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30th January 2024
The new antibiotic combination cefepime/enmetazobactam (brand name Exblifep) has received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) for the treatment of complicated urinary tract infections (cUTI), its manufacturer Advanz Pharma has announced.
The intravenous formulation is a fixed-dose combination of enmetazobactam – a novel extended-spectrum-lactamase inhibitor belonging to the penicillanic acid sulfone class – with the 4th generation cephalosporin cefepime.
This enhances the efficacy of cefepime against resistant bacteria, including extended spectrum beta-lactamase (ESBL)-producing pathogens.
Cefepime/enmetazobactam has been given the green light in the EU for the treatment of adult patients with cUTIs, including pyelonephritis; hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP); and the treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed.
The drug was designed as a new antibiotic combination to combat the growing antimicrobial resistance in Gram-negative bacteria, Advanz Pharma said.
The CHMP recommendation was based on the results of the phase 3 randomised, double-blind, multi-centre ALLIUM trial, which was undertaken at 112 sites in 19 countries.
The trial considered how the efficacy of cefepime/enmetazobactam compared with piperacillin/tazobactam for the treatment of cUTIs or acute pyelonephritis (AP) and the primary efficacy outcome was clinical cure and microbiological eradication.
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 two-hour infusion every eight hours for seven days (up to 14 days in patients with a positive blood culture at baseline).
Cefepime/enmetazobactam demonstrated statistically significant superior overall treatment success (clinical cure combined with microbiological eradication) at a test-of-care visit compared with piperacillin/tazobactam in cUTI, including AP, caused by Gram-negative pathogens (79.1% vs 58.9%).
Statistically significantly superior results were also observed among patients with infections caused by ESBL-producing pathogens (73.7% vs 51.5%, respectively).
Cefepime/enmetazobactam demonstrated a tolerable safety profile, comparable to piperacillin/tazobactam.
Treatment-related serious adverse events were reported in 0.2% of patients treated with cefepime/enmetazobactam versus 0.6% of patients treated with piperacillin/tazobactam.
The European Medicines Agency noted the most common side effects as pain and inflammation at the infusion site, diarrhoea, skin rash and headache.
According to Advanz Pharma, cefepime/enmetazobactam has shown promising in vitro activity against the more resistant beta-lactamase mutations OXA-48 and AmpC, which are increasing in Europe and for which there are few therapeutic alternatives.
21st April 2023
Urinary tract infections (UTIs) have a lifetime incidence of 50-60% in adult women. While commonly treated with antibiotics, UTIs often recur in 16% of women. An uncomplicated UTI is mainly due to Escherichia coli but recent data indicates antimicrobial resistance is on the increase.
GSK’s novel and investigational, first-in-class, antibiotic, gepotidacin (GD) was non-inferior to nitrofurantoin in two phase III trials in women with an uncomplicated UTI (uUTI). The drug inhibits bacterial DNA replication by blocking two essential topoisomerase enzymes. Consequently, mutations in both enzymes would be needed for resistance to occur. While GD appears effective in uncomplicated UTI’s according to a phase 2 trial, there is an absence of phase 3 studies.
GSK describes the findings from two near identical, randomised, double-blind studies, EAGLE-2 and EAGLE-3. Both involved women and adolescents with an uUTI and had nitrofurantoin (100mg twice daily) as an active comparator. The primary efficacy endpoint was therapeutic success (TS) which was a combination of clinical and microbiological success. GD was given at a dose of 1,500 mg twice daily for 5 days. Participant assessment took place 10-13 days after initiation of treatment.
Gepotidacin and therapeutic success
In EAGLE-2 the TC was 50.6% with gepotidacin and 47% with nitrofurantoin. In EAGLE-3, a higher proportion of participants receiving gepotidacin achieved a TS (58.5% vs 43.6%). Furthermore, across both trials, 94% of gepotidacin patients did not receive an additional antibiotic for their uUTI through to the follow-up visit on day 28. The clinical cure rates were similar for gepotidacin and nitrofurantoin in both trials. However, the microbiological cure rate was higher with gepotidacin in EAGLE-3 (72.2% vs 57.2%).
The safety and tolerability profile of gepotidacin in the EAGLE-2 and EAGLE-3 phase III trials was consistent with previous trials of gepotidacin.
GSK expects to submit data to the FDA in the second quarter of 2023.
3rd March 2023
The introduction of an antimicrobial stewardship intervention to older adult care facilities, significantly reduced the level of antibiotic prescribing for frail older adults with a suspected urinary tract infection according to the findings of a cluster, randomised trial by European researchers.
Antimicrobial resistance poses a global, major threat to human health and is recognised as a leading cause of deaths around the world. Older and frail adults are often prescribed antibiotics for a urinary tract infection (UTI) and often in the presence of non-specific symptoms such as confusion. Moreover, the presence of asymptomatic bacteriuria is a common finding which has become recognised as an important contributor to inappropriate antimicrobial use that ultimately promotes emergence of antimicrobial resistance. To date antibiotic stewardship interventions in long-term care facilities suggest that such programs collectively suggest potential to reduce antimicrobial use though the available interventions vary considerably with respect to design and intensity.
In the current study, researchers made use of a multifaceted antibiotic stewardship intervention that included a decision tool for appropriate use of antibiotics for a UTI and which was previously developed by an international expert team. The researchers wanted to find out if the intervention was effective in reducing antibiotic prescribing for suspected urinary tract infections in various older adult care settings, in comparison to usual care, in several European countries. The team used a pragmatic, parallel, cluster randomised controlled trial, with a 5 month baseline data collection period and a 7 month follow-up. They set the primary outcome as the number of antibiotic prescriptions for a suspected UTI per person-year, whereas secondary outcomes focused on the level of complications, hospital admissions and all-cause mortality.
Antimicrobial stewardship and treatment of suspected urinary tract infections
A total of 1,041 participants with a mean age of 86.3 years (70.9% female) were included and of whom, 502 were randomised to the antibiotic stewardship intervention.
During the baseline period, there was no difference in the level of antibiotic prescribing for a suspected UTI in the two groups (0.50 per person year vs 0.44 per person year, intervention vs usual care). However, during the follow-up period, the corresponding rates were 0.27 per person-year (intervention ) and 0.58 per person-year (usual care). This equated to an adjusted rate ratio of 0.42 (95% CI 0.26 – 0.68, p < 0.001).
Furthermore, there were no differences between groups with respect to either complications, hospital admissions or all-cause mortality.
The authors concluded that their antimicrobial stewardship intervention safely reduced antibiotic prescribing for a suspected UTI in frail older adults.
Citation
Hartman EAR et al. Effect of a multifaceted antibiotic stewardship intervention to improve antibiotic prescribing for suspected urinary tract infections in frail older adults (ImpresU): pragmatic cluster randomised controlled trial in four European countries. BMJ 2023
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