Expert Review of Anti-infective Therapy

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

Addressing clinical safety of antimicrobial

resistance: personal perspectives

Petros I Rafailidis & Matthew E Falagas

To cite this article: Petros I Rafailidis & Matthew E Falagas (2019): Addressing clinical safety
of antimicrobial resistance: personal perspectives, Expert Review of Anti-infective Therapy, DOI:
10.1080/14787210.2019.1687294

To link to this article: https://doi.org/10.1080/14787210.2019.1687294

Accepted author version posted online: 31

Oct 2019.

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

Journal: Expert Review of Anti-infective Therapy

DOI: 10.1080/14787210.2019.1687294
Article type: Perspective
Addressing clinical safety of antimicrobial resistance: personal perspectives

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Petros I Rafailidis,1,2 and Matthew E Falagas*,1,3,4

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1
Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece
2
Democritus University of Thrace, Alexandroupolis, Greece

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3
Department of Medicine, Henry Dunant Hospital Center, Athens, Greece
4
Department of Medicine, Tufts University School of Medicine, Boston,
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Massachusetts, USA
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*Corresponding author:
Matthew Ε Falagas,
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Alfa Institute of Biomedical Sciences (AIBS),

9 Neapoleos Street, 151 23 Marousi, Athens, Greece
Tel: +30 694 61 10 000
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Fax: +30 210 68 39 605

E-mail: m.falagas@aibs.gr
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 Abstract

Introduction: Antimicrobial resistance is an important challenge for patients,

societies, practicing physicians and health care organizations worldwide. Predictions
in regard to the morbidity and mortality of antimicrobial resistance are grave
especially in the setting of an era where the pipeline of production of antimicrobial
agents is relatively dry.

Areas covered: Herein, a viewpoint will be provided regarding antimicrobial

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bacterial resistance as a clinical safety need based on personal experience and data
from the literature.

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Expert opinion: A variety of antibiotics has been produced during the last decade but

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novelty regarding truly new antimicrobial agents is rather little, as these new
antibiotics are mainly based on modifications of known pharmaceutical molecules.
Therefore, as there is still a desperate need to address optimal clinical safety in regard
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to antimicrobial resistance, we believe that strong financial incentives and rewards to
producers of antimicrobial agents (especially new in concept) are necessary.
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Furthermore, global surveillance of antimicrobial resistance as suggested by the
World Health Organization, coordination of measures of justified and appropriate use
of antibiotics and application of strict infection control principles are needed to lessen
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the negative clinical impact of antimicrobial resistance.

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Keywords: MDR, XDR, PDR, bacteria, antimicrobial resistance, antibiotics

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 1. Introduction

Antibiotics have proved to be an extraordinary invention of humanity to combat

infectious diseases. Unfortunately, from an evolutionary standpoint, the continuous
use of an antibiotic class will most likely lead to the development of a number of
strains that will have resistance to the specific drug. This has been witnessed in the
last decades as there is no antibiotic class immune to antimicrobial resistance.
However, antimicrobial resistance is not a phenomenon of the current era as genes

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encoding resistance to antibiotics have been found in deoxyribonucleic acid recovered

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from sediments dating back thousands of years [1].1 The indiscriminate use of
antibiotics in patients, but also in animals in the agriculture sector, has also played a

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significant role for the collateral damage of antimicrobial resistance [2].2

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Therefore, it comes not as a surprise that bacteria have become resistant to various
categories of antibiotics; unfortunately so, to many different classes of antibiotics at
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the same time. These bacteria that are defined as multidrug-resistant bacteria (MDR),
extensively drug-resistant (XDR) and pandrug- resistant (PDR) [3]3 are causing
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infections worldwide, not only in the most vulnerable of patients but also in previous
relatively healthy patients, thus raising concerns for the present and future. However,
while antimicrobial resistance levels of Gram-negative bacteria are very high, there
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are reports of decreasing resistance of some Gram-positive bacteria during the last
decade in some countries; rates of bacteremia due to methicillin-resistant
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Staphylococcus aureus (MRSA) and Enterococcus faecalis and Enterococcus faecium

decreased in the USA while remained relatively stable in Europe [4].
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There are dire predictions that mortality may reach 10 million in 2050 [5], although
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some scientists have disputed these number [6]. Nevertheless, what is undisputable is
the significantly increased morbidity and mortality associated with various MDR,
XDR and PDR bacteria reported in the literature over the last few years [7-9]. Thus it
is fully justified that the World Health Organization (WHO) regards antimicrobial
resistance “as a global health security threat that requires concerted cross-sectional
action by governments and society as a whole” and considers surveillance of
antimicrobial resistance [10] as well as improved awareness and understanding of
antimicrobial resistance through education and training as essential [11].
 2. Methods
We aim to provide our perspective regarding the unmet clinical safety need
antimicrobial resistance of Gram-negative and Gram-positive bacteria, based on our
experience and literature data. While other classes of antimicrobial resistance such as
that of mycobacteria, fungi, protozoa and viruses are not less important, our
perspective will focus on antimicrobial resistance of bacteria.

3. Discussion/ viewpoint

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Humans, as the dominant species on this planet, do not realize on many occasions that
they form part of an ecosystem that involves the presence of other organisms, both

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macroorganisms and microorganisms. This biodiversity has driven many aspects of
human history. While, the dominance on macroorganisms is undisputed with the

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extinction of many species and that of many others endangered, extinction or more
realistically repetitive victory on microorganisms is most often not possible. The
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medical and broader scientific community most likely considers the presence of
antimicrobial resistance present in microorganisms, an unmet clinical safety need.
This is not without reason. The morbidity and mortality, let alone the financial cost
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[12], that is associated with infections due to MDR, XDR and PDR bacteria is
enormous.
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Bacteria constitute a significant part of human life as they form the flora of the skin
and gastrointestinal tract [13]. This is a phenomenon of symbiosis, a mutual
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beneficent relationship between humans and bacteria rather than a parasitic behaviour
[13]. In many occasions however this symbiosis may lead to infections once the
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immunity of the host is compromised [14]. Furthermore, infections occur once

bacteria and other microorganisms attack the host via various portals of entry through
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the respiratory system, the gastrointestinal system, breaches of the skin and through
devices needed in many aspects of modern medicine. Obviously infections due to
bacterial pathogens need antimicrobial treatment in many occasions. However, there
are infections such as upper respiratory system infections that are caused by viruses
and for which antibiotics are prescribed without any impact on their outcome [15].
Indeed, as viruses are epidemiologically frequent causes of acute tonsillitis, sinusitis
and bronchitis antibiotics are completely unnecessary for their treatment. Clinical
acumen and experience analysing the history and information obtained from physical
 examination, the use of clinical tools (i.e. such as the Centor criteria) and at times the
use of appropriate diagnostic tests (rapid diagnostic tests, procalcitonin levels etc.) are
needed to prescribe antibiotics only when justified.

Physicians, for the sake of their patients’ lives, would like to prevail always once
infections due to bacteria are managed. Ideally, the constant production of new
antibiotics eternally, especially novel in conception in regard of what part of the
bacterial machinery they attack, would be welcomed so that the armamentarium of

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physicians is substantially empowered. Furthermore, thinking out of the box to
produce other new therapeutic approaches could be a possible way to deal with the

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continuously growing issue of antimicrobial resistance. Whilst it is completely logical
to ask the industry to invest in the production of new antimicrobial agents, the

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availability of these medications can provide a temporal advantage for humans over
bacteria, only for a relatively limited time at the best. Initially a hidden creeping
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minimal inhibitory concentration regarding the specific antibiotic (that goes under the
radar of antimicrobial surveillance on many occasions) evolves into full-blown
documented antimicrobial resistance [16-18]. The scientific community, health care
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providers patients and policy makers gradually during the last century witnessed that
there is a time period of a few years usually that bacteria became resistant to one or
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more classes of antibiotics [19]. Thus while antibiotics (representing modifications of

other antibiotics or discovered in the past) were introduced in the management of
infectious diseases during the last decades, antimicrobial resistance has increased
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dramatically [20].
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Antimicrobial resistance has various dimensions. The number of antibiotic classes

microorganisms can become resistant theoretically varies from none to all. The time
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needed to reach the antimicrobial resistance varies. Additionally intrinsic resistance of

microorganisms to antibiotics is another important aspect of antibiotic use in which
the physician should differentiate the in vitro results from the possibility of effective
treatment by using the specific agent (use of carbapenems in Stenotrophomonas
maltophilia infections). Intrinsic resistance to some antibiotic classes should be
known by treating physicians in order to avoid the reading of misleading in vitro
results[21].While exceptionally rare exceptions occur such as the persistent
susceptibility of Streptococcus pyogenes to penicillin or Treponema pallidum
 susceptibility to penicillin, the majority of Gram-positive bacteria and Gram-negative
bacteria have developed antimicrobial resistance to various classes of antibiotics.

Bacteria have evaded the attack by humans by elaborating various mechanisms of

antimicrobial resistance: production of enzymes capable of destroying antibiotics such
as beta-lactamases, loss of porins that hamper the move of antibiotics into the
bacterium, creation of efflux pumps that essentially eject the antibiotic, modification
by gene production of antibiotic binding sites on the bacterial cell wall such as

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mutation of penicillin-binding proteins[22]. The production of beta-lactamases by
bacteria has occurred as an epidemic on a global level and includes productions of

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various enzyme categories such as extended spectrum beta-lactamases, metallo beta-
lactamases, penicillinases and cephalosporinases and oxacillinases[23]. Biofilm

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production is another bacterial strategy that hampers further the effect of
antimicrobial agents[24]. Environmental pollution of wastewater with antibiotics
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produced in factories producing antimicrobial agents in Asia is a significant factor
that has been associated with antimicrobial resistance[25].
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These counter weapon strategies by bacteria that evolved in parallel with the
invention of newer antibiotics has led to a competitive race with very significant
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clinical safety issues expressed as survival and quality of life of patients. Magical
solutions are not in vision, but novel approaches are needed to try to tackle the issue
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of antimicrobial resistance. A relative dry pipeline of antibiotic production has as

early as 2010, caused the Infectious Diseases Society of America to express its
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concerns, the 10X 20 initiative, and call for the production of 10 new antibacterial
agents until 2020[26]. There is indeed a belief in the scientific community that more,
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novel and broader in variety antimicrobial agents are needed to fight infections[20];
ideally so with a constantly rising production of new effective and safe antimicrobial
agents. The pharmaceutical sector has addressed in some way this call, meeting at
least partially the challenge. Despite a reported decreased antibiotic pipeline
production, a variety of new antibiotics have entered the therapeutic arena during the
last decade such as 5th generation cephalosporins (ceftobiprol and ceftaroline),
lipopeptides (daptomycin), lipoglycopeptides (oritavancin, dalbavancin and
telavancin), oxazolidinones (linezolid and tedizolid), macrocyclics (fidaxomicin) and
 glycylcyclines (tigecycline). Living in an era of extended spectrum beta lactamases,
further attempts of the pharmaceutical sector led to the production of new
combinations of beta lactams with beta lactamase inhibitors such as ceftazidime-
avibactam, meropenem-vaborbactam, ceftolazone-tazobactam and imipenem-
cilastatin-relebactam. Other antibiotics are a Pseudomonas-sparing once daily
administered carbapenem (ertapenem), a fluoroquinolone with MRSA coverage
(delafloxacin) and a modified aminoglycoside (plazomicin). On many occasions these
new additions in our therapeutic armamentarium are targeting the ESKAPE bacteria

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(Enterococcus, Staphylocococcus, Klebsiella, Acinetobacter, Pseudomonas,
Enterobacter). As we are approaching 2020, strictly speaking numerically the 10X20

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initiative target has been reached. However, one has to acknowledge that novelty in
concept regarding these newer antibiotics is relatively little as they are generated

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through modification of known antibiotic classes. We believe while definitely a lot
more should have occurred, these newer antibiotics bring new alternatives as they
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bear new properties against resistance mechanisms. They cannot be considered as
resistance breakers, although one has to think whether there is indeed such a
possibility with any potential new human invention of antimicrobial agents.
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On other occasions physicians we and other physicians had and still have to resort to
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“old” antibiotics such as polymyxins [colistin (colistimethate sodium) and

polymyxins B] and fosfomycin to treat infections due to MDR, XDR and PDR
bacteria such as Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella
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pneumoniae and Enterobacter aerogenes.[27-29] as there were no therapeutic

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alternatives to combat these culprits. While colistin had its own documented position
in the population of cystic fibrosis patients, it was successfully used in our and others’
patient populations, especially the critically ill with hospital-acquired infections.
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Colistin administered through the intravenous and at times also by nebulization[30]

and fosfomycin proved to be effective and safe antibiotics (monitoring of renal
function tests is mandatory when colistin is administered). Nevertheless, the
occurrence of plasmid mediated colistin resistance mechanism genes[31] compounded
by the use of colistin led to the appearance of colistin-resistant bacteria thus
mandating its prudent use in order to preserve this valuable antibiotic[32].
The management of infections due to MDR, XDR and PDR bacteria needs at times
combination regimens of various antibiotics[33]. Synergistic regimens in general have
 been used to combat infections due to microorganisms such as Brucella spp., M.
tuberculosis and HIV mainly for their advantage of compound effectiveness.
However the theoretical advantage of decreased resistance by use of many agents has
not been verified through the use of multiple antimicrobial agents. Indeed, multidrug-
resistant tuberculosis constitutes one of the most formidable challenges of our time.
Nevertheless, one cannot ignore an ideal example of success of a combination
regimen, at least for the time being, the treatment success of Hepatitis C virus
infection with the use of the direct-antiviral agents[34]. This success, based on our

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current knowledge, would be definitely an example to follow if possible.

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Beyond the approaches of the pharmaceutical sector and those of physicians and
healthcare providers globally, WHO has focused its efforts and coordination in

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regard to combat antimicrobial resistance through the Global Antibiotic and
Development Partnership, the Interagency Coordination Group on Antimicrobial
Resistance, the Global Resistance Surveillance System[10,11]. Furthermore, every
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November since 2015, WHO through the World Antibiotic Awareness Week raises
public awareness through various activities. An additional very important step to
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address this worldwide epidemic of antimicrobial resistance is the coordinated
effort of WHO with the Food and Agriculture Organization of the United Nations
and the World Organization for Animal Health to optimize the use of antibiotics in
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humans and animals. In addition, scientists have proposed various measures to

combat antimicrobial resistance[35,36].
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Medicine should lead to a lengthy and full of quality life of patients in general and
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also specifically those with infectious diseases. Increasing age of a population but
also the total increase of the world population leads per se to the theoretical
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possibility that every member of the society will have more infectious episodes in
his life and thus will possibly need more courses of antibiotics. Thus even at a
constant rate of antibiotic use the possibility of emergence of resistant strains most
likely will increase.

Furthermore, many medical interventions such as immunomodulatory treatments for

rheumatic diseases, targeted treatment of cancer diseases have led to protracted
survival and also higher quality of life but there is an occasional price to pay, that of
 infections. In many instances these revolutionizing immunomodulatory interventions
compromise the immune system and thus while offering a well-deserved survival
benefit they are associated with an increase in infections [37,38]. It is the interaction
with the specific host that leads to the outcome of any therapeutic intervention.
Antibiotics function optimally to eradicate infections when an acceptably working
immune system is present. Therefore, it is well known that in neutropenic patients
protracted duration of antibiotic treatment is necessary and this can lead in a
probabilistic model to antimicrobial resistance[39].

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There is an ethical aspect associated with the use of antibiotics so that we can inherit
effective and safe antibiotics to the next generations. In order to preserve as long as

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possible the therapeutic value of antimicrobial agents we have summarized a list of
various approaches to try to address antimicrobial resistance (Table 1); among them

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antimicrobial stewardship is a key element. We would like to address that meta-
analyses have shown that the duration of antimicrobial treatment against many
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infections can be shortened without a negative impact on the infection outcome[40].
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4. Expert opinion

There is still a desperate need to address optimal clinical safety in regard to

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antimicrobial resistance. A variety of antibiotics has been produced during the last
decade but novelty regarding truly new antimicrobial agents is rather little, as these
new antibiotics are mainly based on modifications of known pharmaceutical
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molecules. However, we believe that society should not negate the efforts of
individuals, organizations, and of the pharmaceutical industry to adjust to the
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evolutionary battle between man and microorganisms. Indeed, we believe that strong
financial incentives and rewards to producers of antimicrobial agents especially new
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in concept are more than necessary. In addition, we believe that global surveillance of
antimicrobial resistance as suggested by the World Health Organization, coordination
of measures of justified and appropriate use of antibiotics and application of strict
infection control principles at the international, national, local but also personal level
are needed to lessen the negative clinical impact of antimicrobial resistance.
 Funding

This paper was not funded.

Declaration of Interest

M E Falagas participated in advisory boards of AstraZeneca, Infectopharm,

Tetraphase, Shionogi, and Xellia; received lecture honoraria from Cipla, Merck, and

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Pfizer; and received research support from Shionogi and Tetraphase. The authors have
no other relevant affiliations or financial involvement with any organization or entity

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with a financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript.

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Reviewer disclosures
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Peer reviewers on this manuscript have no relevant financial or other relationships to
disclose.
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 TABLE 1. Measures and strategies that help decrease the evolving problems
related to antimicrobial resistance.

• Surveillance with patient cultures for MDR, XDR and PDR bacteria,
especially in the ICU setting
• Prevention through strict measures of personal hygiene (hand washing, gowns,
gloves, masks, use of antiseptic with monitoring and feedback for health care
providers)

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• Isolation or cohorting of patients when necessary with dedicated nursing
staff/physician /utensils/medical equipment)

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• Search and destroy policies for bacteria associated with morbidity and
mortality i.e. MRSA

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• National and international policies needed to be applied to address the issue of
antimicrobial resistance
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• Necessary physician prescription for all classes of antibiotics to be obtained
from community pharmacies
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• Infectious disease specialist input/agreement in hospital regarding type and
also duration of antibiotic treatment (antimicrobial stewardship) as well as an
interdisciplinary approach (physician, surgeon, clinical microbiologist,
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infectious diseases specialist, clinical pharmacist)

• Knowledge of the intrinsic antimicrobial resistance of the microorganism (i.e.
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S. maltophilia to carbapenems) when prescribing

• Source control of infections whenever possible to decrease the needed time of
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administration of antibiotics and to improve outcome i.e. intraabdominal

infections
•
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Physicians/Surgeons abiding by guidelines for fewer indications for

endocarditis prophylaxis
• Decrease in spectrum of antibiotics prescribed
• Decrease in use for surgical prophylaxis when not indicated ie not for clear
surgeries
• Decrease of the total duration and correct timing of perioperative
administrations of surgical antibiotic prophylaxis
 • Employ correctly antimicrobial surgical prophylaxis only when necessary
according to type of surgery (not in clean)
• Decreased use of antibiotics in animals
• Decreased use in humans i.e. Bronchitis, sinusitis, asymptomatic bacteriuria
• No use of antibiotics in viral infections especially tonsillopharyngitis (clinical
Centor criteria and rapid diagnostic tests and cultures if needed)
• Decreased duration of antibiotic regimens (short versus long) as per guidelines

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and findings of meta-analyses

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• Avoid treating viral infections with antibiotics
• Avoid treating colonization with parenteral antibiotics especially in the ICU,

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except if consideration with decolonization with oral administration of
antibiotics

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• Avoid antibiotic combination regimens except if definitively needed and
indicated
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• Downgrade empiric antibiotic to culture based treatments ASAP
• Prevention of biofilm formation i.e. coating of medical devices
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• Use of new rapid diagnostic tests in the community (physicians’ practices) to
verify bacterial cause of infection such as to those to identify S. pyogenes in
acute tonsillopharyngitis
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• Employ in hospital rapid molecular diagnostic tests (i.e. for example Septicyte
Lab® or Septifast®) for identification of infection-positive sepsis used in
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conjunction with clinical assessments and other laboratory tests

• Use of tests in association with clinical acumen when doubtful/borderline
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cases i.e. Procalcitonin based algorithms for the treatment of respiratory tract
in infections
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• Know local antimicrobial susceptibility data when prescribing

• Correct use of pharmacodynamics, correct dose of antibiotics for the indicated
diagnosis with proper penetration in the anatomical space
• Extended prolonged administration of antibiotics for antibiotics such as beta-
lactams/carbapenems
• Antibiotics optimal to treat the infections i.e. first choice, second choice etc.
• Relevant antibiotics for community vs hospital acquired infection (i.e.
regarding community acquired or hospital –acquired MRSA)
 • Provide the necessary financial background and motives for the
pharmaceutical industry to produce new antimicrobial agents
• Outpatient Parenteral Antibiotic Treatment whenever possible to reduce
hospital-acquired infections

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