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
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Disclosures
• I have received funding support from the following nonfederal organizations in the past 12 months:
• Merck
• Pfizer
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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
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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
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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
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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?
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Cephamycins
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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
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Cefepime
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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
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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
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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
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Piperacillin-Tazobactam
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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 --
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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
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Ceftolozane-Tazobactam
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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
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Ceftazidime-Avibactam
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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
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