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Transcript of Are There Non-Carbapenem خ²-Lactam Options for Treating ... ... Cefepime: Inoculum Effect •...

  • Are There Non-Carbapenem β-Lactam Options for Treating ESBL Infections?

    Pranita D. Tamma, M.D., M.H.S.

    Assistant Professor, Pediatrics

    Director, Pediatric Antimicrobial Stewardship Program


  • Disclosures

    • I have received funding support from the following nonfederal organizations in the past 12 months:

    • Merck

    • Pfizer


  • Objectives

    • Discuss the role of carbapenems in the treatment of ESBL-producing infections

    • Discuss the role of the following agents in treating ESBL-producing infections

    • Cephamycins

    • Cefepime

    • Piperacillin/Tazobactam

    • Newer β-lactam/β-lactamase inhibitors


  • ESBLs…

    • Since their description in the 1980s, ESBL producing organisms have become recognized as a global threat

    • They have been detected worldwide in several gram- negative organisms, but are most prevalent among E. coli and Klebsiella spp.

    • These enzymes have undergone substantial biochemical alterations resulting in the ability to more efficiently hydrolyze β-lactam antibiotics

    Paterson, et al. Antimicrob Agents Chemother 2003;47:3554. Villegas, et al. PLOS One 2016;

    11:e0154092. Bush. Antimicrob Agents Chemother 2015; 59:3606.CIDEIM

  • Role of Carbapenems

    • Carbapenems are considered the traditional gold standard agents against ESBL infections, even when in vitro activity to other β-lactams is demonstrated

    • Carbapenems are stable to ESBL hydrolytic activity and numerous publications demonstrate their efficacy

    • Carbapenem overutilization stimulates resistance pathways including porin mutations and the selection of carbapenemases

    • Whenever possible, efforts should be made to limit the use of carbapenems


  • Drug Wild type

    AmpC ESBL KPC NDM OXA-48-like

    Ampicillin R1 R R R R R Piperacillin- tazobactam

    S S/R S/R R R R

    Cefoxitin S R S R R R Ceftriaxone S R R R R S/R Cefepime S S S/R R R S/R

    Aztreonam S R R R S R Ertapenem S S S S/R S/R S/R

    Meropenem S S S S/R S/R S/R

    1The majority of K. pneumoniae isolates are resistant to ampicillin due to

    production of narrow-spectrum TEM of SHV β-lactamases

    Anticipated in vitro Susceptibility Pattern for Klebsiella pneumoniae


  • Are There Scenarios Where Non-Carbapenem β-lactams Can Be Considered for ESBL


    • What if non-carbapenem β- lactam MICs are low?

    • What if high-dose, frequent interval βL-βLIs or cefepime is administered?

    • What if extended-infusion non- carbapenem β-lactams are administered?

    • If carbapenem antibiotics are administered when the bacterial burden is highest, can therapy be transitioned to a non- carbapenem after a short period of time?

    • If a βL-βLI is administered, does the type of βLI matter?

    • Tazobactam vs. sulbactam vs. clavulanic acid vs. avibactam

    • Does it matter if the resistance mechanism is a blaTEM-type, blaCTX- M-type versus a blaSHV-type?

    • Does the genus and species of the ESBL-producer matter?

    • Does the source of infection and if source control measures were taken matter?

    • Should the severity of illness determine if a carbapenem or non-carbapenem is administered?


  • Cephamycins


  • Cephamycins • Consistent in vitro activity against ESBL-producing


    • Early concerns of development of cephamycin or carbapenem resistance during cephamycin therapy because of acquisition of outer membrane protein mutations and/or plasmids encoding AmpC β-lactamases during cephamycin exposure

    • Some in vitro data

    • Isolated clinical cases available

    • Unclear how frequently such mutations and gene acquisitions occur and what the predisposing host and environmental factors are

    • Very limited clinical data to support this theory

    • A number of cephamycins are currently available • Cefoxitin, cefotetan, cefmetazole, flomoxef, moxalactam

    Jacoby, et al. Antimicrob Agents Chemother 1990;34:858-62. Paterson & Bonomo, Clin Microbiol

    Rev 2005;18:657.CIDEIM

  • Study Bacteria Sources ICU Outcomes




    K. pneumoniae


    Site: Blood (100%)

    Sources: Pneumonia

    (56%), IAI (19%), urine

    (11%), SSTI 4%)

    ~50% Mortality at 14 days:

    29% cephamycins vs.

    25% carbapenems (ns)




    E. coli (95%), K.

    pneumoniae (5%)

    Site: Urine (100%)

  • My Thoughts on Cephamycins for the Treatment of ESBL Infections…

    • Unclear if similar outcomes between carbapenem

    and cephamycin groups are because of similar activity against

    ESBLs or inability to detect a difference if one exists because of

    small sample sizes & confounding by indication

    • Cephamycins may be useful agents in the treatment of

    nonsevere ESBL-producing infections from urinary

    sources • Recommended for the treatment of UTIs caused by ESBL-

    producing E. coli in the 2014 French guidelines

    • Given the limited data on non-urinary sources and severe

    infections, use of cephamycins for severe ESBL infections

    should be avoided until more data are available • Optimal administration strategy not defined


  • Cefepime


  • Cefepime

    • Enhanced stability compared with earlier cephalosporin generations against degradation by β-lactamases

    • The current EUCAST and CLSI susceptibility breakpoints for cefepime are 1 mcg/ml and 8 mcg/ml (accounting for drug dosing), respectively

    • The CLSI cefepime breakpoint may leave a substantial number of ESBLs in the susceptible range “hidden resistance”

    • A growing body of evidence is challenging the assumption that cefepime is efficacious for the treatment of ESBL producers

    • As a large proportion of microbiology laboratories don’t perform confirmatory ESBL testing, there is concern that critically-ill patients may receive cefepime based on misleading in vitro susceptibility reports


  • Cefepime: Inoculum Effect

    • Inoculum effect: Drug MICs increase dramatically in the presence of an increased bacterial load despite apparent initial susceptibility

    • Has been observed in both in vitro and animal studies with cefepime

    • Both low and high inoculum non-ESBL infections look like top figure for cefepime, PTZ, and meropenem

    • Contribution of this effect towards treatment failures not clear

    Thomson, et al. Antimicrob Agents Chemother 2001;45:3548. Bedenic, et al. Clin Microbiol Infec

    2011; 7:626. Szabo, et al. Antimicrob Agents Chemother 2001;45:1287. Rice, et al. Antimicrob

    Agents Chemother 1991;35:1243. Thauvin-Eliopoulos, et al. Antimicrob Agents Chemother 1997;

    41:1053. Jett, et al. Antimicrob Agents Chemother 1995; 39:1187. Burgess, et al. Diag Microbiol

    Infect Dis 2004; 49:41.

    Low inoculum ESBL

    High inoculum ESBL


  • Cefepime: Failure to Meet PK-PD Targets

    • Wide range of dosing regimens for cefepime, may dramatically alter exposure and outcomes associated with treatment

    • Cefepime MICs for ESBL- producers are often increased compared to non- ESBL producers

    • Relative contribution of ESBL production and organism MIC in determining cefepime activity remains controversial

    • Failures also seen with low MICs

    Nicasio, et al. Antimicrob Agents Chemother 2009; 53:1476. Andes, et al. Interscience Conference on

    Antimicrobial Agents and Chemotherapy, Abstract A-1099, 2001. Wang, et al. Open Forum Infect Dis


  • Study Bacteria Sources ICU Outcomes




    K. pneumoniae

    (96%), E.

    aerogenes (4%)

    Site: Pneumonia (100%) 100% Clinical response:

    69% cefepime

    versus 100%


    (p70% Mortality at 30

    days: 59%

    cefepime vs. 17%



  • My Thoughts on Cefepime for the Treatment of ESBL Infections…

    • Cefepime may be reasonable for non-severe infections

    where the agent can achieve high concentrations to

    ensure pharmacodynamic targets are met • MICs of ≤2 mcg/ml or urinary sources of infection

    • Would recommend every 8 hour dosing

    • Use of continuous infusion cefepime needs to be

    explored for higher cefepime MICs


  • Piperacillin-Tazobactam


  • Piperacillin-Tazobactam

    • Although ESBLs are generally inhibited by PTZ, some organisms produce several ESBLs simultaneously along with AmpCs, providing a complex background that may reduce its effectiveness

    • In vitro, animal data, and case reports suggest efficacy of PTZ reduced when a high inoculum of bacteria is present

    Thomson, et al. Antimicrob Agents Chemother 2001;45:3584. Lopez-Cer