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In Vitro Activities of Ceftazidime-Avibactam and Aztreonam-Avibactam at Different Inoculum Sizes of Extended-Spectrum β-Lactam-Resistant Enterobacterales Blood Isolates.

ABSTRACT: β-lactam-avibactam combinations have been proposed as carbapenem-sparing therapies, but little data exist on their in vitro activities in infections with high bacterial inocula. We investigated the in vitro efficacies and the inoculum effects of ceftazidime-avibactam and aztreonam-avibactam against extended-spectrum β-lactam-resistant Enterobacterales blood isolates. A total of 228 non-repetitive extended-spectrum β-lactam-resistant Escherichia coli and Klebsiella pneumoniae blood isolates were prospectively collected in a tertiary center. In vitro susceptibilities to ceftazidime, aztreonam, meropenem, ceftazidime-avibactam, and aztreonam-avibactam were evaluated by broth microdilution method using standard and high inocula. An inoculum effect was defined as an eightfold or greater increase in MIC when tested with the high inoculum. Of the 228 isolates, 99% were susceptible to ceftazidime-avibactam and 99% had low aztreonam-avibactam MICs (≤8 mg/L). Ceftazidime-avibactam and aztreonam-avibactam exhibited good in vitro activities; MIC₅₀/MIC₉₀ values were 0.5/2 mg/L, 0.125/0.5 mg/L, and ≤0.03/0.25 mg/L, respectively, and aztreonam-avibactam was more active than ceftazidime-avibactam. The frequencies of the inoculum effect with ceftazidime-avibactam and aztreonam-avibactam were lower than with meropenem (14% vs. 38%, p < 0.001 and 30% vs. 38%, p = 0.03, respectively). The β-lactam-avibactam combinations could be useful as carbapenem-sparing strategies, and aztreonam-avibactam has the better in vitro activity but is more subject to the inoculum effect than ceftazidime-avibactam.

SUBMITTER: Bae M

PROVIDER: S-EPMC8698305 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The activities of ceftazidime-avibactam, ceftolozane-tazobactam, and comparators were evaluated for 733 isolates displaying resistance to broad-spectrum cephalosporins and carrying extended-spectrum β-lactamase (ESBL) genes detected by whole-genome sequencing analysis. Isolates were collected during 2017 in U.S. hospitals. The ESBL producers were 486 Escherichia coli, 190 Klebsiella pneumoniae, and 42 Enterobacter cloacae isolates and isolates from 3 other species. The most common groups of ESBL-encoding genes were blaCTX-M-15-like (n = 491 isolates) and blaCTX-M-15 alone (n = 168) or plus blaOXA-1 (n = 260), followed by blaCTX-M-14-like (n = 162), which included blaCTX-M-27 and blaCTX-M-14 (104 and 51 isolates, respectively), and blaSHV-12 and blaSHV-7 (48 and 22 isolates, respectively). ESBL producers carried other β-lactamases, including 1 E. cloacae harboring blaKPC-3 All ESBL-producing isolates were susceptible to ceftazidime-avibactam, and 90.2/83.9% (CLSI/EUCAST breakpoints) were susceptible to ceftolozane-tazobactam. Tigecycline (98.1/95.8% susceptible) and colistin (99.2%) were comparators that displayed the greatest activity against these isolates. Ceftolozane-tazobactam inhibited 91.4/83.9% of isolates carrying blaCTX-M-15-like and 97.5/95.1% of isolates carrying blaCTX-M-14-like, and its activity was more limited against the 91 isolates carrying blaSHV (66.7/61.1% susceptible). Ceftolozane-tazobactam inhibited 95.5% of the E. coli isolates but only 83.0%, 64.3%, and 80.0% of K. pneumoniae, E. cloacae, and other species harboring ESBL-encoding genes (CLSI breakpoints), respectively. Outer membrane protein sequences for ceftolozane-tazobactam-nonsusceptible isolates did not exhibit significant differences compared to those in genetically related ceftolozane-tazobactam-susceptible isolates. Ceftazidime-avibactam was more active than other agents tested, including ceftolozane-tazobactam, and the activity of this combination was stable regardless of species or ESBL gene carried.

Project description:Aztreonam-avibactam, eravacycline, and cefoselis are three novel antimicrobial agents for the treatment of serious infections caused by Gram-negative bacteria. We evaluated the in vitro activities of the above-mentioned three antimicrobial agents against clinical Enterobacterales isolates. A total of 1,202 Enterobacterales isolates, including 10 genera or species, were collected from 26 hospitals that cover seven regions of China. The susceptibilities of the 30 antimicrobial agents were interpreted based on the combination of U.S. Food and Drug Administration and Clinical and Laboratory Standards Institute guidelines. The results indicated that all Enterobacterales isolates showed high susceptibility to aztreonam-avibactam (98.25%), eravacycline (85.69%), and cefoselis (62.73%). The first two antimicrobial agents also demonstrated potent activities against multidrug-resistant and carbapenem-resistant Enterobacterales independent of antimicrobial resistance mechanisms. The rates of susceptibility to aztreonam-avibactam, eravacycline, and cefoselis were lowest in Morganella spp. (84.42%), Proteus spp. (33.65%), and Escherichia coli (40.14%), respectively. In general, the lower rates of susceptibility to eravacycline and cefoselis were in the older inpatient group. The strains isolated from urinary tract exhibited the lowest rate of susceptibility (78.97%) to eravacycline, and the lowest rate of susceptibility (45.83%) to cefoselis was observed in nervous system specimens. The strains isolated from intensive care unit (ICU) wards showed significantly reduced susceptibility to cefoselis compared with those isolated from non-ICU wards. The MIC values of aztreonam-avibactam and ceftazidime-avibactam have poor consistency (weighted kappa = 0.243), as did eravacycline and tigecycline (weighted kappa = 0.478). Cefoselis and cefepime showed highly similar activities against Enterobacterales (weighted kappa = 0.801). Our results support the clinical development of aztreonam-avibactam, eravacycline, and cefoselis to treat infections caused by Enterobacterales. IMPORTANCE Infections caused by multidrug-resistant (MDR) Enterobacterales, especially carbapenem-resistant Enterobacterales (CRE), have been a challenging clinical problem due to the limited therapeutic options. Therefore, the need to develop novel antimicrobial agents and evaluate their activities against Enterobacterales in vitro is urgent. Our results show that the novel antimicrobial agents aztreonam-avibactam and eravacycline retain activities against MDR and CRE isolates, including carbapenemase producers and non-carbapenemase producers. Further analysis combined with clinical information on the strains tested revealed that no significant differences were observed in susceptibility rates of strains with different demographic parameters to aztreonam-avibactam. Age, specimen source, and department were associated with the susceptibility of strains to eravacycline and cefoselis (P ≤ 0.01). Compared with ceftazidime-avibactam, aztreonam-avibactam has its advantages and limitations against Enterobacterales. The potent activity of eravacycline against Enterobacterales was higher than that of tigecycline. Cefoselis and cefepime showed a highly consistent activity against Enterobacterales.

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In Vitro Activities of Ceftazidime-Avibactam and Aztreonam-Avibactam at Different Inoculum Sizes of Extended-Spectrum β-Lactam-Resistant Enterobacterales Blood Isolates.

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