Stewardship / Resistance Scan for Jul 17, 2018

News brief

Meta-analysis suggests fidaxomicin is most effective C diff treatment

A systematic review and meta-analysis of randomized controlled trials examining antibiotic therapy for non-recurrent Clostridium difficile infections has found that fidaxomicin provides a sustained symptomatic cure most frequently, researchers reported yesterday in The Lancet Infectious Diseases.

For the network meta-analysis, researchers from the University of Leeds screened more than 23,000 studies published through June 2017 to compare and rank the efficacy of 13 different treatments for non-recurrent C difficile infections. The primary outcome was sustained symptomatic cure, defined as the number of patients with resolution of diarrhea minus the number with recurrence or death.

The final analysis included 24 randomized controlled trials, which comprised 5,361 patients. The overall quality of evidence was rated as moderate to low. For sustained symptomatic cure, fidaxomicin (odds ratio [OR], 0.67) and teicoplanin (OR, 0.37) were significantly better than vancomycin, while teicoplanin (OR, 0.27), ridinilazole (OR, 0.41), fidaxomicin (OR, 0.49), surotomycin (OR, 0.66), and vancomycin (OR, 0.73) were better than metronidazole. Bacitracin was inferior to teicoplanin (OR, 0.22) and fidaxomicin (OR, 0.40), and tolevamer was inferior to all drugs except for LFF571 (OR, 0.50) and bacitracin (OR, 0.67). Global heterogeneity of the entire network was low.

"The findings of this network meta-analysis suggest that, of the currently approved treatments, fidaxomicin has the strongest evidence for being the most effective treatment in providing a long-term cure against C difficile," the authors write. "Apart from affordability, there is little evidence to support use of metronidazole as a first-line treatment against infections with C difficile."

They add that teicoplanin and ridinilazole could also be effective treatments, but that routine implementation of these drugs should await results from large trials.
Jul 16 Lancet Infect Dis study

Antifungal stewardship reduces antifungal costs, study finds

Introduction of an antifungal stewardship team to a tertiary cardiopulmonary hospital significantly reduced monthly antifungal expenditures, UK researchers reported yesterday in Antimicrobial Agents and Chemotherapy.

The stewardship team, consisting of a medical mycologist and a specialist pharmacist, provided weekly stewardship ward rounds, twice monthly multidisciplinary team meetings, and a dedicated weekly outpatient clinic. Data for the first 18 months of fungal stewardship implementation was recorded.

A total of 178 patients were reviewed by the stewardship team over the 18-month period, with 285 recommendations made to inpatients and 287 recommendations made to outpatients. The most common diagnoses treated were allergic bronchopulmonary asperilligosis and chronic pulmonary asperilligosis. Cystic fibrosis patients were the largest patient group. Among the recommendations of the stewardship team were stepping down treatment to oral antifungals, ensuring appropriate dosing to attain therapeutic levels and avoid toxicity, and stopping treatment in patients without confirmed fungal disease or those likely to only be colonized.

The intervention was associated with an overall reduction in antifungal expenditure of 44.8%, from £290,000 ($380,000) per month to £160,000 ($209,000) per month, largely driven by reduced use of intravenous voriconazole and caspofungin. In addition, there was a reduction in defined daily dose per 100 bed-days of all antifungal medications (P = 0.017). There was no increase in morbidity or mortality.

The authors of the study conclude that with the use of antifungals in patients with chronic respiratory disease likely to continue rising due to better recognition of fungal disease, this stewardship model could be introduced in other facilities where antifungal expenditures are climbing.
Jul 16 Antimicrob Agents Chemother abstract

Spero awarded $16 million to develop treatment for drug-resistant UTI

The Biomedical Advanced Research and Development Authority (BARDA) awarded Spero Therapeutics, Inc, a biopharmaceutical company in Cambridge, Mass., up to $54 million to develop SPR994, Spero's oral carbapenem product candidate.

SP994 would be used to treat complicated urinary tract infections (cUTIs) caused by antibiotic resistant gram-negative bacteria. The award includes an initial $15.7 million, with the potential for an additional $28.5 million to be given over 5 years.

"As part of the inter-agency collaboration with Spero, a series of studies to assess the efficacy of SPR994 in the treatment of infections caused by biodefense threats such as anthrax, plague and melioidosis will be conducted by the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). In addition, the Defense Threat Reduction Agency (DTRA) will provide support up to $10 million to fund the nonclinical biodefense aspects of the inter-agency collaboration," Spero said in a press release.

Spero said it plans to initiate a phase 3 clinical trial of SPR994 for the treatment of cUTI at the end of this year. In preclinical studies, SPR994 showed potent antibiotic activity against gram-negative bacteria, including extended-spectrum beta-lactamases (ESBLs) and ESBL-producing Klebsiella pneumoniae.
Jul 16 Spero press release

News Scan for Jul 17, 2018

News brief

Novel antiviral shows promise for those at high risk for flu complications

A phase 3 study of the novel antiviral baloxavir marboxil suggests that it reduces symptoms in people at high risk of flu complications, Roche announced today. The single-dose oral treatment, discovered in Japan and developed by Roche, has a different mechanism of action than neuraminidase inhibitors like oseltamivir (Tamiflu) and was recently granted fast-track approval by the US Food and Drug Administration.

The multicenter study compared a single dose of baloxavir with placebo and oseltamivir in people age 12 and older who are at high risk of flu complications, Roche said in a news release. The trial was conducted globally by Shionogi, the company that discovered the drug.

When compared with placebo, baloxavir showed superior efficacy in time to improvement of flu symptoms. The drug also showed superior efficacy when compared with both placebo and oseltamivir for reducing time of virus shedding and viral load levels. Also against placebo, the medication significantly reduced the incidence of flu complications.

According to the study, the drug was well tolerated, and researchers didn't see any safety signals. Roche said it will present the full results from the study at upcoming medical meeting.

Sandra Horning, MD, Roche's chief medical officer and head of global product development, said in the release that baloxavir marboxil is the first antiviral to show a clinically meaningful benefit in people who are most susceptible to flu complications. "We plan to submit the results of this second positive phase III study for baloxavir marboxil to healthcare authorities, and look forward to discussing next steps since there are no current antiviral medicines approved to specifically treat this high-risk population," she said.

High-risk groups include adults age 65 and older and those with underlying health conditions such as asthma, chronic lung disease, diabetes, or heart disease.
Jul 17 Roche press release
Jun 27 CIDRAP News scan "Novel one-dose antiviral receives FDA priority review"

Study shows evidence of vertical Zika transmission in Aedes mosquitoes

For the first time, researchers demonstrated natural vertical transmission of the Zika virus among field-collected eggs of Aedes aegypti mosquitoes in the Brazilian Amazon. The findings were published yesterday in PLoS Neglected Tropical Diseases.

The scientists conducted the study in the mid-sized city, Itacoatiara, with the goal of determining if larvae from Ae aegyti and Ae albopictus were infected with flaviviruses. From January to April of 2016, they collected 2,057 specimens (1,793 Ae aegypti and 264 Ae albopictus) in 154 larvae pools. The investigators used RNA extraction tests to determine virus status of the larvae, which would indicate vertical transmission.

One pool each tested positive for Zika and chikungunya viruses. The researchers calculated the infection rate per 1,000 mosquitoes to be 0.45 and 0.44 for chikungunya and Zika, respectively, and the minimum infection rate was 0.45 for both viruses.

"We report the first detection of Zika virus vertical transmission in an Ae. aegypti larvae under the natural conditions found in the field," the authors concluded. They explained that this phenomenon may enhance the virus's epidemic potential, "because mosquitoes that emerge as virus-infected adults will have more opportunity to transmit virus than mosquitos that become infected after blood meal in an infected vertebrate."
Jul 16 PLoS Negl Trop Dis study

Antibodies taken from Ebola survivors may offer novel treatments

Scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID), have discovered a new set of broadly neutralizing monoclonal antibodies (mAbs) in the blood of Ebola survivors, which proved protective against disease caused by Zaire, Bundibugyo, and SudanEbola viruses. The findings were published today in the journal Immunity.

In the study, the researchers analyzed plasma from 17 Ebola survivors and found that two survivors produced antibodies that bound to an essential virus protein, called glycoprotein, from Zaire, Bundibugyo, and Sudan Ebola virus species—the most deadly to humans. Those antibodies prevented the viruses from entering host cells.

Antibody therapy is a promising treatment for Ebola, but the current experimental therapy, ZMapp, targets only one of the five known species of the virus—the Zaire strain.

"These mAbs and related clones are promising candidates for development as broadly protective pan-ebolavirus therapeutic molecules," the authors concluded.
Jul 17 Immunity study