CIDRAP publishes COVID-19 report, says to plan for long haul

Though many organization have published guidance on the best way forward during this COVID-19 pandemic, the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota saw a need for recommendations based on current realities and restrictions, not on technology such as widespread testing that may one day be in place.

So the center, in consultation with Harvard epidemiologist Marc Lipsitch, DPhil, and pandemic flu expert and historian John Barry, MA, yesterday published a report, "The future of the COVID-19 pandemic: lessons learned from pandemic influenza," that details how the novel coronavirus is behaving epidemiologically more like past influenza pandemics and not like any known coronavirus, some of which cause severe disease like SARS (severe acute respiratory syndrome).

"We realize that other expert groups have produced detailed plans for reopening the country after stay-at-home orders and other important mitigations steps are eased," said CIDRAP Director Michael Osterholm, PhD, MPH. "So with this report we sought to add key information and address issues that haven't garnered the attention they deserve—not to duplicate efforts.

"For example, the first CIDRAP Viewpoint report lays out three scenarios for how cases might ebb and flow in the coming months. We are now on virus time, and no one knows exactly how this virus will behave. But, based on what scientists have recorded so far and on previous influenza pandemics, we illustrate some of the possibilities."

Osterholm added, "The key message of this report is that the COVID-19 pandemic likely will not end any time soon, if any of the scenarios we have outlined come to pass. We need to be prepared to deal with this pandemic and its 'aftershocks' for 18 months or more."

The report is the first in a series titled "COVID-19: The CIDRAP Viewpoint" that will also cover crisis communication, testing, contact tracing, surveillance, supply chains, epidemiologic issues, and key areas for research. CIDRAP publishes CIDRAP News.
Apr 30 CIDRAP report landing page

Hydroxychloroquine linked to prolonged QT intervals in COVID-19 patients

New research in JAMA Cardiology today describe prolonged QT internals in COVID-19 patients treated with hydroxychloroquine either alone or combined with the antibiotic azithromycin. The studies are based on hospitalized patients in Lyon, France, and in Boston, and show the QT intervals lengthened in more than 90% of patients.

Hydroxychloroquine was first approved for use in the United States in 1955 as an antimalarial. The drug has anti-inflammatory properties and is widely prescribed for lupus and arthritis, but has recently been thrust in the spotlight as a potential therapeutic for COVID-19.

In the Lyon case series, 37 of 40 (93%) showed an increase in the QT interval after the administration of antiviral hydroxychloroquine therapy, which included azithromycin. The patients were hospitalized in the second half of March, and did not experience ventricular arrhythmias, including torsades de pointes, after being treated with hydroxychloroquine and azithromycin.

In Boston, scientists conducted a cohort study involving 90 patients receiving hydroxychloroquine, and 53 receiving concomitant azithromycin. "Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (3%) had a change in QTc [corrected QT] of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or more and 7 of 53 (13%) had a change in QTc of 60 milliseconds or more," the authors found.

Ten of the 90 patients (11%) stopped taking hydroxychloroquine prior to day 5 of treatment for QT prolongation, the authors said.

"The data … underscore the potential risk associated with widespread use of hydroxychloroquine and the combination of hydroxycholoquine and azithromycin in ambulatory patients with known or suspected COVID-19," wrote Robert O. Bonow, MD, MS, Northwestern University Feinberg School of Medicine, and colleagues in an accompanying editorial on the studies.
May 1 JAMA Cardiol French research letter
May 1 JAMA Cardiol Boston study
May 1 JAMA Cardiol editorial

Study: 26% of US healthcare workers at risk for poor COVID-19 outcomes

A study this week in Annals of Internal Medicine shows that 26.5% of American healthcare workers are at risk for poor outcomes from COVID-19 infections because of age or medical conditions, and a sizable portion of them lack health insurance or paid sick leave.

The study was based on data collected from the 2018 National Health Interview Survey and the March 2019 Current Population Survey, both of which included frontline health workers who have patient contact in hospitals, dental and doctor offices, nursing homes, or in emergency services.

Of 13.79 million healthcare workers with patient contact, 3.66 million (95% confidence interval [CI], 3.20 million to 4.13 million), or 26.6% (95% CI, 23.6% to 29.5%), were at risk for poor COVID-19 outcomes because of age or chronic conditions, the authors found. Of those at risk, 7.5% said they lacked health insurance or paid sick leave in the past 12 months.

"Our data indicate that millions of health workers likely to be exposed to SARS–CoV-2 have medical conditions that increase their risk for poor COVID-19 outcomes," the authors concluded. "Many lack health insurance and paid sick leave, and more than 600,000 live in poverty, potentially compromising their ability to maintain social distancing outside their workplace."
Apr 28 Ann Intern Med study

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

Drug firm teams with nonprofit to develop new antibiotic

The Global Antibiotic Research and Development Partnership (GARDP) this week announced a partnership with Venatorx Pharmaceuticals to accelerate development of an investigational beta-lactam/beta-lactamase inhibitor combination for treating multidrug-resistant hospital infections.

GARDP and Venatorx, of Malvern, Pennsylvania, will collaborate to complete the development of cefipime/taniborbactam, which is currently being evaluated in a phase 3 trial of patients who have complicate urinary tract infections. Additional clinical trials in adults with multidrug-resistant infections and in children with serious bacterial infections are also planned.

Taniborbactam is a novel, broad-spectrum beta-lactamase inhibitor that restores the activity of cefepime, a fourth-generation cephalosporin, against carbapenem-resistant Enterobacteriaceae and carbapenem-resistant Pseudomonas aeruginosa. The World Health Organization (WHO) has identified both pathogens as critical threats to global health that urgently require new treatment options.

"More than a hundred thousand people die every year in high-income countries due to hospital infections, and indicators point to a significantly higher burden in low- and middle-income countries," Manica Balasegaram, BMedSci, BMBS, executive director of GARDP, said in a press release. "Our collaboration with Venatorx enables us to accelerate the development of a critically needed treatment for antibiotic-resistant infections in adults and children."
Apr 29 GARDP press release

Fluoroquinolone use in VA hospitals has declined, study finds

Nearly all measures of fluoroquinolone use at Veterans Affairs (VA) hospitals declined from 2014 through 2017, but the decrease in inpatient use was much larger than the decline in fluoroquinolone use at discharge, according to a study yesterday in Open Forum Infectious Diseases.

The study, led by researchers from Michigan Medicine and the VA Ann Arbor Healthcare System, assessed inpatient and discharge fluoroquinolone (ciprofloxacin, moxifloxacin, and levofloxacin) use among veterans hospitalized with infections at 125 VA hospitals from 2014 through 2017. The aim of the study was to measure the decline in fluoroquinolone prescribing, particularly at discharge, since the Veterans Health Administration called for implementation of antibiotic stewardship programs at all hospitals in 2014. Fluoroquinolones have been a particular concern because of their association with Clostridioides difficile infection and adverse events.

Of the 560,219 hospitalizations with infection analyzed, 37.4% involved a fluoroquinolone prescription either during hospitalization (32.5%) or at discharge (19.6%). Hospitals varied appreciably in inpatient, discharge, and total fluoroquinolone use, with 71% of the hospitals in the highest prescribing quartile located in the southern United States.

When they analyzed adjusted rates of fluoroquinolone prescribing longitudinally by year, the researchers found a significant decrease in the proportion of patients who were prescribed any fluoroquinolone during hospitalization (relative risk reduction [RRR], 25.4%; absolute risk reduction [ARR], 9.4%). The decline in the proportion of patients prescribed a fluoroquinolone at discharge was statistically significant, but smaller (RRR, 7.4%; ARR, 1.4%). Over the study period, fluoroquinolone use at discharge accounted for a growing percentage of hospitalization-related fluoroquinolone days (from 52% in 2014 to 61.3% in 2017).

Among the three fluoroquinolones, ciprofloxacin saw the largest decreases in use—mostly due to a decrease in inpatient use—while levofloxacin use was largely stable over time, with small decreases in inpatient use and small increases in discharge use. Moxifloxacin use was low and declined further.

"Fluoroquinolone prescribing at discharge, and levofloxacin prescribing in particular, is a growing target for stewardship," the authors concluded. "Further studies should evaluate whether interventions to reduce total antibiotic duration may be most effective at decreasing post-discharge fluoroquinolone use."
Apr 30 Open Forum Infect Dis abstract

Revised C diff guidance has quickly changed practice, study finds

Originally published by CIDRAP News Apr 29

Revised clinical practice guidelines for CDI have had an immediate and significant impact on treatment, researchers reported yesterday in Clinical Infectious Diseases.

Using US antibiotic prescription data for 2006 through August 2019, researchers from the University of Pittsburgh and the VA Pittsburgh Healthcare System performed an interrupted time-series analysis to compare linear trends for monthly treatment courses of vancomycin, fidaxomicin, and metronidazole. The aim of the analysis was to determine if use of the three drugs changed after publication of revised CDI guidelines from the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) in 2018, which recommended vancomycin or fidaxomicin as preferred treatments for initial and first recurrent non-severe CDI, rather than metronidazole as previously recommended.

The analysis found that cumulative treatment courses of oral vancomycin and fidaxomicin increased by 54% and 48%, respectively, in the 18 months following the guidelines compared with the 18 months before, while those of oral metronidazole decreased by 3%. Monthly vancomycin and fidaxomicin use also significantly increased throughout the period following revised guidelines (P < 0.0001 and P = 0.0002, respectively), while monthly use of metronidazole decreased significantly (P< 0.0001).

The analysis also showed that the monthly increases in vancomycin use and decreases in metronidazole use were significantly greater following publication of the revised IDSA/SHEA guidelines than after the publication of two randomized clinical trials that established the superiority of vancomycin over metronidazole.

The authors say the fact that the data used to revise CDI treatment guidelines were available for years before changes in practice were endorsed by IDSA and SHEA suggests that guidelines for CDI and other infections should be updated more frequently.

"Taken together, our findings support a new IDSA initiative to develop, disseminate, and adopt more timely guidelines and guidance for managing antimicrobial-resistant and other difficult-to-treat infections, as set forth in the society's 2019 Strategic Plan," they wrote. 
Apr 28 Clin Infect Dis abstract

Studies analyze effects of mass azithromycin distribution in Malawi

Originally published by CIDRAP News Apr 28

A new analysis of data from a randomized clinical trial that found that mass distribution of the antibiotic azithromycin to children under 5 years old was associated with reduced childhood mortality in three African countries suggests mortality reduction may be linked to effects on pneumonia, diarrhea, or HIV/AIDS mortality. The findings were published yesterday in the American Journal of Tropical Hygiene and Medicine.

The secondary analysis of results from the MORDOR (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) trial looked specifically at causes of deaths during the trial in Malawi (Niger and Tanzania were the other trial sites). Although the trial was not powered to investigate mortality effects at individual trial sites, investigators used verbal autopsy (VA)—a structured interview with relatives of the deceased to ascertain cause of death—and two different methods of automated VA analysis (InterVA and SmartVA) to assess the major causes of death during the trial and develop a hypothesis about how azithromycin may effect childhood mortality.

A total of 334 communities in Malawi were randomized to receive azithromycin or placebo during the trial, and 1,184 deaths were recorded, of which 1,131 were followed up with VA. Mortality was 9% lower in the azithromycin-treated communities than in communities that received placebo. An intention-to-treat analysis using IntervA suggested fewer HIV/AIDS deaths in azithromycin-treated communities (rate ratio, 0.70; 95% confidence interval [CI], 0.50 to 0.97; P = 0.03) and fewer pneumonia deaths (rate ratio, 0.82; 95% CI, 0.60 to 1.12; P = 0.22). The use of the SmartVA algorithm suggested fewer diarrhea deaths (rate ratio, 0.71; 95% CI, 0.51 to 1.00; P = 0.05) and fewer pneumonia deaths (rate ratio, 0.58; 95% CI, 0.33 to 1.00; P = 0.05).

"Although this study is not able to provide strong evidence on the causes of death in the MORDOR trial, the data have been presented fully to enable generation of hypotheses regarding mechanisms of effect of azithromycin on childhood mortality," the authors wrote. "Larger studies will be required to clearly define the effects of azithromycin on cause-specific childhood mortality."

Another MORDOR analysis published in the same journal found that mass distribution of azithromycin has the potential to be a highly cost-effective intervention for reducing childhood mortality in some settings in Malawi, while a third analysis found that mass distribution of the drug in Malawi had no effect on malaria parasitemia at the community or individual levels.
Apr 27 Am J Trop Med Hyg abstract 1
Apr 27 Am J Trop Med Hyg abstract 2
Apr 27 Am J Trop Med Hyg abstract 3

Rapid MDR-TB susceptibility test tied to faster diagnosis, better outcomes

Originally published by CIDRAP News Apr 28

The use of rapid molecular drug susceptibility testing (DST) in patients with multidrug-resistant tuberculosis (MDR-TB) significantly reduced time to diagnosis and was associated with decreased time to culture conversion and improved treatment outcomes, Chinese and Swedish researchers reported yesterday in the International Journal of Infectious Diseases.

In a study that included 242 MDR-TB patients admitted to two Chinese hospitals from 2012 through 2015, the researchers compared time to diagnosis and treatment outcomes in patients before and after implementation of commercially available rapid molecular DST tools (Genotype MTBDRsI and MTBDRplus Assay) for MDR-TB diagnosis. They assessed clinical improvement by looking at time to sputum culture conversion and final treatment outcomes after 2 years of treatment. A total of 114 patients belonged to the pre-implementation group and 128 to the post-implementation group.

The analysis found that post-implementation patients had a significantly reduced time to MDR-TB diagnosis compared with patients in the pre-implementation group (median: 16 vs 62 days), along with shorter treatment with first-line drugs (median: 11 days vs 59 days) and earlier initiation with second-line drugs (median: 19 vs 69 days). In addition, patients in the post-implementation group had a more rapid culture conversion (median: 12 months vs 24 months) and a higher rate of treatment success (68% vs 47%, P < 0.01).

Multivariate analysis showed that the effect of molecular DST implementation was significantly positively correlated with early sputum culture conversion (adjusted hazard ratio, 1.94; 95% CI, 1.37 to 2.73) and treatment success (adjusted odds ratio, 2.47; 95% CI, 1.38 to 4.42).

The authors says the findings are important because MDR-TB poses a major threat to TB control programs, and conventional phenotypic DST methods are time consuming, prolong the time to effective treatment, and require a TB-containment laboratory, which is not always available in low-income settings.

"Our findings highlight the importance of rapid diagnostic testing for the improvement of MDR-TB treatment outcome," they concluded.
Apr 27 Int J Infect Dis study

Australian study: Antibiotics likely overprescribed for older adults

Originally published by CIDRAP News Apr 27

Priority antibiotics with a high potential for developing resistance are commonly prescribed to older adults in Australia, particularly those with chronic respiratory conditions, but fewer than one fifth of those prescriptions are accompanied by microbiologic tests, researchers reported in BMC Infectious Diseases.

In the study, Australian researchers looked at data on a cohort of older adults (mean age 69 years) that were linked to records of community-based antibiotic prescribing and microbiologic testing. Their aim was to examine the incidence rate of (WHO)-defined Access and Watch antibiotic dispensing among older adults and compare it to the rate of microbiologic testing for bacterial infections. Access antibiotics are first-line options for common infections, while Watch antibiotics are those the WHO considers at greater risk for developing resistance. The WHO recommends that microbiologic assessment accompany use of Watch drugs.

In 2015, among 244,299 participants, there were 63,306 Watch antibiotic prescriptions dispensed and 149,182 microbiology tests conducted; the incidence rate was 0.26 per person-year for Watch group antibiotic dispensing and 0.62 for microbiology testing. Of those antibiotic prescriptions, only 19% were accompanied by microbiology testing within − 14 to + 7 days.

After adjusting for sociodemographic factors and comorbidities, the researchers found that individuals with chronic respiratory diseases were more likely to receive Watch antibiotics than those without—for example, asthma (adjusted incident rate ratio [aIRR], 1.59; 95% confidence interval [CI], 1.52 to 1.66) and chronic obstructive pulmonary disease (COPD) (aIRR, 2.71; 95% CI, 2.48 to 2.95). The rate of microbiology testing, however, was not higher among them (with asthma aIRR, 1.03; 95% CI, 1.00 to 1.05; with COPD aIRR,1.00; 95% CI, 0.94 to 1.06).

The authors of the study say the findings are noteworthy because the use of microbiologic testing can be considered a proxy for assessing the appropriateness of antibiotic use.

"Since watch group antibiotics have high resistance potential, focusing antibiotic stewardship efforts might be needed among older populations with chronic respiratory diseases in the primary care setting," they concluded.
Apr 25 BMC Infect Dis study

Hong Kong study supports adherence to pneumonia treatment guidelines

Originally published by CIDRAP News Apr 27

Researchers in Hong Kong report that adherence to antibiotic treatment guidelines was associated with shorter hospitalization and improved survival in community-acquired pneumonia (CAP) patients, according to a new study in Open Forum Infectious Diseases.

The prospective observational cohort study, conducted by researchers at the Chinese University of Hong Kong, looked at 258 patients hospitalized with CAP in Hong Kong from February 2017 to July 2018. The investigators were interested in looking at clinician adherence to new treatment guidelines for common infectious diseases published in Hong Kong in 2017, particularly the recommendations on empiric antibiotic therapy. They documented disease severity, microbiologic results, antibiotic treatment, and outcomes and performed multivariable logistics regression and Cox proportional hazard models to determine independent factors associated with prolonged hospitalization and mortality.

The researchers identified pathogens in 45% of patients, with 20% having viral pneumonia, 15% having bacterial pneumonia, and 9% having polymicrobial pneumonia. Streptococcus pneumoniae(12%), influenza (12%), and Mycoplasma pneumoniae (1.2%) were the most common atypical viral pathogens. The strong majority of patients were prescribed empirical amoxicillin-clavulanate (79%) or ceftriaxone (8%) with or without doxycycline, which are the recommended regimens for CAP requiring hospitalization.

Non-adherence to local empirical antibiotic treatment guidelines was observed in 25% of patients and, after adjustment for age, underlying chronic illness, and disease severity, was independently associated with prolonged hospitalization (more than 7 days) and higher  mortality (adjusted hazard ratio, 3.88; 95% CI, 1.60 to 9.41).

The authors of the study say non-adherence to local guidelines involved both overtreatment with broad-spectrum antibiotics and undertreatment with inadequate coverage for potential drug-resistant pathogens.

"The findings of our study supported our current treatment guidelines," they wrote.
Apr 24 Open Forum Infect Dis abstract

Biopharma start-up receives financing for novel antibiotic candidate

Originally published by CIDRAP News Apr 27

Biopharma start-up Bugworks, Inc., announced last week that it received $7.5 million in financing to complete early clinical studies on a novel broad-spectrum antibiotic targeting a broad range of antibiotic-resistant pathogens.

The funding from Japanese and South African investors will enable the company to complete phase 1 studies of its GYROX intravenous drug candidate, which targets gram-negative and gram-positive bacteria, including Acinetobacter baumannii, Pseudomonas Aeruginosa, Enterococcus faecium, and Staphylococcus aureus. GYROX is a Gyrase-topoisomerase inhibitor that, according to company officials, has a low risk of developing antimicrobial resistance (AMR) because it inhibits two essential targets in the bacterial replication machinery and has been designed to bypass the efflux-resistance mechanism of the bacteria.

The money will also help advance an oral version of the drug toward clinical development.

"This new financing is an endorsement of our team and differentiated AMR assets, as we bring reputed global investors to aid our mission of pandemic preparedness by defeating superbug infections," Bugworks CEO Anand Anandkumar, MD, said in a company press release.

Bugworks, which is based in Delaware and Bangalore, India, received preclinical funding and support for GYROX from CARB-X (the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator) in 2017.
Apr 23 Bugworks press release