French
investigators have described development of resistance to one of the last
resort therapies used to treat extremely drug-resistant Pseudomonas aeruginosa.
That resistance arose in a single patient over a scant 22 days. They
subsequently identified the single nucleotide mutation in P. aeruginosa that
caused the resistance.
Unexpectedly,
the mutation partially re-sensitized P. aeruginosa to antimicrobials that have
long been in use -- carbapenems and piperacilline-tazobactam -- to which the
bacterium had been fully resistant.
Dr.
Dortet said that using higher doses of ceftolozane-tazobactam to begin with
might limit the appearance of the mutation by killing the pathogens more
rapidly. Dr. Dortet is Associate Professor of Microbiology, University
Paris-Saclay, France.
To
determine the mechanism responsible for causing this resistance, the team
analyzed P. aeruginosa clinical isolates, both susceptible and resistant, that
had been collected from this patient during the infection, and performed whole
genome sequencing on these. That enabled the investigators to identify the
single mutation in a gene that encodes a natural enzyme, cephalosporinase.
(Overexpression of cephalosporinase causes resistance to nearly all
antimicrobials of the ?-lactam family.)
Modeling
the mutant enzyme in silico confirmed its role as the cause of resistance to
ceftolozane-tazobactam, and resensitization to carbapenems and
piperacilline-tazobactam.
"Our
results demonstrated that resistance to this novel molecule can occur rapidly
during treatment," said Dr. Dortet. He noted that at the time the investigators
discovered the mutation, the antibiotic, ceftolozane-tazobactam, had only been
in clinical use for a couple of years.Posted by Dr. Tim Sandle, Pharmaceutical Microbiology
No comments:
Post a Comment
Pharmaceutical Microbiology Resources