New Antibiotic Better For Treating Complicated UTIs

According to research published in The New England Journal of Medicine, Cefepime-taniborbactam, a new antibiotic showed a superiority over meropenem in treating complicated UTIs with pyelonephritis.

Cefepime-taniborbactam demonstrated a 22% higher efficacy in the treatment of complicated Urinary Tract Infections (UTIs) compared to meropenem- the existing therapy for treating complicated UTIs and acute pyelonephritis.

Cefepime-taniborbactam, an antibiotic that has been under investigation for its efficacy against antibiotic-resistant bacteria, was examined in a phase 3 trial. The trial was double-blind and randomized, involving participants from 15 different countries.

Background for The Study

The study was necessary because Enterobacterales species that are resistant to carbapenems and Pseudomonas aeruginosa species that are resistant to multiple drugs pose significant risks to global health.

Therefore, Cefepime–taniborbactam which is a combination β-lactam and β-lactamase inhibitor was investigated to determine its effectiveness against these Enterobacterales and P. aeruginosa species that express both serine and metallo-β-lactamases.

To achieve this, the effectiveness of Cefepime-taniborbactam in treating complicated UTIs was compared to that of Meropenem.

What is Urinary Tract Infection (UTI)?

A urinary tract infection (UTI) refers to an infection occurring in any part of the urinary system, which comprises the kidneys, ureters, bladder, and urethra. Usually, most UTIs affect the lower urinary tract, namely the bladder and urethra.

While infections confined to the bladder can cause discomfort and irritation, complications may arise if the infection spreads to the kidneys.

While infections confined to the bladder can cause discomfort and irritation, complications may arise if the infection spreads to the kidneys. The uncomplicated UTI may become complicated when the infection progresses upwards the urinary tract thereby affecting the ureters and the kidneys.

This may cause pyelonephritis (infection of the kidneys) and other bad health conditions.

Women face a higher risk of UTI compared to men. Risk factors for urinary tract infections in women include frequent sexual intercourse, lack of urination after intercourse, use of a diaphragm, use of a spermicide, and a history of recurrent urinary tract infections.

Symptoms of a urinary tract infection (UTI)

Uncomplicated UTIs may not show symptoms but when they do, they may include persistent and intense urges to urinate, accompanied by a burning sensation during urination.

Individuals may also experience frequent urination with small amounts of urine, cloudy or discolored urine (appearing red, pink, or resembling cola due to blood presence), and urine with a strong odor.

In women, pelvic discomfort, particularly centralized around the pelvic area and the pubic bone region, may also be observed.

Antibiotics Used to Treat UTI

The antimicrobial agents most commonly used to treat uncomplicated urinary tract infections include the combination drug trimethoprim and sulfamethoxazole, trimethoprim, β-lactams, fluoroquinolones, nitrofurantoin, and fosfomycin tromethamine. 

The goal of antimicrobial therapy is to eliminate the infecting organisms from the urinary tract and provide the resolution of symptoms.

The Study Design and Methods

• This was a phase 3 double blind randomized trial. Hospitalized adults with complicated UTIs and pyelonephritis were assigned in a 2:1 ratio to receive either intravenous cefepime–taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days with possible extension to 14 days in case of bacteremia.

• The Study participants were hospitalized adults over 18 years old diagnosed with either complicated urinary tract infections or acute pyelonephritis, exhibiting pyuria, at least one systemic sign, and at least one local sign or symptom.

• The study participants were made up of a “safety group” comprising 657 patients, and a “micro intention-to-treat” group with 436 patients. The safety group (657 patients) were monitored for adverse reactions while the micro intention-to-treat group (436 patients) were assessed for drug’s efficacy.

• Individuals who had already received antibacterial drug therapy for more than 24 hours before randomization or were infected with a meropenem-resistant pathogen were excluded from the study.

• The main measure of success (primary outcome) in the study was achieving both microbiologic and clinical improvement (referred to as composite success) between trial days 19 to 23, within the study group called “microbiologic intention-to-treat (microITT) group.” Those include patients with qualifying gram-negative pathogen that are susceptible to both study medications (cefepime–taniborbactam and Meropenem).

• The effectiveness of each medication was determined by a combination of reduced bacterial levels and the alleviation of infection symptoms and signs.

• In addition, there was a preplanned analysis to assess the superiority of the primary outcome after the confirmation of the noninferiority.

The Study Observations and Analysis

• Between days 19-23, 70.6% of patients receiving cefepime-taniborbactam exhibited successful reduction in both bacteria and symptoms, whereas in the meropenem group, this figure was 58.0%.

• Follow-Up observations showed that cefepime-taniborbactam demonstrated greater efficacy than meropenem, with 89.1% effectiveness recorded less than 24 hours after the last dose. This contrasts with meropenem’s 86%.

• Furthermore, cefepime-taniborbactam maintained 63.8% efficacy up to 35 days after initiating treatment, while meropenem showed 51.7% efficacy during the same duration.

• Adverse reactions, ranging from mild to moderate, were experienced by 35.5% of patients in the cefepime-taniborbactam group, including headache, diarrhea, constipation, hypertension, and nausea, compared to 29% in the meropenem group.

• Overall, discontinuation rates were 3% for cefepime-taniborbactam and 1.8% for meropenem; however, the reasons for discontinuation varied.

The Key Takeaway

The authors of the study concluded that Cefepime-taniborbactam outperformed meropenem in treating complicated urinary tract infections that included pyelonephritis, while at the same time maintained a safety profile comparable to that of meropenem.

Dislosures

This research was financially supported by Venatorx Pharmaceuticals, which obtained funding from various sources including the US Department of Health and Human Services, the Administration for Strategic Preparedness and Response, the Biomedical Advanced Research and Development Authority, the Global Antibiotic Research and Development Partnership, and Everest Medicines.

CERTAIN-1 ClinicalTrials.gov number, NCT03840148.

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Sources

1. Jancel T, Dudas V. Management of uncomplicated urinary tract infections. West J Med. 2002 Jan;176(1):51-5. doi: 10.1136/ewjm.176.1.51.
2. Medscape (2024, Feb 20). New Antibiotic Promising for Complicated UTIs. https://www.medscape.com/viewarticle/new-antibiotic-promising-complicated-utis-2024a100036u? 
3. Wagenlehner, F. M. et al (2024, Feb 15). Cefepime–Taniborbactam in Complicated Urinary Tract Infection. N Engl J Med 2024; 390:611-622
   DOI: 10.1056/NEJMoa2304748