Search

Background: The combination aztreonam/avibactam is currently under Phase 3 trials for the treatment of serious infections caused by Gram-negative bacteria including those with MBLs.Objectives: To investigate the resistance mechanisms in Enterobacterales exhibiting aztreonam/avibactam MICs of ≥4 mg/L.Methods: Among 8787 Enterobacterales, 17 (0.2%) isolates exhibited an aztreonam/avibactam MIC of ≥4 mg/L. Isolates were sequenced and screened for β-lactamases. Sequences of porins, penicillin-binding protein 3 (PBP3) and expression levels of AmpC and AcrA were evaluated.Results: Eleven (11/4154 isolates; 0.26%) Escherichia coli, three (3/1981; 0.15%) Klebsiella pneumoniae and three (3/628; 0.5%) Enterobacter cloacae were identified. All E. coli showed either an 'YRIK' or 'YRIN' insertion in PBP3. In general, these isolates carried blaCMY and/or blaCTX-M variants, except for one isolate from Korea that also produced NDM-5 and one isolate from Turkey that produced OXA-48. Two DHA-1-producing K. pneumoniae overexpressed acrA and had a premature stop codon in either OmpK35 or OmpK36, whereas a third K. pneumoniae carried blaPER-2 and had a premature stop codon in OmpK35. All three E. cloacae expressed AmpC at levels ≥570-fold, but sequence analysis did not reveal known amino acid alterations associated with decreased avibactam binding or increased hydrolysis of β-lactams. Minor amino acid polymorphisms within OmpC, OmpF and PBP3 were noted among the E. cloacae.Conclusions: A small number of isolates (0.2%) met the inclusion criteria. E. coli showed altered PBP3 as the most relevant resistance mechanism, whereas K. pneumoniae had multiple resistance mechanisms. Further investigations are needed to clarify resistance in E. cloacae. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the in vitro activity of oritavancin and other lipoglycopeptides against vancomycin-susceptible and -resistant Enterococcus faecalis.

The article presents a study that compares the in vitro activity of oritavancin against Staphylococcus aureus strains. The isolates include vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-resistant S. aureus, and heteroresistant VISA which are compared with in vitro activity of oritavancin using broth microdilution methodology. Based on the in vitro data, the authors highlighted the potential of oritavancin as a candidate in the treatment of infections caused by S. aureus strains challenged by vancomycin therapy.

Objectives Oritavancin, a lipoglycopeptide, possesses bactericidal activity against Gram-positive bacteria including vancomycin-resistant Staphylococcus aureus and enterococci. To understand the time dependence of oritavancin activity, we have undertaken time–kill experiments against isolates of S. aureus, Enterococcus faecalis and Enterococcus faecium, including recent antibiotic-resistant strains. Methods Six strains of S. aureus [methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA)] and five strains of enterococci [vancomycin-susceptible enterococci (VSE) and vancomycin-resistant enterococci (VRE; both VanA and VanB)] were tested in time–kill assays; oritavancin assays included 0.002% polysorbate-80 to ensure quantitative drug recovery. Oritavancin and comparators vancomycin, teicoplanin, linezolid and daptomycin were tested at static concentrations approximating their free peak (fCmax) and free trough (fCmin) in plasma when administered at standard doses for complicated skin and skin structure infections. Results Oritavancin showed concentration-dependent killing of all strains tested: at its fCmax predicted from a 200 mg dose in humans, oritavancin exerted bactericidal activity (≥3 log kill relative to starting inoculum) against MSSA, MRSA and VRSA within 1 h and against VSE between 11 and 24 h. At predicted fCmax from an 800 mg dose, oritavancin was bactericidal against VISA strains at 24 h and against VRE at 10 h. Conclusions Oritavancin displayed concentration-dependent killing of MSSA, MRSA, VRSA, VISA, VSE and VRE. Oritavancin was more rapidly bactericidal against all strains tested than were vancomycin, teicoplanin, linezolid or daptomycin at physiologically relevant concentrations. These data support the conclusion that oritavancin exerts concentration-dependent bactericidal activity on recent, drug-resistant isolates of S. aureus and enterococci. [ABSTRACT FROM AUTHOR]