The inoculum effect is a laboratory phenomenon in which the minimal inhibitory concentration (MIC) of an
antibiotic is increased when a large number of organisms are exposed. Due to the emergence of extended-spectrum β-lactamase-producing Klebsiella pneumoniae (ESBL-Kpn)
infections, the inoculum effect of ESBL-Kpn on β-
lactams was studied in vitro and in vivo using an experimental model of
pneumonia. The in vitro inoculum effect of 45 clinical ESBL-Kpn isolates on β-
lactams was evaluated at standard (10(5) CFU/mL) and high (10(7) CFU/mL) organism concentrations. The MIC50 of
piperacillin-tazobactam,
cefotaxime and
cefepime was increased eight-fold or more and that of
meropenem was increased two-fold. The in vivo inoculum effect was evaluated in an ESBL-Kpn
pneumonia mouse model treated with bacteriostatic effect-adjusted doses of
piperacillin-tazobactam (1000 mg/kg four times daily, %T>MIC; 32.60%) or
meropenem (100 mg/kg twice daily, %T>MIC; 28.65%) at low/standard (10(4) CFU/mouse) and high (10(6) CFU/mouse) inocula. In mice administered a low inoculum, no mice died
after treatment with
piperacillin-tazobactam or
meropenem, whereas all the control mice died. In contrast, in the high inoculum model, all mice in the
piperacillin-tazobactam-treated group died, whereas all
meropenem-treated mice survived and had a decreased bacterial load in the lungs and no invasion into the blood. In conclusion,
meropenem was more resistant to the inoculum effect of ESBL-Kpn than
piperacillin-tazobactam both in vitro and in vivo. In the management of severe
pneumonia caused by ESBL-Kpn,
carbapenems may be the drugs of choice to achieve a successful outcome.