In the JournalsPerspective

Zemdri noninferior to meropenem for certain UTIs

A daily dose of the aminoglycoside Zemdri was noninferior to meropenem for the treatment of complicated UTIs and acute pyelonephritis caused by Enterobacteriaceae, including multidrug-resistant strains, according to findings recently published in The New England Journal of Medicine.

Last year, the FDA approved Zemdri (plazomicin, Achaogen) to treat UTIs, including pyelonephritis, caused by certain Enterobacteriaceae in adult patients who have limited or no alternative treatment options.

“The previous mainstays of empirical therapy for complicated UTIs, such as fluoroquinolones and cephalosporins, are not widely recommended because of concerns about resistance,” Florian M.E. Wagenlehner, MD, of the Justus Liebig University, Giessen, Germany and colleagues wrote.

“Carbapenems, which have been traditionally reserved for the treatment of multidrug-resistant infections, are increasingly being used to treat complicated UTIs. The incidence of multidrug resistance has continued to increase — and now includes carbapenem resistance; therefore, alternative treatment options are needed,” they added.

Researchers randomly assigned 609 patients with complicated UTIs, including acute pyelonephritis, in a 1:1 ratio to receive either IV plazomicin (15 mg/kg of body weight daily) or meropenem (1 g every 8 hours). Patients could choose to receive oral step-down therapy after at least 4 days of IV therapy for a maximum of 10 days of therapy.

Wagenlehner and colleagues found that at day 5, composite cure was observed in 88% of the patients receiving plazomicin and 91.4% of patients receiving meropenem. A test-of-cure visit showed composite cure in 81.7% of those receiving plazomicin vs. 70.1% of those receiving meropenem. The researchers also found that 78.8% of patients receiving plazomicin had microbiologic eradication, including eradication of Enterobacteriaceae that were not susceptible to aminoglycosides, vs. 68.6% of those taking meropenem. Enterobacteriaceae that produce extended-spectrum beta-lactamases were observed in 82.4% of those receiving plazomicin vs. 75% of those receiving meropenem.

In addition, fewer patients who received plazomicin had microbiologic recurrence or clinical relapse 24 to 32 days after the start of their therapy.

“Findings from this trial suggest that additional data should be generated to guide approaches for managing asymptomatic bacteriuria in patients at risk for recurrent complicated UTIs,” Wagenlehner and colleagues wrote. – by Janel Miller

Disclosures: Wagenlehner reports receiving advisory board fees and participating in a study for Achaogen, Bionorica, OM Pharma/Vifor Pharma, and Shionogi; receiving advisory board fees from AstraZeneca, GlaxoSmithKline, Janssen, Leo Pharma, MerLion, MSD, Pfizer, RosenPharma and VenatoRx; and participating in a study for Deutsches Zentrum für Infektionsforschung, Enteris BioPharma and Helperby Therapeutics. Please see the study for all other authors’ relevant financial disclosures.

 

A daily dose of the aminoglycoside Zemdri was noninferior to meropenem for the treatment of complicated UTIs and acute pyelonephritis caused by Enterobacteriaceae, including multidrug-resistant strains, according to findings recently published in The New England Journal of Medicine.

Last year, the FDA approved Zemdri (plazomicin, Achaogen) to treat UTIs, including pyelonephritis, caused by certain Enterobacteriaceae in adult patients who have limited or no alternative treatment options.

“The previous mainstays of empirical therapy for complicated UTIs, such as fluoroquinolones and cephalosporins, are not widely recommended because of concerns about resistance,” Florian M.E. Wagenlehner, MD, of the Justus Liebig University, Giessen, Germany and colleagues wrote.

“Carbapenems, which have been traditionally reserved for the treatment of multidrug-resistant infections, are increasingly being used to treat complicated UTIs. The incidence of multidrug resistance has continued to increase — and now includes carbapenem resistance; therefore, alternative treatment options are needed,” they added.

Researchers randomly assigned 609 patients with complicated UTIs, including acute pyelonephritis, in a 1:1 ratio to receive either IV plazomicin (15 mg/kg of body weight daily) or meropenem (1 g every 8 hours). Patients could choose to receive oral step-down therapy after at least 4 days of IV therapy for a maximum of 10 days of therapy.

Wagenlehner and colleagues found that at day 5, composite cure was observed in 88% of the patients receiving plazomicin and 91.4% of patients receiving meropenem. A test-of-cure visit showed composite cure in 81.7% of those receiving plazomicin vs. 70.1% of those receiving meropenem. The researchers also found that 78.8% of patients receiving plazomicin had microbiologic eradication, including eradication of Enterobacteriaceae that were not susceptible to aminoglycosides, vs. 68.6% of those taking meropenem. Enterobacteriaceae that produce extended-spectrum beta-lactamases were observed in 82.4% of those receiving plazomicin vs. 75% of those receiving meropenem.

In addition, fewer patients who received plazomicin had microbiologic recurrence or clinical relapse 24 to 32 days after the start of their therapy.

“Findings from this trial suggest that additional data should be generated to guide approaches for managing asymptomatic bacteriuria in patients at risk for recurrent complicated UTIs,” Wagenlehner and colleagues wrote. – by Janel Miller

Disclosures: Wagenlehner reports receiving advisory board fees and participating in a study for Achaogen, Bionorica, OM Pharma/Vifor Pharma, and Shionogi; receiving advisory board fees from AstraZeneca, GlaxoSmithKline, Janssen, Leo Pharma, MerLion, MSD, Pfizer, RosenPharma and VenatoRx; and participating in a study for Deutsches Zentrum für Infektionsforschung, Enteris BioPharma and Helperby Therapeutics. Please see the study for all other authors’ relevant financial disclosures.

 

    Perspective
    Lisa N. Hawes

    Lisa N. Hawes

    The issue at hand in this study is the development of bacteria that are resistant to many of our oral and IV antibiotics over the past decade. Escherichia coli and Klebsiella bacteria are the most common causes of UTIs. There are many reasons for development of resistance genes in these bacteria that are beyond the scope of this study. The critical issue is the absence of viable alternative antibiotics as mutations in bacteria develop faster than our current treatment options.

    Zemdri (plazomicin, Achaogen) is a once daily IV antibiotic in the aminoglycoside class, which is designed to help eradicate these multidrug-resistant bacteria. This well-designed and implemented study showed plazomicin is noninferior to meropenem, a known and effective antibiotic against many of these bacteria, and that plazomicin may be even more effective in the eradication of the bacteria long term.

    Also of note, fewer patients who took plazomicin had recurrence of infection 3 to 4 weeks after treatment. This result is especially significant as many of these patients had complicated UTIs (eg, pyelonephritis, indwelling catheters, urinary retention). In most cases these patients are excluded from studies to favor positive results.

    Aminoglycosides are known to have two critical risks: ototoxicity and kidney function damage; there were some patients who suffered these side effects, but the kidney function change resolved in most patients over time.

    This study proves the noninferiority and safety of plazomicin against multidrug-resistant Enterobacter. More research is needed to determine the best use of this drug, but meantime, Wagenlehner and colleagues present a compelling case for a new antibiotic to fight multi-drug resistant Enterobacter.

    • Lisa N. Hawes, MD
    • urologist
      Chesapeake Urology

    Disclosures: Hawes reports no relevant financial disclosures.