Comparative assessment of inoculum effects on the antimicrobial activity of amoxycillin-clavulanate and piperacillin-tazobactam with extended-spectrum β-lactamase-producing and extended-spectrum β-lactamase-non-producing Escherichia coli isolates.

Abstract

A significant inoculum-size effect has been observed with piperacillin-tazobactam, and has been associated with beta-lactamase production in extended-spectrum beta-lactamase (ESBL) producers. This association has not been previously studied in the case of amoxycillin-clavulanate. Piperacillin-tazobactam and amoxycillin-clavulanate were compared, using high inocula of susceptible strains either harbouring ESBLs or not. Two non-ESBL-producing and 15 amoxycillin-clavulanate-susceptible and piperacillin-tazobactam-susceptible ESBL-producing Escherichia coli isolates, and their respective transconjugants, were tested in dilution susceptibility tests using standard and 100-fold higher inocula. Three ESBL-producing strains and E. coli ATCC 25922 were selected for time-kill studies using standard and high initial inocula. At high inocula, MICs of piperacillin increased >eight-fold for non-ESBL-producing strains, and MICs of piperacillin-tazobactam (8:1 ratio or with tazobactam fixed at 4 mg/L) increased>eight-fold for all ESBL-producing strains. However, amoxycillin MICs were not affected by a high inoculum with non-ESBL-producing strains, whereas the MICs of amoxycillin-clavulanate (2:1 and 4:1) increased <or=four-fold for ESBL producers, using the broth and agar dilution methods. In kinetic studies at a high inoculum, amoxycillin and amoxycillin-clavulanate were bactericidal against E. coli ATCC 25922, whereas piperacillin and piperacillin-tazobactam yielded decreases of <1 log(10) CFU/mL. Similarly, at a high inoculum, only amoxycillin-clavulanate was able to maintain bactericidal rates of killing over 24 h against the ESBL-positive E. coli isolates. The stability of amoxycillin-clavulanate and the contrasting results obtained with piperacillin-tazobactam against high inocula of ESBL-non-producing and ESBL-producing E. coli strains appear to be related to aspects other than the amount of beta-lactamase production.

The Use of Noncarbapenem β-Lactams for the Treatment of Extended-Spectrum β-Lactamase Infections

“…Similar to cefepime, an "inoculum effect" has been proposed. This is supported by in vitro, animal data, and case reports [26,30,[44][45][46]. In the time-kill experiments by Burgess and colleagues described above, PTZ maintained >99% killing against high inoculum non-ESBL K. pneumoniae isolates over a 24-hour period, but this effect was nonsustainable against high-inoculum ESBL infections, where regrowth was observed at 8 hours [32].…”

A Multinational, Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae

“…One issue of importance is whether PTZ and AMC are equally effective. As stated above, AMC does not suffer from inoculum effect (22) and showed better activity than PTZ in an experimental murine sepsis model caused by ESBL-producing E. coli (32). Subgroup analyses did not show differences when PTZ or AMC alone was compared to carbapenems.…”

“…The reasons for raising doubts about the efficacy of BLBLIs in the treatment of severe infections caused by ESBL-E include the fol- lowing. First, the observation that PTZ (but not AMC) is less active in vitro when tested against a high inoculum of bacteria (22). However, such an effect also occurs in non-ESBL producers.…”

Diversity of Escherichia coli Strains Producing Extended-Spectrum β-Lactamases in Spain: Second Nationwide Study

“…Among the ␤-lactam/␤-lactamase inhibitor combinations, piperacillin-tazobactam continues to be the most active agent against this microorganism, probably due to the higher intrinsic activity of piperacillin compared to amoxicillin. The potential use of these combinations in infections caused by ESBLEC is still controversial (9).…”