Comparative bactericidal activity of representative β-lactams against Enterobacterales, Acinetobacter baumannii and Pseudomonas aeruginosa

Abstract

Background There is surprisingly little comparative published data on the bactericidal action of different sub-classes of β-lactams against aerobic Gram-negative rods, and the assumption is that all behave in the same way. Objectives To describe a systematic investigation of a representative penicillin, cephalosporin, monobactam and carbapenem against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. Methods Concentration-time-kill curves (TKC) were determined for three strains each of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. All strains were susceptible to the agents used. The antibiotics were piperacillin/tazobactam, ceftazidime, aztreonam and meropenem. The initial inoculum was 106 cfu/mL and TKC were determined over 48 h. The area-under-the-bacterial-kill curve to 24 h (AUBKC 24 log cfu·h/mL) and 48 h (AUBKC 48) were used to measure antibacterial effect (ABE). Population profiles before and after antibiotic exposure were recorded. Results Against E. coli and K. pneumoniae meropenem had a maximal ABE at ≥MIC × 1 concentrations while piperacillin/tazobactam and ceftazidime had maximal effect at ≥MIC × 4 and aztreonam at ≥MIC × 8 concentrations. Ceftazidime, aztreonam and meropenem had less ABE against K. pneumoniae than E. coli. Against P. aeruginosa, meropenem was most bactericidal, with a maximum ABE at 8×/16 × MIC. Other β-lactams had notably less ABE. In contrast, against A. baumannii, ceftazidime and meropenem had the greatest ABE, with a maximal effect at ≥MIC × 4, concentration changes in population profiles were least apparent with E. coli. Conclusions β-Lactam sub-classes (penicillins, cephalosporins, monobactams and carbapenems) have different antibacterial effects against E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. Extrapolation of in vitro pharmacodynamic findings from one species to another or one sub-class of β-lactam to another is not justified.

Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs

“…Since PBP3 is the common direct target of monobactams 5 , to understand its interaction mode with 33a , we for the first time prepared a truncated PBP3 transpeptidase domain of K. pneumoniae (KnPBP3TP) construct and obtained its cocrystal with 33a (PDB ID: 8GPW) in dimer mode with the resolution of 2.06 Å, based on the high sequence homology between E. coli PBP3 and KnPBP3 genome (Supporting Information Fig. S3 and Table S3 ) 24 .…”

“…1 ), the only marketed monobactam antibiotic, interferes with bacterial cell-wall biosynthesis by targeting penicillin-binding protein 3 (PBP3), the common target of most penicillins and cephalosporins 5 . It is also stable to hydrolysis by metallo- β -lactamase (NDM-1), and has become an attractive lead for developing candidates against MDR Gram-negative strains in the last decades 5 . Our recent derivations 2 and 3 ( Fig.…”

Development of antibacterial drug plus bacteriophage combination assays

“…However, it is also important to note the validation work in this study was primarily for the laboratory techniques used rather than to evaluate the probable clinical value of using single or multiple phage strains in combination with antimicrobials. Most anti-bacterial and phage combination assessment is based on antibacterial synergy combination methods resulting in FIC calculations (8,9) which may be helpful in highly specific strain interactions, but this does have limitations in terms of screening purposes and also provides poorly translatable information. Pharmacodynamic thinking related to antibacterial combinations would indicate that total antibacterial activity is more important than arbitrary definitions of synergy or antagonism in providing useful translational information (10).…”

“…Phage PFU was assessed via plaque assay. Area under the bacterial kill curves were calculated as outlined in Noel et al (8).…”