Zavicefta [1] is a combination of an existing antipseudomonal cephalosporin antibiotic ceftazidime with avibactam, which inhibits beta-lactamase production. It was developed by Pfizer and first approved by FDA in February 2015. Over the following years, it has been approved by FDA to be used for complicated abdominal and urinary tract infections, hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia in both adults and paediatric patients.
Infections caused by carbapenemase-producing Enterobacterales (CPE) are commonly seen in the urinary tract, lungs and non-healing wounds. However, this bacteria group is not well-represented in Zavicefta’s initial clinical study. Initially, the treatment regimen for CPE infections was based on ‘best available therapy’ (BAT), which included second-line antibiotics (gentamicin, colistin, tigecycline and fosfomycin) because of their toxicity. The CAVICOR study [2] published in early 2022 investigated whether treatment of infections caused by CPE with Zavicefta is associated with lower mortality than those treated with BAT and whether Zavicefta has a higher rate of clinical response and microbiological eradication than BAT.
The study [2] included adult patients from 14 tertiary hospitals in Spain from 2014 to 2019 admitted with confirmed CPE infection. The cohort included 339 patients with CPE infections. Ceftazidime/avibactam treatment was used in 189 (55.8%) patients and 150 (44.2%) received BAT at a median of 2 days after diagnosis of infection.
Overall, patients who received Zavicefta had a significantly lower rate of mortality than those on BAT (13.7% [26/189] vs 22.0% [33/150]; P=0.04, Figure 1). Zavicefta was also associated with significantly higher microbiological responses (83.3% [100/120] vs 69.4% [50/72]; P=0.02) and 21-day clinical cure (89.4% [169/189] vs 79.3% [119/150]; P=0.01).
Figure 1 Primary and secondary endpoints comparing Zavicefta vs BAT
Treatment with Zavicefta-containing therapy was associated with a 59% reduction (OR 0.41; 95% CI 0.22–0.80; P=0.01, Figure 2) in the risk of death. Both SOFA scores at diagnosis and INCREMENT-CPE of >7 points were identified as strong predictors of 30-day mortality in CPE infection.
Figure 2 Adjusted multivariate analysis of factors associated with 30-day mortality
More patients with INCREMENT-CPE score of >7 points died within 30 days when they received BAT compared with Zavicefta (46.9% [23/49] vs 21.9% [16/73]; P=0.004, Figure 3).
Figure 3 Survival of patients with (a) INCREMENT-CPE score of ≤7 points and (b) >7 points who received either Zavicefta or BAT
In terms of adverse events, they were reported in 41 (12.1%) patients. Treatment with ceftazidime/avibactam was less related to AEs than BAT (11/189, 5.8% versus 30/150, 20%; P ≤ 0.001). The most frequent AEs were renal failure (18/41, 43.9%) and diarrhoea (9/41, 21.9%). Renal failure was significantly more frequent in patients treated with BAT compared with those treated with ceftazidime/avibactam (3/189, 1.6% versus 15/150, 10%; P ≤ 0.01). Diarrhoea was more frequent in the ceftazidime/avibactam group, although no significant differences were found between groups (5/11, 45.4% versus 4/30, 13.3%; P = 0.07).
The study thus concluded that Zavicefta is an effective alternative for the treatment of CPE infections, especially in patients with INCREMENT-CPE scores of >7 points. Additionally, ceftazidime/avibactam treatment was associated with more clinical improvement and microbiological eradication.
However, there are several limitations. First, it was an observational and retrospective study, in which confounding, and bias were potential issues which can affect the result. Second, the treatment for the patients observed was not randomly assigned and the rationale behind the treating team’s decision for therapy was not considered. Third, it could be possible that the observed differences may, in part, be related to underdosing of the drugs included in the BAT group, due to second-line antibiotics’ strong toxicity. In addition, as a new treatment, greater experience and better management from the treating team with the Zavicefta-treated patients might have occurred. Future randomized controlled trials could potentially confirm or challenge the data.
Reference:
- Castón JJ, Cano A, Pérez-Camacho I, Aguado JM, Carratalá J, Ramasco F, et al. Impact of ceftazidime/avibactam versus best available therapy on mortality from infections caused by carbapenemase-producing Enterobacterales (CAVICOR study). Journal of Antimicrobial Chemotherapy. 2022 Feb 21;77(5):1452–60.
- Avycaz (avibactam and ceftazidime) FDA Approval History [Internet]. Drugs.com. [cited 2023 May 13]. Available from: https://www.drugs.com/history/avycaz.html
