ASP Scan (Weekly) for Nov 08, 2019

Inappropriate hospital antibiotics for kids
Funding for gonorrhea drug candidate
Probiotic-associated bloodstream infections
Preventing pneumonia after cardiac arrest
Rapid viral test and antibiotic use
CARB-X funding milestone
Aminoglycosides for ESBL blood infections
Fecal transplant for C diff
Peer comparison stewardship
New H pylori treatment

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

Australian study: Improvement needed in antibiotic prescribing for kids

Nearly one in five antibiotic prescriptions for hospitalized children in Australia is inappropriate, Australian researchers reported yesterday in the Journal of Antimicrobial Chemotherapy.

The analysis of 4 years of data (2014 through 2017) from the National Antimicrobial Prescribing Survey (NAPS), an online auditing program that covers healthcare facilities in all Australian states and territories, found that among 6,219 prescriptions for 3,715 children in 253 facilities, 19.6% were inappropriate. For 35 facilities that entered data for all 4 years, appropriateness increased from 82.2% in 2014 to 85.3% in 2017, but without a statistically significant trend.

The most frequently inappropriately prescribed antibiotics were cefazolin, amoxicillin, and ceftriaxone. The most frequent reasons for antibiotic prescriptions being deemed inappropriate were "incorrect dose or frequency" or "spectrum too broad." Surgical prophylaxis was inappropriate in 59% of prescriptions.

Analysis of risk factors found that prescribing was more likely to be inappropriate for non-tertiary care facilities (odds ratio, [OR], 1.37; 95% confidence interval [CI], 1.20 to 1.55) and for non-metropolitan facilities (OR, 1.52; 95% CI, 1.30 to 1.77). Older age was significantly associated with inappropriate therapy, with children ages 3 to 12 having the highest risk (OR 6.2; 95% CI, 4.3 to 8.8). Prescriptions for children with a documented indication, children admitted to an ICU, and immunocompromised children were more likely to be appropriate.

The authors of the study conclude, "Almost 20% inappropriate prescribing for hospitalized children demonstrates room for improvement and this figure is higher in non-tertiary and non-major city settings, where fewer resources to support prescribing are available. Healthcare facilities need to work in partnership with governments and other organizations to support appropriate prescribing for children in all environments."
Nov 7 J Antimicrob Chemother study


New gonorrhea drug candidate receives funding boost

Swiss biopharmaceutical company Debiopharm said today that it has received second-phase funding from CARB-X (the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator) for development of a new antibiotic class targeting gonorrhea.

The $1.4 million in funding for Debio1453, an antibiotic development program based on compounds that target an enzyme essential to the growth of Neisseria gonorrhoeae, follows an initial award of $2.6 million from CARB-X in 2017. The second phase of the award was based on achieving targeted milestones.

"This continuation of research funding speaks to our antibiotic program's promising capacity to make a difference in the fight against drug-resistant N. gonorrhoeae," Debiopharm president Thierry Mauvernay said in a company press release.

The company says at the end of the second phase it will select the most suitable compound to enter into clinical trials for uncomplicated gonorrhea infections caused by susceptible and drug-resistant gonorrhea.

Because gonorrhea affects 78 million people worldwide and is becoming increasingly resistant to the last remaining treatment options, the World Health Organization (WHO) has deemed it a priority pathogen. WHO officials have warned that widespread treatment failure could emerge within the next few years if new antibiotics are not developed.
Nov 8 Debiopharm press release


Study describes probiotic-linked bloodstream infections in ICU patients

An epidemiologic and genomic investigation by US and Israeli scientists has found evidence of bloodstream infections in ICU patients linked to a widely used strain of probiotics.

In a letter published yesterday in Nature Medicine, researchers from Boston Children's Hospital, Walter Reed Army Institute of Research, and Technion-Israel Institute of Technology report that ICU patients at Boston Children's who were receiving Lactobacillus rhamnosus strain GG (LGG) probiotics had a markedly higher risk of developing Lactobacillus bacteremia than ICU patients who received no probiotics. Of the 522 patients who received LLG probiotics over a period of 5.5 years, 6 developed Lactobacillus bacteremia (1.1%), compared with only 2 of 21,652 patients who received no probiotics (0.009%). All 6 of the blood isolates from patients receiving the LGG probiotic were identified as L rhamnosus, while the 2 isolates from patients who didn't receive probiotics were identified as other Lactobacillus species.

Whole-genome sequencing further showed that all 6 of the L rhamnosus isolates and 16 isolates from probiotic capsules taken from the same batches given to the patients shared the same reference genome, suggesting high relatedness between the isolates. In addition, much of the genetic diversity among the L rhamnosus blood isolates mirrored pre-existing genetic diversity within the probiotic capsules.

However, the researchers also found genetic mutations in the blood isolates that did not appear in the isolates from the capsules, including one isolate with a mutation that confers resistance to the antibiotic rifampin, a finding that suggests within-host evolution of the probiotic.

"Probiotics have shown significant benefits for acute infectious diarrhea, antibiotic-associated diarrhea, and ulcerative colitis," the authors of the study write. "However, our findings highlight that as ICU patients have increased risk for probiotic-associated bacteremia, these potential benefits must be weighed against this risk when considering the continued use of probiotics in the ICU."
Nov 7 Nat Med study


Study: Antibiotic prophylaxis after cardiac arrest cuts pneumonia risk

Originally published by CIDRAP News Nov 7

A short course of antibiotics for patients receiving targeted temperature management after cardiac arrest reduced incidence of early ventilator-associated pneumonia (VAP), French researchers reported today in the New England Journal of Medicine.

In a randomized, placebo-controlled trial conducted in 16 French ICUs, researchers set to determine whether 2 days of empirical, prophylactic antibiotic therapy could prevent early VAP in patients who were being ventilated after out-of-hospital cardiac arrest related to initial shockable rhythm and treated with targeted temperature management (at 32ºC to 34ºC)—a strategy associated with increased risk of secondary infections.

 A total of 198 adults were enrolled in the study and randomized to receive 2 days of intravenous amoxicillin-clavulanate or placebo. The primary outcome was VAP during the first 7 days of hospitalization; secondary outcomes included late incidence of VAP, length of ICU stay, number of ventilator-free days, mortality at day 28, and intestinal acquisition of multidrug-resistant bacteria at day 7.

A total of 60 cases of VAP were confirmed, including 51 early cases. The incidence of early VAP was lower with antibiotic prophylaxis than with placebo (19 patients [19%) vs 32 patients [34%]; hazard ratio, 0.53; 95% confidence interval [CI], 0.31 to 0.92; P = 0.03). But no significant differences were observed between the antibiotic and placebo groups for incidence of late VAP (4% and 5%, respectively), number of ventilator-free days (21 days and 19 days), ICU length of stay (5 days and 8 days), and mortality at day 28 (41% and 37%). No increase in resistant bacteria was identified in the antibiotic group, and serious adverse events did not differ significantly between the two groups.

The authors of the study note that patients with overt respiration were not included in the study, and that systematic implementation of bundles known to decrease the incidence of VAP in the ICU was highly recommended. In addition, more than one fourth of the VAP cases initially reported by investigators were not confirmed by independent adjudication committee, resulting in lower incidence of VAP compared with previous trials.
Nov 7 N Engl J Med abstract


Rapid viral testing in emergency department linked to lower antibiotic use

Originally published by CIDRAP News Nov 6

The results of a randomized clinical trial show that the use of a rapid, multi-pathogen respiratory panel (RP) in an emergency department (ED) was associated with a trend toward decreased antibiotic use, according to a study yesterday in Open Forum Infectious Diseases.

The trial, conducted by researchers at the University of California, Davis over 2 years, enrolled patients older than 12 months who visited a level 1 ED with symptoms of upper respiratory infection or influenza-like illness and randomly assigned them to receive either usual care plus rapid, multi-respiratory pathogen molecular testing or usual care alone. The primary outcome was antibiotic prescriptions, and secondary outcome included antiviral prescriptions, patient disposition, and length of stay.

Of the 191 patients enrolled in the trial, 93 were randomized to the RP group and 98 to usual care. Fifty-three (57%) of the patients in the RP test group had a virus detected and reported during the ED visit, compared with 7 (7%) in the usual care group; 20 patients (22%) in the RP group received antibiotics, compared with 33 (34%) of the usual care patients (-12 percentage points; 95% CI, -25 to 0.4). Nine of the patients in the RP group received antibiotics despite having a virus detected, but most either had a concomitant bacterial infection diagnosed clinically (8/9) or left the ED before test results were available (3/9).

A post-hoc analysis found that the reduction in antibiotic use was greater in children (-19 percentage points) versus adults (-9 percentage points). No differences were observed in antiviral use, length of stay, or disposition.

"The main effects of rapid RP testing in this study were to increase the proportion of patients with a lab-confirmed viral detection for clinical decision-making by 3-fold and reduce antibiotic prescription by about one third," the researchers write.

The researchers say that while the findings are limited by the small sample size, they suggest that the use of rapid viral tests in the ED could have benefits. They call for more research to determine whether specific groups are likely to benefit from testing and to evaluate the use of rapid diagnostics in combination with antibiotic stewardship strategies.
Nov 5 Open Forum Infect Dis abstract


CARB-X to fund novel gene-targeting antibiotic compounds

Originally published by CIDRAP News Nov 6

CARB-X today announced a milestone in its efforts to fund and promote early development of innovative antibacterial products.

CARB-X is awarding Techulon Inc., of Blacksburg, Virginia, $785,000 to develop a new class of antimicrobial compounds known as peptide-peptide nucleic acids (PPNAs), which target specific genes in drug-resistant pathogens that are essential for survival. The money will specifically fund development of PPNAs targeting the priority pathogens Acinetobacter baumannii and Pseudomonas aeruginosa, using Techulon's Rapidly Adaptable Nano Therapeutic platform.

The Techulon project is the 50th funded by CARB-X since it was established in 2016. The private-public partnership has awarded more than $150 million in non-dilutive funding to accelerate the development of new antibiotics, diagnostics, vaccines, and alternative treatments for drug-resistant bacteria.

"CARB-X is fighting the spread of drug-resistant bacteria by supporting the development of innovative therapeutics and other products that target the most serious bacterial threats. We are making progress," CARB-X Executive Director Kevin Outterson, JD, said in a press release. "The Techulon project is in the early stages of development but if successful and approved for use in patients, it could represent major improvements in the way deadly infections are treated."
Nov 6 CARB-X press release


Study backs use of aminoglycosides for ESBL bloodstream infections

Originally published by CIDRAP News Nov 6

Findings by Israeli researchers support the use of aminoglycosides as a possible treatment for bloodstream infections of urinary source caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-EB).

In a study published today in the Journal of Antimicrobial Chemotherapy, the researchers retrospectively examined 193 patients at an Israeli hospital who had a positive blood culture for ESBL-EB and a positive urine culture with the same bacteria, as well as a clinical diagnosis of urinary tract infection, pyelonephritis, or urosepsis.

The patients were grouped according to the antibiotic treatment they received: aminoglycosides (108 patients) versus carbapenems (73 patients) or piperacillin-tazobactam (12 patients). The primary efficacy outcome was death from any cause at day 30, and secondary outcomes included recurrence of bacteriuria with the same bacteria in 90 days. The primary safety outcome was acute kidney injury (AKI) at 14 days.

Overall, 32 patients (16.6%) died, including 14 of 108 in the aminoglycoside group (13%) and 18 of 85 (21.2%) in the carbapenem and piperacillin-tazobactam groups. Risk factors for mortality included age, high Charlson comorbidity scores, presentation with severe sepsis or septic shock, and infection with bacteria other than Escherichia coli. Bacteriuria recurred in 48.8% of the aminoglycoside patients, compared with 44.7% of patients in the carbapenem and piperacillin-tazobactam patients.

After minimizing confounding, the scientists found that aminoglycosides were non-inferior to carbapenems or piperacillin-tazobactam regarding 30-day mortality (adjusted risk difference, 10.29%; 95% CI, -0.82% to 21.4%), and were also non-inferior in a subgroup of patients who presented without severe sepsis or septic shock. But aminoglycosides did not reach non-inferiority for bacteriuria recurrence (adjusted risk difference, -8.72%; 95% CI, -30.87% to 13.43%). AKI developed at a similar rate in both treatment groups: 12.0% versus 10.6%. Aminoglycosides were more efficacious in E coli infections.

The authors of the study conclude, "This approach supports avoiding excessive use of carbapenems without compromising efficacy and safety of treatment."
Nov 6 J Antimicrob Chemother study


Fecal transplant for C diff tied to fewer bloodstream infections, deaths

Originally published by CIDRAP News Nov 5

Fecal microbiota transplant (FMT) for Clostridioides difficile infection (CDI) was associated with a dramatic decrease in bloodstream infections (BSIs), days of hospitalization, and death rates compared to treatment with antibiotics, according to a prospective cohort study today in the Annals of Internal Medicine.

Italian investigators studied 290 adults hospitalized at a tertiary care hospital in Rome from July 2013 to May 2018 for recurrent CDI (rCDI). Of those patients, 109 were treated with FMT and 181 with antibiotics. The authors said that, on average, patients receiving FMT began therapy with worse clinical conditions than the antibiotics patients.

The researchers found that those in the FMT group had a risk for BSI 24.1 percentage points lower than the patients receiving antibiotics (4.6% vs 28.7%). Length of hospital stay was 13.3 days in patients treated with FMT compared with 29.7 for those treated with antibiotics.

In the whole cohort, 79 of 290 patients (27%) died during the 90-day follow-up period, 21 of them—all in the antibiotics group—because of BSI. Overall 90-day fatality rate was 8.3% in the FMT patients and 38.7% in the antibiotics patients. In addition, 106 FMT patients (97.2%) had sustained CDI cure, far better than the 69 (38.1%) in the antibiotics group.

The authors conclude, "Should our results be confirmed by larger, randomized studies, FMT could be considered an effective treatment option to both cure rCDI and prevent some of its complications, including BSI."
Nov 5 Ann Intern Med abstract


Peer comparison intervention leads to lower antibiotic prescribing rates

Originally published by CIDRAP News Nov 5

Physician education and monthly peer comparison of overall antibiotic prescribing rates led to a decrease in unnecessary antibiotic prescribing within the Veterans Affairs (VA) health system, according to a new study in Antimicrobial Agents and Chemotherapy.

The study looked at an antimicrobial stewardship intervention in seven VA primary care health clinics in Pittsburgh, and compared antibiotic prescribing rates before and after the intervention in 2016 and 2017. Primary care physicians (PCP) were asked to attend an education session and then sent a monthly email comparing their prescribing rate with peers' and a VA system target.

During the intervention period of January through June 2017, there were 73 PCPs caring for 41,191 patients, and 32,982 office visits.

According to the authors, the intervention led to a mean monthly antibiotic prescriptions decline of 76.9 to 49.5 per 1,000 office visits (35.6% reduction, P<0.001).  Among reviewed cases, unnecessary antibiotic prescribing declined (58.8% [80/136] vs. 38.9% [70/180], 33.9% reduction, P=0.0006), and optimally prescribed antibiotics increased (19.9% [27/136] vs. 30% [54/180], 50.8% increase, P=0.05).

There was not, however, a significant difference in the prescribing of guideline-discordant agents (21.4% [12/56] vs 19.1% [21/110], P=0.8) or guideline-concordant agents for a guideline-discordant duration. Inappropriate antibiotic prescriptions were significantly reduced for skin and soft-tissue infections, the authors said.

"This is the first study to show that a stewardship strategy built upon feedback to PCPs about their overall use of outpatient antibiotics, without regard to appropriateness of treatment, is effective in diminishing unnecessary antibiotic usage and optimizing treatment within a healthcare system," the authors concluded.
Nov 5 Antimicrob Agents Chemother study


FDA approves new antibiotic treatment for H pylori infections

Originally published by CIDRAP News Nov 5

The US Food and Drug Administration (FDA) has approved RedHill Biopharma's Talicia (antibiotics amoxicillin and rifabutin combined with proton pump inhibitor omeprazole) for the treatment of Helicobacter pylori infections in adults. RedHill said they plan to launch the drug in the United States in the first quarter of 2020.

Approximately 35% of the US adult population is infected with H pylori, which translates to 2.5 million patients treated annually. Current therapies fail in approximately 25% to 40% of patients who remain H pylori positive due to growing resistance to clarithromycin and metronidazole.

Talicia is designed to address drug resistance and diminished efficacy of clarithromycin-based standard-of-care therapy. The bacteria it is classified as a Group I carcinogen, and is the strongest risk factor for the development of peptic ulcer disease, gastritis and non-cardia gastric cancer, RedHill said.

"Talicia offers patients a much-needed new treatment option for H. pylori with an excellent safety and efficacy profile that is not compromised by clarithromycin or metronidazole resistance. The clinical studies for Talicia demonstrated high efficacy in eradication of H. pylori. Studies with Talicia found zero resistance to rifabutin and showed 17% resistance to clarithromycin," said David Y. Graham, MD,, the lead investigator for Talicia's phase 3 studies in a press release.
Nov 5 RedHill Biopharma press release

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