News Scan for Oct 18, 2019

News brief

Flu drug receives expanded approval for use in high-risk patients

The Food and Drug Administration (FDA) approved the use single-dose Xofluza (baloxavir marboxil) for patients ages 12 and over who are at high risk for influenza complications. Xofluza should only be administered to patients who have been symptomatic for 48 hours or less.

"With the flu season rapidly approaching, we can now offer Xofluza as the first and only FDA-approved treatment option indicated specifically for those at high risk of flu complications," said Levi Garraway, MD, PhD, the chief medical officer and head of global product development for Xofluza's manufacturer, Genentech.

"People with chronic conditions such as asthma, heart disease, and diabetes are at higher risk of developing serious complications from the flu, so it is critical that these patients speak with their healthcare providers about possible treatment at the first signs and symptoms of the disease," Garraway said in a press release.

The expanded approval was based on results from the Phase 3 CAPSTONE-2 study of a single dose of 40 mg or 80 mg of Xofluza compared to oseltamivir (75 mg twice daily for 5 days), or placebo in people 12 years of age or older and were at high-risk for flu complications, Genentech said.

In October 2018, the FDA approved Xofluza for the treatment of acute, uncomplicated flu in otherwise healthy people 12 years of age and older. Xofluza's approval represented the first new antiviral to treat the flu in the United States in 20 years.
Oct 17 Genentech press release 


Early results promising for universal flu vaccines targeting HA stalk

A phase 1 clinical trial that assessed different chimeric hemagglutinin-based universal flu vaccine regimens found that all prompted cross-reactive serum immunoglobulin G (IgG) antibodies targeting the conserved stalk region. A team led by researchers at the Icahn School of Medicine at Mount Sinai published their findings yesterday in The Lancet Infectious Diseases.

The stalk portion of the flu virus's hemagglutinin protein is more conserved than the more variable head portion and has been a target for the development of better and more broadly protective flu vaccines.

For the study, researchers looked at several chimeric hemagglutinin (cHA)-based vaccination regimens to see if they would trigger antibodies that would broadly protect against flu. The regimens included a chimeric H8/1 HA-based live-attenuated vaccine followed by a nonadjuvanted H5/1 HA-based inactivated vaccine (IIV), the same regimen but with an AS03-adjuvanted IIV boost, and a prime-boost regimen including an adjuvanted cH8/1 IIV prime followed by an adjuvanted cH5/1 IIV boost.

The study took place between Oct 10, 2017, and Nov 27, 2017, among 65 healthy adults in two US centers. Participants were randomly assigned to one of three prime-boost regimens or one of two placebo groups.

After the priming dose, the adjuvanted IIV, but not the live-attenuated vaccine, prompted a substantial IgG antibody response, resulting in a seven times higher increase in anti-H1 stalk antibody titers on day 29. After the booster doses, all vaccine regimens produced detectable anti H1 stalk antibodies, cross-reactive serum antibodies, and peripheral blood permablast responses. Regarding safety, the team found that the regimens were tolerable with no safety concerns.

Florian Krammer, PhD, a study coauthor who is with the department of microbiology at Mount Sinai, said in a press release from the school that the vaccine produced a broad antibody response, not only against currently circulating human flu viruses but also against avian and bat subtypes. "It was surprising to find that the inactivated formulation with adjuvant induced a very strong anti-stalk response already after the prime suggesting that one vaccination might be enough to induce protection against pandemic influenza viruses yet to arise," he said.

He said the results signal progress toward a universal flu vaccine, but the results are interim, with more results expected after the study is completed at the end of 2019.
Oct 17 Lancet Infect Dis abstract
Oct 17 Mount Sinai press release


WHO adds details on Saudi MERS cases recorded in September

Today the World Health Organization (WHO) published new details about the four MERS-CoV cases recorded in Saudi Arabia in September. The cases were reported from Al Qassim (2 cases), Riyadh (1 case), and Al Ahsa (1 case) regions.

None of the cases were secondary case contacts or healthcare workers. All four case-patients were men, with ages ranging from 39 to 74. Only one patient, the man from Al Ahsa, had camel exposure, which included drinking camel milk. Camel exposure has regularly been linked to Middle East respiratory syndrome (MERS-CoV) infections.

The oldest patient, a 74-year-old man from Al Qassim died within 10 days of symptom onset.

From 2012 through Sep 30, 2019, the total number of laboratory-confirmed MERS-CoV infection cases reported globally to WHO is 2,468, with 851 associated deaths. Saudi Arabia has had most of the cases.
Oct 18 WHO update 


ASP Scan (Weekly) for Oct 18, 2019

News brief

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

FDA advisors approve new antibiotic cefiderocol for complicated UTI

Originally published by CIDRAP News Oct 17

In a 14-2 vote, the US Food and Drug Administration (FDA) Antimicrobial Drugs Advisory Committee yesterday recommended that the new antibiotic cefiderocol, made by Shionogi & Co, Ltd, of Japan, be approved for complicated urinary tract infection (cUTI), including pyelonephritis, caused by gram-negative bacteria in patients who have limited or no alternative treatment options available, the company said in a news release.

Committee members weighed an imbalance in deaths in the CREDIBLE-CR trial, a phase 3 study that compared cefiderocol against the best available therapy in patients with cUTIs, severe pneumonia, and bloodstream infections or sepsis caused by carbapenem-resistant infections. Death rates in the cefiderocol group outpaced those in the other group 15.8% to 8.2%, but the data also showed an imbalance in deaths caused by underlying comorbidities, 9.9% to 4.1%. The experts also analyzed data on a separate phase 3 trial and a phase 2 trial.

Isao Teshirogi, PhD, Shionogi president and CEO, said in the release, "Patients with cUTIs caused by Gram-negative pathogens continue to face a serious challenge with high morbidity and mortality rates. If approved, we believe cefiderocol could help address a significant unmet need in an area with limited treatment options to fight these life-threatening infections."

Cefiderocol is a siderophore cephalosporin with a novel method of penetrating the tough outer membrane of gram-negative bacteria, including carbapenem-resistant pathogens. It is eligible to be fast-tracked for FDA approval. 

The FDA is not bound by the committee's vote but typically follows its recommendations.

Some committee member said any FDA approval should carry with it a boxed warning on the drug's label, the strongest the agency uses, according to a story yesterday by MedPage Today. The two committee members who voted no—Peter Weina, MD, PhD, of Defense Health Headquarters in Falls Church, Virginia and Susanne May, PhD, with the University of Washington in Seattle expressed safety concerns and said more research is needed.
Oct 16 Shionogi news release
Oct 16 MedPage Today story


Antibiotic prescribing high for non-bacterial respiratory illness in Japan

Originally published by CIDRAP News Oct 17

About one third of Japanese patients with non-bacterial acute respiratory tract infections (NB-ARTIs) are inappropriately prescribed antibiotics, according to a new study in PLOS One.

The observational study used longitudinal claims data between April 2012 and June 2017. Though the monthly antibiotic prescribing rate per 100 NB-ARTI consultations decreased by 19.2% during the study period, the authors said the average monthly rate was still 31.65 prescriptions per 100 NB-ARTI consultations.

"Approximately 89% of antibiotics prescribed for NB-ARTI during the study period were broad-spectrum antibiotics, specifically third-generation cephalosporins (40.1%), macrolides (34.1%), and fluoroquinolones (14.4%)," the authors said. Adults ages 19 to 29 were the most likely to be prescribed antibiotics for NB-ARTI.

The diagnoses that yielded the highest antibiotic prescriptions were acute bronchitis and acute tonsillitis.

"Identified factors associated with inappropriate antibiotic prescription in our study, such as patients of working-age, clinic types, and specialties of clinics may be associated with patient expectation for antibiotics, time pressure, and diagnostic uncertainty, respectively," the authors concluded. 
Oct 16 PLOS One study 


FDA advisory committee reviewing new drug application for cefiderocol

Originally published by CIDRAP News Oct 16

The FDA Antimicrobial Drugs Advisory Committee is meeting today to discuss the new drug application (NDA) for cefiderocol, an investigational antibiotic developed by Shionogi, Inc, a US-based subsidiary of Japanese pharmaceutical company Shionogi & Co. The company is seeking FDA approval of the drug for the treatment of cUTIs caused by gram-negative bacteria in patients with limited or no alternative treatment options.

As reported by Endpoint News, a website that covers the pharmaceutical industry, one of the questions the committee will be discussing is an imbalance in deaths in the CREDIBLE-CR trial, a phase 3 study that compared cefiderocol against the best available therapy (BAT) in patients with cUTIs, hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), and bloodstream infections or sepsis caused by carbapenem-resistant infections. According to the FDA's briefing document, an independent adjudication committee found that a greater percentage of patients in the cefiderocol group had infection-related death with treatment failure than in the BAT group (15.8% vs 8.2%), but also noted an imbalance in deaths due to underlying comorbidities (9.9% vs 4.1%).

"Whether this difference in mortality is a chance finding or truly reflects a deficit in the activity of cefiderocol in critically ill patients is unclear," the FDA wrote.

The committee will also review the results of two other clinical trials: a phase 2 trial that tested cefiderocol against imipenem-cilastatin for treating cUTIs with or without pyelonephritis caused by gram-negative bacteria, and a phase 3 trial that tested cefiderocol against meropenem for the treatment of HABP caused by gram-negative bacteria.

Cefiderocol is a siderophore cephalosporin with a novel method of penetrating the tough outer membrane of gram-negative bacteria, including carbapenem-resistant pathogens. The drug was designated as a Qualified Infectious Disease Product (QIDP) by the FDA, a designation given to antibacterial or antifungal products that treat serious or life-threatening infections and address unmet medical needs. QIDPs are eligible to be fast-tracked for FDA approval. 

The FDA has assigned an action date of Nov 14 to the drug.
Oct 14 Endpoint News story
Oct 16 FDA briefing document
Oct 26, 2018, CIDRAP News story "Fast-tracked antibiotic shows promise in phase 2 trial
Oct 3 CIDRAP Stewardship/Resistance scan on HABP data


Study analyzes infections, antibiotic use in emergency departments

Originally published by CIDRAP News Oct 16

New data from 145 US emergency departments (EDs) indicates that antibiotic prescribing patterns for the most commonly diagnosed infections generally align to treatment guidelines, according to a study yesterday in the American Journal of Health-System Pharmacy. But researchers also found areas for improvement based on local susceptibility patterns.

For the study, researchers from HCA Healthcare—a large multistate network of hospitals—and Harvard Medical School used electronic medical records to examine ED encounters at 145 HCA hospitals from July 2016 through June 2017. Their aim was to assess the most common diagnoses of infectious origin seen in non-admitted ED patients, the most commonly administered antibiotics in the ED, and the unique patterns of resistance and susceptibility in the 14 geographic areas covered by the network. The generalizability of the results to the national population was assessed using patient demographic data.

Overall, more than 627,000 unique patient encounters and 780,000 antibiotic administrations were assessed. The five most frequently identified infections were UTI, cellulitis, pneumonia, Streptococcal pharyngitis, and otitis media (ear infection). The five most commonly administered antibiotics were ceftriaxone, azithromycin, clindamycin, levofloxacin, and cephalexin. While patterns of treatment generally adhered to treatment guidelines, the analysis found possible overuse of ceftriaxone—which accounted for 30.6% of all antibiotics administered—across all indications.

In addition, the assessment of resistance and susceptibility patterns determined that clindamycin—the antibiotic most commonly used for cellulitis—is becoming less viable for treating Staphylococcus-suspected cellulitis, and that resistance is developing in Escherichia coli to sulfamethoxazole-trimethoprim in regions where the drug is used to treat UTIs.

"The results of this study can be applied to health-system EDs of varying sizes to assess current antimicrobial stewardship program practices and to identify opportunities to optimize empiric antibiotic selection based on susceptibility patterns and evidence-based treatment recommendations," the authors of the study write.
Oct 15 Am J Health Syst Pharm study

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