In Vitro Activity of Aztreonam-Avibactam against Enterobacteriaceae and Pseudomonas aeruginosa Isolated by Clinical Laboratories in 40 Countries from 2012 to 2015

Abstract

The combination of the monobactam aztreonam and the non-␤-lactam ␤-lactamase inhibitor avibactam is currently in clinical development for the treatment of serious infections caused by metallo-␤-lactamase (MBL)-producing Enterobacteriaceae, a difficult-to-treat subtype of carbapenem-resistant Enterobacteriaceae for which therapeutic options are currently very limited. The present study tested clinically significant isolates of Enterobacteriaceae (n ϭ 51,352) and Pseudomonas aeruginosa (n ϭ 11,842) collected from hospitalized patients in 208 medical center laboratories from 40 countries from 2012 to 2015 for in vitro susceptibility to aztreonam-avibactam, aztreonam, and comparator antimicrobial agents using a standard broth microdilution methodology. Avibactam was tested at a fixed concentration of 4 g/ml in combination with 2-fold dilutions of aztreonam. The MIC 90 s of aztreonam-avibactam and aztreonam were 0.12 and 64 g/ml, respectively, for all Enterobacteriaceae isolates; Ͼ99.9% of all isolates and 99.8% of meropenemnonsusceptible isolates (n ϭ 1,498) were inhibited by aztreonam-avibactam at a concentration of Յ8 g/ml. PCR and DNA sequencing identified 267 Enterobacteriaceae isolates positive for MBL genes (NDM, VIM, IMP); all Enterobacteriaceae carrying MBLs demonstrated aztreonam-avibactam MICs of Յ8 g/ml and a MIC 90 of 1 g/ml. Against all P. aeruginosa isolates tested, the MIC 90 of both aztreonam-avibactam and aztreonam was 32 g/ml; against MBL-positive P. aeruginosa isolates (n ϭ 452), MIC 90 values for aztreonam-avibactam and aztreonam were 32 and 64 g/ml, respectively. The current study demonstrated that aztreonam-avibactam possesses potent in vitro activity against a recent, sizeable global collection of Enterobacteriaceae clinical isolates, including isolates that were meropenem nonsusceptible, and against MBL-positive isolates of Enterobacteriaceae, for which there are few treatment options.

NDM Metallo-β-Lactamases and Their Bacterial Producers in Health Care Settings

“…The combination of avibactam with aztreonam can protect the latter from the hydrolysis of ESBLs and AmpC and therefore can expand the spectrum of aztreonam. The combi-nation of aztreonam and avibactam has demonstrated potent in vitro activity against NDM-positive ESBL-producing Enterobacteriaceae (246). Aztreonam-avibactam is currently in clinical development and is not available for clinical use.…”

Transplant tourism complicated by life-threatening New Delhi metallo-β-lactamase-1 infection

“…The use of the beta-lactamase inhibitor avibactam enables aztreonam to remain stable against inactivation despite in vitro resistance to both aztreonam and avibactam individually. Resistance to this combination appears to be rare, 8 but confirmation of activity in vitro should be determined. There is limited clinical experience with this treatment modality, and even less in transplant recipients.…”

“…Resistance to this combination appears to be rare, 8 but confirmation of activity in vitro should be determined. There is limited clinical experience with this treatment modality and even less in transplant recipients.…”

“…6–8 Susceptibility testing of the E. cloacae isolate to aztreonam-avibactam was performed by agar dilution consistent with CLSI M100 (27 th Ed) and M07 (10 th Ed) guidelines using a 4 μg/ml fixed avibactam concentration. While the isolate was resistant to aztreonam (MIC 128 μg/ml) and ceftazidime-avibactam (>256 μg/ml) by E-test, the aztreonam-avibactam agar dilution MIC was 0.25 μg/ml.…”

Carbapenem-resistant Enterobacteriaceae: recent updates and treatment strategies

“…Aztreonam-avibactam은 ceftazidime-avabactam과는 다르게 NDM 등 metallo-β-lactamases 분해효소를 가지고 있는 균에 효과가 있다 [33]. 그 외 IMP, VIM 분해효소에도 효과가 있다는 보고가 있다 [30].…”