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Cefpirome (HR 810): lack of selection of beta-lactamase overproducing variants
Abstract:
With respect to the selection of beta-lactam-resistant variants marked discrepancies between the recently developed cephalosporin HR 810 and other recently developed cephalosporins could be observed: beta-lactam resistant subpopulations did not emerge during a 16-hour culture in the presence of the 20-fold minimal inhibitory concentration in a clinical Enterobacter cloacae isolate (2240/81) in contrast to cefoperazone, cefotaxime, ceftriaxone and ceftazidime. Breakdown of the antibacterial agents during the 16-hour period as evaluated by monitoring their levels in the medium was not responsible for selection of beta-lactam-resistant subpopulations. The study of affinity of various cephalosporins to the chromosomally mediated beta-lactamase of E. cloacae strain 2240/81 revealed low affinity of HR 810 to the enzyme (Ki amounted 4.4 X 10(-3)M). It is suggested that the low affinity of this new agent to the E. cloacae enzyme plays a major role in the lack of selection of resistant subpopulations.
Insights
The new cephalosporin HR 810 did not select for beta-lactam-resistant bacteria in Enterobacter cloacae. This is likely due to its low affinity for the bacterial beta-lactamase enzyme.
Area of Science:
- Microbiology
- Pharmacology
- Biochemistry
Background:
- Beta-lactam antibiotics are crucial for treating bacterial infections.
- The emergence of beta-lactam resistance in bacteria like Enterobacter cloacae is a significant clinical concern.
- Understanding the mechanisms of resistance selection is vital for developing effective antimicrobial strategies.
Purpose of the Study:
- To investigate the potential of the novel cephalosporin HR 810 to select for beta-lactam-resistant subpopulations in Enterobacter cloacae.
- To compare the resistance selection potential of HR 810 with other established cephalosporins.
- To elucidate the role of bacterial beta-lactamase affinity in resistance selection.
Main Methods:
- Culturing a clinical Enterobacter cloacae isolate (2240/81) with a 20-fold minimal inhibitory concentration of various cephalosporins for 16 hours.
- Monitoring the levels of antibacterial agents in the culture medium to assess degradation.
- Determining the affinity of different cephalosporins to the chromosomally mediated beta-lactamase of E. cloacae using enzyme kinetics (Ki values).
Main Results:
- Beta-lactam resistant subpopulations did not emerge in E. cloacae when cultured with HR 810, unlike with cefoperazone, cefotaxime, ceftriaxone, and ceftazidime.
- Antibacterial agent breakdown in the medium did not account for the lack of resistance selection.
- HR 810 exhibited significantly low affinity (Ki = 4.4 x 10(-3)M) to the E. cloacae beta-lactamase.
Conclusions:
- The novel cephalosporin HR 810 demonstrates a reduced capacity to select for beta-lactam-resistant subpopulations in Enterobacter cloacae.
- The low affinity of HR 810 to the E. cloacae beta-lactamase is a key factor contributing to its inability to select for resistance.
- These findings suggest HR 810 may offer an advantage in clinical settings by potentially minimizing the development of antibiotic resistance.