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

Narrow-spectrum antibiotics found safe, effective for moderate pneumonia

A clinical trial in the Netherlands found that an antimicrobial stewardship intervention safely reduced broad-spectrum antibiotic use in patients hospitalized with moderately severe pneumonia, Dutch researchers reported yesterday in The Lancet Infectious Diseases.

In the cross-sectional, stepped-wedge, cluster-randomized non-inferiority trial conducted in 12 Dutch hospitals, investigators enrolled immunocompetent adults who had a working diagnosis of moderately severe community-acquired pneumonia and were admitted to a non-intensive care unit ward. Every 3 months, a block of two hospitals would transition from the control period to the intervention period, with all hospitals eventually transitioning to the intervention period.

The antimicrobial stewardship intervention involved education, engaging local opinion leaders, and prospective audit and feedback of antibiotic use, with the aim of increasing the use of narrow-spectrum agents (benzylpenicillin and amoxicillin) for moderately severe pneumonia. The co-primary outcomes of the trial, which included 4,084 patients in the intention-to-treat analysis, were broad-spectrum days of therapy per patient and 90-day all-cause mortality.

The adjusted mean broad-spectrum days of therapy per patient were reduced from 6.5 days in the control period to 4.8 days in the intervention period, yielding an absolute reduction of 1.7 days (95% confidence interval [CI], 1.1 to 2.4) and a relative reduction of 26.6% (95% CI, 18.0 to 35.3). Crude 90-day mortality was 10.9% (242 of 2228 died) in the control period and 10.8% (199 of 1841) in the intervention period, yielding an adjusted absolute risk difference of 0.4% (90% CI, –2.7 to 2.4), indicating non-inferiority.

The study authors say the findings provide further evidence that antimicrobial stewardship interventions are efficacious in optimizing antibiotic use.

"In addition, our results add to the existing evidence base regarding the efficacy of narrow-spectrum beta-lactam monotherapy for patients with moderately severe community-acquired pneumonia, and thereby provide firm evidence to change clinical practice towards increased use of narrow-spectrum antibiotics, which will reduce antibiotic selective pressure for antimicrobial resistance," they wrote.
Oct 7 Lancet Infect Dis abstract

Molecular test for resistant TB shows high diagnostic accuracy

In another study published yesterday in the same journal, an international team of researchers reported that a rapid, sputum-based, molecular diagnostic test for drug-resistant tuberculosis (DR-TB) showed high diagnostic accuracy and met the World Health Organization's criteria for a next-generation drug susceptibility test.

The prospective study involved individuals presenting with pulmonary TB symptoms and at least one risk factor for drug resistance at four sites in India, Moldova, and South Africa from Jul 31, 2019, through Jun 20, 2021. The Xpert MTB/XDR assay was used as a reflex test to detect resistance to isoniazid, fluoroquinolones, ethionamide, amikacin, kanamycin, and capreomycin in adults who had already tested positive for Mycobacterium tuberculosis complex on other assays. Diagnostic performance was evaluated against phenotypic drug-susceptibility testing and whole-genome sequencing.

Of the 710 patients enrolled, 611 had results from both Xpert MTB/XDR and the composite reference standard for any drug and were concluded in the analysis. Although performance of the assay varied among sites, overall, Xpert MTB/XDR had reasonable to high diagnostic accuracy. Sensitivity for detection of resistance was 94% (460 of 488; 95% CI, 92% to 96%) for isoniazid, 94% (222 of 235; 95% CI, 90% to 96%) for fluoroquinolones, 54% (178 of 328; 95% CI, 50% to 61%) for ethionamide, 73% (60 of 82; 95% CI, 62% to 81%) for amikacin, 86% (181 of 210; 95% CI, 81% to 91%) for kanamycin, and 61% (53 of 87; 95% CI, 49% to 70%) for capreomycin. Specificity was 98% to 100% for all drugs.

Performance was equivalent to that of line-probe assays. The non-determinate rate of Xpert MTB/XDR (ie, invalid M tuberculosis complex detection) was 2.96%.

"The Xpert MTB/XDR assay is an important method to identify and direct treatment of isoniazid-resistant, fluoroquinolone-resistant, and pre-extensively drug-resistant tuberculosis," the authors wrote. "This rapid sputum-based assay has the potential to greatly improve diagnosis and management of DR-TB worldwide."
Oct 7 Lancet Infect Dis abstract

Kids' flu vaccine campaign has mixed impact on antibiotics for respiratory infections

Researchers with Public Health England found that a flu vaccine program for children had a mixed impact on antibiotic prescribing for respiratory infections, according to a study published yesterday in Vaccine.

To assess the impact of the United Kingdom's live attenuated influenza vaccine (LAIV) program for children aged 2 to 3 years on antibiotic prescribing, the researchers calculated antibiotic prescribing incidence rates for respiratory tract infections (RTIs) and urinary tract infections (UTIs) at general practice (GP) levels by age category (children 10 years and younger and adults) and season in LAIV pilot areas from 2013 through 2016.

UTI prescriptions were used for baseline comparison. To estimate the LAIV intervention impact, a random effects model was fitted with factors for period, pilot area, and the interaction between period and pilot area.

RTI antibiotic prescribing rates for children 10 and under and adults showed clear seasonal trends and were lower in LAIV pilot areas and non-pilot areas after the introduction of the program in 2013. The reductions in RTI prescriptions for children were similar in all areas, but the researchers note the reduction may be linked to the start of the UK antimicrobial resistance (AMR) strategy.

The model also showed that, at the GP level, antibiotic prescribing for RTI was significantly inversely related to vaccine uptake in preschool children (2 to 3 years of age), with antibiotic prescribing being reduced by 2.7% (95% CI, 2.1% to 3.4%) for every 10% increase in flu vaccine uptake in pre-school children. 

"In summary, we did not find evidence of a population level impact of the live attenuated influenza vaccination programme for primary school age children on reducing GP antibiotic prescribing rates for respiratory infections for children or adults in England, though we did observe a significant reduction in respiratory antibiotic prescribing with increasing LAIV uptake in children 2–3 years of age at the primary care level," the study authors wrote.

"Our paper highlights the importance of further work to investigate the apparent association between pre-school influenza vaccination and antibiotic prescribing."
Oct 7 Vaccine abstract

Beta-lactam antibiotics first may improve bloodstream infection survival

Originally published by CIDRAP News Oct 7

Administration of a beta-lactam antibiotic before vancomycin in patients with bloodstream infections (BSIs) may reduce early mortality, according to a study published this week in Clinical Infectious Diseases.

In the multicenter observational study, researchers from Johns Hopkins University School of Medicine and Children's Hospital of Philadelphia looked at data on patients 13 years and older who were treated for BSIs from July 2016 through June 2020 and received a beta-lactam before vancomycin.

While the choice and timing of antibiotic administration for BSIs has been thoroughly studied, little attention has been paid to the sequence of antibiotic administration. The study authors hypothesized that, when the causative pathogen is not immediately known, administering a broad-spectrum beta-lactam antibiotic first might improve survival.

The primary outcome of the study was mortality within 7 days from the time of blood culture collection. The secondary outcome was mortality within 48 hours of blood culture collection.

Of 3,376 eligible patients, 2,685 (79.5%) received a beta-lactam and 691 (20.5%) received vancomycin as their initial antibiotic. In an inverse probability of treatment weighting (IPTW) analysis, conducted to ensure that patients who received a beta-lactam first and those who received vancomycin first were similar on all patient variables, administration of a beta-lactam agent prior to vancomycin reduced 7-day mortality by 52% (adjusted odds ratio [aOR], 0.48; 95% CI, 0.33 to 0.69).

Similar results were observed when evaluating 48-hour mortality (aOR, 0.45; 95% CI: 0.24 to 0.83). Administration of vancomycin prior to a beta-lactam was not associated with improved survival in the subgroup of 524 patients who had methicillin-resistant Staphylococcus aureus BSI (aOR, 0.93; 95% CI, 0.33 to 2.63).

The study authors say that with an estimated 13,245 BSIs per year, prioritizing beta-lactam administration has the potential to save 737 lives per year, "underscoring the significant impact of a relatively simple practice change."
Oct 4 Clin Infect Dis abstract

Study finds C difficile is prevalent outside of healthcare settings

Originally published by CIDRAP News Oct 6

A study presented last week at IDWeek 2021 suggests Clostridiodes difficile is more prevalent outside of the hospital than previously thought. And the soles of people's shoes may play a significant role in spread of the bacterium.

Researchers at the University of Houston analyzed environmental samples collected from public areas, healthcare settings, and shoe soles in 11 countries from 2014 through 2017 for the presence of C difficile, which causes severe diarrhea and is the leading cause of hospital-associated infections but is increasingly being reported in community settings. The aim was to examine the prevalence and the strain types of the bacterium in different settings.

Of the 11,986 unique isolates collected, 92% were from the United States, 1.7% were from Taiwan, and 1.6% were from India. Samples were categorized as being from outdoor environments (2,992 isolates), private residences (2,772), shoe soles (1,420), public buildings (1,104), and acute care settings (3,698). Worldwide C difficile sample positivity was 26% and was similar between US and non-US sampling sites.

In the United States, private residences (26.2%) and outdoor environments (24.1%) had the highest positivity rate compared with public buildings (17.2%). In a sub-analysis of 8,571 isolates collected in Texas, positivity rates were highest in outdoor samples (27%) and were similar between private residences (24%) and healthcare buildings (24%). The most prevalent C difficile ribotypes (RTs) overall were F014-020 (16.4%), F106 (14.9%), and FP310 (11%). Shoe soles had the highest positivity rate (45%), with similar RT distribution between shoe soles and environmental samples.

"The results of this study shift our understanding of C. diff, including where it is found, how it is transmitted, and who it affects," co-author Kevin Garey, PharmD, of the University of Houston College of Pharmacy, said in an IDWeek press release. "We can no longer think of C. diff as only existing in healthcare settings, and the population at risk is no longer just the very sick patient in the hospital. Identifying that person at risk anywhere in the world should become a priority regardless of whether the person is in a hospital or the community."

The study authors said removing shoes before entering a home or a common space could help reduce community spread.
Sep 30 IDWeek press release

US stewardship effort tied to lower antibiotics in ambulatory care during COVID

Originally published by CIDRAP News Oct 5

A national ambulatory antibiotic stewardship program was associated with declines in overall and acute respiratory infection (ARI)-related prescribing during the COVID-19 pandemic, US researchers reported last week at ID Week 2021.

Out of 467 ambulatory practices enrolled, 389 completed the Agency for Healthcare Research and Quality (AHRQ) Safety Program for Improving Antibiotic Use, a program that aims to incorporate antibiotic stewardship into practice culture, communication, and decision-making through education and technical support. The program uses webinars, audio presentations, educational tools, and office hours to address attitudes and culture that pose challenges to judicious antibiotic prescribing and to incorporate best practices for managing common infections into clinician workflow.

To evaluate the program's effectiveness, researchers compared total visits to the practices, visits for ARI, and antibiotic prescribing in the pre-intervention (September to November 2019) and intervention (December 2019 to November 2020) periods.

The 389 practices included 162 primary care practices, 160 urgent care clinics, and 49 federally supported practices. Visits per practice-month declined from March to May 2020 but gradually returned to baseline by program end.

Total antibiotic prescribing declined by 9 prescriptions per 100 visits (95% CI, -10 to -8). ARI visits/practice-month declined significantly from March to May 2020, then increased but remained below baseline by program end. ARI-related antibiotic prescriptions decreased by 15/100 ARI visits by program end (95% CI, -17 to -12). The greatest reduction was in penicillin class prescriptions, with a reduction of 7/100 ARI visits by program end (95% CI, -9 to -6).

"We have demonstrated that it is possible to implement stewardship on a large scale in different practices and settings across the country,” Sara Keller, MD, MPH, associate professor at Johns Hopkins University School of Medicine and the study's presenting author, said in an ID Week press release. "To improve antibiotic use is to improve patient safety. There is immense hope in that." 
Sep 30 IDWeek press release

FDA clears new rapid molecular test for antibiotic resistance genes

Originally published by CIDRAP News Oct 4

Diagnostics company OpGen announced today that it has received 510(k) clearance from the US Food and Drug Administration (FDA) to market a new rapid molecular diagnostic tool that could aid in treating antibiotic-resistant or non-susceptible infections.

The Acuitas AMR Gene Panel detects 28 genetic antibiotic resistance markers in bacterial isolates from 26 different pathogens, according to a company press release, and can rapidly and simultaneously test for resistance to select drugs in nine antibiotic classes. OpGen, of Rockville, Maryland, says it's the broadest AMR panel cleared by the FDA.

"The benefits of this AMR panel for predicting antibiotic resistance include the provision of genomic profile data much sooner in about 2.5 hours versus conventional phenotypic information which can take 1-4 days, supports the goal of antimicrobial stewardship, institution of infection control and prevention measures, and alerts the provider to resistant genes representing nine classes of antibiotics," James Snyder, PhD, director of microbiology and molecular diagnostics at the University of Louisville Hospital, said in the release.

OpGen says it plans to launch the device before the end of the year. 
Oct 4 OpGen press release

Risk factors tied to COVID symptoms 2 to 7 months after hospital release

Female sex, middle age, two or more chronic diseases, and more severe initial illness were predictive of difficulty recovering from COVID-19 6 months after release from a hospital, finds a multicenter UK study yesterday in The Lancet Respiratory Medicine.

University of Leicester researchers led the study, which involved an assessment of 1,077 adults 2 to 7 months after release from the hospital for treatment of COVID-19. The patients left the hospital from Mar 5 to Nov 30, 2020.

After a median of 5.9 months of follow-up, 29% of 830 participants said they felt fully recovered, while 20% had a new disability and 19% had to change jobs due to their health.

The researchers identified four clusters involving 767 patients with different degrees of coronavirus-related mental and physical impairment. Seventeen percent had very severe impairments, 21% were severely affected, 17% had moderate impairment with cognitive problems, and 46% were mildly impaired.

Three percent of 113 patients in the very severe group reported feeling fully recovered, as did nine of 129 (7%) in the severe cluster, 36 of 99 (36%) in the moderate group, and 114 of 267 (43%) in the mild cluster. Persistently increased serum C-reactive protein (indicating inflammation) was positively associated with impairment severity. The degree of physical and mental—but not cognitive—impairments were also closely associated with each other.

The authors said that the findings suggest the presence of underlying mechanisms, regardless of the degree of lung injury and perhaps related to lingering systemic inflammation.

"The four clusters highlight the potential to stratify and personalise care, and emphasise the need for wide access to interventions to improve mental, physical, and cognitive health," they wrote, adding that patients will also need a proactive approach and holistic clinical care.

In a related commentary, Linda Denehy, PhD, and Zudin Puthucheary, MBBS, PhD, called for large clinical trials on the effectiveness of individual treatments (eg, drugs, multidisciplinary rehabilitation).

"As with the trajectory of research over the past two decades in critical care, we need to identify responders to specific interventions, map impairments across time, and involve patients and caregivers in the process of recovery," they wrote.
Oct 7 Lancet Respir Med study and commentary

Nursing home profit model linked to higher COVID-19 death rate

Prior to COVID-19 vaccine availability, nursing home residents had a 9.4% COVID-19 death rate and private ownership was tied to a 22% higher risk of death, according to a study published in the Journal of Infectious Diseases yesterday.

The researchers looked at 608,251 residents 65 years and older and using Medicare in US nursing homes from Apr 1 to Dec 22, 2020. About 9.4% died of COVID-19. Higher mortality risk was associated with men (hazard ratio [HR], 1.69), end-stage renal disease (HR, 1.42), cognitive impairment (HR, 1.34), and immunocompromised status (HR, 1.20). Data also showed that residents at for-profit nursing homes had a higher risk of COVID mortality (HR, 1.22).

While residents in a facility with a higher health inspection rating had a lower mortality risk (five stars vs 1 star, HR 0.79), the researchers say that quality measure ratings had inconsistent effects on death compared with hospitalization.

Compared with community rates, mortality was higher in nursing home residents (9.4% vs 0.3%) as was hospitalization rate (10.4% vs 1.2%). Among people who died with COVID-19, however, 46.9% of nursing home residents weren't hospitalized, compared with 15.3% in the community. In general, hospitalization for nursing home residents was less likely if the resident was 85 or older even though they were more likely to die.

Although the researchers say their data suggest that equal access to care can help resolve socioeconomic or racial differences, a commentary by Mack Roach III, MD, and others points out the disproportionate hospitalization and mortality rates among minorities. 

"Clearly, Blacks and other minorities have an increased risk of hospitalization and death due to COVID-19," the commentators write. "However, it is not obvious from the data provided whether the differences in hospitalizations and death are in fact due to the increased comorbidities, which might in turn be due to lack of access to care and appropriate screening for chronic disease prior to the individuals entering a nursing home.

"So, while the results of this study show no obvious evidence of racism in nursing home care, it leaves open the contribution of structural racism to the increased chronic disease burden in minorities."
Oct 7 J Infect Dis study and commentary

Three countries report vaccine-derived polio cases

Madagascar, Nigeria, and the Ukraine reported polio cases involving vaccine-derived subtypes, according to the latest weekly update from the Global Polio Eradication Initiative (GPEI) and the European Centre for Disease Prevention and Control (ECDC) today.

Madagascar reported one new case of circulating vaccine-derived poliovirus type 1 (cVDPV1), in Boeni, where a case was also identified last week. The country has now reported nine cVDPV1 cases for 2021.

In Nigeria, GPEI said 17 cases of circulating vaccine-derived poliovirus type 2 (cVDPV2) were reported; 4 in Bauchi, 3 each in Jigawa and Katsina, 2 each in Borno and Gombe, and 1 each in Kano, Taraba and Yobe. There are now 169 cases reported in 2021. Last year, Nigeria reported only 8 cases.

The ECDC also reported a case of acute flaccid paralysis caused by cVDPV2 in an unvaccinated 18-month-old girl from Rivne oblast, in the Ukraine. She had symptoms Sep 1 and was hospitalized on Sep 3 with paralyzed legs. Her parents refused polio vaccination because of religious beliefs.
Oct 6 GPEI weekly update
Oct 8 ECDC report