Are There Non-Carbapenem خ²-Lactam Options for Treating ... ... Cefepime: Inoculum Effect â€¢...
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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
• I have received funding support from the following nonfederal organizations in the past 12 months:
• Discuss the role of carbapenems in the treatment of ESBL-producing infections
• Discuss the role of the following agents in treating ESBL-producing infections
• Newer β-lactam/β-lactamase inhibitors
• 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 • 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
Study Bacteria Sources ICU Outcomes
Site: Blood (100%)
(56%), IAI (19%), urine
(11%), SSTI 4%)
~50% Mortality at 14 days:
29% cephamycins vs.
25% carbapenems (ns)
E. coli (95%), K.
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
• 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
Site: Pneumonia (100%) 100% Clinical response:
(p70% Mortality at 30
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
• 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