In vitro activities of omadacycline, eravacycline, cefiderocol, apramycin, and comparator antibiotics against Acinetobacter baumannii causing bloodstream infections in Greece, 2020–2021: a multicenter study

Abstract

Resistance of Acinetobacter baumannii to multiple clinically important antimicrobials has increased to very high rates in Greece, rendering most of them obsolete. The aim of this study was to determine the molecular epidemiology and susceptibilities of A. baumannii isolates collected from different hospitals across Greece. Single-patient A. baumannii strains isolated from blood cultures (n = 271), from 19 hospitals, in a 6-month period (November 2020–April 2021) were subjected to minimum inhibitory concentration determination and molecular testing for carbapenemase, 16S rRNA methyltransferase and mcr gene detection and epidemiological evaluation. 98.9% of all isolates produced carbapenemase OXA-23. The vast majority (91.8%) of OXA-23 producers harbored the armA and were assigned mainly (94.3%) to sequence group G1, corresponding to IC II. Apramycin (EBL-1003) was the most active agent inhibiting 100% of the isolates at ≤16 mg/L, followed by cefiderocol which was active against at least 86% of them. Minocycline, colistin and ampicillin-sulbactam exhibited only sparse activity (S <19%), while eravacycline was 8- and 2-fold more active than minocycline and tigecycline respectively, by comparison of their MIC50/90 values. OXA-23-ArmA producing A. baumannii of international clone II appears to be the prevailing epidemiological type of this organism in Greece. Cefiderocol could provide a useful alternative for difficult to treat Gram-negative infections, while apramycin (EBL-1003), the structurally unique aminoglycoside currently in clinical development, may represent a highly promising agent against multi-drug resistant A. baumanni infections, due to its high susceptibility rates and low toxicity.

Apramycin efficacy in the treatment of carbapenem-resistantEnterobacteralesin murine blood stream infection models

“…The genotypic susceptibility to apramycin when screening the NDARO database with most bacteremia pathogens represented by E. coli and K. pneumoniae revealed an overwhelming coverage by apramycin in comparison to other aminoglycosides in clinical use including plazomicin. This in-silico finding is in agreement with recent reports on the in-vitro data for several hundred blood-culture isolates [25, 29], except that it derives its power from an unprecedented larger number of genomes from around the world [16]. The only apramycin resistance gene identified in the 15 380 Enterobacterales blood-culture isolates was aac(3)-IV , which is in support of earlier reports of this gene being the only resistance gene of clinical relevance to apramycin [30].…”

A Review of Omadacycline for Potential Utility in the Military Health System for the Treatment of Wound Infections

“…Omadacycline has in vitro activity against almost all the ESKAPEE pathogens, except for P. aeruginosa . 23 Importantly, it has activity against the four most prevalent bacterial pathogens that have caused wound infections in military healthcare system (MHS) patients in the most recent conflicts: S. aureus , including methicillin-resistant S. aureus (MRSA), 22 -- 27 A. baumannii , 25 , 28 , 29 K. pneumoniae , 22 , 30 , 31 and E. coli 22 , 31 , 32 ( Supplementary Table I ). Minimum inhibitory concentrations inhibiting 50% (MIC 50 ) and 90% (MIC 90 ) of isolates tested have been observed previously at 0.12 and 0.25 mg/L, respectively, against S. aureus (including MRSA).…”

In vitro activity of apramycin (EBL-1003) in combination with colistin, meropenem, minocycline or sulbactam against XDR/PDR Acinetobacter baumannii isolates from Greece

“… 27 In a recent study, conducted in Greece, the dissemination of XDR and PDR bla OXA-23 - armA -harbouring A. baumannii isolates, corresponding to international clone (IC) II (87.8%), was associated with a dramatic decrease of in vitro activity of colistin to only 15.5%, leaving minocycline as the most active agent, with 18.8% of the isolates exhibiting an MIC of ≤4 mg/L. 16 Interestingly, a promising in vitro activity was verified for apramycin (EBL-1003), which exhibited MIC 50 /MIC 90 of 4/8 mg/L and 100% susceptibility according to the preliminary ECOFF (16 mg/L) defined by Juhas et al for A. baumannii. 9 , 16 However, aminoglycoside monotherapy can lead to unfavourable clinical outcomes due to rapid emergence of resistance, while nephrotoxicity is a serious concern with prolonged use.…”

“…Strains used in this study were collected from among 271 A. baumannii blood isolates that were sent to our laboratory from 19 hospitals located in all seven Health Districts of Greece, from November 2020 to April 2021, during a multicentre surveillance study. 16 Identification and MIC determination were performed using the VITEK 2 system (bioMérieux, Marcy-l’Étoile, France). MICs of apramycin, colistin, meropenem, minocycline and sulbactam were determined by the BMD method and results were interpreted in accordance with EUCAST.…”

“…Detection of antimicrobial resistance genes encoding common class D carbapenemases ( bla OXA-51 -like, bla OXA-58 -like, bla OXA-23 -like, bla OXA-40 -like, bla OXA-143 -like and bla OXA-235 -like), class B MBLs ( bla IMP , bla VIM and bla NDM ), RMTase genes ( armA , rmtB and rmtC ), AME genes [ aph(3′)-VI , aac(6′)-Ib , aac(3′)-Ia , aac(3′)-IV and ant(2′)-Ia ] and plasmid-mediated colistin resistance genes were screened by multiplex or simplex PCR protocols as described previously. 16 …”