Synergic post-antibiotic effect of mecillinam, in combination with other beta-lactam antibiotics in relation to morphology and initial killing.
The synergic in-vitro post-antibiotic effect (PAE) of mecillinam, in combination with either ampicillin, aztreonam, ceftazidime or piperacillin, on a reference strain of Escherichia coli was evaluated by bioluminescence assay of bacterial ATP. Ampicillin, ceftazidime and mecillinam alone induced a concentration dependent PAE (greater than 3 h) on E. coli, whereas aztreonam and piperacillin alone induced a short (less than 1 h) non-dose dependent PAE. At most concentrations, the combination of mecillinam and ampicillin, aztreonam, ceftazidime or piperacillin induced longer PAEs on E. coli than the sum of the individual antibiotics' PAEs. Long PAEs were seen concomitantly with the presence of spheroplasts. In addition to the synergistic PAE, the decrease in colony counts and changes in ATP values after a 2 h exposure to mecillinam, in combination with the other beta-lactam antibiotics, were more prominent than the respective values after exposure to the individual antibiotics. The change in ATP was generally less pronounced than the decrease in colony counts. This could be due to lysis of spheroplasts on agar plates, leading to an over-estimation of the initial killing when assayed by viable counting. Mecillinam, which induced long PAEs on E. coli at almost all concentrations in this study, has a high affinity for penicillin binding protein 2 (PBP 2) and induced spheroplast formation at all concentrations. However, mechanisms other than the affinity for PBP 2 and spheroplast formation are involved in the PAE of beta-lactam antibiotics on Gram-negative bacteria; since the PAE was prolonged when mecillinam was combined with ampicillin, aztreonam, ceftazidime or piperacillin, which bind preferentially to PBP 1 and 3.
Hanberger
H
H
Department of Infectious Diseases, University Hospital, Linköping, Sweden.
Nilsson
L E
LE
Svensson
E
E
Maller
R
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D000560:Amdinocillin / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015169:Colony Count, Microbial; D003470:Culture Media; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects* / Q000648:ultrastructure; D008163:Luminescent Measurements; D008826:Microbial Sensitivity Tests
D000900:Anti-Bacterial Agents; D003470:Culture Media; D000255:Adenosine Triphosphate; D000560:Amdinocillin