Introduction 

Difficult-to-treat multidrug-resistant Gram-negative bacteria (MDR-GNB) infections are a serious global health challenge. Avibactam (AVI), a third-generation beta-lactamase inhibitor, when combined with beta-lactam ceftazidime (CAZ), improved the efficacy of the associated antibiotic. Retrospective real-world studies have shown that ceftazidime-avibactam (CAZ-AVI) was effective and safe for treating MDR-GNB infections, however, prospective studies are lacking. Data on microbiological evolution is also needed, considering the risk of bacterial resistance emergence during treatment. 

Aim

To assess the real-world data on use, effectiveness, and tolerability of CAZ-AVI for treating hospitalized patients with infections under routine clinical conditions

Patient Profile 

Method

Study Design

Endpoints

• Effectiveness assessed by all-cause mortality
• Clinical response was assessed either 28 days after CAZ-AVI discontinuation or at hospital discharge, whichever occurred first
• Clinical response was classified as “failure” if the patient died from the initial infection, or if the infections persisted and required another antibiotic or surgery, or if CAZ-AVI was discontinued due an adverse event; and it was classified as “global success” if no failure was observed 
• “Therapeutic success” corresponded to a patient’s outcome not classified as “failure”, did not die and required no other antibiotics during the index hospitalization
• Safety was assessed at 28 days after CAZ-AVI discontinuation or at hospital discharge, whichever occurred first

Results 

Efficacy 

• Global and therapeutic successes with CAZ-AVI were observed in 79% and 63.4% of patients, respectively (Table 1)
• The response of failure was seen in 21%, especially in patients with nosocomial pneumonia (26.1%)
• Clinical response rates were similar whether CAZ-AVI was administered with or without a loading dose, continuously or not and as monotherapy or combined with another antibiotic 
• CAZ-AVI was prescribed as first-line treatment in 28.5% of patients, second-line in 43.8%, third-line in 22.3%, and beyond in 5.5%
• Overall, 77.8% of patients received CAZ-AVI as monotherapy and 22.2% combined with other antibiotics also targeting GN bacteria; in patients receiving combination therapy, CAZ-AVI was associated with aminoglycoside in 19%, fluoroquinolone in 14.3%, trimethoprim-sulfamethoxazole in 10.9%, colistin in 10.5%, monobactam in 10.1%, tetracycline in 5.4%, and carbapenem in 3.9%
• Resistance to carbapenems was observed in 57.9% of cases, whereas resistance to CAZ-AVI was observed in 9.1%
• CAZ-AVI was prescribed for nosocomial pneumonia (34.2 %), complicated urinary tract infections (17.5 %), complicated intra-abdominal infections (14.8 %) and other specified sites (27.6 %; pulmonary, bacteriaemia, bone and joint, skin and soft tissue, vascular, ear, nose and throat) and unspecified infection sites (10.9%); main pathogens were Pseudomonas aeruginosa (52.4%), Klebsiella spp. (34.9%), Enterobacter spp. (18.4%)
• In the microbiologically documented population, global success rates according to the different causal bacteria ranged from 75% to 91.5%
• In patients with CAZ-AVI treatment failure, Klebsiella spp. and Pseudomonas aeruginosa were the most frequent, followed by E. coli and Stenotrophomonas spp.
• Resistance to CAZ-AVI was observed mainly in Pseudomonas aeruginosa and in Klebsiella spp. and global resistance rate was thus 5.4%
• Overall mortality rate at hospital discharge or 28 days after CAZ-AVI discontinuation was 20.2 % (ranging from 6.7% for complicated urinary tract infection to 30.7% for nosocomial pneumonia)      

Table 1: Efficacy of CAZ-AVI

Safety   

• Adverse events (AEs) possibly related to CAZ-AVI were reported in 16.7% patients, including serious AEs in 6.2% patients (3 infections due to Clostridioides difficile, 3 hepatobiliary disorders, 2 nervous system disorders, and 2 respiratory failures)
• One patient had a lung disorder with diminished respiratory function, possibly related to treatment, that led to death

Conclusion 

• CAZ-AVI was effective and well tolerated for treating MDR-GNB infections in real-life settings
• This study also provided exploratory data in other infection types, data on CAZ-AVI in combination with other antibiotics and microbiological data to assess bacterial resistance

Infect Dis Now 2025; 55: 105036