A new formulation of an existing antibacterial agent and a potential therapeutic approach to a challenging clinical problem were the focus of a session on potentially practice-changing clinical trials in antimicrobial therapy presented during IDWeek 2020, an annual scientific meeting on infectious diseases.
“I know it has been a big year for viral disease of course, with COVID, but there has been some really good work that has gone on in the bacterial space, and of course as those of you who are on service know, you may have your fair share of COVID patients, but these are infections that we still deal with on a daily basis,” said, an infectious disease specialist at Weill Cornell Medicine in New York.
He combed through studies published during the previous 12 months in leading medical journals, including the New England Journal of Medicine, JAMA network publications, Lancet Infectious Diseases, Lancet Respiratory Medicine, Clinical Infectious Diseases, and Clinical Microbiology and Infection, looking for randomized trials of interventions to treat bacterial infections, and selecting those most likely to change practice of U.S. infectious diseases practitioners.
He excluded meta-analyses, post hoc analyses, evaluations of diagnostic tests, stewardship, or any studies presented previously at IDWeek.
Two of the trials he highlighted are described here.
Fosfomycin for injection
In the United States, fosfomycin, the only antibiotic in its class, is currently available only in an oral sachet formulation (Monurol), “and typically we’ve only given this for patients with cystitis because we know that we don’t achieve significant levels [of drug] in the kidney or in the bloodstream for other types of infections,” Dr. Satlin said.
In Europe, however fosfomycin for injection (ZTI-01) has been available for several years.
“There’s been a lot of interest in fosfomycin because it has a different mechanism of action from other agents. It’s an epoxide antibiotic that inhibits early peptidoglycan synthesis by binding to MurA,” he explained.
The phase 2/3 randomizedcompared ZTI-01 with piperacillin/tazobactam (pip/taz) for treatment of complicated urinary tract infection (UTI) including acute pyelonephritis.
A total of 465 hospitalized adults with suspected or microbiologically confirmed complicated UTI or acute pyelonephritis were randomized to 6 g of ZTI-01 every 8 hours or 4.5 g of intravenous pip/taz every 8 hours for a fixed 7-day course with no oral switch; patients with concomitant bacteremia (about 9% of the study population) could receive the assigned therapy for up to 14 days.
The primary endpoint of noninferiority of ZTI-01 was met and clinical cure rates were high and similar between the treatments, at approximately 91% each. Treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mostly mild and transient.
The hypokalemia seen in the trial may be attributable to the high salt load of fosfomycin relative to pip/taz, Dr. Satlin said.
“How might this change your practice? Well, if IV fosfomycin is ever FDA [Food and Drug Administration] approved – and my understanding is that the delays have been more related to manufacturing than scientific quality of data – it could potentially be an alternative to beta-lactams and fluoroquinolones” and has activity against most extend spectrum beta-lactamase (ESBL)–producing Enterobacteriaceae, he said.
Fosfomycin susceptibility testing is challenging, however, with no Clinical & Laboratory Standards Institute (CLSI) or FDA breakpoints for Enterobacterales other than Escherichia coli, and there are questions about the step-down therapy.
“Do you just give a 3-gram sachet chaser when they walk out the door? Do you switch to another agent? I think that needs to be worked out,” he said.