Effect of clavulanic acid on the activity of ticarcillin against Pseudomonas aeruginosa

Abstract

We studied the ability of clavulanic acid (CA) to induce beta-lactamase in Pseudomonas aeruginosa isolates and what effect this might have on the susceptibilities to beta-lactam agents. We first used a disk approximation method to test 4 laboratory and 16 clinical P. aeruginosa isolates against antipseudomonal beta-lactam agents for truncation by CA and found this to be very common. All antimicrobial compounds except imipenem demonstrated truncation in the vicinity of CA. We also evaluated the extent to which chromosomal beta-lactamase is induced by CA and found this to occur to some degree in most isolates and to be dependent on the concentration of CA. Finally, we performed time kill curves on these isolates to compare bacterial growth in ticarcillin alone with growth in ticarcillin-CA (the CA at 2 or 4 micrograms/ml). We found that CA at this concentration has neither an antagonistic nor a synergistic antibacterial effect in combination with ticarcillin.

Influence of beta-lactamase inhibitors on the potency of their companion drug with organisms possessing class I enzymes

“…In the current study, the in vitro inducer activity of clavulanate and sulbactam for organisms possessing class I enzymes was demonstrated, confirming results of previous studies (4,11,12,16,(18)(19)(20). This induction was strain and concentration dependent and occurred to a greater extent with clavulanate.…”

“…shown that clavulanate and sulbactam can cause the induction of class I 13-lactamase (4,11,12,16,(18)(19)(20). In vitro antagonism has been demonstrated for most combinations of broad-spectrum ,B-lactams (including ticarcillin and cefoperazone) and clavulanate for organisms possessing class I enzymes (4,10,19).…”

“…In vitro antagonism has been demonstrated for most combinations of broad-spectrum ,B-lactams (including ticarcillin and cefoperazone) and clavulanate for organisms possessing class I enzymes (4,10,19). Although Rolinson (15) suggests that the potential for antagonism is minimal with ticarcillin-clavulanate treatment of these organisms, to date the potential for in vivo antagonism with ,-lactam-,-lactamase inhibitor combinations has not been assessed systematically.…”

“…None of these positive or negative in vivo effects were predicted by in vitro tests. These data suggest that P-lactamase inhibitors can influence the in vivo potency of their companion drug in both a beneficial and detrimental fashion against organisms with class I P-lactamases and that these effects cannot be predicted from in vitro assays.Previous studies have shown that B-lactamase inhibitors are in vitro inducers of chromosomal, class I P-lactamases in certain strains of the family Enterobacteriaceae and Pseudomonas aeruginosa (4,11,12,16,(18)(19)(20). Quantitatively, clavulanate induces higher levels of ,-lactamase than does sulbactam, although induction with these compounds is usually manifest only at high, clinically unachievable concentrations (6,12,(18)(19)(20).…”

“…Quantitatively, clavulanate induces higher levels of ,-lactamase than does sulbactam, although induction with these compounds is usually manifest only at high, clinically unachievable concentrations (6,12,(18)(19)(20). The in vivo effects of these compounds against organisms possessing class I enzymes are unknown.…”