In the Journals

Novel drug combination noninferior to meropenem for treating cUTIs

Mohd Amin Mir, PhD
Mohd Amin Mir

A novel combination that includes ceftriaxone, sulbactam and disodium EDTA, or CSE, was noninferior to meropenem for the treatment of complicated UTIs, or cUTIs, caused by extended-spectrum beta-lactamase-producing, or ESBL-producing, gram-negative bacteria, according to results from the phase 3 PLEA trial.

“The current situation of antibiotic resistance is rather grim and while there are many new antibiotics in development, the pace of antibiotic discovery is not nearly enough to keep up with the rate at which bacteria are becoming resistant. As an interim solution, the concept of using antibiotic resistance breakers (ARBs) to revive the potency of existing antibiotics has been proposed,” Mohd Amin Mir, MSc, MS, PGDPM, director of clinical research at Venus Medicine Research Centre, told Infectious Disease News.

“CSE is a novel combination of ceftriaxone, a third generation beta-lactam cephalosporin; sulbactam, a beta-lactamase inhibitor; and disodium EDTA, an ARB, and it restores the in vitro activity of ceftriaxone against beta-lactamase-producing gram-negative bacteria.”

In a double-blind, randomized noninferiority trial, Mir and colleagues aimed to analyze the efficacy and safety of CSE compared with meropenem in treating cUTI caused by ESBL-producing gram-negative bacteria. Mir said the trial was designed to help bridge the gap in the previously published data on CSE and aid clinicians in making a more informed decision when choosing an agent for multidrug-resistant infections. According to the study, adult patients aged 18 years or older with a cUTI diagnosis were randomly assigned 1:1 to receive either IV CSE every 12 hours or IV meropenem every 8 hours for 14 days.

Of the 230 patients, 74 were treated with CSE and 69 with meropenem. Researchers found that 98% were ceftriaxone nonsusceptible and 83% were ESBL positive at baseline, which Mir said distinguishes the PLEA trial from other cUTI trials. According to the researchers, noninferiority of CSE to meropenem was demonstrated for both the FDA-defined coprimary endpoints of symptomatic resolution at test of cure — 71/74 (95.9%) vs. 62/69 (89.9%) (treatment difference, 6%; 95% CI, –2.6% to 16%) — and both symptomatic resolution and microbiological eradication at test of cure — 70/74 (94.6%) vs. 60/69 (87.0%) (treatment difference, 7.6%; 95% CI, –2.0% to 18.4%).

According to Mir, CSE is already approved in many countries and has a safety database of over 10,000 treated patients. Because this is the first double-blind clinical trial of CSE, it will enable all countries to apply for approval. He said researchers aim to study the clinical benefits of CSE in other patient populations, such as those with renal/hepatic insufficiency, immunosuppression and other confounding factors.

“The result of noninferiority provides useful evidence to suggest that CSE could be used as an alternative to meropenem in patients with cUTI/[acute pyelonephritis] caused by multidrug-resistant bacteria,” Mir concluded. “Substituting meropenem with CSE can vastly help with antibiotic stewardship and even help restore the effectiveness of meropenem over the long run.” – by Caitlyn Stulpin

Disclosures: Mir is an employee of Venus Remedies Limited. Please see the study for all other author’s disclosures.

Mohd Amin Mir, PhD
Mohd Amin Mir

A novel combination that includes ceftriaxone, sulbactam and disodium EDTA, or CSE, was noninferior to meropenem for the treatment of complicated UTIs, or cUTIs, caused by extended-spectrum beta-lactamase-producing, or ESBL-producing, gram-negative bacteria, according to results from the phase 3 PLEA trial.

“The current situation of antibiotic resistance is rather grim and while there are many new antibiotics in development, the pace of antibiotic discovery is not nearly enough to keep up with the rate at which bacteria are becoming resistant. As an interim solution, the concept of using antibiotic resistance breakers (ARBs) to revive the potency of existing antibiotics has been proposed,” Mohd Amin Mir, MSc, MS, PGDPM, director of clinical research at Venus Medicine Research Centre, told Infectious Disease News.

“CSE is a novel combination of ceftriaxone, a third generation beta-lactam cephalosporin; sulbactam, a beta-lactamase inhibitor; and disodium EDTA, an ARB, and it restores the in vitro activity of ceftriaxone against beta-lactamase-producing gram-negative bacteria.”

In a double-blind, randomized noninferiority trial, Mir and colleagues aimed to analyze the efficacy and safety of CSE compared with meropenem in treating cUTI caused by ESBL-producing gram-negative bacteria. Mir said the trial was designed to help bridge the gap in the previously published data on CSE and aid clinicians in making a more informed decision when choosing an agent for multidrug-resistant infections. According to the study, adult patients aged 18 years or older with a cUTI diagnosis were randomly assigned 1:1 to receive either IV CSE every 12 hours or IV meropenem every 8 hours for 14 days.

Of the 230 patients, 74 were treated with CSE and 69 with meropenem. Researchers found that 98% were ceftriaxone nonsusceptible and 83% were ESBL positive at baseline, which Mir said distinguishes the PLEA trial from other cUTI trials. According to the researchers, noninferiority of CSE to meropenem was demonstrated for both the FDA-defined coprimary endpoints of symptomatic resolution at test of cure — 71/74 (95.9%) vs. 62/69 (89.9%) (treatment difference, 6%; 95% CI, –2.6% to 16%) — and both symptomatic resolution and microbiological eradication at test of cure — 70/74 (94.6%) vs. 60/69 (87.0%) (treatment difference, 7.6%; 95% CI, –2.0% to 18.4%).

According to Mir, CSE is already approved in many countries and has a safety database of over 10,000 treated patients. Because this is the first double-blind clinical trial of CSE, it will enable all countries to apply for approval. He said researchers aim to study the clinical benefits of CSE in other patient populations, such as those with renal/hepatic insufficiency, immunosuppression and other confounding factors.

“The result of noninferiority provides useful evidence to suggest that CSE could be used as an alternative to meropenem in patients with cUTI/[acute pyelonephritis] caused by multidrug-resistant bacteria,” Mir concluded. “Substituting meropenem with CSE can vastly help with antibiotic stewardship and even help restore the effectiveness of meropenem over the long run.” – by Caitlyn Stulpin

Disclosures: Mir is an employee of Venus Remedies Limited. Please see the study for all other author’s disclosures.