In vitro and in vivo activities of piperacillin-tazobactam and meropenem at different inoculum sizes of ESBL-producing Klebsiella pneumoniae

• Published in: Clinical microbiology and infection Vol. 20; no. 11; pp. O831 - O839
• Main Authors: Harada, Y., Morinaga, Y., Kaku, N., Nakamura, S., Uno, N., Hasegawa, H., Izumikawa, K., Kohno, S., Yanagihara, K.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-11-2014; Elsevier Limited
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Bacterial Load; Disease Models, Animal; Extended-spectrum β-lactamase; inoculum effect; Klebsiella Infections - drug therapy; Klebsiella pneumoniae; Klebsiella pneumoniae - drug effects; Lung - microbiology; Male; meropenem; Mice, Inbred BALB C; Microbial Sensitivity Tests; Penicillanic Acid - analogs & derivatives; Penicillanic Acid - pharmacology; Penicillanic Acid - therapeutic use; Piperacillin - pharmacology; Piperacillin - therapeutic use; piperacillin-tazobactam; pneumonia; Pneumonia, Bacterial - drug therapy; Survival Analysis; Thienamycins - pharmacology; Thienamycins - therapeutic use; meropenem; pneumonia; inoculum effect; Extended-spectrum β-lactamase; Klebsiella pneumoniae; piperacillin-tazobactam
• ISSN: 1198-743X; 1469-0691
• DOI: 10.1111/1469-0691.12677

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 (105 CFU/mL) and high (107 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 (104 CFU/mouse) and high (106 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.