil microbiomes should be re-evaluated.

"While antibiotic resistance genes are not harmful per se, they will reduce the efficiency of antibiotics during clinical treatments," study author Ville Friman, PhD, of the University of York, said in a university press release. "Keeping the frequency of resistance genes low will hence prolong the long-efficiency of antibiotics. As resistance genes can easily move between environments, agricultural fields could be globally important sources for resistance genes."
Feb 16 Mol Biol Evol abstract
Feb 16 University of York press release


UK study shows sustained drop in outpatient antibiotics during pandemic

Originally published by CIDRAP News Feb 17

A decline in community antibiotic prescribing in North West London that began before the first COVID-19 peak in March 2020 was sustained for 8 months, UK researchers reported this week in Clinical Microbiology and Infection.

In the study, researchers from the UK National Institute for Health Research and Imperial College London analyzed individual prescribing records for 2 million people in North West London from January 2015 through November 2020 and conducted an interrupted time series analysis to determine whether there was a measurable change in antibiotic prescribing in primary care associated with the pandemic and the national response. Antibiotic prescriptions in 2020 were stratified by gender, age-group, ethnic group, and socioeconomic deprivation level, and prescribing records were linked to SARS-CoV-2 test results.

From January through November 2020, 730,001 primary care antibiotic prescriptions were identified. The interrupted time series analysis showed that the antibiotic prescribing volume in North West London had been declining before March 2020 at a rate of 584 items per month, but the rate of decline climbed to 3,504 items per month after March 2020.

The rate of decline was sustained beyond the initial peak of COVID-19 cases, with the antibiotic prescribing volume reaching its lowest level in August 2020. Reduced antibiotic prescribing continued into the second COVID-19 peak, which began in late September. The observed decline, which occurred despite primary care consultation rates returning to normal, was seen across all gender, age, ethnic, and socioeconomic groups.

From January through August 2020, prescribing of penicillins declined the most (57.2% of March levels), followed by macrolides (54.6%) and tetracyclines (45.0%). Among 6,158 COVID-19 patients, the most commonly prescribed antibiotics within 14 days of a positive test were amoxicillin (34.9%) and doxycycline (27.4%).

"The reduction in community prescribing associated with COVID-19 and the national pandemic response could potentially have a favourable impact on antimicrobial resistance," the study authors wrote. "Our results need to be seen in the context of all antibiotic prescribing, and further monitoring is required to see whether this reduction persists and the impact that it will have."
Feb 15 Clin Microbiol Infect study


FDA clears investigational new drug application for bacteriophage therapy

Originally published by CIDRAP News Feb 16

Biotechnology company Adaptive Phage Therapeutics (APT) announced last week that the Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for bacteriophage therapy for the treatment of prosthetic joint infections (PJIs).

Bacteriophages, or phages, are viruses that infect bacteria and can be used to fight bacterial infections.

APT officials say the IND clearance will enable them to initiate a phase 1/2 trial to evaluate the safety and surgery-sparing effect of phages in patients with PJIs who are also being treated with antibiotics. The phages are selected from PhageBank, the company's library of purified phages covering a wide spectrum of specific bacterial diseases, and precisely matched to the bacteria causing the infection using a phage susceptibility test that APT has developed with the Mayo Clinic.

APT will conduct the randomized, controlled trial in collaboration with the Mayo Clinic starting in the second quarter of 2021.

"Phage therapy represents a potentially game-changing new treatment option for PJI and other multi-drug resistant or biofilm-mediated bacterial infections, where current patient outcomes can include loss of limb or even life," Gina Suh, MD, an infectious disease specialist at Mayo Clinic who is leading the collaboration with ATP, said in a company press release.

APT says the first interim data analysis from the trial is expected in the first quarter of 2022.
Feb 10 APT press release


Increased resistance, gene exchange found in Campylobacter from meat

Originally published by CIDRAP News Feb 16

In a study last week in PLOS One, researchers at North Carolina State University (NC State) identified an increase in antimicrobial resistance (AMR) genes and virulence factor distribution in Campylobacter samples isolated from animals and food.

In the study, researchers from NC State's College of Veterinary Medicine evaluated 541 Campylobacter isolates collected from live chickens, turkeys, swine, and cattle, as well as poultry carcasses and retail meat, in North Carolina from January 2018 through December 2019. Campylobacter coli was most prevalent on farms and at production facilities, comprising most isolates from live turkeys (100%), swine (94%), chicken (54%), and chicken carcasses (60%), while Campylobacter jejuni was the prominent species in retail chicken meat (69%).

Whole-genome sequencing of the isolates revealed that 90.4% of C coli and C jejuni isolates (489/541) contained at least one AMR gene and 43.1% (233/541) contained resistance genes to three or more antibiotic classes—a proportion higher than was found in 2017 National Antimicrobial Resistance Monitoring System surveillance. C coli isolates were twice as likely as C jejuni isolates to carry three or more resistance genes (odds ratio, 1.9; 95% confidence interval, 1.3 to 2.7).

AMR gene frequencies were highest against tetracyclines (64.3%), beta-lactams (63.6%), aminoglycosides (38.6%), macrolides (34.8%), quinolones (24.4%), lincosamides (13.5%), and streptothricins (5%).

The analysis also found that 57.6% of C jejuni (114/198) carried virulence factors for Guillain-Barré Syndrome, which can be triggered by Campylobacter infection, and revealed further evidence of C coli and C jejuni interspecies genomic exchange. The authors say that high levels of interspecies genomic exchange between the two species may alter pathogen survivability and resistance trends, and could pose a greater threat to public health.

In 2019, Campylobacter was the leading US cause of foodborne illness.

"This study shows that genomic exchange is happening between C. coli and C. jejuni, and that there is increasing antimicrobial resistance in Campylobacter found in N.C. poultry production," lead author Dawn Hull, a PhD student at NC State, said in a university press release. “Campylobacter is the worldwide leading cause for foodborne illness, so tracking this exchange is crucial to preventing transmission and providing future treatments."
Feb 11 PLOS One study
Feb 15 NC State press release


Phase 2 data support bedaquiline-delamanid combo for resistant TB

Originally published by CIDRAP News Feb 15

The results of a National Institutes of Health-funded phase 2 study indicate the new tuberculosis (TB) drugs delamanid and bedaquiline, when combined, have only a modest effect on the electrical activity of the heart, US, South African, and Peruvian researchers reported last week in the Lancet Infectious Diseases.

In the phase 2 randomized controlled trial, patients in South Africa and Peru with multidrug-resistant or rifampicin-resistant TB were randomized 1:1:1 to receive bedaquiline, delamanid, or both for 24 weeks. The two new drugs are considered critical components of a shorter, less toxic regimen for multidrug-resistant and rifampicin-resistant TB, but the cardiac and microbiologic safety of combining the two has not been well-established.

Both drugs are known to cause modest QTc prolongation, which can lead to an irregular heartbeat and increase the risk of sudden cardiac arrest, but the combined effect on QTc-related cardiac risk is unknown.

A total of 84 participants were enrolled in the trial from August 2016 through July 2018, with 28 in each treatment group and patients with higher-than-normal QTc values excluded. The primary endpoint was mean QTc change from baseline, as measured by electrocardiogram.

The mean change in QTc from baseline was 12.3 milliseconds (ms) in the bedaquiline group (95% confidence interval [CI], 7.8 to 16.7), 8.6 ms in the delamanid group (95% CI, 4.0 to 13.1), and 20.7 ms in the combined group (95% CI, 16.1 to 25.3). There were no grade 3 or 4 (life-threatening) QTc prolongation events, and the maximum QTc increase seen was similar for bedaquiline plus delamanid versus bedaquiline alone.

"These results are reassuring and provide evidence of the safety of concurrent bedaquiline and delamanid use in patients with multidrug-resistant or rifampicin-resistant tuberculosis," the authors wrote.

In addition, exploratory analysis found high rates of 8-week culture conversion in all groups, with early and sustained culture results seen in the combined treatment group. The authors said this is an encouraging sign that the combined treatment is effective but noted that the finding needs to be confirmed in larger clinical trials.
Feb 12 Lancet Infect Dis abstract

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