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

Abstract

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.

• Authors: Y Harada, Y Morinaga, N Kaku, S Nakamura, N Uno, H Hasegawa, K Izumikawa, S Kohno, K Yanagihara
• Journal: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases (Clin Microbiol Infect) Vol. 20 Issue 11 Pg. O831-9 (Nov 2014) ISSN: 1469-0691 [Electronic] England
• PMID: 24813594 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.

Chemical References

• Anti-Bacterial Agents
• Thienamycins
• Piperacillin, Tazobactam Drug Combination
• Penicillanic Acid
• Meropenem
• Piperacillin

Topics

• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Bacterial Load
• Disease Models, Animal
• Klebsiella Infections (drug therapy)
• Klebsiella pneumoniae (drug effects)
• Lung (microbiology)
• Male
• Meropenem
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• Penicillanic Acid (analogs & derivatives, pharmacology, therapeutic use)
• Piperacillin (pharmacology, therapeutic use)
• Piperacillin, Tazobactam Drug Combination
• Pneumonia, Bacterial (drug therapy)
• Survival Analysis
• Thienamycins (pharmacology, therapeutic use)