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  • 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

    CIDEIM

    http://pathology.jhu.edu/pc/images/footerDome.jpg

  • Disclosures

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

    • Merck

    • Pfizer

    CIDEIM

  • 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

    CIDEIM

  • 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

    CIDEIM

  • Drug Wild type

    AmpC ESBL KPC NDM OXA-48-like

    Ampicillin R1 R R R R RPiperacillin-tazobactam

    S S/R S/R R R R

    Cefoxitin S R S R R RCeftriaxone S R R R R S/RCefepime S S S/R R R S/R

    Aztreonam S R R R S RErtapenem 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

    CIDEIM

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

    Infections?

    • 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?

    CIDEIM

  • Cephamycins

    CIDEIM

  • Cephamycins• Consistent in vitro activity against ESBL-producing

    Enterobacteriaceae

    • 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

    Lee

    2006

    n=27

    K. pneumoniae

    (100%)

    Site: Blood (100%)

    Sources: Pneumonia

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

    (11%), SSTI 4%)

    ~50% Mortality at 14 days:

    29% cephamycins vs.

    25% carbapenems (ns)

    Doi

    2013

    n=22

    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

    CIDEIM

  • Cefepime

    CIDEIM

  • 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

    CIDEIM

  • 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

    CIDEIM

  • 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

    2016;3:ofw132.CIDEIM

  • Study Bacteria Sources ICU Outcomes

    Zanetti

    2003*

    n=23

    K. pneumoniae

    (96%), E.

    aerogenes (4%)

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

    69% cefepime

    versus 100%

    carbapenems

    (p70% Mortality at 30

    days: 59%

    cefepime vs. 17%

    carbapenems

    (p

  • 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

    CIDEIM

  • Piperacillin-Tazobactam

    CIDEIM

  • 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-Cerero,

    et al. Clin Microbiol Infect 2010; 16:132. Rice, et al. Antimicrob Agents

    Chemother 1994; 38:2663. Thauven-Eliopolous, et al. Antimicrob Agents

    Chemother 1997; 41:1053. Zimhony, et al. Antimicrob Agents Chemother

    2006; 50:3179.CIDEIM

  • Study Bacteria Sources ICU Outcomes

    Kang

    2012

    n=114

    E. coli (68%), K.

    pneumoniae (32%)

    Site: Bloodstream (100%)

    Sources: Not described

    ~40% Mortality at 30 days:

    22% vs. 27% (ns)

    Rodriguez-

    Baño

    2012

    n=174

    E. coli (100%) Source: Urinary or bililary

    (70%)

    13% Mortality at 30 days:

    9% vs. 17% (ns)

    Harris

    2015

    n=47

    E. coli (86%)

    K. pneumoniae

    (14%)

    Sources: Urinary (47%),

    biliary (13%)

    12% Mortality at 30 days:

    8% vs. 17% (ns)

    Ofer-

    Friedman

    2015

    n=79

    E. coli (53%), K.

    pneumoniae (28%),

    P. mirabilis (19%)

    Sources: Pneumonia (34%),

    SSTI (28%), biliary (17%),

    IAI (9%)

    >50% Mortality at 30 days:

    60% vs. 34%

    (p=0.10)

    Mortality at 90

    days: 80% vs. 48%

    (p=0.03)

    Tamma

    2015

    n=213

    K. pneumoniae

    (68%), E. coli, (31%)

    Sources: Catheter (46%),

    urine (21%), IAI (17%) biliary

    (9%), pneumonia (9%)

    34% Mortality at 30 days:

    26% vs. 11%

    (p

  • Why the Conflicting Results?Studies in favor of PTZ(Rodriguez-Baño, Guittierez-

    Guittierez, Ng)

    Studies against PTZ

    (Ofer-Friedman & Tamma)

    Organisms

    included

    100% E. coli 53% E. coli

    73% E. coli 31% E. coli

    67% E. coli --

    Source of

    bacteremia

    30% high inoculum 83% high inoculum

    43% high inoculum 70% high inoculum

    18% high inoculum

    ICU

    admission

    13% >50%

    11% 34%

    9% --

    Median

    PTZ MIC

    2 mcg/ml 8 mcg/ml

    Not provided 8 mcg/ml

    Not provided --

    PTZ

    dosage

    4.5 grams q6h Not provided

    4.5 grams q6h 40% received 4.5 grams q6h

    4.5 grams q6h --

    CIDEIM

  • Objective To determine if PTZ results in equivalent outcomes as

    meropenem for ceftriaxone non-susceptible bacteremia

    Methods - Multicenter, randomized, open-label, non-inferiority trial

    - Meropenem (1 g q8h) vs. PTZ (4.5 g q6h)

    - Target enrollment is 454 patients

    - Estimated study completion date: December 2018

    - Clinicaltrials.gov: NCT02176122

    Meropenem vs. PTZ for Definitive Treatment of

    Bloodstream Infections Due to Ceftriaxone Non-

    Susceptible E. coli and Klebsiella spp. (MERINO trial)

    Harris, et al. Trials 2015; 16:24.CIDEIM

  • My Thoughts on βL-βLI for the Treatment of ESBL Infections…

    • Existing evidence indicates for low-moderate severity infections, urinary/biliary sources, or piperacillin MICs ≤4 mcg/ml, PTZ works as well as carbapenems

    • Consider 4.5 gram every 6 hour PTZ dosing

    • Or, 4.5 grams every 8 hours as extended infusion

    • For severely-ill patients (particularly if PTZ MICs >4 mcg/ml, non-urinary/biliary sources, or K. pneumoniaeinfections), may be reasonable to initially start with carbapenems

    CIDEIM

  • Ceftolozane-Tazobactam

    CIDEIM

  • Ceftolozane-Tazobactam: FDA Approved December 2014

    • FDA approved for the treatment of complicated urinary

    tract infections and complicated intra-abdominal

    infections for patients 18 years of age and older

    • Ceftolozane demonstrates good activity against

    Enterobacteriaceae

    • Similar to other oxymino-cephalosporins, its activity is

    limited against ESBLs

    • Tazobactam is a potent, irreversible inhibitor of most

    ESBLs

    Zhanel, et al. Drugs 2014;74:31. Craig, et al. Antimicrobial agents and chemotherapy 2013;57:1577.CIDEIM

  • Ceftolozane-Tazobactam: FDA Approved December 2014

    • Activity against ESBL E. coli is greater than against ESBL

    K. pneumoniae

    • MIC50/90 of this agent for ESBL-producing E. coli and K.

    pneumoniae are 0.5/4 and 4/>32 mcg/ml, respectively

    • blaCTX-M genes predominate in E. coli, whereas often a preponderance of blaTEM/SHV in K. pneumoniae, with variations in local epidemiology

    • Compared to meropenem for cIAI in Phase 2&3 studies• Total of 54 patients with ESBL-producing Enterobacteriaceae

    • No differences in outcomes, but neither study was designed to evaluate this question

    Sader, et al. J of Antimicrob Chemo 2014;69:2713. Farrell, et al. Int J of Antimicrob Agents 2014;43:533. Sader, et al. Journ of infection 2014;69:266. Farrell, et al. Antimicrobial Ag Chemo 2013;57:6305.Walkty, et al. Antimicrobial agents and chemotherapy 2013;57:5707.CIDEIM

  • My Thoughts on Ceftolozane-Tazobactam for the Treatment of ESBL

    Infections…

    • Further clinical reports evaluating its efficacy for ESBL infections are needed

    • Since the same βLI (i.e., tazobactam) is used in piperacillin/tazobactam, it likely has similar activity to this agent for ESBL-producing infections

    • Significant expense of utilizing this new cephalosporin/βLI agent is a limiting factor if alternative, generic options are available

    CIDEIM

  • Ceftazidime-Avibactam

    CIDEIM

  • Ceftazidime-AvibactamFDA Approved February 2015

    • Ceftazidime-avibactam has excellent in vitro activity against ESBL-producing Enterobacteriaceae

    • In vitro results more favorable than ceftolozane-tazobactam

    • MIC50/90 of this agent for ESBL-producing E. coli and K. pneumoniae are 0.12/0.25 and 0.5/1 mcg/ml, respectively

    • Phase 2 & 3 clinical data indicate it is effective and well-tolerated for complicated urinary tract infections and intra-abdominal infections

    • Did not specifically include confirmed ESBL isolates

    http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Antinfective

    DrugsAdvisoryCommittee/UCM425459.pdf.CIDEIM

  • Summarizing My Thoughts…

    • For mild-moderate infections, particularly those from urinary sources or with low MICs, non-carbapenems can be considered with PTZ having the most favorable data available

    • For severe, invasive infections, carbapenems are still first-line options but de-escalation to non-carbapenem β-lactams can be considered when a response is observed

    CIDEIM