Inoculum Effect on the Efficacies of Amoxicillin-Clavulanate, Piperacillin-Tazobactam, and Imipenem against Extended-Spectrum β-Lactamase (ESBL)-Producing and Non-ESBL-Producing Escherichia coli in an Experimental Murine Sepsis Model

Abstract

Escherichia coli is a common etiologic agent of intra-abdominal infections (IAI) (1) associated with a heavy bacterial burden (2) and of urinary tract infections and bacteremia (3-5), among others. The recommendations for empirical antimicrobial therapy for high-risk, severe, community-acquired, extrabiliary complicated IAI and health care-associated complicated IAI include piperacillin-tazobactam or carbapenems (6). Recently, data from an observational study suggested that amoxicillin-clavulanate and piperacillin-tazobactam are as effective as carbapenems in patients with bacteremia due to extended-spectrum ␤-lactamase (ESBL)-producing E. coli; however, most of the patients in that study had urinary or biliary tract infections and the number of patients with heavy bacterial loads was probably low (7). In this context, it is important to note that, in some areas, many ESBLproducing and non-ESBL-producing isolates of Klebsiella pneumoniae and E. coli are susceptible in vitro to piperacillin-tazobactam and imipenem, but the MICs may increase substantially if the susceptibility tests are performed with an inoculum concentration higher than the standard one (8-11). Recently, we have demonstrated, using a microdilution method and time-kill assays, that the reduction of in vitro activity at a high inoculum concentration does not occur with the amoxicillin-clavulanate combination against clinical non-ESBL-producing and ESBL-producing E. coli strains (9). Previously, when several Enterobacteriaceae species produced complex beta-lactamase patterns or ESBL (12, 13), both piperacillin-tazobactam and carbapenem compounds showed increased MICs when inoculum concentrations higher than the standard one are used. On the other hand, some authors have raised doubts about the existence of an inoculum effect (14), but in fact, little is known about the real in vivo impact of this effect. Thus, the objective of this study was to compare the in vivo efficacies of amoxicillin-clavulanate, piperacillin-tazobactam, and imipenem against different tissue bacterial concentrations of two clinical E. coli strains in an experimental murine sepsis model.

A Multinational, Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae

“…One issue of importance is whether PTZ and AMC are equally effective. As stated above, AMC does not suffer from inoculum effect (22) and showed better activity than PTZ in an experimental murine sepsis model caused by ESBL-producing E. coli (32). Subgroup analyses did not show differences when PTZ or AMC alone was compared to carbapenems.…”

Use of β-Lactam/β-Lactamase Inhibitors for Extended-Spectrum-β-Lactamase Infections: Defining the Right Patient Population

“…In the past, the inoculum effect observed in vitro (1,2), data from animal studies (3,4), coexpression of additional ␤-lactamases not effectively inhibited by ␤-lactamase inhibitors (␤LI) (5), and concerns regarding inadequate pharmacokinetic-pharmacodynamic drug target attainment with standard ␤-lactam (␤L)/␤LI dosing regimens (6, 7) have tempered the enthusiasm for prescribing these agents for the treatment of invasive ESBL infections. However, more recently, and in large part due to the multicenter efforts led by several Spanish investigators (8,9), such concerns have been largely alleviated.…”

The Resistant-Population Cutoff (RCOFF): a New Concept for Improved Characterization of Antimicrobial Susceptibility Patterns of Non-Wild-Type Bacterial Populations

“…In agreement with this observation, clinical guidelines recommend the use of carbapenems for treatment of serious infections due to ESBLpositive E. coli isolates (20,21). However, the emergence of strains resistant to carbapenems has triggered the search for alternative therapeutic options, such as beta-lactam-inhibitor combinations (22,23).…”