Stewardship / Resistance Scan for Feb 21, 2019

XDR gonorrhea clone
New metallo-beta-lactamase
Fast track for pneumonia antibiotic

Genomic analysis shows UK, Australian XDR gonorrhea cases are related

An international team of scientists reported today in Eurosurveillance that the three extensively drug-resistant (XDR) gonorrhea cases identified in Australia and the United Kingdom in 2018 were caused by a single XDR clone.

The three cases, which were identified in February, March, and April 2018, all displayed ceftriaxone resistance and high-level azithromycin resistance, a combination that had not previously been reported. Dual therapy with ceftriaxone and azithromycin is the first-line treatment for gonorrhea.

The UK case involved a man who reported sexual contact with a woman in Thailand; the Australia cases included a man who reported having sex with a woman in Southeast Asia and a woman with no travel history outside of Australia.

Genomic analysis of four isolates (two from the UK case, one each from the Australia cases) revealed that all four shared the same Neisseria gonorrhoeae multi-antigen sequence type (ST 16848), multilocus sequence type (ST 12039) and NG-sequence typing for antimicrobial resistance type (NG-STAR 996), and all harbored the same ceftriaxone resistance–conferring penA allele and copies of the genetic mutation responsible for high-level azithromycin resistance.

Phylogenetic analysis showed that the sequences from the two UK isolates and the isolate from the Australian woman were indistinguishable, and separated from the male Australian case by one single nucleotide polymorphism. These findings suggest the three cases are highly related and of the same gonococcal clone, which the authors of the study named A2543. They warn that the clone could be present elsewhere, but may not have been detected because of a lack of testing and surveillance.

"The isolation of these A2543 clone XDR gonococci within a short time period, with epidemiological links to south-east Asia in two of three cases, suggests that this clone may be circulating in Asia, which is concerning," they write. "Further spread of this A2543 XDR strain would have serious implications for the current first-line NG treatment recommendations."
Feb 21 Eurosurveill rapid communication


Canadian researchers report novel metallo-beta-lactamase gene, CAM-1

Canadian scientists report identifying a novel metallo-beta-lactamase gene, CAM-1, which confers resistance to the antibiotic carbapenem, in clinical Pseudomonas aeruginosa isolates, according to data published yesterday in the Journal of Antimicrobial Chemotherapy.

Using whole-genome sequencing, the researchers analyzed four clinical isolates of P aeruginosa from three patients hospitalized in Alberta in 2008 and 2009 that were negative by polymerase chain reaction for KPC, OXA-48, NDM, VIM, IMP, GES, and NMC/IMI carbapenemase genes. They used bioinformatic analysis; cloning, antimicrobial susceptibility testing, and biochemical and phenotypic characterization; and single-nucleotide variant typing to further assess the isolates.

The group, which included scientists from the Public Health Agency of Canada, called the novel gene Central Alberta Metallo-beta-lactamase, or CAM-1. The gene conferred carbapenem resistance to an Escherichia coli TOP10 strain but could not be transferred by conjugation.

The authors said no additional CAM-1 genes have been identified in the province in more recently hospitalized patients.
Feb 20 J Antimicrob Chemother report


FDA approves New Drug Applications for Nabriva's pneumonia antibiotic

Nabriva Therapeutics of Dublin announced that the US Food and Drug Administration (FDA) has accepted its New Drug Applications (NDAs) and granted priority review for both the oral and intravenous (IV) formulations of lefamulin, a first-in-class, semi-synthetic pleuromutilin antibiotic for treating community-acquired bacterial pneumonia (CABP).

The goal date for the completion of the FDA's review is Aug 19. In addition to authorizing priority review, the FDA has also granted lefamulin Qualified Infectious Disease Product and fast-track designations.

Jennifer Schranz, MD, Nabriva's chief medical officer, said in a company news release. "We believe lefamulin has the potential to provide a much-needed monotherapy treatment option for adults with CABP. As demonstrated in our clinical program, the ability to switch from IV to oral administration and the short-course oral regimen has the potential to position lefamulin, if approved, as a monotherapy option for patients in the hospital, transition of care and ambulatory care settings."

The company said the two NDAs are supported by two phase 3 clinical trials—known as LEAP 1 and LEAP 2—that evaluated the safety and efficacy of IV and oral lefamulin compared with moxifloxacin in adults with CABP, including the option to switch from IV to oral administration and a short course of oral treatment with lefamulin. "In both LEAP 1 and LEAP 2, lefamulin was demonstrated to be non-inferior to moxifloxacin, and met both the FDA and European Medicines Agency (EMA) primary and secondary efficacy endpoints for the treatment of CABP," the company said.

Lefamulin was also generally well tolerated in the trials. Nabriva plans to submit a marketing authorization application for lefamulin in Europe in the first quarter of 2019.
Feb 19 Nabriva news release
Dec 21, 2018,
CIDRAP News scan on NDA application

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