B-lactam/B-lactamase Inhibitors for Treatment of Bacteremia due to ESBL-producing E.coli

Abstract & Commentary

By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine. Dr. Winslow is a speaker for Cubist Pharmaceuticals and GSK, and is a consultant for Siemens Diagnostics.

This article originally appeared in the January 2012 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, FIDSA, and peer reviewed by Timothy Jenkins, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University, and Dr. Jenkins is Assistant Professor of Medicine, University of Colorado, Denver Health Medical Center. Dr. Deresinski does research for the National Institutes of Health, and is an advisory board member and consultant for Merck, and Dr. Jenkins reports no financial relationships relevant to this field of study.

Synopsis: A post hoc analysis of patients with bacteremia due to ESBL-producing E.coli (ESBL-EC) from 6 published cohorts was performed. Treatment with B-lactam/B-lactamase inhibitors (BLBI) vs. carbapenems did not show any difference in mortality or length of hospital stay.

Source: Rodriguez-Bano, J, et al. B-lactam/B-lactamase inhibitor combinations for the treatment of bacteremia due extended-spectrum B-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis 2011; epub ahead of print, Nov 4, 2011.

A post hoc analysis was performed on patients with ESBL-EC bloodstream infections from 6 published prospective cohorts. Mortality and length of hospital stay in patients treated with BLBLI (amoxicillin-clavulanic acid or piperacillin-tazobactam) vs. carbapenem were compared in 2 cohorts: empirical therapy (ETC) and definitive therapy (DTC). Multivariate analysis was used to minimize confounding.

ETC included 103 patients (72 BLBLI, 31 carbapenem) and DTC included 174 patients (54 BLBLI, carbapenem 120). In the ETC, day 30 mortality rate was 9.7% for patients treated with BLBI and 19.4% for carbapenems. In the DTC, day 30 mortality rate was 9.3% in BLBI-treated patients and 16.7% for carbapenem-treated patients. After adjustment for confounders, no association between mortality nor hospital length of stay was seen for BLBI vs. carbapenem therapy in either empiric or definitive therapy of bacteremia due ESBL-EC.


ESBL-producing gram negative bacteria have emerged as a cause of serious infections over the last 30 years. These Ambler Class A B-lactamases are generally identified in vitro by resistance to first, second, many third generation cepalasporins, and often resistance to fourth generation cephalosporins, however they remain susceptible in vitro to BLBLI and carbapenems. Reluctance to use BLBLI to treat ESBL-EC infections is due to the fact that routine in vitro antibacterial susceptibility testing is performed with a fairly low standardized inoculum of 10e5 cfu/mL. It has been shown that the MIC's of ESBL-producing organisms often increase significantly when the inocula reach 10e7 cfu/mL or greater, as would be expected in some infected tissues in vivo. This effect is thought to be due to the overproduction of B-lactamase "overwhelming" the B-lactamase inhibitor. Due to this theoretical concern, it has largely been dogma that BLBLIs should not be used for treatment of life-threatening infections due to ESBL-expressing bacteria, and rather that carbapenems (which are resistant to hydrolysis by ESBL) should be used.

Unfortunately, carbapenem resistance has been increasing dramatically over the past few years and can be due to a variety of mechanisms including hydrolysis by carbapenemases from Ambler classes A, B, and D B-lactamases. The Ambler class B enzyme (metallo-B-lactamase), NDM-1, has now been recognized on most continents and is of great concern. This paper suggests that treatment of ESBL-EC infections with BLBLI may be effective in many circumstances. Certainly the results of this post hoc analysis suggest that BLBLI should be compared to carbapenem therapy of ESBL-expressing bacterial infections in a prospective randomized clinical trial.