In vitro killing of parenteral beta-lactams against standard and high inocula of extended-spectrum beta-lactamase and non-ESBL producing Klebsiella pneumoniae

Minimum inhibitory concentrations and time-kill curves were performed against 8 Klebsiella pneumoniae (4 non-extended-spectrum beta-lactamase[ESBL] and 4 ESBL) for piperacillin/tazobactam (40/5 μg/mL), cefepime (20 μg/mL), and meropenem (4 μg/mL) by using a standard and high inocula. Imipenem was evaluated only at the standard inoculum for the non-ESBL and ESBL isolates. Samples were withdrawn at 7 predetermined time-points over 24 hours and plated on trypticase soy agar plates. Minimum inhibitory concentrations were: piperacillin/tazobactam 4 to 8 μg/mL (ESBL and non-ESBL), cefepime 1 to 2 μg/mL (ESBL) and 0.06 to 0.125 μg/mL (non-ESBL), imipenem 0.125 to 0.25 μg/mL (ESBL and non-ESBL), and meropenem 0.03 to 0.06 μg/mL (ESBL and non-ESBL). Each antibiotic reached and maintained bactericidal killing (≥3 log killing) for 24 hours against all non-ESBL isolates for both the standard and high inoculum. Cefepime, imipenem, and meropenem showed the same bactericidal activity against each ESBL isolate at the standard inoculum, whereas piperacillin/tazobactam showed bactericidal killing against only 1 ESBL isolate. At the high inoculum, cefepime and piperacillin/tazobactam were unable to maintain bactericidal activity against any of the ESBL isolates. Only meropenem was able to maintain bactericidal killing over 24 hours against the ESBL isolates at the high inoculum. In summary, meropenem and imipenem maintained bactericidal activity against non-ESBL and ESBL K. pneumoniae irrespective of the inoculum size. While piperacillin/tazobactam and cefepime are bactericidal against non-ESBL K. pneumoniae, their activity against ESBL K. pneumoniae is limited and based on the size of the inoculum. Until more data are available, piperacillin/tazobactam and cefepime should not be used for the treatment of ESBL K. pneumoniae.