Our weekly wrap-up of antimicrobial stewardship & antimicrobial resistance scans
PhRMA report highlights challenges to antibiotic development
A new report from the pharmaceutical industry shows there are nearly 90 drugs in clinical development against drug-resistant infections—not nearly enough to meet the growing challenge of antimicrobial resistance (AMR).
The report from the Pharmaceutical Research and Manufacturers of America (PhRMA) profiles the 89 drugs from US-based companies that are in clinical trials or awaiting review by the US Food and Drug Administration, along with the bacterial pathogens they target. The list includes antibiotics and non-traditional antibacterial products, including bacteriophages, live therapeutic products, and monoclonal antibodies.
But like a recent report from the World Health Organization (WHO), the PhRMA report notes the lack of innovative antibacterial drugs in the pipeline and highlights the scientific and financial challenges that hinder antibiotic research and development and have led many companies to abandon the antibiotic market.
"Unfortunately, the treatments we need to combat this growing threat are dwindling and the current pipeline is insufficient to deal with the growing threat of AMR [antimicrobial resistance] as many biopharmaceutical companies have abandoned research into new infectious disease treatments," the report states. "The findings here confirm what has been warned about by others: there are too few antimicrobial medicines in development targeting priority pathogens identified by the CDC [Centers for Disease Control and Prevention] and WHO as posing the greatest risk to public health to meet current and anticipated needs."
The report concludes that without policy interventions, the broken market for new antibiotics will persist at the expense of patients and global health.
Apr 29 PhRMA Medicines in Development for AMR 2021 report
Review finds delayed antibiotics effective for respiratory infections
A systematic review and meta-analysis of individual patient data from 13 studies found that delayed antibiotic prescribing for respiratory infections appears to be a safe and effective strategy for most patients, including those in higher-risk subgroups, an international team of researchers reported this week in the BMJ.
The researchers looked at data from nine randomized controlled trials and four observational studies involving 55,682 patients who belonged to a delayed antibiotic prescription group and an immediate or no-antibiotic prescription group. The primary outcome analyzed was the average symptom severity 2 to 4 days after the initial consultation, measured on a seven-item scale (ranging from normal  to as bad as could be ). The secondary outcomes were duration of illness after initial consultation, complications resulting in admission to a hospital or death, reconsultation with the same or worsening illness, and patient satisfaction.
No difference was found in symptom severity for delayed versus immediate antibiotics (adjusted mean difference, -0.003; 95% confidence interval [CI], -0.12 to 0.11) or delayed versus no antibiotics (0.02; 95% CI, -0.11 to 0.15). Symptom duration was slightly longer in those given delayed versus immediate antibiotics (11.4 vs 10.9 days) but was similar for delayed versus no antibiotics.
Complications resulting in hospital admission or death were lower with delayed antibiotics than with no antibiotics (odds ratio [OR], 0.62; 95% CI, 0.30 to 1.27) and with delayed versus immediate antibiotics (OR, 0.78; 95% CI, 0.53 to 1.13). A significant reduction in reconsultation rates (OR, 0.72; 95% CI, 0.60 to 0.87) and an increase in patient satisfaction (adjusted mean difference, 0.09; 95% CI, 0.06 to 0.11) were observed in delayed versus no antibiotics.
Subgroup analysis showed that children younger than 5 years had a slightly higher follow-up symptom severity with delayed antibiotics than with immediate antibiotics (adjusted mean difference, 0.10; 95% CI, 0.03 to 0.18), but no increased severity was found in older age groups.
The study authors say that while delayed antibiotic prescribing and no antibiotic prescribing were equally effective for clinical outcomes, the increased patient satisfaction and lower reconsultation rate suggests it could be a stewardship strategy that works for both patients and providers.
"Delayed prescribing could be used as a standalone interventional approach, but it might also be a way of resolving mismatched expectations between clinician and patient," they wrote.
Apr 28 BMJ study
Outpatient UTI stewardship tied to more guideline-concordant prescribing
An outpatient stewardship program implemented at a primary care clinic and an urgent care clinic in North Carolina was associated with an increase in guideline-concordant antibiotic prescribing for urinary tract infection (UTI), researchers reported this week in Open Forum Infectious Diseases.
The quasi-experimental study conducted by researchers at Duke University looked at the effect of a two-phase intervention implemented at the clinics from August 2017 through July 2019. Phase 1 included the development of clinic-specific antibiograms and UTI diagnosis and treatment guidelines, which were presented during educational sessions with clinic providers. Phase 2 consisted of clinic- and provider-specific feedback emails showing trends in UTI diagnoses, guideline concordance, and antibiotic prescribing.
The primary outcome of the study was the percent of encounters with first- or second-line antibiotics prescribed according to clinic-specific guidelines from August 2016 through July 2019.
The researchers collected data on 4,724 patients and 6,381 UTI encounters. Immediately after phase 1, a 21.8% increase in the percentage of prescriptions for guideline-concordant prescriptions was observed (95% CI, 11.5% to 32%), followed by a 0.5% decline for each 2-week period afterward. Guideline concordance stabilized after implementation of phase 2, and further decline was not seen (-0.6%; 95% CI, -1.6% to 0.4%).
Overall, the mean percent of guideline concordance at the primary care clinic increased from 65% at baseline to 72.6% in phase 1 and 75% in phase 2; at the urgent care clinic, it rose from 35.8% to 57.3% to 61%. The shift in prescribing resulted in a 52% decline in fluoroquinolone use at both clinics. The mean number of UTI diagnoses per 2-week period also declined at both clinics.
"The present study suggests that the provision of clinic-specific urinary antibiograms along with treatment guidelines, clinician education, and data feedback to clinicians was successful at increasing guideline concordance, including a robust shift away from fluoroquinolones towards other agents with narrower spectrum and lower collateral damage, and reducing UTI diagnoses," the study authors wrote.
Apr 28 Open Forum Infect Dis abstract
Study suggests link between prenatal, early antibiotics and eczema
Originally published by CIDRAP News Apr 29
A large cohort study conducted in Sweden suggests antibiotic use in prenatal and early postnatal life may be linked to increased risk of eczema (atopic dermatitis) in children, researchers reported today in JAMA Network Open.
In a nationwide, prospective cohort study, a team lead by researchers from Sweden's Karolinska Institutet examined data on mother-child pairs from Sweden's Medical Birth Register, looking at children born from Mar 1, 2006, through Dec 31, 2010, to determine whether maternal exposure to antibiotics during pregnancy and childhood exposure to antibiotics during the first year of life were associated with the risk of eczema, which causes skin inflammation. The hypothesis is that disturbances to the gut microbiome that may result from exposure to antibiotics utero and in early life could be among the environmental factors linked to the condition, but previous studies have produced inconsistent results.
Among the 722,767 children identified in the study, 153,407 were exposed to antibiotics in utero and 172,405 were exposed during the first year of life.
In a multivariable-adjusted analysis, antibiotic use at any time during pregnancy was associated with a 10% higher rate of eczema (adjusted hazard ratio [aHR], 1.10; 95% CI, 1.09 to 1.12). However, when the researchers further explored this association using sibling control participants to adjust for familial factors, no association between prenatal antibiotic exposure and atopic dermatitis was observed (aHR, 0.96; 95% CI, 0.92 to 1.00).
Multivariable-adjusted analysis showed that the use of antibiotics during the first year of life was associated with a 52% increased risk of eczema (aHR, 1.52; 95% CI, 1.50 to 1.55). The sibling-control analysis found a 24% increased risk (aHR, 1.24; 95% CI, 1.20 to 1.29).
In a commentary on the study, Ayman Grada, MD, of Boston University, and Christopher Bunick, MD, PhD, of Yale, write, "These collective findings strongly warrant additional investigation to explore the impact of antibiotics in [atopic dermatitis] and other inflammatory diseases. ... It is important to avoid painting narrow-spectrum and broad-spectrum antibiotics with the same brush because narrow-spectrum and targeted antibiotics are among the main ways physicians will practice antibiotic stewardship in the future."
Apr 29 JAMA Netw Open study
Apr 29 JAMA Netw Open commentary
ASP network boosts stewardship activity at community hospitals
Originally published by CIDRAP News Apr 28
Community hospitals participating in a collaborative network focused on antibiotic stewardship program (ASP) implementation saw an increase in ASP activities and a decline in antibiotic use over 42 months, researchers reported yesterday in Clinical Infectious Diseases.
In the study, researchers with the Duke Center for Antimicrobial Stewardship and Infection Prevention analyzed ASP practices and antibiotic use at 17 community hospitals belonging to the Duke Antimicrobial Stewardship Outreach Network (DASON). Among the services that hospitals in the network receive are onsite consultation from infectious disease physicians and pharmacists, a shared database for routine feedback and benchmarking of antibiotic prescribing, and educational programs.
ASP practice was assessed using structured interviews, and monthly hospital-level antibiotic use rates were measured in days of therapy (DOT) per 1,000 patient days (PD).
Analyzed data included more than 2.5 million DOT and almost 3 million PD from January 2013 to December 2018. The participating hospitals increased their ASP activities over the study period, with significant increases in the number of hospitals implementing formulary restriction processes (initial 65% vs 94%) and prospective audit and feedback (56% vs 94%).
During the first month after entry in the network, the median rate of all antibiotic use among DASON hospitals was 925 DOT/1,000 PD, with a flat trend over the first 12 months. But after a year, the monthly antibiotic use rate trended down slowly. The relative rate (RR) comparing month 42 to month 13 showed a decline of 5% (RR, 0.95; 95% confidence interval [CI], 0.91 to 0.99). The observed median antibiotic use rate at month 42 was 867 DOT/1,000 PD.
Fluoroquinolone use dropped significantly, while other antibiotic classes demonstrated a non-significant downward trajectory after year one. Large variation was seen in hospital-specific antibiotic use.
"In summary, the DASON model provides distinct advantages for individual hospital ASPs compared to 'going it alone,' including access to stewardship expertise, educational resources, and shared data infrastructure to further optimize program activities," the study authors wrote. "Ultimately, this network served an individual hospital's priorities for program implementation but also produced larger, network-level effects."
Apr 27 Clin Infect Dis abstract
X-Biotix announces suspension of antibacterial research program
Originally published by CIDRAP News Apr 28
Biotechnology company X-Biotix Therapeutics of Waltham, Massachusetts, announced this week that it is suspending its current antibacterial research efforts, citing a lack of funding for early-stage antibiotic research and development (R&D).
X-Biotix was founded in 2016 and has focused on delivering small-molecule, first-in-class antibiotics that target multidrug-resistant gram-negative pathogens and defeat known antibiotic-resistance mechanisms. Among its projects, the company has been working on developing antibiotics that target the LpxA and LpxC enzymes, which play a role in constructing the tough outer membrane of gram-negative bacteria.
The company said it's now changing its strategy and will instead focus on submitting manuscripts that describe its process in identifying and developing novel small-molecule antibiotic scaffolds and on strengthening its intellectual property position. The company also said it will explore out-licensing or new funding opportunities for some of its research programs.
"This issue is driven by a critical lack of sustained sources of funding to support early-stage research in this field, combined with lack of an appropriate market infrastructure to support the successful commercialization of novel antibiotics," Stephen Isaacs, PhD, chairman of X-Biotix, said in a company press release. "Policy makers must enact market-based reforms, including reimbursement reform and commercial 'pull' incentives, in order to revitalize the antibiotics market and drive sustainable investments in antibiotics R&D."
X-Biotix is the latest in a line of companies abandoning antibiotic development because of lack of funding and the broken market for new antibiotics, which do not provide companies with a strong return on investment. According to research from the Pew Charitable Trusts' antibiotic resistance project, private investors poured $9.7 billion into R&D efforts for oncology drugs in 2019, while research into antibiotics received only $132 million.
Apr 26 X-Biotix press release
CARB-X to fund development rapid diagnostic test for sepsis
Originally published by CIDRAP News Apr 27
CARB-X announced today that it is awarding up to $3 million to GenomeKey of Bristol, United Kingdom, to develop an innovative rapid diagnostic test for sepsis.
GenomeKey's diagnostic project uses technology that combines innovative methods to separate bacterial DNA from human DNA in whole blood with next-generation DNA sequencing and machine learning to interpret antimicrobial susceptibility. The aim is determine, within 4 hours, what bacteria are causing the infection in sepsis patients and which antibiotics would be most effective. Conventional laboratory tests take 24 to 73 hours to produce results.
Globally, an estimated 11 million people die each year from sepsis, which occurs when the immune system has an overwhelming reaction to an infection that has entered the bloodstream. Quick, appropriate treatment is considered vital.
GenomeKey could be eligible for up to $6.5 million in additional funding from CARB-X (the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator) if the project achieves certain milestones.
"Prompt diagnosis and treatment provide the best chance for reducing death rates and improving recovery from sepsis," CARB-X Research and Development Chief Erin Duffy, PhD, said in a CARB-X press release. "GenomeKey's innovative technology aims to accelerate diagnosis and deliver vital antibacterial susceptibility information that could take the guesswork out of treatment decisions in the first critical hours of illness."
Apr 27 CARB-X press release
Study: Variation in clinic visits drives differences in antibiotic prescribing
Originally published by CIDRAP News Apr 27
Differences in antibiotic prescribing rates between high-prescribing areas of Massachusetts and low-prescribing areas were primarily due to variation in outpatient visits for respiratory conditions, rather than provider prescribing practices, researchers reported today in the Journal of Infectious Diseases.
In the study, researchers at Harvard University and the Massachusetts Department of Public Health examined medical and pharmacy claims data from the Massachusetts All-Payer Claims Database from January 2011 through September 2015 to determine geographic variation in outpatient visit rates and antibiotic prescribing rates per visit for 20 medical conditions. They defined high-prescribing census tracts as those with a per capita prescribing rate above the state median rate per 1,000 people per month, and low-prescribing census tracts as those with a prescribing rate below the state median rate.
The mean antibiotic prescribing rate in high-prescribing census tracts was 71.7 per 1,000 people per month, compared with 54.9 prescriptions in the low-prescribing tracts. In an age-stratified analysis, geographic differences in outpatient visit rates accounted for 45.2% of the gap in antibiotic prescribing between high- and low-prescribing tracts, while differences in prescribing practices accounted for just 25.8% of the gap.
In particular, geographic differences in outpatient visit rates for sinus infection, sore throat, and ear infection with pus accounted for 30.3% of the gap, a greater contribution than visits for the other 17 conditions combined (14.9%). The contributions from sore throat and ear infection were mostly attributable to higher outpatient visit rates among children under 10 in high-prescribing tracts.
When the researchers looked at predictors of outpatient visits for respiratory illness, they found fewer outpatient visits in census tracts with a higher social deprivation index (i.e., lower socioeconomic status).
"Taken together, our findings suggest that the variation in antibiotic prescribing rates across Massachusetts census tracts is not primarily due to variation in prescribing practices, but rather to variation in outpatient visit rates that may be associated with reduced healthcare access in the most impoverished areas of Massachusetts and/or an inflated tendency to seek medical care for respiratory illness in wealthier areas," the study authors wrote.
They add that interventions to reduce antibiotic consumption should address the drivers of outpatient visits for respiratory illness.
Apr 27 J Infect Dis abstract
Study finds high broad-spectrum antibiotic use in Indonesian hospitals
Originally published by CIDRAP News Apr 26
A point-prevalence study (PPS) conducted in six Indonesian hospitals found a high rate of empirical use of broad spectrum antibiotics, researchers reported today in JAC-Antimicrobial Resistance.
The hospital-wide PPS was conducted at six hospitals in Jakarta from March 2019 to August 2019. Eligible patients included everyone who received one or more antimicrobials on the day of the survey or surgical prophylaxis less than 24 hours prior to the survey. The analysis focused on antibiotics for systemic use, and researchers classified antibiotics according to the WHO's AWaRe (Access, Watch, and Reserve) classification system.
Of 1,602 hospitalized patients on the day of the survey, 993 (62%) received one or more antimicrobial, and of the 1,666 antimicrobial prescriptions, 1,273 (76.4%) were antibiotics. Antimicrobial use was highest in patients in intensive care units (86.8%), followed by surgical wards (66%), mixed medical-surgical wards (65%), and medical wards (51.4%). The most common prescribing reasons were pneumonia (27.7%), skin and soft-tissue infections (8.3%), and gastrointestinal prophylaxis (7.9%).
The most prescribed antibiotic classes were third-generation cephalosporins (44.3%), fluoroquinolones (13.5%), carbapenems (7.4%), and penicillins with beta-lactamase inhibitor (6.8%). According to the AWaRe classification, Watch antibiotics—broad-spectrum agents with an increased risk of developing resistance—accounted for 67.4% of antibiotics prescribed, while Access antibiotics accounted for 28% and Reserve antibiotics accounted for 2.4%. This pattern was similar across indications and ward types.
The researchers also found that hospital antibiotic guidelines were not available for 28.1% of prescriptions, and, when they were available, compliance was only 52.2%. In addition, the reason for the antibiotic prescription, the stop/review date, and the planned duration were poorly documented.
The authors note that the proportion of inpatients receiving antimicrobials in the study was significantly higher than has been reported in global PPS datasets.
"In conclusion, we observed high levels of parenteral, empirical use of broad-spectrum antibiotics in Indonesian hospitals, and inadequate performance on key quality indicators of prescribing," the study authors wrote. "Despite important progress in AMS [antimicrobial stewardship], supported by national policies, the study findings highlighted the need to strengthen AMS to increase use of narrower-spectrum antibiotics through culture-guided, targeted treatment and hospital guideline compliance."
Apr 26 JAC-Antimicrob Resist study