D Angelo Et Al., 2016

Expert Opinion on Pharmacotherapy
ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20
Treatment options for extended-spectrum beta-

lactamase (ESBL) and AmpC-producing bacteria
Ryan G. D'Angelo PharmD, Jennifer K. Johnson Ph.D., D(ABMM), Jacqueline T.

Bork M.D & Emily L. Heil PharmD, BCPS AQ-ID AAHIVP
To cite this article: Ryan G. D'Angelo PharmD, Jennifer K. Johnson Ph.D., D(ABMM), Jacqueline
T. Bork M.D & Emily L. Heil PharmD, BCPS AQ-ID AAHIVP (2016): Treatment options for
extended-spectrum beta-lactamase (ESBL) and AmpC-producing bacteria, Expert Opinion on
Pharmacotherapy, DOI: 10.1517/14656566.2016.1154538
To link to this article: http://dx.doi.org/10.1517/14656566.2016.1154538
Accepted author version posted online: 18

Feb 2016.
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Download by: [University of York] Date: 21 February 2016, At: 06:26

1
Publisher: Taylor & Francis
Journal: Expert Opinion on Pharmacotherapy
DOI: 10.1517/14656566.2016.1154538
Review
Treatment options for extended-spectrum beta-lactamase (ESBL) and AmpC-
producing bacteria
Ryan G. D’Angelo, PharmD

PGY-2 Pharmacotherapy Resident
Downloaded by [University of York] at 06:26 21 February 2016
University of Maryland School of Pharmacy

20 N. Pine ST
S436
Baltimore, MD 21201
rdangelo@rx.umaryland.edu
Phone: 410-706-1458
Fax: 410-706-4725
Jennifer K. Johnson, Ph.D., D(ABMM)

Associate Professor, Departments of Pathology and Epidemiology and Public Health
University of Maryland School of Medicine
Director, Microbiology and Virology Laboratories
University of Maryland Medical Center
22 S. Greene St
Baltimore, MD 21201
Jacqueline T. Bork, M.D.

Clinical Associate
The Johns Hopkins Hospital
Brady 522B
600 N. Wolfe St
Baltimore, MD 21287
Emily L. Heil, PharmD, BCPS AQ-ID AAHIVP

Clinical Pharmacy Specialist, Department of Pharmacy
University of Maryland Medical Center
22 S. Greene St
Baltimore, MD 21201
Declaration of Interest:
2
The authors have no relevant affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock ownership or options, expert testimony,
grants or patents received or pending, or royalties.
Abstract
Introduction: Extended spectrum β-lactamases (ESBL) and AmpC β-lactamases are increasing
causes of resistance in many Gram-negative pathogens of common infections. This has led to a
growing utilization of broad spectrum antibiotics, most predominately the carbapenem agents.
As the prevalence of ESBL and AmpC-producing isolates and carbapenem resistance has
increased, interest in effective alternatives for the management of these infections has also
developed.
Areas Covered: This article summarizes clinical literature evaluating the utility of carbapenem-
sparing regimens for the treatment of ESBL and AmpC-producing Enterobacteriaceae, mainly β-
lactam-β-lactamase inhibitor combinations and cefepime (FEP).
Expert Opinion: Based on available data, the use of piperacillin-tazobactam (PTZ) and FEP in
the treatment of ESBL-producing Enterobacteriaceae cannot be widely recommended. However,
certain infections and patient characteristics may support for effective use of these alternative
agents. In the treatment of infections caused by AmpC-producing Enterobacteriaceae, FEP has
been shown to be a clinically useful carbapenem-sparing alternative. Carbapenems and FEP
share many structurally similar characteristics in regards to susceptibility to AmpC β-lactamases,
which further create confidence in the use FEP in these situations. Patient and infection specific
characteristics should be used to employ FEP optimally.

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Key Words: multidrug resistance, infectious diseases, Enterobacteriaceae, ESBL, AmpC
List of Abbreviations
Adjusted odds ratio aOR
Amikacin AMK
Aminoglycoside AG
Amoxicillin clavulanic acid AMC
Ampicillin sulbactam SAM
Aztreonam ATM
Β-lactam/β-lactamase inhibitor BLBLI
Blood stream infection BSI
Carbapenem-resistant Enterobacteriaceae CRE

Cefepime FEP
Cefmetazole CMZ
Cefotaxime CTX
Ceftazidime CAZ
Ceftriaxone CRO
Ciprofloxacin CIP
Community acquire pneumonia CAP
Confidence Interval CI
Definitive therapy cohort DTC
Doripenem DOR
Empirical therapy cohort ETC
Ertapenem ETP
Extended spectrum β-lactamase ESBL
Flomoxef FMF
Fluoroquinolone FQ
Fosfomycin FOF
Healthcare-associate pneumonia HCAP
Imipenem IPM
Intensive care unit ICU
Meropenem MEM
Minimum inhibitory concentration MIC
Odds ratio OR
Piperacillin tazobactam PTZ
Urinary tract infection UTI
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1. Introduction
Globally, increasing resistance of the Enterobacteriaceae to β-lactams is one of the top threats
in the antibiotic resistance crisis [1]. Organisms belonging to the Enterobacteriaceae family are
common Gram-negative pathogens in urinary tract infections (UTIs), community acquired

pneumonia (CAP) and healthcare-associated pneumonia (HCAP), bloodstream infections (BSIs)
and a multitude of intra-abdominal infections [2]. Previously, expanding resistance was
associated with nosocomial infections but prevalence is increasing within the community setting
[3–5]. The primary mechanism of resistance is the production of β-lactamase enzymes, which
have the ability to hydrolyze the penicillins, cephalosporins and/or aztreonam (ATM) causing
resistance against many broad spectrum β-lactams [6,7]. Although carbapenems undergo
hydrolysis by β-lactamases, the reaction rate at which this occurs does not lead to clinically
relevant resistance, which is the reason carbapenems are used as first line agents when treating
organisms that produce some β-lactamases [6,7]. Two particularly troublesome groups are the
extended spectrum β-lactamases (ESBL) and AmpC β-lactamases, which have increased globally
with some countries reporting a prevalence as high as 40% of tested isolates [8].
In the 1980s the third generation cephalosporins brought a new array of antibiotics effective
for treating broad spectrum β-lactamases [6]. Unfortunately, as quickly as 1983, reports became
available of plasmid encoded β-lactamases capable of hydrolyzing these new third generation
cephalosporins, but not the cephamycins (cefoxitin and cefotetan) [6,7]. These became known as
the ESBLs. This distinctive resistance pattern, as well as their inhibition by β-lactamase
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inhibitors such as clavulanic acid or tazobactam, characterizes most ESBLs. Because ESBLs are
expressed primarily on plasmids, transmission from patient to patient can lead to significant
increases in resistant Gram-negative infection outbreaks within institutions.
AmpC β-lactamases have also proven to be an increasing threat to antimicrobial resistance.
Unlike the ESBLs, a large proportion of AmpC β-lactamase expression is inducible making it
even more difficult to identify in clinical practice [9]. AmpC β-lactamases, in addition to
chromosomal encoding, can be expressed on plasmids. In some institutions ESBLs and AmpC β-
lactamases are produced in upwards of 50% of clinical isolates [5,10,11]. With prevalence
increasing worldwide, practitioners are now facing these difficult clinical situations in every day
practice with a dwindling armamentarium of effective agents for life-threatening infections.
Carbapenems have become first-line empiric options when concerns for ESBLs or AmpC β-
lactamases exist due to extensive research illustrating their effectiveness [12–14]. Unfortunately,
increasing use of carbapenems is leading to a concordant increase in carbapenem resistance.
While this has occurred, significant interest has accrued evaluating the development of
carbapenem resistant Gram-negative bacilli. Expectedly, one of the strongest predictors for
carbapenem resistance is previous exposure to a carbapenem [1,15,16]. In as little as three days
of carbapenem exposure, a 5.9 times risk of developing carbapenem resistant Gram-negative
bacilli has been demonstrated compared to patients who did receive carbapenem therapy leading
to significantly increased mortality [15,16].The availability of newer, carbapenem sparing agents
is lagging behind our understanding of the biochemical properties of these enzymes leading to an
amplified obligation for accurately identifying and implementing effective antibiotic regimens as
early as possible.
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With the difficulty in choosing appropriate treatment for ESBL and AmpC β-lactamase
expressing Enterobacteriaceae, accurate interpretation of resistance patterns and current evidence
supporting treatment regimens is fundamental for all clinicians to optimize care for patients. We
performed a literature review to identify data regarding ESBL and AmpC mechanisms of
resistance, identification of ESBL and AmpC resistance patterns, and evidence based treatment
options.
2. Methods
2.1 Literature Review
A literature search was performed using PubMed and Cochrane database from January
2000 through July 2015. The following terms were searched in combination: extended spectrum
β-lactamases, AmpC, Enterobacteriaceae, antibiotic resistant, urinary tract infection,
pyelonephritis, bacteremia, community acquire pneumonia, nosocomial pneumonia, intra-
abdominal infection, critically ill, treatment, European committee on antimicrobial susceptibility,
and clinical laboratory standards institute. References of retrieved articles, guidelines and review
articles were manually searched to ensure identification of studies not found in the initial
literature search.
3. Mechanisms of Resistance
According to the Ambler classification ESBLs belong to Class A, whereas AmpCs belong to
Class C illustrating that serine is contained within the active site for both enzymes, but the gene
sequences of each are uniquely different leading to differences in β-lactam hydrolysis between
AmpC and ESBLs [17]. Further classifications of AmpC and ESBLs are beyond the scope of
this paper but understanding the mechanisms of resistance for each class can allow clinicians to
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identify organisms producing these β-lactamases and choose the most appropriate antibiotic
regimen as early as possible.
3.1 ESBL Resistance
ESBL enzymes, enzymes that hydrolyze the beta-lactam ring, are the result of structural
mutations of β-lactamases due to selective pressure from antibiotic exposure. Compared to
narrow-spectrum β-lactamases, the ESBLs have the similar ability to hydrolyze penicillins, early
generation cephalosporins and ATM, but also have the ability to hydrolyze the 3rd generation
cephalosporins. However, in-vitro they will be susceptible to β-lactamase inhibitors and the
cephamycins [18,19]. The most well-known β-lactamases associated with Enterobacteriaceae
ESBLs include the ampicillin-hydrolyzing TEM-type and SHV-type which develop from
mutations of the narrow-spectrum TEM and SHV-type β-lactamases, whereas, the CTX-M-type
ESBLs are acquired from other bacterial genera [6,19,20]. For TEM-type ESBLs, bla TEM-1
structural mutations and single amino acid substitutions, expand resistance from ampicillin,
penicillin and first generation cephalosporins to extended spectrum cephalosporins (e.g.,
ceftriaxone [CRO] and cefotaxime [CTX]) and ATM [6,20].
SHV-type 1 and 2, which are found predominately in Klebsiella pneumoniae, are capable of
hydrolyzing penicillins and first generation cephalosporins [20]. Substitutions with as few as one
amino acid can confer extensive expansion of resistance to 3rd generation cephalosporins or
ATM [6]. Similar to TEM, mutations within the bla SHV-1 allows for expanded hydrolysis to
extended-spectrum cephalosporins such as CTX and ceftazidime (CAZ), and ATM [6,20].
CTX-M ESBLs, as their name suggests, have the most potent hydrolytic activity against
CTX [6]. Cefepime (FEP) also undergoes extensive hydrolysis by CTX-M ESBLs [6,20]. These
mutations lead to enhanced hydrolysis causing an opening of the β-lactam ring.

8
A single organism may harbor multiple types of ESBLs and as such, it is nearly impossible to
determine the exact ESBL subtype purely based on susceptibility reports. Despite expanded
resistance to many β-lactams based on ESBL subtype, one class of β-lactams maintains their
antimicrobial activity in the presence of ESBL production, the cephamycins. Escherichia coli, K.
pneumoniae and K. oxytoca are the most commonly studied ESBL-producing organisms due to
the ability to confirm the presence of the β-lactamase. Further details regarding structural
differences and β-lactamase classification are outside the scope of this article but can be found
at: http://www.lahey.org/Studies.
3.2 AmpC β-lactamase Resistance
Similar to ESBLs, AmpC-producing organisms will typically confer resistance to penicillins
and most cephalosporins through hydrolysis and opening of the β-lactam ring, but unlike the
ESBLs, AmpC-producing organisms are inherently resistant to the activity of the cephamycins.
Genes encoding for AmpC β-lactamases can be chromosomally or plasmid mediated, but
generally only chromosomal AmpC will undergo hyper-production in the appropriate
environment [19]. Typical organisms capable of this chromosomally mediated AmpC hyper-
productive state include some of the Gram-negative bacilli commonly known as the SPACE
organisms i.e., Serratia spp., Pseudomonas, Acinetobacter spp., Citrobacter spp., Enterobacter
spp., and Morganella spp.
Ampicillin, amoxicillin, cefazolin are regarded as strong inducers and excellent substrates of
AmpC β-lactamases. β-lactamase inhibitors are also inducers of AmpC and can lead to treatment
failure with agents that originally appeared susceptible [21]. AmpC β-lactamases generally reside
within the periplasm where many β-lactam agents exhibit their antimicrobial effects. Porin entry
of these agents is the often the rate-limiting step in hydrolysis by AmpC β-lactamases [22,23]. β-
9
lactams such as FEP, due to its zwitterionic structure, that do not specifically require porins for
entry to the periplasmic space can overcome the rate of inactivation by AmpC β-lactamases
[19,23,24].
The resistance mechanisms of AmpC β-lactamases is by far one of the more difficult
resistance concepts to grasp, even for many experts in the field of infectious diseases. AmpC
genes located on plasmids are generally constitutively produced, whereas chromosomally
mediated AmpC may undergo hyper-production. In the presence of antimicrobials that hydrolyze
the bacterial cell wall, a series of 1,6-anhydro-N-acteylmuramic acid peptides are produced and
as they build up they compete with UDP-N-acetylmuramic acid peptides for binding with AmpR,
a transcriptional regulatory enzyme that at a baseline state represses AmpC production [9,25].
With increasing 1,6-anhydro-N-acteylmuramic acid peptide binding and decreased UDP-N-
acetylmuramic acid peptide binding, AmpR undergoes a conformational change leading to
increased transcription of AmpC. Another regulatory protein, AmpD, is responsible for cleavage
of stem peptides from 1,6-anhydro-N-acteylmuramic acid which decreases their affinity to bind
to AmpR [9,25].
Induction of AmpC transcription occurs as higher concentrations of 1,6-anhydro-N-
acteylmuramic acid is produced and the AmpD enzyme is unable to cleave all of the stem
peptides leading to higher proportion of AmpR repression and increasing AmpC transcription.
However, true induction is thought to be less frequently the cause of increased AmpC
transcription, as induction only explains the wild-type resistance profile of the AmpC producing
organisms. Stable de-repression is felt to be the more likely cause of AmpC overexpression
leading to resistance to antimicrobials which may have been susceptible in vitro. This most
commonly occurs secondary to an AmpD mutation, which ultimately prevents any cleavage of
10
stem peptides from1,6-anhydro-N-acteylmuramic acid thus allowing for increased binding to
AmpR and over transcription of AmpC. A simplified representation of induction and stable de-
repression can be found in Figure 1. These resistance mechanisms, especially stable de-
repression, make identifying the most clinically prudent empiric antimicrobial therapy difficult.
4. Differentiating ESBL and AmpC β-lactamases
Because ESBLs and AmpC β-lactamases in a de-repressed variant will cause hydrolysis of β-
lactams it can be difficult to identify the likely cause of resistance on clinical susceptibility
reports (Table 2). Both the AmpC β-lactamases in a de-repressed variant and ESBLs share the
hydrolytic activity to the penicillins and the 1st and 3rd generation cephalosporins. However,
there are a few key differences that can assist clinicians in the differentiation of the β-lactamases
that will allow optimization of antimicrobial agents and decrease the potential risk of treatment
failure. Because AmpC β-lactamases in a de-repressed variant are inherently resistant to the
inhibition of some of the β-lactamase inhibitors, organisms actively producing AmpC β-
lactamases may be resistant to agents such as, amoxicillin-clavulanate (AMC), ampicillin-
sulbactam (SAM) and in some cases piperacillin-tazobactam (PTZ). The difference in
susceptibility of different BLBLIs is due to different affinity and hydrolysis rates of specific β-
lactamase inhibitors; clavulanic acid is a poor inhibitor of nearly all AmpCs whereas sulbactam
and tazobactam may be able to inhibit the hydrolytic activity of some AmpCs produced by
certain isolates [9].
Conversely, ESBL producing organisms may or may not be resistant to these same agents
depending on previous antibiotic exposure and ESBL subtype. AmpC β-lactamase producing
organisms will often be susceptible to ATM where as ESBL producing organisms will be
11
fundamentally resistant to ATM. Even in a wild-type strain, AmpC β-lactamases will also retain
hydrolytic activity against the cephamycins, whereas, ESBLs are often susceptible to
cephamycins. While the 4th generation cephalosporin, FEP, is very stable against AmpC β-
lactamases, and relatively stable against ESBLs compared to the third generation cephalosporins,
there is established evidence that resistance is emerging [26]. Because of this occurrence,
susceptibility or resistance to FEP will not always allow for differentiation between AmpC β-
lactamases and ESBLs. General susceptibility patterns for ESBL and AmpC β-lactamase
producing organisms can be found in Table 1.

Even with these general patterns of resistance, organisms have the potential for harboring
multiple mechanisms of resistance, each with their own mutations that can disrupt the clinicians’
ability to differentiate what type of resistance the organism(s) is capable of producing.
5. Literature Review of Treatment Options
5.1 ESBL Treatment
Few studies have specifically examined the role non-carbapenem agents have in the
treatment of these organisms, and as such the current mainstay of treatment for ESBL-producing
Enterobacteriaceae remains the carbapenems.
Studies of β-lactam/β-lactamase inhibitors (BLBLIs) such as PTZ have shown conflicting
results depending on the types of infections present (Table 2). In a retrospective analysis of
patients (n=23) with positive ESBL-producing E. coli, K. pneumoniae, or K. oxytoca cultures
with a primary urinary source PTZ was shown to have 100% clinical success irrespective of the
isolates’ MIC [27]. Success decreased modestly to 91% in isolates obtained from non-urinary
12
sources as long as the MIC was ≤16/4 mcg/mL and decreased significantly to <20% when the
MIC rose above 16/4 mcg/mL [27]. Similar results were identified in another retrospective study
evaluating infections with ESBL-producing E. coli and K. pneumoniae from multiple sources
[28]. Out of 522 total infections, 287 were UTIs, 60 were skin structure, 60 were bacteremia, 55
were hospital acquired pneumonia, 31 were intra-abdominal, and 29 were not classified.
Treatment consisted primarily of BLBLI (vast majority were treated with cefoperazone-
sulbactam) at approximately 80%, followed by fluoroquinolones and aminoglycosides. Clinical
success was similar between carbapenem and non-carbapenem therapy, 85.71% and 79.64%
respectively (p=0.152). The clinical success reported with BLBLIs in these two studies is likely
due to the high proportion of patients with urinary sources of infection as BLBLI achieves and
maintains concentrations well above the MICs for Enterobacteriaceae at this site.
Recently, however, in a single-center, retrospective analysis of patients with bacteremia
empiric PTZ therapy was compared to treatment with meropenem (MEM) [13]. A total of 213
patients with positive E. coli, Klebsiella spp., or Serratia marcescens cultures were included in
the retrospective evaluation, 103 receiving PTZ (48%) and 110 receiving MEM (52%). All
patients receiving PTZ had isolates considered susceptible with MICs ≤16 mcg/mL; 85% of
isolates had an MIC of ≤8 mcg/mL. Upon identification of ESBL status, all patients were
converted to MEM therapy. Out of the 313 patients included in the study 20.6% had likely
urinary sources of bacteremia (19.4% for PTZ and 20.2% for MEM, p=0.89). A total of 17
deaths (17%) occurred in the PTZ group compared to 9 deaths (8%) in those treated empirically
with MEM. After adjustment for age, Pitt bacteremia score and intensive care unit level, there
was a 1.92 times increased risk of death at the 14 day follow up point for those who received
empiric PTZ therapy compared to MEM (95% CI, 1.07-3.45). Of note, the most common source
13
of bacteremia was central-line associated which is usually less responsive to therapy than urinary
or biliary sources which predominated in the previous studies. In addition, most patients in this
study received 3.375g every 6 hours and only 39% of patients received high dose PTZ therapy.
While no differences in outcomes were noted between doses in the study, given the small sample
size it is unclear if larger quantities of PTZ could overcome the capacity of ESBLs to hydrolyze
the drug.
Complicating the evidence for the use of BLBLI in bacteremia due to ESBL further, a large
post hoc analysis evaluating patients from 6 prospective cohorts compared mortality associated
with the use of BLBLIs and carbapenems [29]. Of 287 patients with bacteremia, 192 were
identified as having ESBL-producing E. coli. The authors identified 103 patients who received
empiric therapy with a BLBLI (n = 72) or carbapenem (n = 31). Empiric therapy was defined as
antimicrobial therapy administered prior to susceptibility results becoming available. Of the 72
patients receiving empiric BLBLI therapy, 44% were changed to therapy with a carbapenem
while 47% received definitive therapy with a BLBLI. The mortality rate for patients given
BLBLI empiric and definitive therapy was 5.9% compared to 9.4% of patients who were
switched to definitive therapy with carbapenem (p=0.6). For patients given empiric and
definitive therapy with carbapenems mortality was 16.7%; no patients were switched to receive
BLBLI definitive therapy after being empirically given a carbapenem. For patients given empiric
therapy, higher mortality was seen in isolates with PTZ MIC ≤4 (4.5%) compared to those with
an MIC >4 (23%), however, this difference was not statistically significant due to the low
frequency of mortality in the analysis (p=0.09). A total of 174 patients were included in the
definitive therapy cohort: 54 received a BLBLI and 120 received a carbapenem. Antibiotics
given after identification of susceptibility reports were defined as definitive therapy. Similar
14
mortality rates were seen at days 7, 14 and 30 between the BLBLI and carbapenem groups (1.9%
and 4.2%, 5.6% and 11.7%, 9.3% and 16.7%, respectively [p=0.4 by log-rank test]). Between the
empiric and definitive therapy groups, urinary or biliary source of bacteremia was consistent,
72% and 78% in BLBLI empiric and definitive therapy and 58% and 66% in carbapenem
empiric and definitive therapy. In both the empiric and definitive therapy cohorts, mortality was
associated with non-urinary or non-biliary source, Pitt bacteremia score, and presentation with
sepsis or septic shock. Although the results of this study provides strengthened evidence that use
of BLBLI therapy is comparable to carbapenem therapy, especially for bacteremia originating

from low inoculum infections (e.g., urinary tract) or with concomitant surgical intervention of
the inoculum (e.g., biliary tract), control of confounding variables such as nosocomial vs.
community acquisition, and applicability to ESBL producing organisms other than E. coli is
limited. In addition, the use of high dose PTZ (4.5 gram intravenously (IV) every 6 hours) was
specifically chosen over standard dosing of 3.375 grams IV every 6 hours [30]. As the study was
done in Spain where the CTX-M ESBLs have a significantly higher prevalence over other
ESBLs, dosing is of particular importance because the CTX-M ESBLs are increasingly inhibited
with higher amounts of both piperacillin and/or tazobactam (28,29).
The potential role for FEP in management of ESBL-producing Enterobacteriaceae also
remains relatively unclear but Lee et al. shed some light on its clinical utility [31]. In a
multicenter, retrospective study among septic patients with ESBL-producing E. coli and K.
pneumoniae bacteremia, FEP and carbapenem therapy were compared for crude 30-day mortality
rates. One hundred ninety-seven patients were included in the analysis, with 112 patients in the
empirical therapy cohort (ETC) and 178 in the definitive therapy cohort (DTC). In the ETC, 21
patients were given FEP and 91 were given a carbapenem. In this cohort, 30-day mortality rates
15
were lower when isolates had a FEP MIC ≤1 mcg/mL (0%), compared to higher FEP MICs
(MIC 2-8 mcg/mL: [40%]; MIC ≥16: [100%]; p=0.037). For patients given FEP with susceptible
isolates compared to carbapenem, crude 30-day mortality was not statistically different, 64.7%
vs. 39.3% (p=0.07), however, this may have been due lack of reaching sufficient power. Similar
results were found in the DTC, where 17 patients received FEP and 161 received a carbapenem.
A lower 30-day mortality with FEP MIC ≤1 mcg/mL (16.7%) was noted compared to higher
MICs (MIC 2-8 mcg/mL: [45.5%]; MIC ≥16: [100%]; p=0.035). Patients treated with FEP had
higher clinical failure (OR, 6.2; 95% CI, 1.7-22.5; p=0.002) and 30-day mortality (OR, 7.1; 95%
CI, 2.5-20.3; p <0.001). Among 17 propensity score-matched patients given FEP or carbapenem
treatment, there was a higher association with mortality for those given FEP therapy (adjusted
odds ratio [aOR], 6.8; 95% CI, 1.5-31.2; p=0.01). A major drawback of the study was that there
was not a description of the dosing regimen for FEP therapy (31). One thing that is well
described by other pharmacokinetic studies of FEP, is the difficulty in achieving adequate serum
concentrations for organisms with MICs ≥2 mcg/mL [31]. Dosing regimens for FEP of 2 g every
12 hours have been shown in Monte Carlo simulations, to not achieve adequate levels whereas 2
g every 8 hours is sufficient for organisms with MICs 4-8 mcg/mL [33]. Unfortunately, no data
is available at this time that describes the clinical outcomes associated with more aggressive
dosing for infections due to Enterobacteriaceae with elevated MICs. In the United States, the
Clinical & Laboratory Standards Institute guidelines have been used to standardize MIC
breakpoints within microbiology labs. In regards to the Enterobacteriaceae, FEP susceptibility is
defined as an MIC ≤2 mcg/mL, but also there is a susceptible dose-dependent category for
isolates with MICs 4-8 mcg/mL illustrating that higher doses of FEP would be required for
effective antimicrobial activity [34]. This can lead to misinterpretation of susceptibility reports
16
and ineffective therapy due to inadequate concentrations of FEP in regards to the bacterial
inoculum. Of note, the MIC breakpoint for Enterobacteriaceae for FEP by the European
Committee on Antimicrobial Susceptibility Testing (EUCAST) is ≤1 mcg/mL [35].
Most recently, Matsumura and colleagues evaluated the clinical utility of cefmetazole and
flomoxef in the treatment of E. coli bacteremia [36]. In this retrospective, multi-center study
conducted in Japan, 71 patients were included in the ETC; 26 patients received cefmetazole
(CMZ) or flomoxef (FMF) compared to 45 patients who received MEM. One-hundred thirteen
subjects were included in the DTC; 59 patients were treated with CMZ or FMF compared to 54
MEM treated patients. Patients in the ETC treated with CMZ of FMF had significantly lower
rates of hematological malignancy or intravascular catheterization compared to those treated
with MEM; 0% vs. 29%, and 23% vs. 53%, respectively. Additionally, those patients treated
with MEM in the ETC had significantly higher Sepsis-related Organ Failure Assessment scores
compared to those given CMZ or FMF. UTIs and intra-abdominal infections comprised the most
frequent sources of infection, 85% of infections CMZ/FMF treated group (ETC and DTC), 74%
(ETC) and 73% (DTC) in the MEM treated group. Overall 30-day mortality rates, adjusted for
hematologic malignancy and neutropenia, were similar for the ETC given CMZ/FMF compared
to those given MEM (hazard ratio [HR], 0.87; 95% CI, 0.11-6.52). Similarly, the DTC
propensity score adjusted for a number of variables (e.g. hospital stay, solid malignancy,
transplantation, chemotherapy, and neutropenia) CMZ/FMF showed similar clinical utility
compared to MEM ([HR], 1.04; 95% CI, 0.24-4.49). Based on the results of the study by
Matsumura et al., these β-lactam agents may provide a useful carbapenem-sparing alternative in
the case of uncomplicated UTIs caused by E. coli, however, certain limitations exist. Due to
significantly higher rates of hematologic malignancy, chemotherapy or immunosuppression

17
and/or neutropenia within the study, patients with these conditions would like benefit from more
aggressive therapy with carbapenem agents.
Particular interest is increasing regarding newer agents, such as ceftazidime-avibactam
(CAZ-AVI), and their role in treating ESBL-producing Enterobacteriaceae. Shortly after the
release of the phase 2 trials for CAZ-AVI for the treatment of UTI and intra-abdominal
infections, a post-hoc analysis was completed evaluating the clinical efficacy of CAZ-AVI
compared to carbapenem therapy [37]. Within the microbiologically evaluable population a total
of 35 isolates were positive for ESBL production in the CAZ-AVI group and 24 isolates in the
carbapenem treated group. In both groups, a high frequency of multiple ESBL genes were
identified, with the most common genes coding for CTX-M-14, CTX-M-15 and bla oxa-1/30 . Of the
patients treated with CAZ-AVI, 85.7% had a favorable clinical response compared to 79.2% of
those treated with carbapenem therapy. Unfortunately, no statistical analysis was performed to
identify differences in these favorable outcomes, however, these preliminary results will likely
lead to further inquiry of the role of CAZ-AVI in treating ESBL-producing Enterobacteriaceae.
With the relatively small number of available well designed prospective studies and
restriction of most studies evaluating E. coli and Klebsiella spp., absolute recommendations
regarding the optimal treatment of ESBL-producing Enterobacteriaceae is nearly impossible at
this time. However, newer evidence is emerging that suggests there may be a potential role for
certain β-lactam agents in treating ESBL-producing isolates.
5.2 AmpC Treatment
Due to the difficulty in identifying the presence of AmpC β-lactamases, well designed studies
evaluating treatment of these organisms are currently scarce. Similar to ESBL-producing

18
organisms, carbapenems have emerged as a primary agent for management of SPACE and
SPICE organisms as they generally harbor chromosomal AmpC β-lactamases. As carbapenem
use has increased over the last decade, researchers have investigated the use of FEP based on its
physical properties and relatively low affinity for AmpC β-lactamases (Table 3). FEP has caught
the attention of many researchers and is currently the most evaluated non-carbapenem
therapeutic strategy (Table 3).
During a retrospective analysis of a matched cohort, a total of 78 patients with primarily

blood stream infections, pneumonia, and intra-abdominal infections with confirmed AmpC-
producing β-lactamase Enterobacteriaceae were evaluated [38]. Patients were either given FEP
or MEM and were evaluated for 30 day mortality and overall length of hospital stay. A separate
propensity matched cohort of 64 patients was also evaluated to provide a better comparison for
FEP vs. MEM patients. In the propensity matched cohort, 10 deaths (31.2%) occurred in the FEP
group and 11 deaths (34.3%) in the MEM group (p=0.99). Overall hospital length of stay was
also similar between FEP and MEM groups, 12.6 days and 14.6 days, respectively (p=0.63). No
collected baseline characteristics were significantly different in the two groups, specifically
McCabe score, ICU stay, or location of infection. During the univariate analysis to identify
variables associated with mortality, the odds ratio of 30 day mortality for patients receiving FEP
compared to MEM was 0.60 (95% CI, 0.23-2.31; p=0.36), and mortality was independently
associated with higher McCabe score (OR, 2.63; 95% CI, 1.88-5.68) and mechanical ventilation
(OR, 3.0; 95% CI, 1.01-8.95). Although the retrospective nature of study and relatively small
sample size introduce potential limitations, the results obtained from this study strengthened the
hypothesis that FEP may be clinically useful for treating AmpC-producing Enterobacteriaceae
and allow for decreased use of carbapenems.

19
Shortly after the release of the previous study results, Siedner et al. published results of their
study evaluating the use of FEP compared to other antibiotics for treatment of Enterobacter spp.
bacteremia [39]. Two hundred seventy-one retrospective cases were identified between two large
tertiary care centers. All patients had confirmed bacteremia and were given at least 1 antibiotic
agent. Clinical failure was defined by the persistence of bacteremia ≥1 day from the time of the
original blood culture. Due to the retrospective nature, many patients received more than 1
antibiotic (n = 176), but was not clearly described by the authors. However, the authors did make
a significant effort to control for this and other confounding factors. In the crude analysis group
patients who received FEP (n = 36) compared to those who received a carbapenem (n = 16),
there was no statistically significant difference in in-hospital mortality, 17% vs 26%, respectively
(p=0.38), but there was a higher incidence of persistent bacteremia in carbapenem monotherapy
group (25%) compared to those in the FEP monotherapy group (0%) (p=0.002). When patients
were matched based on the hospital location, time of bacteremia during hospitalization and
delays in antibiotic initiation, mortality again remained similar between FEP and carbapenem
treated patients, 30% and 17% for monotherapy, respectively (p=0.46), and 24% and 13% for
combination therapy, respectively (p=0.21). In this analysis, persistence of bacteremia was also
similar between FEP and carbapenem monotherapy, 0% and 25%, respectively (p=0.11) and
combination therapy, 11% and 15%, respectively (p=0.61). Although the results of this study
were slightly more limited due to confounders and small sample size, the well-designed
propensity score matched cohort analysis allows for meaningful interpretation and comparison of
FEP and carbapenem therapy for AmpC-producing Enterobacter spp.
Further literature evaluating treatment of AmpC-producing organisms with carbapenems
compared to FEP was released by Blanchette et al. in 2014 [40]. This retrospective, matched,
20
case-control study included a total of 48 patients, 16 in the ertapenem (ETP) treated group and
32 in the FEP treated group. Patients were matched on the basis of age, patient location at the
time of positive culture, and urinary vs. non-urinary source of infection. Although no genotypic
evaluation for AmpC status was performed, this study included infections due to SPICE
organisms, with a majority of cultures positive for Citrobacter spp. (19%) and Enterobacter spp.
(67%). There was no difference in positive clinical response between ETP (69%) and FEP
(89%), (p=0.14), which was defined as a white blood cell count and temperature within normal
limits, and resolution of the principle signs of infection upon discontinuation of the study
antibiotic. Of note, a large majority of patients in both the ETP and FEP group were located on
medical or surgical (81%) services at the time of positive culture, and the median (IQR)
APACHE II score was similar, 11 (9.5, 15) for ETP and 13.5 (10.18.3) for FEP (p=0.15).
Urinary sources of infection were the most common in both groups (31%), whereas bacteremia
accounted for 25% of the FEP treated patients compared to 13% of the ETP treated patients
(p=0.46), pneumonia in 16% of FEP treated patients and 25% of ETP treated patients (p=0.46),
intra-abdominal in 9% of FEP treated patients and 19% of ETP treated patients (p=0.39), and
skin and soft tissue in 22% of FEP treated patients and 13% of ETP treated patients (p=0.7). One
potential confounding variable that impacts the reliability of the study results was that in the ETP
treated group, the median time to appropriate antibiotic therapy was 2 days compared to 1 day in
the FEP group. This could have accounted for lower clinical responsiveness of patients receiving
ETP. The most concerning limitation of the study is related to the lack of clinically objective
outcomes, as clinical success was based on surrogate markers. No evaluation for hospital or ICU
length of stay or mortality was performed. Despite this limitation, the study performed by
21
Blanchette et al. lends credence to the previously described literature illustrating FEP’s utility in
treating AmpC-producing organisms, especially the Enterobacter spp. and Citrobacter spp.
Adding evidence for the efficacy of FEP for AmpC-producing Enterobacter cloacae was the
recent evaluation for FEP susceptible dose-dependent isolates [53]. In a retrospective cohort of
144 patients with bacteremia from a variety of sources, FEP and carbapenems displayed similar
crude 30-day mortality rates, 26.4% vs. 22.2%, (p=0.7). Patients included in the analysis were
similar with the exception that more neutropenia was present in those who received FEP.
However, it is important to note that those patients with an isolate FEP MIC of ≥4 mcg/mL had a
significantly higher mortality (OR, 8.7; 95% CI, 2.52-30.02; p=0.001). Additionally, higher 30-
day mortality was noted in patients with isolates co-producing ESBL (OR, 6.44; 95% CI, 1.68-
24.77; p=0.006), a Pitt bacteremia score ≥4 (OR, 5.49; 95% CI, 1.76-17.11; p=0.005), or a
rapidly progressing underlying fatal disease (OR, 4.57; 95% CI, 1.29-19.13; p=0.03). The data
reported in this study emphasize the importance of using FEP only in isolates with MICs ≤2
mcg/mL.
Although FEP has been the primary focus of researchers over the last 5 years, interest in the
clinical utility of BLBLIs for the treatment of certain AmpC-producing organisms remains. A
meta-analysis conducted by Harris and colleagues, recently evaluated a limited number of
studies comparing the carbapenem-sparing alternatives (FEP, BLBLIs, and fluoroquinolones
[FQ]) for the treatment of Enterobacter, Citrobacter and Serratia species. A total of 11 studies
were ultimately included, as 22 studies were excluded for lack of identifiable organisms, data or
incorrect antibiotics being used. As expected, no randomized controlled trials were identified and
the majority of included studies were retrospective in nature. The authors reported that the
primary infection included bloodstream infections with Enterobacter species and mortality was
22
utilized as the primary outcome. Surprisingly, in the unadjusted analysis, only the use of FQs
was associated with decreased mortality compared to carbapenem therapy (OR, 0.38; 95% CI,
0.19-0.78). Of note, there was concern for selection bias in patients given FQ therapy as these
patients may have had less severe or uncomplicated disease process’. BLBLIs and FEP therapy
were found to not be associated with significantly poorer outcomes when unadjusted and
adjusted for age, gender, and illness severity compared to carbapenem therapy (Table 3).
Overall, the meta-analysis included a small patient population; a total of 27, 104 and 34 received
BLBLI, FQ and cefepime respectively, and 207 patients receiving carbapenem therapy. Although
this meta-analysis sought out to illustrate the clinical utility of previously studied carbapenem-
sparing therapy, the authors identify that the lack of prospective studies, geographical limitations
and heterogeneity identified in each meta-analysis severely limits the external applicability to
clinical practice and further identifies the need for randomized controlled trials to improve
understanding of carbapenem alternative therapies for AmpC-producing organisms.
6 Conclusion
Currently, there is an overall lack of well-designed prospective trials evaluating the use of
carbapenem sparing antimicrobials in the treatment of ESBL and AmpC-producing organisms.
Future randomized trials evaluation empiric therapies are unlikely to occur due to logistical
issues, although randomized studies evaluating definitive therapy after pathogen isolation would
be possible and of interest to the healthcare community at large.
In addition to further investigating the use of agents such as PTZ and FEP for the management of
ESBL and AmpC producing organisms, new agents to the market may have a role in the
management of these organisms. Ceftolozane-tazobactam is a novel cephalosporin co-
formulated with an existing β-lactamase inhibitor that provides coverage of some ESBLs from
23
the TEM, SHV, and CTX-M groups and some AmpCs. CAZ-AVI combines an existing third
generation cephalosporin with a novel β-lactamase inhibitor, avibactam, which is active against
some ESBLs and AmpCs. While these agents are promising additions to the antibiotic
armamentarium, there is currently relatively little data on their use outside of their FDA
approved indications. They are also limited by cost and the desire to preserve them as “last
resort” agents. Practitioners will need to preserve the use of current carbapenems and newer
agents to prevent future resistance, thus identifying appropriate uses of alternative agents is of
the upmost importance.

7 Expert Opinion
Most clinicians will continue to utilize carbapenem therapy for first line treatment of ESBL
and AmpC-producing organisms as little evidence suggests a suitable alternative, in most cases.
As mentioned previously, however, as carbapenems are used more liberally the emergence of
carbapenem-resistant Enterobacteriaceae (CRE) will likely follow in an exponential fashion. As
difficult as it is to answer, the question of when and in what circumstances is non-carbapenem
therapy safe must be assessed by any practitioner who will come in contact with these clinical
circumstances. Current carbapenem shortages are also increasing pressure on clinicians to utilize
effective alternative treatment strategies, as anti-infective agent shortages have shown a negative
impact on patient care [55].
In regards to management of ESBL infections, carbapenems seem to have potential
significant mortality benefit compared to alternative therapy but this is mainly based on 2
retrospective analyses. For severe infections such as in patients with profound sepsis or septic
shock carbapenems will likely provide a better treatment strategy compared to PTZ or FEP
24
therapy, especially as empiric therapy when patients are known to have a history of infection(s)
due to ESBL-producing Enterobacteriaceae. We feel that for clinical situations where PTZ or
FEP therapy is used as empiric therapy and ESBL production is discovered on the basis of
susceptibility testing, these agents may still be effective when patients meet certain criteria. If the
infection source is an area where high concentrations of antimicrobial agents are normally
achieved such as urine and the patient is clinically improving, PTZ and FEP may be an adequate
option, especially for those with an MIC ≤4 mcg/mL and MIC <2 mcg/mL, respectively. Dose
escalation (PTZ 4.5 g every 6 hours; FEP 2 g every 8 hours) would be required when the MIC is
2-8 mcg/mL. In clinical scenarios where a history of ESBL is present, broad spectrum coverage
with a carbapenem is the ideal choice until further susceptibility information can be obtained.
Similar to ESBL-producing Enterobacteriaceae, carbapenems are generally regarded as the
first line treatment option for AmpC β-lactamase-producing Enterobacteriaceae. However, due to
FEP’s pharmacokinetic and pharmacodynamic properties, its clinical usefulness is under extreme
interest for carbapenem-sparing therapy. Because it does not rely on porin channels for entry into
the periplasmic space it should theoretically attain effective concentrations leading to cell-wall
hydrolysis, in the absence of other resistance mechanisms such as efflux pumps. Clinical trials
evaluating the effectiveness of FEP have illustrated the beneficial role FEP may have in the
treatment of AmpC-producing Enterobacteriaceae and Enterobacter spp. Limiting FEP use in
patients with low inoculum infections (i.e. skin/soft tissue infection, UTI), isolates with FEP
MIC ≤2 mcg/mL, and those patients that are able to have source control performed, such as in
the case of intra-abdominal infections, seem to be reasonable options. On the contrary, in
patients with severe pneumonia or ventilator associated pneumonia or those patients unable to
25
undergo source control should receive a carbapenem to maintain the highest likelihood of
attaining a positive outcome.
Currently, many studies are ongoing that may shed further light on the optimal strategy for
carbapenem alternative treatments. Studies such as MERINO trial (Meropenem versus PTZ for
definitive treatment of bloodstream infections due to ceftriaxone non-susceptible E. coli
and Klebsiella spp.) and the INCREMENT study (Impact of Specific Antimicrobials and MIC
Values on the Outcome of Bloodstream Infections Due to Extended-spectrum Beta-lactamases or

Carbapenemase-producing Enterobacteriaceae), have the potential to significantly promote the
role of carbapenem alternatives in the treatment of ESBLs [41]. Specifically, the INCREMENT
project will evaluate clinical outcomes of mortality from 72 hours to 30 days. Furthermore,
future trials evaluating the effectiveness of newer agents such as CAZ-AVI and ATM-avibactam,
and the role of older agents such as fosfomycin, may introduce clinicians to added carbapenem-
sparing regimens. Until then, the judicial use of carbapenem alternatives will rely on institutional
and community resistance patterns and expert clinical judgement [41,42].
Article highlights box

Article highlights.
• Carbapenem antimicrobials have emerged as first-line therapy for ESBL and AmpC-
producing Enterobacteriaceae. Due to concerns of increasing carbapenem resistance,
interest in the use of carbepenem-sparing agents has recently increased.
• With different resistance profiles of ESBL and AmpC β-lactamases, certain β-lactam
agents may have successful use in certain clinical situations.
• β-lactam β-lactamase inhibitor agents such as PTZ have displayed conflicting success
in the treatment of ESBL-producing Enterobacteriaceae dependent on site of and
severity of infection.
• FEP has been found to have similar clinical success to carbapenems in patients with
infection with AmpC β-lactamase-producing organisms; however, greater success is
seen in low inoculum infections such as urinary and biliary tract infections.
This box summarizes key points contained in the article.
26
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unfavorable outcome in patients infected by cefepime susceptible-dose dependent isolates.
Antimicrob Agents Chemother. 2015 Sep 28 [Epub ahead of print]54. Harris PNA, Wei JY, Shen AW,
et al. Carbapenem versus alternative antibiotics for the treatment of bloodstream infections caused
by Enterobacter, Citrobacter or Serratia species: a systematic review with meta-analysis. J
Antimicrob Chemother. 2016 Nov;71:296-306
55. Griffith MM, Gross AE, Sutton SH, et al. The impact of anti-infective drug shortages on hospitals in
the united states: trends and causes. Clin Infect Dis. 2012 Jan;54(5):684-91
31
Figure Legend:
Figure 1. AmpC Hyper-productive States – Induction and Stable De-repression
Figure 1. AmpC Hyper-productive States – Induction and Stable De-repression

A B
1: Beta-lactam causes increased release of large 1: Beta-lactam causes increased release of large
cell wall peptides, AmpD unable to cleave all cell cell wall peptides, mutated AmpD unable to cleave
wall fragments, 2: Small cell wall peptides enter any cell wall fragments, 2: Large cell wall peptides
cell, 3: Large cell wall fragments inhibit binding of enter cell, 3: Large cell wall fragments inhibit
UDP to some AmpR, 4: AmpR incompletely binding of UDP to any AmpR, 4: AmpR inactivated
represses some AmpC transcription; increased but and unable to represses any transcription of AmpC;
low levels of AmpC generated high level of AmpC generated
32
Table 1. General susceptibility pattern and EUCAST and CLSI Breakpoints of Select Antimicrobials
for ESBL and AmpC-producing Enterobacteriaceae.
Antibiotic ESBL AmpC EUCAST MIC CLSI MIC
(mg/L) (mcg/mL)
S R S I R
Penicillin R R - - - - -
Amoxicillin-clavulanate S/I/R R ≤8 ≥8 ≤8/4 16 ≥32/16
Ampicillin-sulbactam S/I/R R ≤8 ≥8 ≤8/4 16/8 ≥32/16
a
Mecillinam S S ≤8 ≥8 ≤8 16 ≥32
Cefazolin R R - - ≤2 4 ≥8
Ceftriaxone R R ≤1 ≥2 ≤1 2 ≥4
Cefotetan S R - - ≤16 32 ≥64
Piperacillin-tazobactam S/I/R S/I/R ≤8 ≥16 ≤16/4 32/4-64/4 ≥128/4
Cefepime S/I/R S/I/R ≤1 ≥4 ≤2 4-8b ≥16
Ertapenem S S ≤0.5 ≥1 ≤0.5 1 ≥2

Meropenem S S ≤2 ≥8 ≤1 2 ≥4
Aztreonam R S ≤1 ≥4 ≤4 8 ≥16
I-Intermediate; MIC-minimum inhibitory concentration; R-resistant; S-sensitive
a
EUCAST provides breakpoints of mecillinam for uncomplicated urinary tract infection only
b
CLSI uses susceptible dose dependent (SDD) for cefepime instead of intermediate to delineate
that higher doses must be achieved at the site of infection for effective microbiological activity
33
Table 2. Efficacy of antimicrobial agents for treatment for ESBL-producing organisms based on infection site.
Infection Type / Description Antibiotic(s) Organism(s) / Clinical Outcomes Comments
Reference Studied β-Lactamase
Types
UTI
Rodríguez-Baño J, et An observational case- AMC 500 mg/125 mg ESBL-producing E. 84% of subjects treated with AMX-CLV Of the cases of patients with ESBL-
al. 2008 [43] control analysis of 112 Q 8 hours coli determined to reach clinical cure producing E. coli, 5% developed
community dwelling FOF 3 g x 1 dose 93% of subjects treated with fosfomycin bacteremia.
patients with tromethamine determined to reach
community acquired of clinical cure, although no statistical

health care associated analysis was performed.
UTI aimed to evaluate
efficacy of fosfomycin Clinical cure rate was significantly
and AMC higher in isolates with MIC ≤8 mcg/mL
compared to MIC ≥16 mcg/mL for AMX-
CLV (p=0.02).
Park SH, et al. 2014 A retrospective cohort Carbapenems ESBL-producing E. Clinical efficacy of non-carbapenem Non-carbapenem therapy consisted
[44] study of 150 patients Non-carbapenems coli therapy (for community onset of: AG (44.7%), FQ (17.9%), BL/BLI
with community onset pyelonephritis was similar to that of (19.4%), SXT-TMP (7.5%)
acute pyelonephritis carbapenem therapy (aHR, 0.96; 95% CI,
evaluating carbapenem 0.41-2.27) Seven patients in the non-
and non-carbapenem carbapenem group received
definitive therapy inappropriate therapy for the entire
efficacy duration
Bacteremia
Tamma PD, et al. 2015 Retrospective analysis PTZ ESBL-producing E. For patients receiving empiric PTZ All patients were given definitive
[13] of 213 bacteremic MEM coli, Klebsiella therapy (48%), 14 day mortality was carbapenem therapy after ESBL status
patients to determine spp., or P. 17% compared to 8% in patients who was determined
the mortality impact of marcescens received empiric carbapenem therapy
empiric treatment with (52%). All isolates had PTZ MICs ≤16 mcg/mL,
BLBLI or carbapenem with the majority having MICs ≤8
therapy A 1.92 times increased risk of death at mcg/mL (86%)
14 days was associated with empiric PTZ
therapy after adjustment for age, Pitt
bacteremia score and ICU level of care
(95% CI,1.07-3.45)
Rodríguez-Baño J, et A post hoc analysis of PTZ ESBL-producing E. Of 103 patients analyzed for empiric Majority of bacteremia was due to
34
al. 2012 [22] 192 patients with AMC coli therapy, 72 received empiric therapy urinary and/or biliary sources.
bacteremia evaluating IPM with a BLBLI and 31 received a
mortality impact of ETP carbapenem. Dose regimens:
BLBLI and carbapenem MEM PTZ 4500 mg/6 hours
therapy Seven day, 14 day and 30 day mortality AMC 1200 mg/8 hours
rates were similar between subjects IPM 500 mg/6 hours
receiving BLBLIs and carbapenems, 2.8% MEM 1 g/8 hours
versus 9.7%, 9.7% versus 16.1%, and ETP 1 g/24 hours
9.7% versus 19.4%, respectively (p=0.2).
For patients who received empiric and

definitive therapy with carbapenems
mortality was 16.7%, compared to 9.4%
those who received BLBLI empiric
therapy and carbapenem definitive
therapy (p=>0.1).
A Cox regression analysis revealed BLBLI

definitive therapy was not associated
with mortality (HR, 0.76; 95% CI, 0.28-
2.07).
Ofer-Friedman H, et A retrospective cohort PTZ ESBL-producing E. Median PTZ MICs in the carbapenem Carbapenem cases defined as
al. 2015 [45] analysis of 79 patients ETP coli, K. group was 8 mg/L and 4 mg/L in the PTZ patients who received ≥2 doses of
with non-urinary MEM pneumoniae, P. group (p=0.09). carbapenem from 3 days prior to or
sources of bacteremia, IPM mirabilis 14 days following culture date
from two DOR Out of the 10 patients receiving PTZ
geographically distinct 80% died within 90 days, compared to PTZ cases defined as patients who
institutions, evaluating 48% of the 60 carbapenem patients (OR, received ≥2 doses of PTZ from 3 days
mortality impact by 4.5; 95% CI, 1.01-34; p=0.05). prior to or 14 days following culture
comparing PTZ and date
carbapenem Thirty day mortality was 60% in the PTZ
group, compared 34% of carbapenem Patients who received 1 or more
patients (OR, 3; p=0.10) doses of both or with other agents
were not included
In the multivariate analysis of 90 day
mortality, PTZ therapy was associated
with significantly higher mortality (OR,
7.9; 95% CI, 1.2-53: p=0.03)
35
Kang CI, et al. 2012. A retrospective analysis PTZ ESBL-producing E. Thirty six patients received empiric Twenty three patients in the PTZ
[46] of 114 patients with Carbapenem (not coli and K. therapy with PTZ and 78 received a empiric therapy group received
bacteremia patients further defined) pneumoniae carbapenem definitive therapy with an alternative
comparing 30 day agent
mortality rates In the 36 patients of PTZ group, the 30
between PTZ and day mortality rate was 22.2% compared
carbapenem therapy to 26.9% in the carbapenem group
(p=0.59)
After adjustment for confounding

variables in the multivariate analysis, no
difference in mortality rate was
identified between PTZ and
carbapenem empiric therapy (OR, 0.63;
95% CI, 0.17-2.27; p=0.34)
Chopra T, et al. 2012 A retrospective cohort Primarily MEM ESBL-producing E. Forty three patients received FEP No association with FEP MIC and
[47] of 113 patients FEP coli and K. monotherapy and 26 received FEP as mortality was identified (no analysis
evaluating mortality pneumoniae part of combination therapy. provided)
impact of treatment Carbapenem monotherapy was given to
with FEP or 14 patients and 30 received
carbapenem therapy carbapenem as part of combination
therapy.
No significant difference in mortality

rates for FEP vs carbapenem therapy,
35% and 38%.
During multivariate analysis FEP and

carbapenem therapy were not
associated with increased mortality (OR,
1.66; 95% CI 0.71-3.87), (OR 0.61; 95%
CI 0.26-1.5), respectively
Tumbarello M, et al. Retrospective Not well described: ESBL-producing E. Inadequate empiric therapy, based on in Inadequate therapy also included
2007 [48] evaluation of 186 Β-lactam/β-lactamase coli, K. vitro susceptibility testing, was initiation with agent(s) with activity
patients who inhibitor pneumoniae, and administered to 47.8% of patients ( (based on in vitro susceptibility
developed bloodstream AG P. mirabilis 42.7% received a cephalosporin, 32.6% testing) >72 hours after bloodstream
infection evaluating Carbapenems were given a FQ, 13.5% were given a infection onset
36
impact of initial CIP AG, and 11.2% were given an BLBLI

therapy on mortality
Inadequate empiric therapy was
identified as a variable independently
associated with increased 21 day
mortality rate
Group who received inadequate

treatment had a 59.5% 21 day mortality
rate compared to 18.5% mortality rate

in those treated with adequate empiric
therapy (OR [95% CI], 2.38 [1.76-3.22];
p=<0.001)
In the group who initially received

inadequate therapy but was corrected
based on in vitro susceptibility, 21 day
mortality rate was 52%, compared to
18% for those who received adequate
therapy within hours of BSI onset (OR,
2.18; 95% CI, 1.58-3.01; p=<0.001)
Of the 97 patients who received

adequate therapy from the start based
on in vitro susceptibility, 21 day
mortality rates were highest with FQs
(44.4%; OR, 4.05; 95% CI, 1.89-8.65; p=<
0.001 and lowest with carbapenems
(5.5%; OR, 0.14; 95% CI, 0.02-1.03; p=
0.01)
Retamar P, et al. 2013 A retrospective analysis PTZ ESBL-producing E. Thirty nine patients received PTZ All patients received PTZ therapy
[49] of 39 patients with coli monotherapy, irrespective of PTZ MIC
bacteremia evaluating All patients with urinary sources of
the impact of PTZ MIC Low MIC (≤2 mg/L) was identified in bacteremia survived, regardless of
on mortality 46.1% of isolates, 25.6% had MIC
intermediate MIC (4-8 mg/L), and 28.2%
had high MIC (>8 mg/L)
37
Overall all cause 30 day mortality was

17.9%, and when all patients were
considered presentation with severe
sepsis or shock was associated with
increased mortality
Mortality was significantly lower in

patients with low and intermediate
MICs combined (57.1%) compared to
high MIC (57.1%) (RR, 0.21; 95% CI,

0.06-0.75; p=0.01)
Mortality in patients with low MIC (0%)

was significantly lower than
intermediate and high MIC (41.1%) (RR,
0.13; 95% CI, 0.01-0.98, p=0.002)
Hyle EP, et al. 2005 A retrospective No description of ESBL-producing E. Inadequate initial antimicrobial therapy Inadequate therapy was defined as
[50] evaluation of 187 specific antimicrobials coli and K. was given to 59.9% of patients. Of >48 hours elapsing between the time
patients who used pneumoniae those, 21.4% died. In patients who a culture was obtained and initiation
developed urinary tract received adequate initial antimicrobial of treatment with an antimicrobial
infection, pneumonia, therapy (40.1%), 10.7% died (OR [95% agent to which the infecting organism
bacteremia, wound or CI], 2.28 [0.92-6.24]; p=0.06) was ultimately shown to be
intra-abdominal susceptible
infection with ESBL Patients with non-urinary sources of
producing organisms infection had significantly higher risk of
mortality, despite adequacy of initial
antimicrobial therapy (OR [95% CI], 0.71
[0.17-2.88])
In the multivariate analysis, inadequate

initial therapy was a major predictor for
patients with non-urinary sources of
infection (adjusted OR [95% CI], 10.4
[1.91-52.96]; p=0.007)
Paterson DL, et al. A prospective Primarily IPM ESBL-producing K. Use of carbapenem therapy was Forty nine cases of bacteremia were
2004 [34] observational study of CIP pneumoniae associated with statistically significant treated with monotherapy,
71 patients with Cephalosporins lower 14 day mortality compared to carbapenems in 27 cases,
bacteremia evaluating BLBLIs non-carbapenem therapy (OR, 0.173; ciprofloxacin in 11 cases,
38
the mortality of AMK 95% CI, 0.039-0.755; p=0.012) cephalosporins in 5 cases, BLBLIs in 4
carbapenem vs non- cases and amikacin in 2 cases
carbapenem therapy Carbapenem therapy was
independently associated with a lower Ten of 15 cases used carbapenem
risk of all-cause mortality (OR, 0.09; 95% therapy in combination with a non-
CI, 0.01-0.65; p=0.017), and mortality carbapenem agent.
attributed to K. pneumoniae bacteremia
(OR, 0.04; 95% CI, 0.002-0.5; p=0.013)
Miscellaneous
Trivedi M, et al. 2012 522 patients with UTI, Carbapenems ESBL-producing E. Successful treatment with carbapenems Majority of infections were UTI
[28] pneumonia, Non-carbapenems coli and K. (86%) and non-carbapenem therapy (80%) (54.87%) followed by bacteremia
bacteremia, intra- pneumoniae as was similar, (p=0.152), however, no and soft tissue infections (11.34%
abdominal or soft predominate baseline severity of illness scores were and 11.85% respectively)
tissue infections organisms evaluated between the two groups.
admitted to a tertiary Non-carbapenems therapy
care center In patients with UTI, more non-carbapenem consisted of:
agents (n=192) were used compared to cefoperazone/sulbactam (~60%),
carbapenems (n=68). PTZ (~20%), FQ (~15%), AG(~10%),
other (~5%)
In non-urinary infections, carbapenem and
non-carbapenem agents were used is
similar frequencies, although no statistical
analysis was performed.
Lee NY, et al. 2012 Retrospective analysis FEP ESBL-producing E. The empiric therapy cohort included 112 In the definitive therapy cohort,
[31] of 197 patients with ETP coli, K. patients, 21 were treated empirically with lower FEP MIC was associated
Enterobacteriaceae IPM pneumoniae, E. FEP and 91 were treated with a with lower mortality rates; MIC ≤1
bacteremia evaluating MEM cloacae carbapenem. Mortality rates were higher in (16.7%), MIC 2-8 (45.5%), and MIC
30 day mortality in patients treated with FEP despite in vitro ≥16 (100%) (p=0.035)
patients receiving activity compared to carbapenem
empiric and definitive treatment, 47.1% vs 11.9% (p=0.002). No significant difference in
therapy with FEP or hospital length of stay was found
carbapenem therapy A total of 178 patients were included in the between FEP and carbapenem
definitive therapy cohort. Patients receiving therapy
FEP therapy had more clinical failure (OR,
6.2; 95% CI, 1.7-22.5; p=0.002),
microbiological failure (OR, 5.5; 95% CI 1.3-
39
25.6; p=0.04), and 30 day mortality (OR,

7.1; 95% CI, 2.5-20.3; p=<0.001).
Mendes RE, et al. A post-hoc analysis of CAZ-AVI + ESBL-producing Although no statistical analyses were The primary ESBLs identified in the
2015. [37] the phase trials metronidazole E. coli and/or K. performed on the rates of favorable CAZ-AVI group were: CTX-M-15
evaluating clinical IPM pneumoniae outcomes between treatment groups, alone (22.8%), CTX-M-15 plus
efficacy of CAZ-AVI among those treated with CAZ-AVI, 85.7% additional ESBLs (51.4%), or other
compared to had favorable responses compared to ESBL enzymes (25.7%).
carbapenem therapy 79.2% in the carbapenem group.
for UTI and intra- The primary ESBLs identified in the
abdominal infections When evaluated based on type of ESBL carbapenem group were: CTX-M-
gene, those treated with CAZ-AVI and 15 alone (30%), CTX-M-15 plus
with the CTX-M-15 100% (8/8) had additional ESBLs (63.3%), or other
favorable outcomes compared to 60% ESBL enzymes (20%).
(6/10) in the carbapenem group.
Favorable response was defined as
When CTX-M-15 and other ESBLs were eradication of all pathogens from
identified 77.8% (14/18) had favorable urine and blood in the UTI group,
outcomes when treated with CAZ-AVI and resolution or significant
compared to 89.5% (17/19) in the improvement of signs/symptoms
carbapenem group. in the intra-abdominal infection
group.
LaBombardi VJ, et al. 13 patients with FEP ESBL-producing E. Of the 11 patients, 3 experienced clinical One of the patients who
2006 [51] pneumonia, UTI, otitis coli or K. failure or persistence of infection while experienced clinical failure had an
media and/or sepsis pneumonia being treated with FEP isolate with an initial FEP MIC of
with an ESBL isolate >64 but continued to receive FEP
Gavin PJ, et al. 2006 23 patients with PTZ or PTZ with GEN ESBL-producing E. PTZ therapy was 100% effective for clinical 4 patients developed clinical
[27] positive ESBL urine, or SAM for <48 hours coli or K. success in UTI sources failure with PTZ therapy were 2
blood, sputum skin and pneumonia, were treated successfully with
soft tissue and/or and/or K. oxytoca PTZ therapy achieved 91% success in MEM
abdominal cultures patients with non-urinary sources in
evaluated for clinical isolates with MIC ≤16/4 mcg/mL but only
cure with PTZ 20% successful when the MIC was >16/4
treatment mcg/mL (p=0.027)
Zanetti G, et al. 2003 A randomized, FEP ESBL-producing K. Out of the original 209 patients, 23 (16%) Duration of therapy was similar
[52] controlled, blinded trial IPM-cilastin pneumoniae were found to have an ESBL organism as between FEP and IPM, 9.1 and 9.4,
of 209 nosocomial P. aeruginosa the likely pathogen respectively
pneumonia patients
40
evaluating clinical Among the ESBL infected patients, clinical All FEP MICs were determined to
response between FEP response was achieved in 30% of the FEP be susceptible in the FEP treated
and IPM-cilastin treated patients compared to 100% in the group
IPM-cilastin group
All-cause 30 day mortality rates were 26%

and 19% in the FEP and IPM-cilastin groups,
respectively, (p=0.25)
AG: aminoglycoside; AMC: amoxicillin-clavulanic acid; AMK: amikacin; BLBLI: β-lactam β-lactamase inhibitor; CAZ-AVI: ceftazidime-avibactam; CI: confidence interval; CIP:
ciprofloxacin; DOR: doripenem; ETP: ertapenem; FEP: cefepime; FOF: fosfomycin; FQ: fluoroquinolone; ICU: intensive care unit; IPM: imipenem; MEM: meropenem; MIC: minimum
inhibitory concentration; OR: odds ratio; PTZ: piperacillin-tazobactam; SAM: ampicillin-sulbactam; UTI: urinary tract infection
41
Table 3. Efficacy of non-carbapenem agents for treatment for AmpC-producing organisms

Infection Type / Description Antibiotic(s) Organism(s) / Clinical Outcomes Comments
Reference Studied β-Lactamase
Types
Blancette LM, et al. Retrospective, FEP Serratia spp., A total of 16 patients were given ETP A majority of patients included in
2014 [40] matched, case-control ETP Citrobacter spp., compared to 32 who were given FEP the study were on
study of 48 patients Enterobacter spp. Medical/Surgical services at the
with bacteremia, Univariate analysis revealed that there was time of positive culture, 81% in
pneumonia, skin and no statistical difference in clinical both ETP and FEP treated groups
soft tissue infection, treatment success for patients give ETP

intra-abdominal compared to FEP, 69% vs. 89%, Phenotypic evaluation for AmpC-
infection, or UTI respectively, (p=0.14) production was used to identify
admitted to an cases
academic hospital Rates of secondary superinfection were
evaluating clinical similar between ETP and FEP, 25% vs. 17%,
responsiveness to respectively, (p=1)
carbapenem or FEP
In patients with culture positive infection
after study drug completion, rates of study
organism resistance to study drugs were
similar between ETP and FEP, 38% vs. 33%,
respectively, (p=1)
Tamma PD, et al. 2013 78 patients with MEM AmpC-producing In the propensity score-matched cohort 30- No patients treated with MEM
[38] confirmed bacteremia, FEP Enterobacter spp., day mortality was similar between FEP and developed MEM resistant isolates
pneumonia, intra- S. marcescens, or MEM (31.2% and 34.3% respectively, with 30 days from initial isolate
abdominal infection Citrobacter spp. p=0.99)
admitted to tertiary One patient treated with FEP
care center treated Median duration of hospital stay was developed an E. cloacae resistant
with MEM or FEP similar between FEP and MEM (12.6 days isolate at a different collection site
and 14.6 days respectively, p=0.63) 6 days after initiation of FEP
therapy
Siedner MJ, et al. 2014 Retrospective analysis FEP Enterobacter spp. Of 36 patients who received FEP FEP MIC was associated with
[39] of 368 patients with Carbapenem (not monotherapy none had persistent persistent bacteremia, 3% for MIC
bacteremia comparing further defined) bacteremia compared to 4 of 16 who ≤2 and 26% for MIC ≥4 (p=<0.001)
efficacy of FEP and received carbapenem monotherapy
carbapenem therapy (p=<0.01)
42
In hospital mortality was similar between

carbapenem therapy (aOR, 1.82; 95% CI,
0.82-3.8; p=0.11) and FEP therapy (aOR,
1.5; 95% CI, 0.73-3.47; p=0.25)
Harris PNA, et al. 2015 A systematic review Carbapenems E. cloacae A total of 8 studies were included in the There was considerable
[54] and meta-analysis of 11 BLBLIs E. aerogenes analysis of BLBLIs compared to heterogeneity identified in the
studies reviewing FQs S. marcescens carbapenems (I-squared, 65.5%; p=0.005), target organism(s) within the
carbapenem and Cefepime C. freundii 2 of the studies showed a higher mortality studies.
alternative antibiotics M. morganii rate with the use of BLBLIs. When these
for bloodstream studies were removed, heterogeneity Within the three meta-analysis
infections caused by became non-significant. Additionally, when conducted a total of 207 patients
AmpC-producing adjusted for gender, age, and severity of were administered carbapenem
Enterobacter, illness no significant difference in mortality therapy while 27 received BLBLI,
Citrobacter or Serratia was identified (aOR, 0.94; 95% CI, 0.22- 104 received FEP, and 34 received
spp. 4.12). a FQ, owing to a very limited
sample size to evaluate.
A total of 8 studies were included in the
meta-analysis evaluating cefepime
compared to carbapenems (I-squared,
31.6%; p=0.176). When adjusted for
gender, age, and severity of illness no
significant difference in mortality was
identified (aOR, 0.64; 95% CI, 0.21-2.00).
A total of 8 studies were included in the

meta-analysis evaluating FQs compared to
carbapenems (I-squared, 35.1%; p=0.148).
When adjusted for gender, age, and
severity of illness no significant difference
in mortality was identified (aOR, 0.59; 95%
CI, 0.14-2.52).
aOR: adjusted odds ratio; BLBLI: β-lactam β-lactamase inhibitor; CI: confidence interval; ETP: ertapenem; FEP: cefepime; FQ: fluoroquinolone; MEM: meropenem; MIC: minimum
inhibitory concentration; UTI: urinary tract infection

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Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Treatment options for extended-spectrum beta-

Ryan G. D'Angelo PharmD, Jennifer K. Johnson Ph.D., D(ABMM), Jacqueline T.

To link to this article: http://dx.doi.org/10.1517/14656566.2016.1154538

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Download by: [University of York] Date: 21 February 2016, At: 06:26

Publisher: Taylor & Francis

Journal: Expert Opinion on Pharmacotherapy

Treatment options for extended-spectrum beta-lactamase (ESBL) and AmpC-

Ryan G. D’Angelo, PharmD

University of Maryland School of Pharmacy

Jennifer K. Johnson, Ph.D., D(ABMM)

Jacqueline T. Bork, M.D.

Emily L. Heil, PharmD, BCPS AQ-ID AAHIVP

lactam-β-lactamase inhibitor combinations and cefepime (FEP).

the treatment of ESBL-producing Enterobacteriaceae cannot be widely recommended. However,

agents. In the treatment of infections caused by AmpC-producing Enterobacteriaceae, FEP has

been shown to be a clinically useful carbapenem-sparing alternative. Carbapenems and FEP

share many structurally similar characteristics in regards to susceptibility to AmpC β-lactamases,

characteristics should be used to employ FEP optimally.

Key Words: multidrug resistance, infectious diseases, Enterobacteriaceae, ESBL, AmpC

Carbapenem-resistant Enterobacteriaceae CRE

common Gram-negative pathogens in urinary tract infections (UTIs), community acquired

pneumonia (CAP) and healthcare-associated pneumonia (HCAP), bloodstream infections (BSIs)

and a multitude of intra-abdominal infections [2]. Previously, expanding resistance was

increases in resistant Gram-negative infection outbreaks within institutions.

AmpC β-lactamases have also proven to be an increasing threat to antimicrobial resistance.

practice with a dwindling armamentarium of effective agents for life-threatening infections.

increasing use of carbapenems is leading to a concordant increase in carbapenem resistance.

carbapenem resistance is previous exposure to a carbapenem [1,15,16]. In as little as three days

of carbapenem exposure, a 5.9 times risk of developing carbapenem resistant Gram-negative

to significantly increased mortality [15,16].The availability of newer, carbapenem sparing agents

expressing Enterobacteriaceae, accurate interpretation of resistance patterns and current evidence

2.1 Literature Review

β-lactamases, AmpC, Enterobacteriaceae, antibiotic resistant, urinary tract infection,

pyelonephritis, bacteremia, community acquire pneumonia, nosocomial pneumonia, intra-

abdominal infection, critically ill, treatment, European committee on antimicrobial susceptibility,

regimen as early as possible.

3.1 ESBL Resistance

mutations of β-lactamases due to selective pressure from antibiotic exposure. Compared to

cephamycins [18,19]. The most well-known β-lactamases associated with Enterobacteriaceae

penicillin and first generation cephalosporins to extended spectrum cephalosporins (e.g.,

ceftriaxone [CRO] and cefotaxime [CTX]) and ATM [6,20].

mutations lead to enhanced hydrolysis causing an opening of the β-lactam ring.

3.2 AmpC β-lactamase Resistance

Similar to ESBLs, AmpC-producing organisms will typically confer resistance to penicillins

generally only chromosomal AmpC will undergo hyper-production in the appropriate

spp., and Morganella spp.

genes located on plasmids are generally constitutively produced, whereas chromosomally

With increasing 1,6-anhydro-N-acteylmuramic acid peptide binding and decreased UDP-N-

acetylmuramic acid peptide binding, AmpR undergoes a conformational change leading to

Induction of AmpC transcription occurs as higher concentrations of 1,6-anhydro-N-

stem peptides from1,6-anhydro-N-acteylmuramic acid thus allowing for increased binding to

4. Differentiating ESBL and AmpC β-lactamases

inhibition of some of the β-lactamase inhibitors, organisms actively producing AmpC β-

lactamases may be resistant to agents such as, amoxicillin-clavulanate (AMC), ampicillin-

sulbactam (SAM) and in some cases piperacillin-tazobactam (PTZ). The difference in

certain isolates [9].