Beta-lactamase induction antagonizes beta-lactam susceptibilities in Citrobacter diversus and Enterobacter cloacae clinical isolates.

Inducible beta-lactamases were obtained after exposure to several beta-lactams in clinical isolates of Enterobacter cloacae and Citrobacter diversus. Enzyme production was related to the inducer and medium composition. beta-lactamase is able to inactivate only labile compounds, thus generating minimum inhibitory concentrations higher than in the absence of the inducer; imipenem susceptibilities usually were not changed.

Overview of synergy with reference to double beta-lactam combinations.

Combination antimicrobial therapy is used to expand the bacterial coverage over a single agent, to prevent the emergence of resistant organisms, to decrease toxicity by allowing lower doses of both agents, or for synergy. Synergy is one of the most common of these reasons, especially in serious infections. The introduction of new broad-spectrum beta-lactam antimicrobials has led to their combination in the treatment of seriously ill patients. Whereas a combination of an aminoglycoside and a beta-lactam antimicrobial is frequently synergistic, much less is known about synergy between combinations of beta-lactams. In vitro testing shows most combinations of two beta-lactams to be indifferent or additive in their effects; rarely does synergy occur. Antagonism can sometimes be seen, particularly with combinations involving cefoxitin or imipenem, especially if the treated organism is Enterobacter or Pseudomonas. Results of clinical trials comparing double beta-lactam (DBL) therapy with aminoglycoside/beta-lactam combinations show no difference in clinical response rates. Highly active DBL combinations may substitute for standard aminoglycoside-containing regimens in certain situations, even though they are not reliably synergistic. However, in the treatment of seriously ill patients such combinations may be less desirable.

Characterization of beta-lactamases in Mycobacterium fortuitum including a role in beta-lactam resistance and evidence of partial inducibility.

The beta-lactamases from the 3 biovariants of M. fortuitum were compared on the basis of substrate profiles, susceptibility to enzyme inhibitors, and inducibility in the presence of selected beta-lactams. Despite differences in the distribution of beta-lactamase bands observed when enzymes from different isolates were subjected to isoelectric focusing, substrate profiles for the 3 biovariants were similar. All demonstrated a comparable broad spectrum hydrolytic activity for both cephalosporins and penicillins. The MIC for amoxicillin were reduced 4- to 16-fold when combined with the beta-lactamase inhibitor clavulanic acid, but not to a clinically susceptible range. The degree of reduction in MIC for amoxicillin correlated well with the susceptibility of enzyme to inhibition by clavulanic acid as determined in an in vitro assay. Although all M. fortuitum strains produce beta-lactamase under routine growth conditions, 90% of strains demonstrated an increase in the amount of this enzyme when cultured in the presence of selected beta-lactams as potential inducers. Quantitative assays and isoelectric focusing further indicated that this apparent induction of beta-lactamase is a simple enhancement of the same enzyme(s) produced in the absence of a known inducer. This is the first demonstration of any inducibility among mycobacterial beta-lactamases and suggests that synthesis of these enzymes in M. fortuitum is under some form of regulatory control. These results indicate that the beta-lactamases have a role in resistance of M. fortuitum to the beta-lactams. Other factors, such as permeability and penicillin-binding proteins, were not evaluated.