Epidemiology of Bloodstream Infections Caused by Escherichia coli and Klebsiella pneumoniae That Are Piperacillin-Tazobactam-Nonsusceptible but Ceftriaxone-Susceptible

Abstract

BackgroundPiperacillin-tazobactam-nonsusceptible (TZP-NS) Enterobacteriaceae are typically also resistant to ceftriaxone. We recently encountered bacteremias due to Escherichia coli (Ec) and Klebsiella pneumoniae (Kp) that were TZP-NS but ceftriaxone-susceptible (CRO-S).MethodsWe reviewed all Ec and Kp bacteremias from 2011 to 2015 at our center and assessed the prevalence, antimicrobial susceptibilities, genetic profiles, patient characteristics, treatments, and outcomes of TZP-NS/CRO-S infections. We identified risk factors for TZP-NS/CRO-S infections compared with Ec and Kp bacteremias that were TZP-S and CRO-S (Control Group 1) and compared outcomes of patients with TZP-NS/CRO-S bacteremias, Control Group 1, and patients bacteremic with extended-spectrum β-lactamase (ESBL)–producing Ec and Kp.ResultsThere were 1857 Ec and Kp bacteremia episodes, of which 78 (4.2%) were TZP-NS/CRO-S (Ec: 50/1227 [4.1%]; Kp: 28/630 [4.4%]). All TZP-NS/CRO-S isolates were also ampicillin-sulbactam-NS. Of 32 TZP-NS/CRO-S isolates that were sequenced, 28 (88%) harbored blaTEM-1 or blaSHV-1, none had an ESBL or AmpC β-lactamase gene, and many sequence types were represented. Independent risk factors for TZP-NS/CRO-S bacteremia were exposure to β-lactam/β-lactamase inhibitors (BL/BLIs; adjusted odds ratio [aOR], 5.5; P < .001) and cephalosporins (aOR, 3.0; P = .04). Thirty-day mortality after TZP-NS/CRO-S bacteremia was 25%, which was similar to control groups and was similar in patients treated empirically with BL/BLIs compared with those treated with cephalosporins or carbapenems. Targeted therapy with cephalosporins did not yield a higher 30-day mortality rate than carbapenem therapy.ConclusionsTZP-NS/CRO-S Ec and Kp are emerging causes of bacteremia, and further research is needed to better understand the epidemiology, resistance mechanisms, and clinical impact of these strains.

Piperacillin/tazobactam resistance in a clinical isolate of Escherichia coli due to IS26-mediated amplification of blaTEM-1B

“…Although, the exact mechanism of amplification/hyperproduction has remained elusive. Due to the emergence of a TZP-resistant but 3rd generation cephalosporins and carbapenems susceptible E. coli and K. pneumoniae phenotype 12 – 14 , as well as the increasing reliance on TZP as an empirical treatment 6 and the recent interest in the use of TZP as a carbapenem sparing treatment for extended-spectrum β-lactamase infections 33 , 34 , it is of growing importance to understand the mechanism of amplification. In this study we had the opportunity to compare a pair of clonal isolates which have evolved within a patient to become TZP-resistant but remain cephalosporin/carbapenem susceptible, allowing us to build on recent studies and identify the mechanism of IS 26 -mediated amplification of bla TEM-1B which leads to TZP-resistance.…”

“…A phenotype in Klebsiella pneumoniae and E. coli clinical isolates has emerged which has been classified as TZP-non-susceptible but susceptible to 3rd generation cephalosporins and carbapenems 12 – 14 , indicating a different resistance mechanism. While still relatively rare, one study in the United States found that the frequency of this phenotype was between 1.9 and 5.6% of E. coli and K. pneumoniae isolated from the bloodstream between 2011 and 2015, and specifically 4.1% of all E. coli over the study period 14 . The same study reported that risk factors associated with the TZP-non-susceptible but 3rd generation cephalosporin and carbapenem susceptible phenotype included exposure to β-lactam/β-lactamase inhibitors and cephalosporins within the previous 30 days 14 .…”

“…While still relatively rare, one study in the United States found that the frequency of this phenotype was between 1.9 and 5.6% of E. coli and K. pneumoniae isolated from the bloodstream between 2011 and 2015, and specifically 4.1% of all E. coli over the study period 14 . The same study reported that risk factors associated with the TZP-non-susceptible but 3rd generation cephalosporin and carbapenem susceptible phenotype included exposure to β-lactam/β-lactamase inhibitors and cephalosporins within the previous 30 days 14 . Resistance to TZP, but 3rd generation cephalosporin and carbapenem susceptible, has been linked to the presence of β-lactamases which hydrolyse piperacillin but not 3rd generation cephalosporins.…”

Fast-track identification of CTX-M-extended-spectrum-β-lactamase- and carbapenemase-producing Enterobacterales in bloodstream infections: implications on the likelihood of deduction of antibiotic susceptibility in emergency and internal medicine departments

“…Of note, among CTX-M-CA-np E. coli and K. pneumoniae , 10.1% ( n =15) that were classified as AmpC/ESBL-np showed in vitro TZP resistance and third-generation cephalosporin susceptibility. These strains were considered an emerging cause of BSI [ 25 ] and were the target of phenotypic and genotypic characterization [ 26 ] that did not fully elucidate the underlying resistance mechanism, even though they showed TZP activity on a murine model. Due to limited evidence on its generalizability to clinical practice, further studies are needed before considering TZP as a valid option against these strains in BSI patients.…”

Piperacillin/tazobactam resistant, cephalosporin susceptibleEscherichia colibloodstream infections are driven by multiple acquisition of resistance across diverse sequence types

“…Increasing the concentration of tazobactam alongside a fixed dose of piperacillin has also rescued TZP effectiveness against TEM-1 hyperproducers in a neutropenic mouse model (25), and could be a viable strategy to protect its future effectiveness. It is worth noting observational clinical data (51), and in vivo experimental data (52), suggesting TZP may be effective against some organisms with in vitro phenotypic resistance to TZP.…”