Novel Drug Combination Noninferior for Treatment of cUTI


A novel combination of ceftriaxone, sulbactam and disodium EDTA (CSE) was found noninferior to meropenem to treat cUTIs caused by gram-negative pathogens.

CSE, a novel combination of ceftriaxone, sulbactam and disodium ethylenediaminetetraacetic acid (EDTA) could be an alternative to meropenem for treatment of complicated urinary tract infections (cUTI), including acute pyelonephritis (AP), a recent study found.

The double-blind, randomized, noninferiority study, published in Open Forum Infectious Diseases, found that CSE was effective and well-tolerated for treating multidrug-resistant gram-negative pathogens. It included 230 patients at 17 sites in India who received either intravenous CSE every 12 hours, or intravenous meropenem every 8 hours, for 5 to 14 days.

“In the present era where antimicrobial resistance is increasing at an unprecedented rate and new antibiotic development isn’t nearly enough to keep pace with it, fixed-dose combinations have an extremely important role to play,” corresponding author Mohd Amin Mir, MS, MSc, PGDPM, director of clinical research at Venus Medicine Research Centre in India, told Contagion®.

“In our research, we compared the novel combination of ceftriaxone-sulbactam-EDTA to meropenem, a widely used last-line carbapenem antibiotic. This is the first combination that aims to salvage ceftriaxone with the help of a known inhibitor, sulbactam, and a known metal chelator, disodium EDTA. The result of noninferiority provides useful evidence to suggest that the combination could be used as an alternative to meropenem in patients with cUTI/AP caused by multidrug-resistant bacteria. Substituting meropenem with CSE can vastly help with antibiotic stewardship and even help restore the effectiveness of meropenem over the long run.”

Most pathogens in the study were Escherichia coli or Pseudomonas aeruginosa, of which most (98%) were non-susceptible to ceftriaxone. Pathogens producing extended-spectrum 𝛽-lactamase (ESBL) were present in 83% of cases.

CSE yielded higher clinical cure and microbiological eradication rates than meropenem (95.9% and 94.6% compared with 89.9% and 88.4%, respectively), and fewer patients in the CSE group reported recurrence (3% compared with 10%, respectively).

Most adverse events were mild or moderate and were resolved, including general weakness (3.1%), thrombophlebitis (1.8%), phlebitis (0.9%), gastritis (1.3%) and vomiting (0.9%). Serious adverse events were reported in 1 patient, including multiple organ dysfunction syndrome and septic shock resulting in death; this was deemed unrelated to the study drug.

Further research could involve investigating CSE for treating patients with co-morbidities including renal/hepatic insufficiency and immunosuppression.

“CSE is an attempt to create a combination that can help bridge the gap between the discovery of new agents and the growing resistance,” Amin Mir told Contagion®. “It is by no means a holistic solution to the problem of drug resistance; however, it does open avenues to explore other non-traditional approaches that can be brought to the clinic much faster as compared to new drugs. As a carbapenem sparing treatment, it can be of great value to health care providers who wish to limit carbapenem use and to implement antibiotic stewardship in their hospitals. As for clinicians, we hope that CSE will help them in treating patients more effectively and in a much safer way.”

Health care systems have focused on reducing UTIs, which are common among hospitalized patients and can result in serious complications, including death. Those efforts have included reducing catheter use and research and development of new, less invasive technology such external female catheters.

Antimicrobial resistance is a growing concern, and investigators have found that urine cultures are being ordered unnecessarily and antibiotics overused, underscoring the need to improve antimicrobial stewardship.

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