Introduction

Ceftazidime-avibactam (CZA) combination is effective against a wide range of gram-negative bacteria, including carbapenemase-producing Enterobacterales. In randomized controlled trials, it has been effective in numerous infections caused by multidrug-resistant organism. However, now studies have raised concern regarding the emerging resistance to CZA among clinical Escherichia coli (E. coli) isolates.

Aim

To investigate the prevalence of CZA susceptibility among clinical E. coli isolates, encompassing carbapenem-resistant strains, and the global trends in carbapenemase prevalence within this subset from 2014 to 2021 using Antimicrobial Testing Leadership and Surveillance (ATLAS) database

Patient Profile

• Total of 49,394 E. coli clinically relevant pathogen isolates were collected from patients with documented infections (acquired in a community or health care setting)

Method

Study Design

• A surveillance study continuous for a period of 8 years

Endpoints

• Breakpoints for CZA resistance (≤8 mg/L indicated susceptibility and ≥16 mg/L indicated resistance)
• Carbapenem-resistant E. coli (CREC) isolates were defined as those with meropenem MICs ≥4 mg/L
• E. coli isolates exhibiting carbapenem resistance were further examined for the presence of clinically relevant β-lactamase genes. The screened genes encompassed Klebsiella pneumoniae carbapenemase (bla_KPC), oxacillinases (bla_OXA-48-like genes in the Enterobacterales) and New Delhi metallo-beta-lactamases (MBLs) (bla_NDM)
• The deduced amino acid sequences of the complete coding region were compared to publicly available databases to identify the carbapenemase variants

Results

Efficacy

• The countries with the highest nonsusceptible rates of E.coli for meropenem were India (16.6%), followed by Pakistan (6.7%), Ukraine (5.4%), Qatar (5.3%), and Guatemala (3.2%)
• For CZA, the nonsusceptible rate of E. coli was highest in India (15.6%), followed by Qatar (4.0%), Guatemala (3.9%), China (2.6%), and Thailand (2.5%)
• During the study period, the nonsusceptible rates of meropenem and CZA in E. coli increased in Asia, Latin America, and Africa/Middle East
• Isolates from the medical intensive care unit (ICU, odds ratio [OR], 3.25 and 4.62) and surgical ICU (OR, 2.87 and 3.98) were associated with a higher risk of both meropenem as well as CZA nonsusceptible rates
• Compared to intestinal specimens, respiratory and genitourinary specimens had the highest OR (2.32 and 2.17) associated with CZA resistance and respiratory specimens had the highest OR (1.8) associated with meropenem resistance
• The isolates in Asia had a significantly higher nonsusceptible rate of meropenem and the highest OR (17.31) compared to North America
• Analysis of carbapenemase distribution showed an increase in the percentage of bla_NDM-positive isolates and a decrease in bla_KPC-positive isolates worldwide
• In Asia, bla_NDM was the most common carbapenemase, followed by bla_OXA, and bla_KPC was rare
• In a total of 141 bla_OXA-positive (without bla_MBL isolates) in the world, 1.4% were resistant to CZA and found in India and Thailand
• A gradual decline in the prevalence of bla_OXA-positive E. coli without concomitant carriage of metallo-β-lactamase genes occurred in the worldwide surveillance

Conclusion

• An increasing CREC and CZA resistance in Asia, Latin America and Africa/the Middle East has been found from E. coli isolates collected in ATLAS database from 2014-2021
• This surveillance showed the highest resistance seen in ICU and respiratory isolates
• It is important to monitor the recent phenomenon of decreasing bla_KPC-positive isolate percentages and increasing bla_NDM-positive E. coli isolates

Int J Antimicrob Agents 2024; 63: 107103