Expert Review of Anti-infective Therapy

ISSN: 1478-7210 (Print) 1744-8336 (Online) Journal homepage: https://www.tandfonline.com/loi/ierz20

Extended spectrum β-lactamase producing

enterobacteriaceae: carbapenem sparing options

Abdullah Tarık Aslan & Murat Akova

To cite this article: Abdullah Tarık Aslan & Murat Akova (2019): Extended spectrum β-lactamase
producing enterobacteriaceae: carbapenem sparing options, Expert Review of Anti-infective
Therapy, DOI: 10.1080/14787210.2019.1693258

To link to this article: https://doi.org/10.1080/14787210.2019.1693258

Accepted author version posted online: 13

Nov 2019.

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Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group

Journal: Expert Review of Anti-infective Therapy

DOI: 10.1080/14787210.2019.1693258
Article type: Review

Extended spectrum β-lactamase producing enterobacteriaceae: carbapenem sparing

options

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Abdullah Tarık Aslan1, Murat Akova*2

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Hacettepe University Faculty of Medicine, Department of Internal Medicine, Sihhiye, Ankara
06100, Turkey

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2
Hacettepe University Faculty of Medicine, Department of Infectious Diseases and Clinical
Microbiology, Hacettepe University Sıhhıye Campus, Sihhiye, Ankara 06100, Turkey
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*Corresponding author:

Murat Akova
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Hacettepe University Faculty of Medicine

Department of Infectious Diseases and Clinical Microbiology

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Hacettepe University Sıhhıye Campus

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Sihhiye, Ankara 06100

Phone (312) 305-1279 Fax (312) 310-4179

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Email: makova@hacettepe.edu.tr
Abstract

Introduction: Carbapenems have an important place in our antibiotic armamentarium and have been trusted
to effectively treat infections caused by ESBL-producing Enterobacteriaceae for many years. However, the
utility of carbapenems has been compromised by the emergence of resistance especially in
Enterobacteriaceae. Therefore, carbapenem-sparing alternative antibiotics are of extreme importance in
clinical practice.

Areas covered: We reviewed studies addressing currently available antibiotic options used as both empiric and

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definitive therapy for the treatment of infections due to ESBL-producing Enterobacteriaceae published in the

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PubMed/MEDLINE, Web of Science and Scopus databases without any date restriction. Current treatment
alternatives included beta-lactam/beta-lactamase inhibitor combinations, cefepime, cephamycins,

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fluoroquinolones, aminoglycosides, fosfomycin, pivmecillinam, temocillin and, various oral alternative agents.
We also summarized the clinical and molecular epidemiology, early prediction methods and impact of initial

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empirical therapy and de-escalation approach for ESBL-producing Enterobacteriaceae infections.

Expert opinion: The current literature would endorse the carbapenem utilization for patients with severe and
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high inoculum-high risk infections. However, for milder infections particularly for urinary tract infections,
various carbapenem-sparing antibiotics can be considered in selected cases. For infections including easily
drainable intra-abdominal infections and catheter-related infections in which catheter removal is readily
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available more reliable data are needed to recommend non-carbapenem antibiotics confidently.
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Article highlights

• Determining the appropriate empirical therapy for ESBL-producing Enterobacteriaceae infections is a

great challenge in modern era.
• The utility of carbapenems has been compromised by the emergence of resistance especially in
Enterobacteriaceae. Therefore, carbapenem-sparing alternative antibiotics are of extreme importance
in clinical practice.
• Currently, available scientific evidence indicates that type-2 carbapenems remain the best alternatives
for treating severe infections caused by ESBL-producing Enterobacteriaceae. However, this conclusion

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is mostly derived by observational studies and only one randomized, prospective trial with some

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limitations supported this suggestion.
•

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Alternatives to carbapenems in this setting include PTZ, fosfomycin and amikacin and they seem to be
considered only for low risk-low inoculum infections such as UTIs.

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For infections including easily drainable intra-abdominal infections and catheter-related infections in
which catheter removal is readily available more reliable data are needed to recommend non-
carbapenem antibiotics confidently.
•
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Newer BLBLIs (ceftazidime-avibactam and ceftolozane-tazobactam) should be reserved only for
infections with carbapenem -resistant organisms and resistant P. aeruginosa infections respectively.
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• Oral treatment alternatives merit further studies in community-onset infections caused by ESBL-
producing Enterobacteriacea..
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1. Introduction and global epidemiology of ESBL-producing bacteria

CTX-M type ESBLs in community acquired Escherichia coli and hospital acquired Klebsiella spp., particularly
blaCTX-M-15 have spread across the globe (1). Dissemination of this particular ESBL gene has been enabled by
highly virulent epidemic strains of E. coli (i.e. ST131) and plasmids such as epidemic IncFII plasmids (2,3). These
strains frequently carry multi-drug resistance elements with blaCTX-M-15 including resistance determinants for
fluoroquinolones, trimethoprim sulfamethoxazole (TMP-SMX) and gentamicin (4,5).

According to the 2017 EARS-Net surveillance; population weighted mean rate of the third generation

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cephalosporin (3rd GC) resistance was 14.9% and 31.2% in invasive isolates of E. coli and Klebsiella

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penumoniae, respectively, in EU/EAA countries. More than 80% of isolates in both species were ESBL
producers. The resistance rates were highest in Eastern and Southern European countries as compared with

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Northern and Western Europe (6). In the US, the incidence of infections with ESBL-producing organisms have
steadily increased and reached 15% in Klebisellae and 12% in E. coli in 2013 (7,8). In Southeast and East Asia,

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the detection rates of nosocomial ESBL-positive E. coli isolates were 20–40%, and the rates showed an
increasing tendency in many countries reaching 60–70% in China (9). In long-term care facilities, the ESBL
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detection rates were reported to be 10–60% in Europe and ~50% in China (10). The ESBL fecal colonization
prevalence in the community was 14% as the global average rate; 4% in Europe, 2% in North America and the
rates were ~46% in Western Pacific (11). The bla CTX-M-15 is currently the most common ESBL gene worldwide
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(12). The blaCTX-M-14 gene is also frequently detected in certain regions of Europe such as Spain and is prevalent
in East and Southeast Asia (12, 13).
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2. Clinical characteristics of infections caused by ESBL-producing bacteria

The World Health Organization prioritized Enterobacteriaceae resistant to the 3rd GCs as one of the most
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hazardous pathogens for public health because of easy transmission of ESBL genes leading rapid increase in
prevalence particularly in the community, and limitations in antibiotic choices for treatment (14).
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The residential care facilities are very important reservoirs for ESBL-producing pathogens in the community as
a result of various comorbidities, catheter use, greater transmission opportunities and antibiotic overuse
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(15,16). Most of infections caused by these microorganisms involve urinary tract infections (UTIs) (13).

Life-threating bloodstream and intra-abdominal infections have also been encountered particularly with CTX-M
type ESBL-producing E. coli in both community- and in- hospital settings in several countries (17, 18). In
addition to previous exposure to broad spectrum antibiotics leading colonisation with these bacteria,
uncontrolled usage of antibiotics in veterinary medicine and food producing animals are also responsible for
emergence and rapid dissemination of ESBLs (19, 20). Other environmental sources such as urban
wastewaters, contaminated drinking water and spreading via international travel have been identified as
alternative acquisition modes of ESBL genes in the community (21-23).
3. Early prediction methods, impact of initial empirical antimicrobial therapy and de-escalation

Infections caused by ESBL-producing organisms are associated with high rate of mortality (24-27), prolonged
infection-related hospital stay (14,28,29) and increased healthcare associated costs (30-33). Therefore,
selecting appropriate antibiotic therapy in early empirical period is highly important but turns to be a challenge
in face of increased prevalence of antimicrobial resistance. Although some studies asserted no significant
impact of inappropriate initial empirical antimicrobial therapy on mortality (34,35), many others consistently
demonstrated otherwise (36-39). This controversy may be partly explained by the resistance profile of the
offending pathogen, the source and severity of infections, (not) achieving appropriate source control, baseline

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comorbidities and place of acquisition of infection (e.g. community-onset vs hospital-acquired).

Several ESBL-prediction scores have been developed and the decision analysis usually includes factors such as

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previous infection or colonization, age, recent hospitalization, presence of co-morbidities and previous
exposure to antibiotics (40,41). Using these scores may improve appropriateness of empirical antimicrobial

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therapy and reduce carbapenem utilization. However, in the wake of an era with emerging community-
acquired ESBL-related infections, the predictability of these infections has further decreased (42).
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Two different researchers investigated the effects of transition to oral step-down therapy between 2-5 days of
bacteremia and early de-escalation of therapy for infections due to Enterobacteriaceae, respectively. Both
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found that oral step-down therapy and early de-escalation were not associated with higher rates of 30-day
mortality and clinical failure compared to controls. Switch to oral step-down therapy shortened the duration of
hospitalization significantly (43,44). These findings might indirectly suggest that the empirical therapy is
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important for clinically relevant outcomes such as mortality but definitive therapy is particularly related with
ecological impact and cost.
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4. Carbapenem sparing therapeutic options for infections caused by ESBL-producing bacteria

A systematic literature search using PubMed/MEDLINE, Scopus and Web of Science databases was performed
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without any date limitation. Key terms included ESBL or extended-spectrum β-lactamases, bacteremia,
bactereamia, bloodstream infection, urinary tract infection, complicated urinary tract infection, intra-
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abdominal infection, biliary tract infection, sepsis, septic shock, pneumonia, high inoculum infection, low
inoculum infection, piperacillin-tazobactam, ciprofloxacin, levofloxacin, quinolones, fluoroquinolones, cefepime,
cephamycins, cefmetazole, cefoxitin, flomoxef, moxalactam, carbapenem, doripenem, meropenem,
ertapenem, fosfomycin, aminoglycosides, amikacin, plazomicin, mecillinam/pivmecillinam, amoxicillin-
clavulanate, cefoperazon-sulbactam, trimethoprim-sulfamethoxazole, nitrofurantion, ceftazidime-avibactam,
ceftolozane-tazobactam and temocillin. Full text articles in English language were considered. Articles were
screened by title and abstract for possible inclusion, and references within articles of interest were scanned to
capture additional sources. Priority was given for clinical studies, randomized controlled trials and meta-
analyses published after 2011.
4.1. Cephamycins

Cephamycins (e.g. cefoxitin, cefotetan, flomoxef, moxalactam and cefmetazole) appear to be a reasonable
option against ESBL-producing organisms owing to sufficient in vitro activity (45). However, clinical data
evaluating cephamycins for ESBL-producing Enterobacteriaceae are limited and usually included few patients.
In a multicenter retrospective cohort study, Matsumura et al. (46) compared patients receiving cefmetazole or
flomoxef with those given carbapenems for a bloodstream infection (BSI) with ESBL-producing E. coli.
Propensity score adjusted analysis showed that therapy with cefmetazole or flomoxef were not associated with
higher rate of mortality in empirical (adjusted HR, 0.87; CI, 0.11 to 6.52) and definitive treatment cohorts as

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compared to those receiving a carbapenem (adjusted HR, 1.04; CI, 0.24 to 4.49). Clinical success rates were also

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similar for both treatment groups. However, there were some important limitations; (i) urinary tract infection
(UTI) as a bacteremia source was significantly more frequent in cephamycin group and primary bacteremia was

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more common in carbapenem group, (ii) cefmetazole and flomoxef were evaluated as a combined treatment
group. Thus, we cannot discriminate the activities of cefmetazole and flomoxef from each other, (iii) SOFA

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score was significantly higher in those treated with carbapenems. Also, severe sepsis and septic shock were
more frequent in carbapenem receiving patients but this difference did not reach statistical significance (27%
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vs 47% p:0.13), (iv) Patients receiving cephamycins were infected with highly susceptible pathogens (MIC50≤
1ug/ml for both cefmetazole and flomoxef), (v) the number of patients included in treatment arms were quite
few to provide a statistical power. Thus, the outcomes obtained from this study cannot be evaluated as a
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robust evidence for adequacy of cephamycins in BSIs due to ESBL-producing Enterobacteriaceae. In another
retrospective single center study, Fukuchi and colleagues (47) found that 30-days mortality rates of patients
with BSIs caused by Enterobacteriaceae, mostly E. coli (93%), were similar for cefmetazole and a carbapenem
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when used as definitive therapies. This study had also similar limitations with the previous study. In addition,
the authors did not investigate the effects of confounding factors on study outcome. Other studies
demonstrated high rate of cefmetazole resistance (40%) in ESBL-producing Enterobacteriaceae isolates
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particularly having blaCTX-M-14 and blaCTX-M-15 genes (48), and significantly higher sepsis related mortality rates in
patients treated with flomoxef than those treated with a carbapenem (49). Furthermore, the combined
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expression of ESBLs and AmpC diminish susceptibility rates to many antibiotics involving cephamycins,
extended spectrum cephalosporins, β-lactam/β-lactamase inhibitor combinations, and even carbapenems (50).
AmpC is usually encoded by chromosomal genes, however acquisition of plasmid mediated AmpC is not
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uncommon (51). Furthermore, cephamycins are not readily available for routine use in many countries. When
one considers these data in addition to the fact that optimum doses of cephamycins are not defined for various
type of infections and for varying MIC levels, these antibiotics might only be recommended for definitive
treatment of non-severe UTIs caused by ESBL-producing Enterobacteriaceae.

4.2. Cefepime

Cefepime, an oxyimino-cephalosporin, has enhanced activity against Enterobacteriaceae since it resists to

degradation by Amp-C β-lactamases and slightly more resistant against ESBLs (except CTX-M-10 and TEM-10)
than other cephalosporins (52). However, the activity of cefepime can be impaired by high inoculum infections
(53-56). The main pharmacokinetic/pharmacodynamic (PK/PD) target of cefepime, similar to other β-lactams, is
drug levels above the MIC for approximately 40-50% of dosing interval (57,58). Thus, rapid bacterial recovery
occurs when antibiotic concentrations fall below the MIC of the antibiotic. A study demonstrated that this
target attainment with 1-2 gr bid cefepime among gram negative organisms can be reached in less than 30% of
cases (59). Another study showed that if 67% fT>MIC is accepted as the target, the probability of target
attainment was achieved 90%, 80% and 45% for MICs of 2, 4 and 8 μg/mL respectively, with standard cefepime
dosing (i.e. 2 g bid) (60). In a retrospective cohort analysis, mortality rates for individuals treated with cefepime

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1-2 g bid at an MIC 8 mg/L and >8 mg/L were 56.3% and 53.3%, respectively (61). These studies indicate that

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the success of cefepime therapy is possibly dictated by the low MICs and availability of target attainment of
serum concentrations of cefepime.

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The results from published studies comparing the efficacy of cefepime with carbapenems for the treatment of

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ESBL-producing Enterobacteriaceae infections produced conflicting results. In a retrospective observational
study, sepsis related mortality rates due to monobacterial BSIs with ESBL-producing E. coli, K. pneumoniae or
Enterobacter cloacae were higher with cefepime than those treated with a carbapenem (47.1% vs. 11.9%
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P=0.002). Thirty-day mortality rates were also higher in the cefepime group (58.8% vs 17.9%, P=0.001). In
multivariate analysis, definitive cefepime therapy was found as an independent risk factor for 30-day mortality.
Moreover, patients with a BSI caused by an isolate with cefepime MIC ≤1 mg/L had more clinical success and
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less sepsis-related mortality as compared with those isolates with cefepime MIC 2-8 mg/L (62). In another
retrospective study, MIC of cefepime was identified as a significant prognostic factor for bacteriological
eradication but not for clinical failure. The possible explanation of this conflicting results is that
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aminoglycosides or fluoroquinolones were invariably administered with cefepime in the second study (63).
Furthermore, clinicians should be aware of the risk pertaining with unacceptably high rate of major error of
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cefepime susceptibility test result against ESBLs producers with Vitek2 microdilution method (64).

A retrospective cohort study with BSIs caused by ESBL-producing E. coli in patients with leukemia and
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hematopoietic stem cell transplantation explored efficacy of carbapenems, cefepime or piperacillin-

tazobactam. 14-day mortality rates were observed as 8%, 0% and 19% in cefepime, piperacillin-tazobactam and
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carbapenem groups, respectively. In multivariate analysis, empiric treatment with cefepime was not associated
with increased 14-day or 30-day mortality (65). Although other studies showed evidence in the affirmative of
the results in previously mentioned studies, several methodological errors and low number of patients
analysed in these trials would prevent from constructing causal relationships (66-68).

Overall, administration of cefepime for severe infections caused by ESBL producers cannot be safely
recommended. However, one can consider prescribing cefepime regimen of 2 g bid or tid with prolonged
infusion (i.e. 3-4 hours) for non-severe infections (e.g. UTIs, non-bacteremic skin and soft tissue infections) with
ESBL producers with low cefepime MIC values. But even in such cases some caution would be appropriate.
4.3. β-lactam/β-lactamase inhibitor (BLBLI) combinations

Piperacillin-tazobactam (PTZ) has a good in vitro activity against ESBL-producing E. coli, but K. pneumoniae are
usually less susceptible (69-71). High inoculum infections such as bacteremia, pneumonia and osteoarticular
infections might adversely affect the activity of BLBLIs (55, 72). While amoxicillin-clavulanate (AMC) was able to
sustain bactericidal activity against ESBL-producing E. coli for 24 hours in case of high bacterial load, PTZ had a
substantial inoculum effect for both ESBL-producing and non-ESBL producing E. coli (73).

The PK-PD models proved a 99% success rate of achieving the target (time above the MIC 50%) against ESBL

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producers by using 4.5 gram qid if the MIC of the isolate is ≤ 8 mg/L. However, success rate diminished to 57%

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when the MIC is 16 mg/L (74). Piperacillin-tazobactam dosage is particularly important in critically ill patients
since these patients often show different PKs through changes in key variables (e.g. renal clearance, increased

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capillary permeability, hypoalbuminemia and increased volume of distribution) (74). In many studies,
prolonged or continuous infusion of PTZ was found to be associated with better results in critically ill patients

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and gram negative infections (76- 78) than those with standard usage, although studies challenging these
results were also published (79). an
Piperacillin-tazobactam did not show the same bactericidal activity to ESBL-producers and non-ESBL-producers
despite the presence of the same MIC (56). MICs of BLBLIs are dependent on type of ESBL (SHV group is more
resistant), porin mutations, the amount of β-lactamase produced, the rate of enzyme resynthesis, concomitant
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expression of AmpC, presence of early OXA-type enzymes (e.g. OXA-1), simultaneous expression of multiple
type of ESBLs, inhibitor resistant ESBL co-production and methods used for MIC determination (80). In a survey
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including ESBL-producing isolates of Enterobacteriaceae from 72 US hospitals, PTZ susceptibility rates were
67.2%, 92.9% and 45.8% for isolates having CTX-M-15-like and CTX-M-14-like ESBLs and SHV-type enzymes,
respectively (81). Therefore, knowing molecular epidemiology of ESBLs and local resistance patterns might be
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useful before deciding empirical therapy with PTZ.

Several observational studies were published comparing PTZ and carbapenems as empirical or definitive
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therapy for infections caused by ESBL-producing Enterobacteriaceae with conflicting results.

In a post hoc analysis of six Spanish prospective cohort studies, authors investigated BLBLIs (AMC and PTZ) for
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both the empirical and definitive treatment of ESBL-producing E. coli bacteremia. Mortality rates were similar
in both therapy groups receiving BLBLIs or carbapenems (82). Predominant type of ESBL was CTX-M-14 and the
prevalence of AmpC beta-lactamase production in Enterobacteriaceae isolates was reported as <5% in Spain at
that time (83). Main sources of bacteremia were low inoculum infections (e.g. UTIs) or infections in which
bacterial load can be reduced efficiently with surgical interventions (e.g. cholangitis) and >90% of patients were
treated with 4.5 gram PTZ qid. Mortality at 30 days in patients empirically treated with PTZ 4.5 grams qid was
only 4.5 % when the MIC was ≤4 mg/L, and 23% if the MIC was >4 mg/L (82). Similar results observed with 39
patients having bacteremia with ESBL- producing E. coli and treated with PTZ, empirically. None of the patients
with bacteremia originated from urinary tract were dead irrespective of PTZ MICs. However, in patients having
bacteremia from a non-urinary tract source, lower mortality rate was significantly associated with lower MIC (≤
2 mg/L). Of note, low MIC group mostly included patients with intra-abdominal infection in whom, source
control with surgical intervention might be a critical confounding factor (84). In contrast, Tamma et al. (85)
reported significantly lower 14-day mortality rate with empirical meropenem therapy than with PTZ empirical
therapy. These conflicting results may be due to the type of infections treated in different trials where efficacy
of PTZ may differ. Tazobactam is mainly excreted in the urine (86). Therefore, high concentrations of PTZ in
urine can kill ESBL-producing E. coli more efficiently since inoculum effects of gram negative organisms are low
in urinary tract infections. CTX-M type ESBLs can be inhibited more efficiently with tazobactam than SHV and
TEM type ESBLs which are encoded more frequently by Klebsiella spp (87). High dose PTZ (i.e. 4.5 gram qid)

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would help to attain PK/PD target (88). Thus, the failure of PTZ in the study by Tamma et al. (85) could be
explained by the fact that the study included bacteremia cases caused by E. coli, K. pneumoniae, Klebsiella

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oxytoca and Proteus mirabilis. Most of the patients were treated with 3.375 gram PTZ qid and only 39% of
patients received 4.5 gram of PTZ qid. Source of bacteremia cases were central line associated in 44%. The

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second most common source was pneumonia which imply a high inoculum of bacteria in a compartment where
penetration of antibiotics may be impaired (85). Also, distribution of MIC values for PTZ were as follows:
2μg/ml (1%), 4μg/ml (39%), 8μg/ ml (46%), and 16μg/ml (14%). As compared with the study by Rodríguez-
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Baño et al. (82), the MIC values of PTZ were higher in isolates included in the study by Tamma et al. (85).

In a multicenter, multinational, retrospective study (INCREMENT-ESBL), 365 and 601 patients were analysed in
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an empirical and a targeted treatment cohort, respectively. CTX-M-, SHV- and TEM-type ESBLs were produced
in 77.3%, 10.6% and 12.1% of isolates, respectively. In the empirical therapy cohort, there were no difference
between BLBLIs and carbapenem groups in terms of 14-day clinical cure/improvement and 30-day crude
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mortality rates. In the targeted therapy cohort, the cure/improvement rates and 30-day mortality rates with
BLBLIs and carbapenems were 90.2% vs. 85.5% and 9.8% vs. 13.9%, respectively. The adjusted odds ratio (OR)
was 1.61 (95% confidence interval [CI]) value 0.58-4.86) for cure/improvement and 0.59 (0.19-1.71) for 30-day
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crude mortality. No difference can be detected between AMC and PTZ against carbapenems in subgroup
analysis. Only 11% of patients admitted to ICU, the most of the microorganisms were isolated from urinary or
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biliary sources and the vast majority of patients (83%) received 4.5 gram PTZ qid (89).

The outcomes in patients with BSIs from the original INCREMENT cohort revealed that 30-day mortality rate
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was significantly higher in patients with ESBL-producing K. penumoniae BSI than ESBL-producing E. coli BSI
(33.7% vs 17.4% OR: 1.64, p=0.016). Seventy six per cent of 286 isolates in which PCR analyses for ESBL genes
were detected had CTX-M type ESBLs. Clinical characteristics and 30-day mortality rates were similar in CTX-M
and non-CTX-M groups (90). Similarly, in a single center Italian study; BSIs with ESBL-producing Proteus spp
were also found as an independent risk factor for 30-day mortality (91).

Gudiol et al. (92) conducted a multicentric retrospective cohort study involving neutropenic patients with an
hematological malignancy. One hundred and seventy four patients in empirical treatment cohort and 251
patients in definitive treatment cohort were included. In both crude analysis and propensity score matched
analysis, there were no significant difference in 30-day case fatality rates and in other secondary outcomes. In
propensity score matched empirical and definitive therapy cohorts, the 30-day mortality rates were 20% and
11% for the former and 13% and 7% for the latter for the BLBLIs and carbapenem groups, respectively. The
most common source of BSIs was endogenous and followed by catheter-related BSIs and urinary tract
infections.

Ng et al (93) conducted a multicentre retrospective cohort study in patients who had ESBL-producing E. coli and
K. pneumoniae bacteraemia treated with PTZ or a carbapenem. After adjusting for confounders, empiric PTZ
administration was not associated with increased 30-day mortality rate (OR 1.00, 95% CI; 0.45-2.17).

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Furthermore, empirical use of PTZ caused fewer multi-drug resistant bacterial and fungal infections as
compared with a carbapenem.

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A meta-analysis of 21 studies compared carbapenems with other alternatives for the treatment of bacteremia
with ESBL-producing Enterobacteriaceae. Mortality was not increased with BLBLIs in both empiric (relative risk

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[RR]:0.91, 95% CI, 0.66-1.25) and definitive therapies (RR:0.52, 95% CI, 0.23-1.13) as compared with
carbapenems. However, the mortality rate was higher in patients treated with non-BLBLI carbapenem-sparing
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options than those treated with a carbapenem alone in both therapy groups. But one should be aware that
several observational studies included in this meta-analysis did not perform multivariate and propensity score
analyses to eliminate effects of other confounders and potential bias in the selection of antibiotics. Also, many
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patients who were treated with BLBLIs in empirical treatment period received a carbapenem as a definitive
therapy (94).
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Another two systematic reviews and meta-analyses revealed similar results by comparing BLBIs and
carbepenems in terms of mortality in BSIs caused by ESBL-producing Enterobacteriaceae (95,96).
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One possible advantage of prescribing PTZ may be reduction of selection pressure on ESBL producers. Several
investigators reported substantially lower frequency of ESBL-producing Enterobactericeae in patients with
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previous exposure to PTZ compared to oxyimino β-lactams and fluoroquinolones (4,97). Mclaughlin et al. (98)
also showed that PTZ was associated with lower rate of carbapenem resistance in Enterobactericeae spp. than
type-2 carbapenems . However, others pointed out that excessive use of PTZ can facilitate acquisition of OXA-
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type β-lactamases and inhibitor-resistant TEM genes (99). Piperacillin-tazobactam might also exert broader
selective pressure than ertapenem given the anti-pseudomonal coverage of the former.

A recent multinational, multicenter, parallel group, randomized, prospective, non-inferiority clinical trial
(MERINO) included 391 participants from 26 centers in 9 countries and found that the 30-day mortality rate for
patients with ceftriaxone-nonsusceptible E. coli or K. pneumoniae BSIs treated with PTZ was 12.3%, compared
with 3.7% for patients who were treated with meropenem as definitive therapy (100). The difference in the 30-
day mortality rate exceeded the non-inferiority margin of 5%. Therefore, the authors recommended against
the use of PTZ to treat ceftriaxone-nonsusceptible E. coli or K. pneumoniae BSIs. However, there have been
several criticisms for this study that deserve mention here (101-103): There were imbalances in study arms
favouring meropenem (i.e. more UTIs in meropenem arm, cases with quick SOFA score >2 were more frequent
in PTZ arm). Randomization occurred after a 48-h empirical therapy and in 40.7% of enrolled patients the
infection was already partially resolved at the time of enrolment. A substantial proportion of patients
randomized to carbapenem arm received PTZ or other antibiotics and vice versa. Adequate source control was
not described, although, if present, it could affect mortality. All deaths were not associated with primary
infection but rather related with underlying comorbidities (mainly metastatic cancers). The geographical
differences in resistance rates would also have affected the results, as blaSHV- producing Enterobacteriaceae

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have been common in many countries where the trial was conducted which accounted for 8 of the 23 deaths

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(35%) in the PTZ arm. Nonsusceptibility to PTZ might be higher than identified as 10% and 67% of isolates had
ampC and blaOXA-1 genes, respectively. Finally, a narrower-than-usual non- inferiority margin (i.e. -5% vs -15%

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used in similar trials) might have adversely affected non-inferiority of PTZ.

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Cefoperazone-sulbactam is another BLBLI combination and has been widely used in Asia particularly in China
for the treatment of infections caused by Enterobacteriaceae. However; very limited clinical studies have been
published until now to use for ESBL producers (104). Additional data are needed for any suggestion in clinical
practice with this agent.
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In conclusion, current available data indicate that type-2 carbapenems (meropenem or imipenem) seem to be
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the preferred choice of therapy for high inoculum infections caused by ESBL-producing Enterobactericeae. The
role of PTZ, if any, in such infections would require further controlled studies for definitive therapy. Piperacillin
tazobactam can be suggested with appropriate dose and infusion regimens if MIC value of the culprit
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microorganism is low and adequate source control is provided or in those clinically stable patients with low
inoculum infections.
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4.4. Temocillin
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Temocillin, the 6-α-methoxy derivative of ticarcillin, which is active against ESBL- and derepressed AmpC-beta-
lactamases can be considered as a potential carbapenem-sparing agent (105). Optimal dose of temocillin (2
gram bid) was significantly associated with favourable outcomes in limited number of observational studies
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(106). The fact that temocillin is only licensed in England, Belgium and France currently limits its use. Large
scale, randomized studies are required to establish the efficacy of this drug against ESBL-producing
Enterobacteriaceae among different type of infections.

4.5. Fosfomycin

Fosfomycin is a bactericidal, low molecular weight, broad-spectrum antibiotic and exerts its bactericidal activity
against several multi-drug resistant gram negative bacteria by irreversible inhibition of early steps of
peptidoglycan synthesis (107). Fosfomycin, primarily excreted by kidneys and has very good tissue penetration
in soft tissues, lungs, bone, cerebrospinal fluid, and heart valves (108). Especially for the urinary tract, the drug
achieves high concentrations for a prolonged period of time. Optimal PK/PD index has not been determined,
yet. During monotherapy with fosfomycin, rapid resistance may develop. In vitro studies also demonstrated
appearance of resistant subpopulations within 30-40 h of drug exposure (107). Therefore, other than acute
cystitis the drug should be used in combinations for treating any other infections. The fosA3 gene which is
responsible for plasmid-mediated fosfomycin resistance is usually co-harboured with blaCTX-M gene in E. coli
thus compromising the efficacy of the drug against ESBL producers (109). Bi et al (109) from China
demonstrated fosfomycin resistance rate among ESBL-producing E. coli as 6.7%. Seventy per cent of these
isolates acquired fosfomycin resistance via plasmid-mediated fos A3 gene. On the other hand, frequencies of

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chromosomal mutations in both genes of mur A and glpT-uhpT membrane transporters were 12.5% in the
same E. coli isolates. Lu et al. (110) reported that fosfomycin resistance rate among ESBL-producing K.

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pneumoniae isolates were 27.8%. Among fosfomycin resistant K. pneumoniae isolates, mutations rates in
murA and membrane transporter genes were 70% and 97%, respectively. Fosfomycin resistance can also be

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affected by the in vitro sensitivity method used. Approved MIC detection method is agar dilution using agar
media supplemented with 25 ugr/ml of glucose-6-phosphate (111). Resistance rates are higher in studies in
which disk diffusion or microbroth dilution susceptibility testing were used than in studies with a reference
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agar dilution (112).

In a randomized controlled trial fosfomycin was non-inferior to piperacillin-tazobactam in complicated UTIs

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including some ESBL-producing Enterobacteriaceae (113). Oral formulation (fosfomycin trometamol) has been
used to treat cystitis (114) or chronic bacterial prostatitis due to ESBL-producing Enterobacteriaceae (115). In a
retrospective single institution study, fosfomycin and ertapenem were compared as step down therapy in
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outpatients with UTI caused by ESBL-producing Enterobacteriaceae and 30 day re-admission/re-visit rates were
evaluated as primary outcome (116). Fosfomycin was primarily administered as 3 gram/every 72 hours (62%)
or 3 gram/every 48 hours orally (23%). There were no difference between fosfomycin and ertapenem in terms
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of 30 day re-admission/re-visit rates. Şenol et al. (113) compared fosfomycin vs carbapenems

(imipenem/cilastatin or meropenem) for complicated UTIs caused by ESBL-producing E. coli. Twenty seven
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patients were treated with 3 gram fosfomycin orally every other day for 3 doses and 20 patients with
conventional doses of imipenem/cilastatin or meropenem. Clinical success and relapse/re-admission rates
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were similar in the two treatment groups.

Fosfomycin therapy can be recommended for uncomplicated UTIs with ESBL-producing E. coli as a step-down
outpatient therapy. However, complicated UTIs, prostatitis, UTIs with K. pneumoniae would require more data
from well-designed studies. A randomized clinical trial (“FOREST”) comparing the safety and efficacy of
fosfomycin versus meropenem in bacteremic UTIs caused by ESBL-producing E. coli have been ongoing (117).

4.6. Fluoroquinolones
Fluoroquinolones appear to have lost a great part of their activity against Enterobacteriaceae prior to the
emergence of contemporary ESBL types such as CTX-M-15 in specific molecular epidemiological investigations
(118). These early evolutionary changes that were seen in Enterobacteriaceae in 1980s are still prevailing in
most E. coli and K. pneumoniae strains today (119,120). In parallel with in vitro susceptibility studies, empirical
therapy with carbapenems was found superior for treatment outcomes than fluoroquinolones in many clinical
studies (121- 123). Nonetheless, it may be noteworthy reviewing its efficacy in susceptible isolates. Tumbarello
et al. (124) demonstrated that, 8 of the 16 patients with bacteraemia caused by ESBL-producing
Enterobacteriaceae who were treated with ciprofloxacin, died. Among these patients, the ciprofloxacin MIC
was 0.5-1 mg/L. In contrast to this study, a meta-analysis showed that fluoroquinolones were associated with

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increased mortality compared with carbapenems in empirical treatment, but not as a targeted therapy (in
infections with susceptible isolates) (94). Thus, these drugs cannot be recommended for the treatment for

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severe infections caused by ESBL-producing Enterobacteriaceae. However, fluoroquinolones may be
considered in targeted therapy or in oral de-escalating therapy for mild infections (e.g. UTIs) caused by

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quinolone-susceptible ESBL-producing Enterobacteriaceae with limited supporting data.

4.7. Aminoglycosides
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Aminoglycosides are other potential options as carbapenem-sparing therapy for UTIs in monotherapy and in
monotherapy or combination therapy of intra-abdominal infections (125). A study from Korea evaluated in
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vitro activities of 21 different antimicrobial agents alone or in combination with aminoglycosides against ESBL-
producing E. coli isolates. Among 291 isolates, amikacin resistance was 11.7% in contrast 51.9% for gentamicin.
Importantly, combination of amikacin with PTZ elevated PTZ susceptibility rate from 57.0% to 92.8% (126). In
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some clinical studies, aminoglycosides were reported as a reasonable carbapenem-sparing options for UTIs
with ESBL-producing Enterobacteriaceae (127-129). Enterobacteriacea have developed resistance to
aminoglycosides by various mechanisms among which the most common is enzymatic modification by
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aminoglycoside-modifying enzymes (AMEs). These enzymes can be frequently co-produced by various ESBLs,
but with mostly CTX-M types on the same plasmid (130). A novel aminoglycoside, plazomicin, derived from
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sisomicin is an appealing alternative antibiotic against multidrug-resistant organisms (131). Plazomicin is

completely resistant to inactivation by AMEs (132). Also, it is currently approved for complicated UTIs caused
by plazomicin-susceptible gram-negative bacteria including those with carbapenem resistance.
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4.8. Mecillinam/Pivmecillinam

Pivmecillinam is a pro-drug of mecillinam which is an amidinopenicillin with selective activity against gram-
negative bacteria. Raja et al (133) reported pivmecillinam susceptibility rate against ESBL-producing
Enterobacteriaceae as >95%. In another series, this rate was found as 85% (134). In a Norwegian prospective
multicenter observational study, 400 mg tid pivmecillinam therapy was equally effective against community
acquired UTIs caused by ESBL-producing E. coli vs. non-ESBL-producing strains (135). However, 200 mg tid
regimen was associated with significantly higher clinical failure rate when it was administered ≤ 5 days in
patients infected with ESBL (+) E. coli. Other small scale studies produced similar results for this indication
(136,137). Unfortunately, mecillinam/pivmecillinam is not available in several countries.

The use of pivmecillinam can be considered in lower UTI with ESBL-producing Enterobacteriaceae but should
not be utilized in high inoculum infections because of absence of supporting data.

4.9. New β-lactam/β-lactamase Inhibitor (BLBLIs) Combinations

Ceftolozane is particularly active against P. aeruginosa but can be degraded by ESBL enzymes. Combination

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with tazobactam extends its activity against ESBLs including TEM, SHV, CTX-M types (138,139). In vitro

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susceptibility rates for ESBL-producing E. coli and K. pneumoniae were reported as 92.8% and 73.5%,
respectively (140). Pooled analysis of two double-blind, randomized, controlled trials (ASPECT-cUTI) and

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(ASPECT-cIAI) compared efficacy of ceftolozane-tazobactam with levofloxacin and meropenem, respectively. In
vitro susceptibility rates for ESBL-producing E. coli and K. pnemoniae were 95% and 56.7% according to FDA

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criteria, respectively. The clinical cure rates were 97.4% (76/78) for ceftolozane-tazobactam [ESBL-E. coli,
98.0%; ESBL-K. pneumoniae, 94.4%], 82.6% for levofloxacin and 88.5% for meropenem (141). The results may
be supportive for ceftolozane-tazobactam to be used in these infections as a carbapenem sparing drug.
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Ceftazidime-avibactam is a combination of ceftazidime with a novel non-BLBLI within the diazabicyclooctane
chemical class and protects ceftazidime from hydrolysis by class A (TEM, SHV, CTX-M, KPC), class C (AmpC) and
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some class D (OXA) beta-lactamases (142,143). Ceftazidime-avibactam is usually more active in vitro against
ESBL producers than ceftolozane-tazobactam. (144). However, so far there has been no clinical study
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investigating clinical efficacy of this combination for infections caused by ESBL-producing Enterobacteriaceae.
For antimicrobial stewardship purposes, this combination should be reserved for carbapenem-resistant Gram-
negative bacteria (141).
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4.10. Oral antibiotic alternatives of carbapenems for the treatment of ESBL-producing Enterobacteriaceae
infections
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Increasing prevalence of infections with community-onset ESBL-producing Enterobacteriaceae revived

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forgotten old antibiotics as possible candidates for these infections, particularly in UTIs. In some clinical and in-
vitro susceptibility studies, fosfomycin, pivmecillinam and nitrofurantion were evaluated against ESBL-
producing isolates and infections with these pathogens. Fosfomycin is licenced for intravenous use only in a
few countries. Its main limitation is the development of overt resistance or hetero-resistance during treatment.
Use of fosfomycin in clinical setting was described above in detail. However, there is currently no convincing
data about the efficacy and safety of fosfomycin for the treatment of severe infections and/or infections with
high bacterial loads even with iv formulation.

In a study with 238 eligible cases, E. coli (83.6%) was the most common causative pathogen. Sixty patients
received oral antimicrobial treatment after a median of four days of appropriate iv therapy, and 178 patients
completed treatment with iv therapy. Fluoroquinolones (58.3%) were the most commonly prescribed oral
agents, followed by TMP-SMX and AMC. Oral antimicrobial treatment was not associated with treatment
failure (adjusted OR 0.66; 95% CI 0.18–2.44) and hospitalization length was shorter in the oral treatment group
(6.2 days versus 10.7 days; P < 0.01). Acute pyelonephritis recurrence caused by ESBL-producing
Enterobacteriaceae infection within 2 months was not associated with oral antimicrobial treatment (adjusted
HR 0.56; 95% CI 0.16–2.00). Using oral agents reduced hospital stay without adverse effects on treatment
outcome. However, the number of cases was insufficient to analyse the clinical efficacy of each oral
antimicrobial agent individually (145).

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As previously mentioned, fluoroquinolone resistance is highly prevalent among ESBL-producing
Enterobacteriaceae and only few data available for treating infections with these bacteria. Targeted therapy for

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infections caused by susceptible isolates could be an option with these antibiotics. In future studies,
fluoroquinolones should be evaluated in definitive treatment of infections caused by susceptible isolates as an

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oral switch option, since there are few specific data about their effectiveness (146). Furthermore, recent
cautionary data about fluoroquinolone toxicity should be considered while prescribing fluoroquinolones (147).
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Regarding TMP-SMX, although some ESBL isolates may be susceptible, co-resistance against TMP-SMX is quite
common and there are no studies in the literature that have been analysed this treatment option.
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Amoxicillin-clavulanate is a good option for susceptible isolates albeit susceptibility rate is low in many
countries (82). As a favourable feature, it does not suffer from the inoculum effect (73), and it may be used for
oral switch treatment. But, again more robust data are required to recommend oral treatment with AMC for
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infections with ESBL-producing Enterobacteriaceae.

Nitrofurantoin is active in-vitro against common causes of UTI including E. coli and Citrobacter spp.. However,
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Klebsiellae and Enterobacter spp. are less susceptible. Nitrofurantoin suggested as a preferred drug in an
international consensus guideline for UTI in 2010 (148). It may lead to major hepatic and pulmonary toxicity,
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but the true incidence is unclear (149). For the short-term treatment of uncomplicated urinary tract infection in
otherwise healthy young women, nitrofurantoin is a safe and effective choice. However, reliable clinical data to
utilize nitrofurantoin for UTIs with ESBL-producing Enterobacteriaceae are lacking.
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5. Conclusion

Currently, available scientific evidence indicates that type-2 carbapenems remain the best alternatives for
treating severe infections caused by ESBL-producing Enterobacteriaceae. However, this conclusion is mostly
derived by observational studies and only one randomized, prospective trial with some limitations supported
this suggestion. Alternatives to carbapenems in this setting include PTZ, fosfomycin and amikacin and they
seem to be considered only for low risk-low inoculum infections such as UTIs. On the other hand
fluoroquinolones and cefepime appear to be inappropriate options as carbapenem-sparing antibiotics.
Additional data are needed to establish the exact role of cefoperazone-sulbactam and temocillin which are not
widely available molecules. The new BLBLI combinations such as ceftolozane-tazobactam and ceftazidime-
avibactam should not be used as primary agents for these infections.

6. Expert opinion

Extended spectrum beta-lactamase producing gram-negative bacteria are frequent culprits in different types of
infections in clinical practice worldwide. Although the data are limited to determine the best available therapy
for infections caused by these pathogens, type-2 carbapenems seem to be the best option. The available

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clinical evidence dictates that carbapenem-sparing antibiotics should not be administered for high inoculum
infections, critically ill (e.g. septic shock) and immunocompromised patients. Also, level of evidence is

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insufficient to offer alternative antibiotics to carbapenems for non-biliary intra-abdominal infections and
catheter-related infections. ESBL-producing organisms are frequently resistant to non-beta-lactam antibiotics

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including fluoroquinolones, aminoglycosides and TMP-SMX due to co-expression of resistance determinants
against these antibiotics. Another important threat to public health is the rapid dissemination of ESBL genes in
the community and increasing prevalence of community-onset infections caused by ESBL-producing organisms.
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Not only UTIs but also BSIs and other invasive infections can be seen in the community setting with these
bacteria. International travel, urban wastewaters, food animals, companion animals and contaminated drinking
waters have been identified as possible sources for transmission of ESBL-producing organisms to humans in the
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community. Predictability of infections caused by ESBL producers has been further mitigated due to
widespread dissemination of these organisms in the community. Therefore, administration of appropriate
empirical therapy for these infections is a great challenge in modern era. The following suggestions for future
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research should be taken into account for ameliorating the problem caused by ESBL-producing bacterial
infections:
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1- Rapid diagnostic methods should be explored to shorten time interval between taking sample for culture
and identification of species, in-vitro susceptibilities and resistance determinants. Rapid diagnostics will
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provide relevant information not only for determination of appropriate therapy much earlier but also for
implementing the appropriate infection control measures. Therefore, affordable, user-friendly and accurate
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point-of-care tests are urgently needed in routine practice.

2- In the literature, non-carbapenem antibiotics are usually compared with carbapenems as monotherapy for
the treatment of infections with ESBL-producing organisms. However, combination of antibiotics could be
investigated as carbapenem sparing alternatives in well-designed clinical studies. Beta-lactam/beta-lactamase
inhibitor combinations plus aminoglycosides or cefepime plus aminoglycosides can be considered as most
suitable options for comparison with carbapenems in clinical studies for severe infections with ESBL producers.
3- Newer BLBLIs (ceftazidime-avibactam and ceftolozane-tazobactam) should be reserved for infections with
carbapenem-resistant organisms and resistant P. aeruginosa infections, respectively, but their role in infections
with ESBL-producing pathogens should also be established.
4- Efficacy of BLBLIs and other alternatives should be compared with carbapenems in infections where an
effective source control can be provided. Examples are intra-abdominal infections that can be drained and
catheter-related infections in which catheter removal is performed.
5- Efficacy of cephamycins, fosfomycin, pivmecillinam, temocillin and aminoglycosides in complicated UTIs
should be investigated and also optimal dose and duration of therapies with these antibiotics according to
varied MIC values should be determined by future studies.
6- Local molecular epidemiologic data and resistance patterns should be screened periodically to determine
optimal therapies in a particular region.
7- Prediction score models or decision tree algorithms may be useful for early prediction of infections caused

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by ESBL-producing organisms and decreasing unnecessary carbapenem prescription. Validation studies of
previous prediction score models and decision tree algorithms or constructing new ones can be performed in

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future studies.
8- Oral treatment alternatives merit further studies including infections caused by ESBL-producing

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Enterobacteriacea particularly as options for ambulatory therapy of community-acquired, mild infections.

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Funding

This work had no funding

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a
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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.
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Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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