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New drug combination highly effective against urinary tract infections – global trial

An international study led by a Rutgers scientist comparing new and older treatments against complicated urinary tract infections has found a new drug combination to be more effective, especially against hard-to-eliminate, drug-resistant infections.

Researchers in the ALLIUM phase three clinical trial showed that a combination of the drugs cefepime and enmetazobactam was more effective in treating both complicated urinary tract infections and acute pyelonephritis (AP), a bacterial infection causing kidney inflammation, than a standard treatment combining piperacillin and tazobactam. Urinary tract infections are considered complicated when they are associated with risk factors – including fevers, sepsis, urinary obstruction or catheters – that increase the danger of failing antibiotic therapy.

“This new antibiotic was superior to the standard-of-care therapy,” said lead author and principal investigator Keith Kaye, chief of the Division of Allergy, Immunology and Infectious Diseases and a professor of medicine at Rutgers Robert Wood Johnson Medical School, adding that it represented an exciting treatment option.

In the study, published in the Journal of the American Medical Association (JAMA), the researchers wrote that the drug combination also fights an often-dangerous category of bacterial illnesses caused by pathogens, known as extended spectrum beta-lactamase (ESBL) infections, named for an enzyme produced by the bacteria. ESBL-producing bacteria can't be killed effectively by many of the antibiotics conventionally used to treat infections, such as penicillins and cephalosporins.

“We are looking for antibiotics that are active against resistant bacteria, such as ESBLs, and this new combination was highly effective,” Kaye said.

The trial, with more than 1 000 participants, was conducted at 90 sites in Europe, North and Central America, South America and South Africa from September 2018 to November 2019. Some 79% of the patients receiving the new combination of cefepime and enmetazobactam were successfully treated for their illness, as opposed to 58.9% receiving the conventional treatment of piperacillin and tazobactam.

Of the 20% of patients from the overall group belonging to the subset of those with ESBL infections, 73% receiving cefepime and enmetazobactam achieved a clinical cure, as opposed to 51% of the patients on the standard therapy.

The antibiotic cefepime is a fourth-generation cephalosporin that was approved for use in the 1990s and is available generically. Enmetazobactam, an experimental drug made by the French biopharmaceutical company, Allecra Therapeutics, is a beta-lactamase inhibitor, meaning it attacks the beta-lactamases, including the types of enzymes produced by ESBL-producing bacteria. The drug combination has been granted Qualified Infectious Disease Product and Fast Track designation by the US Food and Drug Administration (FDA).

Kaye said he expected the company to apply for FDA approval early next year.

More than 2.8m antimicrobial-resistant infections occur in the US annually, and more than 35 000 people die from them. The US Centres for Disease Control & Prevention (CDC) has characterised ESBLs as a serious threat to human health.

Study details

Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis

Keith Kaye, Adam Belley, Philip Barth, Omar Lahlou, Philipp Knechtle, Paola Motta, Patrick Velicitat.

Published in JAMA on 4 October 2022.

Key Points
Question How does the efficacy of cefepime/enmetazobactam compare with piperacillin/tazobactam for the treatment of complicated urinary tract infection (UTI) or acute pyelonephritis?
Findings In this randomised clinical trial that included 1034 patients, the proportion of patients infected with gram-negative pathogens who achieved clinical cure and microbiological eradication at the test-of-cure visit was 79.1% with cefepime/enmetazobactam compared with 58.9% with piperacillin/tazobactam, a difference that met the prespecified noninferiority margin of −10% as well as the prespecified criterion for superiority in favor of cefepime/enmetazobactam.
Meaning Among patients with complicated UTI or acute pyelonephritis due to gram-negative pathogens, cefepime/enmetazobactam, compared with piperacillin/tazobactam, met criteria for noninferiority as well as superiority with respect to the primary efficacy outcome of clinical cure and microbiological eradication.

Abstract

Importance
Cefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination and a potential empirical therapy for resistant gram-negative infections.

Objective
To evaluate whether cefepime/enmetazobactam was noninferior to piperacillin/tazobactam for the primary outcome of treatment efficacy in patients with complicated urinary tract infections (UTIs) or acute pyelonephritis.

Design, Setting, and Participants
A phase 3, randomised, double-blind, active-controlled, multicentre, noninferiority clinical trial conducted at 90 sites in Europe, North and Central America, South America, and South Africa. Recruitment occurred between September 24, 2018, and November 2, 2019. Final follow-up occurred November 26, 2019. Participants were adult patients aged 18 years or older with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by gram-negative urinary pathogens.

Interventions
Eligible patients were randomised to receive either cefepime, 2 g/enmetazobactam, 0.5 g (n = 520), or piperacillin, 4 g/tazobactam, 0.5 g (n = 521), by 2-hour infusion every 8 hours for 7 days (up to 14 days in patients with a positive blood culture at baseline).

Main Outcomes and Measures
The primary outcome was the proportion of patients in the primary analysis set (patients who received any amount of study drug with a baseline gram-negative pathogen not resistant to either treatment and ≥105 colony-forming units [CFU]/mL in urine culture or the same pathogen present in concurrent blood and urine cultures) who achieved overall treatment success (defined as clinical cure combined with microbiological eradication [<103 CFU/mL in urine] of infection). Two-sided 95% CIs were computed using the stratified Newcombe method. The prespecified noninferiority margin was −10%. If noninferiority was established, a superiority comparison was also prespecified.

Results
Among 1041 patients randomised (mean age, 54.7 years; 573 women [55.0%]), 1034 (99.3%) received study drug and 995 (95.6%) completed the trial. Among the primary analysis set, the primary outcome occurred in 79.1% (273/345) of patients receiving cefepime/enmetazobactam compared with 58.9% (196/333) receiving piperacillin/tazobactam (between-group difference, 21.2% [95% CI, 14.3% to 27.9%]). Treatment-emergent adverse events occurred in 50.0% (258/516) of patients treated with cefepime/enmetazobactam and 44.0% (228/518) with piperacillin/tazobactam; most were mild to moderate in severity (89.9% vs 88.6%, respectively). A total of 1.7% (9/516) of participants who received cefepime/enmetazobactam and 0.8% (4/518) of those who received piperacillin/tazobactam did not complete the assigned therapy due to adverse events.

Conclusions and Relevance
Among patients with complicated UTI or acute pyelonephritis caused by gram-negative pathogens, cefepime/enmetazobactam, compared with piperacillin/tazobactam, met criteria for noninferiority as well as superiority with respect to the primary outcome of clinical cure and microbiological eradication. Further research is needed to determine the potential role for cefepime/enmetazobactam in the treatment of complicated UTI and pyelonephritis.

 

JAMA article – Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis (Open access)

 

See more from MedicalBrief archives:

 

Antibiotics may increase, not reduce, risk of further UTIs – Harvard/MIT/Washington study

 

ALTAR trial supports antibiotic alternative for recurrent urinary tract infections

 

Rapid test to check antibiotic efficacy against urinary-tract bacteria

 

Ibuprofen not a safe alternative to antibiotics for UTIs

 

 

 

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