The results of a phase 3 clinical trial that was central to regulatory approval of plazomicin was published today in the New England Journal of Medicine, demonstrating that the drug was noninferior to meropenem for the treatment of complicated urinary tract infections (cUTIs) caused by multidrug-resistant Enterobacteriaceae.
Data from a phase 3 trial evaluating the drug in patients with carbapenem-resistant Enterobacteriaceae (CRE) infections, which had to be shut down because not enough people could be enrolled, also appeared today in the journal. An expert told CIDRAP News, however, that the results of that trial might be of even greater interest.
Drug approved in June 2018
Plazomicin, an aminoglycoside antibiotic developed by Achaogen, Inc. of San Francisco, was approved by the US Food and Drug Administration (FDA) in June 2018, supported in part by data from the EPIC (Evaluating Plazomicin in cUTI) trial, a randomized controlled noninferiority trial that tested the drug in patients with cUTIs, including acute pyelonephritis (severe kidney infection). The results of the trial showed higher rates of microbiologic eradication and composite cure at the test-of-cure visit in the patients who received plazomicin than those who received meropenem, along with lower rates of microbiologic recurrence and relapse.
Plazomicin, which was engineered to avoid enzymes that have made Enterobacteriaceae resistant to other aminoglycosides, gives clinicians another option for treating cUTIs cause by Enterobacteriaceae. These infections have been growing increasingly resistant to the drugs traditionally used to treat them—fluoroquinolones and cephalosporins—and as a result, clinicians have been increasingly relying on carbapenems.
But the authors of the study note that, with the emergence of cUTIs caused by multidrug-resistant strains of Enterobacteriaceae, including carbapenem-resistant strains, alternatives are needed.
Results from the EPIC trial
For the EPIC trial, which was designed and funded by Achaogen, an international team of researchers enrolled patients with cUTIs, including pyelonephritis, from 68 sites in North America and Europe. A total of 609 patients were selected and randomly assigned on a 1:1 basis to receive either plazomicin or meropenem administered intravenously.
The primary end points of the trial, measured in 388 patients in the microbiologic modified intention-to-treat population, were composite cure (clinical cure and microbiologic eradication) at day 5 and at the test-of-cure visit (15 to 19 days after initiation of therapy). Additional end points were clinical cure and microbiologic eradication during late follow-up. The noninferiority margin was 15 percentage points.
At day 5, composite cure was observed in 88% of the plazomicin patients (168 of 191) and 91.4% (180 of 197) of the meropenem patients (difference, –3.4 percentage points; 95% confidence interval [CI], –10.0 to 3.1). At the test-of-cure visit, composite cure was observed in 81.7% of the plazomicin group (156 of 191 patients) and 70.1% of the meropenem group (138 of 197 patients), for a difference of 11.6 percentage points (95% CI, 2.7 to 20.3). In addition, a higher percentage of patients in the plazomicin group were found to have microbiologic eradication at the test-of-cure visit, including eradication of Enterobacteriaceae that were not susceptible to aminoglycosides (78.8% vs 68.8%).
Twenty-four to 32 days after initiation of therapy, fewer patients in the plazomicin arm had microbiologic recurrence (3.7% vs 8.1%) or clinical relapse (1.6% vs 7.1%) than in the meropenem arm. The authors of the study say this last finding is particularly noteworthy.
"The lower incidence of microbiologic recurrence and clinical relapse in the plazomicin group than in the meropenem group at late follow-up suggests that the greater microbiologic eradication with plazomicin has additional clinical benefit for patients with complicated UTIs, including acute pyelonephritis," they write.
Data from the CARE trial
While the results of the EPIC trial helped pave the way for plazomicin to be approved for treatment of cUTIs, the results from another trial that had to be stopped prematurely because of low enrollment suggest that the drug could also be a critical tool for treating patients with CRE infections.
In a letter to the editor, James McKinnell, MD, an infectious disease specialist and assistant professor of medicine at the David Geffen School of Medicine at UCLA, and colleagues report the results of the CARE (Combating Antibiotic Resistant Enterobacteriaceae) trial, which aimed to evaluate the efficacy and safety of plazomicin compared with colistin as part of a combination therapy regimen for bloodstream infections and hospital-acquired or ventilator-associated pneumonia caused by CREs.
Although the trial (which was also designed and funded by Achaogen) had to be stopped prematurely because only 39 out of 2,000 screened patients were enrolled, the data from those patients favored plazomicin.
Among the 37 patients with confirmed CRE infections, the primary end point—a composite of death from any cause or significant disease-related complications—occurred in 24% of patients (4 of 17) who received plazomicin in combination with adjunctive meropenem or tigecycline, compared with 50% of the patients (10 of 20) who received colistin. In a secondary analysis of time to death, fewer deaths were observed at day 14 among patients in the plazomicin group, a trend that continued through day 60.
The data also showed that fewer patients in the plazomicin group (2 of 12, 16.7%) had a clinically meaningful increase in serum creatinine concentration—a measure of decreased kidney function—than in the colistin group (8 of 16, 50%).
An option for CRE infections
McKinnell, who's also a consultant for Achaogen, said he believes the results indicate the drug is definitely a better option for CRE infections than colistin, an antibiotic that has become a last resort therapy for CREs and other multidrug-resistant pathogens, but has high kidney toxicity.
"The performance from the plazomicin arm was better than expected, to be honest," McKinnell told CIDRAP News. "For serious CRE infections, this is clearly an option."
The FDA, however, said it could not approve plazomicin for multidrug-resistant bloodstream infections because the CARE trial did not provide substantial evidence of its efficacy.
"I was very surprised that the FDA didn't approve the drug for CRE infections," McKinnell said. "The data that the company presented, to me, were impactful and meaningful."
Since another clinical trial is unlikely given the enrollment problems in the CARE trial and the FDA's reaction, McKinnell said that means the choice of whether to use plazomicin off-label in patients with CRE infections bloodstream infections or pneumonia will fall to clinicians, and will have to be made based on limited data. "This leaves it to the physicians to attempt to use the drug when it's not been [thoroughly] studied," he said.
Jason Gallagher, PharmD, a clinical professor at Temple University School of Pharmacy who was not involved in either study, said he thinks the data from the CARE trial is more clinically interesting than the results from EPIC trial.
"We don't need new drugs for UTIs, but we need new drugs," Gallagher said. "The CARE study involved people who were very ill with an extremely resistant organism, and that's the area of interest. People aren't going to run away prescribing plazomicin for UTIs based on the EPIC study, but they very well may use it for CREs based on this study."
Gallagher said that while he's not surprised that the FDA didn't approve plazomicin for CRE infections, he think there's enough information to support off-label use of the drug in patients with the multidrug-resistant pathogens. "It's better than most of the things we have for CRE already," he said.
See also:
Feb 21 N Engl J Med plazomicin for cUTIs study
Feb 21 N Engl J Med plazomicin for CRE infections letter
Feb 21 N Engl J Med editorial
