International Journal of Antimicrobial Agents 48 (2016) 239–246

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International Journal of Antimicrobial Agents

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / i j a n t i m i c a g

Review

Ten key points for the appropriate use of antibiotics in hospitalised

patients: a consensus from the Antimicrobial Stewardship and
Resistance Working Groups of the International Society
of Chemotherapy
Gabriel Levy Hara a,*, Souha S. Kanj b, Leonardo Pagani c,d, Lilian Abbo e,
Andrea Endimiani f, Heiman F.L. Wertheim g,h, Carlos Amábile-Cuevas i, Pierre Tattevin j,
Shaheen Mehtar k, Fernando Lopes Cardoso l, Serhat Unal m, Ian Gould n
a
Hospital Carlos G. Durand, Buenos Aires, Argentina
b American University of Beirut Medical Centre, Beirut, Lebanon
c Infectious Diseases Unit, Bolzano Central Hospital, Bolzano, Italy
d Antimicrobial Stewardship Programme, Annecy-Genevois Hospital Centre, Annecy, France
e
University of Miami Miller School of Medicine, Miami, FL, USA
f Institute for Infectious Diseases, University of Bern, Bern, Switzerland
g Nuffield Department of Medicine, University of Oxford, UK
h
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
i Fundación Lusara, Mexico City, Mexico
j Infectious Diseases and Intensive Care Unit, Pontchaillou University Hospital, Rennes, France
k Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
l
Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
m Department of Infectious Diseases, Medical Faculty, Hacettepe University, Ankara, Turkey
n Medical Microbiology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Scotland, UK

A R T I C L E I N F O A B S T R A C T

Article history: The Antibiotic Stewardship and Resistance Working Groups of the International Society for Chemother-
Received 7 March 2016 apy propose ten key points for the appropriate use of antibiotics in hospital settings. (i) Get appropriate
Accepted 18 June 2016 microbiological samples before antibiotic administration and carefully interpret the results: in the absence
of clinical signs of infection, colonisation rarely requires antimicrobial treatment. (ii) Avoid the use of
Keywords: antibiotics to ‘treat’ fever: use them to treat infections, and investigate the root cause of fever prior to
Antimicrobial resistance
starting treatment. (iii) Start empirical antibiotic treatment after taking cultures, tailoring it to the site
Antimicrobial stewardship
of infection, risk factors for multidrug-resistant bacteria, and the local microbiology and susceptibility
Prudent use of antibiotics
Combination therapy patterns. (iv) Prescribe drugs at their optimal dosing and for an appropriate duration, adapted to each
clinical situation and patient characteristics. (v) Use antibiotic combinations only where the current ev-
idence suggests some benefit. (vi) When possible, avoid antibiotics with a higher likelihood of promoting
drug resistance or hospital-acquired infections, or use them only as a last resort. (vii) Drain the infected
foci quickly and remove all potentially or proven infected devices: control the infection source. (viii) Always
try to de-escalate/streamline antibiotic treatment according to the clinical situation and the microbio-
logical results. (ix) Stop unnecessarily prescribed antibiotics once the absence of infection is likely. And
(x) Do not work alone: set up local teams with an infectious diseases specialist, clinical microbiologist,
hospital pharmacist, infection control practitioner or hospital epidemiologist, and comply with hospital
antibiotic policies and guidelines.
© 2016 Published by Elsevier B.V.

Introduction

Antibiotic resistance is significantly increasing. Recently, the World

* Corresponding author. Hospital Carlos G. Durand, Buenos Aires, Argentina. Fax:
+54 11 4982-2126.
E-mail address: glevyhara@fibertel.com.ar (G. Levy Hara).
Health Organization (WHO) [1], the US Centers for Disease Preven-
tion and Control (CDC), the European Centre for Disease Control and
Prevention (ECDC) [2], a UK report [3] and a US White House doc-
ument [4] highlighted it as a major public health crisis. This came

http://dx.doi.org/10.1016/j.ijantimicag.2016.06.015
0924-8579/© 2016 Published by Elsevier B.V.
240 G. Levy Hara et al. / International Journal of Antimicrobial Agents 48 (2016) 239–246

Table 1
Ten key points for the appropriate use of antibiotics in hospitalised patients.

1. Get appropriate microbiological samples before antibiotic administration and carefully interpret the results: in the absence of clinical signs of infection, colonisation
rarely requires antimicrobial treatment.
2. Avoid the use of antibiotics to ‘treat’ fever: investigate the root cause of fever and treat only significant bacterial infections.
3. When indicated, start empirical antibiotic treatment after taking cultures, tailoring it to the site of infection, risk factors for multidrug-resistant bacteria, and the
local microbiology and susceptibility patterns.
4. Prescribe drugs at their optimal dose, mode of administration and for the appropriate length of time, adapted to each clinical situation and patient characteristics.
5. Use antibiotic combinations only in cases where the current evidence suggests some benefit.
6. When possible, avoid antibiotics with a higher likelihood of promoting drug resistance or hospital-acquired infections, or use them only as a last resort.
7. Drain the infected foci quickly and remove all potentially or proven infected devices: control the infection source.
8. Always try to de-escalate/streamline antibiotic treatment according to the clinical situation and the microbiological results; switch to the oral route as soon as
possible.
9. Stop antibiotics as soon as a significant bacterial infection is unlikely.
10. Do not work alone: set up local teams with an infectious diseases specialist, clinical microbiologist, hospital pharmacist, infection control practitioner or hospital
epidemiologist, and comply with hospital antibiotic policies and guidelines.

coincidentally with the call for financial ‘incentives’ to encourage
the pharmaceutical industry to return to the search for new anti-
biotics [5].
Whilst some mechanisms of antimicrobial resistance can be
traced back to ancient bacteria [6], evidence—although scarce—
indicates that it was rare in clinical isolates from the ‘pre-antibiotic
era’ [7]. Moreover, whilst there are many studies correlating anti-
microbial usage and the emergence of resistance [8], other societal
factors, such as corruption [9], also play a significant role.
In 2011, the Antimicrobial Stewardship Working Group of the
International Society of Chemotherapy (ISC) published the ‘10 Com-
mandments’ for the appropriate use of antibiotics in the outpatient
setting [10]. The present Ten Key Points—named so to avoid reli-
gious undertones that might prevent a wider reach for these
recommendations—are targeted to healthcare workers in hospi-
tals. Many of these key points were included in a revision of quality
indicators for measuring appropriateness of antibiotic use to treat
infections in hospitalised adult patients [11]. Also, a well-designed
‘Day 3 bundle’ to improve the re-assessment of inpatient empiri-
cal antibiotic prescriptions [12] included some of these concepts.
This consensus summarises the key issues regarding the ratio-
nal use of antibiotics in hospitalised patients. The aim is to provide
essential concepts that should be kept in mind to improve overall
antibiotic management in these settings.
Methodology
This consensus was achieved by clinical microbiologists and in-
fectious diseases (ID) physicians for the ISC Antimicrobial
Stewardship Working Group.
Initially, the group agreed on defining the ten key points and the
main issues to be discussed in each one, followed by a revision of
original articles and guidelines related to every key point identi-
fied through MEDLINE, EMBASE, LILACS, Cochrane Library and
different websites up to April 2016. The manuscript was circu-
lated four times for discussion and corrections. Overall, the whole
process began in April 2014 and finished in May 2016.
Consensus document
The ISC Antimicrobial Stewardship and Resistance Working
Group’s ten key points for the appropriate use of antibiotics in
hospitalised patients are summarised in Table 1.
1. Get appropriate microbiological samples before antibiotic
administration and carefully interpret the results: in the
absence of clinical signs of infection, colonisation rarely requires
antimicrobial treatment
The first relevant question when receiving the results from the
microbiology laboratory is the following: Is the reported bacterium
actually causing an infection, or is it just a coloniser or a contami-
nant? The human body is colonised by trillions of micro-organisms,
a complex community called the microbiota, formerly the ‘bacte-
rial flora’ or ‘commensal flora’ [13] (Table 2). Administering
antibiotics disrupts this microbiota [14].
Next, prescribers should raise the following questions. Is this
species a common member of the microbiota? Is this species a common
cause of this specific infection? Does the patient have predisposition
to be infected with such a micro-organism? Does the patient have any
signs or symptoms suggesting an infection in the body site from where
the sample was taken? Is the cultured pathogen also seen in the Gram
stain, and does the stain show evidence of being a representative
sample?
At 48–72 h after hospitalisation, patients often become colonised
with healthcare-associated bacteria, which progressively and par-
tially replace the normal microbiota. This new ‘flora’ may vary between
institutions, but Gram-negative bacilli (GNB), both Enterobacteriaceae
(similar to those found in the normal microbiota, but generally more
resistant to antibiotics) and non-fermenters (such as Pseudomonas
aeruginosa and Acinetobacter spp.) are usually found. Hence, pre-
scribers should be familiar with both the normal and pathological
microbiota and be able to recognise the main pathogens associated
with common infections.
Many microbiology results can be misleading due to a poor sam-
pling collection technique and confusion as to whether the isolated

Table 2
Culturable components of the human microbiota, often reported by the clinical laboratory.

Body location Relevant species or groups

Skin
Oropharynx
Lower gastrointestinal tract
Anterior urethra and vagina
Staphylococcus epidermidis, Staphylococcus aureus, Corynebacterium, Propionibacterium acnes and sometimes Streptococcus pyogenes
S. epidermidis, Streptococcus spp. (e.g. S. mitis, S. salivarius, S. mutans), non-pathogenic Neisseria spp., other facultative and strict anaerobes
(e.g. Peptostreptococcus spp., Bacteroides spp.) and sometimes S. aureus, Streptococcus pneumoniae, Haemophilus influenzae and different
genus of Enterobacteriaceae (mainly Escherichia coli, Klebsiella pneumoniae and Proteus spp.)
Enterobacteriaceae, enterococci and anaerobes (Bacteroides fragilis group and others)
S. epidermidis and Enterobacteriaceae, and Lactobacillus spp. in the vagina
 G. Levy Hara et al. / International Journal of Antimicrobial Agents 48 (2016) 239–246
bacteria are causing an infection or are just a contaminant. Ex-
amples of these common mistakes are:
1. Taking blood cultures without proper aseptic techniques. This
frequently leads to the isolation of coagulase-negative staphy-
lococci, a common contaminant.
2. Taking a wound swab specimen for skin and soft-tissue infec-
tions, including surgical site infections (SSIs), instead of obtaining
it through a deep needle aspiration, which avoids skin colonisers
or contaminants [15,16]. Needle aspiration—preferably from the
edge of the lesion in cases of cellulitis, or from the side of the
wound in SSI—provides more reliable results.
3. Obtaining sputum samples in patients with hospital-acquired
pneumonia provides reliable results in about 50% of cases. In ven-
tilated patients, samples should be obtained by endotracheal
aspirate, bronchoalveolar lavage or protected specimen brushes
[17].
4. Obtaining urine samples directly from the bag or the urinary cath-
eter, instead of changing the device, or taking urine through the
catheter port [18] are also bad techniques that very frequently
result in erroneous information.
Clinical criteria should always be applied to differentiate con-
taminants from bacteria actually causing the infection. Nonetheless,
the decision to initiate antibiotics can become a difficult task and
a consultation from an ID specialist and/or an antimicrobial stew-
ardship (AMS) team may be needed.
Apart from obtaining good-quality specimens, practitioners
should avoid sending unnecessary samples for microbiological
studies (e.g. samples from uninfected decubitus ulcers, urine in most
asymptomatic patients) that could drive the misuse of antibiotics.
Practitioners should include in the request form for the labora-
tory some valuable information (e.g. ward of admission, length of
stay, suspected focus of infection and recently prescribed antibi-
otics). This will allow the microbiologist to interpret the findings,
decide on the need for additional studies and tailor the list of drugs
to be tested for susceptibility.
2. Avoid the use of antibiotics to ‘treat’ fever: investigate the
root cause of fever and treat only significant bacterial infections
Fever is not always a sign of infection! A temperature chart alone
should not guide antimicrobial use, since infected patients usually
present with additional signs suggesting the focus of infection. A
thorough history and physical examination should guide the iden-
tification of the most likely source of infection, followed by
appropriate investigations based on clinical suspicion (both micro-
biological and non-microbiological). Antibiotics should not be
prescribed without a clear suspicion or evidence of infection.
The presence of fever as the only sign in an otherwise clinical-
ly stable patient must raise the suspicion of a non-infectious origin.
Other clinical conditions or situations in a moderate to severely ill
patient (e.g. phlebitis, reaction to drugs, non-specific post-surgical
fever, etc.) should also be considered. In a landmark study on the
causes of acute fever, 26% of the episodes were of non-infectious
origin [19]. Another study showed that only 30% of febrile epi-
sodes were linked to bacterial infections, whereas other conditions
(e.g. stroke, myocardial infarction) accounted for 20% [20]. In a recent
systematic, evidence-based review, the incidence of hospital-
acquired fever ranged from 2% to 17%; fever was attributed to
bacterial infection in 37–74% of patients and to non-infectious ae-
tiology in 3–52% [21]. The most common infectious causes included
urinary tract infection, pneumonia, sinusitis and bloodstream in-
fection; the most common non-infectious causes were procedure-
related (e.g. blood transfusion), malignancies and ischaemic
conditions (e.g. myocardial infarction, pulmonary embolism).
241
Of note, these criteria also apply for biological biomarkers such
as C-reactive protein: levels above normal values without signs of
infections do not require the use of antibiotics.
3. When indicated, start empirical antibiotic treatment after
taking cultures, tailoring it to the site of infection, risk factors
for multidrug-resistant (MDR) bacteria, and the local
microbiology and susceptibility patterns
Physicians have a double and somewhat contradictory respon-
sibility: prompt initiation of proper antibiotics can save lives, whilst
excessive use may select for resistance that can harm the patient
and the community. This is an ethical conundrum that has only re-
cently started to be addressed [22]. Some initial questions that may
help to ascertain the actual need for antibiotic treatment and to
decide on adequate empirical initial treatment are:
1. How serious is the current infectious episode?
2. Has the patient already received antibiotics? Which ones?
3. Has the patient had MDR bacteria isolation in previous cul-
tures? Which ones?
4. How long has he/she been hospitalised?
5. Has the patient been admitted to a general ward or the in-
tensive care unit (ICU)? For how long?
6. Has he/she been under mechanical ventilation? For how long?
7. Has the patient undergone other invasive procedures? Which
ones? When?
8. Are there any implanted devices/grafts?
9. What are the patterns of antimicrobial resistance of the prev-
alent bacteria in this specific hospital unit?
10. Is there any recent or ongoing outbreak in the unit?
11. Is the patient immunocompromised or at higher risk for atyp-
ical presentation of infections?
Ideally, every hospital should develop an evidence-based policy
for antibiotic use in common clinical scenarios. It is important to
distinguish between community-acquired and hospital-associated
infections, as bacteria and resistance profiles are substantially dif-
ferent. Empirical treatment must be selected based on the suspicion
of the most likely primary focus—and therefore the most probable
causative organisms. The severity of the episode should also be con-
sidered; patients more seriously ill will benefit from earlier broader-
spectrum therapy [23]. In septic shock, appropriate treatment during
the first hour improves patients’ outcomes [24]. It is also impor-
tant to know the antimicrobial history (both as an outpatient and
in recent hospitalisations) and the resistance patterns of all units
where the patient has been admitted.
4. Prescribe drugs at their optimal dose, mode of
administration and for the appropriate length of time, adapted
to each clinical situation and patient characteristics
To achieve optimal drug exposure, maximise bacterial killing and
improve patient outcome, it is imperative to consider pharmacokinetic/
pharmacodynamic aspects [25,26]. Briefly, some important issues are
described below.
4.1. Pharmacodynamics. Time- and concentration-dependent anti-
biotics. The activity of time-dependent antibiotics (e.g., β-lactams,
lincosamides, linezolid) mostly depends on the time interval that
concentrations are above the minimum inhibitory concentration
(MIC), referred to as the T>MIC, for the pathogen involved.
On the other hand, for some concentration-dependent antibi-
otics, such as aminoglycosides and daptomycin, the efficacy mostly
depends on the quotient of the maximum plasma concentration
(Cmax) to the MIC (Cmax/MIC). For others (i.e. fluoroquinolones, poly-
myxins, tetracyclines), the activity depends on the quotient of the
area under the concentration–time curve over 24 h (AUC0–24) to the
242 G. Levy Hara et al. / International Journal of Antimicrobial Agents 48 (2016) 239–246

MIC (AUC0–24/MIC). For concentration-dependent antibiotics, high Table 3

initial doses are essential to attain the maximum bactericidal effect Current recommendations for shorter antibiotic therapy.

as early as possible. Localisation Current duration References

Despite being time-dependent antibiotics, higher doses of suggested
carbapenems in prolonged infusion have also shown benefits, in Intra-abdominal infections
combination with another active drug for the treatment of Patients with good surgical outcome 4–7 days [43,44]
carbapenemase-producing Enterobacteriaceae [27,28]. Carbapenems Patients still septic and/or with 7–10 days after [45]
inadequate source control clinical resolution
display significant efficacy when free drug concentrations remain Ventilator-associated pneumonia
above the MIC for ≥40–50% of the time between dosing intervals. No epidemiological suspicion or 8 days [46]
For example, administering 2 g of meropenem during a 3-h infu- isolation of non-fermenter GNB
sion every 8 h is beneficial if the MIC for the infecting organism is Epidemiological suspicion or 14 days [41,47]
isolation of non-fermenter GNB
≤8 mg/L, as the probability of attaining the target of 50%T>MIC is >80%
Urinary tract infections
[29,30]. Complicated, requiring 7–10 days [48]
The vancomycin profile is still under debate. It is mostly con- hospitalisation
sidered to be a time-dependent antibiotic [31], although some Catheter-associated: prompt 7 days [18]
authors [32] suggest that an AUC/MIC > 400 is the target to achieve resolution of symptoms
Catheter-associated: delayed 10–14 days
an optimal clinical response [33]. On the other hand, T>MIC is con- response or with bacteraemia
sidered necessary for maximising vancomycin bactericidal activity, Bacteraemia
especially against meticillin-resistant Staphylococcus aureus (MRSA) Initial good outcome 7–10 days [24]
isolates with MICs of 1.5–2 mg/L, which are associated with clini- Persistently septic episode 7–10 days after
clinical resolution
cal failure [34–36]. In these cases it is recommended to maintain
Staphylococcus aureus bacteraemiaa 14 days [49]
trough levels at 15–20 mg/L. In seriously ill patients, a loading dose
of 25–30 mg/kg can rapidly reach this target. Alternative drugs, such GNB, Gram-negative bacilli.
a Infective endocarditis, thrombophlebitis or metastatic infections should be ruled
as daptomycin, could also be considered. out.
Regarding concentration-dependent antibiotics, there may be per-
sistent growth suppression even when drug levels fall below the
MIC owing to their post-antibiotic effect (PAE). The duration of PAE
5. Use antibiotic combinations only in cases where the current
is also concentration-dependent: the higher the drug concentra-
evidence suggests some benefit
tion, the longer the duration. Their concentration-dependent
The use of combination therapy to treat serious healthcare-
bactericidal activity, coupled with a significant PAE, supports once-
associated, extensively-drug resistant (XDR) and pandrug-resistant
daily dosing to increase the Cmax/MIC ratio. Some fluoroquinolones
bacterial infections is increasingly common despite the paucity of
(i.e. levofloxacin) and aminoglycosides have this profile. Especial-
clinical evidence [50]. In general, meta-analyses of observational
ly for aminoglycosides, large single doses can provide the highest
studies have shown a benefit from combination therapy, whilst those
Cmax/MIC ratio at infection sites and may result in faster bacterial
including randomised clinical trials have not [51,52]. Current evi-
clearance and lower toxicity. As the active transport process leading
dence regarding combination antibiotic therapy in selected situations
to nephrotoxicity is saturable, once-daily dosing of aminoglycosides
is discussed below.
results in a decreased uptake of the drug into the proximal renal
tubular epithelial cells [37].
5.1. P. aeruginosa and Acinetobacter spp. The superiority of com-
bination therapy in XDR P. aeruginosa infections has not been
4.2. Pharmacokinetics. Lipophilicity and volume of distribution. Li- definitively demonstrated. Published meta-analyses did not strat-
pophilic antibiotics (e.g., fluoroquinolones, linezolid, rifampin, ify for the resistance status, as they included mostly studies
macrolides) usually have a larger volume of distribution (Vd), can conducted in the pre-XDR era [53–55]; the study by Kumar et al
enter the cells and be more active against susceptible intracellular [56] did not focus on XDR P. aeruginosa.
pathogens, are more likely to reach less vascularised and/or damaged Acinetobacter spp. is increasingly becoming XDR with few re-
tissues, and are metabolised in the liver. In contrast, hydrophilic maining therapeutic options and there are no well-designed clinical
agents (e.g. β-lactams, aminoglycosides, glycopeptides) have a smaller trials comparing treatments. A retrospective study showed that co-
Vd, limited cell penetration, are less active against intracellular patho- listin combined with a carbapenem, sulbactam or tigecycline resulted
gens, may not attain effective concentrations in less irrigated tissues, in better outcomes compared with colistin monotherapy [57].
and are usually excreted unchanged through renal clearance [38]. However, a recently published systematic review showed conflict-
Protein binding: Only the free or unbound antibiotic exerts an- ing results [58].
tibacterial activity, and it is actually the free fraction of the drug Considering the current difficulties to precisely define whether
that is relevant for pharmacodynamic considerations. This is par- combination therapy is actually needed for all infections involv-
ticularly important for highly bound antibiotics, such as ceftriaxone, ing these GNB, it seems prudent to start with two presumably active
ertapenem, daptomycin or teicoplanin, for which variations in protein drugs (i.e. colistin, carbapenems, aminoglycosides, tigecycline or
levels (e.g. in cancer, cachexia and elderly patients) may lead to im- fosfomycin, depending upon local resistance) in the following situ-
portant changes in their levels [39]. ations in which MDR bacteria are suspected or confirmed [24,58,59]:
Liver and renal function: Liver and renal function must be con- (a) severe sepsis or septic shock; (b) sepsis in neutropenic patients
sidered when defining dosing. Doses must be adjusted properly in or other immunocompromised conditions; and (c) septic patients
order to minimise adverse effects and drug interactions. with recent ICU admissions. The duration of combination treat-
Finally, shorter antimicrobial courses are safer, cheaper, and ment will depend on various factors, such as clinical evolution and
reduce the risk of adverse events and selection of resistance [40]. final results of drug susceptibility testing.
The use of procalcitonin to guide the initiation and duration of an-
tibiotic treatment in patients with different infections has been 5.2. Carbapenemase-producing Enterobacteriaceae. Some observa-
supported [41,42]. Table 3 lists some of the evidence to shorten treat- tional studies showed that combination therapy against carbapenemase-
ments in hospitalised patients. producing Enterobacteriaceae (mainly KPC-producers) is associated with
 G. Levy Hara et al. / International Journal of Antimicrobial Agents 48 (2016) 239–246
a significantly lower risk of mortality than monotherapy [27,60]. This
was more evident among patients with septic shock and in those with
severe underlying diseases [27]. Carbapenem-containing combina-
tion regimens were superior to combination regimens without
carbapenems when the MIC was ≤8 mg/L. Similar observations have
been recently published from an Italian cohort [61]. One of the reasons
for these results may be that colistin is frequently prescribed in sub-
optimal doses and without a loading dose. For carbapenems, it may be
possible to achieve a T>MIC during significant proportions of the dosing
interval for organisms with MICs up to 8 mg/L. There is no such benefit
when carbapenems are used as monotherapy or when the MIC is
≥16 mg/L [62]. The International Working Group recommendations
stress that carbapenems should not be used if the MIC is usually >8 mg/L
or is not available in order to avoid further selection of resistance [28].
6. When possible, avoid antibiotics with a higher likelihood of
promoting drug resistance or hospital-acquired infections, or
use them only as a last resort
All antibiotics exert a selective pressure favouring resistant vari-
ants. Although it is not possible to reach a general consensus
regarding the ranking of antibiotics for their risk of selecting bac-
terial resistance [63], some antimicrobials have stronger effects and
collateral damage than others. This may be the consequence of their
pharmacodynamics and mechanism of action. Another influenc-
ing factor is their pharmacokinetics. For instance, second-generation
macrolides may promote resistance more effectively than erythro-
mycin because of their extended half-lives [64], with subinhibitory
resistance-fostering concentrations remaining for a longer period
of time. Some antibiotics, especially those targeting DNA replica-
tion (e.g. quinolones), activate the SOS responses, enhancing adaptive
resistance and gene transfer [65].
The spread of third-generation cephalosporin (3GC)- and/or
ciprofloxacin-resistant Enterobacteriaceae, carbapenem-resistant P.
aeruginosa and Acinetobacter spp., MRSA and other MDR patho-
gens in hospitals is frequently related to the high selective pressure
of commonly used antimicrobials [66]. The relationship between
antibiotic use and the emergence of MDR pathogens is very complex
because there are many variables at play [67]. However, it is gen-
erally accepted that there are three main effects, as follows.
6.1. Ecological impact on the overall bacterial population. This phe-
nomenon assumes the presence of pre-existing resistance (usually
intrinsic, but also potentially acquired) in key pathogens, which would
confer a survival advantage when broad-spectrum agents are used,
enabling spread through colonisation of body sites depleted of their
normal microbiota [67,68]. The use of quinolones, cephalosporins,
macrolides, lincosamides, streptogramins and β-lactam/β-lactamase
inhibitors is associated with the emergence of MRSA [67,68].
Carbapenem and quinolone use drives the selection and spread of
carbapenem- and quinolone-resistant P. aeruginosa [69,70]. The steady
increase of 3GC-resistant Enterobacteriaceae (especially Klebsiella
pneumoniae) in the hospital setting has been associated with the
massive use of quinolones [71]. The indiscriminate use of metroni-
dazole (e.g. in abdominal surgery) is also linked to an increase of
infections due to 3GC-resistant Enterobacteriaceae [72]. Carbapenem
use increase infections due to carbapenem-resistant P. aeruginosa/
Acinetobacter spp. as well as selection of Stenotrophomonas maltophilia
[71,73,74]. Ceftriaxone promotes the selection and spread of extended-
spectrum β-lactamase (ESBL)-producing and/or ciprofloxacin-
resistant Escherichia coli more than cefotaxime [70]. On the other hand,
the use of piperacillin/tazobactam is associated with reduced rates
of infections due to ESBL-producing K. pneumoniae and E. coli [75].
However, the same drug might stimulate the selection of MDR
Acinetobacter spp. [71].
243
6.2. Induction of resistance in specific pathogens. Most of the 3GCs
and other β-lactams are able to induce overexpression of chromo-
somal AmpC β-lactamases in ‘SPACE’ organisms (i.e. Serratia
marcescens, Providencia, Pseudomonas, Acinetobacter spp., Citrobacter
freundii and Enterobacter spp.), making them susceptible almost only
to carbapenems among the β-lactams [76,77]. However, beyond the
good activity of carbapenems against pathogens harbouring AmpC,
cefepime is resistant to the hydrolytic action of these enzymes (in
the absence of concurrent resistance mechanisms, e.g. ESBL pro-
duction) and could be considered the drug of choice. In such
situations, therefore, carbapenems should be avoided whenever pos-
sible as they must be reserved for situations when other options
are not available [78,79].
6.3. Rapid acquisition of resistance mutations. Point mutations in a
single gene can lead to resistance to some antibiotics. For in-
stance, rifampicin and fosfomycin resistance develops quickly during
treatment, so they should not be used as monotherapy, with the
exception of fosfomycin for cystitis [80].
In summary, there is not a unique strategy to avoid the promo-
tion of resistance. It is important to avoid the routine use of the same
few antibiotics for all situations.
7. Drain the infected foci quickly and remove all potentially or
proven infected devices: control the infection source
Source control is defined as procedure(s) that eliminate infec-
tious foci, control factors that promote on-going infection, and correct
or control anatomic derangements to restore normal physiologi-
cal function [44]. The need to promptly drain residual collections
in septic patients [81] has been again recently stressed by the Sur-
viving Sepsis Campaign [24]. In severely ill patients, infection source
control should ideally be performed within 12 h from diagnosis.
Merely changing antibiotics will not be of benefit and may con-
tribute to increased morbidity and mortality.
Another example relates to the management of infected central
venous catheters. Short-term catheters infected with GNB, S. aureus,
enterococci, fungi and mycobacteria should be removed [82]. If cath-
eter salvage is attempted, the device should nevertheless be removed
if blood cultures remain positive after 72 h of appropriate therapy.
8. Always try to de-escalate/streamline antibiotic treatment
according to the clinical situation and the microbiological
results; switch to the oral route as soon as possible
After the initial 72 h of treatment, some important items should
be considered for improving antibiotic use. Pulcini et al grouped four
measures in a ‘Day 3 bundle’: existence of an antibiotic plan (name,
dose, route, interval of administration and planned duration); review
of the diagnosis; adaptation to microbiological results; and
intravenous-to-oral (i.v.-to-p.o.) switch [12]. As soon as microbio-
logical results become available, empirical antibiotic treatment
should be streamlined accordingly by choosing the most active
drug(s) with the least toxicity, the narrowest spectrum and the lowest
cost. This would lead to cost savings both directly through lower-
ing treatment expenses and indirectly through controlling the impact
on nosocomial biota. De-escalation therapy has been shown to be
safe for sepsis and septic shock and was associated with lower
mortality [83]; despite this, two recent studies showed that
de-escalation was only performed in around 50% of cases with a
microbiologically documented cause of sepsis [83,84]. Moreover, a
recently published systematic review showed considerable vari-
ability in the definition of de-escalation therapy [85]. It was more
frequently done in patients with broad-spectrum and/or appropri-
ate antimicrobial therapy, when more agents were used, and in the
absence of MDR pathogens. De-escalation showed a reduction in
mortality.
244 G. Levy Hara et al. / International Journal of Antimicrobial Agents 48 (2016) 239–246
The reliability of the results from the microbiology laboratory
is essential to allow de-escalation of antibiotic therapy.
Finally, i.v.-to-p.o. switch after 48–72 h should be considered on
the basis of the clinical condition and when: (a) the antibiotic is orally
available; (b) oral intake and gastrointestinal absorption are not im-
paired; and (c) it is adequate in terms of diagnosis (i.e. not in
endocarditis or meningitis) [11]. This measure contributes to low-
ering costs, diminishing the chances of intravenous line
contamination and shortening hospitalisation.
9. Stop antibiotics as soon as a significant bacterial infection
is unlikely
As stated in key point 8, reviewing the diagnosis after Day 3 is
part of the improving process of antibiotic prescribing [12]. Fre-
quently, once an antibiotic treatment has begun, physicians fear
interrupting it, even if initiated without clear evidence of infec-
tion. In these cases, antimicrobial treatment should be immediately
withdrawn. Furthermore, some argue ‘stopping antibiotics too early
increases bacterial resistance’. This is a baseless argument: the cause
of increasing resistance is the misuse of drugs, not their early dis-
continuation. It is important to remember that although one single
dose of antibiotic may select for resistance, the risk gradually in-
creases with the duration of treatment.
When there is a low clinical suspicion of an infectious episode,
cultures return negative and the patient is clinically stable, antibi-
otics should be discontinued. For example, in patients with a low
suspicion for ventilator-associated pneumonia, interruption of an-
tibiotics after 72 h was associated with a reduction of bacterial
resistance emergence and superinfection without affecting mor-
tality [86]. Another common situation is the misuse of antibiotics
in patients with indwelling urinary catheters just because the urinary
sediment looks turbid. Treatment of asymptomatic bacteriuria should
be strongly discouraged.
Measuring procalcitonin levels can also be of help to discontin-
ue antibiotics in some situations.
10. Do not work alone: set up local teams with an infectious
diseases specialist, clinical microbiologist, hospital pharmacist,
infection control practitioner or hospital epidemiologist, and
comply with hospital antibiotic policies and guidelines
There are many important actors devoted to improve the use of
antibiotics at each institution, and they will usually be glad to col-
laborate with the AMS team. Some of these pivotal members are
discussed below [87–90].
10.1. Infectious diseases physicians. ID physicians have a role in as-
sisting patients, interact as consulting specialists, providing advice
on the characteristics of antibiotics and local ‘flora’, among other
tasks. It is essential for prescribers to get a dynamic interaction with
the ID consultant or clinical microbiologist, whenever available.
In a review of 31 studies evaluating the impact of ID physi-
cians on antibiotic use in acute-care hospitals, Pulcini et al found
that ID intervention resulted in a significant improvement of an-
tibiotic prescribing as well as decreased antibiotic consumption [91].
In an acute care hospital, Schmitt et al showed that when
matched for patient demographics, co-morbidities and hospital char-
acteristics, an ID intervention resulted in significantly lower mortality
and re-admissions compared with non-ID intervention [92].
Moreover, patients receiving ID intervention within 2 days of ad-
mission had significantly lowered 30-day mortality and re-admission
rates, hospital and ICU lengths of stay, and Medicare charges com-
pared with patients receiving later ID consultancy.
10.2. Clinical microbiologists. In many regions, clinical microbiolo-
gists are more numerous than ID physicians [89]. They can provide
local epidemiology and updated resistance data, treatment recom-
mendations, and suggestions for additional consultations. For
example, the presence of an ESBL or a carbapenemase is fre-
quently remarked in the microbiological report, along with the
recommendation of seeking ID advice for this clinical situation. More-
over, the clinical microbiologist can provide a selective antibiotic
susceptibility test report—basically reporting only first-line
therapies—that guides physicians to select narrow-spectrum drugs
with lower risk of selecting resistance.
10.3. Clinical pharmacists. Clinical pharmacists may be able to assist
prescribers in many essential pharmacological issues, such as loading
dose, drug interactions, adverse events, combinations, dose adjust-
ments, i.v.-to-p.o. switch and de-escalation.
10.4. Infection control nurses or officers. Infection control nurses or
officers have a pivotal role and a good understanding of many related
issues: antimicrobial resistance; epidemiology; antimicrobial pre-
scription patterns and infection control activities.
In fact, AMS is just one of many measures needed to prevent and
manage antibiotic resistance in the hospital. A well-functioning in-
fection prevention and control programme is fundamental to furnish
a tailor-made stewardship strategy at each institution. Without it,
all proposed key points would be insufficient to curb bacterial
resistance.
Other important components that should be co-opted to the AMS
team are hospital managers/authorities; representatives of the ICU,
Internal Medicine, Surgery and Paediatrics Units; and an informa-
tion system specialist.
There are many variations in antibiotic prescribing habits even
between doctors in the same hospital. It is recommended to develop
a multidisciplinary local antibiotic policy to be periodically updated.
Effective policies and guidelines should be evidence-based. It is essen-
tial to adapt recommendations to local patterns of resistance and the
availability of antibiotics, avoiding those with a high impact on the
microbiota. Local guidelines should be widely disseminated and fre-
quently reminded (e.g. during ward rounds and clinical consultations).
Lack of compliance of patients and clinicians with their antibiotic pro-
tocols is among the main causes of a poor clinical outcome.
Final considerations
The non-clinical use of antibiotics and their massive release into
the environment may exert the most relevant pressure in the emer-
gence and selection of resistant bacteria [93]. However, there are
important ‘hotspots’ where pathogenic bacteria and huge amounts
of various antibiotics coincide, fostering resistance emergence, ex-
change of resistance genes and their spread. Hospitals are among
such hotspots. From the clinical point of view, we are now facing
the threat of a lack of effective antibiotics to treat some infections.
AMS within hospitals should aim at ‘lowering the temperature’ of
these hotspots, thus reducing the unnecessary exposure of bacte-
ria to antibiotics that may be needed in selected cases. Resistance
can diminish as a consequence of prudent usage of antibiotics, and
a reduced growth pace is certainly attainable. This is necessary to
survive until a new wave of antibiotic research and development
yields new drugs. It would also be a way to guarantee a future to
affected patients and to future generations.
Funding: None.
Competing interests: None declared.
Ethical approval: Not required.
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